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Иммуносупрессивная терапия пролиферативного волчаночного нефрита

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Referencias

References to studies included in this review

Abedi 2007 {published data only}

Abedi A, Nakhjavani MR, Gafari N, Argani H. Comparison between corticosteroid and mycophenolate mofetil and corticosteroid and cyclophosphamide in the treatment of lupus nephritis [abstract no: FO031]. Nephrology Dialysis Transplantation 2007;22(Suppl 6):vi14. CENTRAL

ACCESS 2014 {published data only}

ACCESS Trial Group. Treatment of lupus nephritis with abatacept: the Abatacept and Cyclophosphamide Combination Efficacy and Safety Study.[Erratum appears in Arthritis Rheumatol. 2015 Feb;67(2):487 Note: Aranow, Cynthia [added]]. Arthritis & Rheumatology 2014;66(11):3096‐104. [MEDLINE: 25403681]CENTRAL
Shidham GB, Birmingham DJ, Rovin B, Hebert LA. 24 hour protein: creatinine ration (24 PCR), not spot PCR (Spot PCR), should be used to monitor the treatment of severe lupus nephritis (LN): the experience of ACCESS [abstract no: FR‐PO604]. Journal of the American Society of Nephrology 2016;27(Abstract Suppl):501A. CENTRAL
Shidham GB, Birmingham DJ, Rovin B, Hebert LA. Ability of spot urine protein/creatinine ratio (spot PCR) to correctly identify the proteinuria endpoints of complete remission (CR), partial remission (PR), and treatment failure (TF) as determined by 24 hour urine PCR (24 PCR): experience of abatacept and cyclophosphamide combination efficacy and safety study (ACCESS) [abstract no: TH‐PO764]. Journal of the American Society of Nephrology 2015;26(Abstract Suppl):265A. CENTRAL
Wofsy D, Askanase A, Cagnoli PC, Chatham WW, Contreras G, Dall'Era M, et al. Treatment of lupus nephritis with abatacept plus low‐dose pulse cyclophosphamide followed by azathioprine (the Euro‐Lupus regimen): twenty‐four week data from a double‐blind controlled trial [abstract no: 884]. Arthritis & Rheumatology 2013;66(10 Suppl):S379‐80. [EMBASE: 71318364]CENTRAL
Wofsy D, Hillson JL, Diamond B. Abatacept for lupus nephritis: alternative definitions of complete response support conflicting conclusions. Arthritis & Rheumatology 2012;64(11):3660‐5. [MEDLINE: 22806274]CENTRAL
Wofsy D, Hillson JL, Diamond B. Comparison of alternative primary outcome measures for use in lupus nephritis clinical trials. Arthritis & Rheumatology 2013;65(6):1586‐91. [MEDLINE: 23529285]CENTRAL
Wofsy D, Shropshire SM, Hillson JL, Diamond B. Abatacept for lupus nephritis: alternative outcome measures support opposing interpretations of data from a multicenter, randomized, double‐blind, placebo‐controlled phase II/III study [abstract]. Arthritis & Rheumatology 2011;63(10 Suppl 1):S964‐5. [EMBASE: 70784721]CENTRAL

ALMS 2007 {published and unpublished data}

Appel GB, Contreras G, Dooley MA, Ginzler EM, Isenberg D, Jayne D, et al. Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis. Journal of the American Society of Nephrology 2009;20(5):1103‐12. [MEDLINE: 19369404]CENTRAL
Appel GB, Dooley MA, Ginzler EM, Isenberg D, Jayne D, Solomons N, et al. Mycophenolate mofetil compared with intravenous cyclophosphamide as induction therapy for lupus nephritis: Aspreva Lupus Management Study (ALMS) results [abstract no: SA‐FC057]. Journal of the American Society of Nephrology 2007;18(Abstracts):47A. CENTRAL
Clancy RM, Ginzler EM, Kim M. Association of adiponectin and soluble endothelial protein C receptor (sEPCR) with longitudinal assessments in the induction phase of a randomized multicenter trial comparing mycophenolate mofetil and intravenous cyclophosphamide [abstract no: 263]. ACR/ARHP Annual Scientific Meeting; 2009 Oct 17‐21; Philadelphia (PA). 2009. CENTRAL
Dall'Era M, Stone D, Levesque V, Cisternas M, Wofsy D. Identification of biomarkers that predict response to treatment of lupus nephritis with mycophenolate mofetil or pulse cyclophosphamide. Arthritis Care & Research 2011;63(3):351‐7. [MEDLINE: 21080348]CENTRAL
Dooley MA, Appel GB, Ginzler EM, Isenberg D, Jayne D, Wofsy D, et al. Aspreva lupus management study (ALMS): maintenance results analysis by racial subgroup [abstract no: OP0168]. Annals of the Rheumatic Diseases 2011;70(Suppl 3):125. CENTRAL
Dooley MA, Jayne D, Ginzler EM, Isenberg D, Olsen NJ, Wofsy D, et al. Mycophenolate versus azathioprine as maintenance therapy for lupus nephritis. New England Journal of Medicine 2011;365(20):1886‐95. [MEDLINE: 22087680]CENTRAL
Ginzler E. Contribution of vascular well being to the therapeutic response in the induction phase of a randomized multicenter trial comparing MMF to IVC [abstract no: 2063]. ACR/ARHP Annual Scientific Meeting; 2008 Oct 24‐29; San Francisco (CA). 2008. CENTRAL
Ginzler EM, Appel GB, Dooley MA, Isenberg D, Jayne D, Solomons N, et al. Mycophenolate mofetil and intravenous cyclophosphamide in the Aspreva Lupus Management Study (ALMS): efficacy by racial group [abstract no: L13]. ACR/ARHP Annual Scientific Meeting; 2007 Nov 6‐11; Boston (MA). 2007. CENTRAL
Ginzler EM, Wofsy D, Isenberg D, Gordon C, Lisk L, Dooley MA, et al. Nonrenal disease activity following mycophenolate mofetil or intravenous cyclophosphamide as induction treatment for lupus nephritis: findings in a multicenter, prospective, randomized, open‐label, parallel‐group clinical trial. Arthritis & Rheumatism 2010;62(1):211‐21. [MEDLINE: 20039429]CENTRAL
Isenberg D. Lessons from the Aspreva Lupus Management Study [abstract no: SP0073]. Annals of the Rheumatic Diseases 2009;68(Suppl 3):23. CENTRAL
Isenberg D, Appel GB, Contreras G, Dooley MA, Ginzler EM, Jayne D, et al. Influence of race/ethnicity on response to lupus nephritis treatment: the ALMS study. Rheumatology 2010;49(1):128‐40. [MEDLINE: 19933596]CENTRAL
Isenberg D, Appel GB, Dooley MA, Ginzler EM, Jayne D, Lisk L, et al. Mycophenolate mofetil compared with intravenous cyclophosphamide as induction for lupus nephritis: ALMS results and BILAG responses [abstract no: OP‐0018]. Annals of the Rheumatic Diseases 2008;67(Supp II):53. CENTRAL
Isenberg D, Appel GB, Dooley MA, Ginzler EM, Jayne D, Solomons N, et al. Mycophenolate mofetil (MMF, Cellcept) for induction and maintenance treatment of lupus nephritis (LN): baseline demographics of patients from the phase III randomized, controlled ASPREVA Lupus Management Study (ALMS) [abstract no: AB0424]. Annals of the Rheumatic Diseases 2007;66(Suppl II):606. CENTRAL
Jayne DR, Appel GB, Dooley MA, Ginzler E, Isenberg D, Wofsy D, et al. Results of the Aspreva Lupus Management Study (ALMS) maintenance phase [abstract no: TH‐FC111]. Journal of the American Society of Nephrology 2010;21:25A. CENTRAL
Nadig RS. Efficacy, toxicity and tolerability of mycophenolate mofetil in patients with lupus nephritis, based on dose/weight ratio [abstract no: 431]. ACR/ARHP Annual Scientific Meeting; 2007 Nov 6‐11; Boston (MA). 2007. CENTRAL
Schwartz N, Patel T, Ginzler EM, Solomons N, Buyon JP, Clancy RM. Response to MMF therapy for lupus nephritis is independent of genetic variation of inosine monophosphate dehydrogenase [abstract no: 837]. Arthritis & Rheumatology 2012;64(10 Suppl):S365. [EMBASE: 70998834]CENTRAL
Schwartz N, Patel T, Ginzler EM, Solomons N, Buyon JP, Clancy RM. Response to MMF therapy for lupus nephritis is independent of genetic variation of inosine monophosphate dehydrogenase [abstract no: 837]. Arthritis & Rheumatology 2012;64(10 Suppl):S365. [EMBASE: 70998834]CENTRAL
Silva‐Fernandez L, Nadig RS, von Gizycki H, Ginzler EM. Efficacy, toxicity and tolerability of mycophenolate mofetil in patients with lupus nephritis, based on dose/weight ratio [abstract no: 431]. ACR/ARHP Annual Scientific Meeting; 2007 Nov 6‐11; Boston (MA). 2007. CENTRAL
Sinclair A, Appel G, Dooley MA, Ginzler E, Isenberg D, Jayne D, et al. Mycophenolate mofetil as induction and maintenance therapy for lupus nephritis: rationale and protocol for the randomized, controlled Aspreva Lupus Management Study (ALMS). Lupus 2007;16(12):972‐80. [MEDLINE: 18042591]CENTRAL
Sinclair A, Appel G, Dooley MA, Ginzler E, Isenberg D, Jayne D, et al. Protocol for the Aspreva Lupus Management Study (ALMS) [abstract no: F‐PO882]. Journal of the American Society of Nephrology 2005;16:528A. CENTRAL
Stone DH, Dall'Era M, Levesque V, Cisternas MG, Wofsy D. Identification of biomarkers that predict response to treatment of lupus nephritis with mycophenolate mofetil (MMF) or pulse cyclophosphamide (IV) [abstract no: 2073]. ACR/ARHP Annual Scientific Meeting; 2009 Oct 17‐21; Philadelphia (PA). 2009. CENTRAL
Sundel R, Solomons N, Lisk L, Aspreva Lupus Management Study (ALMS) Group. Efficacy of mycophenolate mofetil in adolescent patients with lupus nephritis: evidence from a two‐phase, prospective randomized trial. Lupus 2012;21(13):1433‐43. [MEDLINE: 22922564]CENTRAL
Sundel RP, Lisk L. Mycophenolate mofetil compared with intravenous cyclophosphamide as induction treatment for pediatric lupus nephritis: a randomized trial [abstract no: 1274]. ACR/ARHP Annual Scientific Meeting; 2008 Oct 24‐29; San Francisco, CL. 2008. CENTRAL
Walsh M, Solomons N, Lisk L, Jayne DR. Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis with poor kidney function: a subgroup analysis of the Aspreva Lupus Management Study. American Journal of Kidney Diseases 2013;61(5):710‐5. [MEDLINE: 23375819]CENTRAL
Wofsy D, Appel GB, Dooley MA, Ginzler EM, Isenberg D, Jayne D, et al. Aspreva lupus management study maintenance results [abstract no: CS12.6]. Lupus 2010;19(1 Suppl):27. CENTRAL
Wofsy D, Appel GB, Dooley MA, Ginzler EM, Isenberg D, Jayne D, et al. Mycophenolate mofetil compared with intravenous cyclophosphamide in the treatment of lupus nephritis: predictors of response [abstract no: SAT0188]. Annals of the Rheumatic Diseases 2008;67(Suppl II):493. CENTRAL

APRIL‐LN 2012 {published data only}

Ginzler EM, Wax S, Rajeswaran A, Copt S, Hillson J, Ramos E, et al. Atacicept in combination with MMF and corticosteroids in lupus nephritis: results of a prematurely terminated trial. Arthritis Research & Therapy 2012;14(1):R33. [MEDLINE: 22325903]CENTRAL

AURA‐LV 2016 {published data only}

Dooley MA, Pendergraft WF, Ginzler EM, Olsen NJ, Tumlin J, Rovin B, et al. Speed of remission with the use of voclosporin, MMF and low dose steroids: results of a global lupus nephritis study [abstract no: 5L]. Arthritis & Rheumatology 2016;68(Suppl 10):4362‐3. [EMBASE: 613889173]CENTRAL
Parikh SV, Pendergraft WF, Tumlin JA, Saxena R, Solomons N, Huizinga RB. Treatment of active lupus nephritis with voclosporin: 48 week data from the AURA‐LV study [abstract no: 4]. American Journal of Kidney Diseases 2017;69(5):A2. CENTRAL
Pendergraft WF, Tumlin JA, Rovin B, Dooley MA, Jayne DR, Wofsy D, et al. AURA‐LV: successful treatment of active lupus nephritis with voclosporin [abstract no: HI‐OR05]. Journal of the American Society of Nephrology 2016;27(Abstract Suppl):2B. CENTRAL

Balletta 1992 {published data only}

Balletta M, Sabella D, Magri P, Sepe V, Stanziale P, Di Luccio R, et al. Cyclosporin plus steroids versus steroids alone in the treatment of lupus nephritis. Contributions to Nephrology 1992;99:129‐30. [MEDLINE: 1458919]CENTRAL

Bao 2008 {published and unpublished data}

Bao H, Liu ZH, Xie HL, Hu WX, Zhang HT, Li LS. Successful treatment of class V+IV lupus nephritis with multi‐target therapy. Journal of the American Society of Nephrology 2008;19(10):2001‐10. [MEDLINE: 18596121]CENTRAL
Bao H, Xie HL, Zhang HT, Zhang X, Hu WX, Liu ZH, et al. Successful treatment of class V+IV lupus nephritis with multi‐target immunosuppressive therapy [abstract no: SA‐FC060]. Journal of the American Society of Nephrology 2007;18(Abstracts):48a. CENTRAL

Barron 1982 {published data only}

Barron KS, Person DA, Brewer EJ, Beale MG, Robson AM. Pulse methylprednisolone therapy in diffuse proliferative lupus nephritis. Journal of Pediatrics 1982;101(1):137‐41. [MEDLINE: 7045314]CENTRAL

Belmont 1995 {published data only}

Belmont HM, Kitsis E, Skovron ML, McCullagh E, Abramson S. Misoprostol and prednisone treatment of lupus nephritis. American Journal of Therapeutics 1995;2(12):928‐32. [PUBMED: 11854810]CENTRAL

BELONG 2013 {published data only}

Mysler E, Spindler A, Guzman R, Renato B. Study design and baseline patient characteristics of BELONG, the randomized double‐blind, placebo‐controlled phase III trial of ocrelizumab, a humanized anti‐CD20 antibody, in lupus nephritis [abstract no: PO2.E20]. Lupus 2010;19(1 Suppl):156. CENTRAL
Mysler EF, Spindler AJ, Guzman R, Bijl M, Jayne D, Furie RA, et al. Efficacy and safety of ocrelizumab in active proliferative lupus nephritis: results from a randomized, double‐blind, phase III study. Arthritis & Rheumatism 2013;65(9):2368‐79. [MEDLINE: 23740801]CENTRAL
Mysler EF, Spindler AJ, Guzman R, Bijl M, Jayne D, Furie RA, et al. Efficacy and safety of ocrelizumab, a humanized antiCD20 antibody, in patients with active proliferative lupus nephritis (LN): results from the randomized, double‐blind phase III BELONG Study [abstract]. Arthritis & Rheumatism 2010;62(Suppl 10):1455. [EMBASE: 70380848]CENTRAL

Boedigheimer 2017 {published data only}

Boedigheimer MJ, Martin DA, Amoura Z, Sanchez‐Guerrero J, Romero‐Diaz J, Kivitz A, et al. Safety, pharmacokinetics and pharmacodynamics of AMG 811, an anti‐interferon‐gamma monoclonal antibody, in SLE subjects without or with lupus nephritis. Lupus Science & Medicine 2017;4(1):e000226. [MEDLINE: 29018537]CENTRAL

Boletis 1999 {published data only}

Boletis JN, Boki C, Michael S, Stamatiadis DN, Nakopoulou L, Moutsopoulos C. Comparative study of pulse treatment with cyclophosphamide or immunoglobulin to sustain the remission of lupus nephritis [abstract]. Journal of the American Society of Nephrology 1998;9(Program & Abstracts):140A‐1A. CENTRAL
Boletis JN, Ioannidis JP, Boki KA, Moutsopoulos HM. Intravenous immunoglobulin compared with cyclophosphamide for proliferative lupus nephritis. Lancet 1999;354(9178):569‐70. [MEDLINE: 10470708]CENTRAL

Boumpas 1992 {published data only}

Austin HA, Fessler BJ, Boumpas DT, Vaughan EM, Klippel JH, Balow JE. Prognostic indicators supporting use of short courses of pulse immunosuppression for severe lupus nephritis (LN) [abstract no: 130]. Journal of the American Society of Nephrology 1995;6(3):411. CENTRAL
Boumpas DT, Austin HA, Vaughn EM, Klippel JH, Steinberg AD, Yarboro CH, et al. Controlled trial of pulse methylprednisolone versus two regimens of pulse cyclophosphamide in severe lupus nephritis. Lancet 1992;340(8822):741‐5. [MEDLINE: 1356175]CENTRAL
Illei GG, Takada K, Parkin D, Austin HA, Crane M, Yarboro CH, et al. Renal flares are common in patients with severe proliferative lupus nephritis treated with pulse immunosuppressive therapy: long‐term followup of a cohort of 145 patients participating in randomized controlled studies. Arthritis & Rheumatism 2002;46(4):995‐1002. [MEDLINE: 11953977]CENTRAL

Cade 1973 {published data only}

Cade R, Spooner G, Schlein E, Pickering M, DeQuesada A, Holcomb A, et al. Comparison of azathioprine, prednisone, and heparin alone or combined in treating lupus nephritis. Nephron 1973;10(1):37‐56. [MEDLINE: 4695164]CENTRAL

Chan 2000 {published data only}

Chan T, Wong W, Lau C, Tsang EW, Ji Y, Mok M, et al. Prolonged follow‐up of patients with diffuse proliferative lupus nephritis (DPLN) treated with prednisolone and mycophenolate mofetil (MMF) [abstract no: A1010]. Journal of the American Society of Nephrology 2001;12(Program & Abstracts):195A. CENTRAL
Chan TM. Mycophenolate mofetil in the treatment of lupus nephritis: 7 years on. Lupus 2008;17(7):617‐21. [MEDLINE: 18625633]CENTRAL
Chan TM, Li FK, Tang CS, Wong RW, Fang GX, Ji YL, et al. Efficacy of mycophenolate mofetil in patients with diffuse proliferative lupus nephritis. Hong Kong‐Guangzhou Nephrology Study Group. New England Journal of Medicine 2000;343(16):1156‐62. [MEDLINE: 11036121]CENTRAL
Chan TM, Tse KC, Tang CS, Mok MY, Li FK, Hong Kong Nephrology Study Group. Long‐term study of mycophenolate mofetil as continuous induction and maintenance treatment for diffuse proliferative lupus nephritis. Journal of the American Society of Nephrology 2005;16(4):1076‐84. [MEDLINE: 15728784]CENTRAL
Karassa FB, Isenberg DA. Efficacy of mycophenolate mofetil in patients with diffuse proliferative lupus nephritis. New England Journal of Medicine 2001;344(5):382‐3. [MEDLINE: 11195799]CENTRAL

Chen 2011 {published data only}

Chen W, Liu Q, Chen W, Fu P, Liao Y, Zhang J, et al. A prospective multicenter randomized trial of treatment of active lupus nephritis with tacrolimus versus cyclophosphamide/azathioprine in Chinese adults [abstract no: SU248]. World Congress of Nephrology; 2009 May 22‐26; Milan (Italy). 2009. CENTRAL
Chen W, Liu Q, Chen W, Tang X, Fu P, Liu F, et al. Outcomes of maintenance therapy with tacrolimus versus azathioprine for active lupus nephritis: a multicenter randomized clinical trial. Lupus 2012;21(9):944‐52. [MEDLINE: 22438027]CENTRAL
Chen W, Tang X, Liu Q, Chen W, Fu P, Liu F, et al. Short‐term outcomes of induction therapy with tacrolimus versus cyclophosphamide for active lupus nephritis: a multicenter randomized clinical trial. American Journal of Kidney Diseases 2011;57(2):235‐44. [MEDLINE: 21177013]CENTRAL

Clark 1981 {published data only}

Clark WF, Lindsay RM, Cattran DC, Chodirker WB, Barnes CC, Linton AL. Monthly plasmapheresis for systemic lupus erythematosus with diffuse proliferative glomerulonephritis: a pilot study. Canadian Medical Association Journal 1981;125(2):171‐4. [MEDLINE: 7272867]CENTRAL
Clark WF, Lindsay RM, Chodirker WB, Cattran D, Linton AL. Elective plasmapheresis in S.L.E. nephritis: pilot for a controlled prospective study [abstract]. Kidney International 1979;16(6):928. CENTRAL

Clark 1984 {published data only}

Clark WF, Balfe JW, Cattran DC. Long‐term plasma exchange in patients with systemic lupus erythematosus and diffuse proliferative glomerulonephritis. Plasma Therapy & Transfusion Technology 1984;5(3):353‐60. [EMBASE: 14000064]CENTRAL
Clark WF, Cattran D, Balfe JW, Williams W, Lindsay RM, Linton AL. Chronic plasma exchange in SLE nephritis [abstract]. Kidney International 1983;24(3):424. CENTRAL
Clark WF, Cattran DC, Balfe JW, Williams W, Lindsay RM, Linton AL. Chronic plasma exchange in systemic lupus erythematosus nephritis. Proceedings of the European Dialysis & Transplant Association 1983;20:629‐35. [MEDLINE: 6361759]CENTRAL
Clark WF, Williams W, Cattran DC, Balfe JW, Chodirker WB, Koval JJ, et al. A controlled trial of chronic plasma exchange therapy in S.L.E. nephritis [abstract]. Kidney International 1984;25(1):161. CENTRAL
Clark WF, Williams W, Cattran DC, Chodirker WB, Koval JJ, Lindsay RM, et al. Controlled trial of chronic plasma exchange therapy in SLE nephritis [abstract]. Kidney International 1982;21(1):147. CENTRAL
Linton AL, Williams W, Cattran D, Lindsay R, Clark W. Controlled trial of chronic plasma exchange in SLE nephritis [abstract]. Australasian Society of Nephrology.19th Annual Scientific Meeting. 2nd Asian Congress of Nephrology; 1983 Feb 14‐18; Melbourne, Australia. 1983:48. CENTRAL

Contreras 2004 {published and unpublished data}

Contreras G, Pardo V, Leclercq B, Gomez E, Reich J, O'Nan P, et al. Maintenance therapy for proliferative forms of lupus nephritis: a randomized clinical trial comparing quarterly intravenous cyclophosphamide (IVCY) versus oral mycophenolate mofetil (MMF) or azathioprine (AZA) [abstract no: F‐FC069]. Journal of the American Society of Nephrology 2002;13(Sept Program & Abstracts):15A. CENTRAL
Contreras G, Pardo V, Leclercq B, Lenz O, ONan P, Tozman E, et al. Lupus nephritis: sequential therapy with short‐term intravenous cyclophosphamide followed by maintenance oral mycophenolate mofetil or oral azathioprine is more efficacious and safer than long‐term intravenous cyclophosphamide [abstract no: SA‐FC173]. Journal of the American Society of Nephrology 2003;14(Nov):38A. CENTRAL
Contreras G, Pardo V, Leclercq B, Lenz O, Tozman E, O'Nan P, et al. Sequential therapies for proliferative lupus nephritis. New England Journal of Medicine 2004;350(10):971‐80. [MEDLINE: 14999109]CENTRAL
Contreras G, Roth D, Berho M, Perez G, Gomez E, Acosta M, et al. Immunosupressive therapy for proliferative lupus nephritis: preliminary report of a prospective, randomized clinical trial with mycophenolate mofetil (MMF) [abstract]. Journal of the American Society of Nephrology 1999;10(Program & Abstracts):99A. CENTRAL
Contreras G, Tozman E, Nahar N, Metz D. Maintenance therapies for proliferative lupus nephritis: mycophenolate mofetil, azathioprine and intravenous cyclophosphamide. Lupus 2005;14(Suppl 1):S33‐8. [MEDLINE: 15803929]CENTRAL

CYCLOFA‐LUNE 2010 {published and unpublished data}

Dostal C, Tesar V, Rysava R, Rovensky J, Rychlik I, Hrneio Z, et al. Cyclofa‐Lune (2002) lupus nephritis ‐ randomized controlled multicentric therapeutic comparative study with cyclosporin A versus cyclophosphamide: running evaluation [abstract no: THU0390]. Annual European Congress of Rheumatology EULAR 2004; 2004 Jun 9‐12, Berlin (Germany). 2004. CENTRAL
Zavada AJ, Pesickova S, Rysava R, Horak P, Hrncir Z, Rovensky J, et al. Extended follow‐up of a investigator‐initiated trial comparing two sequential induction and maintenance treatment regimens for proliferative lupus nephritis based either on cyclophosphamide or cyclosporine [abstract no: 596]. Arthritis and Rheumatism 2013;65(10 Suppl):S256‐S7. [EMBASE: 71318082]CENTRAL
Zavada J, Pesickova S, Rysava R, Olejarova M, Horak P, Hmcir Z, et al. Cyclosporine A or intravenous cyclophosphamide for lupus nephritis: the Cyclofa‐Lune study. Lupus 2010;19(11):1281‐9. [MEDLINE: 20605876]CENTRAL
Zavada J, Pesickova SS, Rysava R, Horak P, Hrncir Z, Lukac J, et al. Extended follow‐up of the CYCLOFA‐LUNE trial comparing two sequential induction and maintenance treatment regimens for proliferative lupus nephritis based either on cyclophosphamide or on cyclosporine A. Lupus 2014;23(1):69‐74. [MEDLINE: 24213308]CENTRAL

Decker 1975 {published data only}

Austin HA, Klippel JH, Balow JE, le Riche NG, Steinberg AD, Plotz PH, et al. Therapy of lupus nephritis. Controlled trial of prednisone and cytotoxic drugs. New England Journal of Medicine 1986;314(10):614‐9. [MEDLINE: 3511372]CENTRAL
Austin HA, Klippel J, le Riche N, Decker JL, Balow JE. Immunosuppressive therapy of lupus nephritis [abstract]. Kidney International 1985;27(1):204. [CENTRAL: CN‐00550415]CENTRAL
Austin, HA 3rd, Muenz LR, Joyce KM, Antonovych TA, Kullick ME, Klippel JH, et al. Prognostic factors in lupus nephritis. Contribution of renal histologic data. American Journal of Medicine 1983;75(3):382‐91. [MEDLINE: 6351607]CENTRAL
Carette S, Klippel JH, Decker JL, Austin HA, Plotz PH, Steinberg AD, et al. Controlled studies of oral immunosuppressive drugs in lupus nephritis. A long‐term follow‐up. Annals of Internal Medicine 1983;99(1):1‐8. [MEDLINE: 6344715]CENTRAL
Decker JL, Klippel JH, Plotz PH, Steinberg AD. Cyclophosphamide or azathioprine in lupus glomerulonephritis. A controlled trial: results at 28 months. Annals of Internal Medicine 1975;83(5):606‐15. [MEDLINE: 1106278]CENTRAL
Decker JL, Steinberg AD, Reinertsen JL, Plotz PH, Balow JE, Klippel JH. NIH conference. Systemic lupus erythematosus: evolving concepts. Annals of Internal Medicine 1979;91(4):587‐604. [MEDLINE: 158324]CENTRAL
Dinant HJ, Decker JL, Klippel JH, Balow JE, Plotz PH, Steinberg AD. Alternative modes of cyclophosphamide and azathioprine therapy in lupus nephritis. Annals of Internal Medicine 1982;96(6 Pt 1):728‐36. [MEDLINE: 7046543]CENTRAL
Steinberg AD, Steinberg SC. Long‐term preservation of renal function in patients with lupus nephritis receiving treatment that includes cyclophosphamide versus those treated with prednisone only. Arthritis & Rheumatology 1991;34(8):945‐50. [MEDLINE: 1859488]CENTRAL

Deng 2016 {published data only}

Deng F, Hong D, Wang L. A clinical research of the effect of leflunomide as an induction treatment for proliferative lupus nephritis [abstract no: FR‐PO593]. Journal of the American Society of Nephrology 2016;27(Abstract Suppl):499A. CENTRAL

Derksen 1988 {published data only}

Derksen RH, Hene RJ, Kallenberg CG, Valentijn RM, Kater L. Prospective multicentre trial on the short‐ term effects of plasma exchange versus cytotoxic drugs in corticosteroid‐resistant lupus nephritis. Netherlands Journal of Medicine 1988;33(3‐4):168‐77. [MEDLINE: 3067098]CENTRAL

Donadio 1972 {published data only}

Donadio JVJ, Holley KE, Wagoner RD, Ferguson RH, McDuffie FC. Further observations on the treatment of lupus nephritis with prednisone and combined prednisone and azathioprine. Arthritis & Rheumatism 1974;17(5):573‐81. [MEDLINE: 4278104]CENTRAL
Donadio JVJ, Holley KE, Wagoner RD, Ferguson RH, McDuffie FC. Treatment of lupus nephritis with prednisone and combined prednisone and azathioprine. Annals of Internal Medicine 1972;77(6):829‐35. [MEDLINE: 4566283]CENTRAL

Donadio 1976 {published data only}

Donadio JV, Holley KE, Ferguson RH, Ilstrup D. Long‐term treatment of diffuse proliferative lupus nephritis (DPLN) with prednisone and combined prednisone and cyclophosphamide [abstract]. Kidney International 1977;12(6):465. CENTRAL
Donadio JV, Holley KE, Ferguson RH, Ilstrup DM. Progressive lupus glomerulonephritis. Treatment with prednisone and combined prednisone and cyclophosphamide. Mayo Clinic Proceedings 1976;51(8):484‐94. [MEDLINE: 950801]CENTRAL
Donadio JV, Holley KE, Ferguson RH, Ilstrup DM. Treatment of diffuse proliferative lupus nephritis with prednisone and combined prednisone and cyclophosphamide. New England Journal of Medicine 1978;299(21):1151‐5. [MEDLINE: 309095]CENTRAL

Doria 1994 {published data only}

Doria A, Piccoli A, Vesco P, Vaccaro E, Marson P, De Silvestro G, et al. Therapy of lupus nephritis. A two‐year prospective study. Annales de Medecine Interne 1994;145(5):307‐11. [MEDLINE: 7985937]CENTRAL

Dyadyk 2001 {published and unpublished data}

Dyadyk A, Vasilenko I, Bagriy A, Dyadyk O, Yarovaya N, Roschin Y, et al. Azathioprine and cyclophosphamide in treatment of patients with diffuse proliferative lupus nephritis ‐ a randomized controlled study [abstract]. Nephrology Dialysis Transplantation 2001;16(6):A57. CENTRAL
Dyadyk OI, Vasilenko IV, Bagriy AE, Kholopov LS, Dyadyk OO, Yarovaya NF, et al. Azathioprine and cyclophosphamide in diffuse proliferative lupus nephritis treatment ‐ a randomized controlled study [abstract no: SAT0125]. Annals of the Rheumatic Diseases 2007;66(Suppl II):467. CENTRAL

El‐Sehemy 2006 {published data only}

Abd‐ELHady El‐Sehemy M, Al‐Saaran AM, Al‐Saeed Baddour NM, El‐Sayed Moez P, Adam AG. Comparative clinical prospective therapeutic study between cyclophosphamide, cyclosporine and azathioprine in the treatment of lupus nephritis [abstract]. 41st Congress. European Renal Association. European Dialysis and Transplantation Association; 2004 May 15‐18; Lisbon (Portugal). 2004:48. CENTRAL
Abd‐ELHady El‐Sehemy M, Al‐Saaran AM, Al‐Saeed Baddour NM, El‐Sayed Moez P, Gaber Adam A. Cyclosporine but not cyclophosphamide is a rescue therapy in resistant lupus nephritis even in class iv proliferative GN [abstract]. 41st Congress. European Renal Association. European Dialysis and Transplantation Association; 2004 May 15‐18; Lisbon (Portugal). 2004:48. CENTRAL
Adam AG, El‐Sehemy MS, Baddour NM, Moez PE, Al Saaran AM. Prospective comparative study between azathioprine "AZA", cyclophosphamide "CYP", cyclosporine "CsA" and mycophenolate mofetil "MMF" in the treatment of lupus nephritis: is CYP still the preferred therapy against the new‐comer MMF. AZA: an old drug with still a great potential? [abstract no: F‐PO258]. Journal of the American Society of Nephrology 2004;15(Oct):122A. CENTRAL
El‐Sehemy MS, Al‐Saaran AM, Baddour NM, Adam AG, Moez PE. Comparative clinical prospective therapeutic study between cyclophosphamide, cyclosporine and azathioprine in the treatment of lupus nephritis. Egyptian Journal of Immunology/Egyptian Association of Immunologists 2006;13(1):39‐52. [MEDLINE: 17974149]CENTRAL

El‐Shafey 2010 {published and unpublished data}

El Shafey EM, Abdou SH, Shareef MM. Is mofetil superior to pulse intravenous cyclophosphamide for induction therapy of proliferative lupus nephritis in Egyptian patients?. Clinical & Experimental Nephrology 2010;14(3):214‐21. [MEDLINE: 20169461]CENTRAL

Florez‐Suarez 2004 {published and unpublished data}

Flores‐Suarez LF, Villa AR. Open randomized trial comparing mycophenolate mofetil (MMF) vs intravenous cyclophosphamide (IV‐CYC) as induction therapy for severe lupus nephritis (LN) [abstract no: F‐PO257]. Journal of the American Society of Nephrology 2004;15(Oct):122A. CENTRAL
Flores‐Suarez LF, Villa AR. Preliminary results of an open randomised clinical trial comparing mycophenolate mofetil (MMF) vs intravenous cyclophosphamide (IV‐CYC) as induction therapy for severe lupus nephritis [abstract no: THU0413]. Annual European Congress of Rheumatology EULAR 2004; 2004 Jun 9‐12, Berlin, Germany. 2004. CENTRAL

Fries 1973 {published data only}

Fries JF, Sharp GC, McDevitt HO, Holman HR. Cyclophosphamide therapy in systemic lupus erythematosus and polymyositis. Arthritis & Rheumatism 1973;16(2):154‐62. [MEDLINE: 4716431]CENTRAL

Fu 1997 {published data only}

Fu LW, Yang LY, Chen WP, Lin CY. Clinical efficacy of cyclosporin A neoral in the treatment of paediatric lupus nephritis with heavy proteinuria. British Journal of Rheumatology 1998;37(2):217‐21. [MEDLINE: 9569080]CENTRAL
Fu LW, Yang LY, Chen WP, Lin CY. Cyclosporin pharmacokinetics following administration of capsules and Neoral in paediatric patients with lupus nephritis. British Journal of Clinical Pharmacology 1997;44(2):125‐7. [MEDLINE: 9278195]CENTRAL

Furie 2014 {published data only}

Furie R, Nicholls K, Cheng TT, Houssiau F, Burgos‐Vargas R, Chen SL. Efficacy and safety of abatacept over 12 months in patients with lupus nephritis: results from a multicenter, randomized, double‐blind, placebo‐controlled phase II/III study [abstract]. Arthritis & Rheumatism 2014;63(10 Suppl 1):S962‐3. [EMBASE: 70785447]CENTRAL
Furie R, Nicholls K, Cheng TT, Houssiau F, Burgos‐Vargas R, Chen SL, et al. Efficacy and safety of abatacept in lupus nephritis: a twelve‐month, randomized, double‐blind study. Arthritis & Rheumatology 2014;66(2):379‐89. [MEDLINE: 24504810]CENTRAL
Wofsy D, Hillson JL, Diamond B. Abatacept for lupus nephritis: alternative definitions of complete response support conflicting conclusions. Arthritis & Rheumatism 2012;64(11):3660‐5. [MEDLINE: 22806274]CENTRAL
Wofsy D, Hillson JL, Diamond B. Comparison of alternative primary outcome measures for use in lupus nephritis clinical trials. Arthritis & Rheumatism 2013;65(6):1586‐91. [MEDLINE: 23529285]CENTRAL

Ginzler 1976 {published data only}

Ginzler E, Diamond H, Guttadauria M, Kaplan D. Prednisone and azathioprine compared to prednisone plus low‐dose azathioprine and cyclophosphamide in the treatment of diffuse lupus nephritis. Arthritis & Rheumatism 1976;19(4):693‐9. [MEDLINE: 782464]CENTRAL

Ginzler 2005 {published and unpublished data}

Appel G, Ginzler E, Radhakrishnan J, Aranow C, Buyon J, Dooley M, et al. Multicenter controlled trial of mycophenolate mofetil (MMF) vs intravenous cyclophosphamide (IVC) as induction therapy for severe lupus nephritis (LN) [abstract no: SA‐FC171]. Journal of the American Society of Nephrology 2003;14(Nov):38A. CENTRAL
Burchardi C, Schlondorff D. Induction therapy for active lupus nephritis: mycophenolate mofetil versus cyclophosphamide. Nature Clinical Practice Nephrology 2006;2(6):314‐5. [MEDLINE: 16932452]CENTRAL
Elliott JR, Manzi S. Induction therapy for active lupus nephritis: mycophenolate mofetil is superior to cyclophosphamide. Nature Clinical Practice Rheumatology 2006;2(7):354‐5. [MEDLINE: 16932717]CENTRAL
Ginzler EM, Dooley MA, Aranow C, Kim MY, Buyon J, Merrill JT, et al. Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis. New England Journal of Medicine 2005;353(21):2219‐28. [MEDLINE: 16306519]CENTRAL
Karassa FB. Mycophenolate mofetil or intravenous cyclophosphamide in lupus nephritis. New England Journal of Medicine 2006;354(7):764‐5. [MEDLINE: 16481648]CENTRAL
Radhakrishnan J, Ginzler E, Appel G. Mycophenolate mofetil (MMF) vs. intravenous cyclophosphamide (IVC) for severe lupus nephritis (LN): subgroup analysis of patients with membranous nephropathy (SLE‐V) [abstract no: TH‐FC036]. Journal of the American Society of Nephrology 2005;16:8A. CENTRAL
Radhakrishnan J, Moutzouris D, Ginzler E, Appel G. Lupus membranous nephropathy IV cyclophosphamide (IVC) vs. mycophenolate mofetil (MMF) [abstract no: SA‐PO2951]. Journal of the American Society of Nephrology 2008;19(Abstracts Issue):779A. CENTRAL
Robert C, Mo S, Kim M, Ginzler EM. Should therapy go beyond the control of immediate injury? Biomarkers of the vasculature and their association with longitudinal assessments in the induction phase of a randomized multicenter trial comparing mycophenolate mofetil and intravenous cyclophosphamide [abstract no: PO1.B.31]. Lupus 2010;19(1 Suppl):55. CENTRAL

Gourley 1996 {published data only}

Gourley MF, Austin HA, Scott D, Yarboro CH, Vaughan EM, Muir J, et al. Methylprednisolone and cyclophosphamide, alone or in combination, in patients with lupus nephritis. A randomized, controlled trial. Annals of Internal Medicine 1996;125(7):549‐57. [MEDLINE: 8815753]CENTRAL
Illei GG, Austin HA, Crane M, Collins L, Gourley MF, Yarboro CH, et al. Combination therapy with pulse cyclophosphamide plus pulse methylprednisolone improves long‐term renal outcome without adding toxicity in patients with lupus nephritis. Annals of Internal Medicine 2001;135(4):248‐57. [MEDLINE: 11511139]CENTRAL
Illei GG, Takada K, Parkin D, Austin HA, Crane M, Yarboro CH, et al. Renal flares are common in patients with severe proliferative lupus nephritis treated with pulse immunosuppressive therapy: long‐term followup of a cohort of 145 patients participating in randomized controlled studies. Arthritis & Rheumatism 2002;46(4):995‐1002. [MEDLINE: 11953977]CENTRAL

Grootscholten 2006 {published and unpublished data}

Arends S, Grootscholten C, Bijl M, Berger SP, De Sevaux R, Voskuyl AE, et al. Cyclophosphamide versus azathioprine/methylprednisolone: long‐term follow‐up of the first Dutch lupus nephritis study [abstract]. Lupus 2011;20(4):350. [EMBASE: 70414154]CENTRAL
Arends S, Grootscholten C, Derksen RH, Berger SP, de Sevaux RG, Voskuyl AE, et al. Long‐term follow‐up of a randomised controlled trial of azathioprine/methylprednisolone versus cyclophosphamide in patients with proliferative lupus nephritis. Annals of the Rheumatic Diseases 2012;71(6):966‐73. [MEDLINE: 22128082]CENTRAL
Grootscholten C, Bajema IM, Florquin S, Steenbergen EJ, Peutz‐Kootstra CJ, Goldschmeding R, et al. Interobserver agreement of scoring of histopathological characteristics and classification of lupus nephritis. Nephrology Dialysis Transplantation 2008;23(1):223‐30. [MEDLINE: 17981886]CENTRAL
Grootscholten C, Bajema IM, Florquin S, Steenbergen EJ, Peutz‐Kootstra CJ, Goldschmeding R, et al. Treatment with cyclophosphamide delays the progression of chronic lesions more effectively than does treatment with azathioprine plus methylprednisolone in patients with proliferative lupus nephritis. Arthritis & Rheumatism 2007;56(3):924‐37. [MEDLINE: 17328070]CENTRAL
Grootscholten C, Bijl M, Ligtenberg G, Hagen EC, van den Wall Bake AW, de Glas‐Vos JW, et al. Is azathioprine an alternative for cyclophosphamide in the treatment of patients with proliferative lupus nephritis? Two year results of the Dutch Lupus Nephritis Study [abstract no: OP0176]. Annual European Congress of Rheumatology EULAR; 2004 Jun 9‐12; Berlin (Germany). 2004. CENTRAL
Grootscholten C, Dieker JW, McGrath FD, Roos A, Derksen RH, van der Vlag J, et al. A prospective study of anti‐chromatin and anti‐C1q autoantibodies in patients with proliferative lupus nephritis treated with cyclophosphamide pulses or azathioprine/methylprednisolone. Annals of the Rheumatic Diseases 2007;66(5):693‐6. [MEDLINE: 17135217]CENTRAL
Grootscholten C, Ligtenberg G, Hagen EC, van den Wall Bake AW, de Glas‐Vos JW, Bijl M, et al. Azathioprine/methylprednisolone versus cyclophosphamide in proliferative lupus nephritis. A randomized controlled trial. Kidney International 2006;70(4):732‐42. [MEDLINE: 16820790]CENTRAL
Grootscholten C, Ligtenberg G, van Houwelingen HC, Derksen RHW, Berden JH. Randomized controlled trial comparing cyclophosphamide pulse therapy with azathioprine/methylprednisolone in proliferative lupus nephritis [abstract no: SU‐FC047]. Journal of the American Society of Nephrology 2004;15(Oct):54A. CENTRAL
Grootscholten C, Snoek FJ, Bijl M, van Houwelingen HC, Derksen RH, Berden JH, et al. Health‐related quality of life and treatment burden in patients with proliferative lupus nephritis treated with cyclophosphamide or azathioprine/methylprednisolone in a randomized controlled trial. Journal of Rheumatology 2007;34(8):1699‐707. [MEDLINE: 17659757]CENTRAL
Ligtenberg G, Grootscholten CM, Derksen RH, Berden JH. Cyclophosphamide pulse therapy versus azathioprine and methylprednisolone pulses in proliferative lupus nephritis: first results of a randomized, prospective multicenter study [abstract no: F‐FC067]. Journal of the American Society of Nephrology 2002;13(Program & Abstracts):14A. CENTRAL

Hahn 1975 {published data only}

Hahn BH, Kantor OS, Osterland CK. Azathioprine plus prednisone compared with prednisone alone in the treatment of systemic lupus erythematosus. Report of a prospective controlled trial in 24 patients. Annals of Internal Medicine 1975;83(5):597‐605. [MEDLINE: 1106277]CENTRAL

Hong 2007 {published and unpublished data}

Hong R, Haijin Y, Xianglin W, Cuilan H, Nan C. A preliminary study of tacrolimus versus cyclophosphamide in patients with diffuse proliferative lupus nephritis [abstract no: SaP131]. Nephrology Dialysis Transplantation 2007;22(Suppl 6):vi276. CENTRAL

Houssiau 2002 {published data only}

Dall'Era M, Cisternas MG, Smilek DE, Straub L, Houssiau FA, Cervera R, et al. Predictors of long‐term renal outcome in lupus nephritis trials: lessons learned from the Euro‐Lupus Nephritis cohort. Arthritis & Rheumatology 2015;67(5):1305‐13. [MEDLINE: 25605554]CENTRAL
Houssiau FA. The 10‐year followup of the Euro‐Lupus Nephritis Trial (ELNT), a randomized prospective trial comparing low‐dose (LD) versus high‐dose (HD) intravenous (IV) cyclophosphamide (CY) followed by azathioprine (AZA) as treatment of proliferative lupus nephritis [abstract no: 2060]. ACR/ARHP Annual Scientific Meeting; 2008 Oct 24‐29; San Francisco (CA). 2008. CENTRAL
Houssiau FA, Cosyns J, Cervera R. The Euro‐Lupus Nephritis Trial: 5‐year follow‐up [abstract no: OP0054]. Annual European Congress of Rheumatology EULAR; 2003 June 18‐21; Lisbon (Portugal). 2003. CENTRAL
Houssiau FA, Vasconcelos C, D'Cruz D, Sebastiani G, de Ramon Garrido E, Danieli M, et al. Long term outcome of patients randomized in the Euro‐Lupus Nephritis Trial: further evidence that a low‐dose IV cyclophosphamide induction regimen achieves good results [abstract no: OP0034]. Annals of the Rheumatic Diseases 2006;65(Suppl II):64. CENTRAL
Houssiau FA, Vasconcelos C, D'Cruz D, Sebastiani GD, Garrido Ed Ede R, Danieli MG, et al. Immunosuppressive therapy in lupus nephritis: the Euro‐Lupus Nephritis Trial, a randomized trial of low‐dose versus high‐dose intravenous cyclophosphamide. Arthritis & Rheumatism 2002;46(8):2121‐31. [MEDLINE: 12209517]CENTRAL
Houssiau FA, Vasconcelos C, D'Cruz D, Sebastiani GD, de Ramon Garrido E, Danieli MG, et al. Early response to immunosuppressive therapy predicts good long‐term renal outcome in lupus nephritis: lessons from the Euro‐Lupus Nephritis trial (ELNT) [abstract no: 67]. Lupus 2004; 7th International Congress on SLE and Related Conditions; 2004 May 9‐13; New York (NY). 2004. CENTRAL
Houssiau FA, Vasconcelos C, D'Cruz D, Sebastiani GD, de Ramon Garrido E, Danieli MG, et al. Early response to immunosuppressive therapy predicts good long‐term renal outcome in proliferative lupus glomerulonephritis: lessons from the Euro‐Lupus Nephritis Trial [abstract no: OP0174]. Annual European Congress of Rheumatology EULAR; 2004 Jun 9‐12; Berlin (Germany). 2004. CENTRAL
Houssiau FA, Vasconcelos C, D'Cruz D, Sebastiani GD, de Ramon Garrido E, Danieli MG, et al. Early response to immunosuppressive therapy predicts good renal outcome in lupus nephritis: lessons from long‐term followup of patients in the Euro‐Lupus Nephritis Trial. Arthritis & Rheumatism 2004;50(12):3934‐40. [MEDLINE: 15593207]CENTRAL
Houssiau FA, Vasconcelos C, D'Cruz D, Sebastiani GD, de Ramon Garrido E, Danieli MG, et al. The 10‐year follow‐up data of the Euro‐Lupus Nephritis Trial comparing low‐dose and high‐dose intravenous cyclophosphamide. Annals of the Rheumatic Diseases 2010;69(1):61‐4. [MEDLINE: 19155235]CENTRAL

Jayne 2013 {published data only}

Jayne D, Appel G, Chan TM, Barkay H, Weiss R, Wofsy D. A randomized controlled study of laquinimod in active lupus nephritis patients in combination with standard of care [abstract no: LB0003]. Annals of the Rheumatic Diseases 2013;72(Suppl 3):164. CENTRAL

Kaballo 2016 {published data only}

Kaballo BG, Ahmed AE, Nur MM, Khalid IO, Abu‐Aisha H. Mycophenolate mofetil versus azathioprine for maintenance treatment of lupus nephritis. Saudi Journal of Kidney Diseases & Transplantation 2016;27(4):717‐25. [MEDLINE: 27424688]CENTRAL

Kamanamool 2017 {published data only}

Kamanamool N, Ingsathit A, Rattanasiri S, Ngamjanyaporn P, Kasitanont N, Chawanasuntorapoj R, et al. Comparison of disease activity between tacrolimus and mycophenolate mofetil in lupus nephritis: a randomized controlled trial. Lupus 2017;27(4):647‐56. [MEDLINE: 29105558]CENTRAL
Sumethkul V. Comparison between tacrolimus (TAC) and mycophenolate mofetil (MMF) for induction of remission in lupus nephritis. clinicaltrials.gov/ct2/show/NCT01580865 (first received 17 April 2012). CENTRAL

Lewis 1992 {published data only}

Chen YE, Korbet SM, Katz RS, Schwartz MM, Lewis EJ. The value of a partial remission in severe lupus nephritis [abstract no: SA‐PO743]. Journal of the American Society of Nephrology 2006;17(Abstracts):731A. CENTRAL
Chen YE, Korbet SM, Katz RS, Schwartz MM, Lewis EJ, Collaborative Study Group. Value of a complete or partial remission in severe lupus nephritis. Clinical Journal of the American Society of Nephrology: CJASN 2008;3(1):46‐53. [MEDLINE: 18003764]CENTRAL
Clough JD, Lewis EJ, Lachin JM. Treatment protocols of the lupus nephritis collaborative study of plasmapheresis in severe lupus nephritis. The Lupus Nephritis Collaborative Study Group. Progress in Clinical & Biological Research 1990;337:301‐7. [MEDLINE: 2352989]CENTRAL
Korbet SM, Schwartz MM, Evans J, Lewis EJ, Collaborative Study Group. Severe lupus nephritis: racial differences in presentation and outcome. Journal of the American Society of Nephrology 2007;18(1):244‐54. [MEDLINE: 17167111]CENTRAL
Korbet SM, Whittier WL, Lewis EJ. Complete remission rate and outcome in severe lupus nephritis: the impact of baseline serum creatinine [abstract no: TH‐PO769]. Journal of the American Society of Nephrology 2015;26(Abstract Suppl):266A. CENTRAL
Lachin JM, Lan SP. Termination of a clinical trial with no treatment group difference: the Lupus Nephritis Collaborative Study. Controlled Clinical Trials 1992;13(1):62‐79. [MEDLINE: 1315665]CENTRAL
Levey AS, Lan SP, Corwin HL, Kasinath BS, Lachin J, Neilson EG, et al. Progression and remission of renal disease in the Lupus Nephritis Collaborative Study. Results of treatment with prednisone and short‐term oral cyclophosphamide. Annals of Internal Medicine 1992;116(2):114‐23. [MEDLINE: 1727614]CENTRAL
Lewis E, Lachin J, Lupus Nephritis Collaborative Study Group (LNCSG). Primary outcomes in the controlled trial of plasmapheresis therapy (PPT) in severe lupus nephritis [abstract]. Kidney International 1987;31(1):208. CENTRAL
Lewis EJ. Plasmapheresis therapy is ineffective in SLE. Lupus Nephritis Collaborative Study Group. Journal of Clinical Apheresis 1992;7(3):153. [MEDLINE: 1286995]CENTRAL
Lewis EJ, Hunsicker LG, Lan SP, Rohde RD, Lachin JM, Lupus Nephritis Collaborative Study Group. A controlled trial of plasmapheresis therapy in severe lupus nephritis. The Lupus Nephritis Collaborative Study Group. New England Journal of Medicine 1992;326(21):1373‐9. [MEDLINE: 1569973]CENTRAL
Patel SB, Korbet SM, Lewis EJ. The prognosis of severe lupus nephritis based on the Modification of Diet in Renal Disease (MDRD) study estimated glomerular filtration rate. Lupus 2011;20(3):256‐64. [MEDLINE: 21138981]CENTRAL
Pohl M, Berl T, Lan S, Lupus Nephritis Collaborative Study Group (LNCS). Plasmapheresis (PP) does not enhance the susceptibility to infections in immunosuppressed patients with lupus nephritis [abstract]. Kidney International 1989;35(1):230. CENTRAL
Pohl MA, Lan SP, Berl T. Plasmapheresis does not increase the risk for infection in immunosuppressed patients with severe lupus nephritis. The Lupus Nephritis Collaborative Study Group. Annals of Internal Medicine 1991;114(11):924‐9. [MEDLINE: 2024858]CENTRAL

Li 2009c {published and unpublished data}

Li EK, Tam LS, Zhu TY, Kwok CL, Leung YY, Szeto CC. Rituximab monotherapy is an effective induction therapy in proliferative lupus nephritis: a pilot study [abstract no: THU0223]. Annals of the Rheumatic Diseases 2009;68(Suppl 3):247. CENTRAL
Li EK, Tam LS, Zhu TY, Li M, Kwok CL, Li TK, et al. Is combination rituximab with cyclophosphamide better than rituximab alone in the treatment of lupus nephritis?. Rheumatology 2009;48(8):892‐8. [MEDLINE: 19478041]CENTRAL

Li 2012 {published and unpublished data}

Li X, Ren H, Zhang Q, Zhang W, Wu X, Xu Y, et al. Mycophenolate mofetil or tacrolimus compared with intravenous cyclophosphamide in the induction treatment for active lupus nephritis. Nephrology Dialysis Transplantation 2012;27(4):1467‐72. [MEDLINE: 21917733]CENTRAL
Li X, Ren H, Zhang W, Xu Y, Shen P, Zhang Q, et al. Induction therapies for proliferative lupus nephritis: mycophenolate mofetil, tacrolimus and intravenous cyclophosphamide [abstract]. Journal of the American Society of Nephrology 2009;20:391A. CENTRAL

Liou 2007 {published data only}

Liou C, Ni Z, Qian J, Lin A, Zhang W, Fang W, et al. Treatment of lupus nephritis type_and_with leflunomide: A two year prospective sequential therapies [abstract no: M‐PO‐1081]. 4th World Congress of Nephrology.19th International Congress of the International Society of Nephrology (ISN); 2007 Apr 21‐25; Rio de Janeiro, Brazil. 2007:349. CENTRAL

Liu 2015 {published data only}

Liu Z, Zhang H, Liu Z, Xing C, Fu P, Ni Z, et al. Multitarget therapy for induction treatment of lupus nephritis: a randomized trial.[Summary for patients in Ann Intern Med. 2015 Jan 6;162(1):I24; PMID: 25383607]. Annals of Internal Medicine 2015;162(1):18‐26. [MEDLINE: 25383558]CENTRAL

Loo 2010 {published data only}

Loo CY, Kong NCT, Shahrir M, Suriani A, Halim AG, Rozita M, et al. Plasmapheresis versus immunoadsorption in severe lupus nephritis (LN) [abstract no: M‐PO‐0967]. 4th World Congress of Nephrology.19th International Congress of the International Society of Nephrology (ISN); 2007 Apr 21‐25; Rio de Janeiro, Brazil. 2007:319. CENTRAL
Loo CY, Mohamed Said MS, Mohd R, Abdul Gafor AH, Saidin R, Halim NA, et al. Immunoadsorption and plasmapheresis are equally efficacious as adjunctive therapies for severe lupus nephritis. Transfusion & Apheresis Science 2010;43(3):335‐40. [MEDLINE: 21051293]CENTRAL

Lui 1997 {published and unpublished data}

Lui SF, Cheng IKP, Tong KL, Li CS, Wong KC, Chan TM, et al. Treatment of type iv lupus nephritis (LN) ‐ comparison of 2 triple therapy regimens: cyclosporin a (CSA), prednisolone (PRED), azathioprine (AZA) vs. oral cyclophosphamide (POCP), prednisolone, azathioprine [abstract no: P1613]. Nephrology 1997;3(Suppl 1):S476. CENTRAL

LUNAR 2012 {published and unpublished data}

Appel GB, Looney RJ, Eisenberg RA, Rovin BH, Ginzler EM, Adler SG, et al. Protocol for the Lupus Nephritis Assessment with rituximab (LUNAR) Study [abstract no: F‐PO1121]. Journal of the American Society of Nephrology 2006;17(Abstracts):573A. CENTRAL
Furie R, Looney J, Rovin B, Latinis K, Appel G, Sanchez‐Guerrero J, et al. Efficacy and safety of rituximab (RTX) in patients (Pts) with proliferative lupus nephritis (LN): results from randomized, double‐blind phase III LUNAR study at week 52 [abstract no: CS6.6]. Lupus 2010;19(1 Suppl):15. CENTRAL
Furie R, Looney J, Rovin B, Latinis K, Appel G, Sanchez‐Guerrero J, et al. Efficacy and safety of rituximab in patients with proliferative lupus nephritis: results from the randomized, double‐blind phase III LUNAR study [abstract no: SAT0185]. Annals of the Rheumatic Diseases 2010;69(Suppl 3):549. CENTRAL
Furie R, Looney RJ, Rovin B, Latinis KM, Appel G, Sanchez‐Guerrero J, et al. Efficacy and safety of rituximab in subjects with active proliferative lupus nephritis (LN): results from the randomized, double‐blind phase III LUNAR study [abstract no: 1149]. ACR/ARHP Annual Scientific Meeting; 2009 Oct 17‐21; Philadelphia (PA). 2009. CENTRAL
Furie R, Rovin B, Appel G, Kamen D, Fervenza F, Spindler A, et al. Effect of rituximab (RTX) on anti‐dsDNA and C3 levels and relationship to response: results from the LUNAR trial [abstract no: PO2.E.22]. Lupus 2010;19(1 Suppl):157. CENTRAL
Furie R, Rovin B, Appel G, Kamen D, Fervenza FC, Spindler A, et al. Effect of rituximab (RTX) on anti ‐double‐stranded DNA antibody and c3 levels and relationship to response: results from the LUNAR trial [abstract no: SAT0186]. Annals of the Rheumatic Diseases 2010;69(Suppl 3):550. CENTRAL
Furie R, Rovin B, Appel G, Kamen DL, Fervenza FC, Spindler A, et al. Effect of rituximab (RTX) on anti‐dsDNA and C3 levels and relationship to response: results from the LUNAR trial [abstract no: 271]. ACR/ARHP Annual Scientific Meeting; 2009 Oct 17‐21; Philadelphia (PA). 2009. CENTRAL
Furie R, Rovin BH, Kamen DL, Latinis KL, Appel GB, Sanchez‐Guerrero J, et al. Trial design and baseline characteristics of patients in the randomized double‐blind, placebo‐controlled phase III lupus nephritis assessment with rituximab study (LUNAR) [abstract no: THU‐0242]. Annals of the Rheumatic Diseases 2009;68(Suppl 3):253. CENTRAL
Rovin B, Appel G, Furie R, Fervenza F, Guerrero JS, Lenz O, et al. Trial design and baseline characteristics of patients in the randomized double‐blind, placebo‐controlled phase III LUpus Nephritis Assessment with Rituximab study (LUNAR) [abstract no: M353]. World Congress of Nephrology; 2009 May 22‐26; Milan, Italy. 2009. CENTRAL
Rovin B, Appel G, Furie R, Kamen DL, Fervenza FC, Spindler A, et al. Effect of Rituximab (RTX) on anti‐dsDNA and C3 levels and relationship to response: Results from the LUNAR Trial [abstract no: F‐PO1281]. Journal of the American Society of Nephrology 2009;20:406A. CENTRAL
Rovin BH, Appel G, Furie R, Looney J, Latinis K, Fervenza FC, et al. Efficacy and safety of rituximab (RTX) in subjects with proliferative lupus nephritis (LN): results from the randomized, double‐blind phase III LUNAR study [abstract no: SA‐FC332]. Journal of the American Society of Nephrology 2009;20:77A. CENTRAL
Rovin BH, Furie R, Latinis K, Looney RJ, Fervenza FC, Sanchez‐Guerrero J, et al. Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the Lupus Nephritis Assessment with Rituximab study. Arthritis & Rheumatism 2012;64(4):1215‐26. [MEDLINE: 22231479]CENTRAL

MAINTAIN Nephritis 2010 {published and unpublished data}

Houssiau FA, D'Cruz D, Sangle S, Remy P, Vasconcelos C, Petrovic R, et al. Azathioprine versus mycophenolate mofetil for long‐term immunosuppression in lupus nephritis: results from the MAINTAIN Nephritis Trial. Annals of the Rheumatic Diseases 2010;69(12):2083‐9. [MEDLINE: 20833738]CENTRAL
Houssiau FA, D'Cruz D, Sangle S, Remy P, Vasconcelos C, Petrovic R, et al. Longterm renal outcome in lupus nephritis patients can be predicted by the kinetics of proteinuria drop in response to therapy: data from the MAINTAIN NEPHRITIS trial [abstract no: SAT0193]. Annals of the Rheumatic Diseases 2010;69(Suppl 3):552. CENTRAL
Houssiau FA, D'Cruz DP, Sangle SR, Remy P, Vasconcelos C, De Ramon Garrido E, et al. Azathioprine versus mycophenolate mofetil for maintenance immunosuppression of proliferative lupus nephritis: results of a randomized trial (MAINTAIN) [abstract no: 1150]. ACR/ARHP Annual Scientific Meeting; 2009 Oct 17‐21; Philadelphia (PA). 2009. CENTRAL
Stoenoiu MS, Aydin S, Tektonidou M, Ravelingien I, le Guern V, Fiehn C, et al. Repeat kidney biopsies fail to detect differences between azathioprine and mycophenolate mofetil maintenance therapy for lupus nephritis: data from the MAINTAIN Nephritis Trial. Nephrology Dialysis Transplantation 2012;27(5):1924‐30. [MEDLINE: 22110048]CENTRAL
Tamirou F, D'Cruz D, Sangle S, Remy P, Vasconcelos C, Fiehn C, et al. Long‐term follow‐up of the MAINTAIN Nephritis Trial, comparing azathioprine and mycophenolate mofetil as maintenance therapy of lupus nephritis. Annals of the Rheumatic Diseases 2016;75(3):526‐31. [MEDLINE: 25757867]CENTRAL
Tamirou F, Lauwerys BR, Dall'Era M, MacKay M, Rovin B, Cervera R, et al. A proteinuria cut‐off level of 0.7 g/day after 12 months of treatment best predicts long‐term renal outcome in lupus nephritis: data from the MAINTAIN Nephritis Trial. Lupus Science & Medicine 2015;2(1):e000123. [MEDLINE: 26629352]CENTRAL

Mehra 2018 {published data only}

Mehra S, Usdadiya JB, Jain VK, Misra DP, Negi VS. Comparing the efficacy of low‐dose vs high‐dose cyclophosphamide regimen as induction therapy in the treatment of proliferative lupus nephritis: a single center study. Rheumatology International 2018;38(4):577‐68. [MEDLINE: 29450636]CENTRAL

Mendonca 2017 {published data only}

Mendonca S, Gupta D, Ali S, Gupta P. Mycophenolate mofetil or cyclophosphamide in Indian patients with lupus nephritis: Which is better? A single‐center experience. Saudi Journal of Kidney Diseases & Transplantation 2017;28(5):1069‐77. [MEDLINE: 28937065]CENTRAL

Mitwalli 2011 {published data only}

Mitwalli AH, Al Wakeel JS, Hurraib S, Aisha A, Al Suwaida A, Alam A, et al. Comparison of high and low dose of cyclophosphamide in lupus nephritis patients: a long‐term randomized controlled trial. Saudi Journal of Kidney Diseases & Transplantation 2011;22(5):935‐40. [MEDLINE: 21912022]CENTRAL

Mok 2016 {published and unpublished data}

Mok C, Ying K, Tong K, Siu Y, To C, Yim C, et al. Mycophenolate mofetil versus tacrolimus for active lupus nephritis: an extended observation of a randomized controlled trial [abstract no: 1073]. ACR/ARHP Annual Scientific Meeting; 2008 Oct 24‐29; San Francisco (CA). 2008. CENTRAL
Mok CC. Factors determining response in patients with acute lupus nephritis treated with glucocorticoids and mycophenolate mofetil (MMF) [abstract]. Arthritis and Rheumatism 2009;60(Suppl 10):923. CENTRAL
Mok CC, Ho LY, To CH, Chan KL. Factors associated with renal remission, relapse and long‐term renal function decline in lupusnephritis treated with combined prednisolone and mycophenolate mofetil (MMF) or tacrolimus(TAC) [abstract no: 988]. Arthritis & Rheumatology 2015;67(10 Suppl):988. [EMBASE: 72094876]CENTRAL
Mok CC, To CH, Ying KY, Yim C, Ng WL. Factors associated with long‐term renal function deterioration in lupus nephritis treated initially with combined prednisolone and mycophenolate mofetil (MMF) or tacrolimus (TAC) [abstract no: 600]. Arthritis & Rheumatism 2013;65(Suppl 10):S258‐9. [EMBASE: 71318086]CENTRAL
Mok CC, Ying KY, Ng CW, Ng WL. Risk of renal flares and decline in renal function in patients with active lupus nephritis treated with mycophenolate mofetil (MMF) [abstract no: SAT0202]. Annals of the Rheumatic Diseases 2010;69(3):555. CENTRAL
Mok CC, Ying KY, Yim CW, Ng WL. Risk of renal flares and decline in renal function in patients with active lupus nephritis treated with mycophenolate mofetil (MMF) [abstract]. Arthritis and Rheumatism 2010;60(10 Suppl):477. [EMBASE: 70381867]CENTRAL
Mok CC, Ying KY, Yim CW, Siu YP, Tong KH, To CH, et al. Tacrolimus versus mycophenolate mofetil for induction therapy of lupus nephritis: a randomised controlled trial and long‐term follow‐up. Annals of the Rheumatic Diseases 2016;75(1):30‐6. [MEDLINE: 25550339]CENTRAL
Mok CC, Ying S, Yim CW, Ng WL. Factors determining response in patients with active lupus nephritis treated with glucocorticoids and mycophenolate mofetil (MMF) [abstract no: PO2.E.17]. Lupus 2010;19(1 Suppl):155. CENTRAL
Mok CC, Ying S, Yim CW, Ng WL. Tacrolimus (TAC) versus mycophenolate mofetil (MMF) for the treatment of membranous lupus nephritis: a randomized controlled trial [abstract no: OP0069]. Annals of the Rheumatic Diseases 2010;69(3):75. CENTRAL
Mok CC, Ying S, Yim CW, Ng WL. Tacrolimus (Tac) versus mycophenolate mofetil (MMF) for the treatment of membranous lupus nephritis: a randomized controlled trial [abstract no: CS6.8]. Lupus 2010;19(1 Suppl):16. CENTRAL
Mok CC, Ying SK, Tong KH, Siu YP, To CH, Yim CW, et al. Mycophenolate mofetil versus tacrolimus for active lupus nephritis: an extended observation of a randomized controlled trial [abstract no: THU0220]. Annals of the Rheumatic Diseases 2009;68(Suppl 3):246. CENTRAL

Moroni 2006 {published and unpublished data}

Doria A, Ponticelli C, Mosca M, Ferraccioli GF, Moroni G, Todesco S, et al. A randomized trial comparing cyclosporine versus azathioprine for maintenance therapy in diffuse lupus nephritis [abstract]. Lupus 2004; 7th International Congress on SLE and Related Conditions; 2004 May 9‐13; New York (NY). 2004. CENTRAL
Moroni G, Doria A, Mosca M, Alberighi O, Ferraccioli G, Todesco S, et al. A randomized pilot trial comparing cyclosporine and azathioprine for maintenance therapy in diffuse lupus nephritis over four years. Clinical Journal of the American Society of Nephrology: CJASN 2006;1(5):925‐32. [MEDLINE: 17699309]CENTRAL
Moroni G, Doria A, Mosca M, Ferraccioli G, Todesco S, Manno C, et al. A randomized trial comparing cyclosporine versus azathioprine for maintenance therapy in diffuse lupus nephritis [abstract no: F‐PO255]. Journal of the American Society of Nephrology 2004;15(Oct):121A. CENTRAL
Moroni G, Doria A, Mosca M, Ferraccioli G, Todesco S, Schena P, et al. A randomized trial comparing cyclosporine versus azathioprine for maintenance therapy in diffuse lupus nephritis [abstract no: MO30]. 41st Congress. European Renal Association. European Dialysis and Transplantation Association; 2004 May 15‐18; Lisbon, Portugal. 2004:224. CENTRAL
Mosca M, Doria A, Moroni G, Ferrara R, Todesco S, Ponticelli C, et al. Induction therapy with oral cyclophosphamide in lupus nephritis [abstract no: THU0166]. Annual European Congress of Rheumatology EULAR; 2002 June 12‐15; Stockholm, Sweden. 2002. CENTRAL

Mulic‐Bacic 2008 {published and unpublished data}

Mulic‐Bacic S, Antic D, Krizic M, Hajdarovic A, Mulic E. Mycophenolate mofetil or intravenous cyclophosphamide in treatment of lupus nephritis [abstract no: FRI0201]. Annals of the Rheumatic Diseases 2008;67(Suppl II):349. CENTRAL

MyLupus 2011 {published and unpublished data}

Jayne D, Amoura Z, Zeher M, Boletis J, Hiepe F. Enteric‐coated mycophenolate sodium in patients with lupus nephritis: rationale and design of a multicenter randomized steroid‐sparing trial [abstract no: M‐PO‐1114]. 4th World Congress of Nephrology. 19th International Congress of the International Society of Nephrology (ISN); 2007 Apr 21‐25; Rio de Janeiro, Brazil. 2007:357. CENTRAL
Jayne DR, Zeher M. Enteric‐coated mycophenolate sodium (ED‐MPS) for the treatment of lupus nephritis ‐ MyLupus study [abstract no: SA‐PO2253]. Journal of the American Society of Nephrology 2010;21:626A. CENTRAL
Zeher M, Doria A, Lan J, Aroca G, Jayne D, Boletis I, et al. Efficacy and safety of enteric‐coated mycophenolate sodium in combination with two glucocorticoid regimens for the treatment of active lupus nephritis. Lupus 2011;20(14):1484‐93. [MEDLINE: 21976398]CENTRAL
Zeher M, Doria A, Lan JL, Aroca G, Amoura Z, Jayne D, et al. Efficacy and safety of enteric‐coated mycophenolate sodium (EC‐MPS) in combination with two corticosteroid regimens for the treatment of lupus nephritis flare – results of the MYLUPUS study [abstract no: SAT0213]. Annals of the Rheumatic Diseases 2010;69(3):559. CENTRAL
Zeher M, Lan J, Doria A, Amoura Z, Jayne D, Hiepe F. Enteric coated mycophenolate sodium (EC‐MPS) treatment of lupus nephritis flare ‐ interim results from a multicenter, randomized trial [abstract no: THU0234]. Annals of the Rheumatic Diseases 2009;68(Suppl 3):250. CENTRAL

Nakamura 2002e {published data only}

Nakamura T, Ushiyama C, Hara M, Osada S, Ugai K, Shimada N, et al. Comparative effects of plasmapheresis and intravenous cyclophosphamide on urinary podocyte excretion in patients with proliferative lupus nephritis. Clinical Nephrology 2002;57(2):108‐13. [MEDLINE: 11863119]CENTRAL

Ong 2005 {published data only}

Ong LM, Hooi LS, Lim TO, Goh BL, Ahmad G, Ghazalli R, et al. Randomized controlled trial of pulse intravenous cyclophosphamide versus mycophenolate mofetil in the induction therapy of proliferative lupus nephritis. Nephrology 2005;10(5):504‐10. [MEDLINE: 16221103]CENTRAL
Ong LM, Hooi LS, Lim TO, Goh BL, Ahmad G, Ghazalli R, et al. Randomized controlled trial of pulse intravenous cyclophosphamide versus mycophenolate mofetil in the induction therapy of proliferative lupus nephritis [abstract no: FC30041]. Nephrology 2005;10(Suppl):A121. CENTRAL

Pal 2017 {published data only}

Pal A, Roychowdhury A, Ghosh P. Comparison of tacrolimus‐azathioprine combination versus cyclophosphamide for induction treatment of proliferative lupus nephritis [abstract no: OC014]. Indian Journal of Rheumatology 2017;12(5 Suppl 1):S9. [EMBASE: 619738235]CENTRAL

Rathi 2016 {published data only}

Goyal A, Rathi M, Jha V, Sharma A, Joshi K, Nada R, et al. Randomized controlled trial of low dose intravenous cyclophosphamide versus oral mycophenolate mofetil in treatment of lupus nephritis [abstract no: FR‐OR053]. Journal of the American Society of Nephrology 2013;24(Abstracts):48A‐9A. CENTRAL
Rathi M, Goyal A, Gupta PK, Jaryal A, Sharma A, Jha V, et al. Randomized controlled trial of low‐dose intravenous cyclophosphamide versus oral mycophenolate mofetil in treatment of lupus nephritis [abstract]. Nephrology Dialysis Transplantation 2014;29(Suppl 3):iii28‐iii2. [EMBASE: 71491534]CENTRAL
Rathi M, Goyal A, Jaryal A, Sharma A, Gupta PK, Ramachandran R, et al. Comparison of low‐dose intravenous cyclophosphamide with oral mycophenolate mofetil in the treatment of lupus nephritis. Kidney International 2016;89(1):235‐42. [MEDLINE: 26489028]CENTRAL
Rathi M, Jaryal A, Goyal A, Sharma A, Gupta P, Gupta K. Outcomes in lupus nephritis patients previously randomized to receive either low dose cyclophosphamide versus oral mycophenolate mofetil on azathioprine maintenance [abstract no: 2941]. Arthritis & Rheumatology 2015;67(Suppl 10):2941. [EMBASE: 72096818]CENTRAL

Rovin 2016 {published data only}

Aranow C, van Vollenhoven R, Rovin B, Wagner C, Zhou B, Gordon R, et al. A phase 2, multicenter, randomized, double‐blind, placebo‐controlled, proof‐of‐concept study to evaluate the efficacy and safety of sirukumab in patients with active lupus nephritis [abstract no: 2835]. Arthritis & Rheumatology 2014;66(Suppl 10):S1239. [EMBASE: 71738820]CENTRAL
Rovin B, van Vollenhoven R, Aranow C, Wagner C, Gordon R, Zhuang Y, et al. A multicenter, randomized, double‐blind, placebo‐controlled study to evaluate the efficacy and safety of treatment with sirukumab (CNTO 136) in patients with active lupus nephritis. Arthritis & Rheumatology 2016;68(9):2174‐83. [MEDLINE: 27110697]CENTRAL
Rovin, BH, van Vollenhoven R, Aranow C, Wagner C, Gordon R, Hsu B, et al. Efficacy and safety of sirukumab in patients with active lupus nephritis: results from a phase 2, multicenter, randomized, double‐blind, placebo‐controlled, proof‐of‐concept study [abstract no: TH‐PO426]. Journal of the American Society of Nephrology 2014;25:204A. CENTRAL

Sabry 2009 {published and unpublished data}

Sabry A, Abo‐Zenah H, Medhat T, Sheashaa H, Mahmoud K, El‐Huseini A. A comparative study of two intensified pulse cyclophosphamide remission‐inducing regimens for diffuse proliferative lupus nephritis: an Egyptian experience. International Urology & Nephrology 2009;41(1):153‐61. [MEDLINE: 18214709]CENTRAL
Sabry A, Sheashaa H, Mahmoud K, El‐Huseini A, El Dahshan K. A comparative study of two intensified pulse cyclophosphamide remission‐inducing regimen for diffuse proliferative lupus nephritis: an Egyptian experience [abstract no: FP036]. Nephrology Dialysis Transplantation 2007;22(Suppl 6):vi28. CENTRAL

Sedhain 2016 {published data only}

Sedhain A, Hada R, Agrawal RK, Baral A, Bhattarai GR. Effect of cyclophosphamide versus mycophenolate mofetil in induction therapy of lupus nephritis in Nepalese population [abstract no: FR‐PO598]. Journal of the American Society of Nephrology 2016;27(Abstract Suppl):500A. CENTRAL

Sesso 1994a {published data only}

Sesso R, Monteiro M, Sato E, Kirsztajn G, Silva L, Ajzen H. A controlled trial of pulse cyclophosphamide versus pulse methylprednisolone in severe lupus nephritis. Lupus 1994;3(2):107‐12. [MEDLINE: 7920609]CENTRAL
Sesso R, Monteiro M, Silva L, Sato E, Ajzen H. Pulse cyclophosphamide (CY) versus pulse methylprednisolone (MP) in severe lupus nephritis [abstract no: 97P]. Journal of the American Society of Nephrology 1993;4(Program & Abstracts):286. CENTRAL

SIMPL 2014 {published data only}

Galbraith L, Manns B, Hemmelgarn B, Walsh M. The Steroids In the Maintenance of remission of Proliferative Lupus nephritis (SIMPL) pilot trial. Canadian Journal of Kidney Health & Disease 2014;1:30. [MEDLINE: 25780619]CENTRAL

Steinberg 1971 {published data only}

Steinberg AD, Kaltreider HB, Staples PJ, Goetzl EJ, Talal N, Decker JL. Cyclophosphamide in lupus nephritis: a controlled trial. Annals of Internal Medicine 1971;75(2):165‐71. [MEDLINE: 4104337]CENTRAL

Sun 2015 {published data only}

Sun J, Zhang H, Ji Y, Gui M, Yi B, Wang J, et al. Efficacy and safety of cyclophosphamide combined with mycophenolate mofetil for induction treatment of class IV lupus nephritis. International Journal of Clinical & Experimental Medicine 2015;8(11):21572‐8. [MEDLINE: 26885107]CENTRAL

Wallace 1998 {published data only}

Wallace DJ, Goldfinger D, Pepkowitz SH, Fichman M, Metzger Al, Schroeder JO, et al. Randomized controlled trial of pulse/synchronization cyclophosphamide/apheresis for proliferative lupus nephritis. Journal of Clinical Apheresis 1998;13(4):163‐6. [MEDLINE: 9886795]CENTRAL

Yap 2017 {published data only}

Yap DY, Lee P, Yam I, Tam CH, Wong S, Yung S, et al. Effect of cyclophosphamide and mycophenolate mofetil on lymphocyte subsets in patients with active lupus nephritis effect of cyclophosphamide and mycophenolate mofetil on lymphocyte subsets in patients with active lupus nephritis [abstract no: MP230]. Nephrology Dialysis Transplantation 2017;32(Suppl 3):iii510. [EMBASE: 617289724]CENTRAL

Yee 2004 {published data only}

Yee CS, Gordon C, Dostal C, Petera P, Dadoniene J, Griffiths B, et al. EULAR randomised controlled trial of pulse cyclophosphamide and methylprednisolone versus continuous cyclophosphamide and prednisolone followed by azathioprine and prednisolone in lupus nephritis. Annals of the Rheumatic Diseases 2004;63(5):525‐9. [MEDLINE: 15082482]CENTRAL

Zhang 1995a {published data only}

Zhang J, Yang H. Cyclophosphamide (CTX) pulse therapy in lupus nephritis (LN): short term is better [abstract no: T235]. Nephrology Dialysis Transplantation 2003;18(Suppl 4):356. CENTRAL
Zhang JH, Yang H. Cyclophosphamide (CYX) pulse therapy in lupus nephritis (ln): short term is better [abstract]. ISN XIII International Congress of Nephrology; 1995 Jul 2‐6; Madrid (Spain). 1995:290. CENTRAL

References to studies excluded from this review

Andrade‐Ortega 2010 {published data only}

Andrade‐Ortega L, Irazoque‐Palazuelos F, Lopez‐Villanueva R, Barragan‐Navarro Y, Bourget‐Pietrasanta F, Diaz‐Ceballos ML, et al. Efficacy of rituximab versus cyclophosphamide in lupus patients with severe manifestations. A randomized and multicenter study [Eficacia de rituximab comparado con ciclofosfamida en pacientes con manifestaciones graves de lupus eritematoso generalizado. Estudio aleatorizado y multicentrico]. Reumatologia Clinica 2010;6(5):250‐5. [EMBASE: 2010499791]CENTRAL

Antunes 2001 {published data only}

Antunes I, Woronik V, Sabagga E, Machado MM, Barros RT. ACE inhibition reduces proteinuria, hematuria and renal expression of inflammatory mediators in human lupus nephritis [abstract]. Journal of the American Society of Nephrology 2001;12(Program & Abstracts):90A. [CENTRAL: CN‐00444198]CENTRAL

ASPEN 2008 {published data only}

Linnik MD, Tansey MJ, Joh T. Dose dependent reduction in anti‐dsDNA antibody levels observed with abetimus sodium through 52 weeks in the phase 3 ASPEN study (abetimus sodium in patients with a history of lupus nephritis) [abstract no: 1077]. ACR/ARHP Annual Scientific Meeting; 2008 Oct 24‐29; San Francisco (CA). 2008. CENTRAL
Tansey MJ, Joh T, Linnik MD. Interim analysis reveals dose dependent reduction in anti‐dsDNA antibody levels with Abetimus sodium through 52 weeks in the phase 3 ASPEN study (Abetimus Sodium in Patients with a history of lupus Nephritis) [abstract no: SA‐PO2958]. Journal of the American Society of Nephrology 2008;19(Abstracts issue):781A. CENTRAL
Tansey MJ, Joh T, Linnik MD. Interim analysis reveals dose dependent reduction in anti‐dsDNA antibody levels with Abetimus sodium through 52 weeks in the phase 3 ASPEN study (Abetimus Sodium in patients with a History of lupus Nephritis) [abstract no: THU0237]. Annals of the Rheumatic Diseases 2009;68(Suppl 3):251. CENTRAL

ATLAS 2016 {published data only}

Furie R, Malyar V. Efficacy, safety, and tolerability of BIIB023 as an adjunct to standard of care in subjects with lupus nephritis [abstract no: 749]. Arthritis & Rheumatology 2017;68(Suppl 10):749. CENTRAL
Rovin B, Wofsy D, Jayne DR, Mysler E, Smirnakis K, Duffield JS, et al. Results from the ATLAS Trial: a phase 2 study to evaluate efficacy and safety of BIIB023 in subjects with lupus nephritis [abstract no:TH‐OR051]. Journal of the American Society of Nephrology 2016;27(Abstract Suppl):13A. CENTRAL

Austin 2009 {published and unpublished data}

Austin HA, Illei GG, Braun MJ, Balow JE. Randomized, controlled trial of prednisone, cyclophosphamide, and cyclosporine in lupus membranous nephropathy. Journal of the American Society of Nephrology 2009;20(4):901‐11. [MEDLINE: 19297556]CENTRAL
Austin HA, Balow JE. Long‐term observations in a prospective clinical trial of prednisone, cyclosporine and cyclophosphamide for lupus membranous nephropathy (LMN) [abstract no: SU‐FO048]. Journal of the American Society of Nephrology 2004;15(Oct):54A. CENTRAL
Austin HA, Vaughan EM, Balow JE. Lupus membranous nephropathy: randomized controlled trial of prednisolone, cyclosporine and cyclophosphamide [abstract no: A0439]. Journal of the American Society of Nephrology 2000;11:81A. CENTRAL
Austin HA, Vaughan EM, Boumpas DT, Klippel JH, Balow JE. Lupus membranous nephropathy: controlled trial of prednisolone, pulse cyclophosphamide, and cyclosporine A [abstract no: A0411]. Journal of the American Society of Nephrology 1996;7(9):1328. CENTRAL

Balow 1981 {published data only}

Balow JE, Dinant HJ, Decker JL, Klippel JH, Plotz PH, Steinberg AD. Clinical trial of cyclophosphamide plus azathioprine and pulse cyclophosphamide in lupus nephritis [abstract]. Kidney International 1981;19:119. CENTRAL

Balow 1984 {published data only}

Balow J, Austin H, Muenz L, Joyce K, Klippel J, Antonovych T. Influence of treatment on the evolution of renal pathology in lupus nephritis [abstract]. Kidney International 1984;25(1):158. CENTRAL

Ble 2011 {published data only}

Ble A, Mosca M, Di Loreto G, Guglielmotti A, Biondi G, Bombardieri S, et al. Antiproteinuric effect of chemokine C‐C motif ligand 2 inhibition in subjects with acute proliferative lupus nephritis. American Journal of Nephrology 2011;34(4):367‐72. [MEDLINE: 21876349]CENTRAL

Chanchairujira 2009 {published data only}

Chanchairujira T, Mahasukont J, Shayakul C, Ong‐Aj‐Yooth L, Cheunsuchon B, Parichaitiranond P. Histopathological outcome in proliferative lupus nephritis patients who did not achieve good response after randomized to eurolupus or high‐dose IV cyclophosphamide [abstract no: TH‐PO861]. Journal of the American Society of Nephrology 2009;20:309A. CENTRAL

Clark 1993 {published and unpublished data}

Clark WF, Parbtani A, Naylor CD, Levinton CM, Muirhead N, Spanner E, et al. Fish oil in lupus nephritis: clinical findings and methodological implications. Kidney International 1993;44(1):75‐86. [MEDLINE: 8355469]CENTRAL
Clark WF, Parbtani A, Naylor CD, Muirhead N, Huff MW, Philbrick DJ, et al. Fish oil in lupus nephritis a double‐blind randomized crossover study [abstract no: 37P]. Journal of the American Society of Nephrology 1992;3(3):309. CENTRAL

Clark 2001a {published and unpublished data}

Clark WF, Kortas C, Heidenheim AP, Garland J, Spanner E, Parbtani A. Flaxseed in lupus nephritis: a two‐year nonplacebo‐controlled crossover study. Journal of the American College of Nutrition 2001;20(2 Suppl):143‐8. [MEDLINE: 11349937]CENTRAL
Clark WF, Parbtani A, Macdonald G, Heidenheim P, Holub B, Kortas C. Flaxseed in lupus nephritis: a two year randomized cross‐over study [abstract no: T141]. Journal of the American Society of Nephrology 1998;9(Program & Abstracts):143A. CENTRAL

CONTROL 2016 {published data only}

Anutrakulchai S, Panaput T, Wongchinsri J, Chaishayanon S, Satirapoj B, Traitanon O, et al. A multicentre, randomised controlled study of enteric‐coated mycophenolate sodium for the treatment of relapsed or resistant proliferative lupus nephritis: an Asian experience. Lupus Science & Medicine 2016;3(1):e000120. [MEDLINE: 26835147]CENTRAL

Davis 1999 {published data only}

Davis JC, Manzi S, Yarboro C, Rairie J, Mcinnes I, Averthelyi D, et al. Recombinant human Dnase I (rhDNase) in patients with lupus nephritis. Lupus 1999;8(1):68‐76. CENTRAL

Daza 2005 {published data only}

Daza L, Kornhauser C, Zamora L, Flores J. Captopril effect on prostaglandin E2, thromboxane B2 and proteinuria in lupus nephritis patients. Prostaglandins & Other Lipid Mediators 2005;78(1‐4):194‐201. CENTRAL

Deng 2017a {published and unpublished data}

Deng D, Zhang P, Guo Y, Lim TO. A randomised double‐blind, placebo‐controlled trial of allogeneic umbilical cord‐derived mesenchymal stem cell for lupus nephritis. Annals of the Rheumatic Diseases 2017;76(8):1436‐9. [MEDLINE: 28478399]CENTRAL

Feng 2014 {published data only}

Feng X, Gu F, Chen W, Liu Y, Wei H, Liu L, et al. Mizoribine versus mycophenolate mofetil or intravenous cyclophosphamide for induction treatment of active lupus nephritis. Chinese Medical Journal 2014;127(21):3718‐23. [MEDLINE: 25382325]CENTRAL

Frutos 1997 {published data only}

Frutos MA, Valera A, Martinez JM, Martin‐Reyes G, Lopez de Novales E. Intravenous cyclophosphamide pulse therapy for severe lupus nephritis: finding an optimal dose and duration [abstract no: P1614]. Nephrology 1997;3(Suppl 1):S476. CENTRAL

Hebert 1987 {published data only}

Hebert I, Nielsen E, Pohl M, Lachin J, Hunsicker L, Lewis E. Clinical course of severe lupus nephritis during the controlled clinical trial of plasmapheresis [abstract]. Kidney International 1987;31(1):201. CENTRAL

Khajehdehi 2012 {published data only}

Khajehdehi P, Zanjaninejad B, Aflaki E, Nazarinia M, Azad F, Malekmakan L, et al. Oral supplementation of turmeric decreases proteinuria, hematuria, and systolic blood pressure in patients suffering from relapsing or refractory lupus nephritis: a randomized and placebo‐controlled study. Journal of Renal Nutrition 2012;22(1):50‐7. [MEDLINE: 21742514]CENTRAL

Kuo 2001 {published data only}

Kuo GM, Boumpas DT, Illei GG, Yarboro C, Pucino F, Burstein AH. Fludarabine pharmacokinetics after subcutaneous and intravenous administration in patients with lupus nephritis. Pharmacotherapy 2001;21(5):528‐33. [MEDLINE: 11349741]CENTRAL

Li 2005 {published data only}

Li L, Zhang H, Shen S, Hu W, Liu Z. Controlled trial of tacrolimus (FK506) vs intravenous cyclophosphamide (IVC) as induction therapy for severe lupus nephritis [abstract no: F‐PO1006]. Journal of the American Society of Nephrology 2005;16:556A. CENTRAL

Li 2014a {published data only}

Li M, Ma JJ, Zhao XL, Zhu Y. Treating lupus nephritis by a drug pair of radix astragali and rehmanniae radix combined with glucocorticoid: a preliminary clinical study. Zhongguo Zhongxiyi Jiehe Zazhi [Chinese Journal of Integrated Traditional and Western Medicine] 2014;34(8):956‐9. [MEDLINE: 25223180]CENTRAL

LJP 394‐90‐05 2003 {published data only}

Alarcon‐Segovia D, Tumlin J, Furie R, McKay J, Cariel M, Linnik M, et al. SLE trial shows fewer renal flares in LJP 394‐treated patients with high affinity antibodies to LJP 394: 90‐05 trial results [abstract]. Arthritis & Rheumatism 2000;43:S272. CENTRAL
Alarcon‐Segovia D, Tumlin JA, Furie RA, McKay JD, Cardiel MH, Strand V, et al. LJP 394 for the prevention of renal flare in patients with systemic lupus erythematosus: results from a randomized, double‐blind, placebo‐controlled study. Arthritis & Rheumatism 2003;48(2):442‐54. [MEDLINE: 12571854]CENTRAL
Hura C, Tumlin JA, Heilbrunn KR. Integrated safety results from studies of LJP394 in SLE patients [abstract no: F‐PO218]. Journal of the American Society of Nephrology 2004;15(Oct):113A. CENTRAL
Linnik MD, Hu JZ, Heilbrunn KR, Strand V, Hurley FL, Joh T. Anti‐dsDNA antibodies and exacerbation of renal disease in patients with systemic lupus erythematosus: results from 2 randomized controlled trials with LJP394 [abstract]. Lupus 2004; 7th International Congress on SLE and Related Conditions; 2004 May 9‐13; New York (NY). 2004. CENTRAL
Linnik MD, Hu JZ, Heilbrunn KR, Strand V, Hurley FL, Joh T, et al. Relationship between anti‐double‐stranded DNA antibodies and exacerbation of renal disease in patients with systemic lupus erythematosus. Arthritis & Rheumatism 2005;52(4):1129‐37. [MEDLINE: 15818711]CENTRAL
Linnik MD, Joh T, Tumlin JA. Reductions in anti‐dsDNA antibodies and reduced risk of SLE renal flare and major SLE flare [abstract no: SA‐PO695]. Journal of the American Society of Nephrology 2003;14(Nov):450A. CENTRAL
Tumlin JA, Cardiel MH, Furie RA, Wallace DJ, Hura C. Renal flare in SLE patients with impaired renal function in a RCT of LJP 394 [abstract no: SA‐PO693]. Journal of the American Society of Nephrology 2003;14(Nov):449A. CENTRAL
Tumlin JA, Cardiel MH, Furie RA, Wallace DJ, Hura C, Foster T, et al. Reductions in 24 hour urine protein levels associated with treatment of lupus patients withLJP 394 in two randomized, placebo controlled, double‐blind clinical trials [abstract]. Lupus 2004; 7th International Congress on SLE and Related Conditions; 2004 May 9‐13; New York (NY). 2004. CENTRAL
Tumlin JA, Hura C, Joh T, Heilbrunn KR. Reductions in 24‐hour urine protein levels associated with treatment of SLE patients with LJP394 in two randomized, placebo‐controlled clinical trials [abstract no: F‐PO256]. Journal of the American Society of Nephrology 2004;15(Oct):121A. CENTRAL
Tumlin JA, Linnik MD, Appel GB. The B‐cell tolerogen LJP‐394 reduces renal flares in patients with lupus nephritis: a prospective, double‐blinded, placebo controlled trial [abstract]. Journal of the American Society of Nephrology 2001;12(Program & Abstracts):253A. CENTRAL

LJP 394‐90‐09 2005 {published and unpublished data}

Cardiel MH, LJP 394‐90‐09 Study Investigators. Randomized, placebo controlled, double blind phase III trial for the evaluation of LJP 394 (Abetimus sodium) in the treatment of patients with SLE who are at risk of renal flare [abstract no: OP0053]. Annual European Congress of Rheumatology EULAR; 2003 June 18‐21; Lisbon (Portugal). 2003. CENTRAL
Cardiel MH, Tumlin JA, Furie RA, Wallace DJ, Joh T, Linnik MD, et al. Abetimus sodium for renal flare in systemic lupus erythematosus: results of a randomized, controlled phase III trial. Arthritis & Rheumatism 2008;58(8):2470‐80. [MEDLINE: 18668592]CENTRAL
Hura C, Tumlin JA, Heilbrunn KR. Integrated safety results from studies of LJP394 in SLE patients [abstract no: F‐PO218]. Journal of the American Society of Nephrology 2004;15(Oct):113A. CENTRAL
Linnik MD, Hu JZ, Heilbrunn KR, Strand V, Hurley FL, Joh T. Anti‐dsDNA antibodies and exacerbation of renal disease in patients with systemic lupus erythematosus: results from 2 randomized controlled trials with LJP394 [abstract]. Lupus 2004; 7th International Congress on SLE and Related Conditions; 2004 May 9‐13; New York (NY). 2004. CENTRAL
Linnik MD, Hu JZ, Heilbrunn KR, Strand V, Hurley FL, Joh T, et al. Relationship between anti‐double‐stranded DNA antibodies and exacerbation of renal disease in patients with systemic lupus erythematosus. Arthritis & Rheumatism 2005;52(4):1129‐37. [MEDLINE: 15818711]CENTRAL
Linnik MD, Joh T, Tumlin JA. Reductions in anti‐dsDNA antibodies and reduced risk of SLE renal flare and major SLE flare [abstract no: SA‐PO695]. Journal of the American Society of Nephrology 2003;14(Nov):450A. CENTRAL
Tumlin JA, Cardiel MH, Furie RA, Wallace DJ, Hura C. Renal flare in SLE patients with impaired renal function in a RCT of LJP 394 [abstract no: SA‐PO693]. Journal of the American Society of Nephrology 2003;14(Nov):449A. CENTRAL
Tumlin JA, Cardiel MH, Furie RA, Wallace DJ, Hura C, Foster T, et al. Reductions in 24 hour urine protein levels associated with treatment of lupus patients with LJP 394 in two randomized, placebo controlled, double‐blind clinical trials [abstract]. Lupus 2004; 7th International Congress on SLE and Related Conditions; 2004 May 9‐13; New York (NY). 2004. CENTRAL
Tumlin JA, Hura C, Appel G. Efficacy results from a RCT of LJP 394 in SLE patients with history of renal disease [abstract no: SA‐PO694]. Journal of the American Society of Nephrology 2003;14(Nov):449A‐50A. CENTRAL
Tumlin JA, Hura C, Heilbrunn KR. The effect of LJP394 and concomitant immunosuppressive agents on levels of anti‐dsDNA antibodies in SLE patients [abstract no: PUB137]. Journal of the American Society of Nephrology 2004;15(Oct):791A. CENTRAL
Tumlin JA, Hura C, Joh T, Heilbrunn KR. Reductions in 24‐hour urine protein levels associated with treatment of SLE patients with LJP394 in two randomized, placebo‐controlled clinical trials [abstract no: F‐PO256]. Journal of the American Society of Nephrology 2004;15(Oct):121A. CENTRAL
Wallace DJ, Cardiel MH, Tumlin JA, Furie R, Hura C, Strand V, et al. Safety results from a RCT of LJP 394 in SLE patients with a history of renal disease [abstract no: SA‐PO692]. Journal of the American Society of Nephrology 2003;14(Nov):449A. CENTRAL

Lu 2002 {published data only}

Lu L. Study on effect of Cordyceps sinensis and artemisinin in preventing recurrence of lupus nephritis. Zhongguo Zhongxiyi Jiehe Zazhi [Chinese Journal of Integrated Traditional and Western Medicine] 2002;22(3):169‐71. [MEDLINE: 12585097]CENTRAL

Miyasaka 2009 {published data only}

Miyasaka N, Kawai S, Hashimoto H. Efficacy and safety of tacrolimus for lupus nephritis: a placebo‐controlled double‐blind multicenter study. Modern Rheumatology 2009;19(6):606‐15. [MEDLINE: 19688181]CENTRAL

NCT00001212 {published data only}

NCT00001212. Immunosuppressive drug therapy in membranous lupus nephropathy. www.clinicaltrials.gov/ct2/show/NCT00001212 (first received 3 November 1999). CENTRAL

NCT00404157 {published data only}

Garg J. A study to evaluate the safety of rituximab retreatment in subjects with lupus nephritis previously enrolled in study U2970g. www.clinicalTrials.gov/show/NCT00404157 (first received 27 November 2006). CENTRAL

NCT00429377 {published data only}

NCT00429377. Phase 3 study of tacrolimus (FK506) for lupus nephritis: a placebo controlled, double‐blind multicenter, comparative study. www.clinicaltrials.gov/ct2/show/NCT00429377 (first received 29 January 2007). CENTRAL

NCT00436438 {published data only}

NCT00425438. A randomized, open‐label study to compare the effect of cellcept plus corticosteroids, and cyclophosphamide plus corticosteroids followed by azathioprine, on remission rate in patients with lupus nephritis. www.clinicaltrials.gov/ct2/show/NCT00425438 (first received 23 January 2007). CENTRAL

NCT00539799 {unpublished data only}

Jayne D, Walsh M. Corticosteroids in the maintenance therapy of proliferative lupus nephritis: a randomized pilot study (SIMPL). www.clinicaltrials.gov/ct2/show/NCT00539799 (first received 4 October 2007). CENTRAL

NCT00659217 {published and unpublished data}

Tan JM. Effect of mesenchymal stem cell transplantation for lupus nephritis. www.clinicaltrials.gov/ct2/show/NCT00659217 (first received 14 April 2008). CENTRAL

NCT01299922 {published data only}

Praga M, Gema FJ. Phase III, open, randomized, parallel‐group clinical trial, to evaluate the efficacy and safety of treatment with prednisone, cyclosporine, mycophenolic acid versus prednisone and mycophenolic acid in lupus nephritis type III‐IV‐V. www.clinicaltrials.gov/ct2/show/NCT01299922 (first received 18 February 2011). CENTRAL

NCT01342016 {published data only}

NCT01342016. A randomized, double‐blind double dummy, parallel control and multi‐center clinical trial to compare the efficacy and safety of tacrolimus capsules in treatment of lupus nephritis with leflunomide tablets. www.clinicaltrials.gov/ct2/show/NCT01342016 (first received 25 April 2011). CENTRAL

NCT01930890 {published data only}

NCT01930890. BIIB023 long‐term extension study in subjects with lupus nephritis. www.clinicaltrials.gov/ct2/show/NCT01930890 (first received 29 August 2013). CENTRAL

NCT02176486 {published data only}

NCT02176486. A phase 1b, randomized, double‐blind, placebo‐controlled, safety, tolerability and pharmacokinetic study of multiple rising doses of MLN9708 for the treatment of subjects with ISN/RPS class III or IV lupus nephritis. www.clinicaltrials.gov/ct2/show/NCT02176486 (first received 25 June 2014). CENTRAL

Pierucci 1989 {published data only}

Pierucci A, Simonetti BM, Pecci G, Feriozzi S, Mavrikakis G, Cinotti GA, et al. Low does aspirin in patients with lupus nephritis [abstract]. Kidney International 1988;33(1):281. CENTRAL
Pierucci A, Simonetti BM, Pecci G, Mavrikakis G, Feriozzi S, Cinotti GA, et al. Acute effects of a thromboxane receptor antagonist on renal function in patients with lupus nephritis [abstract]. Kidney International 1987;31(1):283. CENTRAL
Pierucci A, Simonetti BM, Pecci G, Mavrikakis G, Feriozzi S, Cinotti GA, et al. Improvement of renal function with selective thromboxane antagonism in lupus nephritis. New England Journal of Medicine 1989;320(7):421‐5. [MEDLINE: 2643773]CENTRAL

Schaumann 1992 {published data only}

Schaumann D, Hein R, Neumann KH, Brunkhorst R, Schmidt RE, Koch KM. Short term cyclophosphamide (CP) bolus therapy for lupus nephritis [abstract]. Journal of the American Society of Nephrology 1994;5(3):360A. CENTRAL
Schaumann D, Hein R, Schmidt RE, Brunkhorst R, Neumann KH, Deicher H, et al. Intravenous cyclophosphamide (CP) pulse therapy for lupus nephritis ‐ duration of induction therapy [abstract no: 028]. International Symposium on Pathogenesis, Pathophysiology & Therapy of Glomerulonephritis; 1992 Dec 3‐5; Bruges, Belgium. 1992:60. CENTRAL

Su 2007 {published data only}

Su L, Mao JC, Gu JH. Effect of intravenous drip infusion of cyclophosphamide with high‐dose Astragalus injection in treating lupus nephritis. Zhong Xi Yi Jie He Xue Bao [Journal of Chinese Integrative Medicine] 2007;5(3):272‐5. [MEDLINE: 17498486]CENTRAL

Sztejnbok 1971 {published data only}

Sztejnbok M, Stewart A, Diamond H, Kaplan D. Azathioprine in the treatment of systemic lupus erythematosus. A controlled study. Arthritis & Rheumatism 1971;14(5):639‐45. CENTRAL

Wallace 2006 {published data only}

Wallace DJ, Lisse J, Stohl W, McKay J, Boling E, Merrill JT, et al. Belimumab (BmAb) reduces SLE disease activity and demonstrates durable bioactivity at 76 weeks [abstract no: 2012]. ACR/ARHP Annual Scientific Meeting; 2006 Nov 11‐15; Washington (DC). 2006. CENTRAL

Wang 2007 {published data only}

Wang J, Hu W, Xie H, Zhang H, Chen H, Zeng C, et al. Induction therapies for class IV lupus nephritis with non‐inflammatory necrotizing vasculopathy: mycophenolate mofetil or intravenous cyclophosphamide. Lupus 2007;16(9):707‐12. [MEDLINE: 17728363]CENTRAL

Witte 1993 {published data only}

Hein R, Neumann KH, Koch KM, Deicher H, Schmidt RE. Cyclophosphamide pulse therapy of systemic lupus erythematosus with renal involvement [Cyclophosphamid‐Stosstherapie des systemischen Lupus erythematodes mit Nierenbeteiligung]. Immunitat und Infektion 1991;19(2):57‐8. [MEDLINE: 1855811]CENTRAL
Witte T, Schaumann D, Hein R, Helmchen U, Neumann KH, Koch KM, et al. Cyclophosphamide bolus therapy in lupus nephritis [Cyclophosphamid‐Bolustherapie bei Lupusnephritis]. Deutsche Medizinische Wochenschrift 1993;118(27‐28):1005‐10. [MEDLINE: 8334946]CENTRAL
Witte T, Schaumann D, Hein R, Neumann KH, Koch KM, Deicher H, et al. Cyclophosphamide bolus therapy in lupus nephritis ‐ status of the clinical study [Cyclophosphamidbolus‐Therapie bei Lupusnephritis‐‐Stand der Therapiestudie]. Immunitat und Infektion 1993;21(Suppl 1):24‐6. [MEDLINE: 8344680]CENTRAL

Yap 2012 {published data only}

Yap DY, Yu X, Chen XM, Lu F, Chen N, Li XW, et al. Pilot 24 month study to compare mycophenolate mofetil and tacrolimus in the treatment of membranous lupus nephritis with nephrotic syndrome. Nephrology 2012;17(4):352‐7. [MEDLINE: 22295934]CENTRAL

Ye 2001 {published data only}

Ye Z, Tan YH, Hong XP, Feng XX, Xiao XL. MMF vs CTX in the treatment of severe SLE patients [abstract no: P1610]. Lupus 2001;10(Suppl):S99. CENTRAL

Yoshida 1996 {published data only}

Yoshida T, Kameda H, Ichikawa Y, Tojo T, Homma M. Improvement of renal function with a selective thromboxane A2 synthetase inhibitor, DP‐1904, in lupus nephritis. Journal of Rheumatology 1996;23(10):1719‐24. [MEDLINE: 8895147]CENTRAL
Yoshida T, Kameda H, Masashi A, Homma M, Ikeda Y. Improvement of renal function with selective thromboxane A2 synthetase inhibitor, DP‐1904 in lupus nephritis. Advances in Experimental Medicine & Biology 1997;433:113‐7. [MEDLINE: 9561116]CENTRAL

Zhang 2015c {published and unpublished data}

Zhang J, Zhao Z, Hu X. Effect of Rituximab on serum levels of anti‐C1q and antineutrophil cytoplasmic autoantibodies in refractory severe lupus nephritis. Cell Biochemistry & Biophysics 2015;72(1):197‐201. [MEDLINE: 25490907]CENTRAL

Zheng 2005a {published data only}

Zheng WC, Hu SJ, Fang Q. Intervention of liuwei dihuang pill on lupus nephropathy treated with cyclophosphamide and glucocorticoids. Zhongguo Zhongxiyi Jiehe Zazhi [Chinese Journal of Integrated Traditional and Western Medicine] 2005;25(11):983‐5. CENTRAL

2nd Dutch Lupus Trial {published data only}

Bijl M. Comparison of short course cyclophosphamide followed by mycophenolate mofetil versus long course cyclophosphamide in the treatment of proliferative lupus nephritis. www.controlled‐trials.com/ISRCTN34634478 (first received 27 January 2006). CENTRAL

ChiCTR‐TRC‐09000587 {published data only}

Li Z. The intensive therapy of severe lupus nephritis: a multicenter, randomized, controlled prospective clinical trial. www.chictr.org.cn/showprojen.aspx?proj=8948 (first received 1 October 2009). CENTRAL

ChiCTR‐TRC‐10000931 {published data only}

Mei C. Treatment of severe lupus nephritis with tacrolimus (FK 506) based immunosuppression. www.chictr.org.cn/showprojen.aspx?proj=8607 (first received 9 July 2010). CENTRAL

CTRI/2016/01/006488 {published data only}

Gupta KL. Comparison of two steroid dose regimen in lupus nephritis. www.ctri.nic.in/Clinicaltrials/pdf_generate.php?trialid=13735&EncHid=&modid=&compid=%27,%2713735det%27 (first received 7 January 2016). CENTRAL

CTRI/2017/05/008697 {published data only}

Gupta KL. A study to compare the efficacy of cyclophosphamide versus multi‐drug therapy in the treatment of lupus nephritis. www.ctri.nic.in/Clinicaltrials/showallp.php?mid1=19083&EncHid=&userName=CTRI/2017/05/008697 (first received 30 May 2017). CENTRAL

ISRCTN66475575 {published data only}

Chartapisak W. Enteric coat mycophenolate sodium versus intravenous cyclophosphamide for severe paediatric lupus nephritis. www.isrctn.com/ISRCTN66475575 (first received 29 July 2009). CENTRAL

NCT00302549 {published data only}

Li LS. To compare the efficacy and safety of FK506 vs IVC in the treatment of class III‐IV LN. www.clinicaltrials.gov/ct2/show/NCT00302549 (first received 14 March 2006). CENTRAL

NCT00705367 {published data only}

NCT00705367. Phase I study in China ‐ tolerability of a single dose of abatacept 30 mg/kg. www.clinicaltrials.gov/show/NCT00705367 (first received 26 June 2008). CENTRAL

NCT00881309 {published data only}

Hu W. To compare the efficacy and safety of tripterygium (TW) vs AZA in the maintenance therapy for lupus nephritis. www.clinicaltrials.gov/ct2/show/NCT00881309 (first received 14 April 2009). CENTRAL

NCT01056237 {published data only}

Liu ZH. Long‐term study of multi‐target therapy as maintenance treatment for lupus nephritis. www.clinicaltrials.gov/ct2/show/NCT01056237 (first received 26 January 2010). CENTRAL

NCT01172002 {published data only}

NCT01172002. A randomized multicenter trial comparing leflunomide and azathioprine as remission‐maintaining treatment for proliferative lupus glomerulonephritis. www.clinicaltrials.gov/ct2/show/NCT01172002 (first received 27 July 2010). CENTRAL

NCT01284725 {published data only}

Belaigues, B. Weaning of Immunosuppression in Nephritis of Lupus (WIN‐Lupus). www.clinicaltrials.gov/ct2/show/NCT01284725 (first received 21 January 2011). CENTRAL

NCT01639339 {published data only}

NCT01639339. A phase 3, randomized, double‐blind, placebo‐controlled study to evaluate the efficacy and safety of belimumab plus standard of care versus placebo plus standard of care in adult subjects with active lupus nephritis (BLISS‐LN). www.clinicaltrials.gov/ct2/show/NCT01639339 (first received 10 July 2012). CENTRAL

NCT01714817 {published data only}

NCT01714817. Efficacy and safety study of abatacept to treat lupus nephritis. www.clinicaltrials.gov/ct2/show/NCT01714817 (first received 26 October 2012). CENTRAL

NCT01845740 {published data only}

Wegener W. Phase Ib study of SC milatuzumab in SLE. www.clinicaltrials.gov/ct2/show/NCT01845740 (first received 3 May 2013). CENTRAL

NCT01861561 {published data only}

Piyaphanee N, Pattaragarn A. Efficacy and infectious complications of induction therapy with low‐dose versus high‐dose intravenous cyclophosphamide for proliferative lupus nephritis in children. www.clinicaltrials.gov/ct2/show/NCT01861561 (first received 19 May 2013). CENTRAL

NCT02226341 {published data only}

NCT02226341. Open‐label prospective randomized study to determine the efficacy and safety of two dosing regimens of ACTHar in the treatment of proliferative lupus nephritis. www.clinicaltrials.gov/ct2/show/NCT02226341 (first received 25 August 2014). CENTRAL

NCT02256150 {published data only}

NCT02256150. A multi‐center, randomized, controlled, open‐label clinical study to evaluate the efficacy and safety of mizoribine in comparison with cyclophosphamide in the treatment of lupus nephritis. www.clinicaltrials.gov/ct2/show/NCT02256150 (first received 1 October 2014). CENTRAL

NCT02260934 {published data only}

Diamond B, Wofsy D, Dall'Era M, Aranow C. Rituximab plus cyclophosphamide followed by belimumab for the treatment of lupus nephritis (ITN055AI) (CALIBRATE). www.clinicaltrials.gov/ct2/show/NCT02260934 (first received 6 October 2014). CENTRAL

NCT02457221 {published data only}

NCT02457221. A phase III, randomized, open, parallel‐controlled, multi‐center study to compare the efficacy and safety of tacrolimus capsules and cyclophosphamide injection in treatment of lupus nephritis. www.clinicaltrials.gov/ct2/show/NCT02457221 (first received 22 May 2015). CENTRAL

NCT02547922 {published data only}

NCT02547922. A multicentre, randomised, double‐blind, placebo‐controlled, phase 2 study evaluating the efficacy and safety of anifrolumab in adult subjects with active proliferative lupus nephritis (TULIP‐LN1). www.clinicaltrials.gov/ct2/show/NCT02547922 (first received 31 August 2015). CENTRAL

NCT02550652 {published data only}

NCT02550652. A randomized, double‐blind, placebo‐controlled, multi‐center study to evaluate the safety and efficacy of obinutuzumab in subjects with ISN/RPS 2003 class III or IV lupus nephritis. www.clinicaltrials.gov/ct2/show/NCT02550652 (first received 14 September 2015). CENTRAL

NCT02630628 {published data only}

Chan DT. A randomized open‐label study to evaluate the efficacy and safety of tacrolimus and corticosteroids in comparison with mycophenolate mofetil and corticosteroids in subjects with class III/IV±V lupus nephritis. www.clinicaltrials.gov/ct2/show/NCT02630628 (first received 5 December 2015). CENTRAL

NCT02770170 {published data only}

NCT02770170. A double‐blind, randomised, placebo‐controlled trial evaluating the effect of BI 655064 administered as sub‐cutaneous injections, on renal response after one year treatment in patients with lupus nephritis. www.clinicaltrials.gov/ct2/show/NCT02770170 (first received 11 May 2016). CENTRAL

NCT02936375 {published data only}

Bao C. Iguratimod as treatment for active lupus nephritis. www.clinicaltrials.gov/ct2/show/NCT02936375 (first received12 October 2016). CENTRAL

NCT02954939 {published data only}

Yap D. A randomized, controlled double‐blind study comparing the efficacy and safety of orelvo (voclosporin) (23.7 mg twice daily) with placebo in achieving renal response in subjects with active lupus nephritis. www.clinicaltrials.gov/ct2/show/NCT02954939 (first received 13 September 2016). CENTRAL

NCT03021499 {published data only}

Dooley MA. Aurinia renal response in active lupus with voclosporin. www.clinicaltrials.gov/ct2/show/NCT03021499 (first received 16 January 2017). CENTRAL

NCT03214731 {published data only}

Yu XQ. Efficacy and safety of artesunate plus standard of care in active lupus nephritis. www.clinicaltrials.gov/ct2/show/NCT03214731 (first received 12 July 2017). CENTRAL

PER‐062‐15 {published data only}

PER‐062‐15. A multicentre, randomised, double‐blind, placebo‐controlled, phase 3 study evaluating the efficacy and safety of two doses of anifrolumab in adult subjects with active proliferative lupus nephritis. www.ins.gob.pe/ensayosclinicos/rpec/recuperarECPBNuevoEN.asp?numec=062‐15 (first received 4 May 2016). CENTRAL

RING 2015 {published data only}

Houssiau FA. RING, an investigator‐initiated trial aimed at testing the efficacy of rituximab in refractory lupus nephritis: rationale, trial design and call for participation [abstract]. Clinical & Experimental Rheumatology 2015;33(3 Suppl 90):S30. [EMBASE: 71976757; NCT01673295]CENTRAL

RITUXILUP 2013 {published data only}

Lightstone L. Phase 3 open label randomised multicentre controlled trial of rituximab and mycophenolate mofetil without oral steroids for the treatment of lupus nephritis (RITUXILUP). www.clinicaltrials.gov/ct2/show/NCT01773616 (first received 23 January 2013). CENTRAL

Adler 2006

Adler M, Chambers S, Edwards C, Neild G, Isenberg D. An assessment of renal failure in an SLE cohort with special reference to ethnicity, over a 25‐year period. Rheumatology 2006;45(9):1144‐7. [MEDLINE: 16527882]

ANZDATA 2016

Australia, New Zealand Dialysis, Transplant Registry. ANZDATA Registry. 39th Report, Chapter 1: Incidence of End Stage Kidney Disease. www.anzdata.org.au/anzdata/AnzdataReport/39thReport/c01_incidence_v5.0_20170418.pdf (accessed 17 May 2018).

Bansal 1997

Bansal VK, Beto JA. Treatment of lupus nephritis: a meta‐analysis of clinical trials. American Journal of Kidney Diseases 1997;29(2):193‐9.

Begg 1996

Begg C, Cho M, Eastwood S, Horton R, Moher D, Olkin I, et al. Improving the quality of reporting of randomized controlled trials. The CONSORT statement. JAMA 1996;276(8):637‐9. [MEDLINE: 8773637]

Cao 2015

Cao H, Rao Y, Liu L, Lin J, Yang H, Zhang X, et al. The efficacy and safety of leflunomide for the treatment of lupus nephritis in Chinese patients: systematic review and meta‐analysis. PLoS ONE [Electronic Resource] 2015;10(12):e0144548. [MEDLINE: 26670616]

Cervera 2009

Cervera R, Khamashta MA, Hughes GR. The Euro‐lupus project: epidemiology of systemic lupus erythematosus in Europe. Lupus 2009;18(10):869‐74. [MEDLINE: 19671784]

Chen 2017

Chen Y, Sun J, Zou K, Yang Y, Lin G. Treatment for lupus nephritis: an overview of systematic reviews and meta‐analyses. Rheumatology International 2017;37(7):1089‐99. [MEDLINE: 28493175]

Contreras 2006

Contreras G, Lenz O, Pardo V, Borja E, Cely C, Iqbal K, et al. Outcomes in African Americans and Hispanics with lupus nephritis. Kidney International 2006;69(10):1846‐51. [MEDLINE: 16598205]

Costenbader 2011

Costenbader KH, Desai A, Alarcon GS, Hiraki LT, Shaykevich T, Brookhart MA, et al. Trends in the incidence, demographics, and outcomes of end‐stage renal disease due to lupus nephritis in the US from 1995 to 2006. Arthritis & Rheumatism 2011;63(6):1681‐8. [MEDLINE: 21445962]

Daleboudt 2011

Daleboudt GM, Berger SP, Broadbent E, Kaptein AA. Health‐related quality of life in patients with systemic lupus erythematosus and proliferative lupus nephritis. Psychology Health & Medicine 2011;16(4):393‐404. [MEDLINE: 21749237]

Deeks 2001

Deeks JJ. Systematic reviews in health care: Systematic review of evaluations of diagnostic and screening tests. BMJ 2001;323(7305):157‐62. [PUBMED: 11463691]

Deng 2012

Deng J, Huo D, Wu Q, Yang Z, Liao Y. A meta‐analysis of randomized controlled trials comparing tacrolimus with intravenous cyclophosphamide in the induction treatment for lupus nephritis. Tohoku Journal of Experimental Medicine 2012;227(4):281‐8. [MEDLINE: 22820853]

Dooley 1997

Dooley MA, Hogan S, Jenette C, Falk R. Cyclophosphamide therapy for lupus nephritis: poor renal survival in black Americans. Glomerular Disease Collaborative Network. Kidney International 1997;51(4):1188‐95. [MEDLINE: 9083285]

Feng 2013

Feng L, Deng J, Huo DM, Wu QY, Liao YH. Mycophenolate mofetil versus azathioprine as maintenance therapy for lupus nephritis: a meta‐analysis. Nephrology 2013;18(2):104‐10. [MEDLINE: 23113811]

Fernandes das Neves 2015

Fernandes das Neves M, Irlapati RV, Isenberg D. Assessment of long‐term remission in lupus nephritis patients: a retrospective analysis over 30 years. Rheumatology 2015;54(8):1403‐7. [MEDLINE: 25725362]

GRADE 2008

Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck‐Ytter Y, Alonso‐Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008;336(7650):924‐6. [MEDLINE: 18436948]

GRADE 2011

Guyatt GH, Oxman AD, Schunemann HJ, Tugwell P, Knottnerus A. GRADE guidelines: a new series of articles in the Journal of Clinical Epidemiology. Journal of Clinical Epidemiology 2011;64(4):380‐2. [MEDLINE: 21185693]

Hanly 2016

Hanly JG, O'Keeffe AG, Su L, Urowitz MB, Romero‐Diaz, Gordon C, et al. The frequency and outcome of lupus nephritis: results from an international inception cohort study. Rheumatology 2016;55(2):252‐62. [MEDLINE: 26342222]

Hannah 2016

Hannah J, Casian A, D'Cruz D. Tacrolimus use in lupus nephritis: a systematic review and meta‐analysis. Autoimmunity Reviews 2016;15(1):93‐101. [MEDLINE: 26427983]

Higgins 2003

Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta‐analyses. BMJ 2003;327(7414):557‐60. [MEDLINE: 12958120]

Higgins 2011

Higgins JP, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration. 2011. Available from www.cochrane‐handbook.org.

Houssiau 2010

Houssiau FA, Vasconcelos C, D'Cruz D, Sebastiani GD, de Ramon Garrido E, Danieli MG, et al. The 10‐year follow‐up data of the Euro‐Lupus Nephritis Trial comparing low‐dose and high‐dose intravenous cyclophosphamide. Annals of the Rheumatic Diseases 2010;69(1):61‐4. [MEDLINE: 19155235]

Ioannidis 2000

Ioannidis JP, Boki KA, Katsorida ME, Drosos AA, Skopouli FN, Boletis JN, et al. Remission, relapse, and re‐remission of proliferative lupus nephritis treated with cyclophosphamide. Kidney International 2000;57(1):258‐64. [MEDLINE: 10620207]

Isenberg 2010

Isenberg D, Appel GB, Contreras G, Dooley MA, Ginzler EM, Jayne D, et al. Influence of race/ethnicity on response to lupus nephritis treatment: the ALMS study. Rheumatology 2010;49(1):128‐40. [MEDLINE: 19933596]

Kamanamool 2010

Kamanamool N, McEvoy M, Attia J, Ingsathit A, Ngamjanyaporn P, Thakkinstian A. Efficacy and adverse events of mycophenolate mofetil versus cyclophosphamide for induction therapy of lupus nephritis: systematic review and meta‐analysis. Medicine 2010;89(4):227‐35. [MEDLINE: 20616662]

Korbet 2007

Korbet SM, Schwartz MM, Evans J, Lewis EJ, Collaborative Study Group. Severe lupus nephritis: racial differences in presentation and outcome. Journal of the American Society of Nephrology 2007;18(1):244‐54. [MEDLINE: 17167111]

Lee 2010

Lee Y, Woo JH, Choi SJ, Ji JD, Song GG. Induction and maintenance therapy for lupus nephritis: a systematic review and meta‐analysis. Lupus 2010;19(6):703‐10. [MEDLINE: 20064907]

Lee 2011

Lee YH, Lee HS, Choi SJ, Dai Ji J, Song GG. Efficacy and safety of tacrolimus therapy for lupus nephritis: a systematic review of clinical trials. Lupus 2011;20(6):636‐40. [MEDLINE: 21382917]

Lee 2015

Lee YH, Song GG. Relative efficacy and safety of tacrolimus, mycophenolate mofetil, and cyclophosphamide as induction therapy for lupus nephritis: a Bayesian network meta‐analysis of randomized controlled trials. Lupus 2015;24(14):1520‐8. [MEDLINE: 26162684]

Liang 2006

Renal Disease Subcommittee of the American College of Rheumatology Ad Hoc Committee on Systemic Lupus Erythematosus Response, Criteria. The American College of Rheumatology response criteria for proliferative and membranous renal disease in systemic lupus erythematosus clinical trials. Arthritis & Rheumatism 2006;54(2):421‐32. [MEDLINE: 16453282]

Liu 2012

Liu LL, Jiang Y, Wang LN, Yao L, Li ZL. Efficacy and safety of mycophenolate mofetil versus cyclophosphamide for induction therapy of lupus nephritis: a meta‐analysis of randomized controlled trials. Drugs 2012;72(11):1521‐33. [MEDLINE: 22818016]

Mak 2009

Mak A, Cheak AA, Tan JY, Su HC, Ho RC, Lau CS. Mycophenolate mofetil is as efficacious as, but safer than, cyclophosphamide in the treatment of proliferative lupus nephritis: a meta‐analysis and meta‐regression. Rheumatology 2009;48(8):944‐52. [MEDLINE: 19494179]

Maneiro 2014

Maneiro JR, Lopez‐Canoa N, Salgado E, Gomez‐Reino JJ. Maintenance therapy of lupus nephritis with mycophenolate or azathioprine: systematic review and meta‐analysis. Rheumatology 2014;53(5):834‐8. [MEDLINE: 24369416]

McElhone 2006

McElhone K, Abbott J, Teh LS. A review of health related quality of life in systemic lupus erythematosus. Lupus 2006;15(10):633‐43. [MEDLINE: 17120589]

Mills 2013

Mills EJ, Thorlund K, Ioannidis JP. Demystifying trial networks and network meta‐analysis. BMJ 2013;346:f2914. [MEDLINE: 23674332]

Moher 1999

Moher D, Cook DJ, Eastwood S, Olkin I, Rennie D, Stroup DF. Improving the quality of reports of meta‐analyses of randomised controlled trials: the QUOROM statement. Quality of Reporting of Meta‐analyses. Lancet 1999;354(9193):1896‐900. [MEDLINE: 10584742]

Mok 2002

Mok CC, Ho CT, Chan KW, Lau CS, Wong RW. Outcome and prognostic indicators of diffuse proliferative lupus glomerulonephritis treated with sequential oral cyclophosphamide and azathioprine. Arthritis & Rheumatism 2002;46(4):1003‐13. [MEDLINE: 11953978]

Moore 2006

Moore RA, Derry S. Systematic review and meta‐analysis of randomised trials and cohort studies of mycophenolate mofetil in lupus nephritis. Arthritis Research & Therapy 2006;8(6):R182. [MEDLINE: 17163990]

Moroni 2007

Moroni G, Quaglini S, Gallelli B, Banfi G, Messa P, Ponticelli C. The long‐term outcome of 93 patients with proliferative lupus nephritis. Nephrology Dialysis Transplantation 2007;22(9):2531‐9. [MEDLINE: 17510096]

Murphy 2013

Murphy G, Lisnevskaia L, Isenberg D. Systemic lupus erythematosus and other autoimmune rheumatic diseases: challenges to treatment. Lancet 2013;382(9894):809‐18. [MEDLINE: 23972423]

Palmer 2017

Palmer SC, Tunnicliffe DJ, Singh‐Grewal D, Mavridis D, Tonelli M, Johnson DW, et al. Induction and maintenance immunosuppression treatment of proliferative lupus nephritis: a network meta‐analysis of randomized trials. American Journal of Kidney Disease 2017;70(3):324‐36. [MEDLINE: 28233655]

Ponticelli 1998

Ponticelli C, Moroni G. Flares in lupus nephritis: incidence, impact on renal survival and management. Lupus 1998;7(9):635‐8. [MEDLINE: 9884102]

Radhakrishnan 2010

Radhakrishnan J, Moutzouris DA, Ginzler EM, Solomons N, Siempos II, Appel GB. Mycophenolate mofetil and intravenous cyclophosphamide are similar as induction therapy for class V lupus nephritis. Kidney International 2010;77(2):152‐60. [MEDLINE: 19890271]

Rovin 2014

Rovin BH, Parikh SV. Lupus nephritis: the evolving role of novel therapeutics. American Journal of Kidney Diseases 2014;63(4):677‐90. [MEDLINE: 24411715]

Schünemann 2011a

Schünemann HJ, Oxman AD, Higgins JP, Vist GE, Glasziou P, Guyatt GH. Chapter 11: Presenting results and 'Summary of findings' tables. In: Higgins JP, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane‐handbook.org.

Schünemann 2011b

Schünemann HJ, Oxman AD, Higgins JP, Deeks JJ, Glasziou P, Guyatt GH. Chapter 12: Interpreting results and drawing conclusions. In: Higgins JP, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane‐handbook.org.

Sexton 2014

Sexton DJ, Reule S, Solid C, Chen S, Collins AJ, Foley RN. ESRD from lupus nephritis in the United States. Clinical Journal of the American Society of Nephrology: CJASN 2014;10(2):251‐9. [MEDLINE: 25534208]

Singh 2016

Singh JA, Hossain A, Kotb A, Oliveira A, Mudano AS, Grossman J, et al. Treatments for lupus nephritis: a systematic review and network metaanalysis. Journal of Rheumatology 2016;44(6):1801‐15. [MEDLINE: 27585688]

So 2011

So MW, Koo BS, Kim YG, Lee CK, Yoo B. Predictive value of remission status after 6 months induction therapy in patients with proliferative lupus nephritis: a retrospective analysis. Clinical Rheumatology 2011;30(11):1399‐405. [MEDLINE: 21594768]

Strand 2000

Stand V, Gladman D, Isenberg D, Petri M, Smolen J, Tugwell P. Endpoints: consensus recommendations from OMERACT IV. Outcome Measures in Rheumatology. Lupus 2000;9(5):322‐7. [MEDLINE: 10878722]

Sutanto 2013

Sutanto B, Singh‐Grewal D, McNeil HP, O'Neill S, Craig JC, Jones J, et al. Experiences and perspectives of adults living with systemic lupus erythematosus: thematic synthesis of qualitative studies. Arthritis Care & Research 2013;65(11):1752‐65. [MEDLINE: 23609952]

Tektonidou 2016

Tektonidou MG, Dasgupta A, Ward MM. Risk of end‐stage renal disease in patients with lupus nephritis, 1971‐2015: a systematic review and Bayesian meta‐analysis. Arthritis & Rheumatology 2016;68(6):1432‐41. [MEDLINE: 26815601]

Tench 2000

Tench, CM, McCurdie I, White PD, D'Cruz DP. The prevalence and associations of fatigue in systemic lupus erythematosus. Rheumatology 2000;39(11):1249‐54. [MEDLINE: 11085805]

Tian 2014

Tian SY, Feldman BM, Beyene J, Brown PE, Uleryk EM, Silverman ED. Immunosuppressive therapies for the induction treatment of proliferative lupus nephritis: a systematic review and network metaanalysis. Journal of Rheumatology 2014;41(10):1998‐2007. [MEDLINE: 25225281]

Tian 2015

Tian SY, Feldman BM, Beyene J, Brown PE, Uleryk EM, Silverman ED. Immunosuppressive therapies for the maintenance treatment of proliferative lupus nephritis: a systematic review and network metaanalysis. Journal of Rheumatology 2015;42(8):1392‐400. [MEDLINE: 26077406]

Touma 2011

Touma Z, Gladman DD, Urowitz MB, Beyene J, Uleryk EM, Shah PS. Mycophenolate mofetil for induction treatment of lupus nephritis: a systematic review and metaanalysis. Journal of Rheumatology 2011;38(1):69‐78. [MEDLINE: 20952473]

Tunnicliffe 2015

Tunnicliffe DJ, Singh‐Grewal D, Kim S, Craig JC, Tong A. Diagnosis, monitoring, and treatment of systemic lupus erythematosus: a systematic review of clinical practice guidelines. Arthritis Care & Research 2015;67(10):1440‐52. [MEDLINE: 25778500]

van Vollenhoven 2017

van Vollenhoven R, Voskuyl A, Bertsias G, Aranow C, Aringer M, Arnaud L, et al. A framework for remission in SLE: consensus findings from a large international task force on definitions of remission in SLE (DORIS). Annals of the Rheumatic Diseases 2017;76(3):554‐61. [MEDLINE: 27884822]

Vu 1999

Vu TV, Escalante A. A comparison of the quality of life of patients with systemic lupus erythematosus with and without endstage renal disease. Journal of Rheumatology 1999;26(12):2595‐601. [MEDLINE: 10606368]

Walsh 2007

Walsh M, James M, Jayne D, Tonelli M, Manns BJ, Hemmelgarn BR. Mycophenolate mofetil for induction therapy of lupus nephritis: a systematic review and meta‐analysis. Clinical Journal of the American Society of Nephrology: CJASN 2007;2(5):968‐75. [MEDLINE: 17702723]

Weidenbusch 2013

Weidenbusch M, Rommele C, Schrottle A, Anders HJ. Beyond the LUNAR trial. Efficacy of rituximab in refractory lupus nephritis. Nephrology Dialysis Transplantation 2013;28(1):106‐11. [MEDLINE: 22764193]

Zakharova 2016

Zakharova EV, Makarova TA, Zvonova EV, Anilina AM, Stolyarevich ES. Immunosuppressive treatment for lupus nephritis: long‐term results in 178 patients. BioMed Research International 2016:7407919. [MEDLINE: 28050564]

Zhang 2016

Zhang X, Ji L, Yang L, Tang X, Qin W. The effect of calcineurin inhibitors in the induction and maintenance treatment of lupus nephritis: a systematic review and meta‐analysis. International Urology & Nephrology 2016;48(5):731‐43. [MEDLINE: 26781720]

Zhou 2011

Zhou DJ, Wu XC. Meta‐analysis of calcineurin inhibitor in the treatment of lupus nephritis. Zhonghua Erke Zazh [Chinese Journal of Pediatrics] 2011;49(4):287‐93. [MEDLINE: 21624207]

Zhu 2007

Zhu B, Chen N, Lin Y, Ren H, Zhang W, Wang W, et al. Mycophenolate mofetil in induction and maintenance therapy of severe lupus nephritis: a meta‐analysis of randomized controlled trials. Nephrology Dialysis Transplantation 2007;22(7):1933‐42. [MEDLINE: 17405792]

References to other published versions of this review

Flanc 2003

Flanc R, Roberts M, Chadban S, Kerr P, Edworthy S, Atkins R. Treatment for lupus nephritis. Cochrane Database of Systematic Reviews 2003, Issue 4. [DOI: 10.1002/14651858.CD002922]

Flanc 2004a

Flanc RS, Roberts MA, Strippoli GF, Chadban SJ, Kerr PG, Atkins RC. Treatment for lupus nephritis. Cochrane Database of Systematic Reviews 2004, Issue 1. [DOI: 10.1002/14651858.CD002922.pub2]

Flanc 2004b

Flanc RS, Roberts MA, Strippoli GF, Chadban SJ, Kerr PG, Atkins RC. Treatment of diffuse proliferative lupus nephritis: a meta‐analysis of randomized controlled trials. American Journal of Kidney Diseases 2004;43(2):197‐208. [MEDLINE: 14750085]

Henderson 2012

Henderson L, Masson P, Craig JC, Flanc RS, Roberts MA, Strippoli GF, et al. Treatment for lupus nephritis. Cochrane Database of Systematic Reviews 2012, Issue 12. [DOI: 10.1002/14651858.CD002922.pub3]

Henderson 2013

Henderson LK, Masson P, Craig JC, Roberts MA, Flanc RS, Strippoli GFM, et al. Induction and maintenance treatment of proliferative lupus nephritis: a meta‐analysis of randomized controlled trials. American journal of kidney diseases 2013;61(1):74‐87. [MEDLINE: 23182601]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Abedi 2007

Methods

  • Study design: parallel RCT

  • Study timeframe: not reported

  • Duration of follow‐up: 18 months

Participants

  • Country: Iran

  • Setting: not reported

  • Inclusion criteria: SLE patients with newly diagnosed lupus nephritis, WHO class III or IV (biopsy proven)

  • Number (randomised): 30 (numbers per group not reported)

  • Mean age ± SD (years): not reported

  • Sex (M/F): not reported

  • Exclusion criteria: not reported

Interventions

Induction therapy: duration of treatment was 18 months

  • Treatment group 1

    • MMF: 2 g/d

  • Treatment group 2

    • IV CPA: 0.75 to 1 g/month for 6 months then every 3 months for 1 year

  • Both groups

    • Corticosteroids

Outcomes

  • Complete remission

  • Partial remission

  • Proteinuria

  • Serum albumin

  • Hb, ESR, serum complement, urinary activity

  • Serious infection

  • Leucopenia

  • Amenorrhoea

  • Diarrhoea

Notes

  • Abstract‐only publication

  • Funding source not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Study was described as randomised, method of randomisation was not reported

Allocation concealment (selection bias)

Unclear risk

Insufficient information to permit judgement

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label study

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Selective reporting (reporting bias)

High risk

Data unable to be meta‐analysed

Other bias

Unclear risk

Abstract‐only publication; insufficient information to permit judgement

ACCESS 2014

Methods

  • Study design: double‐blind, parallel RCT

  • Study timeframe: November 2008 to June 2012

  • Duration of follow‐up: 24 and 52 weeks

Participants

  • Countries: USA and Mexico

  • Setting: multicentre (19 sites)

  • Inclusion criteria: ≥16 years; diagnosis of SLE (ACR criteria) positive ANA and/or positive anti‐double‐stranded DNA (anti‐dsDNA) antibody test result at study entry; active lupus nephritis defined by kidney biopsy findings within the last 12 months of proliferative nephritis (ISN/RPS criteria (class III or class IV with or without features of class V)) and UPCR of > 1

  • Number (randomised/analysed): treatment group (66/66); control group (68/68)

  • Mean age ± SD (years): treatment group (32 ± 10.1); control group (32.7 ± 12)

  • Sex (M/F): treatment group (8/58); control group (12/56)

  • Exclusion criteria: not reported

Interventions

Induction therapy: duration of treatment was 6 months

  • Treatment group

    • Abatacept: monthly infusions at doses that were adjusted for body weight according to the abatacept dose that is recommended for rheumatoid arthritis (for < 60 kg, 500 mg; for 60‐100 kg; 750 mg for > 100 kg, 1 g)

  • Control group

    • Placebo

  • Both groups

    • Six IV pulses of 500 mg of CPA at two‐week intervals followed by oral AZA at 2 mg/kg/d based on the ELNT regimen

    • Oral glucocorticoid treatment was begun at 60 mg/d for 2 weeks in all subjects, followed by a prescribed taper to 10 mg/d over the next 10 weeks

Outcomes

  • Death (all causes)

  • Complete response: UPCR of 0.5 based on a 24 h urine collection, SCr level of 1.2 mg/dL or 125% of baseline, and adherence to the prednisone taper to 10 mg/d by week 12

  • Partial response: UPCR required only 50% improvement from baseline (rather than a decline to < 0.5 based in complete response) on a 24 h urine collection, SCr level of 1.2 mg/dL or 125% of baseline, and adherence to the prednisone taper to 10 mg/d by week 12

  • Relapse: renal flare was defined as the recurrence of proteinuria of > 1 g/24 h; for all others, a renal flare was defined as either of the following: SCr level at least 25% higher than baseline or above the upper limit of normal, plus proteinuria at least 75% of baseline; or doubling of the UPCR compared with the lowest previous value

  • Major infection

Notes

  • The ACCESS study did not use an initial IV pulse MP, but rather left that decision to the site investigator’s discretion, unlike Euro‐lupus nephritis treatment regimen

  • Funding source: NIH National Institute of Allergy and Infectious Diseases contract N01‐AI‐15416, protocol number ITN034AI

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Study was described as randomised, method of randomisation was not reported

Allocation concealment (selection bias)

Unclear risk

Insufficient information to permit judgement

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Double‐blind with identical placebo

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No missing outcome data

Selective reporting (reporting bias)

Low risk

Study protocol available and pre‐specified outcomes were reported

Other bias

High risk

Some authors involved in data acquisition and analysis are employees of pharmaceutical companies

ALMS 2007

Methods

  • Study design: open‐label, parallel RCT

  • Study timeframe (enrolment): 27 July 2005 to 6 October 2006

  • Duration of follow‐up (median): 6 months (induction therapy) and 36 months (maintenance therapy)

Participants

  • Country: international (countries not reported)

  • Setting: multinational (˜ 100 sites)

  • Inclusion criteria: aged 12 to 75 years with diagnosis of SLE (ACR criteria), biopsy‐proven lupus nephritis (active or chronic) within 6 months before randomisation, ISN/RPS 2003 class III, IV‐S, IV‐G, V, III+V, IV+V, class III or V must have proteinuria > 2 g/d; class III (22); IV (147); III/V (7); IV/V (16); V (35)

  • Number (randomised/analysed)

    • Induction therapy: treatment group 1 (185/185); treatment group 2 (185/185)

    • Maintenance therapy: treatment group 1 (116/116); treatment group 2 (111/111)

  • Mean age ± SD (years)

    • Induction therapy: treatment group 1 (32.4 ± 11.2); treatment group 2 (31.3 ± 10.3)

    • Maintenance therapy: treatment group 1 (31.8 ± 10.6); treatment group 2 (31 ± 10.8)

  • Sex (M/F)

    • Induction therapy: treatment group 1 (28/157); treatment group 2 (29/156)

    • Maintenance therapy: treatment group 1 (15/101); treatment group 2 (17/94)

  • Exclusion criteria: treatment with MMF or IV CPA within the previous year; continuous dialysis for > 2 weeks before randomisation or anticipated duration > 8 weeks; pancreatitis, GI haemorrhage within 6 months or active peptic ulcer within 3 months; severe viral infection; severe cardiovascular disease; bone marrow insufficiency with cytopenias not attributable to SLE; current infection requiring IV antibiotics

Interventions

Induction therapy: duration of therapy was 6 months

  • Treatment group 1

    • Oral MMF: titrated from 0.5 g twice daily in week 1 to 1.0 g twice daily in week 2, target dose 1.5 g twice daily in week 3

  • Treatment group 2

    • IV CPA: monthly pulses 0.5 to 1.0 g/m2

  • Both groups

    • Oral prednisolone with defined taper, maximum starting dose 60 mg/d

Maintenance therapy: duration of therapy was 36 months

  • Treatment group 1

    • Oral MMF: 2 g/d

    • AZA placebo

  • Treatment group 2

    • Oral AZA: 2 mg/kg/d

    • MMF placebo

  • Both groups

    • Oral prednisolone with defined taper, maximum starting dose 10 mg/d

Outcomes

Induction therapy

  • Death (all causes)

  • Stable kidney function: stabilisation ± 25% or improvement in SCr

  • Complete renal remission: return to normal creatinine, proteinuria ≤ 0.5 g/d and inactive urine sediment

  • Partial renal remission: prespecified decrease in UPCR (fall in < 3.0 g/d protein if baseline ≥ 3 or ≥ 50% reduction if < 3 at baseline and stabilisation of SCr ± 25%)

  • Major infection

  • Systemic disease activity and damage

  • Adverse events (reported by > 10% participants)

Maintenance therapy

  • Death

  • ESKD

  • doubling of SCr

  • Renal flare: proteinuric or nephritic

  • Complete renal remission

  • Combined renal and extra‐renal remission

Notes

  • Funding source: Aspreva Pharmaceuticals Corporation as part of the Roche‐Aspreva collaboration agreement

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Participants randomly assigned (1:1, stratified by race and biopsy class, non‐blocked) but sequence of generation is not reported

Allocation concealment (selection bias)

Low risk

Central, computerised, interactive voice response system. Method would not allow investigator/participant to know or influence intervention group

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Induction therapy ‐ Open‐label study; maintenance therapy ‐ double‐blind

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Primary outcome assessed by blinded Clinical EndPoints Committee

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No missing outcome data; Induction therapy (group 1: 1 lost to follow‐up; group 2: 2 lost to follow‐up)

Selective reporting (reporting bias)

Low risk

Study protocol available and pre‐specified outcomes were reported

Other bias

High risk

Sponsored by Aspreva Pharmaceuticals Corporation included in the data analysis & authorship

APRIL‐LN 2012

Methods

  • Study design: double‐blind, double dummy RCT

  • Study timeframe: not reported

  • Duration of follow‐up: 12 months planned

Participants

  • Country: USA

  • Setting: multicentre (4 sites)

  • Inclusion criteria: diagnosis of SLE (ACR criteria); positive ANA test (Hep‐2 ANA ≥ 1:80) and/or anti‐dsDNA ≥ 30 IU/mL); biopsy proven (within the 12 months preceding study entry) class III or IV lupus nephritis (ISN/RPS 2003 classification criteria); active lupus nephritis, defined by proteinuria (UPCR > 1.0 mg/mg) and haematuria (> 10 RBC/HPF with or without RBC casts)

  • Number (randomised): treatment group (4); control group (2)

  • Age range 18 to 54 years

  • Sex (M/F): 2/4

  • Exclusion criteria: causes of haematuria of non‐glomerular origin; kidney disease unrelated to SLE; calculated eGFR ≤ 30 mL/min/1.73 m2 at screening

Interventions

Induction therapy: duration of therapy was 12 months

  • Treatment group

    • SC atacicept: 150 mg twice weekly for 4 weeks then 150 mg weekly for a planned 48 weeks

  • Control group

    • SC placebo

  • Both groups

    • On study Day 14, patients commenced MMF (500 mg, twice daily, orally) and prednisone or equivalent (the lesser of 0.8 mg/kg/d or 60 mg/d, orally). MMF dose was increased to 1,000 mg twice daily at Day 7, thereafter up to a maximum of 1.5 g twice daily by Day 1

Outcomes

  • Major infection

  • Treatment failure

Notes

  • Follow‐up was planned for 12 months

  • Early termination of the project

  • Funding source: Merck Serono S.A.; ZymoGenetics Inc; EMD Serono Inc

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Study was described as randomised, method of randomisation was not reported

Allocation concealment (selection bias)

Unclear risk

Insufficient information to permit judgement

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Double‐blind, double‐dummy placebo study

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No missing outcome data

Selective reporting (reporting bias)

High risk

Study protocol available and not all prespecified outcomes were reported

Other bias

High risk

Sponsor involved in authorship. The study was terminated early; there were differences in characteristics (for example eGFR) between groups at baseline

AURA‐LV 2016

Methods

  • Study design: double‐blind, parallel RCT

  • Study timeframe: not reported

  • Duration of follow‐up: 24 and 48 weeks

Participants

  • Country: > 20 countries (not reported)

  • Setting: multinational (number of sites not reported)

  • Inclusion criteria: patients aged 18 to 75 years; diagnosis of SLE (ACR criteria); biopsy proven classes III, IV‐S or IV‐G, (A) or (A/C); or Class V, alone or in combination with Class III or IV (ISN/RPS 2003) (within 6 months prior to screening (Visit 1); laboratory evidence of active nephritis at screening, defined as Class III, IV‐S or IV‐G (confirmed proteinuria ≥ 1,500 mg/24 h, UPCR of ≥ 1.5 mg/mg; Class V (alone or in combination with Class III or IV: proteinuria ≥ 2,000 mg/24 h, a UPCR of ≥ 2 mg/mg)

  • Number (randomised): 265 patients (numbers not reported for groups)

  • Mean age ± SD (years): not reported

  • Sex (M/F): not reported

  • Exclusion criteria: eGFR of ≤ 45 mL/min/1.73 m2; currently requiring or expected to require HD or PD during the study period; previous kidney transplant or planned transplant within study period; in the opinion of the investigator, subject does not require long‐term immunosuppressive treatment (in addition to corticosteroids); current or medical history of: pancreatitis or GI haemorrhage within 6 months prior to screening; active unhealed peptic ulcer within 3 months prior to screening; congenital or acquired immunodeficiency; clinically significant drug or alcohol abuse 2 years prior to screening; malignancy within 5 years of screening, with the exception of basal and squamous cell carcinomas treated by complete excision; cervical dysplasia that is cervical intraepithelial neoplasia 1, but have been treated with conization or loop electrosurgical excision procedure, and have had a normal repeat PAP are allowed; lymphoproliferative disease or previous total lymphoid irradiation; severe viral infection (e.g. CMV, HBV, HCV) within 3 months of screening; or known HIV infection; active TB, or known history of TB; other known clinically significant active medical conditions, such as severe cardiovascular disease including congestive heart failure, history of cardiac dysrhythmia or congenital long QT syndrome; liver dysfunction at screening and confirmed before randomisation; chronic obstructive pulmonary disease or asthma requiring oral steroids; bone marrow insufficiency unrelated to active SLE (according to Investigator judgment) with WCC < 2500/mm3; absolute neutrophil count < 1.3 x 103/μL; thrombocytopenia (platelet count < 50,000/mm3); active bleeding disorders; current infection requiring IV antibiotics; any overlapping autoimmune condition for which the condition or the treatment of the condition may affect the study assessments or outcomes; overlapping conditions for which the condition or treatment is not expected to affect assessments or outcomes are not excluded; pregnant, breast feeding or, if of childbearing potential, not using adequate contraceptive precautions

Interventions

Induction therapy: duration of therapy was 6 months

  • Treatment group 1

    • Low‐dose oral voclosporin: 23.7 mg twice/d

  • Treatment group 2

    • High‐dose oral voclosporin: 39.5 mg twice/d

  • Control group

    • Oral placebo

  • Both groups

    • Oral MMF and corticosteroids

Outcomes

  • Death

  • Complete remission

  • Major infection

Notes

  • Abstract‐only publications

  • Funding source: Aurinia Pharmaceuticals Inc

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Study was described as randomised, method of randomisation was not reported

Allocation concealment (selection bias)

Unclear risk

Insufficient information to permit judgement

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Double‐blind

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Outcome assessor blinded according to protocol

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No missing outcome data

Selective reporting (reporting bias)

High risk

Not all pre‐specified outcomes reported

Other bias

High risk

Pharma funded; some authors involved are employees of Aurinia

Balletta 1992

Methods

  • Study design: parallel RCT

  • Study timeframe: not reported

  • Duration of follow‐up: > 12 months

Participants

  • Country: Italy

  • Setting: not reported

  • Inclusion criteria: lupus nephritis shown on biopsy (diffuse proliferative, mesangioproliferative, membranoproliferative, focal proliferative, diffuse proliferative)

  • Number (randomised): treatment group (5); control group (5)

  • Mean age ± SD (years): treatment group (25.6 ± 6.2); control group (23.4 ± 3.7)

  • Sex (M/F): treatment group (0/5); control group (1/4)

  • Exclusion criteria: not reported

Interventions

Induction therapy

  • Treatment group

    • Oral CSA: 1.5 mg/kg twice/d

    • Prednisolone: as per control

  • Control group

    • Prednisolone: pulse, 2 to 3 mg/kg/d for 3 consecutive days, then oral dose 1 mg/kg/d for 2 months and tapered

Outcomes

  • SCr

  • CrCl

  • Proteinuria

Notes

  • 6/10 participants had biopsy

  • Funding source: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Study was described as randomised, method of randomisation was not reported

Allocation concealment (selection bias)

Unclear risk

Insufficient information to permit judgement

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No missing outcome data

Selective reporting (reporting bias)

High risk

Not all expected outcomes are reported

Other bias

Low risk

The study appears to be free of other sources of bias

Bao 2008

Methods

  • Study design: open‐label RCT

  • Study timeframe: September 2005 to December 2006

  • Duration of follow‐up: 6 months prolonged to 9 months if complete remission not achieved within 6 months

Participants

  • Country: China

  • Setting: single centre

  • Inclusion criteria: aged 12 to 60 years; diagnosis of SLE (ACR 1997 criteria); SLEDAI ≥ 12', biopsy‐proven lupus nephritis class IV + V (ISN/RPS 2003) within 3 weeks before enrolment; overt proteinuria (≥ 1.5 g/d) ± active urine sediment

  • Number (randomised/analysed): treatment group 1 (20/20); treatment group 2 (20/20)

  • Mean age ± SD (years): treatment group 1 (27.2 ± 7.1); treatment group 2 (30.6 ± 4.6)

  • Sex (M/F): treatment group 1 (4/16); treatment group 2 (2/18)

  • Exclusion criteria: creatinine > 3.0 mg/dL (265.2 μmol/L) or CrCl < 30 mL/min/1.73 m2 on repeated testing; deranged liver function tests; abnormal glucose; known hypersensitivity or contraindication to any of the regimens; use of CPA, MMF or TAC within the past 12 weeks; pregnancy or lactation; cerebral lupus; leflunomide and methotrexate forbidden

Interventions

Induction therapy

  • Treatment group 1

    • MMF: 1.0 g/d twice daily (0.75 g/d twice daily if ≤ 50 kg)

    • TAC: 4 mg/d twice daily (3 mg/d twice daily if ≤ 50 kg)

  • Treatment group 2

    • IV CPA: 0.75g/m2 of body surface area first month then adjusted to 0.5 to 1.0 g/m2 monthly based on WCC (≤ 2.5)

  • Both groups

    • IV MP: 0.5 g/d for 3 days then oral prednisolone (0.6 to 0.8 mg/kg/d for 4 wk) followed by a taper (reduced by 5 mg/d every week to 20 mg/d then 2.5 mg every week until maintenance dosage of 10 mg/d)

Outcomes

  • Death (all causes)

  • Doubling of SCr

  • Deterioration of kidney function

  • Stable kidney function (normal value SCr or no more than 15% above baseline)

  • Complete remission: proteinuria (< 0.4 g/24 h), normal urine sediment, serum albumin ≥ 3.5 g/dL, normal SCr or not > 15% from baseline

  • Partial remission: resumption of normal or at least 50% improvement in proteinuria and haematuria, serum albumin ≥ 3.5 g/dL, normal SCr or not > 15% from baseline

  • Major infection

  • Herpes zoster virus infection

  • Irregular menstruation

  • GI syndrome

  • Alopecia

  • Leucopenia

  • Proteinuria

Notes

  • Funding source: Roche China and Astellas Ireland Co. Ltd

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

A computer‐generated randomisation list was drawn up by a statistician with a block of every four participants. They enrolled participants were allocated the next available number upon entry into the study

Allocation concealment (selection bias)

Unclear risk

A computer‐generated randomisation list was given to the pharmacy department. Each patient collected medication directly from the pharmacy department. Unclear whether participants and or investigators might have an opportunity to influence assignment

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label study

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Adjudication of primary and key secondary outcome judged at coordinating centre by personnel who had no knowledge of the treatment assignment and ratings were confirmed by repeat testing after a 1 month interval

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No missing outcome data

Selective reporting (reporting bias)

Low risk

All expected outcomes were reported

Other bias

Low risk

Supported by Roche China and Astellas Ireland. Co. Ltd. Partially supported but no role in design, study or analysis

Barron 1982

Methods

  • Study design: quasi‐RCT

  • Study timeframe: 1965 to 1980

  • Duration of follow‐up: mean follow‐up 59 months (range: 7 to 137 months)

Participants

  • Country: USA

  • Setting: single centre

  • Inclusion criteria: children with SLE (ACR criteria) and severe biopsy‐proven lupus nephritis, defined by a nephrotic urine sediment and impaired kidney function with a CrCl between 25 and 80 mL/min. If CrCl > 80 mL/min, the candidate had to have very active renal histology with crescents or necrosis in more than 25% of glomeruli; renal biopsies were obtained during the 6 weeks before study entry and were evaluated by light and electron microscopy

  • Number (randomised): treatment group 1 (15); treatment group 2 (7)

  • Mean age (at onset) ± SD (years):treatment group 1 (11.9 ± 2.9); treatment group 2 (11.4 ± 3.6)

  • Sex (M/F): treatment group 1 (2/13); treatment group 2 (1/6)

  • Exclusion criteria: drug‐induced SLE

Interventions

Induction therapy

  • Treatment group 1

    • High dose oral corticosteroid: prednisone 2 mg/kg/d for 3 to 6 months then tapered

  • Treatment group 2

    • Pulse MP then oral prednisone: 30 mg/kg body weight (maximum 1 g) IV, total of 6 treatments every other day; following completion of MP, oral prednisone 2mg/kg/d by then tapered

Outcomes

  • Death (all causes)

  • CrCl

  • C3, ANA

  • Exacerbations

  • Infection

  • Aseptic necrosis

Notes

  • Funding source: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

High risk

Participants were entered in alternating fashion into one of two treatment groups

Allocation concealment (selection bias)

High risk

Knowledge of prior allocation due to lack of random sequence generation and blinding

Blinding of participants and personnel (performance bias)
All outcomes

High risk

No blinding due to lack of allocation concealment

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

High risk

Other patients were randomised, but only those with > 6 months follow‐up included in analysis. It is unclear how many other patients were randomised.

Selective reporting (reporting bias)

High risk

Not all of the pre‐specified primary outcomes were reported

Other bias

Low risk

The study appears to be free of other sources of bias

Belmont 1995

Methods

  • Study design: parallel RCT (pilot study)

  • Study timeframe: not reported

  • Duration of follow‐up: 18 months

Participants

  • Country: USA

  • Setting: multicentre (number of sites not reported)

  • Inclusion criteria: aged 18 to 70 years; SLE (ACR criteria); active kidney disease (in the absence of infection, at least one of the following: (1) RBC casts, (2) WBC casts plus either haematuria (> 10/HPF) or pyuria (> 10/HPF), (3) proteinuria at ≥ 3 g, (4) proteinuria ≥ 1.5 g plus (a) haematuria or (b) pyuria or (c) a 25% decrease in C3 and/or C4

  • Number (randomised): treatment group (7); control group (7)

  • Mean age ± SD: 35 ± 2 years

  • Sex (M/F): 3/11

  • Proliferative lupus nephritis: 7/14

  • Exclusion criteria: not reported

Interventions

Induction therapy

  • Treatment group

    • Oral misoprostol: 20 µg orally 4 times daily

  • Control group

    • Oral placebo: identical capsule

  • Both groups

    • Oral prednisone: 1 mg/kg, 4 times/d

Outcomes

  • SCr

  • doubling of SCr

  • CrCl

  • ESKD

  • Complete remission of proteinuria

  • C3, C4

  • Anti‐dsDNA

Notes

  • Funding source: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Participants randomly assigned but methods of sequence generation are not described

Allocation concealment (selection bias)

Unclear risk

Insufficient information to permit judgement

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Double‐blind study

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Reasons for missing outcome data unlikely to be related to true outcome

Selective reporting (reporting bias)

Low risk

Study protocol available and pre‐specified outcomes were reported

Other bias

Low risk

The study appears to be free of other sources of bias

BELONG 2013

Methods

  • Study design: double‐blind, parallel RCT

  • Study timeframe: terminated 19 October 2009

  • Duration of follow‐up: 48 weeks treatment period extended to 96 week open‐label

Participants

  • Country: 23 countries

  • Setting: multinational (123 sites)

  • Inclusion criteria: aged ≥ 16 years; SLE (ACR criteria) including a history of anti‐dsDNA positivity and active lupus nephritis (defined as UPCR ≥ 1 with biopsy‐proven (within 6 months prior to randomisation)); Class III or IV with coexisting class V permitted or class III or IV GN provided that ≤ 50% of glomeruli showed sclerosis or fibrosis (WHO criteria or ISN/RPS criteria)

  • Number (randomised/analysed): treatment group 1 (127/73); treatment group 2 (126/75); control group (125/75)

  • Mean age, range (years): treatment group 1 (30.6, 16 to 60); treatment group 2 (31.9, 16 to 69); control group (31.3, 17 to 66)

  • Sex (M/F): treatment group 1 (18/109); treatment group 2 (12/114); control group (19/106)

  • Exclusion criteria: lupus class III (C), IV‐S(C) and IV‐G(C); retinitis; poorly controlled seizure disorder; acute confusional state; myelitis; stroke or stroke syndrome; cerebellar ataxia or dementia; severe renal impairment; estimated glomerular filtration rate <25 mL/min/1.73 m2; ESKD requiring dialysis or transplant; thrombocytopenia; or experiencing or at high risk of developing clinically significant bleeding or organ dysfunction

Interventions

Induction therapy: duration of treatment 48 weeks

  • Treatment group 1

    • IV ocrelizumab: 1000 mg infusion on days 1 and 15 followed by a single infusion at week 16 and every 16 weeks

  • Treatment group 2

    • IV ocrelizumab: 400 mg infusion on days 1 and 15 followed by a single infusion at week 16 and every 16 weeks

  • Control group

    • Placebo

  • All groups

    • Groups were treated with background induction therapy at the discretion of the investigator MMF (target dose 3 g/d) or CPA (ELNT regimen: 0.5 g IV every 2 weeks). Patients receiving MMF continued to receive MMF, while patients receiving the ELNT CPA regimen were subsequently treated with azathioprine (AZA; 2 mg/kg up to 200 mg/d, dose selected by the investigator). IV MP (up to 3 g/d) was also permitted by day 15, given in divided pulses, and oral steroids (0.5–0.75 mg/kg (60 mg/d)) were allowed with taper to 10 mg over 10 weeks. Before each infusion, patients were administered IV MP (100 mg), acetaminophen/paracetamol (1 g), and an antihistamine (50 mg IV diphenhydramine HCl or equivalent)

Outcomes

  • Complete renal response (normal SCr (25% increase from baseline) and improvement in UPCR to < 0.5)

  • Partial renal response (SCr 25% above baseline, and 50% improvement in UPCR, and if baseline ratio > 3.0, then UPCR < 3.0)

  • Death

  • Major infection

  • Adverse events

  • Proteinuria

  • CrCl

Notes

  • Funding source: Genentech and Hoffman‐La Roche

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Study was described as randomised, method of randomisation was not reported

Allocation concealment (selection bias)

Unclear risk

Insufficient information to permit judgement

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Double‐blind, placebo‐controlled study

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

High risk

Study was terminated before completion. Only 36.8% of patients completed the 48‐week treatment period and were included in the analysis

Selective reporting (reporting bias)

Low risk

Study protocol available and pre‐specified outcomes were reported

Other bias

High risk

Genentech and Hoffman‐La Roche funded the study and were involved in study design; Conflict of interest of authors relating to the pharmaceutical companies that funded the study; High drop‐out rates (around 52%) with the early termination of the study; The 1000 mg ocrelizumab‐treated group had slightly higher proportion of Caucasian patients and a lower proportion of Asian patients than the other two groups

Boedigheimer 2017

Methods

  • Study design: double‐blind, phase 1b, parallel RCT

  • Study timeframe: 3 March 2009 to 3 June 2014

  • Duration of follow‐up: 6 months

Participants

  • Country: USA, Mexico, France, Malaysia, Hong Kong

  • Setting: multinational (11 sites)

  • Inclusion criteria: aged 18 to 70 years; SLE (ACR criteria) with the presence of ANA at least 6 months before randomisation; any concurrent SLE medications (e.g. MMF, AZA, leflunomide, methotrexate, antimalarials) were at a stable dose for ≥ 30 days before randomisation; concurrent prednisone was 20 mg/d (or equivalent) and for subjects without lupus nephritis could be increased or decreased once by 5 mg/d within 30 days before randomisation; subjects met current recommendations for immunisations; subjects with lupus nephritis were required to have biopsy‐proven active disease within 18 months of randomisation according to WHO or ISN/RPS classification class III or IV; UPCR > 1 or 24 h urine protein > 1 g following ≥ 12 weeks of standard‐of‐care induction treatment with prednisone plus CPA or MMF, then maintained on prednisone at 20 mg/d (or equivalent) and MMF or AZA

  • Number (randomised/analysed): treatment group (21/21); control group (0/21)

  • Mean age ± SD (years): treatment group (30.0 ± 8.1); control group (36.9 ± 11.7)

  • Sex (M/F): treatment group (7/7); control group (3/4)

  • Ethnicity: treatment group (Caucasian 6, African American 0, Hispanic 12, Asian 3, Other 0); control group (Caucasian 2, African American 0, Hispanic 2, Asian 3, Other 0)

  • Exclusion criteria: any disorder that would interfere with study evaluations including unstable or severe disease; presence or history of vasculitis or active central nervous system lupus requiring therapy within 3 years; uncontrolled hypertension; low CrCl (< 50 mL/min); low Hb levels, thrombocytopenia, neutropenia or low total WCC; poorly controlled diabetes; evidence of viral, bacterial or fungal infection within 30 days of randomisation or evidence of parasitic infestation; history of repeated infections or predisposition to infections; receipt of CPA, CSA, TAC, sirolimus, IVIG or plasmapheresis within 3 months of randomisation; or receipt of an investigational drug or device within 30 days or 5 half‐lives of randomisation

Interventions

Induction therapy

  • Treatment group

    • SC AMG 811: 20, 60 or 120 mg administered

  • Control group

    • SC placebo

  • Both groups

    • Concomitant therapy could include prednisone, MMF, AZA, methotrexate and antimalarials

Outcomes

  • Death

  • Major infection

  • Adverse events

  • Proteinuria

  • Disease activity

Notes

  • Study included both patients with SLE with and without lupus nephritis, we have extracted data for patients with lupus nephritis only

  • Funding source: Amgen

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Study was described as randomised, method of randomisation was not reported

Allocation concealment (selection bias)

Unclear risk

Insufficient information to permit judgement

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Double‐blind study

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No missing outcome data

Selective reporting (reporting bias)

High risk

Not all expected clinical outcomes reported

Other bias

High risk

Phase 1b study, study underpowered; study sponsor involved in data acquisition, data analysis and reporting of the study

Boletis 1999

Methods

  • Study design: parallel RCT (pilot study)

  • Study timeframe: not reported

  • Duration of follow‐up: 18 months

Participants

  • Country: Greece

  • Setting: not reported

  • Inclusion criteria: lupus nephritis warranting CPA therapy; already received 6 months of CPA (1 g/m2 once a month for 6 months and 0.5 mg/kg daily prednisone) with satisfactory response (absence of major side‐effects requiring interruption of therapy); inactive or substantially improved urine sediment, and proteinuria of less than 1 g/d (for patients with baseline proteinuria < 3 g/d) or < 3 g/d (for patients with baseline proteinuria > 3 g/d)

  • Number (randomised/analysed): treatment group 1 (9); treatment group 2 (5)

  • Mean age ± SD (years): treatment group 1 (30.4 ± 10.9); treatment group 2 (32.4 ± 11.7)

  • Sex (M/F): treatment group 1 (3/6); treatment group 2 (2/3)

  • Exclusion criteria: previous CPA for more than 6 months, pregnancy, aged < 18 or > 75 years, history of malignant disorders

Interventions

Maintenance therapy: duration of treatment was 18 months

  • Treatment group 1

    • IV CPA: every 2 months for 6 months and then every 3 months for 12 months

  • Treatment group 2

    • IVIG: 400 mg/kg monthly for 18 months

Both groups

  • Clinicians were allowed to increase the dose of prednisone if relapse or deterioration of kidney disease

Outcomes

  • SCr

  • CrCl

  • Proteinuria

Notes

  • Funding source: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Study was described as randomised, method of randomisation was not reported

Allocation concealment (selection bias)

Low risk

Randomisation was done with sealed envelopes

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Whether participants and investigators were blinded was not described and treatment options were quite different suggesting that personnel were not blinded

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No missing outcome data

Selective reporting (reporting bias)

Low risk

Study protocol available and pre‐specified outcomes were reported

Other bias

Low risk

The study appears to be free of other sources of bias

Boumpas 1992

Methods

  • Study design: open‐label, parallel RCT

  • Study timeframe: 1981 to 1986

  • Duration of follow‐up: 10 years

Participants

  • Country: USA

  • Setting: not reported

  • Inclusion criteria: age range 10 to 48 years; SLE (ACR 1982 criteria) and severe lupus nephritis defined by a nephritic urine sediment and impaired kidney function with a CrCl between 25 to 80 mL/min; if the CrCl was > 80 mL/min, the candidate had to have very active renal histology with crescents or necrosis in more than 25% of glomeruli; renal biopsies were obtained during the 6 weeks before study entry and were evaluated by light and electron microscopy

  • Number (randomised): treatment group 1 (20); treatment group 2 (20); control group (25)

  • Mean age ± SE (years): treatment group 1 (30 ± 2); treatment group 2 (30 ± 2); control group (31 ± 2)

  • Sex (M/F): treatment group 1 (3/17); treatment group 2 (1/19); control group (1/24)

  • Exclusion criteria: pregnancy; received cytotoxic drugs for more than 10 weeks; active infections; insulin‐dependent DM, previous malignancy

Interventions

Induction therapy

  • Treatment group 1

    • IV CPA: single doses 0.5 to 1 g/m2 monthly for 6 months

  • Treatment group 2

    • IV CPA: single doses 0.5 to 1 g/m2 monthly for 6 months then 3 monthly for 18 months

  • Control group

    • IV MP: 3 doses 1 g/m2, then monthly single doses for 6 months

Other/additional treatment

  • Patients were treated with prednisone 0.5 mg/kg/d and continuing for 4 weeks then tapered at a rate of 5 mg every other day but the minimum dose to prevent extra‐renal disease

Outcomes

  • ESKD

  • Doubling of SCr

  • Major infection

  • Herpes zoster virus

  • Malignancy

  • Haemorrhagic cystitis

  • Premature ovarian failure

  • Osteonecrosis

  • Relapse

  • Stable kidney function

Notes

  • 2 withdrawals

  • Funding source: NIH trial

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"Patients were assigned randomly to one of three treatment groups". No further details on randomisation

Allocation concealment (selection bias)

Low risk

Allocation drawn from a set of masked cards

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label study

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No missing outcome data

Selective reporting (reporting bias)

Low risk

Study protocol available and pre‐specified outcomes were reported

Other bias

Low risk

The study appears to be free of other sources of bias

Cade 1973

Methods

  • Study design: quasi‐RCT

  • Study timeframe: not reported

  • Duration of follow‐up: 36 months

Participants

  • Country: USA

  • Setting: single centre

  • Inclusion criteria: Diagnosis of SLE; biopsy and functional findings of active proliferative GN due to SLE; renal biopsy classification as proliferative GN closely approximates those used by Baldwin 1970

  • Number (randomised): treatment group 1 (15); treatment group 2 (13); treatment group 3 (13); treatment group 4 (13)

  • Mean age, range (years): treatment group 1 (26.1, 12 to 51); treatment group 2 (30.5, 11 to 62); treatment group 3 (22.4, 12 to 51); treatment group 4 (24.8, 14 to 51)

  • Sex (M/F): treatment group 1 (1/12); treatment group 2 (1/12); treatment group 3 (3/10); treatment group 4 (6/7)

  • Exclusion criteria: lupus glomerulitis; focal proliferative disease or predominantly membranous lupus nephritis

Interventions

Induction therapy

  • Treatment group 1

    • Oral prednisone: 60 to 100 mg/d for 6 months then slowly tapered to the lowest dose that controlled the patients symptoms

  • Treatment group 2

    • Oral AZA: started at 1.0 to 1.5 mg/kg/d, increased to 1.5 to 2.0 mg/kg/d after 6 to 8 weeks if the patient had not improved by clinical or laboratory criteria

  • Treatment group 3

    • Oral prednisone: 60 to 100 mg/d for 6 months then slowly tapered to the lowest dose that controlled the patients symptoms

    • Oral AZA: started at 1.0 to 1.5 mg/kg/d, increased to 1.5 to 2.0 mg/kg/d after 6 to 8 weeks if the patient had not improved by clinical or laboratory criteria

  • Treatment group 4

    • Oral AZA: started at 1.0 to 1.5 mg/kg/d, increased to 1.5 to 2.0 mg/kg/d after 6 to 8 weeks if the patient had not improved by clinical or laboratory criteria

    • SC heparin: doses ranging from 20,000 units every 8 hours to 5000 units every 6 hours

Outcomes

  • Death (all causes)

  • ESKD

  • CrCl

Notes

  • Funding source: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

High risk

Chronological appearance

Allocation concealment (selection bias)

High risk

Assigned in alternate fashion by division secretary

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label study

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Insufficient information to permit judgement

Selective reporting (reporting bias)

Low risk

All pre‐specified outcomes are reported

Other bias

Low risk

The study appears to be free of other sources of bias

Chan 2000

Methods

  • Study design: parallel RCT

  • Study timeframe: November 1996 and October 1998

  • Duration of follow‐up: median follow‐up was 63 months

Participants

  • Country: Hong Kong

  • Setting: multicentre

  • Inclusion criteria: diagnosis of SLE (ACR criteria); biopsy‐proven diffuse proliferative lupus nephritis (class IV) (WHO classification), urinary protein excretion of ≥ 1 g/d, a serum albumin ≤ 3.5 g/dL, SCr < 3.4 mg/dL (300 µmol/L)

  • Number (randomised/analysed): treatment group 1 (33/32); treatment group 2 (31/30)

  • Mean age ± SD (years): treatment group 1 (38.1 ± 10.2); treatment group 2 (41.8 ± 8.9)

  • Sex (M/F): treatment group 1 (6/26); treatment group 2 (4/26)

  • Exclusion criteria: SCr > 4.2 mg/dL; life‐threatening complications; history of poor compliance; pregnancy; women unwilling to use contraception; CPA in the last 6 months; oral prednisolone 0.4 mg/kg/d for more than 2 weeks

Interventions

Induction and maintenance therapy

  • Treatment group 1

    • Oral MMF 1 g twice daily for 6 months then 500 mg twice daily for 6 months followed by AZA 1 to 1.5 mg/kg/d for at least 1 year then tapered. From Jan 2002, protocol changed to reducing dose of MMF to 750 mg twice daily at 6 months then 500 mg twice daily at 12 months and continued for further 12 months before tapering

  • Treatment group 2

    • Oral CPA 2.5 mg/kg/d for 6 months followed by AZA 1.5 to 2 mg/kg/d for 6 months then 1 to 1.5 mg/kg/d for at least 1 year before tapering

Other information

  • Both groups received prednisolone 0.8 mg/kg/d and tapered to 10 mg/d at 6 months then maintenance dose of 5 to 7.5 mg/kg at 12 to 15 months

  • MMF dosing subsequently changed from 2002: MMF 1 g twice daily reduced to 750 mg twice daily after 6 months then 500 mg twice daily for at least 1 year before tapering

Outcomes

  • Death

  • ESKD

  • Doubling of SCr

  • Doubling kidney function

  • Relapse

  • Major infection

  • Herpes zoster virus infection

  • Ovarian failure

  • Bone toxicity

  • Alopecia

  • GI upset

  • Lymphopenia

  • Complete remission of proteinuria: < 0.3 g/24 h

  • Partial remission of proteinuria: > 50% reduction in proteinuria, proteinuria between 0.3 and 3 g/24 h

  • SCr

  • CrCl

  • Daily proteinuria

Notes

  • Follow‐up: 3585 patient‐months (median follow‐up 63 months); 2 withdrawals (1 in each group); 62/64 followed‐up

  • Funding source: Roche pharmaceuticals supplied MMF

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Participants randomly assigned by drawing envelopes to one of two treatment groups in an open‐label manner

Allocation concealment (selection bias)

Unclear risk

Insufficient information to permit judgement

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

"...Clinical status was reviewed and categorised at the coordinating centre by personnel who had no knowledge of the treatment assignment...."

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No missing outcome data

Selective reporting (reporting bias)

Low risk

Study protocol available and pre‐specified outcomes were reported

Other bias

Low risk

The study appears to be free of other sources of bias

Chen 2011

Methods

  • Study design: open‐label, parallel RCT

  • Study timeframe: June 2006 to March 2008

  • Duration of follow‐up: 6 month follow‐up; extended median follow‐up was 6 months

Participants

  • Country: China

  • Setting: multicentre (9 sites)

  • Inclusion criteria: aged 14 to 65 years; diagnosis of SLE (ACR criteria); biopsy‐proven (within 6 months) lupus nephritis class III, IV‐S, IV‐G, (A) or (A/C), or class V alone or in combination with class III or IV (ISN/RPS 2003 criteria); laboratory tests documented the presence of active nephritis, defined as proteinuria (protein excretion > 1 g/24 h) or increased SCr (> 1.3 mg/dL) with active urinary sediment (any of > 5 RBC/HPF, > 5 WBC/HPF, or RBC casts in the absence of infection or other causes) in patients with class IV‐S or IV‐G and significant proteinuria (protein excretion > 2 g/24 h) or increased SCr (> 1.3 mg/dL) in patients with class III or V

  • Number (randomised/analysed)

    • Induction therapy: treatment group 1 (42/39); treatment group 2 (39/34)

    • Maintenance therapy: treatment group 1 (34/34); treatment group 2 (36/36)

  • Mean age ± SD (years)

    • Induction therapy: treatment group 1 (32.0 ± 10.8); treatment group 2 (31.9 ± 10.1)

    • Maintenance therapy: treatment group 1 (30.7 ± 10.2); treatment group 2 (33.1 ± 10.9)

  • Sex (M/F)

    • Induction therapy: treatment group 1 (5/37); treatment group 2 (7/32)

    • Maintenance therapy: treatment group 1 (5/29); treatment group 2 (4/32)

  • Exclusion criteria: SCr > 4 mg/dL; cerebral lupus; severe infection; pregnancy; women unwilling to use contraception; MMF, CPA, CSA, methotrexate or other immunosuppression within the 1 month before randomisation

Interventions

Induction therapy: duration of therapy was 6 months

  • Treatment group 1

    • Oral TAC: 0.05 mg/kg divided in 2 doses with target trough of 5 to 10 ng/mL

  • Treatment group 2

    • IV CPA: 750 mg/m2 of body surface area every 4 weeks for a total of 6 pulses (25% decrease in dose if older than 60 years or creatinine > 3.4 mg/dL)

  • Both groups

    • Oral prednisolone: 1 mg/kg/d (maximum 60 mg) tapered by 10 mg/d every 2 weeks to 40 mg, followed by decrease of 5 mg/d every 2 weeks until a dose of 10 mg/d achieved

Long‐term maintenance therapy: duration of therapy was 6 months

  • Treatment group 1

    • Oral TAC: trough blood concentrations were maintained at 4–6 ng/mL.

  • Treatment group 2

    • AZA: 2 mg/kg/d

  • Both groups

    • Oral prednisone: 10 mg/d

Outcomes

  • Death

  • Major infection

  • Herpes zoster virus infection

  • Ovarian failure

  • Alopecia

  • GI upset

  • Lymphopenia

  • Complete renal remission: daily proteinuria < 0.3 g/24 h, normal urinary sediment, serum albumin ≥ 3.5 g/dL and stable kidney function

  • Partial renal remission: protein excretion of 0.3 to 2.9 g/24 h and a decrease of at least 50% of baseline level), serum albumin level of at least 3.0 g/dL and stable kidney function

  • Treatment failure: failure to meet complete or partial remission

  • SCr

  • Daily proteinuria

Notes

  • Funding source: Scientific and Technologic Committee of Guangdong province, the Department of Health, Guangzhou city, the Ministry of Education, Peoples' Republic of China and the 5010 Clinical Program of Sun Yat‐sen University. Astellas Pharmaceutics supplied TAC

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomisation was conducted at a central office using a computer‐based random allocation sequence table; randomisation not stratified by centre or baseline characteristic

Allocation concealment (selection bias)

Low risk

Allocation concealment performed by enclosing assignments in sequentially numbered, opaque, closed envelopes

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label study

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Low risk

The primary outcome (complete remission) and secondary outcomes partial remission and treatment failure were reported on an intention to treat bases. The attrition rate for secondary safety outcomes were 92.8% (39/42) for the TAC group and 87.2% for the IV CPA group.

Selective reporting (reporting bias)

Low risk

Study protocol available and prespecified outcomes were reported

Other bias

Low risk

Astellas Pharmaceutics supplied TAC but had no role in the design or conduct of the study or analysis or interpretation of results

Clark 1981

Methods

  • Study design: open‐label RCT

  • Study timeframe: from February 1978

  • Duration of follow‐up: 12 months

Participants

  • Country: Canada

  • Setting: not reported

  • Inclusion criteria: Diagnosis of SLE (ACR criteria) and had increased DNA, low complement; presence of ANA; renal biopsy showing diffuse proliferative GN; CrCl > 30 mL/min at study entry

  • Number: treatment group 1 (6); treatment group 2 (6)

  • Mean age ± SD (years): not reported

  • Sex (M/F): not reported

  • Exclusion criteria: not reported

Interventions

Induction therapy

  • Treatment group 1

    • Corticosteroids

    • AZA

  • Treatment group 2

    • Corticosteroids

    • AZA

    • Plasmapheresis

Outcomes

  • Death

  • ESKD

  • Doubling of SCr

  • SCr

  • CrCl

  • Proteinuria

Notes

  • Funding source: Physicians' Services Incorporated Foundation

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Study was described as randomised, method of randomisation was not reported

Allocation concealment (selection bias)

Unclear risk

Insufficient information to permit judgement

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label study

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No missing outcome data

Selective reporting (reporting bias)

Low risk

Study protocol available and pre‐specified outcomes were reported

Other bias

Low risk

Supported from a grant from Physicians' Services Incorporated Foundation. The study appears to be free of other sources of bias

Clark 1984

Methods

  • Study design: parallel RCT

  • Study timeframe: not reported

  • Duration of follow‐up: 19 months

Participants

  • Country: Canada. West Indies

  • Setting: multinational (3 sites)

  • Inclusion criteria: diagnosis of SLE (ACR criteria) and had at least one episode of ANA positivity; elevated DNA binding and complement depression; renal biopsy showing diffuse proliferative GN

  • Number (randomised): treatment group 1 (19); treatment group 2 (20)

  • Mean age ± SD (years): treatment group 1 (25 ± 2); treatment group 2 (26 ± 2)

  • Sex (M/F): treatment group 1 (1/18); treatment group 2 (5/15)

  • Exclusion criteria: CrCl < 30 mL/min or SCr > 3 mg/dL

Interventions

Induction therapy

  • Treatment group 1

    • Steroids ± cytotoxics

  • Treatment group 2

    • Conventional therapy

    • PEX: 4 L within the first two weeks, thereafter one 4 L PEX every 3‐4 weeks. In two centres patients received replacement with 5% human serum albumin and in one centre replacement was with plasma

Outcomes

  • Death

  • ESKD

  • Doubling of SCr

  • SCr

Notes

  • Funding source: Physicians' Services Incorporated Foundation

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Study was described as randomised, method of randomisation was not reported

Allocation concealment (selection bias)

Unclear risk

"Designated non‐medical person at each Centre who removed a pre‐folded slip of paper from a bowl"

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label study

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No missing outcome data

Selective reporting (reporting bias)

High risk

Not all relevant outcomes are reported

Other bias

Low risk

Supported from a grant from Physicians' Services Incorporated Foundation. The study appears to be free of other sources of bias

Contreras 2004

Methods

  • Study design: open‐label, parallel RCT

  • Study timeframe: August 1996 and May 2003

  • Duration of follow‐up: 72 months

Participants

  • Country: USA

  • Setting: single centre

  • Inclusion criteria: diagnosis of SLE (ACR criteria); ≥ 18 years; histologic diagnosis of proliferative lupus nephritis (WHO class III, IV, or Vb); classes III (12), IV (46) or Vb (1)

  • Number (randomised/analysed): treatment group 1 (19/19); treatment group 2 (20/20); treatment group 3 (20/20)

  • Mean age ± SD (years): treatment group 1 (33 ± 10); treatment group 2 (33 ± 12); treatment group 3 (32 ± 11)

  • Sex (M/F): treatment group 1 (1/19); treatment group 2 (2/18); treatment group 3 (1/19)

  • Exclusion criteria: CrCl that was consistently < 20 mL/min; any clinically significant infection; pregnancy; the receipt of more than seven doses of IV CPA, or the receipt of AZA for longer than 8 weeks

Interventions

Maintenance therapy: duration of therapy 1 to 3 years

  • Treatment group 1

    • IV CPA: 0.5 to 1.0 g/m2 every 3 months

  • Treatment group 2

    • AZA: 1 to 3 mg/kg/d

  • Treatment group 3

    • MMF: 500 to 3000 mg/d

  • All groups

    • Induction therapy of 7 monthly boluses of IV CPA 0.5 to 1.0 g/m2 and corticosteroids and maintenance therapy included prednisolone (up to 0.5 mg/kg/d)

Outcomes

  • ESKD

  • Death

  • Doubling of SCr

  • Stable kidney function

  • Relapse: doubling of the UPCR (proteinuric) or an increase in SCr level of 50% or more for more than 1 month (nephritic)

  • Major infection

  • Herpes zoster virus infection

  • Malignancy

  • Ovarian failure

Notes

  • Funding source: Roche

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

High risk

"After induction, participants were randomly assigned, in order of enrolment by means of sealed envelopes (stratified in two groups: blacks and other participants)." ‐ consecutive sequence generation

Allocation concealment (selection bias)

Low risk

Sealed envelopes used

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label study

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No missing outcome data

Selective reporting (reporting bias)

Low risk

Study protocol available and pre‐specified outcomes were reported

Other bias

High risk

Roche pharmaceutical providing research nurse support and MMF 1999 to 2003. Authors received fees for lectures and a grant from Roche Pharmaceuticals.

CYCLOFA‐LUNE 2010

Methods

  • Study design: open‐label, parallel RCT

  • Study timeframe: January 2002 to December 2006

  • Duration of follow‐up: median extended follow‐up 7.7 years (range 5.0 to 10.3 years)

Participants

  • Country: Czech Republic; Slovakia

  • Setting: multinational (8 sites)

  • Inclusion criteria: ACR criteria for SLE; biopsy‐proven lupus nephritis (WHO or ISN/RPS criteria) and clinical activity as defined by presence of at least two of the following: abnormal proteinuria (more than 500 mg/24 h), abnormal microscopic haematuria, or C3 hypocomplementaemia

  • Number (analysed): treatment group 1 (21); treatment group 2 (19)

  • Mean age ± SD (years): treatment group 1 (30 ± 9); treatment group 2 (28 ± 5)

  • Sex (M/F): treatment group 1 (6/15); treatment group 2 (5/14)

  • Exclusion criteria: previous CPA or CSA ever before; treatment with immunosuppressive drugs or corticosteroids within the last 3 months; persistent elevation of SCr > 140 µmol/L; pregnancy or lactation; bone marrow insufficiency not attributable to SLE; severe co‐existing conditions such as infection, liver disease, or active peptic ulcer

Interventions

Induction and maintenance therapy: duration of therapy was 9 months induction therapy and 9 months maintenance therapy

  • Treatment group 1

    • Intermittent IV CPA: 10 mg/kg x 8 over 9 months followed by 4 or 5 oral pulses (10 mg/d in 6 to 8 week intervals)

  • Treatment group 2

    • Daily oral CSA: 4 to 5 mg/kg/d for 9 months followed by tapering dose of 3.75 to 1.25 mg/kg/d for further 9 months

  • Both groups

    • MP 0.8 mg/kg/d tapering to 0.2 mg/kg/d over 8 weeks. Additional 1 to 3 doses of MP (15 mg/kg) were administered if felt insufficient control of kidney or extra‐kidney disease, or a 30% to 50% increase in oral steroids with a change in timing of CPA or increase in dose of CSA was also allowed

Outcomes

  • Death

  • Renal relapse: signs of renal activity

  • Major infection

  • Herpes zoster virus

  • Ovarian failure

  • Bladder toxicity

  • Alopecia

  • Lymphopenia

  • Complete renal remission: SCr within the normal range with stable or improved values as compared with baseline (no more than 15% above baseline), AND inactive urinary sediment, AND normal range proteinuria (< 0.3 g/24 h)

  • Partial renal remission: SCr within the normal range with stable or improved values as compared with baseline (no more than 15% above baseline), AND at least 50% decrease in proteinuria to less than 3 g/d if nephrotic at baseline, or to 0.5 g/d if baseline non‐nephrotic, AND either inactive urinary sediment or at least 25% improvement in C3 complement (patients with complete remission are counted within this less strict category as well

  • SCr

  • Proteinuria

Notes

  • Funding source: IGA Ministry of Health Czech Republic

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomisation 1:1, non‐blocked methods for sequence generation not reported

Allocation concealment (selection bias)

Low risk

Central computerised system

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label study

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No missing outcome data

Selective reporting (reporting bias)

Low risk

Study protocol available and pre‐specified outcomes were reported

Other bias

Low risk

Research grants from the IGA Ministry of Health, Czech Republic. The study appears to be free of other sources of bias

Decker 1975

Methods

  • Study design: open‐label, parallel RCT

  • Study timeframe: 1969 to 1981

  • Duration of follow‐up: median 7 years

Participants

  • Country: USA

  • Setting: multicentre (number of sites not reported)

  • Inclusion criteria: Diagnosis of SLE (ACR criteria); clinical or histologic evidence of active lupus GN (mostly proliferative lesions) (WHO classification criteria)

  • Number (randomised/analysed): treatment group 1 (30/28); treatment group 2 (20/19); treatment group 3 (18/18); treatment group 4 (23/22); treatment group 5 (20/20)

  • Age: median age 27 years (age for individual groups not reported)

  • Sex (M/F): 15/92 (sex for individual groups not reported)

  • Biopsy‐proven lupus nephritis: (60/107)

  • Exclusion criteria: CrCl < 20 mL/min; major infection within 2 weeks; pregnancy; leucocyte count < 2000/mm3; cytotoxic therapy within 8 weeks; sensitivity to study drugs

Interventions

Induction therapy: duration of therapy until 18 months of remission had been achieved or 4 years of protocol therapy

  • Treatment group 1

    • Prednisolone alone: 1 mg/kg for 4 to 8 weeks, then tapering

  • Treatment group 2

    • AZA: up to 4 mg/kg/d

  • Treatment group 3

    • Oral CPA: up to 4 mg/kg/d

  • Treatment group 4

    • CPA and AZA: up to 1 mg/kg/d of each

  • Treatment group 4

    • IV pulse CPA: IV every 3 month 0.5 to 1.0 g/m2

  • Additional treatment

    • Groups 2 to 4 were also treated with low‐dose prednisone (up to 0.5 mg/kg/d)

Outcomes

  • Death

  • ESKD

  • Doubling of SCr

  • Toxicity

  • Stable kidney function

  • Herpes zoster virus infection

  • Major infection

  • Cancer

  • Premature ovarian failure

  • Haemorrhagic cystitis

Notes

  • Funding source: NIH trial

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"...drawing marked card sequence from a table of random numbers...”

Allocation concealment (selection bias)

Unclear risk

Insufficient information to permit judgement

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Low risk

3.6% (4/111) of participants excluded as they did not complete 3 months of treatment

Selective reporting (reporting bias)

Low risk

All expected outcomes were reported

Other bias

High risk

Patients were assigned to treatment groups 1, 2 and 3 from the beginning of the study (1969). Treatment groups 4 and 5 were introduced in January 1973. Pooling of multiple studies

Deng 2016

Methods

  • Study design: parallel RCT

  • Study timeframe: not reported

  • Duration of follow‐up: not reported

Participants

  • Country: China

  • Setting: not reported

  • Inclusion criteria: biopsy‐proven proliferative lupus nephritis

  • Number: 30 (numbers not available for groups)

  • Mean age ± SD (years): not reported

  • Sex (M/F): not reported

  • Exclusion criteria: not reported

Interventions

Induction therapy: duration of therapy was 6 months

  • Treatment group 1

    • CPA: route of administration and dosage not reported

  • Treatment group 2

    • Leflunomide: route of administration and dosage not reported

  • Both groups

    • Prednisone: dosage not reported

Outcomes

  • Adverse events

  • Proteinuria

  • Serum albumin

Notes

  • Abstract‐only publication

  • Funding source: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Insufficient information to permit judgement

Allocation concealment (selection bias)

Unclear risk

Insufficient information to permit judgement

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Selective reporting (reporting bias)

High risk

Not all pre‐specified outcomes found on the protocol are reported; data could not be meta‐analysed

Other bias

High risk

Primary outcomes identified on clinicaltrials.gov page not reported. Focus on p‐values in the results, with no reporting of the continuous or categorical data

Derksen 1988

Methods

  • Study design: parallel RCT

  • Study timeframe: 1981 to 1985

  • Duration of follow‐up: 26 weeks

Participants

  • Country: Netherlands

  • Setting: multicentre (5 sites)

  • Inclusion criteria: diagnosis of SLE (ARA criteria); presence of active lupus nephritis, defined by a decreased CrCl, an active urine sediment (> 5 RBC/HPF and cellular casts) and proteinuria > 0.5 g/24 h; biopsy‐proven proliferative lupus nephritis (class III or IV WHO classification criteria); insufficient response of kidney function to treatment with corticosteroids alone given in a single daily dose of 1‐1.5 mg/kg for at least 3 weeks

  • Number (randomised): treatment group 1 (11); treatment group 2 (9)

  • Mean age, range SD (years): treatment group 1 (28, 15 to 55); treatment group 2 (36, 18 to 60)

  • Sex (M/F): treatment group 1 (3/8); treatment group 2 (2/7)

  • Exclusion criteria: deterioration of kidney function could be explained by other causes, such as the use of NSAIDs, infection or hypotension; patients with active renal insufficiency with oliguria/anuria (dialysis indications), and patients with psychiatric manifestations

Interventions

Induction therapy: duration of therapy was 26 weeks

  • Treatment group 1

    • Prednisone ± cytotoxics (oral AZA or CPA 2 mg/kg if kidney function and haematological functions permitted)

  • Treatment group 2

    • PEX alone: short course

  • Both groups

  • Daily oral prednisone (1.5 mg/kg) until the time of randomisation, the dose was gradually reduced (a decrease in daily dose of 10 mg, once a week) until a daily dose of 1 mg/kg was reached

Outcomes

  • Death

  • ESKD

  • CrCl

Notes

  • Funding source: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Drawing lots from card sequence

Allocation concealment (selection bias)

Unclear risk

Insufficient information to permit judgement

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Selective reporting (reporting bias)

High risk

Not all expected outcomes are reported

Other bias

High risk

Pooling interventions in cytotoxic group

Donadio 1972

Methods

  • Study design: open‐label, parallel RCT

  • Study timeframe: not reported

  • Duration of follow‐up: 3 years

Participants

  • Country: USA

  • Setting: single centre

  • Inclusion criteria: histologic evidence of kidney disease; one or more of the following: serositis, arthralgia, and arthritis, skin rash consistent with SLE and haematological abnormalities that included leukopenia, thrombocytopenia or a circulating anticoagulant

  • Number (randomised): treatment group (7); treatment group (9)

  • Age range: 17 to 68 years

  • Sex (M/F): 2/14

  • Exclusion criteria: received > 7.5 mg prednisone daily in the previous 6 months (except a dose of 20 mg daily for a maximum of 2 weeks); previous cytotoxic medication other than antimalarial treatment

Interventions

Induction therapy

  • Treatment group

    • Prednisone + AZA (2 mg/kg/body weight for 6 months); average duration of therapy was 26 months for AZA

  • Control group

    • Prednisone: 60 mg/d for 2 months, 40 mg/d by 3 months, 30 mg/d by 4 months, 25 mg/d by 5 months and 20 mg/d by 6 months

Outcomes

  • Death

  • Complete remission

  • Relapse

  • Toxicity

  • CrCl

  • Proteinuria

  • Leucopenia (WCC < 3000/mL3)

Notes

  • Funding source: Mayo Foundation

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Participants allocated within each category to treatment group A or B according to random selection. Table of random numbers used. Each incoming set of 4 participants assigned to 2 As and 2 Bs in random order

Allocation concealment (selection bias)

Unclear risk

Insufficient information to permit judgement

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label study

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Selective reporting (reporting bias)

High risk

One or more reported primary outcomes were not pre‐specified

Other bias

Low risk

The study appears to be free of other sources of bias

Donadio 1976

Methods

  • Study design: open‐label, parallel RCT

  • Study timeframe: commenced December 1971

  • Duration of follow‐up: 4 years

Participants

  • Country: USA

  • Setting: single centre

  • Inclusion criteria: SLE fulfilled 4 or more criteria used for the classification of the disease; a positive LE‐cell preparation or rosettes of neutrophils or nucleolysis; a positive antinuclear‐antibody test in titres ≥ 1:32 or elevated levels of anti‐nDNA; CrCl < 80 mL/min/1.73 m2 or a reduction of 25% in the CrCl as compared with the initial clearance of a maximal period of three months; and adequate renal biopsy showing diffuse proliferative GN

  • Number (randomised): treatment group (24); control group (26)

  • Mean age, range (years): treatment group (30.2, 16 to 60); control group (32.3, 17 to 50)

  • Sex (M/F): treatment group (5/19); control group (4/22)

  • Exclusion criteria: Previous CPA or immunosuppressive drugs in the last 6 months

Interventions

Induction therapy

  • Treatment group

    • Oral CPA: 2 mg/kg/d for 6 months

    • Maintenance dose of prednisone to control other systemic manifestations

  • Control group

    • Prednisone: 60 mg/d tapered after 1 to 3 months

Outcomes

  • ESKD

  • Death

  • Toxicity

  • Major infection

  • Treatment failure: ESKD or final CrCl increased by 25%

  • Relapse: reappearance of systematic features, reductions in CrCl, increased proteinuria and changes in anti‐nDNA and CH50 levels

  • Current status on kidney function

  • Proteinuria

  • Avascular necrosis

Notes

  • Funding source: Mayo Foundation and Constance Belden Memorial Fund

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Random number tables used

Allocation concealment (selection bias)

Unclear risk

Insufficient information to permit judgement

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label study

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Selective reporting (reporting bias)

Low risk

All expected outcomes are reported

Other bias

Low risk

The study appears to be free of other sources of bias

Doria 1994

Methods

  • Study design: parallel RCT

  • Study timeframe: 1988 to 1993

  • Duration of follow‐up: every 4 weeks for 24 months and then every 8 weeks thereafter

Participants

  • Country: Italy

  • Setting: single centre

  • Inclusion criteria: SLE (1982 ACR criteria); biopsy‐proven class IV lupus nephritis (WHO classification criteria); normal kidney function (SCr ≤ 1.2 mg/dL)

  • Number (randomised): treatment group 1 (7); treatment group 2 (5); control group (6)

  • Mean age, range (years): treatment group 1 (30, 20 to 55); treatment group 2 (23, 15 to 32); control group (25, 15 to 46)

  • Sex (M/F): 2/16 (not reported for individual groups)

  • Exclusion criteria: Pregnancy; aged < 15 and > 80 years; infections; insulin‐dependent DM; history of malignancy; immunosuppressive therapy within a 6 month period prior to renal biopsy

Interventions

Induction therapy

  • Treatment group

    • Standard therapy

    • PEX: 3 x times weekly for 1 week then twice a week for 2 weeks then once a week for 2 months then once a fortnight for 3 months. 50% of the patient's plasma volume was removed and replaced with a 4% human albumin solution

  • Treatment group 2

    • Standard therapy

    • IV MP: 500 mg daily for 3 consecutive days

  • Control group

    • Standard therapy

      • Prednisone: 2 mg/kg/d for 4 weeks with slow tapering (5 mg every 10 days)

      • AZA: 2 mg/kg/d

Outcomes

  • Death

  • ESKD

  • Doubling of SCr

  • 24 h urinary protein

  • Partial remission

  • Complete remission

  • Herpes zoster virus

  • Leucopenia

Notes

  • Funding source: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Study was described as randomised, method of randomisation was not reported

Allocation concealment (selection bias)

Unclear risk

Insufficient information to permit judgement

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label study

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No missing outcome data

Selective reporting (reporting bias)

Low risk

All relevant outcomes reported

Other bias

Low risk

The study appears to be free of other sources of bias

Dyadyk 2001

Methods

  • Study design: parallel RCT

  • Study timeframe: not reported

  • Duration of follow‐up: 19 years

Participants

  • Country: Ukraine

  • Setting: not reported

  • Inclusion criteria: diffuse proliferative lupus nephritis class IV (WHO classification criteria)

  • Number (randomised/analysed): treatment group 1 (21/21); treatment group 2 (38/38)

  • Mean age: 36 years (not reported for groups)

  • Sex (M/F): treatment group 1 (4/17); treatment group 2 (5/33)

  • Exclusion criteria: not reported

Interventions

Induction therapy

  • Treatment group 1

    • AZA: 1.5 to 2.0 mg/kg/d; mean total duration of therapy (18.9 months)

  • Treatment group 2

    • CPA: 1.5 to 3.5 mg/kg/d; mean total duration of therapy (21.7 months)

Outcomes

  • Death (all causes)

  • Complete remission

  • Partial remission

Notes

  • Abstract‐only publications

  • 5 and 10 year survival follow‐up

  • Funding source: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Study was described as randomised, method of randomisation was not reported

Allocation concealment (selection bias)

Unclear risk

Insufficient information to permit judgement

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label study

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Selective reporting (reporting bias)

High risk

Not all relevant reported outcomes are reported

Other bias

Low risk

The study appears to be free of other sources of bias

El‐Sehemy 2006

Methods

  • Study design: parallel RCT

  • Study timeframe: commenced January 2004

  • Duration of follow‐up: 6 months

Participants

  • Country: Egypt

  • Setting: single centre

  • Inclusion criteria: all SLE patients; class III (1), class IV (10), class Vc (5), class Va or b (4), class V (1), unclassified (1)

  • Number (randomised/analysed): treatment group 1 (7/7); treatment group 2 (7/7); treatment group 3 (8/8)

  • Age range (years): treatment group 1 (18 to 29); treatment group 2 (19 to 24); treatment group 3 (18 to 27)

  • Sex (M/F): all female

  • Exclusion criteria: uncontrolled infection; CNS manifestations; known neoplastic disease; intention to become pregnant; previous immunosuppressive drugs < 3 months prior to study

Interventions

Induction therapy: duration of therapy not reported

  • Treatment group 1

    • CPA: 0.75 mg/m2

  • Treatment group 2

    • CSA: 1 to 2 mg/kg/d

  • Treatment group 3

    • AZA: 1 to 2 mg/kg/d

  • All groups

    • MP 500 to 1000 mg/kg/d for 3 to 5 days then oral prednisolone 0.5 mg/kg/d for 4 weeks then tapered dose

Outcomes

  • Major infection

  • Ovarian failure

  • Proteinuria

  • CrCl

Notes

  • Three participants from group 1 and one participant from group 3 shifted to group II due to side effects or no response

  • Funding source: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Study was described as randomised, method of randomisation was not reported

Allocation concealment (selection bias)

Unclear risk

Insufficient information to permit judgement

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No missing outcome data

Selective reporting (reporting bias)

High risk

Not all expected patient outcomes reported

Other bias

High risk

Baseline kidney function highly different between groups. Reported outcomes with patients transferred to different groups

El‐Shafey 2010

Methods

  • Study design: open label, RCT

  • Study timeframe: February 2006 to December 2008

  • Duration of follow‐up: 24 weeks

Participants

  • Country: Egypt

  • Setting: single centre

  • Inclusion criteria: diagnosis of SLE (ACR criteria); newly diagnoses active proliferative class III or IV lupus nephritis (WHO classification criteria); ≥15 years

  • Number (randomised/analysed/completed 24 week induction phase): treatment group 1 (24/24/20); treatment group 2 (23/23/19)

  • Mean age ± SD (years): treatment group 1 (22.8 ± 5.8); treatment group 2 (23.8 ± 5.6)

  • Sex (M/F): treatment group 1 (1/23); treatment group 2 (1/22)

  • Exclusion criteria: eGFR < 30 mL/min, SCr > 200 μmol/L, WCC < 3.5 x 109/L, major infection, history of cancer, alcohol or substance abuse, active peptic ulcer disease, pregnant or lactating women, allergy to MMF or CPA and use of study drugs in preceding 6 months

Interventions

Induction therapy: duration of therapy was 6 months

  • Treatment group 1

    • MMF: 1 g twice daily for 6 months

  • Treatment group 2

    • IV CPA: 0.5 to 1.0 g/m2 for 6 months, median monthly dose 0.75 g/m2

  • Both groups

    • Prednisolone: 60 mg/d for 4 to 6 weeks, then 40 mg/d for 2 weeks followed by tapering dose to 5 to 10 mg/d

Outcomes

  • Death (all causes)

  • ESKD

  • Remission: combined complete and partial remission at 6 months

  • Complete renal remission: normal SCr, proteinuria < 0.5 g/d and urine RBC < 5 per HPF, without RBC cast

  • Partial renal remission: improvement of 50% in all abnormal renal measurements without deterioration (within 20%) of any measurement

  • Major infection

  • Herpes zoster virus

  • Menstrual irregularities

  • Diarrhoea

  • Lymphopenia

  • SCr

  • eGFR

  • Proteinuria

Notes

  • Funding source: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Study was described as randomised, method of randomisation was not reported

Allocation concealment (selection bias)

Unclear risk

Insufficient information to permit judgement

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label study

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Selective reporting (reporting bias)

Low risk

Study protocol available and pre‐specified outcomes were reported

Other bias

Low risk

The study appears to be free of other sources of bias

Florez‐Suarez 2004

Methods

  • Study design: parallel RCT

  • Study timeframe: not reported

  • Duration of follow‐up: 1year

Participants

  • Country: Mexico

  • Setting: not reported

  • Inclusion criteria: lupus nephritis patients type IV and V

  • Number (randomised): 20 (numbers per group not reported)

  • Mean age ± SD (years): not reported

  • Sex (M/F): not reported

  • Exclusion criteria: not reported

Interventions

Induction therapy: duration of treatment was 12 months

  • Treatment group 1

    • MMF: up to 2 g/d

  • Treatment group 2

    • IV CPA: monthly (does not reported)

  • Both groups

    • Prednisone

Outcomes

  • Complete remission

  • Partial remission

  • Treatment failure

  • Death

Notes

  • Abstract‐only publication; authors contact ‐ no reply

  • Funding source: Roche Mexico

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Study was described as randomised, method of randomisation was not reported

Allocation concealment (selection bias)

Unclear risk

Insufficient information to permit judgement

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label study

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Selective reporting (reporting bias)

High risk

Data unable to be meta‐analysed

Other bias

High risk

abstract‐only publication; funded by Roche Mexico

Fries 1973

Methods

  • Study design: open‐label, RCT

  • Study timeframe: not reported

  • Duration of follow‐up: 40 months

Participants

  • Country: USA

  • Setting: single centre

  • Inclusion criteria: SLE with antinuclear antibodies; involvement of two or more organs

  • Number (randomised/lupus nephritis): treatment group (10/5); control group (12/5)

  • Mean age ± SD (years): not reported

  • Sex (M/F): not reported

  • Exclusion criteria: not reported

Interventions

Induction therapy

  • Treatment group

    • CPA: adjusted on the basis of weekly WCC, attempting to maintain a WCC between 3500 and 4000 cells/cu mm

  • Control group

    • Prednisone: 1 mg/kg/d

Outcomes

  • Relapse

  • Failure or response of treatment

Notes

  • Significant cross‐over

  • Funding source: Clinical Research centre Grant RR‐70 and Biotechnology Resources Branch of the National Institutes of Health RR00311‐04

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Study was described as randomised, method of randomisation was not reported

Allocation concealment (selection bias)

Unclear risk

Insufficient information to permit judgement

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label study

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Selective reporting (reporting bias)

High risk

Not all relevant reported outcomes are reported

Other bias

High risk

Heavy cross‐over between groups

Fu 1997

Methods

  • Study design: parallel RCT

  • Study timeframe: July 1994 to December 1995

  • Duration of follow‐up: 1 year

Participants

  • Country: Taiwan

  • Setting: single centre

  • Inclusion criteria: diagnosis of SLE (ACR 1982 revised criteria); class III‐IV lupus nephritis proven by biopsy (WHO classification criteria) with heavy proteinuria and normal SCr

  • Number (randomised): treatment group 1 (20); treatment group 2 (20)

  • Mean age ± SD (years): treatment group 1 (10.2 ± 3.4); treatment group 2 (10.4 ± 3.1)

  • Sex (M/F): not reported

  • Exclusion criteria: not reported

Interventions

Maintenance therapy: duration of treatment was 12 months

  • Treatment group 1

    • Oral CPA: 2 mg/kg/d

    • Prednisolone: 2 mg/kg/d

  • Treatment group 2

    • CSA: 5 mg/kg/d every 12 h

  • Both groups

    • Oral prednisolone 2 mg/kg/d for 4 weeks ± pulsed MP (if unresponsive). Dose of prednisolone tapered to 0.5 to 1 mg/kg as maintenance therapy for > 1 year before randomisation

Outcomes

  • Proteinuria

  • SCr

  • CrCl

  • Height velocity

  • Height SDS

Notes

  • Funding source: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Participants randomly assigned (1:1, stratified by race and biopsy class, non‐blocked) by a central computerised, interactive voice response system random number table

Allocation concealment (selection bias)

Low risk

Used sealed, completely opaque, envelopes numbered in sequence according to a table of random numbers

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label study

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No missing outcome data

Selective reporting (reporting bias)

High risk

Not all of the study’s prespecified primary outcomes were reported

Other bias

Low risk

Funding source not declared. The study appears to be free of other sources of bias

Furie 2014

Methods

  • Study design: double‐blind, parallel RCT

  • Study timeframe: not reported

  • Duration of follow‐up: 12 months

Participants

  • Countries: North America, Europe, South America, Asia, Australia, India, South Africa, Turkey

  • Setting: multinational (85 sites)

  • Inclusion criteria: aged ≥ 18 years; diagnosis of SLE (ACR criteria); class III or IV GN (ISN/RPS 2003 criteria or WHO 1982 classification), complement C3 or C4 levels below the lower limit of normal or elevated anti‐dsDNA antibody titres at the time of screening were further requirements for eligibility as were UPCR of ≥ 0.44 mg/mg (50 mg/mmol) at the time of screening and active urinary sediment (> 5 RBC or >8 WBC/HPF or cylinduria at time of screening or the current flare

  • Number (randomised/analysed): treatment group 1 (99/99); treatment group 2 (99/99); control group (100/100)

  • Mean age ± SD (years): treatment group 1 (30.5 ± 10.6); treatment group 2 (31 ± 9.5); control group (31.8 ± 9)

  • Sex (M/F): treatment group 1 (13/86); treatment group 2 (15/84); control group (19/81)

  • Exclusion criteria: evidence of severe, rapidly advancing kidney failure (i.e. increase in SCr levels of ≥ 1 mg/dL within 1 month prior to screening or a SCr level of > 3 mg/dL); evidence of severe unstable and or progressive central nervous system lupus; use of immunosuppressive or immunomodulatory agents during the study except for antimalarial agents and protocol defined MMF and glucocorticoids

Interventions

Induction therapy: duration of therapy was 12 months

  • Treatment group 1

    • Abatacept 10/10 regimen: weight tiered (500 mg for patients weighing < 60 kg, 750 mg for patients 60–100 kg, 1,000 mg for patients >1 00 kg) on days 1, 15, 29, 57, 85, 113, 141, 169, 197, 225, 253, 281, 309, and 337

  • Treatment group 2

  • Abatacept 30/10 regimen: 30 mg/kg on days 1, 15, 29, and 57, followed by abatacept approximating 10 mg/kg (weight tiered: 500 mg for patients weighing <60 kg, 750 mg for patients 60–100 kg, 1,000 mg for patients >100 kg) on days 85, 113, 141, 169, 197, 225, 253, 281, 309, and 337

  • Control group

    • Placebo: consisted of dextrose 5% in water or normal saline on days 1, 15, 29, 57, 85, 113, 141, 169, 197, 225, 253, 281, 309, and 337

  • All groups

    • MMF (dosage based on race and prior treatment) and prednisone (or prednisone equivalent), followed by adjustment or taper

Outcomes

  • Death (all causes)

  • ESKD

  • Complete response: 1) eGFR 90% of screening level if normal at screening visit, or eGFR 90% of 6‐month, pre‐flare value if abnormal at screening, 2) UPCR 0.26 g/g (30 mg/mmol), and 3) inactive urinary sediment (RBC and WBC/HPF within normal limits of central laboratory assessments; no RBC or WBC casts)

  • Partial response: SCr level normal or 125% of baseline; UPCR 50% of baseline and 3.0 g/g (339 mg/mmol) if nephrotic, or 1.0 g/g (133 mg/mmol) if non‐nephrotic; urinary sediment inactive or 50% reduction in RBC/HPF from baseline; for confirmation, assessed on day 337 and confirmed on day 365

  • Major infection

  • Herpes zoster virus

Notes

  • Funding source: Bristol Myers Squibb

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Study was described as randomised, method of randomisation was not reported, however patients were stratified according to prior treatment

Allocation concealment (selection bias)

Unclear risk

Insufficient information to permit judgement

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Double‐blind, double dummy placebo study

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Not all relevant reported outcomes are reported

Selective reporting (reporting bias)

Low risk

Study protocol available and pre‐specified outcomes were reported

Other bias

High risk

Sponsor included in data analysis/authorship

Ginzler 1976

Methods

  • Study design: cross‐over RCT

  • Study timeframe: not reported

  • Duration of follow‐up: 4 months then crossed over

Participants

  • Country: USA

  • Setting: single centre

  • Inclusion criteria: diagnosis of SLE (ARA criteria); active kidney disease as manifested by either 1) the new appearance of hypocomplementaemia, azotaemia (SCr > 1.2 mg%), urinary protein excretion >200 mg/24 h; cellular casts or more than 10 RBC/HPF in the urine sediment, or hypertension, or 2) deterioration in renal status in a patient with previously known renal disease, including either the new development of any of the above manifestations, or a 50% increase in SCr, or a 200% increase in urinary protein excretion; a renal biopsy demonstrating diffuse proliferative or membranous GN

  • Number (randomised): treatment group 1 (8); treatment group 2 (6)

  • Mean age ± SD (years): treatment group 1 (28.2 ± 8.5); treatment group 2 (25.8 ± 6.2)

  • Sex (M/F): not reported

  • Exclusion criteria: SCr > 3 mg/dL, previous exposure to cytotoxic drugs

Interventions

Induction therapy: duration of treatment was 4 months

  • Treatment group 1

    • Oral AZA: 1.25 mg/kg/d

    • CPA: 1.25 mg/kg/d

  • Treatment group 2

    • AZA: 2.5 mg/kg/d

  • Both groups

    • Prednisone prior to randomisation (minimum dose of 1 mg/kg/d for 3 weeks); steroid dose was tapered throughout the study by a maximum of 5 mg decrements at each clinic visit, in accordance with parameters of clinical disease activity

Outcomes

  • Death

  • ESKD

  • Toxicity

  • Proteinuria

  • CrCl

  • Ovarian failure

  • Infection

Notes

  • Funding source: Supported by a grant from Lupus Erythematosus Foundation

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Study was described as randomised, method of randomisation was not reported

Allocation concealment (selection bias)

Unclear risk

Insufficient information to permit judgement

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Double‐blind with a cross‐over to other treatment under certain conditions (predetermined therapeutic failures)

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No missing outcome data

Selective reporting (reporting bias)

Low risk

Study protocol available and prespecified outcomes were reported

Other bias

High risk

Cross‐over design and reporting of results, difficult to separate treatment effects

Ginzler 2005

Methods

  • Study design: open‐label, non‐inferiority RCT

  • Study timeframe: December 1999 to October 2003

  • Duration of follow‐up: 24 weeks

Participants

  • Country: USA

  • Setting: multicentre (19 sites)

  • Inclusion criteria: diagnosis of SLE (ACR criteria), biopsy‐proven lupus nephritis class III, IV or V, clinical activity defined by one of; incident decrease in kidney function, proteinuria (> 0.5 g/24 h), microscopic haematuria (> 5 RBC/HPF); participants with class III or V required to have SCr > 1.0 mg/dL or proteinuria > 2 g/24 h

  • Number (randomised/analysed): treatment group 1 (71/71); treatment group 2 (69/69)

    • 113 had diffuse proliferative lupus nephritis; 27 had pure membranous

  • Mean age ± SD (years): treatment group 1 (32.5 ± 10); treatment group 2 (31.0 ± 9.0)

  • Sex (M/F): treatment group 1 (10/61); treatment group 2 (4/65)

  • Ethnicity (Black/white/Hispanic/Asian/other): treatment group 1(43/12/10/6/0); treatment group 2 (36/12/18/2/1)

  • Exclusion criteria: CrCl < 30 mL/min, SCr > 3.0 mg/dL; severe co‐existing conditions precluding immunosuppression or requiring IV antibiotics; prior treatment with MMF; treatment with IV CPA in last 12 months; treatment within last 30 days; pregnancy or lactation

Interventions

Induction therapy: duration of therapy was 24 weeks

  • Treatment group 1

    • MMF: 0.5 g twice daily to increase to max 1 g 3 times/d

  • Treatment group 2

    • IV CPA: 0.5 g/m2 BSA increased to 1.0 g/m2

  • Both groups

    • Prednisone at a dose of 1 mg/kg/d, with tapering by 10 to 20% at 1 week or 2 week intervals, on the basis of clinical improvement

    • The new appearance or worsening of manifestations of extrarenal disease could be treated with one 3‐day pulse of IV MP or increased dose of prednisone to a maximum of 2 mg/kg/d

Outcomes

  • Death

  • ESKD

  • Doubling of SCr

  • Relapse

  • Stable kidney function

  • Major infection

  • Herpes zoster

  • Ovarian failure

  • GI upset

  • Diarrhoea

  • Lymphopenia (< 800 lymphocytes/mm3)

  • Complete remission in proteinuria

  • Partial remission in proteinuria

  • Complete renal remission: defined at 24 weeks as return to within 10% of normal values of SCr levels, proteinuria, and urine sediment

  • Partial renal remission: defined at 24 weeks as improvement of 50% in all abnormal renal measurements, without worsening (within 10 percent) of any measurement

  • Treatment failure: patients in whom treatment failed included all those without complete or partial remission at 24 weeks, plus those who stopped treatment for any reason

  • SCr

  • Daily proteinuria

Notes

  • 1 participant on MMF crossed‐over to CPA and 2 participants on IV CPA crossed over to MMF

  • Funding source: FDA's Orphan Products Development program and a supplemental grant from Roche Laboratories

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Treatment assigned at central site with the use of sealed envelopes

Allocation concealment (selection bias)

Low risk

Sealed envelopes used

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label study

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No missing outcome data

Selective reporting (reporting bias)

High risk

Due to early termination, primary outcome as per protocol not reported; Not all expected outcomes reported

Other bias

High risk

The study was terminated early and there was heavy cross‐over between study arms. Funding provided by a supplemental grant from Roche laboratories

Gourley 1996

Methods

  • Study design: open‐label, parallel RCT

  • Study timeframe: from mid 1990

  • Duration of follow‐up: > 5 years

Participants

  • Country: USA

  • Setting: single centre

  • Inclusion criteria: SLE; GN was defined as a sediment on 2 or more urinalysis that showed either 10 or more RBC/HPF or erythrocyte or leukocyte casts (without evidence of infection) or both plus biopsy‐proven active proliferative lupus GN (within 3 months of study entry); 79/82 class III/IV on biopsy; 3/82 no biopsy

  • Number (randomised): treatment group 1 (27); treatment group 2 (28); control group (27)

  • Mean age (years): treatment group 1 (30); treatment group 2 (31); control group (30)

  • Sex (M/F): treatment group 1 (6/21); treatment group 2 (3/25); control group (5/22)

  • Exclusion criteria: cytotoxic drug treatment > 2 weeks and with 6 weeks of start date; 10 weeks of CPA therapy; pulse therapy of corticosteroids within 6 weeks of start of study; oral corticosteroids > 0.5 mg/kg/d; active or chronic infection; pregnancy; insulin‐dependent DM; allergy to study medication

Interventions

Induction therapy

  • Treatment group 1

    • IV CPA: 0.75 g/m2 boluses monthly for 6 months then 3 monthly for at least 2 years

  • Treatment group 2

    • IV MP: as per control group

    • IV CPA: as per treatment group 1

  • Control group

    • IV MP: 3 doses (1 g/m2) over 3 consecutive days then one dose monthly for 12 months

  • All groups

    • Initially given oral prednisone (0.5 mg/kg/d) for 4 weeks. The prednisone dose was then tapered by 5 mg every other day each week to the minimal dose required to control extrarenal disease or 0.25 mg/kg every other day, whichever was greater

    • For severe extrarenal flares of lupus, patients were permitted to receive prednisone, 1.0 mg/kg per day for 2 weeks

Outcomes

  • Death

  • ESKD

  • Doubling of SCr

  • Renal remission

  • Treatment failure: ≥ 10 RBC/HPF, cellular casts, proteinuria (>1 g of protein/d)

  • Relapse: reactivation of renal disease after 6 or more months of remission

  • One or more infections

  • Herpes zoster virus infection

  • Amenorrhoea

  • Avascular necrosis

Notes

  • 2 participants lost to follow‐up

  • Funding source: Arthritis Foundation

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Masked cards from table of random numbers

Allocation concealment (selection bias)

Unclear risk

Using masked card but no description methods of allocation concealment

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label study

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Outcome data with the exception of adverse events, were collected in a blinded manner

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No missing outcome data; participants at endpoints censored but considered in final analysis

Selective reporting (reporting bias)

Low risk

Study protocol available and prespecified outcomes were reported

Other bias

Low risk

The study appears to be free of other sources of bias

Grootscholten 2006

Methods

  • Study design: parallel RCT

  • Study timeframe: September 1995 to September 2001

  • Duration of follow‐up: median follow‐up 5.7 years (interquartile range 4.1 to 7.2 years); unintentional skewed distribution (resulting from stratification per centre and small contribution of some centres). Median extended follow‐up was 9.6 years (range 0.1 to 13.2 years)

Participants

  • Country: Netherlands

  • Setting: multicentre (number of sites not reported)

  • Inclusion criteria: biopsy‐proven lupus nephritis (PALGA), diagnosis of SLE (ACR criteria); 18 to 60 years; CrCl > 25 mL/min; if already known to have proliferative lupus nephritis, renal biopsy < 1 year before; WHO class IV or Vd must have signs of active nephritis or deterioration of kidney function; class III or Vc lupus nephritis had to meet both criteria

  • Number (randomised/analysed): treatment group 1 (50/50); treatment group 2 (37/37)

  • Mean age, range (years): treatment group 1 (30, 24 to 47); treatment group 2 (33, 26 to 39)

  • Sex (M/F): treatment group 1 (6/44); treatment group 2 (9/28)

  • Exclusion criteria: decline in kidney function (> 30% increase in SCr) in month before inclusion; active infection; malignancy < 5 years before randomisation; pregnancy or no contraceptives during first 2.5 years of treatment; hepatitis or cirrhosis of liver; active peptic ulcer; leucocytopenia (< 3 x 109/L) or thrombocytopenia (< 100 x 109/L with suppressed bone marrow; allergy to AZA or CPA

Interventions

Induction and maintenance therapy

  • Treatment group 1

    • IV CPA: 750 mg/m2, 13 pulses in 2 years, oral prednisolone cumulative corticosteroid dose (11 g)

  • Treatment group 2

    • Oral AZA: 2 mg/kg/d in 2 years, IV MP (3 x 3 pulses of 1000 mg) and oral prednisolone (initially 1 mg/kg/d for 4 weeks, 0.75 mg/kg/d for 4 weeks, 0.50 mg/kg/d for 4 weeks and thereafter tapered by 5mg every 4 weeks to a final dose of 10 mg daily after 6 months)

  • Both groups

    • Switched to long‐term AZA (2 mg/kg) plus prednisolone (10 mg/d) after 2 years

Outcomes

  • Death

  • ESKD

  • Doubling of SCr

  • Deterioration of kidney function

  • major infection

  • Ovarian failure

  • Daily proteinuria

  • Renal relapse: could occur after week 12, and was defined as doubling of the lowest obtained SCr so far and/ or development of either a nephrotic syndrome (proteinuria > 3.5 g/d and serum albumin < 30 g/L), while the lowest protein excretion so far had been ≤ 2.0 g/d repeatedly, or proteinuria < 1.5 g/d without other causes, in a previously non‐proteinuric patient

Notes

  • 8/87 class III or Vc class IV or Vd 79/97 13/87 given previous cytotoxics IV CPA:7/50 (14%) AZA: 6/37 (16%) If 1y failure (DSC) switched to other arm of study 1 lost to follow‐up in each group

  • Funding source: Dutch Kidney Foundation, Dutch League against Rheumatism

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomisation performed at a central office with a computer program, using the minimisation determinants: centre, SCr (< 150 or > 150 μmol/L), WHO class III or IV, previous treatment with immunosuppressive medication for lupus nephritis

Allocation concealment (selection bias)

Unclear risk

Central office with computer program. Not sufficiently clear to determine risk

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label study

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No missing outcome data

Selective reporting (reporting bias)

Low risk

Study protocol available and pre‐specified outcomes were reported

Other bias

Low risk

Funding from Dutch Kidney Foundation and Dutch League against Rheumatism. One author disclosed speaking fees from Novartis. The study appears to be free of other sources of bias

Hahn 1975

Methods

  • Study design: open‐label, RCT

  • Study timeframe: not reported

  • Duration of follow‐up: 2 years

Participants

  • Country: USA

  • Setting: single centre

  • Inclusion criteria: SLE diagnosed using established specific criteria (positive antinuclear antibodies, a score of severe points or more on major‐minor criteria scale; all patients also met the preliminary criteria for SLE (ARA); active life‐threatening disease (severe nephritis, central nervous system involvement, haemolytic anaemia, thrombocytopenia, myocarditis, lupus crisis)

  • Number (randomised): treatment group (11); control group (13)

  • Mean age ± SD (years): treatment group (33.5 ± 13.2); control group (31.7 ± 13.9)

  • Sex (M/F): treatment group (2/9); control group (2/11)

  • Exclusion criteria: prior treatment with cytotoxic drugs; 20 mg prednisone/d during the preceding 6 weeks

Interventions

Induction therapy: duration of therapy was 24 months

  • treatment group

    • Oral AZA: 3 to 4 mg/kg/d

    • Prednisone: as per control group

  • Control group

    • Prednisone: daily oral dose of 40 to 60 mg was maintained for 4 to 6 months. After prednisone was maintained at 40 to 60 mg daily for 6 months in both groups, it was tapered slowly (by 5 mg increments every 2 weeks to a level of 30 mg daily, then by 2.5 mg increments every 2 weeks)

Outcomes

  • Death

  • Toxicity

  • Major infection

  • Infection

  • Proteinuria

  • Remission of proteinuria

  • CrCl

  • SCr

Notes

  • 2/24 lost to follow‐up

  • Funding source: US Public Health Service grants AM17469 and AM05548 and Public Health Service Research grant FR‐36 from the General Clinical Research centre Branch, Division of Research Facilities and Resources; and the Arthritis Foundation

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Slips of paper bearing letters A or B sealed in envelopes then placed in a drawer. On randomising patient, envelopes drawn randomly from drawer

Allocation concealment (selection bias)

Low risk

Sealed envelopes used in randomisation

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label study

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No missing outcome data

Selective reporting (reporting bias)

High risk

Not all expected clinical outcomes were reported

Other bias

Low risk

The study appears to be free of other sources of bias

Hong 2007

Methods

  • Study design: open‐label, parallel RCT

  • Study timeframe: not reported

  • Duration of follow‐up: 6 months

Participants

  • Country: China

  • Setting: not reported

  • Inclusion criteria: diffuse proliferative lupus nephritis on renal biopsy; all > 2 g/d proteinuria and SCr < 3 mg/dL

  • Number (randomised/analysed): treatment group 1 (13/13); treatment group 2 (12/12)

  • Mean age ± SD: 30.7± 5.1 years

  • Sex (M/F): 2/23

  • Exclusion criteria: not reported

Interventions

Induction therapy

  • Treatment group 1

    • Oral FK506 (TAC): 0.1 mg/kg/d

  • Treatment group 2

    • IV CPA: 0.5 to 0.75g/m2 monthly

  • Both groups

    • Prednisolone: 0.8 mg/kg/d

Outcomes

  • Stable kidney function

  • No response

  • Infection

  • Complete remission (urinary protein excretion < 0.4 g/24 h, no active urinary sediment (urinary RBC < 10×104/mL), serum albumin > 35 g/L, SCr in normal ranges)

  • Partial remission (between complete remission and no response ‐ referred to urinary protein excretion > 2 g or the reduction less than the baseline value, serum albumin < 30 g/L, or increment of SCr > 50% of the baseline value)

  • Proteinuria

Notes

  • Abstract‐only publication

  • Funding source: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Insufficient information to permit judgement

Allocation concealment (selection bias)

Unclear risk

Insufficient information to permit judgement

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label study

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Selective reporting (reporting bias)

High risk

Not all expected outcomes reported

Other bias

Unclear risk

Abstract‐only publication; insufficient information to permit judgement

Houssiau 2002

Methods

  • Study design: RCT

  • Study timeframe: September 1996 to September 2000

  • Duration of follow‐up: 10 years

Participants

  • Country: Europe (countries not reported)

  • Setting: multinational (19 sites)

  • Inclusion criteria: diagnosis of SLE (ACR criteria); age ≥ 14 years; biopsy‐proven proliferative lupus GN (WHO class III, IV, Vc, or Vd); proteinuria 500 mg/24 h; 69/90 class IV or Vc/Vd

  • Number (randomised): treatment group 1 (46); treatment group 2 (44)

  • Mean age ± SD (years): treatment group 1 (30 ± 11); treatment group 2 (33 ± 12)

  • Sex (M/F): treatment group 1 (3/43); treatment group 2 (3/41)

  • Exclusion criteria: CPA or AZA in previous year; > 15 mg/d prednisolone during preceding month; renal thrombotic microangiopathy; pre‐existing CKD; pregnancy; previous malignancy ‐ except skin or cervical intraepithelial neoplasia's; DM; severe toxicity or immunosuppressive drugs; anticipated poor compliance

Interventions

Induction and maintenance therapy

  • Treatment group 1

    • High dose IV CPA: received 8 pulses within a year (6 monthly pulses followed by 2 quarterly pulses. The initial IV CPA dose was 0.5 g/m2 of body surface area; subsequent doses were increased by 250 mg according to the WBC count nadir measured on day 14, with a maximum of 1,500 mg per pulse

  • Treatment group 2

    • Low dose IV CPA: received 6 fortnightly IV CPA pulses at a fixed dose of 500 mg

  • Both groups

    • All patients received 3 daily pulses of 750 mg of IV MP, followed by oral prednisolone (or equivalent) at an initial dosage of 0.5 mg/kg/d for 4 weeks. A dosage of 1 mg/kg/d was allowed in critically ill patients (those with renal impairment or severe extrarenal disease), glucocorticoid therapy (5–7.5 mg of prednisolone per day) was maintained at least until month 30 after inclusion; after 4 weeks, prednisolone (or equivalent) dosages were tapered by 2.5 mg every 2 weeks.

    • Both treatment arms, AZA (2 mg/kg/d) was started 2 weeks after the last CPA injection and continued at least until month 30 after study inclusion

Outcomes

  • Death

  • ESKD

  • Renal remission: defined as 10 RBC/HPF and a 24‐hour urinary protein level < 1 g, in the absence of a doubling of the SCr level; and the number of severe flares

  • Treatment failure: defined as any of the following 3 features: 1. Absence of a primary response A. For patients with a baseline SCr ≥ 1.3 mg/dL but ≤ 2.6 mg/dL, absence of a primary response was defined as failure of the SCr to decrease to < 1.3 mg/dL at 6 months; B. For patients with a baseline SCr > 2.6 mg/dL, absence of a primary response was defined as failure of the SCr level to improve by 50% at 6 months; C. For patients with nephrotic syndrome at baseline (serum albumin level < 3.5 g/dL and 24‐hour urinary protein level ≥ 3 g/d), but without renal impairment (SCr < 1.3 mg/dL), absence of a primary response was defined as the persistence of nephrotic syndrome at 6 months; 2. A glucocorticoid‐resistant flare (defined as a severe flare that did not respond to a 1‐month increase in the glucocorticoid dosage); 3. A doubling of the SCr over the lowest value reached at any time during the follow‐up and confirmed on 2 consecutive visits 1 month apart

  • Doubling of SCr

  • Relapse: severe renal flare was defined as 1 of the following 3 features: renal impairment, increase in proteinuria, or severe systemic disease. Renal impairment was defined as an SLE‐related increase of 33% in the SCr within a 1‐month period; An increase in proteinuria defined as recurrence or appearance of nephrotic syndrome (albuminaemia ≤ 3.5 g/dL and proteinuria ≥ 3 g/24 h); In patients with low‐grade proteinuria at baseline (≥ 0.5 g but ≤1 g in 24 h); a 3‐fold increase in 24‐hour urinary protein levels within a 3‐month period was also considered a severe flare, provided that it was accompanied by microscopic haematuria and a 33% reduction of serum C3 levels within a 3‐month period

  • Toxicity

  • Proteinuria

  • Infection

  • Herpes zoster virus

  • Ovarian failure

  • Leucopenia: ≤ 4000/μL

Notes

  • Follow‐up: median 41 month follow‐up; 1 patient lost to follow‐up. 73 month follow‐up; 5 participants lost to follow‐up, 10 year follow‐up

  • Funding source: supported by the European League against Rheumatism

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomisation by minimisation

Allocation concealment (selection bias)

Unclear risk

Insufficient information to permit judgement

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No missing outcome data

Selective reporting (reporting bias)

Low risk

Study protocol available and pre‐specified outcomes were reported

Other bias

Low risk

Supported by the European League Against Rheumatism. The study appears to be free of other sources of bias

Jayne 2013

Methods

  • Study design: double‐blind double‐dummy RCT

  • Study timeframe: not reported

  • Duration of follow‐up: 6 months

Participants

  • Country: not reported

  • Setting: multicentre (number of sites not reported)

  • Inclusion criteria: active lupus nephritis

  • Number (randomised): treatment group 1 (16); treatment group 2 (16); control group (15)

  • Mean age ± SD (years): not reported

  • Sex (M/F): not reported

  • Exclusion criteria: not reported

Interventions

Induction therapy: duration of treatment was 6 months

  • Treatment group 1

    • High‐dose laquinimod: oral 1 mg/d

  • Treatment group 2

    • Low‐dose laquinimod: oral 0.5 mg/d

  • Control group

    • Placebo

  • All groups

    • All patients received MMF and prednisone (or equivalent)

Outcomes

  • Death

  • Remission

  • Kidney function

  • Adverse events

Notes

  • Abstract‐only publication

  • Funding source: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Insufficient information to permit judgement

Allocation concealment (selection bias)

Unclear risk

Insufficient information to permit judgement

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Double‐blind, double dummy placebo study

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No missing outcome data

Selective reporting (reporting bias)

High risk

Not all prespecified outcomes were reported

Other bias

Unclear risk

Abstract‐only publication; insufficient information to permit judgement

Kaballo 2016

Methods

  • Study design: parallel RCT

  • Study timeframe: March 2008 to August 2011

  • Duration of follow‐up: 36 months

Participants

  • Country: Sudan

  • Setting: multicentre (2 sites)

  • Inclusion criteria: aged 12 to 75 years and have been diagnosed with SLE (ACR revised criteria); lupus nephritis criteria included persistent proteinuria > 0.5 g/d and presence of active urine sediment; renal biopsies were performed at presentation, only patients who had a histological diagnosis of severe proliferative Class III and IV and/or membranous Class V lupus nephritis (ISN/RPS 2003 classification) were enrolled

  • Number (randomised): treatment group 1 (41); treatment group 2 (40)

  • Mean age ± SD (years): treatment group 1 (27.1 ± 9.8); treatment group 2 (29.4 ± 11.6)

  • Sex (M/F): treatment group 1 (3/38); treatment group 2 (3/37)

  • Exclusion criteria: ESKD; malignancy; severe cardiovascular or liver disease; severe infection

Interventions

Maintenance therapy

  • Treatment group 1

    • Oral MMF: 22 mg/kg/d, range 1000 to 3000 mg/d. The dosages remained unchanged within the 1st year, and then they were reduced by 25% in stable patients after the 1st year and continued for at least another year before further tapering

  • Treatment group 2

    • Oral AZA: 2 mg/kg/d. The dosages remained unchanged within the 1st year, and then they were reduced by 25% in stable patients after the 1st year and continued for at least another year before further tapering

  • Both groups

    • All patients underwent induction therapy using IV pulse CPA (500 mg/m2 of body surface area with a maximum dose ≤ 500 mg) monthly for six months, plus 3 consecutive pulses of IV MP (15 mg/kg/d maximum 500 mg). All patients initially received oral prednisone (1 mg/kg)

Outcomes

  • Death

  • ESKD

  • Complete remission: defined as reduction in proteinuria to ≤0.2 g/d with normal SCr

  • Partial remission: defined as a reduction of proteinuria from nephrotic range to a range between 0.2 and 2.0 g/d or reduction of proteinuria more than 50% with normal SCr

  • Relapse: patients in complete or partial remission, defined by an increase in SCr levels 50% or more over the last value besides a nephritic urinary sediment and generally increased proteinuria (nephritic flare) or by an increase in proteinuria without modification of SCr (proteinuric flare). Proteinuria had to increase by at least 2 g/d if the basal proteinuria was <3.0 g/d, or double if the patient had already nephrotic range proteinuria

  • Doubling of SCr

  • Major infection

  • Alopecia

  • Leucopenia

  • Nausea

  • Vomiting

  • Diarrhoea

  • Proteinuria

Notes

  • Funding source: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Patients stratified by block randomisation (stratification factors were gender, age and weight)

Allocation concealment (selection bias)

Unclear risk

Insufficient information to permit judgement

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No missing outcome data

Selective reporting (reporting bias)

Low risk

Trial registration was not reported, all expected outcomes were reported

Other bias

Low risk

The study appears to be free of other sources of bias

Kamanamool 2017

Methods

  • Study design: open‐label, parallel RCT

  • Study timeframe: 1 April 2012 to 31 March 2016

  • Duration of follow‐up: 12 months

Participants

  • Country: Thailand

  • Setting: multicentre (number of sites not reported)

  • Inclusion criteria: patients with active, biopsy‐proven lupus nephritis Class III, IV or V (ISN/RPS) 2003 criteria within 24 weeks of randomisation and who were ANA (ANA) or anti‐double stranded DNA (anti‐dsDNA) positive

  • Number (randomised/analysed): treatment group 1 (42/42); treatment group 2 (41/41)

    • Treatment group 1: class III or IV (29), class V or III/IV + V (13)

    • Treatment group 2: class III or IV (28), class V or III/IV + V (13)

  • Mean age ± SD (years): treatment group 1 (34.1 ± 11.1); treatment group 2 (31.7 ± 10.5)

  • Sex (M/F): treatment group 1 (1/40); treatment group 2 (3/38)

  • Exclusion criteria: Severe extra‐renal manifestations; previous therapy with calcineurin inhibitor or MMF or CPA within the previous four months before randomisation; allergy to macrolide antibiotics; uncontrolled hypertension (SBP > 160 mm Hg or DBP > 100 mm Hg); severely deteriorated kidney function or rapid progressive crescentic GN; severe myocarditis or cardiomyopathy; requiring plasmapheresis or IVIG; severe infection or active TB; active hepatitis and evidence of chronic liver disease; HIV infection; MD; pregnancy; hypersensitivity or contraindication to MMF, mycophenolic acid, TAC, corticosteroids or any components of these drug products

Interventions

Induction therapy

  • Treatment group 1

    • Oral MMF: initiated at a dose of 500 mg twice daily (patients > 50 kg and eGFR > 60 mL/min) for 2 weeks. It was then advanced to 750 mg twice daily in lupus nephritis patients weighing less than 50 kg, or 1000 mg twice daily in lupus nephritis patients weighing 50 kg or more. Dosage of MMF was prescribed according to the ACR recommendations, which suggest MMF 2 g/d for Asians

  • Treatment group 2

    • Oral TAC: started at a dosage of 0.1 mg/kg/d divided into two daily doses at 12‐hour intervals, and the dosage was titrated to achieve trough blood concentrations of 6–10 ng/mL in the first and second month and then 4–8 ng/mL thereafter

  • Both groups

    • All patients received prednisone at a dose of 0.5 to 0.7 mg/kg/d (maximum 60 mg/d), with tapering by 5 to 10 mg/d every two weeks until a dose of 5 mg/d had been achieved, and this dosage was maintained until the end of 24 weeks

    • All patients who had remission received AZA 1 to 2 mg/kg/d for 24 weeks as standard treatment. For patients who did not respond to the induction therapy, treatment depended on physician decision

Outcomes

  • Death

  • Complete remission

  • SCr

  • Disease activity

Notes

  • Funding source: Astellas Pharma (Thailand) Co., Ltd provided study drug and budget

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"We stratified patients into two strata according to the classification of renal pathology (Class III–IV LN or Class V III/IV LN). Patients were randomly assigned 1:1 to a TAC group or an MMF group."

Allocation concealment (selection bias)

Low risk

To preserve the allocation concealment, the generation of blocks of four to six randomisation lists was electronically produced at Ramathibodi Hospital and web‐based randomizations was used.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label study

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No missing outcome data

Selective reporting (reporting bias)

Low risk

Study protocol available and pre‐specified outcomes were reported

Other bias

Low risk

"Astellas Pharma (Thailand) Co., Ltd. provided study drug and funded the study but had no role in study design, data collection, data analysis, data interpretation or conclusions." The study appears to be free of other sources of bias

Lewis 1992

Methods

  • Study design: open‐label, parallel RCT

  • Study timeframe: 1 April 1981 to 30 September 1986

  • Duration of follow‐up: mean follow‐up 2.5 years with termination of study

Participants

  • Country: USA

  • Setting: multicentre

  • Inclusion criteria: ≥ 16 years; SLE (ARA criteria); qualifying biopsy; 35 participants with class IV disease

  • Number (randomised): treatment group 1 (40); treatment group 2 (46)

  • Mean age ± SD (years): treatment group 1 (31 ± 11); treatment group 2 (33 ± 14)

  • Sex (M/F): treatment group 1 (7/33); treatment group 2 (7/39)

  • Exclusion criteria: pregnancy; SCr > 6 mg/dL; previous plasmapheresis; history of primary myocardial disease; cancer within last 5 years; prednisone‐associated psychosis; peptic ulcer; active liver disease

Interventions

Induction therapy

  • Treatment group 1

    • Oral CPA

    • Corticosteroids

    • PEX: 3 x weekly for 4 weeks

  • Treatment group 2

    • Oral CPA

    • Corticosteroids

Outcomes

  • Death

  • ESKD

  • Remission: SCr ≤ 1.2 mg/dL and a 24‐hour urinary protein of ≤ 0.2 g/d

  • Toxicity

  • Infection

  • Herpes zoster virus infection

  • SCr

  • Proteinuria

Notes

  • Funding source: Public health service

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Stratified according to clinic by central coordination centre

Allocation concealment (selection bias)

Low risk

Generated by Biostatistical Coordinating centre which issued treatment assignments by telephone after confirmation of patient eligibility

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label study

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No missing outcome data; 1 patient lost‐to follow‐up

Selective reporting (reporting bias)

Low risk

Study protocol available and pre‐specified outcomes were reported

Other bias

High risk

The study was terminated early

Li 2009c

Methods

  • Study design: open‐label, pilot RCT

  • Study timeframe: not reported

  • Duration of follow‐up: 48 weeks

Participants

  • Country: Hong Kong

  • Setting: single centre

  • Inclusion criteria: diagnosis of SLE (revised ACR criteria); biopsy‐proven lupus nephritis class III or IV (WHO classification criteria), clinical activity index ≥ 6/24, proteinuria ≥ 1.5 g/24 h, albumin ≤ 35 g/L; 3/19 participants with class IV disease

  • Number (randomised/analysed): treatment group 1 (9/9); treatment group 2 (10/10)

  • Mean age ± SD (years): treatment group 1 (40.3 ± 13.9); treatment group 2 (39.6 ± 8.6)

  • Sex (M/F): treatment group 1 (0/9); treatment group 2 (1/9)

  • Exclusion criteria: severe infection in last 3 months; HIV; HBV or HCV; active TB; pregnancy; on oral/IV CPA, AZA or MMF within 8 weeks or prednisolone ≥ 0.5 mg/kg/d within 4 weeks; history of cancer; DM or kidney failure leading to dialysis

Interventions

Induction therapy

  • Treatment group 1

    • RTX: 1000 mg, treatment repeated on day 15

  • Treatment group 2

    • RTX: 1000 mg, 250 mg MP day 1, followed by IV CPA 750 mg, treatment repeated once on day 15

  • Both groups

    • All participants received 250 mg IV MP on day 1, oral prednisolone 30 mg/d from day 2 to day 5, then 0.5 mg/kg for 4 weeks, then dose reduction 5 mg every 2 weeks

    • Patients were pre‐medicated with chlorpheniramine (10 mg IV) and paracetamol (1 g orally) 30 min before IV infusions

    • All participants on ACEi before the study and continued on same dose

Outcomes

  • Major infection

  • Herpes zoster virus infection

  • Complete response: if the baseline (at week 0) SLEDAI scores were greater than 0 and the follow‐up score was equal to 0

  • Partial response: if the baseline SLEDAI scores were greater than the follow‐up score but the follow‐up score was not equal to 0

  • Treatment failure: worse disease activity

  • CrCl

  • Proteinuria

Notes

  • Funding source: Roche provided the study drug

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomisation according to a randomisation table kept by a third party

Allocation concealment (selection bias)

Low risk

Randomisation table kept by a third party

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label study

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No missing outcome data

Selective reporting (reporting bias)

High risk

Not all expected outcomes were reported

Other bias

Low risk

"...Roche provided study drug but had no role in study design, data collection, data analysis, data interpretation or writing of the report..." The study appears to be free of other sources of bias

Li 2012

Methods

  • Study design: open‐label, parallel RCT

  • Study timeframe:

  • Duration of follow‐up:

Participants

  • Country: China

  • Setting: single centre

  • Inclusion criteria: aged 8 to 65 years; diagnosis of SLE (1997 revised ARA criteria); biopsy‐proven classes III, IV‐S or IV‐G, V, V + III or V + IV lupus nephritis (2003 ISN/ RPS classification criteria) 6 months before randomisation, chronic index ≤ 3 and urinary protein excretion of ≥ 1.0 g/24 h, and/or a recent deterioration in kidney function; 60 participants with classes III, IV and V disease; 35 participants with class IV disease

  • Number (randomised/analysed): treatment group 1 (20/20); treatment group 2 (20/20); treatment group 3 (20/20)

  • Median age, range (years): treatment group 1 (26.5, 16 to 62); treatment group 2 (29, 17 to 50); treatment group 3 (22, 17 to 64)

  • Sex (M/F): treatment group 1 (3/17); treatment group 2 (3/17); treatment group 3 (2/19)

  • Exclusion criteria: treatment with MMF, TAC, CSA or CPA within the previous year; SCr concentration > 5.0 mg/dL; life‐threatening complications such as cerebral lupus, pancreatitis, GI haemorrhage, within 6 months or active peptic ulcer within 3 months, severe infection, severe cardiovascular disease, bone marrow insufficiency with cytopenia not attributable to SLE or poor drug compliance

Interventions

Induction therapy: duration of treatment was 6 months

  • Treatment group 1

    • Oral MMF: 1.5 to 2.0 g/d

  • Treatment group 2

    • Oral TAC: 0.08 to 0.1 mg/kg/d, target 12 hour trough 6 to 8 ng/mL

  • Treatment group 3

    • IV CPA: 0.5 to 0.75 g/1.73 m2

  • All groups

    • All patients received corticosteroids 0.8 to 1 mg/kg/d (max dose 60 mg/d). Reduced by 10 mg every 2 weeks until at 40 mg/d, then reduced by 5 mg/d every 2 weeks to maintenance dose of 10 mg/d

Outcomes

  • Death

  • Stable kidney function

  • Major infection

  • Leucopenia

  • Complete renal remission: urinary protein excretion < 0.3 g/24 h with normal urine sediment, serum albumin concentration > 35 g/L and SCr above baseline values by ≤ 15%

  • Partial renal remission: urinary protein excretion between 0.3 to 2.9 g/24 h, having decreased by at least 50% from baseline values, with a serum albumin concentration of at least 30 g/L and relative stabilisation (± 30%) in SCr

  • Complete remission in proteinuria

  • Doubling of SCr

  • Proteinuria

  • Serum albumin

Notes

  • Funding source: Shanghai Institutes of Health and Chinese National Natural Science Foundation

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Study was described as randomised, method of randomisation was not reported

Allocation concealment (selection bias)

Unclear risk

Insufficient information to permit judgement

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label study

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No missing outcome data

Selective reporting (reporting bias)

Low risk

Study protocol available and pre‐specified outcomes were reported

Other bias

Low risk

The study appears to be free of other sources of bias

Liou 2007

Methods

  • Study design: open‐label, parallel RCT

  • Study timeframe: not reported

  • Duration of follow‐up: 18 months

Participants

  • Country: China

  • Setting: single centre

  • Inclusion criteria: biopsy‐proven lupus nephritis

  • Number (randomised): treatment group 1 (19); treatment group 2 (21)

  • Mean age ± SD (years): not reported

  • Sex (M/F): not reported

  • Exclusion criteria: not reported

Interventions

Induction and maintenance therapy: 6 months induction therapy and 12 months maintenance therapy

  • Treatment group 1

    • Oral leflunomide: 30 mg/d; after 6 months of induction therapy, leflunomide was reduced to 20 mg/d

  • Treatment group 2

    • IV CPA: 1g per month; after 6 months IV CPA was given 1g/3 months for maintenance therapy

  • Both groups

    • All patients received prednisolone 0.8 to 1 mg/kg/d tapered to 10 mg/d

Outcomes

  • Complete renal remission (not defined)

  • Herpes zoster virus infection

  • Proteinuria

  • Serum albumin

  • SCr

Notes

  • Abstract‐only publication

  • Only induction therapy (6 months) reported

  • Funding source: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Insufficient information to permit judgement

Allocation concealment (selection bias)

Unclear risk

Insufficient information to permit judgement

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label study

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Selective reporting (reporting bias)

High risk

Not all expected clinical outcomes are reported

Other bias

Unclear risk

Abstract‐only publication; insufficient information to permit judgement

Liu 2015

Methods

  • Study design: open‐label, parallel RCT

  • Study timeframe: April 2009 to June 2011

  • Duration of follow‐up: 24 weeks

Participants

  • Country: China

  • Setting: multicentre (number of sites not reported)

  • Inclusion criteria: patients aged 18 to 65 years; diagnosis of SLE (ACR criteria); biopsy‐proven class III, IV, V, III+V, and IV+V lupus nephritis (ISN/RPS 2003 classification criteria) within 6 months before study entry; proteinuria (≥1.5 g/d) with a SCr ≤ 3.0 mg/dL)

  • Number (randomised/analysed): treatment group 1 (181/175); treatment group 2 (181/181)

    • Treatment group 1: class III (10), class IV (74), class V (32); class III+IV or IV+V (65)

    • Treatment group 2: class III (9), class IV (76), class V (37); class III+IV or IV+V (52)

  • Median age, IQR (years): treatment group 1 (33.6, 24.2 to 41.5); treatment group 2 (30.3, 23.3 to 38.6)

  • Sex (M/F): treatment group 1 (20/161); treatment group 2 (13/168)

  • Exclusion criteria: treatment with MMF, CPA, TAC, or high‐dose MP; current RRT; plasmapheresis, or IVIG within the 12 weeks before randomisation; abnormal liver function or serum glucose test results; and pathologic chronicity index > 3

Interventions

Induction therapy: duration of therapy was 6 months

  • Treatment group 1

    • IV CPA: initiated at a dose of 0.75 g/m2 body surface area and then adjusted to a dose of 0.5 to 1.0 g/m2 body surface area every 4 weeks for 6 doses

  • Treatment group 2

    • Oral MMF: 0.5 g twice/d

    • Oral TAC: 2 mg twice/d

  • Both groups

    • IV MP pulse therapy (0.5 g/d) for 3 days, followed by oral prednisone (0.6 mg/kg/d) every morning for 4 weeks. The daily dose of prednisone was tapered by 5 mg/d every 2 weeks to 20 mg/d and then by 2.5 mg/d every 2 weeks to a maintenance dose of 10 mg/d

Outcomes

  • Death

  • Complete remission: 24 h urinary protein excretion ≤ 0.4 g, the absence of active urine sediments, serum albumin level ≥ 35 g/L, and normal SCr

  • Partial remission: ≥ 50% reduction in proteinuria and urine protein < 3.5 g/24 h, serum albumin level ≥30 g/L, and normal or ≤ 25% increase in SCr level from baseline

  • Doubling of SCr

  • Major infection

  • Herpes zoster virus infection

  • Menstrual disorder

  • Avascular necrosis

  • Alopecia

  • Leucopenia

  • Upper GI symptoms

  • Diarrhoea

Notes

  • Funding source: National Basic Research Program of China (973 Program, No. 2012CB517600, No. 2012CB517606), National Key Technology R&D Program (2011BAI10B04, 2013BAI09B04).

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomisation list, stratified by centre was created by Rundo International Pharmaceutical Research & Development (Shanghai) Co. Ltd. by using computer generated random‐number sequences

Allocation concealment (selection bias)

Low risk

Sequentially numbered, concealed envelopes containing group assignment were provided to the investigators. After eligible patients provided written informed consent, the envelopes were opened in sequence and patients were randomly assigned, in a 1:1 ratio, to the multi‐target regimen or IV CPA

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label study

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

The outcomes were adjudicated by the Clinical Endpoints Committee, blinded to treatment regimen.

Incomplete outcome data (attrition bias)
All outcomes

High risk

Unclear why 6 patients (3%) in the IV CPA group were not given therapy and not included in the analysis and why patients in the IV CPA group were seen at twice the follow‐up rate then patients in the multi‐target therapy group

Selective reporting (reporting bias)

High risk

Not all prespecified outcomes were reported

Other bias

Low risk

This study appears to be free of other sources of bias

Loo 2010

Methods

  • Study design: open‐label, parallel RCT

  • Study timeframe: not reported

  • Duration of follow‐up: 6 months

Participants

  • Country: Malaysia

  • Setting: single centre

  • Inclusion criteria: aged ≥ 12 years; diagnosis of SLE (ARA 1982 criteria) and biopsy proven severe classes III or IV ± V lupus nephritis (ISN/RPS 2003 classification criteria)

  • Number (randomised/analysed): treatment group 1 (14/14); treatment group 2 (14/14)

  • Mean age ± SD (years): treatment group 1 (31.9 ± 11.6); treatment group 2 (30.2 ± 7.5)

  • Sex (M/F): treatment group 1 (4/10); treatment group 2 (0/14)

  • Ethnicity: treatment group 1 (Chinese (5), Malay (7), Indian (2)); treatment group 2 (Chinese (5), Malay (7), Indian (2))

  • Exclusion criteria: not reported

Interventions

Induction therapy: duration of therapy was 6 months

  • Treatment group 1

    • PEX: 3 sessions (3L per session) following MP treatment. For PEX, the plasma removed was replaced with 2 litres of human albumin 5% and the balance with Hartman’s solution

  • Treatment group 2

    • Immunoadsorption: 3 sessions carried out on a daily or every other day basis for 3 days. Three litres of plasma or 1 plasma volume, whichever was greater was processed at each session

  • Both groups

    • All patients received standard induction IV pulse MP at 250 mg/d for 3 days followed by PEX or immunoadsorption. Followed by IVIG 10 g/d for 3 days. Patients subsequently proceed to the consolidation phase with pulse IV CPA at 10 to 12 mg/kg/dose 2‐weekly for 4 doses, then monthly for four more doses. Patients were then randomised to receive maintenance therapy with either oral CSA or MMF in conjunction with low dose steroid, for a further 12 to 18 months

Outcomes

  • Relapse: nephrotic syndrome

Notes

  • Funding source: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

High risk

Consecutive enrolment

Allocation concealment (selection bias)

Unclear risk

Insufficient information to permit judgement

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label study

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Selective reporting (reporting bias)

High risk

Not all expected outcomes were reported

Other bias

High risk

Marked differences (demographics and clinical characteristics) between groups at baseline

Lui 1997

Methods

  • Study design: parallel RCT

  • Study timeframe: not reported

  • Duration of follow‐up: 12 months

Participants

  • Country: Hong Kong

  • Setting: not reported

  • Inclusion criteria: class IV disease

  • Number (randomised/analysed): treatment group 1 (17/17); treatment group 2 (17/17)

  • Mean age ± SD (years): not reported

  • Sex (M/F): not reported

  • Exclusion criteria: not reported

Interventions

Induction therapy

  • Treatment group 1

    • Oral CSA: 5 mg/kg/d, reduced to 2.5 mg/kg/d

  • Treatment group 2

    • Oral CPA: 1 mg/kg/d

  • Both groups

    • All patients received prednisolone (0.5 mg/kg/d) and AZA (1 mg/kg/d)

Outcomes

  • Failure to respond

  • Partial response

  • Complete response

  • Proteinuria

  • CrCl

  • Infection

  • Herpes zoster virus infection

  • Leucopenia

  • Amenorrhoea

Notes

  • Abstract‐only publication

  • Funding source: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Insufficient information to permit judgement

Allocation concealment (selection bias)

Unclear risk

Insufficient information to permit judgement

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label study

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Selective reporting (reporting bias)

Unclear risk

Insufficient information to permit judgement

Other bias

Unclear risk

Abstract‐only publication; insufficient information to permit judgement

LUNAR 2012

Methods

  • Study design: phase III, double‐blind double‐dummy RCT

  • Study timeframe: January 2006 to January 2008

  • Duration of follow‐up: 12 months

Participants

  • Countries: USA, Latin America

  • Setting: multinational (52 sites)

  • Inclusion criteria: aged 16 to 75 years of age; diagnosis of SLE (ACR criteria); history of ANA positivity; diagnosis of class III or IV lupus nephritis (ISN/RPS 2003 Classification) with either active or active chronic disease; proteinuria (urine polymerase chain reaction > 1.0); If the biopsy was performed > 3 months before screening; an active urinary sediment (> 10 RBC/HPF or the presence of RBC casts)

  • Number (randomised/analysed): treatment group (72/72); control group (72/72)

  • Mean age ± SD (years): treatment group (31.8 ± 9.6); control group (29.4 ± 9.3)

  • Sex (M/F): treatment group (9/63); control group (5/67)

  • Exclusion criteria: active infection; recurrent or chronic infection,; CPA or CNI treatment within 90 days prior to screening; MMF > 2 g daily > 90 d prior to screening; use of prednisolone >20 mg/d > 14 days prior to screening; previous treatment with CAMPATH‐1H; B‐cell targeted therapy; pregnancy or lactation; history of cancer

Interventions

Induction therapy: duration of therapy was 12 months

  • Treatment group

    • IV RTX: 1000 mg (days 1, 15, 168, 182)

  • Control group

    • Placebo

  • Both groups

    • MMF: initial dosage of 1.5 g/d in 3 divided doses, and the dosage was increased to 3 g/d by week 4

    • IV MP: 1,000 mg was administered 30–60 minutes prior to the administration of study drug on day 1 and again within 3 days.

    • Oral prednisone: 0.75 mg/kg/d (maximum 60 mg) was administered until day 16 and tapered to 10 mg/d by week 16

Outcomes

  • Death (all causes)

  • Stable creatinine

  • Major infection

  • Herpes zoster virus infection

  • Complete response: SCr ≤ 115% of baseline if it was normal at baseline; inactive urinary sediment (< 5 RBC/HPF and absence of RBC casts); and UPCR < 0.5

  • Partial response: SCr ≤ 115% of baseline; RBCs/HPF ≤ 50% above baseline and no RBC casts; and at least a 50% decrease in the UPCR to < 1.0 (if the baseline UPCR was ≤ 3.0) or to ≤ 3.0 (if the baseline UPCR was > 3.0)

  • Treatment failure (if criteria for complete response or partial response were not met, for early termination from the study or inability to assess the end point due to missing data, or for initiation of a new immunosuppressant agent prior to week 52

  • Complete response in proteinuria

  • Partial response in proteinuria

  • Serious adverse events

  • Nausea

  • Diarrhoea

Notes

  • Funding source: Genentech and Biogen Idec

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Study was described as randomised, method of randomisation was not reported

Allocation concealment (selection bias)

Unclear risk

Insufficient information to permit judgement

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Double‐blind, double‐dummy placebo study

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No missing outcome data

Selective reporting (reporting bias)

Low risk

Study protocol available and pre‐specified outcomes were reported

Other bias

High risk

Some authors declared grants/research support from Genentech and Aspreva, and sponsor included in data analysis and authorship

MAINTAIN Nephritis 2010

Methods

  • Study design: open‐label, parallel RCT

  • Study timeframe: July 2002 and March 2006

  • Duration of follow‐up: median follow‐up 53 months; extended median follow‐up was 9.16 years (range 1.5 to 13 years)

Participants

  • Country: European (countries not reported)

  • Setting: multinational (27 sites)

  • Inclusion criteria: SLE ≥ 14 years, diagnosis of SLE (ACR criteria), proteinuria ≥ 0.5 g/d, biopsy‐proven lupus nephritis Class III, IV, Vc or Vd lupus nephritis (WHO classification criteria)

  • Number (randomised/analysed): treatment group 1 (52/52); treatment group 2 (53/53)

  • Mean age ± SD (years): treatment group 1 (33 ± 11); treatment group 2 (33 ± 10)

  • Sex (M/F): treatment group 1 (4/48); treatment group 2 (5/48)

  • Exclusion criteria: recent treatment with high dose corticosteroids or immunosuppressive drugs; non‐lupus related renal disease (such as microthrombotic disease associated with antiphospholipid syndrome); pre‐existing chronic kidney failure (defined as a SCr value above the upper normal value for the local laboratory) due to a previous episode of lupus nephritis or other cause; pregnancy or breast feeding; previous malignancy (except skin and cervical intraepithelial neoplasia's); DM; previously documented severe toxicity of immunosuppressants, anticipated non‐compliance with the protocol

Interventions

Maintenance therapy

  • Treatment group 1

    • AZA: 2 mg/kg/d

  • Treatment group 2

    • MMF: 2 g/d

  • Both groups

    • Induction therapy of 3 x 750 mg IV MP followed by oral glucocorticoids 0.5 mg/kg/d and 6 fortnightly pulses IV CPA 500 mg

    • Maintenance treatment started in both groups at week 12

Outcomes

  • Death

  • ESKD

  • Relapse: (i) recurrence or the development of nephrotic syndrome (serum albumin ≤ 3.5 g/dL and proteinuria ≥ 3 g/24 h); (ii) renal impairment (≥ 33% increase of SCr within a 1‐month period directly attributed to lupus nephritis and confirmed 1 week later; flare referred to as ‘renal impairment’) or (iii) a threefold increase of 24 h proteinuria within a 3‐month period accompanied by microscopic haematuria (defined as a number of RBC/HPF superior to upper normal limit for the local laboratory) and ≥ 33% reduction of serum C3 level within a 3‐month period (this definition of renal flare was only applicable to those patients with low‐grade baseline 24 h proteinuria (≥ 0.5 g and < 1 g); this type of renal flare is further referred to as ‘proteinuria increase’

  • Time to renal flare

  • Doubling of SCr

  • Number of withdrawals due to toxicity

  • Number of treatment failures

  • Major infection

  • Herpes zoster virus infection

  • Avascular necrosis

  • Malignancy

  • Alopecia

  • Leucopenia

  • Kidney function over time

  • 24 hour proteinuria over time

Notes

  • Funding source: no external funding

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomisation by minimisation

Allocation concealment (selection bias)

Unclear risk

Insufficient information to permit judgement

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label study

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No missing outcome data

Selective reporting (reporting bias)

Low risk

Study protocol available and pre‐specified outcomes were reported

Other bias

Low risk

No competing interests declared. The study appears to be free of other sources of bias

Mehra 2018

Methods

  • Study design: open‐label, parallel RCT

  • Study timeframe: December 2015 to December 2016

  • Duration of follow‐up: 12 months

Participants

  • Country: India

  • Setting: single centre

  • Inclusion criteria: diagnosis of SLE (ACR criteria); aged > 16 years; proteinuria ≥ 500 mg/24 h and/or urine routine microscopy showing active cellular casts/sediments (> 5 RBC/HPF and > 5 WBC/HPF and cellular casts); biopsy‐proven proliferative class III, IV lupus GN (ISN/RPS) criteria

  • Number (randomised/analysed): treatment group 1 (37/37); treatment group 2 (38/38)

    • Treatment group 1: class III (11), class IV (26); had crescents (14; 38%)

    • Treatment group 2: class III (17), class IV (21); had crescents (8; 21%)

  • Mean age ± SD (years): not reported

  • Sex (M/F): treatment group 1 (3/34); treatment group 2 (4/34)

  • Exclusion criteria: ever treated previously with IV or oral cyclophosphamide, MMF, cyclosporine or steroids > 15 mg/d in the last 3 months; renal thrombotic microangiopathy, pre‐existing chronic kidney failure, previous malignancy (except skin and cervical intraepithelial neoplasia); DM or coronary heart disease; previously documented severe toxicity to immunosuppressive drugs; patients with active acute or chronic infections; pregnancy

Interventions

Induction therapy

  • Treatment group 1

    • High dose IV CPA: four weekly six cycles of 750 mg/m2 with a maximum of 1.5 g per pulse.

  • Treatment group 2

    • Low dose IV CPA: six fortnightly IV CPA cycles at a fixed dose of 500 mg

  • Both groups

    • All participants received 3 daily pulses of 1 g IV MP followed by 1 mg/kg/d of prednisolone for 4 weeks tapered by 5 mg every 2 weeks to reach a dose of 5–7.5 mg/d until completion of 52 weeks. After completion of induction, oral AZA 2 mg/kg was started two weeks after the last CPA dose. For patients with AZA‐related toxicity, the dosage was reduced to 1 mg/kg/d

    • All patients received hydroxychloroquine during the study (5 to 6 mg/kg, 400 mg/d maximum) after normal baseline fundus evaluation

    • Hypertension (DBP > 90 mm Hg) was treated with ACEi (unless contraindicated) and other appropriate drugs

    • Atorvastatin was started for patients with LDL cholesterol > 100 mg/dL

Outcomes

  • Death

  • Complete remission: UPCR < 0.5 g and normal GFR (> 90 mL/ min) or stable (< 10% deterioration from baseline if GFR was previously abnormal) kidney function and inactive urinary sediments.

  • Partial remission: ≥ 50% reduction in proteinuria to sub‐nephrotic levels, normal GFR (> 90 mL/ min) or stable (< 10%) deterioration from baseline if GFR was previously abnormal

  • Renal relapse (not defined)

  • Treatment failure

  • Major infection

  • Herpes zoster virus infection

  • Ovarian failure

  • Bone toxicity: avascular necrosis

  • Alopecia

  • Leucopenia

  • GI disturbance

  • CrCl

Notes

  • Funding source: Investigator initiated

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"Patients were randomised, using block randomization, eight blocks of 10 patients each with 1:1 random allocation was performed using a computer generated random number table."

Allocation concealment (selection bias)

Low risk

"Fellow researcher had given random block and number to patients sequentially, who was unaware of treatment allocation and had no other role in the study."

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label study

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No missing outcome data

Selective reporting (reporting bias)

High risk

Not all expected outcomes were reported and partial remission listed in protocol not reported.

Other bias

Low risk

The study appears to be free of other sources of bias

Mendonca 2017

Methods

  • Study design: open‐label, parallel RCT

  • Study timeframe: November 2014 to November 2015

  • Duration of follow‐up: 6 months

Participants

  • Country: India

  • Setting: single centre

  • Inclusion criteria: SLE according to the SLICC 2012 and the ACR criteria; all biopsy‐proven class III, IV or III/IV +V lupus nephritis was diagnosed based on biopsy findings as per the ISN/RPS

  • Number (randomised/analysed): treatment group 1 (18/17); treatment group 2 (23/23)

    • Treatment group 1: class III (1); class IV (11); class V (2); class III+V or class IV+V (3)

    • Treatment group 2: class III (1); class IV (15); class V (3); class III+V or class IV+V (4)

  • Mean age ± SD (years): treatment group 1 (26.0 ± 10.8); treatment group 2 (25.7 ± 10.3)

  • Sex (M/F): treatment group 1 (3/14); treatment group 2 (5/18)

  • Exclusion criteria: CKD stage‐3 and above; crescentic lupus nephritis; pancreatitis, GI haemorrhage within six months or active peptic ulcer disease within last three months; ongoing infection; bone marrow insufficiency with cytopenias not attributable to SLE; and prior treatment with CPA or MM

Interventions

Induction therapy

  • Treatment group 1

    • Oral MMF: twice daily, titrated from 750 mg twice daily in the 1st week, and 1.0 g twice daily in the 2nd week, to a target dosage of 1.5 g twice daily, if required, based on the disease activity and response. Reduction was permitted to 2 g/d in response to any adverse events

  • Treatment group 2

    • Low dose IV CPA: Pulse CPA (750 mg/m2), which was adjusted to 500 to 1000 mg/m2 every 4 weeks to maintain a nadir leukocyte count of 2.5 to 4.0 × 109/L for a total of 6 pulses. A 25% decrease in dosage for age older than 60 years, and SCr > 3.4 mg/dL was followed

  • Both groups

    • All participants had received unified concomitant corticosteroid therapy according to protocol that consisted of three doses of IV pulse MP 500 mg followed by oral prednisone (or equivalent) at an initial dose of 0.5 mg/kg/d. Prednisolone dosage was tapered by a decrease of 5 mg/d every two weeks until a dose of 10 mg/day was achieved, and this dosage was maintained till the end of six months.

    • Doses of ACEi and/or ARB had been unchanged during the 6 month follow‐up period

    • Target blood pressure was kept at 130/80 mm Hg

    • Hyperlipidaemia was treated using statins and/or fibric acid derivatives as required

Outcomes

  • Death

  • Complete remission: urinary protein excretion < 0.3 g/24 h was accomplished with normal serum albumin levels and/or an improvement in the baseline SCr levels of > 50%

  • Partial remission: improvement of > 50% from baseline proteinuria, serum albumin levels of at least 30 g/L, and SCr level of ≥ 25% from baseline or stable SCr level within 25% of the baseline

  • Treatment failure

  • Major infection

  • Herpes zoster virus infection

  • Diarrhoea

  • Nausea

  • Vomiting

  • CrCl

  • SCr

  • Daily proteinuria

Notes

  • Funding source: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Study was described as randomised, method of randomisation was not reported

Allocation concealment (selection bias)

Unclear risk

Insufficient information to permit judgement

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label study

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No missing outcome data

Selective reporting (reporting bias)

High risk

No protocol available, some expected outcomes not reported

Other bias

Low risk

The study appears to be free of other sources of bias

Mitwalli 2011

Methods

  • Study design: double‐blind, parallel RCT

  • Study timeframe: December 1997 to January 2007

  • Duration of follow‐up: mean follow‐up 6.77 ± 3.3 years

Participants

  • Country: Saudi Arabia

  • Setting: single centre

  • Inclusion criteria: adult patients with newly diagnosed biopsy‐proven lupus nephritis (WHO class IV)

  • Number (randomised/analysed): treatment group 1 (73/73); treatment group 2 (44/44)

  • Mean age ± SD (years): treatment group 1 (36.4 ± 12.7); treatment group 2 (30.3 ± 10.4)

  • Sex (M/F): treatment group 1 (12/61); treatment group 2 (5/39)

  • Exclusion criteria: not reported

Interventions

Induction therapy

  • Treatment group 1

    • IV CPA: 10 mg/kg monthly for 6 months then 2 monthly for 12 months

  • Treatment group 2

    • IV CPA: 5 mg/kg monthly for 6 months then 2 monthly for 36 months

  • Both groups

    • Oral prednisolone: 1 mg/kg/d for 4 weeks followed by taper to 0.2 mg/kg/d alternate days for 24 months

Maintenance therapy both (groups)

  • Hydroxychloroquine: 200 mg/d for 24 months

  • AZA: 1 mg/kg/d for 24 months

Outcomes

  • Death

  • Doubling of SCr

  • Stable kidney function

  • Major infection

  • Ovarian failure

  • Malignancy

  • Lymphopenia

  • Complete remission of proteinuria: < 0.3 g/24 h with normal serum albumin levels and/or an improvement in the baseline SCr levels of > 50%

  • Partial remission of proteinuria: > 50% reduction in proteinuria, serum albumin levels ≥ 30 g/L, and SCr ≥ 25% from baseline or stable SCr level within 25% of the baseline

  • SCr

  • Daily proteinuria

Notes

  • Funding source: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Study was described as randomised, method of randomisation was not reported

Allocation concealment (selection bias)

Unclear risk

Insufficient information to permit judgement

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Double‐blind study

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Outcome assessor was blinded according to the protocol

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No missing outcome data

Selective reporting (reporting bias)

Low risk

All outcomes on clinicaltrials.gov are reported

Other bias

High risk

Marked differences in clinical characteristics between the groups ‐ median cumulative dose of CPA between the groups, high rates of leucopenia in the low dose compared to the high dose CPA group at baseline

Mok 2016

Methods

  • Study design: open‐label, parallel RCT

  • Study timeframe: 2005 to 2012

  • Duration of follow‐up: median 30 months

Participants

  • Countries: Hong Kong, China

  • Setting: multicentre (number of centres not reported)

  • Inclusion criteria: aged ≥ 18 years; diagnosis of SLE (ACR criteria); biopsy‐proven active lupus class III/IV/ V(ISN/RPS 2003 classification) within 4 weeks; SCr < 2.3 mg/dL

  • Number (randomised/analysed): treatment group 1 (74/74); treatment group 2 (76/76)

  • Mean age ± SD (years): treatment group 1 (36.2 ± 14); treatment group 2 (36.1 ± 13.1)

  • Sex (M/F): treatment group 1 (4/70); treatment group 2 (8/68)

  • Exclusion criteria: refusal to be randomised; preference for treatment with conventional regimens such as CPA; planning for pregnancy within 12 months after randomisation

Interventions

Induction therapy and maintenance therapy

  • Treatment group 1

    • TAC: initial dosage 0.1 mg/kg/d in two divided doses, reduced to 0.06 mg/kg/d if clinical response was satisfactory at month in two divided doses for 6 months

  • Treatment group 2

    • MMF: 2 g/d initially, augmented to up to 3 g/d if clinical response was suboptimal in two divided doses for 6 months

  • Both groups

    • Prednisolone: 0.6 mg/kg/d for 6 weeks then tapered by 5 mg/d every week to < 10 mg/d. At end of intervention, if complete clinical response or good partial response, changed to AZA (2 mg/kg/d) for maintenance. Poor responders re‐induced with oral CPA 2 mg/kg/d

Outcomes

  • Death

  • ESKD

  • Doubling of SCr

  • Stable kidney function

  • Relapse

  • Major infection

  • Herpes zoster virus

  • Diarrhoea

  • Nausea

  • Complete renal remission: stabilisation (within 25%) or improvement in SCr with reduction of proteinuria to < 1 g/d (or UPCR < 1.0), resolution of urinary sediment abnormalities (urine RBC < 5/HPF and absence of cellular casts) and persistent improvement in C3 and anti‐dsDNA levels

  • Partial renal remission: stabilisation (within 25%) or improvement in SCr with persistent reduction of proteinuria (if nephrotic range at baseline, a ≥ 50% decrease in proteinuria but < 3 g/d (or UPCR < 3.0); if non‐nephrotic at baseline, a decrease to ≤ 50% of the pre‐treatment value but > 1 g/d (or UPCR > 1.0) and improvement in urinary sediment abnormalities (≥ 50% reduction in haematuria and urine RBC <10/HPF)

  • Treatment failure: deterioration of SCr (> 25%), an increase in proteinuria, or a reduction in proteinuria but not to the extent of complete renal remission or partial renal remission)

  • Renal flare: proteinuric flare ‐ an increase in proteinuria to more than 2g/d (or UPCR >2.0), with or without deterioration in SCr (< 30%), after a complete remission; or doubling of proteinuria (or UPCR), with or without deterioration in SCr (<30%), in patients who achieved partial remission. Nephrotic flare ‐ an increase or recurrence of active urinary sediments (RBC ≥10/HPF or active cellular casts) with a concomitant increase in proteinuria (or UPCR) or deterioration in SCr (≥30%) after excluding other causes (e.g. sepsis, over diuresis, nephrotoxic agents, renal vein thrombosis)

  • Alopecia

  • Proteinuria

  • CrCl

  • Serum albumin

Notes

  • Funding source: no support from any organisation including industry (Roche and Astella)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Participants were randomised by computer‐generated blocks of four in a 1:1 ratio

Allocation concealment (selection bias)

Unclear risk

Central research assistant was responsible for treatment allocation

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label study

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No missing outcome data

Selective reporting (reporting bias)

Low risk

Study protocol available and pre‐specified outcomes were reported

Other bias

Low risk

The study appears to be free of other sources of bias

Moroni 2006

Methods

  • Study design: open label, parallel RCT

  • Study timeframe (recruitment): March 1999 to March 2001

  • Duration of follow‐up: a least 1 year follow‐up, invited to continue to 4 years

Participants

  • Country: Italy

  • Setting: multicentre

  • Inclusion criteria: aged at least 16 years; diagnosis of SLE (ACR criteria) and biopsy‐proven class IV, Vc or Vd lupus nephritis with a chronicity index of ≤ 4 (WHO classification); patients with a new diagnosis of lupus nephritis or were experiencing a new flare of a previously quiescent disease were enrolled if they had active urine sediment (≥ 5 RBC/HPF); proteinuria > 1 g/d in case of new diagnosis or > 2 g if new renal flare; SCr < 4 mg/dL; after induction therapy those with no major extrarenal signs or symptoms of lupus requiring aggressive therapy; SCr ≤ 1.5 mg/dL, proteinuria > 0.5 g/d; CrCl > 60 mL/min; diastolic BP < 90 mm Hg with a maximum of two antihypertensive drugs and the oral prednisone dose ≤ 0.5 mg/kg/d

  • Number (randomised/analysed): treatment group 1 (36/36); treatment group 2 (33/33)

  • Mean age ± SD (years): treatment group 1 (31.7 ± 9.1); treatment group 2 (31.2 ± 11.7)

  • Sex (M/F): treatment group 1 (3/33); treatment group 2 (4/29)

  • Exclusion criteria: potential silent nephritis; renal diseases unrelated to SLE; treatment with CSA or AZA in the 6 months preceding the screening visit; cumulative CPA dose > 200 mg/kg; any contraindication to the study drugs; previous malignancy

Interventions

Maintenance therapy: duration of therapy was 24 months

  • Treatment group 1

    • CSA: 4 mg/kg/d and reduced to maintenance dose (2.5 to 3.0 mg/kg/d) if proteinuria < 1 g/d, if proteinuria was higher the dose was reduced more slowly

  • Treatment group 2

    • AZA: 2 mg/kg/d optional reduction at 1 month to 1.5 mg/kg/d if proteinuria < 1 g/d and SCr stable

  • Both groups

    • Induction therapy: 3 x IV MP 0.5 g if ≤ 50 kg and 1 g if > 50 kg. followed by prednisolone 1 mg/kg/d for 10 to 15 days then tapered

    • During maintenance therapy both groups received oral prednisone which had to be reduced from 0.5 to 0.2 mg/kg/d by the end of the 6 months, in the case of normal levels of SCr and proteinuria of < 0.5 g/d and in absence of extrarenal symptoms. A further reduction or complete withdrawal could be attempted at the investigators discretion

Outcomes

  1. Death

  2. ESKD

  3. Major infection

  4. Lymphopenia

  5. GI disorders

  6. Complete remission proteinuria

  7. Proteinuria at 2 and 4 years

  8. CrCl at 2 and 4 years

  9. 24 hour proteinuria

  10. Renal flare

Notes

  • Funding source: educational grant from Novartis Pharma AG

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomisation according to a coin‐based design

Allocation concealment (selection bias)

Low risk

Stratified by centre and performed centrally. Phone calls to randomisation centre‐computer program assigned participants

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label study

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Blinded endpoint study

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No missing outcome data

Selective reporting (reporting bias)

Low risk

Study protocol available and pre‐specified outcomes were reported

Other bias

High risk

Sponsor included in data management and analysis: Novartis Pharma and authorship

Mulic‐Bacic 2008

Methods

  • Study design: open‐label, parallel RCT

  • Study timeframe: not reported

  • Duration of follow‐up: 24 weeks

Participants

  • Country: Bosnia Herzegovina

  • Setting: not reported

  • Inclusion criteria: active lupus nephritis class III, IV or V (WHO classification criteria)

  • Number (randomised/analysed): treatment group 1 (20/20); treatment group 2 (25/25)

  • Mean age ± SD (years): not reported

  • Sex (M/F): not reported

  • Exclusion criteria: not reported

Interventions

Induction therapy: duration of therapy was 24 months

  • Treatment group 1

    • MMF: 2 g/d for 6 months then 1 g/d for 18 months, administer orally

  • Treatment group 2

    • IV CPA: 0.5 g/m2 monthly

  • Both groups

    • Prednisolone: 0.75 to 1 mg/kg/d with determined tapering

Outcomes

  • Death

  • Stable kidney function

  • Complete remission proteinuria

  • Partial remission proteinuria

  • Complete remission: normalisation of abnormal renal measurements and maintenance of baseline normal measurements

  • Partial remission

Notes

  • Abstract‐only publication

  • Funding source: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Study was described as randomised, method of randomisation was not reported

Allocation concealment (selection bias)

Unclear risk

Insufficient information to permit judgement

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label study

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No missing outcome data

Selective reporting (reporting bias)

High risk

Not all expected clinical outcomes reported and no protocol available; abstract‐only publication

Other bias

Unclear risk

Abstract‐only publication; insufficient information to permit judgement

MyLupus 2011

Methods

  • Study design: open‐label, parallel RCT

  • Study timeframe: February 2007 to November 2009

  • Duration of follow‐up: 6 months

Participants

  • Countries: France, Germany, Italy, Spain, UK, Hungary, Greece, Colombia, Taiwan

  • Setting: multinational (19 sites)

  • Inclusion criteria: aged ≥ 18 years, (i) diagnosis of SLE (ACR criteria); biopsy‐proven (within previous 24 months) proliferative lupus nephritis (class III or IV) (ISN/RPS 2003 classification criteria); proteinuria defined as UPCR > 0.5 at screening and baseline; and clinical activity defined by one or more of the following: SCr > 1 mg/dL; microscopic haematuria (> 5 RBC/HPF) and presence of cellular casts

  • Number (randomised/analysed): treatment group 1 (42/42); treatment group 2 (39/39)

  • Mean age ± SD (years): treatment group 1 (32.2 ± 8.5); treatment group 2 (34.2 ± 10.7)

  • Sex (M/F): treatment group 1 (5/37); treatment group 2 (10/29)

  • Exclusion criteria: CrCl < 30 mL/min; IV glucocorticoids, oral or IV CPA or MMF during the previous 3 months; antibody therapy within the previous 6 months

Interventions

Induction therapy: duration of therapy was 6 months

  • Treatment group 1

    • Standard dose EC‐MPS

    • Prednisolone: 1 mg/kg/d

  • Treatment group 2

  • Reduced dose EC‐MPS

  • Prednisolone: 0.5 mg/kg/d

  • Both groups

    • MP: 0.5 g IV/d for 3 days

    • EC‐MPS started at 1440 mg/d for first 2 weeks then 2160 mg in remaining 22 weeks

    • Prednisolone tapered in both groups according to guidelines

Outcomes

  • Death

  • Infection

  • Herpes zoster virus infection

  • Vomiting

  • Diarrhoea

  • Complete remission: UPCR < 0.5 with normalised urine sediment and SCr within 10% of normal value

  • Partial remission: reduction in UPCR of 50% compared with baseline, and SCr improved or stable (i.e. within 10% of baseline value)

  • Renal flare: A mild SLE flare was diagnosed if SLE increased after partial or complete response, defined as the presence of 1 or 2 BILAG B scores and no A scores and intention by the investigator to increase the glucocorticoid dose; a moderate to severe SLE flare was diagnosed if increased lupus activity after partial or complete response resulted in 1 BILAG A score or 3 BILAG B scores

  • UPCR

  • Creatinine

Notes

  • Funding source: Novartis Pharma AG

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Study was described as randomised, method of randomisation was not reported

Allocation concealment (selection bias)

High risk

Insufficient information to permit judgement

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label study

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No missing outcome data

Selective reporting (reporting bias)

High risk

Not all expected outcomes were reported

Other bias

High risk

Novartis Pharma AG funded. Sponsor involved in authorship, Disclosure of consulting fees from Novartis Pharma, Amgen, BMS and Roche

Nakamura 2002e

Methods

  • Study design: open‐label, parallel RCT

  • Study timeframe: not reported

  • Duration of follow‐up: 6 months

Participants

  • Country: Japan

  • Setting: not reported

  • Inclusion criteria: diagnosis of SLE (ACR criteria); biopsy‐proven diffuse proliferative, class IV lupus nephritis (WHO classification criteria); oral corticosteroid with or without cytotoxic drugs for at least 6 months with treatment resistance

  • Number (randomised): treatment group 1 (10); treatment group 2 (10)

  • Mean age (years): treatment group 1 (30.5); treatment group 2 (29.5)

  • Sex (M/F): treatment group 1 (2/8); treatment group 2 (2/8)

  • Exclusion criteria: not reported

Interventions

Induction therapy: duration of therapy was 6 months

  • Treatment group 1

    • PEX: double filtration 1 to 2 weekly

  • Treatment group 2

    • IV CPA: 0.75 to 1.0 g/m2 once a month for 6 months

  • Both groups

  • Oral prednisone (or equivalent): 1 mg/kg/d tapered to the minimum dose needed to control extrarenal diseases

Outcomes

  • Proteinuria

  • Urinary podocyte number

Notes

  • Funding source: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Study was described as randomised, method of randomisation was not reported

Allocation concealment (selection bias)

Unclear risk

Insufficient information to permit judgement

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label study

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Selective reporting (reporting bias)

High risk

Not all expected outcomes were reported

Other bias

Low risk

The study appears to be free of other sources of bias

Ong 2005

Methods

  • Study design: open‐label, parallel RCT

  • Study timeframe: January 2001 to December 2002

  • Duration of follow‐up: 6 months

Participants

  • Country: Malaysia

  • Setting: multicentre (8 sites)

  • Inclusion criteria: aged > 16 years; diagnosis of SLE (ACR criteria); class III or IV lupus nephritis (WHO classification criteria)

  • Number (randomised/analysed): treatment group 1 (28/25); treatment group 2 (26/19)

  • Mean age ± SD (years): treatment group 1 (30.5 ± 8.7); treatment group 2 (31.3 ± 9.9)

  • Sex (M/F): treatment group 1 (3/23); treatment group 2 (4/15)

  • Exclusion criteria: SCr > 200 µmol/L, WCC < 3.5 x 109/L; major infection; history of cancer; alcohol or substance misuse; pregnancy; active peptic ulcer disease; allergy to MMF or CPA; use of study drugs in preceding 6 months

Interventions

Induction therapy: duration of therapy was 6 months

  • Treatment group 1

    • IV CPA: 0.75 to 1 g/m2 monthly for 6 months

  • Treatment group 2

    • MMF: 1 g orally twice daily for 6 months

  • Both groups

    • Prednisolone: 60 mg/d for 4 to 6 weeks then tapering dose to 5 to 10 mg/d

Outcomes

  • Death

  • ESKD

  • Stable kidney function

  • Major infection

  • Herpes zoster virus

  • Leucopenia (< 3.5 x 109/L)

  • Oligomenorrhoea

  • GI side effects

  • Complete renal remission: stabilisation or improvement in kidney function, RCC < 10, proteinuria < 3 g

  • Combined partial remission: stabilisation or improvement in kidney function, RCC < 10, proteinuria < 3 g if was > 3 g or at least 50% reduction or < 1.0 g if subnephrotic

  • Proteinuria

Notes

  • Funding source: not reported; MMF supplied by Roche Malaysia

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomisation code generated separately for each centre using random permutated block method with randomly varying block size (1:1)

Allocation concealment (selection bias)

Low risk

Randomisation performed centrally

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label study

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No missing outcome data

Selective reporting (reporting bias)

Low risk

Study protocol available and pre‐specified outcomes were reported

Other bias

Low risk

The study appears to be free of other sources of bias

Pal 2017

Methods

  • Study design: open‐label, parallel RCT

  • Study timeframe: not reported

  • Duration of follow‐up: not reported

Participants

  • Country: India

  • Setting: not reported

  • Inclusion criteria: lupus nephritis class III and IV or III/IV + V

  • Number (randomised/analysed): 58 (number per group not reported)

  • Mean age ± SD (years): not reported

  • Sex (M/F): not reported

  • Exclusion criteria: not reported

Interventions

Induction therapy: duration of therapy not reported

  • Treatment group 1

    • Oral TAC: 0.75 mg/kg

    • Oral AZA: 2 mg/kg

  • Treatment group 2

    • IV CPA: 500 mg/m2 monthly

  • Both groups

    • MP: 3 pulsed doses and subsequently, prednisolone was given at doses of 0.5 mg/kg/d for the next 1 month and then tapered as tolerated to 10 mg or less by 3 months

Outcomes

  • Complete renal remission

  • Partial renal remission

  • Daily proteinuria

  • Adverse events

  • Disease activity

Notes

  • Abstract‐only publication

  • Funding source: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Study was described as randomised, method of randomisation was not reported

Allocation concealment (selection bias)

Unclear risk

Insufficient information to permit judgement

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Likely to be an open‐label study

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Selective reporting (reporting bias)

High risk

Not all expected outcomes have been reported

Other bias

Unclear risk

Abstract‐only publication; insufficient information to permit judgement

Rathi 2016

Methods

  • Study design: open‐label, proof‐of‐concept RCT

  • Study timeframe: not reported

  • Duration of follow‐up: 6 months

Participants

  • Country: India

  • Setting: single centre

  • Inclusion criteria: aged 12 to 65 years; diagnosis of SLE (ACR criteria); biopsy‐proven class III, IV, V, III+V, or IV+V lupus nephritis (ISN/RPS 2003 classification criteria)

  • Number (randomised/analysed): treatment group 1 (50/50); treatment group 2 (50/50)

  • Mean age ± SD (years): treatment group 1 (30.6 ± 9.5); treatment group 2 (28.3 ± 9.5)

  • Sex (M/F): treatment group 1 (5/45); treatment group 2 (3/47)

  • Exclusion criteria: crescentic lupus nephritis (> 50% crescents in biopsy); SCr of > 265 μmol/L; neurological or pulmonary lupus; ongoing infection; pregnancy; prior treatment with CPA or MMF

Interventions

Induction therapy

  • Treatment group 1

    • IV CPA: 6 fixed doses 0.5 g administered fortnightly; duration of therapy was 3 months

  • Treatment group 2

    • Oral MMF: initiated at a dose of 0.5 g twice a day and increased every 2 weeks to achieve a target dose of 1.5–3.0 g/d; duration of therapy was 6 months

  • Both groups

  • IV MP: 3 daily boluses (0.75 g each) at the beginning of treatment followed by oral prednisolone (1 mg/kg/d) for 8 weeks and subsequent tapering

  • Hydroxychloroquine: 6 mg/kg, single daily dose

  • ACEi or ARB

Maintenance therapy

  • At the end of induction therapy patients received maintenance therapy AZA (2 mg/kg) and prednisolone (5 to 7.5 mg/d)

Outcomes

  • Death

  • Complete remission: return to normal SCr along with proteinuria ≤ 0.5 g/d and inactive urine sediment

  • Partial remission: defined as treatment response, as a decrease in the UPCR to < 3 in subjects with a baseline ratio ≥ 3 or a decrease in UPCR by ≥ 50% in those with a baseline ratio < 3, along with stabilisation or improvement in SCr (a 24‐week SCr level within 25% of baseline).

  • Herpes zoster virus infection

  • Ovarian failure

  • Alopecia

  • Leucopenia

Notes

  • Funding source: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Study was described as randomised, method of randomisation was not reported

Allocation concealment (selection bias)

Unclear risk

Insufficient information to permit judgement

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label study

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Selective reporting (reporting bias)

Low risk

Study protocol available from Indian clinical trials registry and pre‐specified outcomes were reported

Other bias

High risk

High dropout rate; baseline characteristics different between the two groups with UPCR significantly higher in the CPA group

Rovin 2016

Methods

  • Study design: double‐blind, parallel, proof‐of‐concept RCT

  • Study timeframe: not reported

  • Duration of follow‐up: placebo mean 40.1 weeks; sirukumab mean 36.1 weeks

Participants

  • Countries: 6 (countries not reported)

  • Setting: multinational (18 sites)

  • Inclusion criteria: adults (18 to 70 years); diagnosis of SLE (ACR or SLICC criteria), including seropositivity for ANA and/or anti‐ds DNA autoantibodies; biopsy‐proven (within 14 months of randomisation) Class III or IV lupus nephritis (ISN/RPS 2003 classification criteria), and persistently active (proteinuria > 0.5 g/d or at least one of the following criteria: haematuria (≥ 5 RBC/HPF), anti‐dsDNA‐positive test, or C3 or C4 complement levels below the lower limit of normal; plus disease despite standard‐of‐care induction and maintenance immunosuppressive treatment

  • Number (randomised/analysed): treatment group (21/21); control group (4/4)

    • Treatment group: class III (7); class IV (14)

    • Control group: class III (2); class IV (2)

  • Mean age ± SD (years): treatment group (30.6 ± 7.7); control group (37.8 ± 11.4)

  • Sex (M/F): treatment group (4/17); control group (0/4)

  • Exclusion criteria: received CPA within 3 months of randomisation; unless intolerant, patients were required to be on a stable dose of an ACEi and/or an ARB; poorly controlled hypertension (mean SBP >150 mm Hg) or a pattern of worsening or unstable kidney disease during the 8‐week screening period

Interventions

Induction therapy: duration of therapy was 6 months

  • Treatment group

    • Sirukumab (IL‐6 antibody): 10 mg/kg administered IV every 4 weeks

  • Control group

    • Placebo: administered IV every 4 weeks

  • Both groups

    • MMF (1 to 3 g/d; or the equivalent dose of mycophenolic acid/mycophenolate sodium) or AZA (1 to 3 mg/kg/d), with or without oral corticosteroids (≤ 20 mg/d prednisone or equivalent)

Outcomes

  • Death

  • Major infection

  • Malignancy

  • Diarrhoea

  • Kidney function

Notes

  • Funding source: Janssen Research & development LLC

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Study was described as randomised, method of randomisation was not reported

Allocation concealment (selection bias)

Unclear risk

Insufficient information to permit judgement

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Double‐blind, placebo‐controlled study

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No missing outcome data

Selective reporting (reporting bias)

High risk

Not all pre‐specified outcomes were reported

Other bias

High risk

Marked differences (demographics and clinical characteristics) between groups at baseline. Sponsor involved in authorship

Sabry 2009

Methods

  • Study design: quasi‐RCT

  • Study timeframe: not reported

  • Duration of follow‐up: 1 year

Participants

  • Country: Egypt

  • Setting: single centre

  • Inclusion criteria: ACR criteria for SLE; ≥ 18 years; biopsy‐proven proliferative lupus nephritis (WHO class IV), urine protein > 0.5 g/d

  • Number (randomised/analysed): treatment group 1 (26/26); treatment group 2 (20/20)

  • Mean age ± SD (years): treatment group 1 (26.4 ± 9); treatment group 2 (25.7 ± 7)

  • Sex (M/F): treatment group 1 (4/22); treatment group 2 (2/18)

  • Exclusion criteria: CSA or AZA in previous year or > 15 mg/d prednisolone in previous month; renal thrombotic microangiopathy; pre‐existing CKD; pregnancy; previous malignancy; DM, documented toxicity; anticipated poor compliance

Interventions

Induction therapy: duration of therapy was 12 months

  • Treatment group 1

    • High dose CPA: 6 x monthly pulses + 2 x quarterly pulses. Initial dose (0.5 g/1.73 m2) then dose increased by 250 mg according to WCC on day 14 with final increment to maximum dose of 1 g/1.73m2

  • Treatment group 2

    • Low dose CPA: 6 x monthly pulses + 2 x quarterly pulses fixed dose of 0.5 g/d

  • Both groups

    • Prednisolone (0.5 mg/kg) and AZA (2 mg/kg/d) given in both treatment arms. Prednisolone given at high dose for 4 weeks then given alternate days after being tapered by 5 mg each week to minimal dose to control extrarenal SLE manifestations or 0.25 mg/kg/d. AZA started 2 weeks after last infusion and continued until the end of the study

Outcomes

  • Death

  • ESKD

  • Doubling of SCr

  • Relapse: defined by a doubling of the urinary protein excretion or by an increase in the SCr level by 50% or more for more than 1 month

  • Treatment failure: defined as urinary protein excretion ≥ 3 g/24 h; and/or doubling of SCr or severe flare that was resistant to increased glucocorticoid dose; patients who did not meet complete or partial remission criteria were considered as having treatment failure

  • Major infection

  • Ovarian failure

  • Anaemia

  • Leucopenia

  • GI side effects

  • Proteinuria

  • SCr

  • Serum albumin

Notes

  • Six participants with most severe form of lupus nephritis allocated to high‐dose arm

  • Funding source: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

High risk

All participants meeting inclusion criteria randomised. Manual randomisation to allocate every other patient to either group and then assigned to one of 2 regimens. Six participants with most severe form of lupus nephritis allocated to high dose arm

Allocation concealment (selection bias)

High risk

Use of alternation to allocate

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No missing outcome data

Selective reporting (reporting bias)

Unclear risk

No study protocol available, all expected outcomes were reported

Other bias

Unclear risk

Differences in baseline characteristics between the groups (more severe proteinuria and lower serum albumin in high dose CPA

Sedhain 2016

Methods

  • Study design: open‐label, parallel RCT

  • Study timeframe: January 2014 to June 2015

  • Duration of follow‐up: 6 months

Participants

  • Country: Nepal

  • Setting: single centre

  • Inclusion criteria: biopsy‐proven proliferative lupus nephritis

  • Number (randomised/analysed): 49/42; treatment group 1 (21); treatment group 2 (21)

  • Mean age ± SD (years): not reported

  • Sex (M/F): not reported

  • Exclusion criteria: not reported

Interventions

Induction therapy: duration of therapy was 6 months

  • Treatment group 1

    • MMF: administered orally daily

  • Treatment group 2

    • IV CPA: administered monthly

Outcomes

  • Complete remission: normal SCr and proteinuria ≤ 0.5 g/d

  • Partial remission

  • Treatment failure: no response to therapy

  • Proteinuria

Notes

  • Abstract‐only publication

  • Funding source: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Study was described as randomised, method of randomisation was not reported

Allocation concealment (selection bias)

Unclear risk

Insufficient information to permit judgement

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label study

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Insufficient information to provide judgement

Selective reporting (reporting bias)

Unclear risk

Insufficient information to provide judgement

Other bias

High risk

Characteristics of the six patients unable to complete the study period are not provided and these patients were not included in the analysis; abstract‐only publication

Sesso 1994a

Methods

  • Study design: parallel RCT

  • Study timeframe: September 1990 to December 1992

  • Duration of follow‐up: 15 months

Participants

  • Country: Brazil

  • Setting: single centre

  • Inclusion criteria: aged ≥ 16 years; diagnosis of SLE (ARA criteria); severe lupus nephritis (defined as nephritic urine sediment or urinary protein of > 3.0 g/d and impaired kidney function (CrCl < 80 mL/min or a recent reduction of at least 30%); if CrCl was stable the patient had to have histology of diffuse proliferative GN (WHO classification criteria); 23/29 diffuse proliferative lupus nephritis

  • Number (randomised): treatment group 1 (14); treatment group 2 (15)

  • Mean age ± SE (years): treatment group 1 (30.0 ± 2.7); treatment group 2 (24.3 ± 1.5)

  • Sex (M/F): treatment group 1 (2/12); treatment group 2 (2/13)

  • Exclusion criteria: CrCl < 20 mL/min; SCr > 6 mg/dL; major infection within 2 weeks of study entry; pregnancy; low leucocyte count; pulse MP or CPA within 1 year

Interventions

Induction therapy: duration of therapy was 10 months

  • Treatment group 1

    • IV CPA: 0.5 to 1.0 g/m2, monthly pulse for 4 months, bimonthly for 4 months then quarterly for 6 months

  • Treatment group 2

    • IV MP: 10 to 20 mg/kg; max 1.0 g x 3 daily, then monthly for 4 months, bimonthly for 4 months then quarterly for 6 months

  • Both groups

    • Low dose oral prednisolone: 0.5 mg/kg/d initially then tapered to control extra‐renal manifestations

Outcomes

  • Death

  • ESKD

  • Doubling of SCr

  • Bone toxicity

  • Bladder toxicity

  • Malignancy

  • Major infection

  • Proteinuria

  • Complete remission: improvement of SCr and of urine sediment or proteinuria

  • Partial remission: trend of improvement of SCr and of urine sediment or proteinuria

  • Relapse: worsening of urine sediment, proteinuria and kidney function after having reached initial improvement with therapy, requiring reinstitution of therapy

Notes

  • 2 participants lost to follow‐up

  • Funding source: Instituto Paulista de Estudos e Pesquisas em Nefrologia e Hipertensao

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Study was described as randomised, method of randomisation was not reported

Allocation concealment (selection bias)

Unclear risk

Insufficient information to permit judgement

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No missing outcome data

Selective reporting (reporting bias)

Low risk

All expected outcomes were reported

Other bias

High risk

Proteinuria between groups at baseline was different

SIMPL 2014

Methods

  • Study design: double‐blind, pilot RCT

  • Study timeframe: not reported

  • Duration of follow‐up: 36 months

Participants

  • Country: Canada

  • Setting: single‐centre

  • Inclusion criteria: aged ≥ 18 years; had a history of SLE according to ACR criteria; class III or class IV or class III/IV + V lupus nephritis by the ISN/RPS classification criteria; must have had an index biopsy within the 3 years previous to study enrolment, and could have been induced with CPA, MMF or another immunosuppressant as seen as appropriate by their physician; to be in at least partial remission at the time of randomisation, defined as having a) 0.3 to 2.9 g/d proteinuria, b) serum albumin at least 30 g/L and c) stable kidney function), be receiving between 5 and 20 mg/d of prednisone and provide informed consent

  • Number (randomised/analysed): treatment group 1 (7/7); treatment group 2 (8/8)

    • Treatment group 1: class III (1), class IV (6), class V (5)

    • Treatment group 2: class III (3), class IV (4), class V (3)

  • Mean age ± SD (years): treatment group 1 (28.4 ± 5.6); treatment group 2 (39.2 ± 12.8)

  • Sex (M/F): treatment group 1 (0/7); treatment group 2 (2/6)

  • Exclusion criteria: pregnant; required prednisone for treatment of another medical condition other than SLE; were receiving or expected to receive RRT within the next 6 months

Interventions

Maintenance therapy: duration of therapy was 36 months

  • Treatment group 1

    • Prednisone withdrawal: tapered the dose of prednisone contained in the capsules at a rate of 5 mg/d every 2 weeks until the dose was 10 mg/d, then by 2.5 mg/d every 2 weeks until the dose was 5 mg/d and then by 1 mg/d every 2 weeks until no prednisone and only placebo was contained in the capsules. A capsule containing placebo only was then continued for the duration of the study.

  • Treatment group 2

    • Prednisone: Low‐dose maintenance glucocorticoids were tapered from their steroid dose at the time of randomisation, if necessary, to a target dose of 7.5 mg/d using the same algorithm as the prednisone withdrawal group. Patients who were already on 5 to 7.5 mg/d of prednisone therapy were maintained on their current dose with no changes made to the dose

  • Both groups

    • Hydroxychloroquine, and antihypertensives, NSAIDs and statins were left to the discretion of the patient's usual care providers. Vitamin D and calcium were recommended for all patients in the study as osteoporosis prophylaxis

Outcomes

  • Relapse (composite of renal and major non‐renal flare)

    • Renal flare: defined as the occurrence of any one of the three following events: (1) Increased proteinuria, measured by either 24 hour urine collection or by a urine protein to creatinine ratio, by at least a) 1 g/d if the baseline proteinuria was less than 0.2 g/d or, b) 2 g/d if the baseline proteinuria was between 0.2 and 1 g/d (inclusive), or c) more than double the baseline proteinuria if the baseline proteinuria was greater than 1 g/d; (2) A sustained (i.e. for two consecutive measures) increase in SCr by at least 30% over baseline that was not due to institution of antihypertensive therapy or angiotensin converting enzyme inhibitor therapy and with new haematuria attributable to active SLE; (3) New sustained haematuria attributable to active SLE, and exclusive of menses, infection or medications, that was associated with an increase in proteinuria by at least 0.8 g/d)

    • Major non‐renal flare

  • Major infection

  • Quality of life: SF‐36

Notes

  • 2 participants lost to follow‐up

  • Funding source: centre for Advancement of Health, Calgary

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"Patients were randomly allocated to either the prednisone or placebo group using a random number list generated by an independent statistician. Randomization was blocked and stratified according to the duration of steroid treatment at the time of enrollment (≤12 months or >12 months) and remission status (partial or complete)."

Allocation concealment (selection bias)

Low risk

"Allocation was concealed using sealed, opaque, sequentially numbered envelopes maintained by an independent physician. When a participant was randomised, the independent physician faxed the study number and assigned treatment to the study pharmacy."

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Double‐blind study "Patients, investigators, care providers and data analysts remained blinded to study treatment throughout the trial."

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

"Patients, investigators, care providers and data analysts remained blinded to study treatment throughout the trial."

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No missing outcome data

Selective reporting (reporting bias)

High risk

All prespecified outcomes are reported, but not all expected outcomes are reported

Other bias

High risk

Pilot study ‐ underpowered

Steinberg 1971

Methods

  • Study design: double‐blind, parallel RCT

  • Study timeframe: not reported

  • Duration of follow‐up: 10 weeks

Participants

  • Country: USA

  • Setting: single centre

  • Inclusion criteria: diagnosis of SLE (ARA criteria); a positive lupus erythematosus cell test in the course of the disease; kidney disease unaccounted for by other pathological processes, with at least one of the following: RBC casts in a fresh centrifuged urine sediment; cellular casts and either haematuria (≥ 20 RBC/HPF) or pyuria (e≥ 20 WBC/HPF); proteinuria ≥ 1 g/24 h; CrCl < 50 mL/min; 8/15 diffuse proliferative lupus nephritis

  • Number (randomised/analysed): treatment group (7/9); control group (6/6)

  • Mean age, range (years): treatment group (23, 11 to 36); control group (23, 11 to 36)

  • Sex (M/F): treatment group (0/7); control group (2/6)

  • Exclusion criteria: major infection within the preceding 2 weeks; pregnancy; granulocyte count < 1500/mm3, immunosuppressive therapy within 3 months; severe liver disease

Interventions

Induction therapy: duration of treatment was 10 weeks

  • Treatment group

    • Oral CPA: initial dose of 3 mg/kg/d could be increased to 4 mg/kg/d after 2 weeks

    • Prednisone: 30 mg/d

  • Control group

    • Prednisone: 30 mg/d

  • Both groups

    • Aspirin: 30 mg/d

Outcomes

  • Death

  • Toxicity

  • Alopecia

  • Complete remission of proteinuria

  • Relapse: major SLE flare (criteria not reported)

  • Proteinuria

  • CrCl

Notes

  • 2 participants crossed‐over to CPA therapy following placebo treatment period and were included in the analysis for CPA

  • Funding source: Drug and placebo were supplied through the kindness of Dr Martin E. Vancif, Mead Johnson Laboratories, Evansville, Ind

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Used consecutively numbered envelopes, each containing a randomly assigned prescription for placebo or CPA

Allocation concealment (selection bias)

Low risk

As each patient entered the study, the next sequential envelope was opened in the pharmacy

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Double‐blind study

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No missing outcome data

Selective reporting (reporting bias)

Low risk

Study protocol available and pre‐specified outcomes were reported

Other bias

High risk

Cross‐over of two participants from the placebo to CPA arm were included in the analysis

Sun 2015

Methods

  • Study design: open‐label, parallel RCT

  • Study timeframe: September 2007 to February 2012

  • Duration of follow‐up: 6 months

Participants

  • Country: China

  • Setting: single centre

  • Inclusion criteria: aged 14 to 60 years; SLEDAI ≥ 12; renal‐biopsy‐proven diffuse segment or global (IV‐s of IV‐G) lupus nephritis (ISN/RPS 2003 classification criteria)

  • Number (randomised/analysed): treatment group 1 (40/40); treatment group 2 (42/42)

  • Mean age ± SD (years): treatment group 1 (33.3 ± 11); treatment group 2 (31.9 ± 8.7)

  • Sex (M/F): treatment group 1 (3/37); treatment group 2 (4/38)

  • Exclusion criteria: complicated by uncontrolled severe infections or neuropsychiatric SLE; abnormal liver or kidney function (defined as > 2 times of the normal values of transaminases or > 265.2 μmol/L of SCr level); patients with < 3×109/L of WBC or < 50×109/L of platelets; patients who received any cytotoxic or immunosuppressive drugs like CPA, TAC, MMF, or CSA within 3 months; pregnant or lactating women; patients with cerebrovascular disease, glucose metabolism disorder, or severe cardiopulmonary dysfunction

Interventions

Induction therapy: duration of therapy was 6 months

  • Treatment group 1

    • IV CPA: monthly dose of 0.75 g/m2

  • Treatment group 2

    • IV CPA: monthly dose of 0.4 g/m2

    • Oral MMF: 1.0 g/d

  • Both groups

  • Prednisolone was started at a daily dose of 1.0 mg/kg for both groups, and then the dose was reduced gradually after 4 to 8 weeks until completion of the treatment

Outcomes

  1. Death

  2. Major infection

  3. Leucopenia: WCC < 4000/mm3

  4. Complete remission: < 0.3 g/24 h proteinuria with ≥ 35 g/L of serum albumin and normal SCr level

  5. Partial remission: proteinuria range 0.3 to 2.9 g/24 h with an albumin concentration of ≥ 30 g/L, stable or improved kidney function with reduction of proteinuria by > 50%

  6. Serum albumin

  7. Proteinuria

Notes

  • Funding source: This study was in part supported by the Natural Science Foundation of Hunan Province (No. 13JJ3033)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Study was described as randomised, method of randomisation was not reported

Allocation concealment (selection bias)

Unclear risk

Insufficient information to permit judgement

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label study

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No missing outcome data

Selective reporting (reporting bias)

Low risk

No study protocol available but expected outcomes are reported

Other bias

Low risk

The study appears to be free of other sources of bias

Wallace 1998

Methods

  • Study design: open‐label, parallel RCT

  • Study timeframe: not reported

  • Duration of follow‐up: > 24 months

Participants

  • Country: USA

  • Setting: single centre

  • Inclusion criteria: diagnosis of SLE (ACR criteria); aged ≥ 16 years; class III or IV lupus nephritis on renal biopsy and chronicity index < 6; 2/19 class IV

  • Number (randomised): treatment group 1 (9); treatment group 2 (9)

  • Mean age ± SD (years): treatment group 1 (33.0 ± 10.0); treatment group 2 (32.0 ± 14.0)

  • Sex (M/F): treatment group 1 (1/8); treatment group 2 (0/9)

  • Exclusion criteria: SCr > 3 mg/dL; renal biopsy chronicity index ≥ 6; pregnancy; < 16 years; immunosuppression in last 3 months

Interventions

Induction therapy: duration of treatment was 8 months

  • Treatment group 1

    • PEX: 3 x daily preceding CPA

    • IV CPA: (750 mg/m2 x 6)

  • Treatment group 2

  • IV CPA: 750 mg/m2 x 6 over 8 months

  • Both groups

    • Prednisolone: 1 mg/kg/d for 6 weeks then tapering dose

Outcomes

  • Death

  • ESKD

  • Complete remission: SCr < 1.4 mg/dL, a 24‐h urine protein < 500 mg, absence of urinary casts; normal BP and serum albumin > 4.0 mg/dL

  • SCr

  • Serum albumin

  • Proteinuria

Notes

  • 1 patient lost to follow‐up

  • Funding source: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Study was described as randomised, method of randomisation was not reported

Allocation concealment (selection bias)

Unclear risk

Insufficient information to permit judgement

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label study

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No missing outcome data

Selective reporting (reporting bias)

High risk

Not all expected outcomes were reported

Other bias

Low risk

The study appears to be free of other sources of bias

Yap 2017

Methods

  • Study design: parallel RCT

  • Study timeframe: not reported

  • Duration of follow‐up: 6 months

Participants

  • Country: Hong Kong

  • Setting: not reported

  • Inclusion criteria: active lupus nephritis

  • Number (randomised): treatment group 1 (7); treatment group 2 (7)

  • Mean age ± SD (years): not reported

  • Sex (M/F): not reported

  • Exclusion criteria: not reported

Interventions

Induction therapy: duration of treatment was 6 months

  • Treatment group 1

    • MMF: no details provided

  • Treatment group 2

    • CPA: no details provided

  • Both groups

    • Prednisone or prednisone equivalent: no details provided

Outcomes

  • Immunological function

Notes

  • Funding source: Bristol Myers Squibb

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Study was described as randomised, method of randomisation was not reported

Allocation concealment (selection bias)

Unclear risk

Insufficient information to permit judgement

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Selective reporting (reporting bias)

High risk

Not all relevant clinical outcomes reported

Other bias

Unclear risk

Insufficient information to permit judgement; abstract‐only publication

Yee 2004

Methods

  • Study design: open label, parallel RCT

  • Study timeframe: June 1992 to May 1996

  • Duration of follow‐up: intended to be 5 to 10 years

Participants

  • Countries: Austria, Czech Republic, Lithuania, Slovenia, Sweden, UK

  • Setting: multinational (8 sites)

  • Inclusion criteria: diagnosis of SLE (ACR criteria); biopsy‐proven proliferative lupus nephritis (WHO classification criteria), aged 16 to 65 years

  • Number (randomised/analysed): treatment group 1 (16/13); treatment group 2 (16/16)

    • Treatment group 1: class III (6), class IV (10)

    • Treatment group 2: class III (5), class IV (8)

  • Mean age ± SD (years): treatment group 1 (42.4 ± 11.8); treatment group 2 (32.2 ± 11.7)

  • Sex (M/F): treatment group 1 (2/11); treatment group 2 (2/14)

  • Exclusion criteria: previous CPA or AZA in preceding 3 weeks; pure membranous or mesangial proliferative GN on biopsy; previous treatment with CPA for > 3 months; allergy to study drugs; previous malignancy; primary immunodeficiency (except complement components); non‐lupus‐related kidney disease

Interventions

Induction therapy: duration of treatment was 24 months

  • Treatment group 1

    • Intermittent IV CPA: 10 mg/kg 3 x/wk, max 1 g for 4 doses, then orally (same dose split over 2/7) 4 weekly for 9 months and 6 weekly for 12 months

    • IV MP 6.6 mg/kg before each pulse of CPA then orally at same dose split over 2 days before each oral dose plus oral prednisolone 0.3 mg/kg/d reducing to 0.1 mg/kg/d to maintenance dose of 0.05 to 0.1 mg/kg/d

  • Treatment group 2

    • Oral CPA: 2 mg/kg/d for 3 months then 1.5 mg/kg/d

    • Oral prednisolone: 0.85 mg/kg/d (max dose 60 mg) reducing to 0.11 mg/kg/d by week 53

  • Both groups

    • H2 receptor antagonist (ranitidine 150 mg at night or cimetidine 400 mg at night) and amphotericin lozenges (10 mg four times a day) as prophylaxis while on daily CPA and for two weeks with each pulse of CPA

Outcomes

  • Death

  • ESKD

  • Doubling of SCr

  • Major infection

  • Ovarian failure

  • Malignancy

  • Bladder toxicity

  • Nausea/vomiting

  • Treatment failure: failure to respond to treatment

Notes

  • Study terminated after 4 years due to poor recruitment and high withdrawal rate

  • Funding source: European League Against Rheumatism (EULAR) Standing Committee on International Clinical Studies including Therapeutic Trials (ESCIST); Lupus UK; and the Swedish Medical Research Council (grant 13489).

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Participants were stratified according to the presence of kidney failure and underwent block randomisation to either therapy

Allocation concealment (selection bias)

Unclear risk

Insufficient information to permit judgement

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label study

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No missing outcome data

Selective reporting (reporting bias)

High risk

Not all pre‐specified outcomes reported: alopecia

Other bias

High risk

Study was terminated after four years as patient recruitment was disappointing and many patients had been withdrawn; Many physicians became reluctant to enter patients because of concerns that the oral regimen was slower to work and more toxic than the pulse regimen, following development of severe neutropenia in the continuous group; This led to the premature termination of the study

Zhang 1995a

Methods

  • Study design: open‐label, parallel RCT

  • Study timeframe: not reported

  • Duration of follow‐up: 12 to 39 months

Participants

  • Country: China

  • Setting: single centre

  • Inclusion criteria: biopsy‐proven active lupus nephritis

  • Number (randomised): 36 (numbers per group not reported)

  • Mean age ± SD (years): not reported

  • Sex (M/F): not reported

  • Exclusion criteria: not reported

Interventions

Induction therapy

  • Treatment group 1

    • CPA: monthly pulse 0.5 to 0.8 g/m2 until remission

  • Treatment group 2

    • CPA: monthly pulse 0.5 to 0.8 g/m2 for 1 year

  • Both groups

    • Minimum necessary dose of steroids

Outcomes

  • Remission

  • Relapse

  • Urinalysis

  • Serology

Notes

  • Abstract‐only publications

  • Funding source: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Study was described as randomised, method of randomisation was not reported

Allocation concealment (selection bias)

Unclear risk

Insufficient information to permit judgement

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label study

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Insufficient information to permit judgement

Selective reporting (reporting bias)

High risk

Data unable to be meta‐analysed

Other bias

Unclear risk

Abstract‐only publication; insufficient information to permit judgement

ACEi ‐ angiotensin‐converting enzyme inhibitor; ACR ‐ American College of Rheumatology; ANA ‐ antinuclear antibody; ARA ‐ American Rheumatology Association; ARB ‐ angiotensin receptor blocker; AZA ‐ azathioprine; BILAG ‐ British Isles Lupus Assessment Group; CKD ‐ chronic kidney disease; CMV ‐ cytomegalovirus; CNI ‐ calcineurin; CNS ‐ central nervous system; CPA ‐ cyclophosphamide; CrCl ‐ creatinine clearance; CSA ‐ cyclosporin A; DM ‐ diabetes mellitus; EC‐MPS ‐ enteric‐coated mycophenolate sodium; eGFR ‐ estimated glomerular filtration rate; ELNT ‐ Euro‐lupus nephritis treatment; ESKD ‐ end‐stage kidney disease; GI ‐ gastrointestinal: GN ‐ glomerulonephritis; Hb ‐ haemoglobin; HBV ‐ hepatitis B virus; HCV ‐ hepatitis C virus; HIV ‐ human immunodeficiency virus; HPF ‐ high power field; IA ‐ immunoadsorption; ISN/RPS ‐ International Society of Nephrology/Renal Pathology Society; IV ‐ intravenous; IVIG ‐ intravenous immunoglobulin; M/F ‐ male/female; MMF ‐ mycophenolate mofetil; MP ‐ methylprednisolone; NSAID/s ‐ nonsteroidal anti‐inflammatory drug/s; PEX ‐ plasma exchange or plasmapheresis; PALGA ‐ Dutch Pathology Registry; RBC ‐ red blood cell/s; RCC ‐ red cell count; RCT ‐ randomised controlled trial; RTX ‐ rituximab; SC ‐ subcutaneous; SCr ‐ serum creatinine; SD ‐ standard deviation; SDS ‐ standard deviation score; SLE ‐ systemic lupus erythematosus; SLEDAI ‐ SLE Disease Activity Index; SLICC ‐ Systemic Lupus Collaborating Clinics; TAC ‐ tacrolimus; TB ‐ tuberculosis; WHO ‐ World Health Organization; ISN/RPS ‐ International Society of Nephrology/ Renal Pathology Society; UPCR ‐ urine protein‐to‐creatinine ratio; WBC ‐ white blood cell/s; WCC ‐ white cell count

Characteristics of excluded studies [ordered by study ID]

Study

Reason for exclusion

Andrade‐Ortega 2010

Wrong population: not biopsy‐proven lupus nephritis

Antunes 2001

Wrong intervention: not comparing immunosuppression

ASPEN 2008

Wrong population: not biopsy‐proven lupus nephritis

ATLAS 2016

Wrong population: diagnosis of biopsy‐proven proliferative lupus nephritis at randomisation unclear

Austin 2009

Wrong population: not biopsy‐proven lupus nephritis but membranous

Balow 1981

Wrong population: not biopsy‐proven lupus nephritis

Balow 1984

No relevant outcomes

Ble 2011

Wrong intervention: not immunosuppressive intervention

Chanchairujira 2009

No relevant clinical outcomes

Clark 1993

Wrong population: not biopsy‐proven lupus nephritis

Clark 2001a

Wrong population: not biopsy‐proven lupus nephritis

CONTROL 2016

Wrong population: diagnosis of biopsy‐proven proliferative lupus nephritis at randomisation was unclear

Davis 1999

Wrong population and intervention: not biopsy‐proven lupus nephritis or comparing immunosuppression

Daza 2005

Wrong intervention: not comparing immunosuppression

Deng 2017a

Wrong intervention: not comparing immunosuppression

Feng 2014

Wrong population: not biopsy‐proven lupus nephritis

Frutos 1997

Insufficient information to determine if the study is randomised

Hebert 1987

Wrong population: not biopsy‐proven lupus nephritis

Khajehdehi 2012

Wrong intervention: not immunosuppressive intervention

Kuo 2001

Wrong intervention: not comparing immunosuppression

Li 2005

Insufficient information to determine if the study is randomised

Li 2014a

Wrong intervention: not immunosuppressive intervention

LJP 394‐90‐05 2003

Wrong population: not biopsy‐proven lupus nephritis

LJP 394‐90‐09 2005

Wrong population: not biopsy‐proven lupus nephritis

Lu 2002

Wrong population: not biopsy‐proven lupus nephritis

Miyasaka 2009

Wrong population: included class II and class V lupus nephritis

NCT00001212

Wrong population: membranous lupus nephritis

NCT00404157

The study has been terminated

NCT00429377

The recruitment status of this study is unknown (registered 2007). The completion date of this study has passed and the status has not been verified in more than two years.

NCT00436438

Study terminated early for administrative reasons

NCT00539799

This study was withdrawn prior to enrolment, as the local pharmacy were unwilling to comply with the study protocol

NCT00659217

The recruitment status of this study is unknown (registered 2008). The completion date of this study has passed and the status has not been verified in more than two years

NCT01299922

This study was withdrawn prior to recruitment

NCT01342016

This study has been terminated due to safety concerns of active control drug

NCT01930890

Study was terminated because results from previous studies did not demonstrate sufficient efficacy

NCT02176486

Study was terminated, insufficient enrolment

Pierucci 1989

Wrong population: not comparing immunosuppression

Schaumann 1992

Unclear if biopsy‐proven lupus nephritis

Su 2007

Wrong population: not biopsy‐proven lupus nephritis

Sztejnbok 1971

Wrong population: not biopsy‐proven lupus nephritis

Wallace 2006

Wrong population: not biopsy‐proven lupus nephritis

Wang 2007

Wrong population: non‐invasive necrotising vasculopathy‐severe variant not usually responsive to standard therapy

Witte 1993

Unclear if biopsy‐proven lupus nephritis

Yap 2012

Wrong population: not biopsy‐proven lupus nephritis

Ye 2001

Wrong population: not biopsy‐proven lupus nephritis

Yoshida 1996

Wrong intervention: not comparing immunosuppression

Zhang 2015c

Wrong population: biopsy‐proven proliferative lupus nephritis were excluded

Zheng 2005a

Unclear if biopsy‐proven lupus nephritis

Characteristics of ongoing studies [ordered by study ID]

2nd Dutch Lupus Trial

Trial name or title

Comparison of short course cyclophosphamide followed by mycophenolate mofetil versus long course cyclophosphamide in the treatment of proliferative lupus nephritis

Methods

Multicentre RCT

Participants

Adult, proliferative lupus nephritis, biopsy‐proven, active urinary sediment, proteinuria

Interventions

6 months IV CPA induction followed by either 3 monthly IV CPA or MMF for 18 months, then 2 years AZA in both arms

Outcomes

Renal relapse

Starting date

January 2003

Contact information

Marc Bijl, University Medical Centre Groningen

Notes

ChiCTR‐TRC‐09000587

Trial name or title

The intensive therapy of severe lupus nephritis: a multicenter, randomised, controlled prospective clinical trial

Methods

Multicentre, randomised controlled

Participants

Adult, SLE according to ACR criteria, renal biopsy‐proven lupus nephritis: 24 hours proteinuria (≥ 3.0g/d or +++), erythrocyturia > 5/HPF, leucocyturia or cast (RBC, Hb, tubuli or mixed); SLEDAI score ≥10

Interventions

  1. NIH IV CPA standard program (Induction period, follow‐up once every four weeks; consolidation therapy: follow‐up once every twelve weeks, maintenance therapy: follow‐up once every twelve weeks.

  2. Intensive group: mini‐pulse of CPA, hydroxychloroquine and another immunosuppressive agent, such as MMF, leflunomide, AZA or methotrexate

Outcomes

Serum albumin, SCr, SLEDAI, liver function, adverse events

Starting date

September 2009

Contact information

Zhanguo Li, The department of rheumatology and immunology, People's Hospital, Peking university, Beijing, China

Notes

ChiCTR‐TRC‐10000931

Trial name or title

Treatment of severe lupus nephritis with tacrolimus (FK 506) based immunosuppression

Methods

Multicentre RCT

Participants

Adult; SLE (ACR criteria); SLEDAI > 10 points; biopsy‐proven lupus nephritis severe type III, IV type, V+III type and V+IV‐type lupus nephritis (WHO2004 criteria), heavy‐III, with severe segmental lesions that have loop necrosis or crescent formation of the III‐type lupus nephritis); significant renal disease, proteinuria ≥ 2 g/24 h, with active urine sediment (urine RBC > 400,000/mL, tube urine, leukocytes in urine), SCr < 3mg/dL (265 µmol/L)

Interventions

Tacrolimus (0.5 mg and 1 mg)

Outcomes

Serum albumin, SCr, proteinuria, immunological function, renal biopsy, adverse events

Starting date

2009

Contact information

Changlin Mei, Shanghai Changzheng Hospital, Beijing China

Notes

Sponsor ‐ Astellas Pharma China Inc.

CTRI/2016/01/006488

Trial name or title

Comparison of two steroid dose regimen in lupus nephritis: a randomised controlled trial

Methods

RCT

Participants

12 to 70 years of age, SLE (ACR criteria); biopsy‐proven lupus nephritis (ISN/RPS class III, IV, III+V or IV+V)

Interventions

  1. Low dose oral prednisolone (0.5 mg/kg/d)

  2. Oral prednisolone (1 mg/kg/d)

Patients in both groups will receive IV MP (750 mg) for 3 days, followed by oral prednisolone for a period of 8 weeks followed by a taper. All patients will receive MMF

Outcomes

Complete remission, partial remission, SELENA‐SLEDAI, quality of life, immunological function, adverse events

Starting date

January 2016

Contact information

Krishan Lal Gupta, Department of nephrology, Postgraduate Institute of Medical Education and Research, Chandigarh, India

Notes

CTRI/2017/05/008697

Trial name or title

Randomised controlled trial of multi‐targetted therapy versus low‐dose intravenous cyclophosphamide in the treatment of lupus nephritis

Methods

Parallel RCT

Participants

Adults, SLE ACR criteria; lupus nephritis class III, IV, V, a combination of III+V or IV+V; SCr < 3.0 mg/dL

Interventions

  1. MMF: 1 g/d in 2 divided doses and TAC 0.1 mg/kg/d to target a trough level of 4 to 7 ng/mL. MMF and TAC will be taken morning and evening, before meals, and with a glass of water

  2. CPA: Euro‐lupus Nephritis trial group regimen of six fortnightly IV infusions of a fixed dose of 500 mg CPA

  • All the patients will be given 3 IV infusion of MP (750 mg) followed by 1 mg/kg/d of oral prednisolone for a period of 8 weeks followed by taper to 7.5 mg/d at the end of 6 months

  • All the patients will be given maintenance treatment after completion of induction treatment, in the form of AZA (2 mg/kg) plus low‐dose steroids

Outcomes

  1. Decrease in 24 h proteinuria, defined as decrease in the UPCR to 3 in subjects with baseline nephrotic range proteinuria (≥ 3 UPCR) or decrease in the UPCR by ≥ 50% in subjects with sub‐nephrotic proteinuria (3 UPCR)

  2. Stabilization of SCr (i.e., a week 24 SCr level ± 25% of baseline) or improvement

Starting date

July 2016

Contact information

Krishan Lal Gupta, Department of Nephrology, Nehru Hospital, Post Graduate Institute of Medical Education and Research, Chandigarh, India

Notes

Follow‐up: 6 months

ISRCTN66475575

Trial name or title

Enteric coat mycophenolate sodium versus intravenous cyclophosphamide for severe paediatric lupus nephritis

Methods

Multicentre RCT

Participants

Paediatric lupus nephritis

Interventions

  1. EC‐MPS (myfortic®): 720 to 860 mg/m2/d, oral twice daily + oral steroid

  2. CPA: 750 to 1000 mg/m2/d (maximum dose 1000 mg/d), IV monthly for 6 months then every 3 months + oral steroid

Outcomes

  1. Death

  2. ESKD

  3. Complete remission

  4. Partial remission

  5. Relapse (renal and non‐renal)

  6. Disease activity: SLEDAI

  7. Infection

  8. GI symptoms

Starting date

July 2009

Contact information

Wattana Chartapisak, Department of Pediatrics, Chiang Mai, Thailand

Notes

NCT00302549

Trial name or title

To compare the efficacy and safety of FK506 vs IVC in the treatment of class III‐IV lupus nephritis

Methods

Multicentre RCT

Participants

Adult (18 to 65 years) female patients with SLE according to ACR criteria, SLEDAI > 10; biopsy‐proven

class III or IV lupus nephritis according to the WHO classification criteria within 3 month and have significant active pathological lesion; proteinuria ≥ 2 g/24 h, and an active urine sediment (haematuria with white cells and casts in urine)

Interventions

  1. TAC: 0.1 mg/kg/d

  2. IV CPA

Outcomes

Safety and efficacy

Starting date

May 2004

Contact information

Lei‐shi Li, Research Institute of Nephrology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu, China

Notes

Study was registered over 10 years ago and it is unlikely the study will be published

NCT00705367

Trial name or title

A single centre, randomised, placebo‐controlled, double blind, parallel group study to evaluate the tolerability of a single dose of Abatacept 30 mg/kg via intravenous infusion in Chinese SLE subjects with lupus nephritis

Methods

Single‐centre, double blind and open‐label extension RCT

Participants

Adult; ≥ 18 years of age; SLE and with lupus nephritis currently stable for the last 3 months without change in treatment for lupus nephritis; stable renal disease; no flaring of other organ systems in a minimum of the last 3 months

Interventions

  1. Abatacept: IV 30 mg/kg, single dose at day 1 and IV 10 mg/kg on days 15 and 29 followed by doses every 4 weeks until the end of the study

  2. Placebo: IV

Outcomes

  1. Death

  2. Adverse events

  3. Clinical characteristics: e.g. blood pressure, heart rate

Starting date

August 2008

Contact information

Bristol‐Myers Squibb

Notes

Study includes short‐term follow‐up period and long‐term extension period

NCT00881309

Trial name or title

To compare the efficacy and safety of tripterygium vs azathioprine in the maintenance therapy for lupus nephritis

Methods

RCT

Participants

Adults, class III‐V lupus nephritis (biopsy‐proven)

Interventions

Induction with MMF, CPA, TAC or multi‐target therapy followed by randomisation to either AZA maintenance therapy or tripterygium 90 mg once/d

Outcomes

Complete remission

Starting date

March 2009

Contact information

Weixin Hu, Nanjing University School of Medicine, China

Notes

NCT01056237

Trial name or title

Long‐term study of multi‐target therapy as maintenance treatment for lupus nephritis

Methods

Open‐label RCT

Participants

Adults (18 to 65 years); SLE; diagnosed class Ⅲ, Ⅳ,Ⅳ+Ⅴ, Ⅲ+Ⅴ or Ⅴ lupus nephritis (ISN/RPS 2003 criteria) by renal biopsy; all patients had received induction therapy for 6 months with multi‐therapy (FK506 + MMF) or IV CPA pulses. Patients were recruited when received partial remission or complete remission after 6 months induction therapy

Interventions

  1. Multi‐target therapy: TAC (1 to 3 mg/d) and MMF (0.5 to 0.75 g/d)

  2. AZA: 1.0 to 2.0 mg/kg/d

Outcomes

Safety and efficacy

Starting date

February 2010

Contact information

Zhi‐Hong Liu, Nanjing University School of Medicine

Notes

18 month duration

NCT01172002

Trial name or title

Leflunomide versus AZA for maintenance therapy of lupus nephritis

Methods

Open‐label RCT

Participants

Adults, biopsy‐proven proliferative lupus nephritis

Interventions

Leflunomide versus AZA (maintenance therapy)

Outcomes

Lupus nephritis flare

Starting date

March 2010

Contact information

Bao Chun De, Renji Hospital

Notes

NCT01284725

Trial name or title

Weaning of Immunosuppression in Nephritis of Lupus

Methods

Open‐label RCT

Participants

Adult, biopsy‐proven proliferative lupus nephritis

Interventions

Immunosuppressive treatment discontinuation versus continuation of MMF or AZA

Outcomes

Discontinuation of maintenance immunosuppressive therapy

Starting date

January 2011

Contact information

Noemie Jourde Chiche, Assistance Publique hôpitaux de Marseille

Notes

NCT01639339

Trial name or title

A phase 3, randomised, double‐blind, placebo‐controlled study to evaluate the efficacy and safety of Belimumab plus standard of care versus placebo plus standard of care in adult subjects with active lupus nephritis

Methods

Double‐blind, placebo controlled RCT

Participants

Adult, diagnosis of SLE (ACR criteria), biopsy‐proven lupus nephritis, clinically active lupus nephritis, autoantibody positive

Interventions

Belimumab versus placebo and standard therapy

Outcomes

Renal response, complete renal response, adverse events

Starting date

July 2012

Contact information

GlaxoSmithKline

Notes

NCT01714817

Trial name or title

A phase 3 randomised, double‐blind, placebo‐controlled study to evaluate the efficacy and safety of BMS‐188667 (Abatacept) or placebo on a background of mycophenolate mofetil and corticosteroids in the treatment of subjects with active class III or IV lupus nephritis

Methods

Double‐blind RCT

Participants

Age > 16 years; biopsy‐proven class III or IV lupus nephritis within 12 months; UPCR ≥ 1; SCr ≤ 3 mg/dL (i.e., ≤ 265 µmol/L); active disease within 3 months ‐ based on one of the following (1) worsening of lupus nephritis ‐ UPCR ≥ 3 (2) active urine sediment (3) biopsy within 3 months indicating active class III or IV

Inclusion criteria for the long‐term extension period: achieved complete or partial renal response after completing 2 years of double‐blind treatment

Interventions

  1. BMS‐188667 + MMF + Prednisone: BMS‐188667 30 mg/kg injection by IV on days 1, 15, 29, and 57, followed by a weight‐tiered dose approximating 10 mg/kg injection by IV every 4 weeks, MMF 1.5 g tablet by mouth and prednisone up to 60 mg tablet by mouth daily for 104 weeks

  2. Placebo matching with BMS‐188667 injection by IV on Days 1, 15, 29, and 57, followed by every 4 weeks, MMF 1.5 g tablet by mouth and prednisone up to 60 mg tablet by mouth daily for 104 weeks

Outcomes

Renal response

Starting date

January 2013

Contact information

Bristol‐Myers Squibb

Notes

NCT01845740

Trial name or title

A phase Ib study of milatuzumab administered subcutaneously in patients with active systemic lupus Erythematosus

Methods

Double‐blind RCT

Participants

Adult ≥ 18 years; SLE (ACR criteria); positive ANA (titre ≥ 1:80); at least 1 BILAG A or 2 BILAG B scores in any organ/body system and ≥ 6 SELENA‐SLEDAI score; receiving at least 5.0 mg/d oral prednisone (or equivalent) at stable doses for at least 4 weeks prior to study entry If receiving immunosuppressives or antimalarial agents, at stable doses for at least 4 weeks prior to study entry

Interventions

  1. High dose milatuzumab SC 250 mg

  2. Low dose milatuzumab SC 150 mg

  3. Placebo SC

Outcomes

Safety and efficacy

Starting date

January 2015

Contact information

Heather Horne, Cedars Sinai Medical Center‐Wallace Rheumatic Study centre, California, United States of America

Notes

NCT01861561

Trial name or title

Efficacy and infectious complications of induction therapy with low‐dose versus high‐dose intravenous cyclophosphamide for proliferative lupus nephritis in children

Methods

Open‐label RCT

Participants

Children (≤ 15 years), diagnosis of SLE (ACR 1997 criteria), biopsy‐proven class III or IV lupus nephritis (ISN/RPS 2003 classification criteria)

Interventions

High‐dose IV CPA versus low‐dose IV CPA (induction therapy)

Outcomes

Complete renal response, partial renal response, infection, quality of life, disease activity

Starting date

May 2013

Contact information

Nuntawan Piyaphanee, Siriraj Hospital, Thailand

Notes

NCT02226341

Trial name or title

Open‐label prospective randomised study to determine the efficacy and safety of two dosing regimens of ACTHar in the treatment of proliferative lupus nephritis

Methods

Open‐label RCT

Participants

≥ 16 years, diagnosis of SLE (ACR/SLICC criteria), biopsy‐proven class III or IV ±V lupus nephritis (ISN/RPS 2003 classification criteria)

Interventions

CellCept daily & ACTHar gel biweekly versus CellCept daily & ACTHar gel every other day

Outcomes

Complete response, partial response, renal flares, adverse events, cortisol levels, urinary lymphocytes

Starting date

October 2014

Contact information

Anca D Askanase, Columbia University, USA

Notes

NCT02256150

Trial name or title

A multi‐center, randomised, controlled, open‐label clinical study to evaluate the efficacy and safety of mizoribine in comparison with cyclophosphamide in the treatment of lupus nephritis

Methods

Open‐label RCT

Participants

Adult, diagnosis of SLE (ACR 1997 criteria), biopsy‐proven class III, III+V, IV, IV+V or V (ISN/RPS 2003 classification criteria), proteinuria > 1 g/d, SLEDAI > 8, patient body weight 40‐80kg at screening

Interventions

Mizoribine versus CPA

Outcomes

Complete remission, partial remission, treatment failure, ESKD, doubling of SCr, SCr, eGFR, C3, anti‐dsDNA, anti‐phospholipid, anti‐Sm, SLEDAI

Starting date

November 2014

Contact information

Asahi Kasei Pharma Corporation

Notes

NCT02260934

Trial name or title

Rituximab plus cyclophosphamide followed by belimumab for the treatment of lupus nephritis (ITN055AI)

Methods

Open‐label RCT

Participants

Adult, diagnosis of SLE (ACR criteria), biopsy‐proven proliferative lupus nephritis (ISN/RPS classification criteria), > 5 RBC/HPF in absence of menses and infection, > WBC/HPF in absence of infection or cellular casts, UPCR > 1

Interventions

RTX, CPA and belimumab versus RTX and CPA

Outcomes

Major infection, hypogammaglobulinaemia, complete response, partial response, treatment failure, relapse anti‐dsDNA, C3 and C4, death, leucopenia, ovarian failure, malignancy, thrombocytopenia, adverse advents

Starting date

October 2014

Contact information

Betty Diamond, Feinstein Institute for Medical Research: centre for Autoimmune and Musculoskeletal Diseases, USA

Notes

NCT02457221

Trial name or title

A phase III, randomised, open, parallel‐controlled, multi‐center study to compare the efficacy and safety of tacrolimus capsules and cyclophosphamide injection in treatment of lupus nephritis

Methods

Open‐label RCT

Participants

18‐60 years, 18.5 ≤ BMI < 27, diagnosis of SLE (ACR 1997 criteria), biopsy‐proven class III, IV, V, III+V, IV+V lupus nephritis (ISN/RPS 2003 classification criteria) within 24 weeks of study entry, proteinuria > 1.5 g/d, SCr < 3 mg/dL

Interventions

TAC versus CPA (induction therapy)

Outcomes

Complete remission, partial remission, proteinuria, serum albumin, SCr, eGFR, anti‐dsDNA and ANA, SLEDAI, C3 and C4, renal biopsy active index and chronic index

Starting date

March 2015

Contact information

Astellas Pharma China, Inc.

Notes

NCT02547922

Trial name or title

A multicentre, randomised, double‐blind, placebo‐controlled, phase 2 study evaluating the efficacy and safety of Anifrolumab in adult subjects with active proliferative lupus nephritis

Methods

Double‐blind RCT

Participants

18 to 70 years, fulfil four or more of the ACR 1982 criteria which must include positive ANA, elevated anti‐dsDNA, anti‐Smith; biopsy‐proven class III±V, IV±V, UPCR 1g/d, eGFR ≥ 35 mL/min/1.73 m2, women of childbearing potential must have negative serum beta‐hCG

Interventions

High‐dose anifrolumab, low‐dose anifrolumab versus placebo

Outcomes

Complete renal response, partial renal response, eGFR, proteinuria, urine sediment, adverse events

Starting date

November 2015

Contact information

AstraZeneca Clinical Study Information centre

Notes

NCT02550652

Trial name or title

A randomised, double‐blind, placebo‐controlled, multi‐center study to evaluate the safety and efficacy of Obinutuzumab in patients with ISN/RPS 2003 Class III or IV lupus nephritis

Methods

Double‐blind, placebo‐controlled RCT

Participants

Age 18‐75 years, diagnosis of SLE (ACR criteria), biopsy‐proven class III or IV lupus nephritis (ISN/RPS 2003 classification criteria), proteinuria UPCR > 1.0 g, premenopausal female participants agree to refraining from getting pregnant 18 months, male participants agree to use contraception for 12 month

Interventions

Obinutuzumab versus placebo

Outcomes

Complete renal response, partial renal response, anti‐dsDNA, C3 and C4, disease activity, immune cells (CD‐19 B‐cells, T‐cells, neutrophil), adverse events

Starting date

November, 2015

Contact information

Hoffmann‐La Roche

Notes

NCT02630628

Trial name or title

A randomised open‐label study to evaluate the efficacy and safety of tacrolimus and corticosteroids in comparison with mycophenolate mofetil and corticosteroids in subjects with class III/IV±V Lupus nephritis

Methods

Open‐label RCT

Participants

Adult, biopsy‐proven lupus nephritis Class III/IV±V (ISN/RPS 2003 classification criteria), positive anti‐dsDNA, UPCR > 1.0 g or 24 h urine protein > 1.0 g/d at baseline), with or without haematuria, new or flaring patients

Interventions

TAC versus MMF

Outcomes

Renal response

Starting date

September 2015

Contact information

Tak‐Mao Daniel Chan, The University of Hong Kong

Notes

NCT02770170

Trial name or title

A double‐blind, randomised, placebo‐controlled trial evaluating the effect of BI 655064 administered as sub‐cutaneous injections, on renal response after one year treatment in patients with lupus nephritis

Methods

Double‐blind, placebo‐controlled RCT

Participants

18‐70 years, diagnosis of SLE (ACR criteria), biopsy‐proven class III or IV lupus nephritis (ISN/RPS 2003 classification criteria), proteinuria ≥ 1.0 g/d (UPCR ≥ 100 mg/mmol)

Interventions

BI 655064 (anti‐CD‐40 antibody) versus placebo

Outcomes

Complete renal response, partial response

Starting date

January 2016

Contact information

Boehringer Ingelheim

Notes

NCT02936375

Trial name or title

Iguratimod as treatment for active lupus nephritis

Methods

Open‐label RCT

Participants

Diagnosis of SLE (ACR criteria), biopsy‐proven class III, IV, V, III+IV or IV+V active lupus nephritis, proteinuria 1g/d, body weight ≥ 40 kg, SLEDAI‐2K ≥ 8, agreement of contraception

Interventions

Iguratimod versus CPA and AZA

Outcomes

Renal remission, renal flare, adverse events, disease activity (SLEDAI‐2K, BILAG), patient general assessment

Starting date

March 2017

Contact information

Chunde Bao, RenJi Hospital

Notes

NCT02954939

Trial name or title

The effect of mycophenolate mofetil and cyclophosphamide on the lymphocyte subsets in patients With proliferative Lupus nephritis

Methods

Open‐label RCT

Participants

18 to 80 years , biopsy‐proven class III or IV±V lupus nephritis lupus nephritis (ISN/RPS 2003 classification criteria), active lupus nephritis indicated by proteinuria >1 g/d and/or rise in SCr by 15%

Interventions

MMF (induction and maintenance therapy) versus CPA (induction therapy) and AZA (maintenance therapy)

Outcomes

Lymphocyte subset profile (CD8+ T cells, CD4+ Th1, Th2, Th17 & Treg), Naïve & memory B cells, plasma cells, serum cytokine profile (IL‐2, IL‐5, IL‐6, IL‐7, IL‐10, IL‐17, IL‐21, IL‐23, IFN‐alpha, IFN‐gamma, TGF‐beta)

Starting date

March 2012

Contact information

Desmond Yap, Queen Mary Hospital, Hong Kong

Notes

NCT03021499

Trial name or title

A randomised, controlled double‐blind study comparing the efficacy and safety of voclosporin (23.7 mg twice daily) with placebo in achieving renal response in subjects with active lupus nephritis

Methods

Double‐blind RCT

Participants

Subjects with evidence of active nephritis, defined as follows: Kidney biopsy result within 2 years prior to screening indicating Class III, IV‐S, IV‐G (alone or in combination with Class V), or Class V lupus nephritis with a doubling or greater increase of UPCR within the last 6 months to a minimum of ≥ 1.5 mg/mg for Class III/IV or to a minimum of ≥ 2 mg/mg for Class V at screening. Biopsy results over 6 months prior to screening must be reviewed with a medical monitor to confirm eligibility. Or kidney biopsy result within 6 months prior to screening indicating Class III, IV‐S or IV‐G (alone or in combination with Class V) lupus nephritis with a UPCR of ≥ 1.5 mg/mg at screening. Or kidney biopsy result within 6 months prior to screening indicating Class V lupus nephritis and a UPCR of ≥ 2 mg/mg at screening. Women of childbearing potential must have a negative serum pregnancy test at screening and a negative urine pregnancy test at baseline.

Interventions

  1. Voclosporin oral, 23.7 mg BID

  2. Voclosporin placebo, oral, 3 capsules BID

Outcomes

  1. Renal response

  2. Partial renal response

  3. kidney function

  4. Disease activity ‐ SELENA‐SLEDAI

  5. Quality of life

Starting date

May 2017

Contact information

Mary Anne Dooley, University of North Carolina

Notes

Sponsor ‐ Aurinia Pharmaceuticals Inc.

NCT03214731

Trial name or title

Efficacy and safety of artesunate plus standard of care in active lupus nephritis (AURORA)

Methods

Multicentre, double‐blind RCT

Participants

14 to 65 years; SLE (ACR criteria); renal biopsy within 6 months prior to randomisation with a histological diagnosis (ISN/RPS 2003 classification of lupus nephritis) ‐ class III, IV, V, III+V and IV+V (excluding Class III(C), IV‐S(C), and IV‐G(C)); class IV or IV+V lupus nephritis: proteinuria ≥ 1 g/24 h (or UPCR ≥ 1.0) or SCr > 1.3 mg/dL, with active urinary sediment (> 5 RBC/HPF or > 5 WBC/HPF (or within the reference range of the laboratory) in absence of menses and genitourinary tract infection, or presence of cellular casts (RBC or WBC casts)); Class III, III+V or V lupus nephritis: proteinuria ≥ 2 g/24 h (or UPCR ≥ 2.0) or SCr > 1.3 mg/dL; Provision of written informed consent by subject or guardian

Interventions

  1. High‐dose artesunate: 50 mg

  2. Low‐dose artesunate: 25 mg

  3. Placebo

  • All patients received standard of care

Outcomes

  1. Complete remission

  2. Partial remission

Starting date

September 2017

Contact information

Xue Qing Yu, The 1st Affiliated Hospital, Sun Yet‐sen University, Guangzhou, Guangdong, China

Notes

PER‐062‐15

Trial name or title

A multicentre, randomised, double‐blind, placebo‐controlled, phase 3 study evaluating the efficacy and safety of two doses of anifrolumab in adult subjects with active systemic lupus erythematosus

Methods

Multicentre, double‐blind RCT

Participants

Aged 18 ‐ 70 years; weight ≥ 40.0 kg; adequate peripheral venous access; SLE (ACR criteria); currently receiving at least 1 of the following: (a) a dose of oral prednisone (≤ 40 mg/d) for a minimum of 2 weeks, the dose of oral prednisone the subject is taking must be stable for a minimum of 2 weeks prior to Week 0 (Day 1) (b) Any of the following medications administered for a minimum of 12 weeks prior to signing the informed consent, and at a stable dose for a minimum of 8 weeks prior to Day 1.

Interventions

  1. High‐dose anifrolumab (MEDI‐546) ‐ 150 mg IV administration

  2. Low‐dose anifrolumab (MEDI‐546) ‐ 300 mg IV administration

  3. Placebo IV

  • Investigational product will be administered every 4 weeks from Week 0 to Week 48 for a total of 13 doses.

Outcomes

  1. SLE Responder Index

  2. Disease activity ‐ SLEDAI, BILAG

  3. Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) activity

  4. Immunological function

Starting date

May 2015

Contact information

Luis Fernando Bellatin Vargas, Hogar Clínica, San Juan De Dios‐Arequipa

Notes

RING 2015

Trial name or title

RING, an investigator‐initiated trial aimed at testing the efficacy of rituximab in refractory lupus nephritis: Rationale, trial design and call for participation (abstract)

Methods

RCT

Participants

SLE, age > 15 years old, ISN/RPS Class III, IV or V lupus nephritis (biopsy within 24 months), refractory lupus nephritis with previous treatment with Euro‐lupus/NIH CPA or AZA or MMF, maximum 10 mg prednisolone/d, UPCR > 1 (mg/mg), and female patients on contraception

Interventions

1. RTX

2. Standard of care

Outcomes

Complete response (UPCR ≤ 0.5 (expressed in mg/mg) measured in a 24 h urine collection; and eGFR ≥ 60 mL/min or, if < 60 mL/min at screening, not fallen by > 20% compared to screening; and no increase of glucocorticoids throughout the study (except for two limited courses as per protocol; vide infra); and no introduction of another immunosuppressant.)

Starting date

August 2012

Contact information

Frédéric A. Houssiau, Université Catholique de Louvain, Belgium

Notes

RITUXILUP 2013

Trial name or title

Phase 3 open label randomised multicentre controlled trial of rituximab and mycophenolate mofetil without oral steroids for the treatment of lupus nephritis

Methods

Open‐label RCT

Participants

12 to 75 years, biopsy‐proven lupus nephritis (ISN/RPS 2003 classification criteria), active lupus nephritis UPCR > 1000 mg/mmol, not planning pregnancy during study period

Interventions

RTX versus prednisolone

Outcomes

Complete renal response, major infections, serious adverse and adverse events, disease activity scores, renal flare, serum C3, C4, anti‐dsDNA, quality of life

Starting date

April 2015

Contact information

Liz Lightstone, Hammersmith Hospital, Imperial College Healthcare NHS Trust, United Kingdom

Notes

ACEi ‐ angiotensin‐converting enzyme inhibitor; ACR ‐ American College of Rheumatology; ARA ‐ American Rheumatology Association; ARB ‐ angiotensin receptor blocker; AZA ‐ azathioprine; BILAG ‐ British Isles Lupus Assessment Group; CKD ‐ chronic kidney disease; CMV ‐ cytomegalovirus; CNI ‐ calcineurin; CNS ‐ central nervous system; CPA ‐ cyclophosphamide; CrCl ‐ creatinine clearance; CSA ‐ cyclosporin A; DM ‐ diabetes mellitus; EC‐MPS ‐ enteric‐coated mycophenolate sodium; eGFR ‐ estimated glomerular filtration rate; ELNT ‐ Euro‐lupus nephritis treatment; ESKD ‐ end‐stage kidney disease; ESR ‐ erythrocyte sedimentation rate; GI ‐ gastrointestinal: GN ‐ glomerulonephritis; HBV ‐ hepatitis B virus; HCV ‐ hepatitis C virus; HIV ‐ human immunodeficiency virus; HPF ‐ high power field; IA ‐ immunoadsorption; ISN/RPS ‐ International Society of Nephrology/Renal Pathology Society; IV ‐ intravenous; IVIG ‐ intravenous immunoglobulin; M/F ‐ male/female; MMF ‐ mycophenolate mofetil; MP ‐ methylprednisolone; NSAID/s ‐ nonsteroidal anti‐inflammatory drug/s; PEX ‐ plasma exchange or plasmapheresis; PLAGA ‐ Dutch Pathology Registry; RBC ‐ red blood cell/s; RCC ‐ red cell count; RCT ‐ randomised controlled trial; RTX ‐ rituximab; SC ‐ subcutaneous; SCr ‐ serum creatinine; SD ‐ standard deviation; SELENA ‐ Safety of Estrogens in Lupus Erythematosus National Assessment; SLE ‐ systemic lupus erythematosus; SLEDAI ‐ SLE Disease Activity Index; SLICC ‐ Systemic Lupus Collaborating Clinics; TAC ‐ tacrolimus; TB ‐ tuberculosis; WHO ‐ World Health Organization; ISN/RPS ‐ International Society of Nephrology/ Renal Pathology Society; UPCR ‐ urine protein‐to‐creatinine ratio; WBC ‐ white blood cell/s; WCC ‐ white cell count

Data and analyses

Open in table viewer
Comparison 1. Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Death Show forest plot

8

826

Risk Ratio (M‐H, Random, 95% CI)

1.12 [0.61, 2.06]

Analysis 1.1

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 1 Death.

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 1 Death.

2 Remission Show forest plot

9

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 1.2

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 2 Remission.

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 2 Remission.

2.1 Complete renal remission: MMF versus IV CPA

9

868

Risk Ratio (M‐H, Random, 95% CI)

1.17 [0.97, 1.42]

2.2 Partial renal remission: MMF versus IV CPA

9

868

Risk Ratio (M‐H, Random, 95% CI)

1.02 [0.89, 1.18]

2.3 Complete remission in proteinuria: MMF versus IV CPA

6

686

Risk Ratio (M‐H, Random, 95% CI)

1.16 [0.85, 1.58]

2.4 Partial remission in proteinuria: MMF versus IV CPA

6

744

Risk Ratio (M‐H, Random, 95% CI)

1.03 [0.91, 1.18]

3 Adverse renal outcomes Show forest plot

4

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 1.3

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 3 Adverse renal outcomes.

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 3 Adverse renal outcomes.

3.1 ESKD

3

231

Risk Ratio (M‐H, Random, 95% CI)

0.71 [0.27, 1.84]

3.2 Renal relapse

1

140

Risk Ratio (M‐H, Random, 95% CI)

0.97 [0.39, 2.44]

3.3 Doubling of serum creatinine

1

40

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

4 Stable kidney function Show forest plot

6

641

Risk Ratio (M‐H, Random, 95% CI)

1.05 [0.94, 1.17]

Analysis 1.4

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 4 Stable kidney function.

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 4 Stable kidney function.

5 Ovarian failure Show forest plot

3

539

Risk Ratio (M‐H, Random, 95% CI)

0.36 [0.06, 2.18]

Analysis 1.5

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 5 Ovarian failure.

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 5 Ovarian failure.

6 Menstrual irregularities Show forest plot

2

87

Risk Ratio (M‐H, Random, 95% CI)

0.33 [0.07, 1.59]

Analysis 1.6

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 6 Menstrual irregularities.

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 6 Menstrual irregularities.

7 Infection Show forest plot

7

1452

Risk Ratio (M‐H, Random, 95% CI)

1.13 [0.81, 1.58]

Analysis 1.7

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 7 Infection.

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 7 Infection.

7.1 Major infection

6

699

Risk Ratio (M‐H, Random, 95% CI)

1.02 [0.67, 1.54]

7.2 Herpes zoster virus

6

753

Risk Ratio (M‐H, Random, 95% CI)

1.39 [0.78, 2.46]

8 Malignancy Show forest plot

1

364

Risk Ratio (M‐H, Random, 95% CI)

0.65 [0.11, 3.86]

Analysis 1.8

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 8 Malignancy.

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 8 Malignancy.

9 Leucopenia Show forest plot

6

753

Risk Ratio (M‐H, Random, 95% CI)

0.59 [0.33, 1.08]

Analysis 1.9

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 9 Leucopenia.

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 9 Leucopenia.

10 Bladder toxicity Show forest plot

1

364

Risk Ratio (M‐H, Random, 95% CI)

0.33 [0.01, 7.95]

Analysis 1.10

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 10 Bladder toxicity.

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 10 Bladder toxicity.

11 Alopecia Show forest plot

3

622

Risk Ratio (M‐H, Random, 95% CI)

0.29 [0.19, 0.46]

Analysis 1.11

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 11 Alopecia.

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 11 Alopecia.

12 Gastrointestinal (GI) adverse events Show forest plot

4

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 1.12

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 12 Gastrointestinal (GI) adverse events.

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 12 Gastrointestinal (GI) adverse events.

12.1 Diarrhoea

4

609

Risk Ratio (M‐H, Random, 95% CI)

2.42 [1.64, 3.58]

12.2 Vomiting

3

562

Risk Ratio (M‐H, Random, 95% CI)

0.48 [0.24, 0.97]

12.3 Nausea

3

562

Risk Ratio (M‐H, Random, 95% CI)

0.48 [0.23, 0.98]

12.4 GI upset

3

569

Risk Ratio (M‐H, Random, 95% CI)

0.91 [0.78, 1.06]

13 Daily proteinuria Show forest plot

4

271

Mean Difference (IV, Random, 95% CI)

‐0.08 [‐0.43, 0.26]

Analysis 1.13

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 13 Daily proteinuria.

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 13 Daily proteinuria.

14 Serum creatinine Show forest plot

6

759

Mean Difference (IV, Random, 95% CI)

2.14 [‐3.09, 7.37]

Analysis 1.14

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 14 Serum creatinine.

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 14 Serum creatinine.

Open in table viewer
Comparison 2. Mycophenolate mofetil (MMF) versus oral cyclophosphamide (CPA)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Death Show forest plot

1

62

Risk Ratio (M‐H, Random, 95% CI)

0.19 [0.01, 3.76]

Analysis 2.1

Comparison 2 Mycophenolate mofetil (MMF) versus oral cyclophosphamide (CPA), Outcome 1 Death.

Comparison 2 Mycophenolate mofetil (MMF) versus oral cyclophosphamide (CPA), Outcome 1 Death.

2 Remission Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 2.2

Comparison 2 Mycophenolate mofetil (MMF) versus oral cyclophosphamide (CPA), Outcome 2 Remission.

Comparison 2 Mycophenolate mofetil (MMF) versus oral cyclophosphamide (CPA), Outcome 2 Remission.

2.1 Complete remission in proteinuria

1

62

Risk Ratio (M‐H, Random, 95% CI)

0.98 [0.74, 1.30]

2.2 Partial remission in proteinuria

1

62

Risk Ratio (M‐H, Random, 95% CI)

1.07 [0.44, 2.59]

3 Adverse renal outcomes Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 2.3

Comparison 2 Mycophenolate mofetil (MMF) versus oral cyclophosphamide (CPA), Outcome 3 Adverse renal outcomes.

Comparison 2 Mycophenolate mofetil (MMF) versus oral cyclophosphamide (CPA), Outcome 3 Adverse renal outcomes.

3.1 ESKD

1

62

Risk Ratio (M‐H, Random, 95% CI)

0.19 [0.01, 3.76]

3.2 Renal relapse

1

62

Risk Ratio (M‐H, Random, 95% CI)

1.15 [0.55, 2.37]

3.3 Doubling of serum creatinine

1

62

Risk Ratio (M‐H, Random, 95% CI)

0.63 [0.11, 3.48]

4 Ovarian failure Show forest plot

1

53

Risk Ratio (M‐H, Random, 95% CI)

0.10 [0.01, 0.73]

Analysis 2.4

Comparison 2 Mycophenolate mofetil (MMF) versus oral cyclophosphamide (CPA), Outcome 4 Ovarian failure.

Comparison 2 Mycophenolate mofetil (MMF) versus oral cyclophosphamide (CPA), Outcome 4 Ovarian failure.

5 Infection Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 2.5

Comparison 2 Mycophenolate mofetil (MMF) versus oral cyclophosphamide (CPA), Outcome 5 Infection.

Comparison 2 Mycophenolate mofetil (MMF) versus oral cyclophosphamide (CPA), Outcome 5 Infection.

5.1 Major infection

1

62

Risk Ratio (M‐H, Random, 95% CI)

0.21 [0.05, 0.89]

5.2 Herpes zoster virus

1

62

Risk Ratio (M‐H, Random, 95% CI)

0.38 [0.08, 1.79]

6 Leucopenia Show forest plot

1

62

Risk Ratio (M‐H, Random, 95% CI)

0.06 [0.00, 0.92]

Analysis 2.6

Comparison 2 Mycophenolate mofetil (MMF) versus oral cyclophosphamide (CPA), Outcome 6 Leucopenia.

Comparison 2 Mycophenolate mofetil (MMF) versus oral cyclophosphamide (CPA), Outcome 6 Leucopenia.

7 Bone toxicity Show forest plot

1

62

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

Analysis 2.7

Comparison 2 Mycophenolate mofetil (MMF) versus oral cyclophosphamide (CPA), Outcome 7 Bone toxicity.

Comparison 2 Mycophenolate mofetil (MMF) versus oral cyclophosphamide (CPA), Outcome 7 Bone toxicity.

8 Alopecia Show forest plot

1

62

Risk Ratio (M‐H, Random, 95% CI)

0.05 [0.00, 0.81]

Analysis 2.8

Comparison 2 Mycophenolate mofetil (MMF) versus oral cyclophosphamide (CPA), Outcome 8 Alopecia.

Comparison 2 Mycophenolate mofetil (MMF) versus oral cyclophosphamide (CPA), Outcome 8 Alopecia.

9 Gastrointestinal (GI) adverse events Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 2.9

Comparison 2 Mycophenolate mofetil (MMF) versus oral cyclophosphamide (CPA), Outcome 9 Gastrointestinal (GI) adverse events.

Comparison 2 Mycophenolate mofetil (MMF) versus oral cyclophosphamide (CPA), Outcome 9 Gastrointestinal (GI) adverse events.

9.1 GI upset

1

62

Risk Ratio (M‐H, Random, 95% CI)

2.81 [0.31, 25.58]

10 Daily proteinuria Show forest plot

1

42

Mean Difference (IV, Random, 95% CI)

0.3 [‐0.19, 0.79]

Analysis 2.10

Comparison 2 Mycophenolate mofetil (MMF) versus oral cyclophosphamide (CPA), Outcome 10 Daily proteinuria.

Comparison 2 Mycophenolate mofetil (MMF) versus oral cyclophosphamide (CPA), Outcome 10 Daily proteinuria.

Open in table viewer
Comparison 3. Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Death Show forest plot

2

402

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

Analysis 3.1

Comparison 3 Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA), Outcome 1 Death.

Comparison 3 Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA), Outcome 1 Death.

2 Remission Show forest plot

2

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 3.2

Comparison 3 Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA), Outcome 2 Remission.

Comparison 3 Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA), Outcome 2 Remission.

2.1 Complete renal remission

2

402

Risk Ratio (M‐H, Random, 95% CI)

2.38 [1.07, 5.30]

2.2 Partial renal remission

2

402

Risk Ratio (M‐H, Random, 95% CI)

1.0 [0.78, 1.28]

2.3 Complete remission in proteinuria

2

402

Risk Ratio (M‐H, Random, 95% CI)

2.38 [1.07, 5.30]

2.4 Partial remission in proteinuria

2

402

Risk Ratio (M‐H, Random, 95% CI)

0.98 [0.76, 1.26]

3 Adverse renal outcomes Show forest plot

2

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 3.3

Comparison 3 Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA), Outcome 3 Adverse renal outcomes.

Comparison 3 Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA), Outcome 3 Adverse renal outcomes.

3.1 Doubling of serum creatinine

2

402

Risk Ratio (M‐H, Random, 95% CI)

0.98 [0.10, 9.23]

4 Stable kidney function Show forest plot

2

402

Risk Ratio (M‐H, Random, 95% CI)

1.78 [1.40, 2.26]

Analysis 3.4

Comparison 3 Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA), Outcome 4 Stable kidney function.

Comparison 3 Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA), Outcome 4 Stable kidney function.

5 Ovarian failure Show forest plot

1

34

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

Analysis 3.5

Comparison 3 Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA), Outcome 5 Ovarian failure.

Comparison 3 Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA), Outcome 5 Ovarian failure.

6 Menstrual irregularities Show forest plot

1

323

Risk Ratio (M‐H, Random, 95% CI)

0.28 [0.06, 1.35]

Analysis 3.6

Comparison 3 Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA), Outcome 6 Menstrual irregularities.

Comparison 3 Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA), Outcome 6 Menstrual irregularities.

7 Infection Show forest plot

2

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 3.7

Comparison 3 Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA), Outcome 7 Infection.

Comparison 3 Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA), Outcome 7 Infection.

7.1 Major infection

2

402

Risk Ratio (M‐H, Random, 95% CI)

1.65 [0.11, 24.44]

7.2 Herpes zoster virus

2

402

Risk Ratio (M‐H, Random, 95% CI)

0.80 [0.22, 2.94]

8 Leucopenia Show forest plot

2

402

Risk Ratio (M‐H, Random, 95% CI)

0.23 [0.04, 1.44]

Analysis 3.8

Comparison 3 Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA), Outcome 8 Leucopenia.

Comparison 3 Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA), Outcome 8 Leucopenia.

9 Bone toxicity Show forest plot

1

362

Risk Ratio (M‐H, Random, 95% CI)

3.0 [0.12, 73.16]

Analysis 3.9

Comparison 3 Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA), Outcome 9 Bone toxicity.

Comparison 3 Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA), Outcome 9 Bone toxicity.

10 Alopecia Show forest plot

2

402

Risk Ratio (M‐H, Random, 95% CI)

0.78 [0.36, 1.72]

Analysis 3.10

Comparison 3 Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA), Outcome 10 Alopecia.

Comparison 3 Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA), Outcome 10 Alopecia.

11 Gastrointestinal (GI) adverse events Show forest plot

2

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 3.11

Comparison 3 Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA), Outcome 11 Gastrointestinal (GI) adverse events.

Comparison 3 Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA), Outcome 11 Gastrointestinal (GI) adverse events.

11.1 Diarrhoea

1

362

Risk Ratio (M‐H, Random, 95% CI)

2.33 [0.92, 5.94]

11.2 GI upset

2

402

Risk Ratio (M‐H, Random, 95% CI)

0.21 [0.10, 0.41]

12 Daily proteinuria Show forest plot

1

40

Mean Difference (IV, Random, 95% CI)

‐1.69 [‐2.81, ‐0.57]

Analysis 3.12

Comparison 3 Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA), Outcome 12 Daily proteinuria.

Comparison 3 Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA), Outcome 12 Daily proteinuria.

Open in table viewer
Comparison 4. Mycophenolate mofetil (MMF) + IV cyclophosphamide (CPA) versus IV CPA

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Death Show forest plot

1

82

Risk Ratio (M‐H, Random, 95% CI)

0.95 [0.06, 14.72]

Analysis 4.1

Comparison 4 Mycophenolate mofetil (MMF) + IV cyclophosphamide (CPA) versus IV CPA, Outcome 1 Death.

Comparison 4 Mycophenolate mofetil (MMF) + IV cyclophosphamide (CPA) versus IV CPA, Outcome 1 Death.

2 Remission Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 4.2

Comparison 4 Mycophenolate mofetil (MMF) + IV cyclophosphamide (CPA) versus IV CPA, Outcome 2 Remission.

Comparison 4 Mycophenolate mofetil (MMF) + IV cyclophosphamide (CPA) versus IV CPA, Outcome 2 Remission.

2.1 Complete renal remission

1

82

Risk Ratio (M‐H, Random, 95% CI)

1.22 [0.78, 1.89]

2.2 Partial renal remission

1

82

Risk Ratio (M‐H, Random, 95% CI)

1.03 [0.55, 1.90]

3 Menstrual irregularities Show forest plot

1

75

Risk Ratio (M‐H, Random, 95% CI)

0.49 [0.16, 1.48]

Analysis 4.3

Comparison 4 Mycophenolate mofetil (MMF) + IV cyclophosphamide (CPA) versus IV CPA, Outcome 3 Menstrual irregularities.

Comparison 4 Mycophenolate mofetil (MMF) + IV cyclophosphamide (CPA) versus IV CPA, Outcome 3 Menstrual irregularities.

4 Infection Show forest plot

1

82

Risk Ratio (M‐H, Random, 95% CI)

0.37 [0.14, 0.93]

Analysis 4.4

Comparison 4 Mycophenolate mofetil (MMF) + IV cyclophosphamide (CPA) versus IV CPA, Outcome 4 Infection.

Comparison 4 Mycophenolate mofetil (MMF) + IV cyclophosphamide (CPA) versus IV CPA, Outcome 4 Infection.

4.1 Major infection

1

82

Risk Ratio (M‐H, Random, 95% CI)

0.37 [0.14, 0.93]

5 Leucopenia Show forest plot

1

82

Risk Ratio (M‐H, Random, 95% CI)

0.63 [0.11, 3.60]

Analysis 4.5

Comparison 4 Mycophenolate mofetil (MMF) + IV cyclophosphamide (CPA) versus IV CPA, Outcome 5 Leucopenia.

Comparison 4 Mycophenolate mofetil (MMF) + IV cyclophosphamide (CPA) versus IV CPA, Outcome 5 Leucopenia.

6 Daily proteinuria Show forest plot

1

77

Mean Difference (IV, Random, 95% CI)

‐0.54 [‐1.12, 0.04]

Analysis 4.6

Comparison 4 Mycophenolate mofetil (MMF) + IV cyclophosphamide (CPA) versus IV CPA, Outcome 6 Daily proteinuria.

Comparison 4 Mycophenolate mofetil (MMF) + IV cyclophosphamide (CPA) versus IV CPA, Outcome 6 Daily proteinuria.

Open in table viewer
Comparison 5. Mycophenolate mofetil (MMF) versus tacrolimus (TAC)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Death Show forest plot

3

273

Risk Ratio (M‐H, Random, 95% CI)

1.10 [0.44, 2.77]

Analysis 5.1

Comparison 5 Mycophenolate mofetil (MMF) versus tacrolimus (TAC), Outcome 1 Death.

Comparison 5 Mycophenolate mofetil (MMF) versus tacrolimus (TAC), Outcome 1 Death.

2 Remission Show forest plot

3

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 5.2

Comparison 5 Mycophenolate mofetil (MMF) versus tacrolimus (TAC), Outcome 2 Remission.

Comparison 5 Mycophenolate mofetil (MMF) versus tacrolimus (TAC), Outcome 2 Remission.

2.1 Complete renal remission

3

273

Risk Ratio (M‐H, Random, 95% CI)

1.02 [0.83, 1.26]

2.2 Partial renal remission

2

190

Risk Ratio (M‐H, Random, 95% CI)

0.83 [0.51, 1.36]

2.3 Complete remission in proteinuria

1

40

Risk Ratio (M‐H, Random, 95% CI)

1.0 [0.50, 1.98]

2.4 Partial remission in proteinuria

2

190

Risk Ratio (M‐H, Random, 95% CI)

0.90 [0.79, 1.03]

3 Adverse renal outcomes Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 5.3

Comparison 5 Mycophenolate mofetil (MMF) versus tacrolimus (TAC), Outcome 3 Adverse renal outcomes.

Comparison 5 Mycophenolate mofetil (MMF) versus tacrolimus (TAC), Outcome 3 Adverse renal outcomes.

3.1 ESKD

1

150

Risk Ratio (M‐H, Random, 95% CI)

1.22 [0.51, 2.91]

3.2 Renal relapse

1

150

Risk Ratio (M‐H, Random, 95% CI)

0.67 [0.48, 0.93]

3.3 Renal relapse (nephritic flare)

1

152

Risk Ratio (M‐H, Random, 95% CI)

0.68 [0.36, 1.28]

3.4 Renal relapse (proteinuric flare)

1

150

Risk Ratio (M‐H, Random, 95% CI)

0.67 [0.41, 1.12]

3.5 Deterioration in kidney function

1

150

Risk Ratio (M‐H, Random, 95% CI)

0.54 [0.27, 1.09]

4 Stable kidney function Show forest plot

1

40

Risk Ratio (M‐H, Random, 95% CI)

1.0 [0.50, 1.98]

Analysis 5.4

Comparison 5 Mycophenolate mofetil (MMF) versus tacrolimus (TAC), Outcome 4 Stable kidney function.

Comparison 5 Mycophenolate mofetil (MMF) versus tacrolimus (TAC), Outcome 4 Stable kidney function.

5 Menstrual irregularities Show forest plot

1

40

Risk Ratio (M‐H, Random, 95% CI)

3.0 [0.13, 69.52]

Analysis 5.5

Comparison 5 Mycophenolate mofetil (MMF) versus tacrolimus (TAC), Outcome 5 Menstrual irregularities.

Comparison 5 Mycophenolate mofetil (MMF) versus tacrolimus (TAC), Outcome 5 Menstrual irregularities.

6 Infection Show forest plot

2

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 5.6

Comparison 5 Mycophenolate mofetil (MMF) versus tacrolimus (TAC), Outcome 6 Infection.

Comparison 5 Mycophenolate mofetil (MMF) versus tacrolimus (TAC), Outcome 6 Infection.

6.1 Major infection

2

190

Risk Ratio (M‐H, Random, 95% CI)

2.14 [0.93, 4.92]

6.2 Herpes zoster virus

1

150

Risk Ratio (M‐H, Random, 95% CI)

6.82 [1.60, 28.96]

7 Leucopenia Show forest plot

1

40

Risk Ratio (M‐H, Random, 95% CI)

1.0 [0.07, 14.90]

Analysis 5.7

Comparison 5 Mycophenolate mofetil (MMF) versus tacrolimus (TAC), Outcome 7 Leucopenia.

Comparison 5 Mycophenolate mofetil (MMF) versus tacrolimus (TAC), Outcome 7 Leucopenia.

8 Alopecia Show forest plot

1

150

Risk Ratio (M‐H, Random, 95% CI)

0.07 [0.00, 1.31]

Analysis 5.8

Comparison 5 Mycophenolate mofetil (MMF) versus tacrolimus (TAC), Outcome 8 Alopecia.

Comparison 5 Mycophenolate mofetil (MMF) versus tacrolimus (TAC), Outcome 8 Alopecia.

9 Daily proteinuria (at 24 weeks) Show forest plot

1

150

Mean Difference (IV, Random, 95% CI)

0.18 [‐0.25, 0.61]

Analysis 5.9

Comparison 5 Mycophenolate mofetil (MMF) versus tacrolimus (TAC), Outcome 9 Daily proteinuria (at 24 weeks).

Comparison 5 Mycophenolate mofetil (MMF) versus tacrolimus (TAC), Outcome 9 Daily proteinuria (at 24 weeks).

10 Disease activity Show forest plot

2

Mean Difference (IV, Random, 95% CI)

Subtotals only

Analysis 5.10

Comparison 5 Mycophenolate mofetil (MMF) versus tacrolimus (TAC), Outcome 10 Disease activity.

Comparison 5 Mycophenolate mofetil (MMF) versus tacrolimus (TAC), Outcome 10 Disease activity.

10.1 Renal SLEDAI

2

233

Mean Difference (IV, Random, 95% CI)

‐0.21 [‐2.05, 1.63]

10.2 Extrarenal SLEDAI

2

233

Mean Difference (IV, Random, 95% CI)

‐0.26 [‐0.74, 0.22]

11 Serum creatinine Show forest plot

1

83

Mean Difference (IV, Random, 95% CI)

‐0.01 [‐0.16, 0.14]

Analysis 5.11

Comparison 5 Mycophenolate mofetil (MMF) versus tacrolimus (TAC), Outcome 11 Serum creatinine.

Comparison 5 Mycophenolate mofetil (MMF) versus tacrolimus (TAC), Outcome 11 Serum creatinine.

12 Creatinine clearance Show forest plot

1

40

Mean Difference (IV, Random, 95% CI)

‐1.93 [‐7.77, 3.91]

Analysis 5.12

Comparison 5 Mycophenolate mofetil (MMF) versus tacrolimus (TAC), Outcome 12 Creatinine clearance.

Comparison 5 Mycophenolate mofetil (MMF) versus tacrolimus (TAC), Outcome 12 Creatinine clearance.

Open in table viewer
Comparison 6. Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Death Show forest plot

3

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 6.1

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 1 Death.

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 1 Death.

1.1 Death

3

153

Risk Ratio (M‐H, Random, 95% CI)

0.41 [0.06, 2.69]

1.2 Death: extended follow‐up

1

38

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2 Remission Show forest plot

4

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 6.2

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 2 Remission.

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 2 Remission.

2.1 Complete renal remission

4

178

Risk Ratio (M‐H, Random, 95% CI)

1.35 [0.94, 1.93]

2.2 Partial renal remission

4

178

Risk Ratio (M‐H, Random, 95% CI)

0.88 [0.61, 1.26]

2.3 Complete remission in proteinuria

3

105

Risk Ratio (M‐H, Random, 95% CI)

1.71 [1.08, 2.70]

3 Adverse renal outcomes Show forest plot

2

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 6.3

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 3 Adverse renal outcomes.

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 3 Adverse renal outcomes.

3.1 ESKD: extended follow‐up

1

38

Risk Ratio (M‐H, Random, 95% CI)

1.0 [0.07, 14.85]

3.2 Doubling of serum creatinine

1

40

Risk Ratio (M‐H, Random, 95% CI)

0.33 [0.01, 7.72]

3.3 Doubling of serum creatinine: extended follow‐up

1

38

Risk Ratio (M‐H, Random, 95% CI)

1.0 [0.16, 6.38]

4 Stable kidney function Show forest plot

4

186

Risk Ratio (M‐H, Random, 95% CI)

1.11 [0.61, 2.00]

Analysis 6.4

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 4 Stable kidney function.

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 4 Stable kidney function.

5 Ovarian failure Show forest plot

2

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 6.5

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 5 Ovarian failure.

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 5 Ovarian failure.

5.1 Ovarian failure

2

113

Risk Ratio (M‐H, Random, 95% CI)

0.25 [0.03, 2.18]

5.2 Premature ovarian failure: extended follow‐up

1

27

Risk Ratio (M‐H, Random, 95% CI)

0.31 [0.01, 7.02]

6 Menstrual irregularities Show forest plot

2

54

Risk Ratio (M‐H, Random, 95% CI)

0.41 [0.04, 4.05]

Analysis 6.6

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 6 Menstrual irregularities.

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 6 Menstrual irregularities.

7 Infection Show forest plot

4

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 6.7

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 7 Infection.

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 7 Infection.

7.1 Major infection

3

138

Risk Ratio (M‐H, Random, 95% CI)

0.73 [0.33, 1.63]

7.2 Herpes zoster virus

2

113

Risk Ratio (M‐H, Random, 95% CI)

1.41 [0.38, 5.20]

8 Malignancy: extended follow‐up Show forest plot

1

38

Risk Ratio (M‐H, Random, 95% CI)

5.0 [0.26, 97.70]

Analysis 6.8

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 8 Malignancy: extended follow‐up.

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 8 Malignancy: extended follow‐up.

9 Leucopenia Show forest plot

3

153

Risk Ratio (M‐H, Random, 95% CI)

0.44 [0.13, 1.49]

Analysis 6.9

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 9 Leucopenia.

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 9 Leucopenia.

10 Alopecia Show forest plot

2

113

Risk Ratio (M‐H, Random, 95% CI)

0.21 [0.02, 1.76]

Analysis 6.10

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 10 Alopecia.

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 10 Alopecia.

11 Gastrointestinal (GI) adverse events Show forest plot

1

73

Risk Ratio (M‐H, Random, 95% CI)

0.35 [0.12, 1.01]

Analysis 6.11

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 11 Gastrointestinal (GI) adverse events.

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 11 Gastrointestinal (GI) adverse events.

12 Daily proteinuria Show forest plot

2

156

Mean Difference (IV, Random, 95% CI)

‐0.37 [‐0.67, ‐0.07]

Analysis 6.12

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 12 Daily proteinuria.

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 12 Daily proteinuria.

12.1 At 9 months

1

40

Mean Difference (IV, Random, 95% CI)

‐0.83 [‐1.37, ‐0.29]

12.2 At 12 months

1

38

Mean Difference (IV, Random, 95% CI)

‐0.27 [‐0.43, ‐0.11]

12.3 At 18 months

1

40

Mean Difference (IV, Random, 95% CI)

‐1.0 [‐2.26, 0.26]

12.4 Extended follow‐up

1

38

Mean Difference (IV, Random, 95% CI)

‐0.10 [‐0.49, 0.29]

13 Creatinine clearance Show forest plot

3

Mean Difference (IV, Random, 95% CI)

Subtotals only

Analysis 6.13

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 13 Creatinine clearance.

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 13 Creatinine clearance.

13.1 At 6 months

1

150

Mean Difference (IV, Random, 95% CI)

11.70 [1.61, 21.79]

13.2 At 9 months

1

40

Mean Difference (IV, Random, 95% CI)

14.90 [1.35, 28.45]

13.3 At 12 months

1

38

Mean Difference (IV, Random, 95% CI)

‐15.70 [‐23.71, ‐7.69]

13.4 At 18 months

1

40

Mean Difference (IV, Random, 95% CI)

‐1.40 [‐17.25, 14.45]

14 Serum creatinine Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

Analysis 6.14

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 14 Serum creatinine.

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 14 Serum creatinine.

14.1 At 9 months

1

40

Mean Difference (IV, Random, 95% CI)

12.70 [1.88, 23.52]

14.2 At 18 months

1

40

Mean Difference (IV, Random, 95% CI)

2.70 [‐11.50, 16.90]

14.3 Extended follow‐up

1

38

Mean Difference (IV, Random, 95% CI)

‐8.0 [‐20.35, 4.35]

Open in table viewer
Comparison 7. Cyclophosphamide (CPA) versus azathioprine (AZA)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Death Show forest plot

2

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 7.1

Comparison 7 Cyclophosphamide (CPA) versus azathioprine (AZA), Outcome 1 Death.

Comparison 7 Cyclophosphamide (CPA) versus azathioprine (AZA), Outcome 1 Death.

1.1 At 5 years

2

146

Risk Ratio (M‐H, Random, 95% CI)

1.39 [0.25, 7.77]

1.2 At 10 years

1

59

Risk Ratio (M‐H, Random, 95% CI)

1.93 [1.22, 3.06]

2 Remission in proteinuria Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 7.2

Comparison 7 Cyclophosphamide (CPA) versus azathioprine (AZA), Outcome 2 Remission in proteinuria.

Comparison 7 Cyclophosphamide (CPA) versus azathioprine (AZA), Outcome 2 Remission in proteinuria.

2.1 Complete remission

1

59

Risk Ratio (M‐H, Random, 95% CI)

2.03 [0.64, 6.46]

2.2 Partial remission

1

59

Risk Ratio (M‐H, Random, 95% CI)

1.80 [0.67, 4.81]

3 Adverse renal outcomes Show forest plot

2

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 7.3

Comparison 7 Cyclophosphamide (CPA) versus azathioprine (AZA), Outcome 3 Adverse renal outcomes.

Comparison 7 Cyclophosphamide (CPA) versus azathioprine (AZA), Outcome 3 Adverse renal outcomes.

3.1 ESKD

2

144

Risk Ratio (M‐H, Random, 95% CI)

0.40 [0.15, 1.07]

3.2 ESKD at 9.6 years (median)

1

100

Risk Ratio (M‐H, Random, 95% CI)

1.0 [0.15, 6.82]

3.3 Renal relapse

1

87

Risk Ratio (M‐H, Random, 95% CI)

0.15 [0.03, 0.64]

3.4 Renal relapse at 9.6 years (median)

1

87

Risk Ratio (M‐H, Random, 95% CI)

0.26 [0.10, 0.67]

3.5 Doubling of serum creatinine

2

144

Risk Ratio (M‐H, Random, 95% CI)

0.48 [0.24, 0.95]

3.6 Deterioration of kidney function

1

30

Risk Ratio (M‐H, Random, 95% CI)

0.67 [0.18, 2.42]

4 Stable kidney function Show forest plot

1

57

Risk Ratio (M‐H, Random, 95% CI)

1.32 [0.86, 2.01]

Analysis 7.4

Comparison 7 Cyclophosphamide (CPA) versus azathioprine (AZA), Outcome 4 Stable kidney function.

Comparison 7 Cyclophosphamide (CPA) versus azathioprine (AZA), Outcome 4 Stable kidney function.

5 Ovarian failure Show forest plot

2

126

Risk Ratio (M‐H, Random, 95% CI)

2.11 [0.59, 7.53]

Analysis 7.5

Comparison 7 Cyclophosphamide (CPA) versus azathioprine (AZA), Outcome 5 Ovarian failure.

Comparison 7 Cyclophosphamide (CPA) versus azathioprine (AZA), Outcome 5 Ovarian failure.

6 Menstrual irregularities Show forest plot

1

15

Risk Ratio (M‐H, Random, 95% CI)

1.90 [0.69, 5.23]

Analysis 7.6

Comparison 7 Cyclophosphamide (CPA) versus azathioprine (AZA), Outcome 6 Menstrual irregularities.

Comparison 7 Cyclophosphamide (CPA) versus azathioprine (AZA), Outcome 6 Menstrual irregularities.

7 Infection Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 7.7

Comparison 7 Cyclophosphamide (CPA) versus azathioprine (AZA), Outcome 7 Infection.

Comparison 7 Cyclophosphamide (CPA) versus azathioprine (AZA), Outcome 7 Infection.

7.1 Major infection

1

57

Risk Ratio (M‐H, Random, 95% CI)

1.25 [0.27, 5.86]

7.2 Herpes zoster virus

1

57

Risk Ratio (M‐H, Random, 95% CI)

2.75 [0.68, 11.18]

8 Malignancy Show forest plot

2

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 7.8

Comparison 7 Cyclophosphamide (CPA) versus azathioprine (AZA), Outcome 8 Malignancy.

Comparison 7 Cyclophosphamide (CPA) versus azathioprine (AZA), Outcome 8 Malignancy.

8.1 CPA versus AZA

2

144

Risk Ratio (M‐H, Random, 95% CI)

0.59 [0.13, 2.63]

8.2 10 year follow‐up

1

87

Risk Ratio (M‐H, Random, 95% CI)

0.74 [0.11, 5.01]

9 Bone toxicity Show forest plot

1

87

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

Analysis 7.9

Comparison 7 Cyclophosphamide (CPA) versus azathioprine (AZA), Outcome 9 Bone toxicity.

Comparison 7 Cyclophosphamide (CPA) versus azathioprine (AZA), Outcome 9 Bone toxicity.

10 Bladder toxicity Show forest plot

2

144

Risk Ratio (M‐H, Random, 95% CI)

3.59 [0.19, 66.14]

Analysis 7.10

Comparison 7 Cyclophosphamide (CPA) versus azathioprine (AZA), Outcome 10 Bladder toxicity.

Comparison 7 Cyclophosphamide (CPA) versus azathioprine (AZA), Outcome 10 Bladder toxicity.

Open in table viewer
Comparison 8. Rituximab (RTX) + mycophenolate mofetil (MMF) versus placebo + MMF

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Death Show forest plot

1

144

Risk Ratio (M‐H, Random, 95% CI)

5.0 [0.24, 102.35]

Analysis 8.1

Comparison 8 Rituximab (RTX) + mycophenolate mofetil (MMF) versus placebo + MMF, Outcome 1 Death.

Comparison 8 Rituximab (RTX) + mycophenolate mofetil (MMF) versus placebo + MMF, Outcome 1 Death.

2 Remission Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 8.2

Comparison 8 Rituximab (RTX) + mycophenolate mofetil (MMF) versus placebo + MMF, Outcome 2 Remission.

Comparison 8 Rituximab (RTX) + mycophenolate mofetil (MMF) versus placebo + MMF, Outcome 2 Remission.

2.1 Complete renal response

1

144

Risk Ratio (M‐H, Random, 95% CI)

0.86 [0.51, 1.45]

2.2 Partial renal response

1

144

Risk Ratio (M‐H, Random, 95% CI)

2.0 [1.05, 3.82]

2.3 Complete remission in proteinuria

1

144

Risk Ratio (M‐H, Random, 95% CI)

0.87 [0.63, 1.21]

3 Stable kidney function Show forest plot

1

144

Risk Ratio (M‐H, Random, 95% CI)

1.24 [0.90, 1.71]

Analysis 8.3

Comparison 8 Rituximab (RTX) + mycophenolate mofetil (MMF) versus placebo + MMF, Outcome 3 Stable kidney function.

Comparison 8 Rituximab (RTX) + mycophenolate mofetil (MMF) versus placebo + MMF, Outcome 3 Stable kidney function.

4 Infection Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 8.4

Comparison 8 Rituximab (RTX) + mycophenolate mofetil (MMF) versus placebo + MMF, Outcome 4 Infection.

Comparison 8 Rituximab (RTX) + mycophenolate mofetil (MMF) versus placebo + MMF, Outcome 4 Infection.

4.1 Major infection

1

144

Risk Ratio (M‐H, Random, 95% CI)

1.0 [0.48, 2.08]

4.2 Herpes zoster virus

1

144

Risk Ratio (M‐H, Random, 95% CI)

0.82 [0.36, 1.85]

5 Leucopenia Show forest plot

1

144

Risk Ratio (M‐H, Random, 95% CI)

3.0 [0.85, 10.63]

Analysis 8.5

Comparison 8 Rituximab (RTX) + mycophenolate mofetil (MMF) versus placebo + MMF, Outcome 5 Leucopenia.

Comparison 8 Rituximab (RTX) + mycophenolate mofetil (MMF) versus placebo + MMF, Outcome 5 Leucopenia.

Open in table viewer
Comparison 9. Rituximab (RTX) + cyclophosphamide (CPA) versus RTX

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Remission Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 9.1

Comparison 9 Rituximab (RTX) + cyclophosphamide (CPA) versus RTX, Outcome 1 Remission.

Comparison 9 Rituximab (RTX) + cyclophosphamide (CPA) versus RTX, Outcome 1 Remission.

1.1 Complete renal response

1

19

Risk Ratio (M‐H, Random, 95% CI)

0.9 [0.16, 5.13]

1.2 Partial renal response

1

19

Risk Ratio (M‐H, Random, 95% CI)

0.75 [0.35, 1.62]

2 Infection Show forest plot

1

38

Risk Ratio (M‐H, Random, 95% CI)

0.57 [0.08, 4.20]

Analysis 9.2

Comparison 9 Rituximab (RTX) + cyclophosphamide (CPA) versus RTX, Outcome 2 Infection.

Comparison 9 Rituximab (RTX) + cyclophosphamide (CPA) versus RTX, Outcome 2 Infection.

2.1 Major infection

1

19

Risk Ratio (M‐H, Random, 95% CI)

0.9 [0.07, 12.38]

2.2 Herpes zoster virus

1

19

Risk Ratio (M‐H, Random, 95% CI)

0.30 [0.01, 6.62]

3 Daily proteinuria Show forest plot

1

19

Mean Difference (IV, Random, 95% CI)

‐0.30 [‐2.29, 1.69]

Analysis 9.3

Comparison 9 Rituximab (RTX) + cyclophosphamide (CPA) versus RTX, Outcome 3 Daily proteinuria.

Comparison 9 Rituximab (RTX) + cyclophosphamide (CPA) versus RTX, Outcome 3 Daily proteinuria.

4 Creatinine clearance Show forest plot

1

19

Mean Difference (IV, Random, 95% CI)

‐17.20 [‐50.66, 16.26]

Analysis 9.4

Comparison 9 Rituximab (RTX) + cyclophosphamide (CPA) versus RTX, Outcome 4 Creatinine clearance.

Comparison 9 Rituximab (RTX) + cyclophosphamide (CPA) versus RTX, Outcome 4 Creatinine clearance.

5 Serum creatinine Show forest plot

1

19

Mean Difference (IV, Random, 95% CI)

35.00 [‐27.14, 97.14]

Analysis 9.5

Comparison 9 Rituximab (RTX) + cyclophosphamide (CPA) versus RTX, Outcome 5 Serum creatinine.

Comparison 9 Rituximab (RTX) + cyclophosphamide (CPA) versus RTX, Outcome 5 Serum creatinine.

Open in table viewer
Comparison 10. Abatacept + other immunosuppressive agent (IS) + versus placebo + other IS

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Death Show forest plot

2

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 10.1

Comparison 10 Abatacept + other immunosuppressive agent (IS) + versus placebo + other IS, Outcome 1 Death.

Comparison 10 Abatacept + other immunosuppressive agent (IS) + versus placebo + other IS, Outcome 1 Death.

1.1 Abatacept versus placebo

2

432

Risk Ratio (M‐H, Random, 95% CI)

0.29 [0.10, 0.91]

1.2 High dose abatacept versus placebo

1

199

Risk Ratio (M‐H, Random, 95% CI)

0.29 [0.06, 1.36]

1.3 Low dose abatacept versus placebo

1

199

Risk Ratio (M‐H, Random, 95% CI)

0.29 [0.06, 1.36]

2 Remission Show forest plot

2

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 10.2

Comparison 10 Abatacept + other immunosuppressive agent (IS) + versus placebo + other IS, Outcome 2 Remission.

Comparison 10 Abatacept + other immunosuppressive agent (IS) + versus placebo + other IS, Outcome 2 Remission.

2.1 Complete remission: abatacept versus placebo

2

432

Risk Ratio (M‐H, Random, 95% CI)

1.13 [0.74, 1.71]

2.2 Complete remission: high dose abatacept versus placebo

1

199

Risk Ratio (M‐H, Random, 95% CI)

1.14 [0.46, 2.83]

2.3 Complete remission: low dose abatacept versus placebo

1

199

Risk Ratio (M‐H, Random, 95% CI)

1.39 [0.58, 3.31]

2.4 Partial remission: abatacept versus placebo

2

432

Risk Ratio (M‐H, Random, 95% CI)

0.88 [0.58, 1.33]

2.5 Partial remission: high dose abatacept versus placebo

1

199

Risk Ratio (M‐H, Random, 95% CI)

1.01 [0.51, 2.01]

2.6 Partial remission: low dose abatacept versus placebo

1

199

Risk Ratio (M‐H, Random, 95% CI)

0.65 [0.29, 1.43]

3 Adverse renal outcomes Show forest plot

2

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 10.3

Comparison 10 Abatacept + other immunosuppressive agent (IS) + versus placebo + other IS, Outcome 3 Adverse renal outcomes.

Comparison 10 Abatacept + other immunosuppressive agent (IS) + versus placebo + other IS, Outcome 3 Adverse renal outcomes.

3.1 ESKD: Abatacept versus placebo

1

298

Risk Ratio (M‐H, Random, 95% CI)

0.84 [0.21, 3.45]

3.2 ESKD: high dose abatacept versus placebo

1

199

Risk Ratio (M‐H, Random, 95% CI)

1.01 [0.21, 4.88]

3.3 ESKD: low dose abatacept versus placebo

1

199

Risk Ratio (M‐H, Random, 95% CI)

0.67 [0.11, 3.94]

3.4 Renal relapse: abatacept versus placebo

1

134

Risk Ratio (M‐H, Random, 95% CI)

1.03 [0.22, 4.92]

4 Major Infection Show forest plot

2

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 10.4

Comparison 10 Abatacept + other immunosuppressive agent (IS) + versus placebo + other IS, Outcome 4 Major Infection.

Comparison 10 Abatacept + other immunosuppressive agent (IS) + versus placebo + other IS, Outcome 4 Major Infection.

4.1 Abatacept versus placebo

2

432

Risk Ratio (M‐H, Random, 95% CI)

1.29 [0.81, 2.04]

4.2 High dose abatacept versus placebo

1

199

Risk Ratio (M‐H, Random, 95% CI)

1.37 [0.78, 2.40]

4.3 Low dose abatacept versus placebo

1

199

Risk Ratio (M‐H, Random, 95% CI)

1.07 [0.59, 1.95]

5 Herpes zoster virus Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 10.5

Comparison 10 Abatacept + other immunosuppressive agent (IS) + versus placebo + other IS, Outcome 5 Herpes zoster virus.

Comparison 10 Abatacept + other immunosuppressive agent (IS) + versus placebo + other IS, Outcome 5 Herpes zoster virus.

5.1 Abatacept versus placebo

1

298

Risk Ratio (M‐H, Random, 95% CI)

9.64 [0.57, 164.02]

5.2 High dose abatacept versus placebo

1

199

Risk Ratio (M‐H, Random, 95% CI)

7.07 [0.37, 135.11]

5.3 Low dose abatacept versus placebo

1

199

Risk Ratio (M‐H, Random, 95% CI)

13.13 [0.75, 229.99]

6 Health‐related quality of life Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

Analysis 10.6

Comparison 10 Abatacept + other immunosuppressive agent (IS) + versus placebo + other IS, Outcome 6 Health‐related quality of life.

Comparison 10 Abatacept + other immunosuppressive agent (IS) + versus placebo + other IS, Outcome 6 Health‐related quality of life.

6.1 Physical component

1

134

Mean Difference (IV, Random, 95% CI)

0.0 [‐3.73, 3.73]

6.2 Mental component

1

134

Mean Difference (IV, Random, 95% CI)

‐0.60 [‐4.50, 3.30]

7 Disease activity (BILAG) Show forest plot

1

134

Mean Difference (IV, Random, 95% CI)

‐0.40 [‐1.23, 0.43]

Analysis 10.7

Comparison 10 Abatacept + other immunosuppressive agent (IS) + versus placebo + other IS, Outcome 7 Disease activity (BILAG).

Comparison 10 Abatacept + other immunosuppressive agent (IS) + versus placebo + other IS, Outcome 7 Disease activity (BILAG).

Open in table viewer
Comparison 11. Laquinimod + other immunosuppressive agent (IS) versus placebo + other IS

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Death Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 11.1

Comparison 11 Laquinimod + other immunosuppressive agent (IS) versus placebo + other IS, Outcome 1 Death.

Comparison 11 Laquinimod + other immunosuppressive agent (IS) versus placebo + other IS, Outcome 1 Death.

1.1 Laquinimod versus placebo

1

46

Risk Ratio (M‐H, Random, 95% CI)

1.5 [0.06, 34.79]

1.2 High dose laquinimod versus placebo

1

30

Risk Ratio (M‐H, Random, 95% CI)

3.0 [0.13, 68.26]

1.3 Low dose laquinimod versus placebo

1

31

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2 Complete remission Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 11.2

Comparison 11 Laquinimod + other immunosuppressive agent (IS) versus placebo + other IS, Outcome 2 Complete remission.

Comparison 11 Laquinimod + other immunosuppressive agent (IS) versus placebo + other IS, Outcome 2 Complete remission.

2.1 Complete remission: laquinimod versus placebo

1

46

Risk Ratio (M‐H, Random, 95% CI)

1.55 [0.70, 3.42]

2.2 Complete remission: high dose laquinimod versus placebo

1

30

Risk Ratio (M‐H, Random, 95% CI)

1.2 [0.47, 3.09]

2.3 Complete remission: low dose laquinimod versus placebo

1

31

Risk Ratio (M‐H, Random, 95% CI)

1.88 [0.83, 4.22]

Open in table viewer
Comparison 12. Ocrelizumab + other immunosuppressive agent (IS) versus placebo + other IS

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Death Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 12.1

Comparison 12 Ocrelizumab + other immunosuppressive agent (IS) versus placebo + other IS, Outcome 1 Death.

Comparison 12 Ocrelizumab + other immunosuppressive agent (IS) versus placebo + other IS, Outcome 1 Death.

1.1 Ocrelizumab versus placebo

1

379

Risk Ratio (M‐H, Random, 95% CI)

0.66 [0.23, 1.85]

1.2 High dose ocrelizumab versus placebo

1

253

Risk Ratio (M‐H, Random, 95% CI)

0.81 [0.25, 2.60]

1.3 Low dose ocrelizumab versus placebo

1

251

Risk Ratio (M‐H, Random, 95% CI)

0.50 [0.13, 1.94]

2 Remission Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 12.2

Comparison 12 Ocrelizumab + other immunosuppressive agent (IS) versus placebo + other IS, Outcome 2 Remission.

Comparison 12 Ocrelizumab + other immunosuppressive agent (IS) versus placebo + other IS, Outcome 2 Remission.

2.1 Complete remission: ocrelizumab versus placebo

1

223

Risk Ratio (M‐H, Random, 95% CI)

1.07 [0.74, 1.56]

2.2 Complete remission: high dose ocrelizumab versus placebo

1

148

Risk Ratio (M‐H, Random, 95% CI)

0.91 [0.57, 1.44]

2.3 Complete remission: low dose ocrelizumab versus placebo

1

150

Risk Ratio (M‐H, Random, 95% CI)

1.23 [0.82, 1.85]

2.4 Partial remission: ocrelizumab versus placebo

1

223

Risk Ratio (M‐H, Random, 95% CI)

1.49 [0.89, 2.49]

2.5 Partial remission: high dose ocrelizumab versus placebo

1

148

Risk Ratio (M‐H, Random, 95% CI)

1.78 [1.03, 3.08]

2.6 Partial remission: low dose ocrelizumab versus placebo

1

150

Risk Ratio (M‐H, Random, 95% CI)

1.2 [0.65, 2.20]

3 Major Infection Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 12.3

Comparison 12 Ocrelizumab + other immunosuppressive agent (IS) versus placebo + other IS, Outcome 3 Major Infection.

Comparison 12 Ocrelizumab + other immunosuppressive agent (IS) versus placebo + other IS, Outcome 3 Major Infection.

3.1 Ocrelizumab versus placebo

1

378

Risk Ratio (M‐H, Random, 95% CI)

1.14 [0.95, 1.36]

3.2 High dose ocrelizumab versus placebo

1

252

Risk Ratio (M‐H, Random, 95% CI)

1.05 [0.85, 1.30]

3.3 Low dose ocrelizumab versus placebo

1

251

Risk Ratio (M‐H, Random, 95% CI)

1.22 [1.00, 1.48]

Open in table viewer
Comparison 13. Sirukumab + other immunosuppressive agent (IS) versus placebo + other IS

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Death Show forest plot

1

25

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

Analysis 13.1

Comparison 13 Sirukumab + other immunosuppressive agent (IS) versus placebo + other IS, Outcome 1 Death.

Comparison 13 Sirukumab + other immunosuppressive agent (IS) versus placebo + other IS, Outcome 1 Death.

2 Infection Show forest plot

1

25

Risk Ratio (M‐H, Random, 95% CI)

0.93 [0.66, 1.32]

Analysis 13.2

Comparison 13 Sirukumab + other immunosuppressive agent (IS) versus placebo + other IS, Outcome 2 Infection.

Comparison 13 Sirukumab + other immunosuppressive agent (IS) versus placebo + other IS, Outcome 2 Infection.

2.1 Major infection

1

25

Risk Ratio (M‐H, Random, 95% CI)

0.93 [0.66, 1.32]

3 Malignancy Show forest plot

1

25

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

Analysis 13.3

Comparison 13 Sirukumab + other immunosuppressive agent (IS) versus placebo + other IS, Outcome 3 Malignancy.

Comparison 13 Sirukumab + other immunosuppressive agent (IS) versus placebo + other IS, Outcome 3 Malignancy.

4 Gastrointestinal (GI) adverse events Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 13.4

Comparison 13 Sirukumab + other immunosuppressive agent (IS) versus placebo + other IS, Outcome 4 Gastrointestinal (GI) adverse events.

Comparison 13 Sirukumab + other immunosuppressive agent (IS) versus placebo + other IS, Outcome 4 Gastrointestinal (GI) adverse events.

4.1 Diarrhoea

1

25

Risk Ratio (M‐H, Random, 95% CI)

1.59 [0.10, 26.15]

Open in table viewer
Comparison 14. IV versus oral cyclophosphamide (CPA)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Death Show forest plot

2

67

Risk Ratio (M‐H, Random, 95% CI)

0.80 [0.20, 3.24]

Analysis 14.1

Comparison 14 IV versus oral cyclophosphamide (CPA), Outcome 1 Death.

Comparison 14 IV versus oral cyclophosphamide (CPA), Outcome 1 Death.

2 Adverse renal outcomes Show forest plot

2

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 14.2

Comparison 14 IV versus oral cyclophosphamide (CPA), Outcome 2 Adverse renal outcomes.

Comparison 14 IV versus oral cyclophosphamide (CPA), Outcome 2 Adverse renal outcomes.

2.1 ESKD

2

67

Risk Ratio (M‐H, Random, 95% CI)

0.23 [0.04, 1.28]

2.2 Doubling of serum creatinine

2

67

Risk Ratio (M‐H, Random, 95% CI)

0.67 [0.23, 1.98]

2.3 Deterioration of kidney function

1

38

Risk Ratio (M‐H, Random, 95% CI)

0.72 [0.23, 2.27]

3 Stable kidney function Show forest plot

1

38

Risk Ratio (M‐H, Random, 95% CI)

1.11 [0.77, 1.59]

Analysis 14.3

Comparison 14 IV versus oral cyclophosphamide (CPA), Outcome 3 Stable kidney function.

Comparison 14 IV versus oral cyclophosphamide (CPA), Outcome 3 Stable kidney function.

4 Ovarian failure Show forest plot

2

56

Risk Ratio (M‐H, Random, 95% CI)

0.70 [0.37, 1.30]

Analysis 14.4

Comparison 14 IV versus oral cyclophosphamide (CPA), Outcome 4 Ovarian failure.

Comparison 14 IV versus oral cyclophosphamide (CPA), Outcome 4 Ovarian failure.

5 Infection Show forest plot

2

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 14.5

Comparison 14 IV versus oral cyclophosphamide (CPA), Outcome 5 Infection.

Comparison 14 IV versus oral cyclophosphamide (CPA), Outcome 5 Infection.

5.1 Major infection

2

67

Risk Ratio (M‐H, Random, 95% CI)

1.16 [0.47, 2.90]

5.2 Herpes zoster virus

1

38

Risk Ratio (M‐H, Random, 95% CI)

0.75 [0.28, 2.04]

6 Malignancy Show forest plot

2

67

Risk Ratio (M‐H, Random, 95% CI)

1.43 [0.41, 4.96]

Analysis 14.6

Comparison 14 IV versus oral cyclophosphamide (CPA), Outcome 6 Malignancy.

Comparison 14 IV versus oral cyclophosphamide (CPA), Outcome 6 Malignancy.

7 Bladder toxicity Show forest plot

2

67

Risk Ratio (M‐H, Random, 95% CI)

0.22 [0.03, 1.83]

Analysis 14.7

Comparison 14 IV versus oral cyclophosphamide (CPA), Outcome 7 Bladder toxicity.

Comparison 14 IV versus oral cyclophosphamide (CPA), Outcome 7 Bladder toxicity.

8 Gastrointestinal (GI) adverse events Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 14.8

Comparison 14 IV versus oral cyclophosphamide (CPA), Outcome 8 Gastrointestinal (GI) adverse events.

Comparison 14 IV versus oral cyclophosphamide (CPA), Outcome 8 Gastrointestinal (GI) adverse events.

8.1 GI upset

1

29

Risk Ratio (M‐H, Random, 95% CI)

3.69 [0.43, 31.43]

Open in table viewer
Comparison 15. Low versus high dose cyclophosphamide (CPA)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Death Show forest plot

4

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 15.1

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 1 Death.

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 1 Death.

1.1 At 6 months

1

117

Risk Ratio (M‐H, Random, 95% CI)

1.81 [0.19, 16.85]

1.2 At 12 months

2

121

Risk Ratio (M‐H, Random, 95% CI)

0.97 [0.14, 6.56]

1.3 At 5 years

1

85

Risk Ratio (M‐H, Random, 95% CI)

0.13 [0.01, 2.51]

1.4 At 10 years

1

90

Risk Ratio (M‐H, Random, 95% CI)

0.38 [0.08, 1.87]

2 Remission Show forest plot

3

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 15.2

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 2 Remission.

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 2 Remission.

2.1 Complete renal remission

3

267

Risk Ratio (M‐H, Random, 95% CI)

1.09 [0.63, 1.86]

2.2 Partial renal remission

3

267

Risk Ratio (M‐H, Random, 95% CI)

0.88 [0.69, 1.14]

3 Adverse renal outcomes Show forest plot

3

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 15.3

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 3 Adverse renal outcomes.

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 3 Adverse renal outcomes.

3.1 ESKD

2

135

Risk Ratio (M‐H, Random, 95% CI)

0.49 [0.05, 5.20]

3.2 ESKD at 5 years

1

85

Risk Ratio (M‐H, Random, 95% CI)

2.80 [0.30, 25.81]

3.3 ESKD at 10 years

1

90

Risk Ratio (M‐H, Random, 95% CI)

1.91 [0.37, 9.92]

3.4 Renal relapse

3

211

Risk Ratio (M‐H, Random, 95% CI)

2.75 [0.47, 15.98]

3.5 Doubling of serum creatinine

2

135

Risk Ratio (M‐H, Random, 95% CI)

0.33 [0.04, 3.02]

3.6 Doubling of serum creatinine at 5 years

1

85

Risk Ratio (M‐H, Random, 95% CI)

0.13 [0.02, 1.04]

3.7 Doubling of serum creatinine at 10 years

1

90

Risk Ratio (M‐H, Random, 95% CI)

0.80 [0.26, 2.42]

4 Stable kidney function Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 15.4

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 4 Stable kidney function.

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 4 Stable kidney function.

4.1 At 3 years

1

89

Risk Ratio (M‐H, Random, 95% CI)

0.72 [0.50, 1.03]

4.2 At 5 years

1

85

Risk Ratio (M‐H, Random, 95% CI)

0.96 [0.77, 1.20]

5 Ovarian failure Show forest plot

4

299

Risk Ratio (M‐H, Random, 95% CI)

1.73 [0.70, 4.31]

Analysis 15.5

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 5 Ovarian failure.

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 5 Ovarian failure.

6 Infection Show forest plot

4

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 15.6

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 6 Infection.

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 6 Infection.

6.1 Major infection

4

327

Risk Ratio (M‐H, Random, 95% CI)

1.44 [0.83, 2.49]

6.2 Herpes zoster virus

3

281

Risk Ratio (M‐H, Random, 95% CI)

1.58 [0.41, 6.05]

7 Malignancy Show forest plot

2

206

Risk Ratio (M‐H, Random, 95% CI)

1.44 [0.09, 23.31]

Analysis 15.7

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 7 Malignancy.

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 7 Malignancy.

8 Leucopenia Show forest plot

3

281

Risk Ratio (M‐H, Random, 95% CI)

0.82 [0.13, 5.15]

Analysis 15.8

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 8 Leucopenia.

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 8 Leucopenia.

9 Bone toxicity Show forest plot

2

164

Risk Ratio (M‐H, Random, 95% CI)

2.93 [0.48, 18.02]

Analysis 15.9

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 9 Bone toxicity.

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 9 Bone toxicity.

10 Alopecia Show forest plot

1

75

Risk Ratio (M‐H, Random, 95% CI)

0.28 [0.06, 1.25]

Analysis 15.10

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 10 Alopecia.

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 10 Alopecia.

11 Gastrointestinal (GI) adverse events Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 15.11

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 11 Gastrointestinal (GI) adverse events.

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 11 Gastrointestinal (GI) adverse events.

11.1 GI disturbance

1

75

Risk Ratio (M‐H, Random, 95% CI)

0.11 [0.01, 1.94]

12 Daily proteinuria Show forest plot

3

242

Mean Difference (IV, Random, 95% CI)

‐0.10 [‐0.65, 0.46]

Analysis 15.12

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 12 Daily proteinuria.

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 12 Daily proteinuria.

13 Creatinine clearance Show forest plot

1

117

Mean Difference (IV, Random, 95% CI)

‐12.60 [‐23.63, ‐1.57]

Analysis 15.13

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 13 Creatinine clearance.

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 13 Creatinine clearance.

14 Serum creatinine Show forest plot

3

247

Mean Difference (IV, Random, 95% CI)

2.85 [‐7.61, 13.31]

Analysis 15.14

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 14 Serum creatinine.

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 14 Serum creatinine.

15 Disease activity (SLEDAI) Show forest plot

1

75

Mean Difference (IV, Random, 95% CI)

‐1.50 [‐3.04, 0.04]

Analysis 15.15

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 15 Disease activity (SLEDAI).

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 15 Disease activity (SLEDAI).

Open in table viewer
Comparison 16. Standard versus reduced dose oral corticosteroids

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Death Show forest plot

1

81

Risk Ratio (M‐H, Random, 95% CI)

4.65 [0.23, 93.95]

Analysis 16.1

Comparison 16 Standard versus reduced dose oral corticosteroids, Outcome 1 Death.

Comparison 16 Standard versus reduced dose oral corticosteroids, Outcome 1 Death.

2 Remission Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 16.2

Comparison 16 Standard versus reduced dose oral corticosteroids, Outcome 2 Remission.

Comparison 16 Standard versus reduced dose oral corticosteroids, Outcome 2 Remission.

2.1 Complete renal remission

1

81

Risk Ratio (M‐H, Random, 95% CI)

0.93 [0.39, 2.23]

2.2 Partial renal remission

1

81

Risk Ratio (M‐H, Random, 95% CI)

1.33 [0.78, 2.24]

3 Relapse Show forest plot

1

50

Risk Ratio (M‐H, Random, 95% CI)

2.38 [0.10, 55.72]

Analysis 16.3

Comparison 16 Standard versus reduced dose oral corticosteroids, Outcome 3 Relapse.

Comparison 16 Standard versus reduced dose oral corticosteroids, Outcome 3 Relapse.

4 Infection Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 16.4

Comparison 16 Standard versus reduced dose oral corticosteroids, Outcome 4 Infection.

Comparison 16 Standard versus reduced dose oral corticosteroids, Outcome 4 Infection.

4.1 Major infection

1

81

Risk Ratio (M‐H, Random, 95% CI)

4.64 [0.57, 38.00]

4.2 Herpes zoster virus

1

81

Risk Ratio (M‐H, Random, 95% CI)

13.95 [0.82, 236.48]

5 Gastrointestinal (GI) adverse events Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 16.5

Comparison 16 Standard versus reduced dose oral corticosteroids, Outcome 5 Gastrointestinal (GI) adverse events.

Comparison 16 Standard versus reduced dose oral corticosteroids, Outcome 5 Gastrointestinal (GI) adverse events.

5.1 Diarrhoea

1

81

Risk Ratio (M‐H, Random, 95% CI)

1.16 [0.51, 2.64]

5.2 Vomiting

1

81

Risk Ratio (M‐H, Random, 95% CI)

0.93 [0.25, 3.46]

5.3 Nausea

1

81

Risk Ratio (M‐H, Random, 95% CI)

2.79 [0.30, 25.67]

6 Creatinine clearance Show forest plot

1

74

Mean Difference (IV, Random, 95% CI)

‐5.80 [‐21.08, 9.48]

Analysis 16.6

Comparison 16 Standard versus reduced dose oral corticosteroids, Outcome 6 Creatinine clearance.

Comparison 16 Standard versus reduced dose oral corticosteroids, Outcome 6 Creatinine clearance.

7 Serum creatinine Show forest plot

1

81

Mean Difference (IV, Random, 95% CI)

‐2.40 [‐15.98, 11.18]

Analysis 16.7

Comparison 16 Standard versus reduced dose oral corticosteroids, Outcome 7 Serum creatinine.

Comparison 16 Standard versus reduced dose oral corticosteroids, Outcome 7 Serum creatinine.

Open in table viewer
Comparison 17. IV versus oral corticosteroids

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Death Show forest plot

1

22

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

Analysis 17.1

Comparison 17 IV versus oral corticosteroids, Outcome 1 Death.

Comparison 17 IV versus oral corticosteroids, Outcome 1 Death.

2 Adverse renal outcomes Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 17.2

Comparison 17 IV versus oral corticosteroids, Outcome 2 Adverse renal outcomes.

Comparison 17 IV versus oral corticosteroids, Outcome 2 Adverse renal outcomes.

2.1 Renal relapse

1

22

Risk Ratio (M‐H, Random, 95% CI)

0.95 [0.44, 2.04]

Open in table viewer
Comparison 18. Cyclophosphamide (CPA) + corticosteroids versus corticosteroids

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Death Show forest plot

5

226

Risk Ratio (M‐H, Random, 95% CI)

0.98 [0.53, 1.82]

Analysis 18.1

Comparison 18 Cyclophosphamide (CPA) + corticosteroids versus corticosteroids, Outcome 1 Death.

Comparison 18 Cyclophosphamide (CPA) + corticosteroids versus corticosteroids, Outcome 1 Death.

2 Complete remission of proteinuria Show forest plot

1

13

Risk Ratio (M‐H, Random, 95% CI)

2.63 [0.13, 54.64]

Analysis 18.2

Comparison 18 Cyclophosphamide (CPA) + corticosteroids versus corticosteroids, Outcome 2 Complete remission of proteinuria.

Comparison 18 Cyclophosphamide (CPA) + corticosteroids versus corticosteroids, Outcome 2 Complete remission of proteinuria.

3 Adverse renal outcomes Show forest plot

5

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 18.3

Comparison 18 Cyclophosphamide (CPA) + corticosteroids versus corticosteroids, Outcome 3 Adverse renal outcomes.

Comparison 18 Cyclophosphamide (CPA) + corticosteroids versus corticosteroids, Outcome 3 Adverse renal outcomes.

3.1 ESKD

5

278

Risk Ratio (M‐H, Random, 95% CI)

0.63 [0.39, 1.03]

3.2 Renal relapse

2

84

Risk Ratio (M‐H, Random, 95% CI)

0.23 [0.08, 0.62]

3.3 Doubling serum creatinine

4

228

Risk Ratio (M‐H, Random, 95% CI)

0.59 [0.40, 0.88]

4 Deterioration of kidney function Show forest plot

5

179

Risk Ratio (M‐H, Random, 95% CI)

0.78 [0.52, 1.18]

Analysis 18.4

Comparison 18 Cyclophosphamide (CPA) + corticosteroids versus corticosteroids, Outcome 4 Deterioration of kidney function.

Comparison 18 Cyclophosphamide (CPA) + corticosteroids versus corticosteroids, Outcome 4 Deterioration of kidney function.

5 Stable kidney function Show forest plot

5

278

Risk Ratio (M‐H, Random, 95% CI)

1.20 [1.00, 1.45]

Analysis 18.5

Comparison 18 Cyclophosphamide (CPA) + corticosteroids versus corticosteroids, Outcome 5 Stable kidney function.

Comparison 18 Cyclophosphamide (CPA) + corticosteroids versus corticosteroids, Outcome 5 Stable kidney function.

6 Ovarian failure Show forest plot

3

147

Risk Ratio (M‐H, Random, 95% CI)

2.18 [1.10, 4.34]

Analysis 18.6

Comparison 18 Cyclophosphamide (CPA) + corticosteroids versus corticosteroids, Outcome 6 Ovarian failure.

Comparison 18 Cyclophosphamide (CPA) + corticosteroids versus corticosteroids, Outcome 6 Ovarian failure.

7 Infection Show forest plot

6

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 18.7

Comparison 18 Cyclophosphamide (CPA) + corticosteroids versus corticosteroids, Outcome 7 Infection.

Comparison 18 Cyclophosphamide (CPA) + corticosteroids versus corticosteroids, Outcome 7 Infection.

7.1 Major infection

6

291

Risk Ratio (M‐H, Random, 95% CI)

0.87 [0.50, 1.51]

7.2 Herpes zoster virus

3

199

Risk Ratio (M‐H, Random, 95% CI)

1.77 [0.63, 4.99]

8 Malignancy Show forest plot

2

117

Risk Ratio (M‐H, Random, 95% CI)

0.82 [0.07, 9.90]

Analysis 18.8

Comparison 18 Cyclophosphamide (CPA) + corticosteroids versus corticosteroids, Outcome 8 Malignancy.

Comparison 18 Cyclophosphamide (CPA) + corticosteroids versus corticosteroids, Outcome 8 Malignancy.

9 Bone toxicity Show forest plot

3

197

Risk Ratio (M‐H, Random, 95% CI)

0.84 [0.40, 1.75]

Analysis 18.9

Comparison 18 Cyclophosphamide (CPA) + corticosteroids versus corticosteroids, Outcome 9 Bone toxicity.

Comparison 18 Cyclophosphamide (CPA) + corticosteroids versus corticosteroids, Outcome 9 Bone toxicity.

10 Bladder toxicity Show forest plot

2

65

Risk Ratio (M‐H, Random, 95% CI)

2.66 [0.33, 21.68]

Analysis 18.10

Comparison 18 Cyclophosphamide (CPA) + corticosteroids versus corticosteroids, Outcome 10 Bladder toxicity.

Comparison 18 Cyclophosphamide (CPA) + corticosteroids versus corticosteroids, Outcome 10 Bladder toxicity.

11 Daily proteinuria Show forest plot

3

92

Mean Difference (IV, Random, 95% CI)

0.15 [‐0.23, 0.54]

Analysis 18.11

Comparison 18 Cyclophosphamide (CPA) + corticosteroids versus corticosteroids, Outcome 11 Daily proteinuria.

Comparison 18 Cyclophosphamide (CPA) + corticosteroids versus corticosteroids, Outcome 11 Daily proteinuria.

12 Serum creatinine Show forest plot

1

29

Mean Difference (IV, Random, 95% CI)

‐52.0 [‐111.39, 7.39]

Analysis 18.12

Comparison 18 Cyclophosphamide (CPA) + corticosteroids versus corticosteroids, Outcome 12 Serum creatinine.

Comparison 18 Cyclophosphamide (CPA) + corticosteroids versus corticosteroids, Outcome 12 Serum creatinine.

13 Creatinine clearance Show forest plot

2

63

Mean Difference (IV, Random, 95% CI)

12.23 [‐0.13, 24.58]

Analysis 18.13

Comparison 18 Cyclophosphamide (CPA) + corticosteroids versus corticosteroids, Outcome 13 Creatinine clearance.

Comparison 18 Cyclophosphamide (CPA) + corticosteroids versus corticosteroids, Outcome 13 Creatinine clearance.

Open in table viewer
Comparison 19. Cyclophosphamide (CPA) + azathioprine (AZA) + corticosteroids versus corticosteroids alone

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Death Show forest plot

1

29

Risk Ratio (M‐H, Random, 95% CI)

0.53 [0.17, 1.68]

Analysis 19.1

Comparison 19 Cyclophosphamide (CPA) + azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 1 Death.

Comparison 19 Cyclophosphamide (CPA) + azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 1 Death.

2 Adverse renal outcomes Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 19.2

Comparison 19 Cyclophosphamide (CPA) + azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 2 Adverse renal outcomes.

Comparison 19 Cyclophosphamide (CPA) + azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 2 Adverse renal outcomes.

2.1 ESKD

1

29

Risk Ratio (M‐H, Random, 95% CI)

0.21 [0.04, 1.02]

2.2 Doubling of serum creatinine

1

29

Risk Ratio (M‐H, Random, 95% CI)

0.16 [0.04, 0.69]

3 Stable kidney function Show forest plot

1

29

Risk Ratio (M‐H, Random, 95% CI)

1.59 [0.83, 3.06]

Analysis 19.3

Comparison 19 Cyclophosphamide (CPA) + azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 3 Stable kidney function.

Comparison 19 Cyclophosphamide (CPA) + azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 3 Stable kidney function.

4 Ovarian failure Show forest plot

1

27

Risk Ratio (M‐H, Random, 95% CI)

7.32 [0.49, 108.96]

Analysis 19.4

Comparison 19 Cyclophosphamide (CPA) + azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 4 Ovarian failure.

Comparison 19 Cyclophosphamide (CPA) + azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 4 Ovarian failure.

5 Infection Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 19.5

Comparison 19 Cyclophosphamide (CPA) + azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 5 Infection.

Comparison 19 Cyclophosphamide (CPA) + azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 5 Infection.

5.1 Major infection

1

29

Risk Ratio (M‐H, Random, 95% CI)

0.48 [0.10, 2.30]

5.2 Herpes zoster virus

1

29

Risk Ratio (M‐H, Random, 95% CI)

5.22 [0.33, 81.40]

6 Bladder toxicity Show forest plot

1

29

Risk Ratio (M‐H, Random, 95% CI)

2.43 [0.14, 42.17]

Analysis 19.6

Comparison 19 Cyclophosphamide (CPA) + azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 6 Bladder toxicity.

Comparison 19 Cyclophosphamide (CPA) + azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 6 Bladder toxicity.

Open in table viewer
Comparison 20. Azathioprine (AZA) + corticosteroids versus corticosteroids alone

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Death Show forest plot

3

78

Risk Ratio (M‐H, Random, 95% CI)

0.60 [0.36, 0.99]

Analysis 20.1

Comparison 20 Azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 1 Death.

Comparison 20 Azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 1 Death.

2 Complete remission of proteinuria Show forest plot

2

37

Risk Ratio (M‐H, Random, 95% CI)

0.95 [0.54, 1.69]

Analysis 20.2

Comparison 20 Azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 2 Complete remission of proteinuria.

Comparison 20 Azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 2 Complete remission of proteinuria.

3 Adverse renal outcomes Show forest plot

3

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 20.3

Comparison 20 Azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 3 Adverse renal outcomes.

Comparison 20 Azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 3 Adverse renal outcomes.

3.1 ESKD

2

54

Risk Ratio (M‐H, Random, 95% CI)

0.66 [0.17, 2.55]

3.2 Renal relapse

1

16

Risk Ratio (M‐H, Random, 95% CI)

0.78 [0.22, 2.74]

3.3 Doubling of serum creatinine

1

26

Risk Ratio (M‐H, Random, 95% CI)

0.98 [0.36, 2.68]

4 Stable kidney function Show forest plot

1

26

Risk Ratio (M‐H, Random, 95% CI)

1.01 [0.48, 2.14]

Analysis 20.4

Comparison 20 Azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 4 Stable kidney function.

Comparison 20 Azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 4 Stable kidney function.

5 Ovarian failure Show forest plot

1

24

Risk Ratio (M‐H, Random, 95% CI)

2.58 [0.15, 43.86]

Analysis 20.5

Comparison 20 Azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 5 Ovarian failure.

Comparison 20 Azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 5 Ovarian failure.

6 Infection Show forest plot

2

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 20.6

Comparison 20 Azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 6 Infection.

Comparison 20 Azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 6 Infection.

6.1 Herpes zoster virus

2

42

Risk Ratio (M‐H, Random, 95% CI)

3.56 [0.46, 27.79]

7 Malignancy Show forest plot

1

26

Risk Ratio (M‐H, Random, 95% CI)

2.0 [0.11, 37.22]

Analysis 20.7

Comparison 20 Azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 7 Malignancy.

Comparison 20 Azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 7 Malignancy.

8 Bone toxicity Show forest plot

1

24

Risk Ratio (M‐H, Random, 95% CI)

3.55 [0.43, 29.42]

Analysis 20.8

Comparison 20 Azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 8 Bone toxicity.

Comparison 20 Azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 8 Bone toxicity.

9 Creatinine clearance Show forest plot

1

24

Mean Difference (IV, Random, 95% CI)

5.0 [‐3.14, 13.14]

Analysis 20.9

Comparison 20 Azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 9 Creatinine clearance.

Comparison 20 Azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 9 Creatinine clearance.

Open in table viewer
Comparison 21. Cyclosporin (CSA) + corticosteroids versus corticosteroids alone

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Daily proteinuria Show forest plot

1

10

Mean Difference (IV, Random, 95% CI)

‐1.8 [‐2.59, ‐1.01]

Analysis 21.1

Comparison 21 Cyclosporin (CSA) + corticosteroids versus corticosteroids alone, Outcome 1 Daily proteinuria.

Comparison 21 Cyclosporin (CSA) + corticosteroids versus corticosteroids alone, Outcome 1 Daily proteinuria.

2 Serum creatinine Show forest plot

1

10

Mean Difference (IV, Random, 95% CI)

‐31.90 [‐73.63, 9.83]

Analysis 21.2

Comparison 21 Cyclosporin (CSA) + corticosteroids versus corticosteroids alone, Outcome 2 Serum creatinine.

Comparison 21 Cyclosporin (CSA) + corticosteroids versus corticosteroids alone, Outcome 2 Serum creatinine.

3 Creatinine clearance Show forest plot

1

10

Mean Difference (IV, Random, 95% CI)

‐42.5 [‐85.02, 0.02]

Analysis 21.3

Comparison 21 Cyclosporin (CSA) + corticosteroids versus corticosteroids alone, Outcome 3 Creatinine clearance.

Comparison 21 Cyclosporin (CSA) + corticosteroids versus corticosteroids alone, Outcome 3 Creatinine clearance.

Open in table viewer
Comparison 22. Misoprostol + corticosteroids versus corticosteroids alone

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Adverse renal outcomes Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 22.1

Comparison 22 Misoprostol + corticosteroids versus corticosteroids alone, Outcome 1 Adverse renal outcomes.

Comparison 22 Misoprostol + corticosteroids versus corticosteroids alone, Outcome 1 Adverse renal outcomes.

1.1 Doubling of serum creatinine

1

14

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

Open in table viewer
Comparison 23. Plasma exchange (PE) + immunosuppression (IS) versus IS alone

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Death Show forest plot

2

125

Risk Ratio (M‐H, Random, 95% CI)

1.62 [0.64, 4.09]

Analysis 23.1

Comparison 23 Plasma exchange (PE) + immunosuppression (IS) versus IS alone, Outcome 1 Death.

Comparison 23 Plasma exchange (PE) + immunosuppression (IS) versus IS alone, Outcome 1 Death.

2 Adverse renal outcomes Show forest plot

4

251

Risk Ratio (M‐H, Random, 95% CI)

0.89 [0.51, 1.55]

Analysis 23.2

Comparison 23 Plasma exchange (PE) + immunosuppression (IS) versus IS alone, Outcome 2 Adverse renal outcomes.

Comparison 23 Plasma exchange (PE) + immunosuppression (IS) versus IS alone, Outcome 2 Adverse renal outcomes.

2.1 ESKD

3

143

Risk Ratio (M‐H, Random, 95% CI)

1.24 [0.60, 2.57]

2.2 Doubling of serum creatinine

2

51

Risk Ratio (M‐H, Random, 95% CI)

0.17 [0.02, 1.26]

2.3 Deterioration of kidney function

2

57

Risk Ratio (M‐H, Random, 95% CI)

0.53 [0.06, 4.83]

3 Stable kidney function Show forest plot

3

75

Risk Ratio (M‐H, Random, 95% CI)

1.10 [0.94, 1.30]

Analysis 23.3

Comparison 23 Plasma exchange (PE) + immunosuppression (IS) versus IS alone, Outcome 3 Stable kidney function.

Comparison 23 Plasma exchange (PE) + immunosuppression (IS) versus IS alone, Outcome 3 Stable kidney function.

4 Infection Show forest plot

3

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 23.4

Comparison 23 Plasma exchange (PE) + immunosuppression (IS) versus IS alone, Outcome 4 Infection.

Comparison 23 Plasma exchange (PE) + immunosuppression (IS) versus IS alone, Outcome 4 Infection.

4.1 Major infection

2

125

Risk Ratio (M‐H, Random, 95% CI)

0.69 [0.35, 1.37]

4.2 Herpes zoster virus

2

104

Risk Ratio (M‐H, Random, 95% CI)

1.69 [0.10, 29.42]

5 Leucopenia Show forest plot

1

18

Risk Ratio (M‐H, Random, 95% CI)

2.60 [0.20, 34.07]

Analysis 23.5

Comparison 23 Plasma exchange (PE) + immunosuppression (IS) versus IS alone, Outcome 5 Leucopenia.

Comparison 23 Plasma exchange (PE) + immunosuppression (IS) versus IS alone, Outcome 5 Leucopenia.

6 Daily proteinuria Show forest plot

2

30

Mean Difference (IV, Random, 95% CI)

‐0.56 [‐5.23, 4.11]

Analysis 23.6

Comparison 23 Plasma exchange (PE) + immunosuppression (IS) versus IS alone, Outcome 6 Daily proteinuria.

Comparison 23 Plasma exchange (PE) + immunosuppression (IS) versus IS alone, Outcome 6 Daily proteinuria.

7 Serum creatinine Show forest plot

3

69

Mean Difference (IV, Random, 95% CI)

‐17.90 [‐23.41, ‐12.39]

Analysis 23.7

Comparison 23 Plasma exchange (PE) + immunosuppression (IS) versus IS alone, Outcome 7 Serum creatinine.

Comparison 23 Plasma exchange (PE) + immunosuppression (IS) versus IS alone, Outcome 7 Serum creatinine.

8 Creatinine clearance Show forest plot

1

12

Mean Difference (IV, Random, 95% CI)

26.0 [‐17.60, 69.60]

Analysis 23.8

Comparison 23 Plasma exchange (PE) + immunosuppression (IS) versus IS alone, Outcome 8 Creatinine clearance.

Comparison 23 Plasma exchange (PE) + immunosuppression (IS) versus IS alone, Outcome 8 Creatinine clearance.

9 Disease activity (SLAM) Show forest plot

1

18

Mean Difference (IV, Random, 95% CI)

0.67 [‐3.47, 4.81]

Analysis 23.9

Comparison 23 Plasma exchange (PE) + immunosuppression (IS) versus IS alone, Outcome 9 Disease activity (SLAM).

Comparison 23 Plasma exchange (PE) + immunosuppression (IS) versus IS alone, Outcome 9 Disease activity (SLAM).

Open in table viewer
Comparison 24. Plasma exchange (PE) versus immunosuppression (IS)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Adverse renal outcomes Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 24.1

Comparison 24 Plasma exchange (PE) versus immunosuppression (IS), Outcome 1 Adverse renal outcomes.

Comparison 24 Plasma exchange (PE) versus immunosuppression (IS), Outcome 1 Adverse renal outcomes.

1.1 ESKD

1

20

Risk Ratio (M‐H, Random, 95% CI)

0.24 [0.01, 4.44]

2 Infection Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 24.2

Comparison 24 Plasma exchange (PE) versus immunosuppression (IS), Outcome 2 Infection.

Comparison 24 Plasma exchange (PE) versus immunosuppression (IS), Outcome 2 Infection.

2.1 Major infection

1

20

Risk Ratio (M‐H, Random, 95% CI)

0.4 [0.02, 8.78]

2.2 Herpes zoster virus

1

20

Risk Ratio (M‐H, Random, 95% CI)

0.24 [0.01, 4.44]

3 Leucopenia Show forest plot

1

20

Risk Ratio (M‐H, Random, 95% CI)

0.24 [0.01, 4.44]

Analysis 24.3

Comparison 24 Plasma exchange (PE) versus immunosuppression (IS), Outcome 3 Leucopenia.

Comparison 24 Plasma exchange (PE) versus immunosuppression (IS), Outcome 3 Leucopenia.

4 Alopecia Show forest plot

1

20

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

Analysis 24.4

Comparison 24 Plasma exchange (PE) versus immunosuppression (IS), Outcome 4 Alopecia.

Comparison 24 Plasma exchange (PE) versus immunosuppression (IS), Outcome 4 Alopecia.

5 Daily proteinuria Show forest plot

1

20

Mean Difference (IV, Random, 95% CI)

‐0.10 [‐0.45, 0.25]

Analysis 24.5

Comparison 24 Plasma exchange (PE) versus immunosuppression (IS), Outcome 5 Daily proteinuria.

Comparison 24 Plasma exchange (PE) versus immunosuppression (IS), Outcome 5 Daily proteinuria.

6 Creatinine clearance Show forest plot

1

20

Mean Difference (IV, Random, 95% CI)

15.30 [‐5.40, 36.00]

Analysis 24.6

Comparison 24 Plasma exchange (PE) versus immunosuppression (IS), Outcome 6 Creatinine clearance.

Comparison 24 Plasma exchange (PE) versus immunosuppression (IS), Outcome 6 Creatinine clearance.

Open in table viewer
Comparison 25. Long versus short duration cyclophosphamide (CPA)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Adverse renal outcomes Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 25.1

Comparison 25 Long versus short duration cyclophosphamide (CPA), Outcome 1 Adverse renal outcomes.

Comparison 25 Long versus short duration cyclophosphamide (CPA), Outcome 1 Adverse renal outcomes.

1.1 ESKD

1

40

Risk Ratio (M‐H, Random, 95% CI)

0.4 [0.09, 1.83]

1.2 Doubling of serum creatinine

1

40

Risk Ratio (M‐H, Random, 95% CI)

0.43 [0.13, 1.43]

1.3 Deterioration of kidney function

1

40

Risk Ratio (M‐H, Random, 95% CI)

0.43 [0.13, 1.43]

2 Stable kidney function Show forest plot

1

40

Risk Ratio (M‐H, Random, 95% CI)

1.31 [0.90, 1.89]

Analysis 25.2

Comparison 25 Long versus short duration cyclophosphamide (CPA), Outcome 2 Stable kidney function.

Comparison 25 Long versus short duration cyclophosphamide (CPA), Outcome 2 Stable kidney function.

3 Ovarian failure Show forest plot

1

29

Risk Ratio (M‐H, Random, 95% CI)

2.05 [0.60, 7.02]

Analysis 25.3

Comparison 25 Long versus short duration cyclophosphamide (CPA), Outcome 3 Ovarian failure.

Comparison 25 Long versus short duration cyclophosphamide (CPA), Outcome 3 Ovarian failure.

4 Infection Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 25.4

Comparison 25 Long versus short duration cyclophosphamide (CPA), Outcome 4 Infection.

Comparison 25 Long versus short duration cyclophosphamide (CPA), Outcome 4 Infection.

4.1 Major infection

1

40

Risk Ratio (M‐H, Random, 95% CI)

1.0 [0.07, 14.90]

4.2 Herpes zoster virus

1

40

Risk Ratio (M‐H, Random, 95% CI)

0.5 [0.05, 5.08]

5 Malignancy Show forest plot

1

40

Risk Ratio (M‐H, Random, 95% CI)

3.0 [0.13, 69.52]

Analysis 25.5

Comparison 25 Long versus short duration cyclophosphamide (CPA), Outcome 5 Malignancy.

Comparison 25 Long versus short duration cyclophosphamide (CPA), Outcome 5 Malignancy.

6 Bone toxicity Show forest plot

1

40

Risk Ratio (M‐H, Random, 95% CI)

1.33 [0.34, 5.21]

Analysis 25.6

Comparison 25 Long versus short duration cyclophosphamide (CPA), Outcome 6 Bone toxicity.

Comparison 25 Long versus short duration cyclophosphamide (CPA), Outcome 6 Bone toxicity.

7 Bladder toxicity Show forest plot

1

40

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

Analysis 25.7

Comparison 25 Long versus short duration cyclophosphamide (CPA), Outcome 7 Bladder toxicity.

Comparison 25 Long versus short duration cyclophosphamide (CPA), Outcome 7 Bladder toxicity.

Open in table viewer
Comparison 26. Maintenance: azathioprine (AZA) versus mycophenolate mofetil (MMF)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Death Show forest plot

4

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 26.1

Comparison 26 Maintenance: azathioprine (AZA) versus mycophenolate mofetil (MMF), Outcome 1 Death.

Comparison 26 Maintenance: azathioprine (AZA) versus mycophenolate mofetil (MMF), Outcome 1 Death.

1.1 At end of treatment duration or follow‐up

4

451

Risk Ratio (M‐H, Random, 95% CI)

1.15 [0.34, 3.87]

1.2 At 10 years

1

87

Risk Ratio (M‐H, Random, 95% CI)

0.62 [0.11, 3.54]

2 Renal relapse Show forest plot

4

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 26.2

Comparison 26 Maintenance: azathioprine (AZA) versus mycophenolate mofetil (MMF), Outcome 2 Renal relapse.

Comparison 26 Maintenance: azathioprine (AZA) versus mycophenolate mofetil (MMF), Outcome 2 Renal relapse.

2.1 At end of treatment duration or follow‐up

4

452

Risk Ratio (M‐H, Random, 95% CI)

1.75 [1.20, 2.55]

2.2 At 10 years

1

87

Risk Ratio (M‐H, Random, 95% CI)

1.08 [0.69, 1.69]

3 End‐stage kidney disease Show forest plot

4

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 26.3

Comparison 26 Maintenance: azathioprine (AZA) versus mycophenolate mofetil (MMF), Outcome 3 End‐stage kidney disease.

Comparison 26 Maintenance: azathioprine (AZA) versus mycophenolate mofetil (MMF), Outcome 3 End‐stage kidney disease.

3.1 At end of treatment duration or follow‐up

4

452

Risk Ratio (M‐H, Random, 95% CI)

1.70 [0.52, 5.54]

3.2 At 10 years

1

87

Risk Ratio (M‐H, Random, 95% CI)

0.31 [0.03, 2.88]

4 Doubling of serum creatinine Show forest plot

4

452

Risk Ratio (M‐H, Random, 95% CI)

2.19 [1.03, 4.66]

Analysis 26.4

Comparison 26 Maintenance: azathioprine (AZA) versus mycophenolate mofetil (MMF), Outcome 4 Doubling of serum creatinine.

Comparison 26 Maintenance: azathioprine (AZA) versus mycophenolate mofetil (MMF), Outcome 4 Doubling of serum creatinine.

5 Ovarian failure Show forest plot

2

177

Risk Ratio (M‐H, Random, 95% CI)

0.77 [0.17, 3.42]

Analysis 26.5

Comparison 26 Maintenance: azathioprine (AZA) versus mycophenolate mofetil (MMF), Outcome 5 Ovarian failure.

Comparison 26 Maintenance: azathioprine (AZA) versus mycophenolate mofetil (MMF), Outcome 5 Ovarian failure.

6 Infection Show forest plot

3

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 26.6

Comparison 26 Maintenance: azathioprine (AZA) versus mycophenolate mofetil (MMF), Outcome 6 Infection.

Comparison 26 Maintenance: azathioprine (AZA) versus mycophenolate mofetil (MMF), Outcome 6 Infection.

6.1 Major infection

3

412

Risk Ratio (M‐H, Random, 95% CI)

1.08 [0.60, 1.96]

6.2 Herpes zoster virus

1

105

Risk Ratio (M‐H, Random, 95% CI)

1.27 [0.36, 4.48]

7 Malignancy Show forest plot

3

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 26.7

Comparison 26 Maintenance: azathioprine (AZA) versus mycophenolate mofetil (MMF), Outcome 7 Malignancy.

Comparison 26 Maintenance: azathioprine (AZA) versus mycophenolate mofetil (MMF), Outcome 7 Malignancy.

7.1 At end of treatment duration or follow‐up

3

370

Risk Ratio (M‐H, Random, 95% CI)

4.04 [0.45, 36.07]

7.2 At 10 years

1

87

Risk Ratio (M‐H, Random, 95% CI)

1.87 [0.18, 19.84]

8 Leucopenia Show forest plot

3

412

Risk Ratio (M‐H, Random, 95% CI)

5.61 [1.68, 18.72]

Analysis 26.8

Comparison 26 Maintenance: azathioprine (AZA) versus mycophenolate mofetil (MMF), Outcome 8 Leucopenia.

Comparison 26 Maintenance: azathioprine (AZA) versus mycophenolate mofetil (MMF), Outcome 8 Leucopenia.

9 Bone toxicity Show forest plot

1

105

Risk Ratio (M‐H, Random, 95% CI)

3.06 [0.13, 73.36]

Analysis 26.9

Comparison 26 Maintenance: azathioprine (AZA) versus mycophenolate mofetil (MMF), Outcome 9 Bone toxicity.

Comparison 26 Maintenance: azathioprine (AZA) versus mycophenolate mofetil (MMF), Outcome 9 Bone toxicity.

10 Alopecia Show forest plot

3

412

Risk Ratio (M‐H, Random, 95% CI)

0.95 [0.46, 1.95]

Analysis 26.10

Comparison 26 Maintenance: azathioprine (AZA) versus mycophenolate mofetil (MMF), Outcome 10 Alopecia.

Comparison 26 Maintenance: azathioprine (AZA) versus mycophenolate mofetil (MMF), Outcome 10 Alopecia.

11 Gastrointestinal (GI) adverse events Show forest plot

3

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 26.11

Comparison 26 Maintenance: azathioprine (AZA) versus mycophenolate mofetil (MMF), Outcome 11 Gastrointestinal (GI) adverse events.

Comparison 26 Maintenance: azathioprine (AZA) versus mycophenolate mofetil (MMF), Outcome 11 Gastrointestinal (GI) adverse events.

11.1 GI symptoms

1

105

Risk Ratio (M‐H, Random, 95% CI)

1.02 [0.41, 2.51]

11.2 Nausea

2

307

Risk Ratio (M‐H, Random, 95% CI)

1.08 [0.65, 1.80]

11.3 Diarrhoea

2

307

Risk Ratio (M‐H, Random, 95% CI)

0.74 [0.31, 1.73]

11.4 Vomiting

2

307

Risk Ratio (M‐H, Random, 95% CI)

0.81 [0.18, 3.62]

12 Daily proteinuria Show forest plot

1

81

Mean Difference (IV, Random, 95% CI)

0.40 [‐0.53, 1.33]

Analysis 26.12

Comparison 26 Maintenance: azathioprine (AZA) versus mycophenolate mofetil (MMF), Outcome 12 Daily proteinuria.

Comparison 26 Maintenance: azathioprine (AZA) versus mycophenolate mofetil (MMF), Outcome 12 Daily proteinuria.

Open in table viewer
Comparison 27. Maintenance: azathioprine (AZA) versus cyclosporin (CSA)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Death Show forest plot

1

69

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

Analysis 27.1

Comparison 27 Maintenance: azathioprine (AZA) versus cyclosporin (CSA), Outcome 1 Death.

Comparison 27 Maintenance: azathioprine (AZA) versus cyclosporin (CSA), Outcome 1 Death.

2 Adverse renal outcomes Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 27.2

Comparison 27 Maintenance: azathioprine (AZA) versus cyclosporin (CSA), Outcome 2 Adverse renal outcomes.

Comparison 27 Maintenance: azathioprine (AZA) versus cyclosporin (CSA), Outcome 2 Adverse renal outcomes.

2.1 ESKD

1

69

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2.2 Renal relapse

1

69

Risk Ratio (M‐H, Random, 95% CI)

1.25 [0.51, 3.06]

3 Infection Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 27.3

Comparison 27 Maintenance: azathioprine (AZA) versus cyclosporin (CSA), Outcome 3 Infection.

Comparison 27 Maintenance: azathioprine (AZA) versus cyclosporin (CSA), Outcome 3 Infection.

3.1 Major infection

1

69

Risk Ratio (M‐H, Random, 95% CI)

2.18 [1.01, 4.73]

4 Leucopenia Show forest plot

1

69

Risk Ratio (M‐H, Random, 95% CI)

2.73 [0.95, 7.86]

Analysis 27.4

Comparison 27 Maintenance: azathioprine (AZA) versus cyclosporin (CSA), Outcome 4 Leucopenia.

Comparison 27 Maintenance: azathioprine (AZA) versus cyclosporin (CSA), Outcome 4 Leucopenia.

5 Gastrointestinal (GI) adverse events Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 27.5

Comparison 27 Maintenance: azathioprine (AZA) versus cyclosporin (CSA), Outcome 5 Gastrointestinal (GI) adverse events.

Comparison 27 Maintenance: azathioprine (AZA) versus cyclosporin (CSA), Outcome 5 Gastrointestinal (GI) adverse events.

5.1 GI disturbance

1

69

Risk Ratio (M‐H, Random, 95% CI)

0.30 [0.09, 0.97]

6 Daily proteinuria Show forest plot

1

69

Mean Difference (IV, Random, 95% CI)

0.15 [‐0.23, 0.53]

Analysis 27.6

Comparison 27 Maintenance: azathioprine (AZA) versus cyclosporin (CSA), Outcome 6 Daily proteinuria.

Comparison 27 Maintenance: azathioprine (AZA) versus cyclosporin (CSA), Outcome 6 Daily proteinuria.

7 Disease activity (SLEDAI) Show forest plot

1

69

Mean Difference (IV, Random, 95% CI)

‐3.20 [‐5.77, ‐0.63]

Analysis 27.7

Comparison 27 Maintenance: azathioprine (AZA) versus cyclosporin (CSA), Outcome 7 Disease activity (SLEDAI).

Comparison 27 Maintenance: azathioprine (AZA) versus cyclosporin (CSA), Outcome 7 Disease activity (SLEDAI).

Open in table viewer
Comparison 28. Maintenance: azathioprine (AZA) versus cyclophosphamide (CPA)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Death Show forest plot

1

39

Risk Ratio (M‐H, Random, 95% CI)

0.12 [0.01, 2.03]

Analysis 28.1

Comparison 28 Maintenance: azathioprine (AZA) versus cyclophosphamide (CPA), Outcome 1 Death.

Comparison 28 Maintenance: azathioprine (AZA) versus cyclophosphamide (CPA), Outcome 1 Death.

2 Adverse renal outcomes Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 28.2

Comparison 28 Maintenance: azathioprine (AZA) versus cyclophosphamide (CPA), Outcome 2 Adverse renal outcomes.

Comparison 28 Maintenance: azathioprine (AZA) versus cyclophosphamide (CPA), Outcome 2 Adverse renal outcomes.

2.1 ESKD

1

39

Risk Ratio (M‐H, Random, 95% CI)

0.35 [0.04, 3.09]

2.2 Renal relapse

1

39

Risk Ratio (M‐H, Random, 95% CI)

0.79 [0.34, 1.85]

2.3 Doubling of serum creatinine

1

39

Risk Ratio (M‐H, Random, 95% CI)

0.79 [0.34, 1.85]

3 Bladder toxicity Show forest plot

1

39

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

Analysis 28.3

Comparison 28 Maintenance: azathioprine (AZA) versus cyclophosphamide (CPA), Outcome 3 Bladder toxicity.

Comparison 28 Maintenance: azathioprine (AZA) versus cyclophosphamide (CPA), Outcome 3 Bladder toxicity.

4 Creatinine clearance Show forest plot

1

38

Mean Difference (IV, Random, 95% CI)

‐15.70 [‐23.71, ‐7.69]

Analysis 28.4

Comparison 28 Maintenance: azathioprine (AZA) versus cyclophosphamide (CPA), Outcome 4 Creatinine clearance.

Comparison 28 Maintenance: azathioprine (AZA) versus cyclophosphamide (CPA), Outcome 4 Creatinine clearance.

Open in table viewer
Comparison 29. Maintenance: azathioprine (AZA) versus tacrolimus (TAC)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Adverse renal outcomes Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 29.1

Comparison 29 Maintenance: azathioprine (AZA) versus tacrolimus (TAC), Outcome 1 Adverse renal outcomes.

Comparison 29 Maintenance: azathioprine (AZA) versus tacrolimus (TAC), Outcome 1 Adverse renal outcomes.

1.1 Renal relapse

1

70

Risk Ratio (M‐H, Random, 95% CI)

6.62 [0.35, 123.63]

2 Infection Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 29.2

Comparison 29 Maintenance: azathioprine (AZA) versus tacrolimus (TAC), Outcome 2 Infection.

Comparison 29 Maintenance: azathioprine (AZA) versus tacrolimus (TAC), Outcome 2 Infection.

2.1 Major infection

1

70

Risk Ratio (M‐H, Random, 95% CI)

1.26 [0.30, 5.22]

3 Gastrointestinal (GI) adverse events Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 29.3

Comparison 29 Maintenance: azathioprine (AZA) versus tacrolimus (TAC), Outcome 3 Gastrointestinal (GI) adverse events.

Comparison 29 Maintenance: azathioprine (AZA) versus tacrolimus (TAC), Outcome 3 Gastrointestinal (GI) adverse events.

3.1 GI disturbance

1

70

Risk Ratio (M‐H, Random, 95% CI)

1.89 [0.18, 19.89]

Open in table viewer
Comparison 30. Maintenance: prednisone withdrawal versus prednisone continuation

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Relapse Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 30.1

Comparison 30 Maintenance: prednisone withdrawal versus prednisone continuation, Outcome 1 Relapse.

Comparison 30 Maintenance: prednisone withdrawal versus prednisone continuation, Outcome 1 Relapse.

1.1 Renal relapse

1

15

Risk Ratio (M‐H, Random, 95% CI)

0.38 [0.05, 2.88]

1.2 Non‐renal relapse

1

15

Risk Ratio (M‐H, Random, 95% CI)

0.38 [0.02, 7.96]

2 Major infection Show forest plot

1

15

Risk Ratio (M‐H, Random, 95% CI)

0.57 [0.06, 5.03]

Analysis 30.2

Comparison 30 Maintenance: prednisone withdrawal versus prednisone continuation, Outcome 2 Major infection.

Comparison 30 Maintenance: prednisone withdrawal versus prednisone continuation, Outcome 2 Major infection.

Open in table viewer
Comparison 31. Maintenance: intravenous immunoglobulin (IVIG) versus intravenous cyclophosphamide (IV CPA)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Creatinine clearance Show forest plot

1

13

Mean Difference (IV, Random, 95% CI)

2.20 [‐37.85, 42.25]

Analysis 31.1

Comparison 31 Maintenance: intravenous immunoglobulin (IVIG) versus intravenous cyclophosphamide (IV CPA), Outcome 1 Creatinine clearance.

Comparison 31 Maintenance: intravenous immunoglobulin (IVIG) versus intravenous cyclophosphamide (IV CPA), Outcome 1 Creatinine clearance.

2 Daily proteinuria Show forest plot

1

13

Mean Difference (IV, Random, 95% CI)

‐0.08 [‐0.95, 0.79]

Analysis 31.2

Comparison 31 Maintenance: intravenous immunoglobulin (IVIG) versus intravenous cyclophosphamide (IV CPA), Outcome 2 Daily proteinuria.

Comparison 31 Maintenance: intravenous immunoglobulin (IVIG) versus intravenous cyclophosphamide (IV CPA), Outcome 2 Daily proteinuria.

3 Serum creatinine Show forest plot

1

14

Mean Difference (IV, Random, 95% CI)

‐35.40 [‐128.90, 58.10]

Analysis 31.3

Comparison 31 Maintenance: intravenous immunoglobulin (IVIG) versus intravenous cyclophosphamide (IV CPA), Outcome 3 Serum creatinine.

Comparison 31 Maintenance: intravenous immunoglobulin (IVIG) versus intravenous cyclophosphamide (IV CPA), Outcome 3 Serum creatinine.

Study flow diagram.*Non‐RCTs have been deleted from this update
Figuras y tablas -
Figure 1

Study flow diagram.

*Non‐RCTs have been deleted from this update

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Figuras y tablas -
Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 1 Death.
Figuras y tablas -
Analysis 1.1

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 1 Death.

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 2 Remission.
Figuras y tablas -
Analysis 1.2

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 2 Remission.

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 3 Adverse renal outcomes.
Figuras y tablas -
Analysis 1.3

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 3 Adverse renal outcomes.

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 4 Stable kidney function.
Figuras y tablas -
Analysis 1.4

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 4 Stable kidney function.

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 5 Ovarian failure.
Figuras y tablas -
Analysis 1.5

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 5 Ovarian failure.

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 6 Menstrual irregularities.
Figuras y tablas -
Analysis 1.6

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 6 Menstrual irregularities.

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 7 Infection.
Figuras y tablas -
Analysis 1.7

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 7 Infection.

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 8 Malignancy.
Figuras y tablas -
Analysis 1.8

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 8 Malignancy.

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 9 Leucopenia.
Figuras y tablas -
Analysis 1.9

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 9 Leucopenia.

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 10 Bladder toxicity.
Figuras y tablas -
Analysis 1.10

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 10 Bladder toxicity.

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 11 Alopecia.
Figuras y tablas -
Analysis 1.11

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 11 Alopecia.

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 12 Gastrointestinal (GI) adverse events.
Figuras y tablas -
Analysis 1.12

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 12 Gastrointestinal (GI) adverse events.

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 13 Daily proteinuria.
Figuras y tablas -
Analysis 1.13

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 13 Daily proteinuria.

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 14 Serum creatinine.
Figuras y tablas -
Analysis 1.14

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 14 Serum creatinine.

Comparison 2 Mycophenolate mofetil (MMF) versus oral cyclophosphamide (CPA), Outcome 1 Death.
Figuras y tablas -
Analysis 2.1

Comparison 2 Mycophenolate mofetil (MMF) versus oral cyclophosphamide (CPA), Outcome 1 Death.

Comparison 2 Mycophenolate mofetil (MMF) versus oral cyclophosphamide (CPA), Outcome 2 Remission.
Figuras y tablas -
Analysis 2.2

Comparison 2 Mycophenolate mofetil (MMF) versus oral cyclophosphamide (CPA), Outcome 2 Remission.

Comparison 2 Mycophenolate mofetil (MMF) versus oral cyclophosphamide (CPA), Outcome 3 Adverse renal outcomes.
Figuras y tablas -
Analysis 2.3

Comparison 2 Mycophenolate mofetil (MMF) versus oral cyclophosphamide (CPA), Outcome 3 Adverse renal outcomes.

Comparison 2 Mycophenolate mofetil (MMF) versus oral cyclophosphamide (CPA), Outcome 4 Ovarian failure.
Figuras y tablas -
Analysis 2.4

Comparison 2 Mycophenolate mofetil (MMF) versus oral cyclophosphamide (CPA), Outcome 4 Ovarian failure.

Comparison 2 Mycophenolate mofetil (MMF) versus oral cyclophosphamide (CPA), Outcome 5 Infection.
Figuras y tablas -
Analysis 2.5

Comparison 2 Mycophenolate mofetil (MMF) versus oral cyclophosphamide (CPA), Outcome 5 Infection.

Comparison 2 Mycophenolate mofetil (MMF) versus oral cyclophosphamide (CPA), Outcome 6 Leucopenia.
Figuras y tablas -
Analysis 2.6

Comparison 2 Mycophenolate mofetil (MMF) versus oral cyclophosphamide (CPA), Outcome 6 Leucopenia.

Comparison 2 Mycophenolate mofetil (MMF) versus oral cyclophosphamide (CPA), Outcome 7 Bone toxicity.
Figuras y tablas -
Analysis 2.7

Comparison 2 Mycophenolate mofetil (MMF) versus oral cyclophosphamide (CPA), Outcome 7 Bone toxicity.

Comparison 2 Mycophenolate mofetil (MMF) versus oral cyclophosphamide (CPA), Outcome 8 Alopecia.
Figuras y tablas -
Analysis 2.8

Comparison 2 Mycophenolate mofetil (MMF) versus oral cyclophosphamide (CPA), Outcome 8 Alopecia.

Comparison 2 Mycophenolate mofetil (MMF) versus oral cyclophosphamide (CPA), Outcome 9 Gastrointestinal (GI) adverse events.
Figuras y tablas -
Analysis 2.9

Comparison 2 Mycophenolate mofetil (MMF) versus oral cyclophosphamide (CPA), Outcome 9 Gastrointestinal (GI) adverse events.

Comparison 2 Mycophenolate mofetil (MMF) versus oral cyclophosphamide (CPA), Outcome 10 Daily proteinuria.
Figuras y tablas -
Analysis 2.10

Comparison 2 Mycophenolate mofetil (MMF) versus oral cyclophosphamide (CPA), Outcome 10 Daily proteinuria.

Comparison 3 Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA), Outcome 1 Death.
Figuras y tablas -
Analysis 3.1

Comparison 3 Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA), Outcome 1 Death.

Comparison 3 Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA), Outcome 2 Remission.
Figuras y tablas -
Analysis 3.2

Comparison 3 Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA), Outcome 2 Remission.

Comparison 3 Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA), Outcome 3 Adverse renal outcomes.
Figuras y tablas -
Analysis 3.3

Comparison 3 Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA), Outcome 3 Adverse renal outcomes.

Comparison 3 Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA), Outcome 4 Stable kidney function.
Figuras y tablas -
Analysis 3.4

Comparison 3 Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA), Outcome 4 Stable kidney function.

Comparison 3 Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA), Outcome 5 Ovarian failure.
Figuras y tablas -
Analysis 3.5

Comparison 3 Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA), Outcome 5 Ovarian failure.

Comparison 3 Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA), Outcome 6 Menstrual irregularities.
Figuras y tablas -
Analysis 3.6

Comparison 3 Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA), Outcome 6 Menstrual irregularities.

Comparison 3 Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA), Outcome 7 Infection.
Figuras y tablas -
Analysis 3.7

Comparison 3 Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA), Outcome 7 Infection.

Comparison 3 Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA), Outcome 8 Leucopenia.
Figuras y tablas -
Analysis 3.8

Comparison 3 Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA), Outcome 8 Leucopenia.

Comparison 3 Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA), Outcome 9 Bone toxicity.
Figuras y tablas -
Analysis 3.9

Comparison 3 Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA), Outcome 9 Bone toxicity.

Comparison 3 Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA), Outcome 10 Alopecia.
Figuras y tablas -
Analysis 3.10

Comparison 3 Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA), Outcome 10 Alopecia.

Comparison 3 Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA), Outcome 11 Gastrointestinal (GI) adverse events.
Figuras y tablas -
Analysis 3.11

Comparison 3 Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA), Outcome 11 Gastrointestinal (GI) adverse events.

Comparison 3 Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA), Outcome 12 Daily proteinuria.
Figuras y tablas -
Analysis 3.12

Comparison 3 Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA), Outcome 12 Daily proteinuria.

Comparison 4 Mycophenolate mofetil (MMF) + IV cyclophosphamide (CPA) versus IV CPA, Outcome 1 Death.
Figuras y tablas -
Analysis 4.1

Comparison 4 Mycophenolate mofetil (MMF) + IV cyclophosphamide (CPA) versus IV CPA, Outcome 1 Death.

Comparison 4 Mycophenolate mofetil (MMF) + IV cyclophosphamide (CPA) versus IV CPA, Outcome 2 Remission.
Figuras y tablas -
Analysis 4.2

Comparison 4 Mycophenolate mofetil (MMF) + IV cyclophosphamide (CPA) versus IV CPA, Outcome 2 Remission.

Comparison 4 Mycophenolate mofetil (MMF) + IV cyclophosphamide (CPA) versus IV CPA, Outcome 3 Menstrual irregularities.
Figuras y tablas -
Analysis 4.3

Comparison 4 Mycophenolate mofetil (MMF) + IV cyclophosphamide (CPA) versus IV CPA, Outcome 3 Menstrual irregularities.

Comparison 4 Mycophenolate mofetil (MMF) + IV cyclophosphamide (CPA) versus IV CPA, Outcome 4 Infection.
Figuras y tablas -
Analysis 4.4

Comparison 4 Mycophenolate mofetil (MMF) + IV cyclophosphamide (CPA) versus IV CPA, Outcome 4 Infection.

Comparison 4 Mycophenolate mofetil (MMF) + IV cyclophosphamide (CPA) versus IV CPA, Outcome 5 Leucopenia.
Figuras y tablas -
Analysis 4.5

Comparison 4 Mycophenolate mofetil (MMF) + IV cyclophosphamide (CPA) versus IV CPA, Outcome 5 Leucopenia.

Comparison 4 Mycophenolate mofetil (MMF) + IV cyclophosphamide (CPA) versus IV CPA, Outcome 6 Daily proteinuria.
Figuras y tablas -
Analysis 4.6

Comparison 4 Mycophenolate mofetil (MMF) + IV cyclophosphamide (CPA) versus IV CPA, Outcome 6 Daily proteinuria.

Comparison 5 Mycophenolate mofetil (MMF) versus tacrolimus (TAC), Outcome 1 Death.
Figuras y tablas -
Analysis 5.1

Comparison 5 Mycophenolate mofetil (MMF) versus tacrolimus (TAC), Outcome 1 Death.

Comparison 5 Mycophenolate mofetil (MMF) versus tacrolimus (TAC), Outcome 2 Remission.
Figuras y tablas -
Analysis 5.2

Comparison 5 Mycophenolate mofetil (MMF) versus tacrolimus (TAC), Outcome 2 Remission.

Comparison 5 Mycophenolate mofetil (MMF) versus tacrolimus (TAC), Outcome 3 Adverse renal outcomes.
Figuras y tablas -
Analysis 5.3

Comparison 5 Mycophenolate mofetil (MMF) versus tacrolimus (TAC), Outcome 3 Adverse renal outcomes.

Comparison 5 Mycophenolate mofetil (MMF) versus tacrolimus (TAC), Outcome 4 Stable kidney function.
Figuras y tablas -
Analysis 5.4

Comparison 5 Mycophenolate mofetil (MMF) versus tacrolimus (TAC), Outcome 4 Stable kidney function.

Comparison 5 Mycophenolate mofetil (MMF) versus tacrolimus (TAC), Outcome 5 Menstrual irregularities.
Figuras y tablas -
Analysis 5.5

Comparison 5 Mycophenolate mofetil (MMF) versus tacrolimus (TAC), Outcome 5 Menstrual irregularities.

Comparison 5 Mycophenolate mofetil (MMF) versus tacrolimus (TAC), Outcome 6 Infection.
Figuras y tablas -
Analysis 5.6

Comparison 5 Mycophenolate mofetil (MMF) versus tacrolimus (TAC), Outcome 6 Infection.

Comparison 5 Mycophenolate mofetil (MMF) versus tacrolimus (TAC), Outcome 7 Leucopenia.
Figuras y tablas -
Analysis 5.7

Comparison 5 Mycophenolate mofetil (MMF) versus tacrolimus (TAC), Outcome 7 Leucopenia.

Comparison 5 Mycophenolate mofetil (MMF) versus tacrolimus (TAC), Outcome 8 Alopecia.
Figuras y tablas -
Analysis 5.8

Comparison 5 Mycophenolate mofetil (MMF) versus tacrolimus (TAC), Outcome 8 Alopecia.

Comparison 5 Mycophenolate mofetil (MMF) versus tacrolimus (TAC), Outcome 9 Daily proteinuria (at 24 weeks).
Figuras y tablas -
Analysis 5.9

Comparison 5 Mycophenolate mofetil (MMF) versus tacrolimus (TAC), Outcome 9 Daily proteinuria (at 24 weeks).

Comparison 5 Mycophenolate mofetil (MMF) versus tacrolimus (TAC), Outcome 10 Disease activity.
Figuras y tablas -
Analysis 5.10

Comparison 5 Mycophenolate mofetil (MMF) versus tacrolimus (TAC), Outcome 10 Disease activity.

Comparison 5 Mycophenolate mofetil (MMF) versus tacrolimus (TAC), Outcome 11 Serum creatinine.
Figuras y tablas -
Analysis 5.11

Comparison 5 Mycophenolate mofetil (MMF) versus tacrolimus (TAC), Outcome 11 Serum creatinine.

Comparison 5 Mycophenolate mofetil (MMF) versus tacrolimus (TAC), Outcome 12 Creatinine clearance.
Figuras y tablas -
Analysis 5.12

Comparison 5 Mycophenolate mofetil (MMF) versus tacrolimus (TAC), Outcome 12 Creatinine clearance.

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 1 Death.
Figuras y tablas -
Analysis 6.1

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 1 Death.

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 2 Remission.
Figuras y tablas -
Analysis 6.2

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 2 Remission.

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 3 Adverse renal outcomes.
Figuras y tablas -
Analysis 6.3

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 3 Adverse renal outcomes.

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 4 Stable kidney function.
Figuras y tablas -
Analysis 6.4

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 4 Stable kidney function.

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 5 Ovarian failure.
Figuras y tablas -
Analysis 6.5

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 5 Ovarian failure.

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 6 Menstrual irregularities.
Figuras y tablas -
Analysis 6.6

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 6 Menstrual irregularities.

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 7 Infection.
Figuras y tablas -
Analysis 6.7

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 7 Infection.

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 8 Malignancy: extended follow‐up.
Figuras y tablas -
Analysis 6.8

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 8 Malignancy: extended follow‐up.

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 9 Leucopenia.
Figuras y tablas -
Analysis 6.9

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 9 Leucopenia.

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 10 Alopecia.
Figuras y tablas -
Analysis 6.10

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 10 Alopecia.

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 11 Gastrointestinal (GI) adverse events.
Figuras y tablas -
Analysis 6.11

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 11 Gastrointestinal (GI) adverse events.

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 12 Daily proteinuria.
Figuras y tablas -
Analysis 6.12

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 12 Daily proteinuria.

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 13 Creatinine clearance.
Figuras y tablas -
Analysis 6.13

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 13 Creatinine clearance.

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 14 Serum creatinine.
Figuras y tablas -
Analysis 6.14

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 14 Serum creatinine.

Comparison 7 Cyclophosphamide (CPA) versus azathioprine (AZA), Outcome 1 Death.
Figuras y tablas -
Analysis 7.1

Comparison 7 Cyclophosphamide (CPA) versus azathioprine (AZA), Outcome 1 Death.

Comparison 7 Cyclophosphamide (CPA) versus azathioprine (AZA), Outcome 2 Remission in proteinuria.
Figuras y tablas -
Analysis 7.2

Comparison 7 Cyclophosphamide (CPA) versus azathioprine (AZA), Outcome 2 Remission in proteinuria.

Comparison 7 Cyclophosphamide (CPA) versus azathioprine (AZA), Outcome 3 Adverse renal outcomes.
Figuras y tablas -
Analysis 7.3

Comparison 7 Cyclophosphamide (CPA) versus azathioprine (AZA), Outcome 3 Adverse renal outcomes.

Comparison 7 Cyclophosphamide (CPA) versus azathioprine (AZA), Outcome 4 Stable kidney function.
Figuras y tablas -
Analysis 7.4

Comparison 7 Cyclophosphamide (CPA) versus azathioprine (AZA), Outcome 4 Stable kidney function.

Comparison 7 Cyclophosphamide (CPA) versus azathioprine (AZA), Outcome 5 Ovarian failure.
Figuras y tablas -
Analysis 7.5

Comparison 7 Cyclophosphamide (CPA) versus azathioprine (AZA), Outcome 5 Ovarian failure.

Comparison 7 Cyclophosphamide (CPA) versus azathioprine (AZA), Outcome 6 Menstrual irregularities.
Figuras y tablas -
Analysis 7.6

Comparison 7 Cyclophosphamide (CPA) versus azathioprine (AZA), Outcome 6 Menstrual irregularities.

Comparison 7 Cyclophosphamide (CPA) versus azathioprine (AZA), Outcome 7 Infection.
Figuras y tablas -
Analysis 7.7

Comparison 7 Cyclophosphamide (CPA) versus azathioprine (AZA), Outcome 7 Infection.

Comparison 7 Cyclophosphamide (CPA) versus azathioprine (AZA), Outcome 8 Malignancy.
Figuras y tablas -
Analysis 7.8

Comparison 7 Cyclophosphamide (CPA) versus azathioprine (AZA), Outcome 8 Malignancy.

Comparison 7 Cyclophosphamide (CPA) versus azathioprine (AZA), Outcome 9 Bone toxicity.
Figuras y tablas -
Analysis 7.9

Comparison 7 Cyclophosphamide (CPA) versus azathioprine (AZA), Outcome 9 Bone toxicity.

Comparison 7 Cyclophosphamide (CPA) versus azathioprine (AZA), Outcome 10 Bladder toxicity.
Figuras y tablas -
Analysis 7.10

Comparison 7 Cyclophosphamide (CPA) versus azathioprine (AZA), Outcome 10 Bladder toxicity.

Comparison 8 Rituximab (RTX) + mycophenolate mofetil (MMF) versus placebo + MMF, Outcome 1 Death.
Figuras y tablas -
Analysis 8.1

Comparison 8 Rituximab (RTX) + mycophenolate mofetil (MMF) versus placebo + MMF, Outcome 1 Death.

Comparison 8 Rituximab (RTX) + mycophenolate mofetil (MMF) versus placebo + MMF, Outcome 2 Remission.
Figuras y tablas -
Analysis 8.2

Comparison 8 Rituximab (RTX) + mycophenolate mofetil (MMF) versus placebo + MMF, Outcome 2 Remission.

Comparison 8 Rituximab (RTX) + mycophenolate mofetil (MMF) versus placebo + MMF, Outcome 3 Stable kidney function.
Figuras y tablas -
Analysis 8.3

Comparison 8 Rituximab (RTX) + mycophenolate mofetil (MMF) versus placebo + MMF, Outcome 3 Stable kidney function.

Comparison 8 Rituximab (RTX) + mycophenolate mofetil (MMF) versus placebo + MMF, Outcome 4 Infection.
Figuras y tablas -
Analysis 8.4

Comparison 8 Rituximab (RTX) + mycophenolate mofetil (MMF) versus placebo + MMF, Outcome 4 Infection.

Comparison 8 Rituximab (RTX) + mycophenolate mofetil (MMF) versus placebo + MMF, Outcome 5 Leucopenia.
Figuras y tablas -
Analysis 8.5

Comparison 8 Rituximab (RTX) + mycophenolate mofetil (MMF) versus placebo + MMF, Outcome 5 Leucopenia.

Comparison 9 Rituximab (RTX) + cyclophosphamide (CPA) versus RTX, Outcome 1 Remission.
Figuras y tablas -
Analysis 9.1

Comparison 9 Rituximab (RTX) + cyclophosphamide (CPA) versus RTX, Outcome 1 Remission.

Comparison 9 Rituximab (RTX) + cyclophosphamide (CPA) versus RTX, Outcome 2 Infection.
Figuras y tablas -
Analysis 9.2

Comparison 9 Rituximab (RTX) + cyclophosphamide (CPA) versus RTX, Outcome 2 Infection.

Comparison 9 Rituximab (RTX) + cyclophosphamide (CPA) versus RTX, Outcome 3 Daily proteinuria.
Figuras y tablas -
Analysis 9.3

Comparison 9 Rituximab (RTX) + cyclophosphamide (CPA) versus RTX, Outcome 3 Daily proteinuria.

Comparison 9 Rituximab (RTX) + cyclophosphamide (CPA) versus RTX, Outcome 4 Creatinine clearance.
Figuras y tablas -
Analysis 9.4

Comparison 9 Rituximab (RTX) + cyclophosphamide (CPA) versus RTX, Outcome 4 Creatinine clearance.

Comparison 9 Rituximab (RTX) + cyclophosphamide (CPA) versus RTX, Outcome 5 Serum creatinine.
Figuras y tablas -
Analysis 9.5

Comparison 9 Rituximab (RTX) + cyclophosphamide (CPA) versus RTX, Outcome 5 Serum creatinine.

Comparison 10 Abatacept + other immunosuppressive agent (IS) + versus placebo + other IS, Outcome 1 Death.
Figuras y tablas -
Analysis 10.1

Comparison 10 Abatacept + other immunosuppressive agent (IS) + versus placebo + other IS, Outcome 1 Death.

Comparison 10 Abatacept + other immunosuppressive agent (IS) + versus placebo + other IS, Outcome 2 Remission.
Figuras y tablas -
Analysis 10.2

Comparison 10 Abatacept + other immunosuppressive agent (IS) + versus placebo + other IS, Outcome 2 Remission.

Comparison 10 Abatacept + other immunosuppressive agent (IS) + versus placebo + other IS, Outcome 3 Adverse renal outcomes.
Figuras y tablas -
Analysis 10.3

Comparison 10 Abatacept + other immunosuppressive agent (IS) + versus placebo + other IS, Outcome 3 Adverse renal outcomes.

Comparison 10 Abatacept + other immunosuppressive agent (IS) + versus placebo + other IS, Outcome 4 Major Infection.
Figuras y tablas -
Analysis 10.4

Comparison 10 Abatacept + other immunosuppressive agent (IS) + versus placebo + other IS, Outcome 4 Major Infection.

Comparison 10 Abatacept + other immunosuppressive agent (IS) + versus placebo + other IS, Outcome 5 Herpes zoster virus.
Figuras y tablas -
Analysis 10.5

Comparison 10 Abatacept + other immunosuppressive agent (IS) + versus placebo + other IS, Outcome 5 Herpes zoster virus.

Comparison 10 Abatacept + other immunosuppressive agent (IS) + versus placebo + other IS, Outcome 6 Health‐related quality of life.
Figuras y tablas -
Analysis 10.6

Comparison 10 Abatacept + other immunosuppressive agent (IS) + versus placebo + other IS, Outcome 6 Health‐related quality of life.

Comparison 10 Abatacept + other immunosuppressive agent (IS) + versus placebo + other IS, Outcome 7 Disease activity (BILAG).
Figuras y tablas -
Analysis 10.7

Comparison 10 Abatacept + other immunosuppressive agent (IS) + versus placebo + other IS, Outcome 7 Disease activity (BILAG).

Comparison 11 Laquinimod + other immunosuppressive agent (IS) versus placebo + other IS, Outcome 1 Death.
Figuras y tablas -
Analysis 11.1

Comparison 11 Laquinimod + other immunosuppressive agent (IS) versus placebo + other IS, Outcome 1 Death.

Comparison 11 Laquinimod + other immunosuppressive agent (IS) versus placebo + other IS, Outcome 2 Complete remission.
Figuras y tablas -
Analysis 11.2

Comparison 11 Laquinimod + other immunosuppressive agent (IS) versus placebo + other IS, Outcome 2 Complete remission.

Comparison 12 Ocrelizumab + other immunosuppressive agent (IS) versus placebo + other IS, Outcome 1 Death.
Figuras y tablas -
Analysis 12.1

Comparison 12 Ocrelizumab + other immunosuppressive agent (IS) versus placebo + other IS, Outcome 1 Death.

Comparison 12 Ocrelizumab + other immunosuppressive agent (IS) versus placebo + other IS, Outcome 2 Remission.
Figuras y tablas -
Analysis 12.2

Comparison 12 Ocrelizumab + other immunosuppressive agent (IS) versus placebo + other IS, Outcome 2 Remission.

Comparison 12 Ocrelizumab + other immunosuppressive agent (IS) versus placebo + other IS, Outcome 3 Major Infection.
Figuras y tablas -
Analysis 12.3

Comparison 12 Ocrelizumab + other immunosuppressive agent (IS) versus placebo + other IS, Outcome 3 Major Infection.

Comparison 13 Sirukumab + other immunosuppressive agent (IS) versus placebo + other IS, Outcome 1 Death.
Figuras y tablas -
Analysis 13.1

Comparison 13 Sirukumab + other immunosuppressive agent (IS) versus placebo + other IS, Outcome 1 Death.

Comparison 13 Sirukumab + other immunosuppressive agent (IS) versus placebo + other IS, Outcome 2 Infection.
Figuras y tablas -
Analysis 13.2

Comparison 13 Sirukumab + other immunosuppressive agent (IS) versus placebo + other IS, Outcome 2 Infection.

Comparison 13 Sirukumab + other immunosuppressive agent (IS) versus placebo + other IS, Outcome 3 Malignancy.
Figuras y tablas -
Analysis 13.3

Comparison 13 Sirukumab + other immunosuppressive agent (IS) versus placebo + other IS, Outcome 3 Malignancy.

Comparison 13 Sirukumab + other immunosuppressive agent (IS) versus placebo + other IS, Outcome 4 Gastrointestinal (GI) adverse events.
Figuras y tablas -
Analysis 13.4

Comparison 13 Sirukumab + other immunosuppressive agent (IS) versus placebo + other IS, Outcome 4 Gastrointestinal (GI) adverse events.

Comparison 14 IV versus oral cyclophosphamide (CPA), Outcome 1 Death.
Figuras y tablas -
Analysis 14.1

Comparison 14 IV versus oral cyclophosphamide (CPA), Outcome 1 Death.

Comparison 14 IV versus oral cyclophosphamide (CPA), Outcome 2 Adverse renal outcomes.
Figuras y tablas -
Analysis 14.2

Comparison 14 IV versus oral cyclophosphamide (CPA), Outcome 2 Adverse renal outcomes.

Comparison 14 IV versus oral cyclophosphamide (CPA), Outcome 3 Stable kidney function.
Figuras y tablas -
Analysis 14.3

Comparison 14 IV versus oral cyclophosphamide (CPA), Outcome 3 Stable kidney function.

Comparison 14 IV versus oral cyclophosphamide (CPA), Outcome 4 Ovarian failure.
Figuras y tablas -
Analysis 14.4

Comparison 14 IV versus oral cyclophosphamide (CPA), Outcome 4 Ovarian failure.

Comparison 14 IV versus oral cyclophosphamide (CPA), Outcome 5 Infection.
Figuras y tablas -
Analysis 14.5

Comparison 14 IV versus oral cyclophosphamide (CPA), Outcome 5 Infection.

Comparison 14 IV versus oral cyclophosphamide (CPA), Outcome 6 Malignancy.
Figuras y tablas -
Analysis 14.6

Comparison 14 IV versus oral cyclophosphamide (CPA), Outcome 6 Malignancy.

Comparison 14 IV versus oral cyclophosphamide (CPA), Outcome 7 Bladder toxicity.
Figuras y tablas -
Analysis 14.7

Comparison 14 IV versus oral cyclophosphamide (CPA), Outcome 7 Bladder toxicity.

Comparison 14 IV versus oral cyclophosphamide (CPA), Outcome 8 Gastrointestinal (GI) adverse events.
Figuras y tablas -
Analysis 14.8

Comparison 14 IV versus oral cyclophosphamide (CPA), Outcome 8 Gastrointestinal (GI) adverse events.

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 1 Death.
Figuras y tablas -
Analysis 15.1

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 1 Death.

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 2 Remission.
Figuras y tablas -
Analysis 15.2

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 2 Remission.

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 3 Adverse renal outcomes.
Figuras y tablas -
Analysis 15.3

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 3 Adverse renal outcomes.

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 4 Stable kidney function.
Figuras y tablas -
Analysis 15.4

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 4 Stable kidney function.

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 5 Ovarian failure.
Figuras y tablas -
Analysis 15.5

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 5 Ovarian failure.

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 6 Infection.
Figuras y tablas -
Analysis 15.6

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 6 Infection.

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 7 Malignancy.
Figuras y tablas -
Analysis 15.7

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 7 Malignancy.

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 8 Leucopenia.
Figuras y tablas -
Analysis 15.8

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 8 Leucopenia.

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 9 Bone toxicity.
Figuras y tablas -
Analysis 15.9

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 9 Bone toxicity.

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 10 Alopecia.
Figuras y tablas -
Analysis 15.10

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 10 Alopecia.

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 11 Gastrointestinal (GI) adverse events.
Figuras y tablas -
Analysis 15.11

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 11 Gastrointestinal (GI) adverse events.

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 12 Daily proteinuria.
Figuras y tablas -
Analysis 15.12

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 12 Daily proteinuria.

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 13 Creatinine clearance.
Figuras y tablas -
Analysis 15.13

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 13 Creatinine clearance.

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 14 Serum creatinine.
Figuras y tablas -
Analysis 15.14

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 14 Serum creatinine.

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 15 Disease activity (SLEDAI).
Figuras y tablas -
Analysis 15.15

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 15 Disease activity (SLEDAI).

Comparison 16 Standard versus reduced dose oral corticosteroids, Outcome 1 Death.
Figuras y tablas -
Analysis 16.1

Comparison 16 Standard versus reduced dose oral corticosteroids, Outcome 1 Death.

Comparison 16 Standard versus reduced dose oral corticosteroids, Outcome 2 Remission.
Figuras y tablas -
Analysis 16.2

Comparison 16 Standard versus reduced dose oral corticosteroids, Outcome 2 Remission.

Comparison 16 Standard versus reduced dose oral corticosteroids, Outcome 3 Relapse.
Figuras y tablas -
Analysis 16.3

Comparison 16 Standard versus reduced dose oral corticosteroids, Outcome 3 Relapse.

Comparison 16 Standard versus reduced dose oral corticosteroids, Outcome 4 Infection.
Figuras y tablas -
Analysis 16.4

Comparison 16 Standard versus reduced dose oral corticosteroids, Outcome 4 Infection.

Comparison 16 Standard versus reduced dose oral corticosteroids, Outcome 5 Gastrointestinal (GI) adverse events.
Figuras y tablas -
Analysis 16.5

Comparison 16 Standard versus reduced dose oral corticosteroids, Outcome 5 Gastrointestinal (GI) adverse events.

Comparison 16 Standard versus reduced dose oral corticosteroids, Outcome 6 Creatinine clearance.
Figuras y tablas -
Analysis 16.6

Comparison 16 Standard versus reduced dose oral corticosteroids, Outcome 6 Creatinine clearance.

Comparison 16 Standard versus reduced dose oral corticosteroids, Outcome 7 Serum creatinine.
Figuras y tablas -
Analysis 16.7

Comparison 16 Standard versus reduced dose oral corticosteroids, Outcome 7 Serum creatinine.

Comparison 17 IV versus oral corticosteroids, Outcome 1 Death.
Figuras y tablas -
Analysis 17.1

Comparison 17 IV versus oral corticosteroids, Outcome 1 Death.

Comparison 17 IV versus oral corticosteroids, Outcome 2 Adverse renal outcomes.
Figuras y tablas -
Analysis 17.2

Comparison 17 IV versus oral corticosteroids, Outcome 2 Adverse renal outcomes.

Comparison 18 Cyclophosphamide (CPA) + corticosteroids versus corticosteroids, Outcome 1 Death.
Figuras y tablas -
Analysis 18.1

Comparison 18 Cyclophosphamide (CPA) + corticosteroids versus corticosteroids, Outcome 1 Death.

Comparison 18 Cyclophosphamide (CPA) + corticosteroids versus corticosteroids, Outcome 2 Complete remission of proteinuria.
Figuras y tablas -
Analysis 18.2

Comparison 18 Cyclophosphamide (CPA) + corticosteroids versus corticosteroids, Outcome 2 Complete remission of proteinuria.

Comparison 18 Cyclophosphamide (CPA) + corticosteroids versus corticosteroids, Outcome 3 Adverse renal outcomes.
Figuras y tablas -
Analysis 18.3

Comparison 18 Cyclophosphamide (CPA) + corticosteroids versus corticosteroids, Outcome 3 Adverse renal outcomes.

Comparison 18 Cyclophosphamide (CPA) + corticosteroids versus corticosteroids, Outcome 4 Deterioration of kidney function.
Figuras y tablas -
Analysis 18.4

Comparison 18 Cyclophosphamide (CPA) + corticosteroids versus corticosteroids, Outcome 4 Deterioration of kidney function.

Comparison 18 Cyclophosphamide (CPA) + corticosteroids versus corticosteroids, Outcome 5 Stable kidney function.
Figuras y tablas -
Analysis 18.5

Comparison 18 Cyclophosphamide (CPA) + corticosteroids versus corticosteroids, Outcome 5 Stable kidney function.

Comparison 18 Cyclophosphamide (CPA) + corticosteroids versus corticosteroids, Outcome 6 Ovarian failure.
Figuras y tablas -
Analysis 18.6

Comparison 18 Cyclophosphamide (CPA) + corticosteroids versus corticosteroids, Outcome 6 Ovarian failure.

Comparison 18 Cyclophosphamide (CPA) + corticosteroids versus corticosteroids, Outcome 7 Infection.
Figuras y tablas -
Analysis 18.7

Comparison 18 Cyclophosphamide (CPA) + corticosteroids versus corticosteroids, Outcome 7 Infection.

Comparison 18 Cyclophosphamide (CPA) + corticosteroids versus corticosteroids, Outcome 8 Malignancy.
Figuras y tablas -
Analysis 18.8

Comparison 18 Cyclophosphamide (CPA) + corticosteroids versus corticosteroids, Outcome 8 Malignancy.

Comparison 18 Cyclophosphamide (CPA) + corticosteroids versus corticosteroids, Outcome 9 Bone toxicity.
Figuras y tablas -
Analysis 18.9

Comparison 18 Cyclophosphamide (CPA) + corticosteroids versus corticosteroids, Outcome 9 Bone toxicity.

Comparison 18 Cyclophosphamide (CPA) + corticosteroids versus corticosteroids, Outcome 10 Bladder toxicity.
Figuras y tablas -
Analysis 18.10

Comparison 18 Cyclophosphamide (CPA) + corticosteroids versus corticosteroids, Outcome 10 Bladder toxicity.

Comparison 18 Cyclophosphamide (CPA) + corticosteroids versus corticosteroids, Outcome 11 Daily proteinuria.
Figuras y tablas -
Analysis 18.11

Comparison 18 Cyclophosphamide (CPA) + corticosteroids versus corticosteroids, Outcome 11 Daily proteinuria.

Comparison 18 Cyclophosphamide (CPA) + corticosteroids versus corticosteroids, Outcome 12 Serum creatinine.
Figuras y tablas -
Analysis 18.12

Comparison 18 Cyclophosphamide (CPA) + corticosteroids versus corticosteroids, Outcome 12 Serum creatinine.

Comparison 18 Cyclophosphamide (CPA) + corticosteroids versus corticosteroids, Outcome 13 Creatinine clearance.
Figuras y tablas -
Analysis 18.13

Comparison 18 Cyclophosphamide (CPA) + corticosteroids versus corticosteroids, Outcome 13 Creatinine clearance.

Comparison 19 Cyclophosphamide (CPA) + azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 1 Death.
Figuras y tablas -
Analysis 19.1

Comparison 19 Cyclophosphamide (CPA) + azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 1 Death.

Comparison 19 Cyclophosphamide (CPA) + azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 2 Adverse renal outcomes.
Figuras y tablas -
Analysis 19.2

Comparison 19 Cyclophosphamide (CPA) + azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 2 Adverse renal outcomes.

Comparison 19 Cyclophosphamide (CPA) + azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 3 Stable kidney function.
Figuras y tablas -
Analysis 19.3

Comparison 19 Cyclophosphamide (CPA) + azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 3 Stable kidney function.

Comparison 19 Cyclophosphamide (CPA) + azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 4 Ovarian failure.
Figuras y tablas -
Analysis 19.4

Comparison 19 Cyclophosphamide (CPA) + azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 4 Ovarian failure.

Comparison 19 Cyclophosphamide (CPA) + azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 5 Infection.
Figuras y tablas -
Analysis 19.5

Comparison 19 Cyclophosphamide (CPA) + azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 5 Infection.

Comparison 19 Cyclophosphamide (CPA) + azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 6 Bladder toxicity.
Figuras y tablas -
Analysis 19.6

Comparison 19 Cyclophosphamide (CPA) + azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 6 Bladder toxicity.

Comparison 20 Azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 1 Death.
Figuras y tablas -
Analysis 20.1

Comparison 20 Azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 1 Death.

Comparison 20 Azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 2 Complete remission of proteinuria.
Figuras y tablas -
Analysis 20.2

Comparison 20 Azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 2 Complete remission of proteinuria.

Comparison 20 Azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 3 Adverse renal outcomes.
Figuras y tablas -
Analysis 20.3

Comparison 20 Azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 3 Adverse renal outcomes.

Comparison 20 Azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 4 Stable kidney function.
Figuras y tablas -
Analysis 20.4

Comparison 20 Azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 4 Stable kidney function.

Comparison 20 Azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 5 Ovarian failure.
Figuras y tablas -
Analysis 20.5

Comparison 20 Azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 5 Ovarian failure.

Comparison 20 Azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 6 Infection.
Figuras y tablas -
Analysis 20.6

Comparison 20 Azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 6 Infection.

Comparison 20 Azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 7 Malignancy.
Figuras y tablas -
Analysis 20.7

Comparison 20 Azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 7 Malignancy.

Comparison 20 Azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 8 Bone toxicity.
Figuras y tablas -
Analysis 20.8

Comparison 20 Azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 8 Bone toxicity.

Comparison 20 Azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 9 Creatinine clearance.
Figuras y tablas -
Analysis 20.9

Comparison 20 Azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 9 Creatinine clearance.

Comparison 21 Cyclosporin (CSA) + corticosteroids versus corticosteroids alone, Outcome 1 Daily proteinuria.
Figuras y tablas -
Analysis 21.1

Comparison 21 Cyclosporin (CSA) + corticosteroids versus corticosteroids alone, Outcome 1 Daily proteinuria.

Comparison 21 Cyclosporin (CSA) + corticosteroids versus corticosteroids alone, Outcome 2 Serum creatinine.
Figuras y tablas -
Analysis 21.2

Comparison 21 Cyclosporin (CSA) + corticosteroids versus corticosteroids alone, Outcome 2 Serum creatinine.

Comparison 21 Cyclosporin (CSA) + corticosteroids versus corticosteroids alone, Outcome 3 Creatinine clearance.
Figuras y tablas -
Analysis 21.3

Comparison 21 Cyclosporin (CSA) + corticosteroids versus corticosteroids alone, Outcome 3 Creatinine clearance.

Comparison 22 Misoprostol + corticosteroids versus corticosteroids alone, Outcome 1 Adverse renal outcomes.
Figuras y tablas -
Analysis 22.1

Comparison 22 Misoprostol + corticosteroids versus corticosteroids alone, Outcome 1 Adverse renal outcomes.

Comparison 23 Plasma exchange (PE) + immunosuppression (IS) versus IS alone, Outcome 1 Death.
Figuras y tablas -
Analysis 23.1

Comparison 23 Plasma exchange (PE) + immunosuppression (IS) versus IS alone, Outcome 1 Death.

Comparison 23 Plasma exchange (PE) + immunosuppression (IS) versus IS alone, Outcome 2 Adverse renal outcomes.
Figuras y tablas -
Analysis 23.2

Comparison 23 Plasma exchange (PE) + immunosuppression (IS) versus IS alone, Outcome 2 Adverse renal outcomes.

Comparison 23 Plasma exchange (PE) + immunosuppression (IS) versus IS alone, Outcome 3 Stable kidney function.
Figuras y tablas -
Analysis 23.3

Comparison 23 Plasma exchange (PE) + immunosuppression (IS) versus IS alone, Outcome 3 Stable kidney function.

Comparison 23 Plasma exchange (PE) + immunosuppression (IS) versus IS alone, Outcome 4 Infection.
Figuras y tablas -
Analysis 23.4

Comparison 23 Plasma exchange (PE) + immunosuppression (IS) versus IS alone, Outcome 4 Infection.

Comparison 23 Plasma exchange (PE) + immunosuppression (IS) versus IS alone, Outcome 5 Leucopenia.
Figuras y tablas -
Analysis 23.5

Comparison 23 Plasma exchange (PE) + immunosuppression (IS) versus IS alone, Outcome 5 Leucopenia.

Comparison 23 Plasma exchange (PE) + immunosuppression (IS) versus IS alone, Outcome 6 Daily proteinuria.
Figuras y tablas -
Analysis 23.6

Comparison 23 Plasma exchange (PE) + immunosuppression (IS) versus IS alone, Outcome 6 Daily proteinuria.

Comparison 23 Plasma exchange (PE) + immunosuppression (IS) versus IS alone, Outcome 7 Serum creatinine.
Figuras y tablas -
Analysis 23.7

Comparison 23 Plasma exchange (PE) + immunosuppression (IS) versus IS alone, Outcome 7 Serum creatinine.

Comparison 23 Plasma exchange (PE) + immunosuppression (IS) versus IS alone, Outcome 8 Creatinine clearance.
Figuras y tablas -
Analysis 23.8

Comparison 23 Plasma exchange (PE) + immunosuppression (IS) versus IS alone, Outcome 8 Creatinine clearance.

Comparison 23 Plasma exchange (PE) + immunosuppression (IS) versus IS alone, Outcome 9 Disease activity (SLAM).
Figuras y tablas -
Analysis 23.9

Comparison 23 Plasma exchange (PE) + immunosuppression (IS) versus IS alone, Outcome 9 Disease activity (SLAM).

Comparison 24 Plasma exchange (PE) versus immunosuppression (IS), Outcome 1 Adverse renal outcomes.
Figuras y tablas -
Analysis 24.1

Comparison 24 Plasma exchange (PE) versus immunosuppression (IS), Outcome 1 Adverse renal outcomes.

Comparison 24 Plasma exchange (PE) versus immunosuppression (IS), Outcome 2 Infection.
Figuras y tablas -
Analysis 24.2

Comparison 24 Plasma exchange (PE) versus immunosuppression (IS), Outcome 2 Infection.

Comparison 24 Plasma exchange (PE) versus immunosuppression (IS), Outcome 3 Leucopenia.
Figuras y tablas -
Analysis 24.3

Comparison 24 Plasma exchange (PE) versus immunosuppression (IS), Outcome 3 Leucopenia.

Comparison 24 Plasma exchange (PE) versus immunosuppression (IS), Outcome 4 Alopecia.
Figuras y tablas -
Analysis 24.4

Comparison 24 Plasma exchange (PE) versus immunosuppression (IS), Outcome 4 Alopecia.

Comparison 24 Plasma exchange (PE) versus immunosuppression (IS), Outcome 5 Daily proteinuria.
Figuras y tablas -
Analysis 24.5

Comparison 24 Plasma exchange (PE) versus immunosuppression (IS), Outcome 5 Daily proteinuria.

Comparison 24 Plasma exchange (PE) versus immunosuppression (IS), Outcome 6 Creatinine clearance.
Figuras y tablas -
Analysis 24.6

Comparison 24 Plasma exchange (PE) versus immunosuppression (IS), Outcome 6 Creatinine clearance.

Comparison 25 Long versus short duration cyclophosphamide (CPA), Outcome 1 Adverse renal outcomes.
Figuras y tablas -
Analysis 25.1

Comparison 25 Long versus short duration cyclophosphamide (CPA), Outcome 1 Adverse renal outcomes.

Comparison 25 Long versus short duration cyclophosphamide (CPA), Outcome 2 Stable kidney function.
Figuras y tablas -
Analysis 25.2

Comparison 25 Long versus short duration cyclophosphamide (CPA), Outcome 2 Stable kidney function.

Comparison 25 Long versus short duration cyclophosphamide (CPA), Outcome 3 Ovarian failure.
Figuras y tablas -
Analysis 25.3

Comparison 25 Long versus short duration cyclophosphamide (CPA), Outcome 3 Ovarian failure.

Comparison 25 Long versus short duration cyclophosphamide (CPA), Outcome 4 Infection.
Figuras y tablas -
Analysis 25.4

Comparison 25 Long versus short duration cyclophosphamide (CPA), Outcome 4 Infection.

Comparison 25 Long versus short duration cyclophosphamide (CPA), Outcome 5 Malignancy.
Figuras y tablas -
Analysis 25.5

Comparison 25 Long versus short duration cyclophosphamide (CPA), Outcome 5 Malignancy.

Comparison 25 Long versus short duration cyclophosphamide (CPA), Outcome 6 Bone toxicity.
Figuras y tablas -
Analysis 25.6

Comparison 25 Long versus short duration cyclophosphamide (CPA), Outcome 6 Bone toxicity.

Comparison 25 Long versus short duration cyclophosphamide (CPA), Outcome 7 Bladder toxicity.
Figuras y tablas -
Analysis 25.7

Comparison 25 Long versus short duration cyclophosphamide (CPA), Outcome 7 Bladder toxicity.

Comparison 26 Maintenance: azathioprine (AZA) versus mycophenolate mofetil (MMF), Outcome 1 Death.
Figuras y tablas -
Analysis 26.1

Comparison 26 Maintenance: azathioprine (AZA) versus mycophenolate mofetil (MMF), Outcome 1 Death.

Comparison 26 Maintenance: azathioprine (AZA) versus mycophenolate mofetil (MMF), Outcome 2 Renal relapse.
Figuras y tablas -
Analysis 26.2

Comparison 26 Maintenance: azathioprine (AZA) versus mycophenolate mofetil (MMF), Outcome 2 Renal relapse.

Comparison 26 Maintenance: azathioprine (AZA) versus mycophenolate mofetil (MMF), Outcome 3 End‐stage kidney disease.
Figuras y tablas -
Analysis 26.3

Comparison 26 Maintenance: azathioprine (AZA) versus mycophenolate mofetil (MMF), Outcome 3 End‐stage kidney disease.

Comparison 26 Maintenance: azathioprine (AZA) versus mycophenolate mofetil (MMF), Outcome 4 Doubling of serum creatinine.
Figuras y tablas -
Analysis 26.4

Comparison 26 Maintenance: azathioprine (AZA) versus mycophenolate mofetil (MMF), Outcome 4 Doubling of serum creatinine.

Comparison 26 Maintenance: azathioprine (AZA) versus mycophenolate mofetil (MMF), Outcome 5 Ovarian failure.
Figuras y tablas -
Analysis 26.5

Comparison 26 Maintenance: azathioprine (AZA) versus mycophenolate mofetil (MMF), Outcome 5 Ovarian failure.

Comparison 26 Maintenance: azathioprine (AZA) versus mycophenolate mofetil (MMF), Outcome 6 Infection.
Figuras y tablas -
Analysis 26.6

Comparison 26 Maintenance: azathioprine (AZA) versus mycophenolate mofetil (MMF), Outcome 6 Infection.

Comparison 26 Maintenance: azathioprine (AZA) versus mycophenolate mofetil (MMF), Outcome 7 Malignancy.
Figuras y tablas -
Analysis 26.7

Comparison 26 Maintenance: azathioprine (AZA) versus mycophenolate mofetil (MMF), Outcome 7 Malignancy.

Comparison 26 Maintenance: azathioprine (AZA) versus mycophenolate mofetil (MMF), Outcome 8 Leucopenia.
Figuras y tablas -
Analysis 26.8

Comparison 26 Maintenance: azathioprine (AZA) versus mycophenolate mofetil (MMF), Outcome 8 Leucopenia.

Comparison 26 Maintenance: azathioprine (AZA) versus mycophenolate mofetil (MMF), Outcome 9 Bone toxicity.
Figuras y tablas -
Analysis 26.9

Comparison 26 Maintenance: azathioprine (AZA) versus mycophenolate mofetil (MMF), Outcome 9 Bone toxicity.

Comparison 26 Maintenance: azathioprine (AZA) versus mycophenolate mofetil (MMF), Outcome 10 Alopecia.
Figuras y tablas -
Analysis 26.10

Comparison 26 Maintenance: azathioprine (AZA) versus mycophenolate mofetil (MMF), Outcome 10 Alopecia.

Comparison 26 Maintenance: azathioprine (AZA) versus mycophenolate mofetil (MMF), Outcome 11 Gastrointestinal (GI) adverse events.
Figuras y tablas -
Analysis 26.11

Comparison 26 Maintenance: azathioprine (AZA) versus mycophenolate mofetil (MMF), Outcome 11 Gastrointestinal (GI) adverse events.

Comparison 26 Maintenance: azathioprine (AZA) versus mycophenolate mofetil (MMF), Outcome 12 Daily proteinuria.
Figuras y tablas -
Analysis 26.12

Comparison 26 Maintenance: azathioprine (AZA) versus mycophenolate mofetil (MMF), Outcome 12 Daily proteinuria.

Comparison 27 Maintenance: azathioprine (AZA) versus cyclosporin (CSA), Outcome 1 Death.
Figuras y tablas -
Analysis 27.1

Comparison 27 Maintenance: azathioprine (AZA) versus cyclosporin (CSA), Outcome 1 Death.

Comparison 27 Maintenance: azathioprine (AZA) versus cyclosporin (CSA), Outcome 2 Adverse renal outcomes.
Figuras y tablas -
Analysis 27.2

Comparison 27 Maintenance: azathioprine (AZA) versus cyclosporin (CSA), Outcome 2 Adverse renal outcomes.

Comparison 27 Maintenance: azathioprine (AZA) versus cyclosporin (CSA), Outcome 3 Infection.
Figuras y tablas -
Analysis 27.3

Comparison 27 Maintenance: azathioprine (AZA) versus cyclosporin (CSA), Outcome 3 Infection.

Comparison 27 Maintenance: azathioprine (AZA) versus cyclosporin (CSA), Outcome 4 Leucopenia.
Figuras y tablas -
Analysis 27.4

Comparison 27 Maintenance: azathioprine (AZA) versus cyclosporin (CSA), Outcome 4 Leucopenia.

Comparison 27 Maintenance: azathioprine (AZA) versus cyclosporin (CSA), Outcome 5 Gastrointestinal (GI) adverse events.
Figuras y tablas -
Analysis 27.5

Comparison 27 Maintenance: azathioprine (AZA) versus cyclosporin (CSA), Outcome 5 Gastrointestinal (GI) adverse events.

Comparison 27 Maintenance: azathioprine (AZA) versus cyclosporin (CSA), Outcome 6 Daily proteinuria.
Figuras y tablas -
Analysis 27.6

Comparison 27 Maintenance: azathioprine (AZA) versus cyclosporin (CSA), Outcome 6 Daily proteinuria.

Comparison 27 Maintenance: azathioprine (AZA) versus cyclosporin (CSA), Outcome 7 Disease activity (SLEDAI).
Figuras y tablas -
Analysis 27.7

Comparison 27 Maintenance: azathioprine (AZA) versus cyclosporin (CSA), Outcome 7 Disease activity (SLEDAI).

Comparison 28 Maintenance: azathioprine (AZA) versus cyclophosphamide (CPA), Outcome 1 Death.
Figuras y tablas -
Analysis 28.1

Comparison 28 Maintenance: azathioprine (AZA) versus cyclophosphamide (CPA), Outcome 1 Death.

Comparison 28 Maintenance: azathioprine (AZA) versus cyclophosphamide (CPA), Outcome 2 Adverse renal outcomes.
Figuras y tablas -
Analysis 28.2

Comparison 28 Maintenance: azathioprine (AZA) versus cyclophosphamide (CPA), Outcome 2 Adverse renal outcomes.

Comparison 28 Maintenance: azathioprine (AZA) versus cyclophosphamide (CPA), Outcome 3 Bladder toxicity.
Figuras y tablas -
Analysis 28.3

Comparison 28 Maintenance: azathioprine (AZA) versus cyclophosphamide (CPA), Outcome 3 Bladder toxicity.

Comparison 28 Maintenance: azathioprine (AZA) versus cyclophosphamide (CPA), Outcome 4 Creatinine clearance.
Figuras y tablas -
Analysis 28.4

Comparison 28 Maintenance: azathioprine (AZA) versus cyclophosphamide (CPA), Outcome 4 Creatinine clearance.

Comparison 29 Maintenance: azathioprine (AZA) versus tacrolimus (TAC), Outcome 1 Adverse renal outcomes.
Figuras y tablas -
Analysis 29.1

Comparison 29 Maintenance: azathioprine (AZA) versus tacrolimus (TAC), Outcome 1 Adverse renal outcomes.

Comparison 29 Maintenance: azathioprine (AZA) versus tacrolimus (TAC), Outcome 2 Infection.
Figuras y tablas -
Analysis 29.2

Comparison 29 Maintenance: azathioprine (AZA) versus tacrolimus (TAC), Outcome 2 Infection.

Comparison 29 Maintenance: azathioprine (AZA) versus tacrolimus (TAC), Outcome 3 Gastrointestinal (GI) adverse events.
Figuras y tablas -
Analysis 29.3

Comparison 29 Maintenance: azathioprine (AZA) versus tacrolimus (TAC), Outcome 3 Gastrointestinal (GI) adverse events.

Comparison 30 Maintenance: prednisone withdrawal versus prednisone continuation, Outcome 1 Relapse.
Figuras y tablas -
Analysis 30.1

Comparison 30 Maintenance: prednisone withdrawal versus prednisone continuation, Outcome 1 Relapse.

Comparison 30 Maintenance: prednisone withdrawal versus prednisone continuation, Outcome 2 Major infection.
Figuras y tablas -
Analysis 30.2

Comparison 30 Maintenance: prednisone withdrawal versus prednisone continuation, Outcome 2 Major infection.

Comparison 31 Maintenance: intravenous immunoglobulin (IVIG) versus intravenous cyclophosphamide (IV CPA), Outcome 1 Creatinine clearance.
Figuras y tablas -
Analysis 31.1

Comparison 31 Maintenance: intravenous immunoglobulin (IVIG) versus intravenous cyclophosphamide (IV CPA), Outcome 1 Creatinine clearance.

Comparison 31 Maintenance: intravenous immunoglobulin (IVIG) versus intravenous cyclophosphamide (IV CPA), Outcome 2 Daily proteinuria.
Figuras y tablas -
Analysis 31.2

Comparison 31 Maintenance: intravenous immunoglobulin (IVIG) versus intravenous cyclophosphamide (IV CPA), Outcome 2 Daily proteinuria.

Comparison 31 Maintenance: intravenous immunoglobulin (IVIG) versus intravenous cyclophosphamide (IV CPA), Outcome 3 Serum creatinine.
Figuras y tablas -
Analysis 31.3

Comparison 31 Maintenance: intravenous immunoglobulin (IVIG) versus intravenous cyclophosphamide (IV CPA), Outcome 3 Serum creatinine.

Summary of findings for the main comparison. Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA) for induction therapy

Patient or population: patients with induction therapy in lupus nephritis
Settings: all settings
Intervention: MMF
Comparison: IV CPA

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No. of participants
(studies)

Certainty of evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

IV CPA

MMF

Death
Follow‐up: mean 24 weeks

40 per 1000

53 per 1000
(29 to 98)

RR 1.12
(0.61 to 2.06)

826 (8)

⊕⊝⊝⊝
very low1,2,3

Downgraded as follows:

1 Indirectness: time frame insufficient

2 Total number of events small

3 Severe imprecision (2
grades): risk estimate includes null effect
and estimate consistent with both appreciable benefit and harm

ESKD
Follow‐up: mean 32 weeks

85 per 1000

61 per 1000
(23 to 157)

RR 0.71 (0.27 to 1.84)

231 (3)

⊕⊝⊝⊝
very low1,2,3

Downgraded as follows:

1 Indirectness: time frame insufficient

2 Total number of events small

3 Severe imprecision (2
grades): risk estimate includes null effect
and estimate consistent with both appreciable benefit and harm

Complete renal remission
Follow‐up: mean 24 weeks

222 per 1000

260 per 1000
(216 to 316)

RR 1.17 (0.97 to 1.42)

828 (8)

⊕⊕⊝⊝
low1,2,3

Downgraded as follows:

1 Study limitations

2 Total number of events small

3 Imprecision (2 grades): risk estimate includes null effect and estimate consistent with both appreciable
benefit and harm

Partial renal remission

Follow‐up: mean 24 weeks

415 per 1000

423 per 1000
(369 to 490)

RR 1.02
(0.89 to 1.18)

868 (9)

⊕⊕⊝⊝
low1,2

Downgraded as follows:

1 Study limitations

2 Serious indirectness: differences in the outcome definition between studies.

Ovarian failure

41 per 1000

15 per 1000
(2 to 90)

RR 0.36
(0.06 to 2.18)

539 (3)

⊕⊝⊝⊝
very low1,2,3

Downgraded as follows:

1 Study limitations

2 Severe heterogeneity: point estimates varied widely

3 Total number of events small

4 Severe imprecision (2 grades): risk estimate includes null effect and estimate consistent
with both appreciable benefit and harm

Major infection
Follow‐up: mean 24 weeks

114 per 1000

116 per 1000
(76 to 175)

RR 1.02
(0.67 to 1.54)

699 (6)

⊕⊕⊝⊝
low1,2

Downgraded as follows:

1 Study limitations

2 Total number of events small

3 Severe imprecision (2 grades): risk estimate includes null effect and estimate consistent
with both appreciable benefit and harm

Alopecia
Follow‐up: mean 24 weeks

239 per 1000

69 per 1000
(45 to 110)

RR 0.29
(0.19 to 0.46)

622 (3)

⊕⊕⊕⊝
moderate1,2,3

Downgraded as follows:

1 Study limitations

2 Total number of events small

Upgraded as follows:

3 Large magnitude of effect

Diarrhoea
Follow‐up: mean 24 weeks

100 per 1000

241 per 1000
(163 to 357)

RR 2.42
(1.64 to 3.58)

609 (4)

⊕⊕⊕⊝
moderate1,2,3

Downgraded as follows:

1 Study limitations

2 Total number of events small

Upgraded as follows

3 Large magnitude of effect

*The basis for the assumed risk for partial renal remission was prognostic studies (Fernandes das Neves 2015; Moroni 2007; So 2011; Zakharova 2016); and the assumed risk for other outcomes was calculated using the median control group risk across studies in the meta‐analysis. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI)
CI: Confidence interval; RR: risk ratio

GRADE Working Group certainty of evidence
High certainty: Further research is very unlikely to change our confidence in the estimate of effect
Moderate certainty: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate
Low certainty: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate
Very low certainty: We are very uncertain about the effect estimate

Figuras y tablas -
Summary of findings for the main comparison. Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA) for induction therapy
Summary of findings 2. Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA) for induction therapy

MMF + TAC compared with IV CPA for lupus nephritis

Patient or population: Patients with proliferative lupus nephritis

Settings: all settings

Intervention: MMF + TAC

Comparison: IV CPA

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No. of participants
(studies)

Certainty of evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

IV CPA

MMF + TAC

Complete renal remission

follow‐up: mean 24 weeks

244 per 1000

580 per 1000
(261 to 1000)

RR 2.38 (1.07 to 5.30)

402 (2)

⊕⊕⊝⊝
low1,2,3,4

Downgraded as follows:

1Study limitation: concern regarding the incomplete reporting of IV CPA group

2Heterogeneity: substantial heterogeneity indicated by I2 statistic. Although Chi2 test was satisfied, the small number of studies may make this unreliable.

3Indirectness: Concern regarding the population, as all studies have largely included patients of Asian ethnicity.

Upgraded as follows:

4Large effect size

Partial renal remission

follow‐up: mean 24 weeks

378 per 1000

378 per 1000
(295 to 484)

RR 1.00 (0.78 to 1.28)

402 (2)

⊕⊕⊝⊝
low1,2

Downgraded as follows:

1Study limitation: concern regarding the incomplete reporting of IV CPA group

2 Indirectness: differences in the outcome definition between studies and concern regarding the population, as all studies have largely included patients of Asian ethnicity.

Stable kidney function

follow‐up: mean 24 weeks

284 per 1000

505 per 1000
(397 to 641)

RR 1.78 (1.40 to 2.26)

402 (2)

⊕⊕⊝⊝ low1,2,3,4

Downgraded as follows:

1Study limitation: concern regarding the incomplete reporting of IV CPA group

2 Indirectness (2 grades): differences in the outcome definition between studies and concern regarding the population, as all studies have largely included patients of Asian ethnicity.

3Total number of events small

Upgraded as follows:

4Large effect size

*The basis for the assumed risk was calculated using the median control group risk across studies in the meta‐analyses. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk Ratio

GRADE Working Group certainty of evidence
High certainty: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate certainty: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low certainty: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low certainty: We are very uncertain about the estimate.

Figuras y tablas -
Summary of findings 2. Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA) for induction therapy
Summary of findings 3. Azathioprine (AZA) versus mycophenolate mofetil (MMF) for maintenance therapy

Patient or population: patients with maintenance treatment in lupus nephritis
Settings: all settings
Intervention: AZA
Comparison: MMF

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No. of participants
(studies)

Certainty of evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

MMF

AZA

Death
Follow‐up: 36 to 72 months

22 per 1000

25 per 1000
(7 to 84)

RR 1.15

(0.34 to 3.87)

451 (4)

⊕⊝⊝⊝
Very low1,2,3

Downgraded as follows:

1Total number of events small

2Severe imprecision (2 grades): risk estimate includes null effect and estimate consistent with both appreciable benefit and harm

3Indirectness: time frame insufficient

ESKD
Follow‐up: 36 to 72 months

17 per 1000

30 per 1000

(9 to 96)

RR 1.70

(0.52 to 5.54)

452 (4)

⊕⊝⊝⊝
Very low1,2,3

Downgraded as follows:

1Total number of events small

2Severe imprecision (2 grades): risk estimate includes null effect and estimate consistent with both appreciable benefit and harm

3Indirectness: time frame insufficient

Renal relapse
Follow‐up: 36 to 72 months

152 per 1000

266 per 1000
(183 to 388)

RR 1.75
(1.20 to 2.55)

452 (4)

⊕⊕⊕⊝
moderate1

Downgraded as follows:

1 Total number of events small

Doubling of serum creatinine

Follow‐up: 36 to 72 months

39 per 1000

86 per 1000

(40 to 182)

RR 2.19

(1.03 to 4.66)

452 (4)

⊕⊕⊝⊝
low1,2

Downgraded as follows:

1 Study limitations: (studies generally at unclear or high risk of bias for many domains)

2Total number of events small

Major infection
Follow‐up: median 53 months

91 per 1000

98 per 1000
(55 to 178)

RR 1.08
(0.69 to 1.96)

412 (3)

⊕⊕⊝⊝
low1,2

Downgraded as follows:

1 Total number of events small

2 Imprecision: wide risk estimate includes null effect

Leucopenia
Follow‐up: 36 to 53 months

10 per 1000

54 per 1000
(16 to 179)

RR 5.61
(1.68 to 18.72)

412 (3)

⊕⊕⊝⊝
low1,2

Downgraded as follows:

1Study limitations: (studies generally at unclear or high risk of bias for many domains)

2 Imprecision: wide risk estimates

Alopecia
Follow‐up: median 53 months

67 per 1000

64 per 1000
(31 to 131)

RR 0.95
(0.46 to 1.95)

412 (3)

⊕⊕⊝⊝
low1,2

Downgraded as follows:

1Study limitations: (studies generally at unclear or high risk of bias for many domains)

2 Total number of events small

*The basis for the assumed risk for other outcomes was calculated using the median control group risk across studies in the meta‐analysis. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio

GRADE Working Group certainty of evidence
High certainty: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate certainty: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low certainty: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low certainty: We are very uncertain about the estimate

Figuras y tablas -
Summary of findings 3. Azathioprine (AZA) versus mycophenolate mofetil (MMF) for maintenance therapy
Table 1. Description of health‐related quality of life outcomes

Study ID

Comparison

Therapy

Measure

Time point

Description of results

ACCESS 2014

Abatacept versus placebo

Induction

SF‐36 physical and mental component

(mean ± SD)

6 months

  • In the abatacept group after 6 months of therapy the physical component score increased from 39 ± 11 to 45.3 ± 11. In the placebo + standard of care therapy group after 6 months of therapy, the physical component score increased from 39 ± 10 to 46.5 ± 11

  • In the abatacept group after 6 months of therapy the mental component score increased from 40 ± 13 to 45.9 ± 12. In the placebo + standard of care group after 6 months of therapy, the mental component score increased from 40 ± 13 to 46.5 ± 11

Furie 2014

Abatacept versus placebo

Induction

SF‐36 (adjusted mean change ± SE)

12 months

  • In the high dose abatacept group after 12 months of therapy the adjusted mean ± SE of SF‐36 scores were: physical component 4.2 ± 0.91, mental component 2.5 ± 1.0, physical functioning 2.6 ± 0.96, role‐physical 4.2 ± 1.2, bodily pain 4.5 ± 1.1, general health 4.7 ± 0.9, vitality 3.9 ± 0.98, social functioning 4.0 ± 1.0, role‐emotional 1.6 ± 1.3, and mental health 3.1 ± 1.1

  • In the low dose abatacept group after 12 months of therapy, the adjusted mean ± SE of SF‐36 scores were: physical component, 5.0 ± 0.91, mental component 4.7 ± 1.0, physical functioning 4.2 ± 0.95, role‐physical 6.9 ± 1.2, bodily pain 4.6 ± 1.0, general health 4.4 ± 0.89, vitality 4.6 ± 0.97, social functioning 6.1 ± 1.0, role‐emotional 5.6 ± 1.3, and mental health 4.0 ± 1.1. In the placebo + standard of care group after 12 months of therapy, the adjusted mean ± SE of SF‐36 scores were: physical component 3.8 ± 0.9, mental component 4.4 ± 1.0, physical functioning 2.8 ± 0.94, role‐physical 5.3 ± 1.2, bodily pain 4.3 ± 1.0, general health 4.0 ± 0.88, vitality 4.8 ± 0.96, social functioning 5.1 ± 1.0, role‐emotional 4.7 ± 1.3, and mental health 3.2 ± 1.1

LUNAR 2012

Rituximab versus placebo

Induction

SF‐36 ‐ physical functioning (mean change ± SD)

12 months

  • In the rituximab group after 12 months of therapy the SF‐36 physical functioning score increased by 4.8 ± 10.4

  • In the placebo + standard of care therapy group, after 12 months of therapy the SF‐36 physical functioning score increased by 5.7 ± 9.4

Figuras y tablas -
Table 1. Description of health‐related quality of life outcomes
Table 2. Description of fatigue outcomes

Study ID

Comparison

Therapy

Measure

Time point

Description of results

Furie 2014

Abatacept versus placebo

Induction

Fatigue VAS (adjusted mean change ± SE)

6 months

  • In the high dose abatacept group after 6 months of therapy the fatigue VAS decreased by 12.2 ± 2.7

  • In the low dose abatacept group after 6 months of therapy the fatigue VAS decreased by 12.3 ± 2.7

  • In the placebo + standard of care group after 6 months of therapy the fatigue VAS decreased by 11.1 ± 2.7

Fatigue severity score (adjusted mean change ± SE)

  • In the high dose abatacept group after 6 months of therapy the fatigue VAS decreased by 12.2 ± 2.7

  • In the low dose abatacept group after 6 months of therapy the fatigue VAS decreased by 12.3 ± 2.7

  • In the placebo + standard of care group after 6 months of therapy the fatigue VAS decreased by 11.1 ± 2.7

VAS ‐ visual analogue scale

Figuras y tablas -
Table 2. Description of fatigue outcomes
Table 3. Description of disease activity outcomes

Study ID

Comparison

Measure

Time point

Description of results

Induction therapy

ACCESS 2014

Abatacept versus placebo

BILAG (mean ± SD)

6 months

  • In the placebo + standard of care therapy group after 6 months of therapy the BILAG scores were 3.4 ± 1.8

  • In the abatacept group after 6 months of therapy the BILAG scores were 3.8 ± 3.0

ALMS 2007

MMF versus IV CPA

SLEDAI (mean change ± SD)

6 months

  • In the IV CPA group after 6 months of therapy the SLEDAI scores decreased by 6.6 ± 8.0

  • In the MMF group after 6 months of therapy the SLEDAI scores decreased by 6.2 ± 10.1

  • The mean difference between the groups was 0.41 (95% CI ‐1.48 to 2.30)

Deng 2016

Leflunomide versus CPA

SLEDAI

6 months

"SLEDAI scores were reduced"

El‐Shafey 2010

MMF versus IV CPA

SLAM (mean change ± SD)

6 months

  • In the IV CPA group after 6 months of therapy SLAM scores decreased by 22.1 ± 7.72

  • In the MMF group after 6 months of therapy SLAM scores decreased by 17.84 ± 7.25

Grootscholten 2006

IV CPA versus AZA

SLEDAI

24 months

“SLEDAI and VAS scores did not differ between groups and decreased significantly and paralleled each other (r = 0.673, P<0.01)”

Hong 2007

TAC versus IC CPA

SLEDAI

6 months

“SLEDAI level of FK506 (TAC) group is better than that of CPA group, (P<0.05)”

Houssiau 2002

High CPA versus low CPA

ECLAM

12 months

“ECLAM score significantly improved in both groups during the first year of follow‐up. No significant difference was noted between patients in the low‐dose and high‐dose IV CYC groups for any of the parameters examined (P>0.05)”

Kamanamool 2017

MMF versus TAC

SLEDAI‐2K (mean ± SD)

12 months

  • In the MMF group, mean SLEDAI‐2K was decreased from 11.6 ± 4.8 to 6.3 ± 3.9 after 6 months therapy, and 5.4 ± 4.4 after 12 months

  • In the TAC group, mean SLEDAI‐2K was decreased from 9.0 ± 3.7 to 6.3 ± 5.1 after 6 months and to 7.1 ± 5.4 after 12 months

  • The results showed a similar pattern with respect to renal SLEDAI and modified SLEDAI

Li 2009c

Rituximab versus rituximab + CPA

SLEDAI (mean ± SD)

12 months

  • The overall SLEDAI of both groups at baseline was 9.2 ± 3.4, this decreased to 2.5 ± 2.5 after 12 months of therapy

  • There was significant improvements in SLEDAI in both groups

Li 2012

MMF versus TAC versus IV CPA

SLEDAI (mean ± SD)

6 months

  • In all three groups (IV CPA, MMF, TAC) after 6 months of therapy the SLEDAI across all three groups was 7.7 ± 4.7. In all three groups the SLEDAI scores decreased

Liu 2015

MMF + TAC versus IV CPA

SLEDAI (mean change ± SD)

6 months

  • In the IV CPA group after 6 months of therapy SLEDAI decreased by 11.01 ± 6.07

  • In the MMF+TAC group after 6 months of therapy SLEDAI decreased by 8.55 ± 5.05

Loo 2010

PEX versus IA

SLEDAI

6 months

“The SLEDAI gap between the study groups remained the same throughout the study. The improvements in SLEDAI score of both groups were also significantly demonstrated.”

LUNAR 2012

Rituximab versus placebo

BILAG (Time adjusted area under the curve minus baseline mean ± SD)

12 months

  • In the rituximab group after 12 months of therapy SLEDAI decreased to 8.49 ± 5.79

  • In the placebo + standard of care group after 12 months of therapy SLEDAI decreased to 8.58 ± 5.14

Mehra 2018

High‐dose CPA versus low‐dose CPA

Renal SLEDAI

6 months

At 24 weeks, renal SLEDAI were similar between high‐dose and low‐dose cyclophosphamide

Mok 2016

MMF versus TAC

Renal SLEDAI (mean ± SD)

6 months

  • In the MMF group after 6 months of therapy renal SLEDAI scores were 3.9 ± 3.1

  • In the tacrolimus group after 6 months of therapy renal SLEDAI scores were 3.3 ± 3.1

Extrarenal SLEDAI (mean ± SD)

  • In the MMF group after 6 months of therapy extrarenal SLEDAI scores were 1.7 ± 1.9

  • In the tacrolimus group after 6 months of therapy extrarenal SLEDAI scores were 1.9 ± 1.7

MyLupus 2011

Standard dose PRED versus reduced dose PRED

Global BILAG (mean ± SD)

6 months

For both groups (reduced dose and standard dose corticosteroids) at the end of 6 months of treatment global BILAG reduced from 14 ± 5.4 to 5.0 ± 3.8 (P < 0.001)

SLEDAI (mean ± SD)

For both groups (reduced dose and standard dose corticosteroids) at the end of 6 months of treatment SLEDAI reduced from16.2 ± 6.9 to 6.2 ± 5.1 (P < 0.001)

Ong 2005

MMF versus IV CPA

SLEDAI (mean change ± SD)

6 months

  • In the IV CPA group after 6 months of therapy SLEDAI decreased by 6.8 ± 6.6

  • In the MMF group after 6 months of therapy SLEDAI decreased by ‐7.2 ± 7.7

Rathi 2016

MMF versus IV CPA

SLEDAI

6 months

“SLEDAI improved significantly in both the groups over the study period, and there were no differences between the treatment groups.”

Rovin 2016

Sirukumab versus placebo

SLEDAI‐2K

6 months

“Eighteen patients (14 in the sirukumab group and 4 in the placebo group) had a SLEDAI‐2K RI‐50 response at any time through week 24.”

Physician's and patients global assessment of disease activity

“Neither the patient’s nor the physician’s global assessment scores of disease activity showed notable improvement over time in either treatment group (data not shown)."

Wallace 1998

PE versus standard of care

SLAM (mean ± SD)

12 months

  • In the standard of care group after 12 months of therapy SLAM scores were 6.44 ± 4.16

  • In the PEX group after 12 months of therapy SLAM scores were 7.11 ± 4.78

Maintenance therapy

MAINTAIN Nephritis 2010

AZA versus MMF

SLEDAI

36 months

"SLEDAI and ECLAM scores decreased similarly in both groups"

ECLAM

Moroni 2006

AZA versus CSA

SLEDAI (mean ± SD)

24 months

  • In the AZA group after 24 months of therapy SLEDAI scores were 5.6 ± 3.0

  • In the CSA group after 24 months of therapy SLEDAI scores were 8.8 ± 7.2

AZA ‐ azathioprine; BILAG ‐ British Isles Lupus Assessment Group; CPA ‐ cyclophosphamide; CSA ‐ cyclosporin; ECLAM ‐ European Consensus Lupus Activity Measurement; IA ‐ immunoadsorption; MMF ‐ mycophenolate mofetil; IV ‐ intravenous; PE ‐ plasma exchange; PEX ‐ plasmapheresis; PRED ‐ corticosteroid; SLAM ‐ Systemic Lupus Activity Measure; SLEDAI ‐ Systemic Lupus Erythematosus Disease Activity Index; TAC ‐ tacrolimus

Figuras y tablas -
Table 3. Description of disease activity outcomes
Comparison 1. Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Death Show forest plot

8

826

Risk Ratio (M‐H, Random, 95% CI)

1.12 [0.61, 2.06]

2 Remission Show forest plot

9

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

2.1 Complete renal remission: MMF versus IV CPA

9

868

Risk Ratio (M‐H, Random, 95% CI)

1.17 [0.97, 1.42]

2.2 Partial renal remission: MMF versus IV CPA

9

868

Risk Ratio (M‐H, Random, 95% CI)

1.02 [0.89, 1.18]

2.3 Complete remission in proteinuria: MMF versus IV CPA

6

686

Risk Ratio (M‐H, Random, 95% CI)

1.16 [0.85, 1.58]

2.4 Partial remission in proteinuria: MMF versus IV CPA

6

744

Risk Ratio (M‐H, Random, 95% CI)

1.03 [0.91, 1.18]

3 Adverse renal outcomes Show forest plot

4

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

3.1 ESKD

3

231

Risk Ratio (M‐H, Random, 95% CI)

0.71 [0.27, 1.84]

3.2 Renal relapse

1

140

Risk Ratio (M‐H, Random, 95% CI)

0.97 [0.39, 2.44]

3.3 Doubling of serum creatinine

1

40

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

4 Stable kidney function Show forest plot

6

641

Risk Ratio (M‐H, Random, 95% CI)

1.05 [0.94, 1.17]

5 Ovarian failure Show forest plot

3

539

Risk Ratio (M‐H, Random, 95% CI)

0.36 [0.06, 2.18]

6 Menstrual irregularities Show forest plot

2

87

Risk Ratio (M‐H, Random, 95% CI)

0.33 [0.07, 1.59]

7 Infection Show forest plot

7

1452

Risk Ratio (M‐H, Random, 95% CI)

1.13 [0.81, 1.58]

7.1 Major infection

6

699

Risk Ratio (M‐H, Random, 95% CI)

1.02 [0.67, 1.54]

7.2 Herpes zoster virus

6

753

Risk Ratio (M‐H, Random, 95% CI)

1.39 [0.78, 2.46]

8 Malignancy Show forest plot

1

364

Risk Ratio (M‐H, Random, 95% CI)

0.65 [0.11, 3.86]

9 Leucopenia Show forest plot

6

753

Risk Ratio (M‐H, Random, 95% CI)

0.59 [0.33, 1.08]

10 Bladder toxicity Show forest plot

1

364

Risk Ratio (M‐H, Random, 95% CI)

0.33 [0.01, 7.95]

11 Alopecia Show forest plot

3

622

Risk Ratio (M‐H, Random, 95% CI)

0.29 [0.19, 0.46]

12 Gastrointestinal (GI) adverse events Show forest plot

4

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

12.1 Diarrhoea

4

609

Risk Ratio (M‐H, Random, 95% CI)

2.42 [1.64, 3.58]

12.2 Vomiting

3

562

Risk Ratio (M‐H, Random, 95% CI)

0.48 [0.24, 0.97]

12.3 Nausea

3

562

Risk Ratio (M‐H, Random, 95% CI)

0.48 [0.23, 0.98]

12.4 GI upset

3

569

Risk Ratio (M‐H, Random, 95% CI)

0.91 [0.78, 1.06]

13 Daily proteinuria Show forest plot

4

271

Mean Difference (IV, Random, 95% CI)

‐0.08 [‐0.43, 0.26]

14 Serum creatinine Show forest plot

6

759

Mean Difference (IV, Random, 95% CI)

2.14 [‐3.09, 7.37]

Figuras y tablas -
Comparison 1. Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA)
Comparison 2. Mycophenolate mofetil (MMF) versus oral cyclophosphamide (CPA)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Death Show forest plot

1

62

Risk Ratio (M‐H, Random, 95% CI)

0.19 [0.01, 3.76]

2 Remission Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

2.1 Complete remission in proteinuria

1

62

Risk Ratio (M‐H, Random, 95% CI)

0.98 [0.74, 1.30]

2.2 Partial remission in proteinuria

1

62

Risk Ratio (M‐H, Random, 95% CI)

1.07 [0.44, 2.59]

3 Adverse renal outcomes Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

3.1 ESKD

1

62

Risk Ratio (M‐H, Random, 95% CI)

0.19 [0.01, 3.76]

3.2 Renal relapse

1

62

Risk Ratio (M‐H, Random, 95% CI)

1.15 [0.55, 2.37]

3.3 Doubling of serum creatinine

1

62

Risk Ratio (M‐H, Random, 95% CI)

0.63 [0.11, 3.48]

4 Ovarian failure Show forest plot

1

53

Risk Ratio (M‐H, Random, 95% CI)

0.10 [0.01, 0.73]

5 Infection Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

5.1 Major infection

1

62

Risk Ratio (M‐H, Random, 95% CI)

0.21 [0.05, 0.89]

5.2 Herpes zoster virus

1

62

Risk Ratio (M‐H, Random, 95% CI)

0.38 [0.08, 1.79]

6 Leucopenia Show forest plot

1

62

Risk Ratio (M‐H, Random, 95% CI)

0.06 [0.00, 0.92]

7 Bone toxicity Show forest plot

1

62

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

8 Alopecia Show forest plot

1

62

Risk Ratio (M‐H, Random, 95% CI)

0.05 [0.00, 0.81]

9 Gastrointestinal (GI) adverse events Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

9.1 GI upset

1

62

Risk Ratio (M‐H, Random, 95% CI)

2.81 [0.31, 25.58]

10 Daily proteinuria Show forest plot

1

42

Mean Difference (IV, Random, 95% CI)

0.3 [‐0.19, 0.79]

Figuras y tablas -
Comparison 2. Mycophenolate mofetil (MMF) versus oral cyclophosphamide (CPA)
Comparison 3. Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Death Show forest plot

2

402

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2 Remission Show forest plot

2

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

2.1 Complete renal remission

2

402

Risk Ratio (M‐H, Random, 95% CI)

2.38 [1.07, 5.30]

2.2 Partial renal remission

2

402

Risk Ratio (M‐H, Random, 95% CI)

1.0 [0.78, 1.28]

2.3 Complete remission in proteinuria

2

402

Risk Ratio (M‐H, Random, 95% CI)

2.38 [1.07, 5.30]

2.4 Partial remission in proteinuria

2

402

Risk Ratio (M‐H, Random, 95% CI)

0.98 [0.76, 1.26]

3 Adverse renal outcomes Show forest plot

2

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

3.1 Doubling of serum creatinine

2

402

Risk Ratio (M‐H, Random, 95% CI)

0.98 [0.10, 9.23]

4 Stable kidney function Show forest plot

2

402

Risk Ratio (M‐H, Random, 95% CI)

1.78 [1.40, 2.26]

5 Ovarian failure Show forest plot

1

34

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

6 Menstrual irregularities Show forest plot

1

323

Risk Ratio (M‐H, Random, 95% CI)

0.28 [0.06, 1.35]

7 Infection Show forest plot

2

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

7.1 Major infection

2

402

Risk Ratio (M‐H, Random, 95% CI)

1.65 [0.11, 24.44]

7.2 Herpes zoster virus

2

402

Risk Ratio (M‐H, Random, 95% CI)

0.80 [0.22, 2.94]

8 Leucopenia Show forest plot

2

402

Risk Ratio (M‐H, Random, 95% CI)

0.23 [0.04, 1.44]

9 Bone toxicity Show forest plot

1

362

Risk Ratio (M‐H, Random, 95% CI)

3.0 [0.12, 73.16]

10 Alopecia Show forest plot

2

402

Risk Ratio (M‐H, Random, 95% CI)

0.78 [0.36, 1.72]

11 Gastrointestinal (GI) adverse events Show forest plot

2

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

11.1 Diarrhoea

1

362

Risk Ratio (M‐H, Random, 95% CI)

2.33 [0.92, 5.94]

11.2 GI upset

2

402

Risk Ratio (M‐H, Random, 95% CI)

0.21 [0.10, 0.41]

12 Daily proteinuria Show forest plot

1

40

Mean Difference (IV, Random, 95% CI)

‐1.69 [‐2.81, ‐0.57]

Figuras y tablas -
Comparison 3. Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA)
Comparison 4. Mycophenolate mofetil (MMF) + IV cyclophosphamide (CPA) versus IV CPA

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Death Show forest plot

1

82

Risk Ratio (M‐H, Random, 95% CI)

0.95 [0.06, 14.72]

2 Remission Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

2.1 Complete renal remission

1

82

Risk Ratio (M‐H, Random, 95% CI)

1.22 [0.78, 1.89]

2.2 Partial renal remission

1

82

Risk Ratio (M‐H, Random, 95% CI)

1.03 [0.55, 1.90]

3 Menstrual irregularities Show forest plot

1

75

Risk Ratio (M‐H, Random, 95% CI)

0.49 [0.16, 1.48]

4 Infection Show forest plot

1

82

Risk Ratio (M‐H, Random, 95% CI)

0.37 [0.14, 0.93]

4.1 Major infection

1

82

Risk Ratio (M‐H, Random, 95% CI)

0.37 [0.14, 0.93]

5 Leucopenia Show forest plot

1

82

Risk Ratio (M‐H, Random, 95% CI)

0.63 [0.11, 3.60]

6 Daily proteinuria Show forest plot

1

77

Mean Difference (IV, Random, 95% CI)

‐0.54 [‐1.12, 0.04]

Figuras y tablas -
Comparison 4. Mycophenolate mofetil (MMF) + IV cyclophosphamide (CPA) versus IV CPA
Comparison 5. Mycophenolate mofetil (MMF) versus tacrolimus (TAC)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Death Show forest plot

3

273

Risk Ratio (M‐H, Random, 95% CI)

1.10 [0.44, 2.77]

2 Remission Show forest plot

3

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

2.1 Complete renal remission

3

273

Risk Ratio (M‐H, Random, 95% CI)

1.02 [0.83, 1.26]

2.2 Partial renal remission

2

190

Risk Ratio (M‐H, Random, 95% CI)

0.83 [0.51, 1.36]

2.3 Complete remission in proteinuria

1

40

Risk Ratio (M‐H, Random, 95% CI)

1.0 [0.50, 1.98]

2.4 Partial remission in proteinuria

2

190

Risk Ratio (M‐H, Random, 95% CI)

0.90 [0.79, 1.03]

3 Adverse renal outcomes Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

3.1 ESKD

1

150

Risk Ratio (M‐H, Random, 95% CI)

1.22 [0.51, 2.91]

3.2 Renal relapse

1

150

Risk Ratio (M‐H, Random, 95% CI)

0.67 [0.48, 0.93]

3.3 Renal relapse (nephritic flare)

1

152

Risk Ratio (M‐H, Random, 95% CI)

0.68 [0.36, 1.28]

3.4 Renal relapse (proteinuric flare)

1

150

Risk Ratio (M‐H, Random, 95% CI)

0.67 [0.41, 1.12]

3.5 Deterioration in kidney function

1

150

Risk Ratio (M‐H, Random, 95% CI)

0.54 [0.27, 1.09]

4 Stable kidney function Show forest plot

1

40

Risk Ratio (M‐H, Random, 95% CI)

1.0 [0.50, 1.98]

5 Menstrual irregularities Show forest plot

1

40

Risk Ratio (M‐H, Random, 95% CI)

3.0 [0.13, 69.52]

6 Infection Show forest plot

2

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

6.1 Major infection

2

190

Risk Ratio (M‐H, Random, 95% CI)

2.14 [0.93, 4.92]

6.2 Herpes zoster virus

1

150

Risk Ratio (M‐H, Random, 95% CI)

6.82 [1.60, 28.96]

7 Leucopenia Show forest plot

1

40

Risk Ratio (M‐H, Random, 95% CI)

1.0 [0.07, 14.90]

8 Alopecia Show forest plot

1

150

Risk Ratio (M‐H, Random, 95% CI)

0.07 [0.00, 1.31]

9 Daily proteinuria (at 24 weeks) Show forest plot

1

150

Mean Difference (IV, Random, 95% CI)

0.18 [‐0.25, 0.61]

10 Disease activity Show forest plot

2

Mean Difference (IV, Random, 95% CI)

Subtotals only

10.1 Renal SLEDAI

2

233

Mean Difference (IV, Random, 95% CI)

‐0.21 [‐2.05, 1.63]

10.2 Extrarenal SLEDAI

2

233

Mean Difference (IV, Random, 95% CI)

‐0.26 [‐0.74, 0.22]

11 Serum creatinine Show forest plot

1

83

Mean Difference (IV, Random, 95% CI)

‐0.01 [‐0.16, 0.14]

12 Creatinine clearance Show forest plot

1

40

Mean Difference (IV, Random, 95% CI)

‐1.93 [‐7.77, 3.91]

Figuras y tablas -
Comparison 5. Mycophenolate mofetil (MMF) versus tacrolimus (TAC)
Comparison 6. Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Death Show forest plot

3

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

1.1 Death

3

153

Risk Ratio (M‐H, Random, 95% CI)

0.41 [0.06, 2.69]

1.2 Death: extended follow‐up

1

38

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2 Remission Show forest plot

4

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

2.1 Complete renal remission

4

178

Risk Ratio (M‐H, Random, 95% CI)

1.35 [0.94, 1.93]

2.2 Partial renal remission

4

178

Risk Ratio (M‐H, Random, 95% CI)

0.88 [0.61, 1.26]

2.3 Complete remission in proteinuria

3

105

Risk Ratio (M‐H, Random, 95% CI)

1.71 [1.08, 2.70]

3 Adverse renal outcomes Show forest plot

2

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

3.1 ESKD: extended follow‐up

1

38

Risk Ratio (M‐H, Random, 95% CI)

1.0 [0.07, 14.85]

3.2 Doubling of serum creatinine

1

40

Risk Ratio (M‐H, Random, 95% CI)

0.33 [0.01, 7.72]

3.3 Doubling of serum creatinine: extended follow‐up

1

38

Risk Ratio (M‐H, Random, 95% CI)

1.0 [0.16, 6.38]

4 Stable kidney function Show forest plot

4

186

Risk Ratio (M‐H, Random, 95% CI)

1.11 [0.61, 2.00]

5 Ovarian failure Show forest plot

2

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

5.1 Ovarian failure

2

113

Risk Ratio (M‐H, Random, 95% CI)

0.25 [0.03, 2.18]

5.2 Premature ovarian failure: extended follow‐up

1

27

Risk Ratio (M‐H, Random, 95% CI)

0.31 [0.01, 7.02]

6 Menstrual irregularities Show forest plot

2

54

Risk Ratio (M‐H, Random, 95% CI)

0.41 [0.04, 4.05]

7 Infection Show forest plot

4

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

7.1 Major infection

3

138

Risk Ratio (M‐H, Random, 95% CI)

0.73 [0.33, 1.63]

7.2 Herpes zoster virus

2

113

Risk Ratio (M‐H, Random, 95% CI)

1.41 [0.38, 5.20]

8 Malignancy: extended follow‐up Show forest plot

1

38

Risk Ratio (M‐H, Random, 95% CI)

5.0 [0.26, 97.70]

9 Leucopenia Show forest plot

3

153

Risk Ratio (M‐H, Random, 95% CI)

0.44 [0.13, 1.49]

10 Alopecia Show forest plot

2

113

Risk Ratio (M‐H, Random, 95% CI)

0.21 [0.02, 1.76]

11 Gastrointestinal (GI) adverse events Show forest plot

1

73

Risk Ratio (M‐H, Random, 95% CI)

0.35 [0.12, 1.01]

12 Daily proteinuria Show forest plot

2

156

Mean Difference (IV, Random, 95% CI)

‐0.37 [‐0.67, ‐0.07]

12.1 At 9 months

1

40

Mean Difference (IV, Random, 95% CI)

‐0.83 [‐1.37, ‐0.29]

12.2 At 12 months

1

38

Mean Difference (IV, Random, 95% CI)

‐0.27 [‐0.43, ‐0.11]

12.3 At 18 months

1

40

Mean Difference (IV, Random, 95% CI)

‐1.0 [‐2.26, 0.26]

12.4 Extended follow‐up

1

38

Mean Difference (IV, Random, 95% CI)

‐0.10 [‐0.49, 0.29]

13 Creatinine clearance Show forest plot

3

Mean Difference (IV, Random, 95% CI)

Subtotals only

13.1 At 6 months

1

150

Mean Difference (IV, Random, 95% CI)

11.70 [1.61, 21.79]

13.2 At 9 months

1

40

Mean Difference (IV, Random, 95% CI)

14.90 [1.35, 28.45]

13.3 At 12 months

1

38

Mean Difference (IV, Random, 95% CI)

‐15.70 [‐23.71, ‐7.69]

13.4 At 18 months

1

40

Mean Difference (IV, Random, 95% CI)

‐1.40 [‐17.25, 14.45]

14 Serum creatinine Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

14.1 At 9 months

1

40

Mean Difference (IV, Random, 95% CI)

12.70 [1.88, 23.52]

14.2 At 18 months

1

40

Mean Difference (IV, Random, 95% CI)

2.70 [‐11.50, 16.90]

14.3 Extended follow‐up

1

38

Mean Difference (IV, Random, 95% CI)

‐8.0 [‐20.35, 4.35]

Figuras y tablas -
Comparison 6. Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA)
Comparison 7. Cyclophosphamide (CPA) versus azathioprine (AZA)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Death Show forest plot

2

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

1.1 At 5 years

2

146

Risk Ratio (M‐H, Random, 95% CI)

1.39 [0.25, 7.77]

1.2 At 10 years

1

59

Risk Ratio (M‐H, Random, 95% CI)

1.93 [1.22, 3.06]

2 Remission in proteinuria Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

2.1 Complete remission

1

59

Risk Ratio (M‐H, Random, 95% CI)

2.03 [0.64, 6.46]

2.2 Partial remission

1

59

Risk Ratio (M‐H, Random, 95% CI)

1.80 [0.67, 4.81]

3 Adverse renal outcomes Show forest plot

2

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

3.1 ESKD

2

144

Risk Ratio (M‐H, Random, 95% CI)

0.40 [0.15, 1.07]

3.2 ESKD at 9.6 years (median)

1

100

Risk Ratio (M‐H, Random, 95% CI)

1.0 [0.15, 6.82]

3.3 Renal relapse

1

87

Risk Ratio (M‐H, Random, 95% CI)

0.15 [0.03, 0.64]

3.4 Renal relapse at 9.6 years (median)

1

87

Risk Ratio (M‐H, Random, 95% CI)

0.26 [0.10, 0.67]

3.5 Doubling of serum creatinine

2

144

Risk Ratio (M‐H, Random, 95% CI)

0.48 [0.24, 0.95]

3.6 Deterioration of kidney function

1

30

Risk Ratio (M‐H, Random, 95% CI)

0.67 [0.18, 2.42]

4 Stable kidney function Show forest plot

1

57

Risk Ratio (M‐H, Random, 95% CI)

1.32 [0.86, 2.01]

5 Ovarian failure Show forest plot

2

126

Risk Ratio (M‐H, Random, 95% CI)

2.11 [0.59, 7.53]

6 Menstrual irregularities Show forest plot

1

15

Risk Ratio (M‐H, Random, 95% CI)

1.90 [0.69, 5.23]

7 Infection Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

7.1 Major infection

1

57

Risk Ratio (M‐H, Random, 95% CI)

1.25 [0.27, 5.86]

7.2 Herpes zoster virus

1

57

Risk Ratio (M‐H, Random, 95% CI)

2.75 [0.68, 11.18]

8 Malignancy Show forest plot

2

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

8.1 CPA versus AZA

2

144

Risk Ratio (M‐H, Random, 95% CI)

0.59 [0.13, 2.63]

8.2 10 year follow‐up

1

87

Risk Ratio (M‐H, Random, 95% CI)

0.74 [0.11, 5.01]

9 Bone toxicity Show forest plot

1

87

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

10 Bladder toxicity Show forest plot

2

144

Risk Ratio (M‐H, Random, 95% CI)

3.59 [0.19, 66.14]

Figuras y tablas -
Comparison 7. Cyclophosphamide (CPA) versus azathioprine (AZA)
Comparison 8. Rituximab (RTX) + mycophenolate mofetil (MMF) versus placebo + MMF

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Death Show forest plot

1

144

Risk Ratio (M‐H, Random, 95% CI)

5.0 [0.24, 102.35]

2 Remission Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

2.1 Complete renal response

1

144

Risk Ratio (M‐H, Random, 95% CI)

0.86 [0.51, 1.45]

2.2 Partial renal response

1

144

Risk Ratio (M‐H, Random, 95% CI)

2.0 [1.05, 3.82]

2.3 Complete remission in proteinuria

1

144

Risk Ratio (M‐H, Random, 95% CI)

0.87 [0.63, 1.21]

3 Stable kidney function Show forest plot

1

144

Risk Ratio (M‐H, Random, 95% CI)

1.24 [0.90, 1.71]

4 Infection Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

4.1 Major infection

1

144

Risk Ratio (M‐H, Random, 95% CI)

1.0 [0.48, 2.08]

4.2 Herpes zoster virus

1

144

Risk Ratio (M‐H, Random, 95% CI)

0.82 [0.36, 1.85]

5 Leucopenia Show forest plot

1

144

Risk Ratio (M‐H, Random, 95% CI)

3.0 [0.85, 10.63]

Figuras y tablas -
Comparison 8. Rituximab (RTX) + mycophenolate mofetil (MMF) versus placebo + MMF
Comparison 9. Rituximab (RTX) + cyclophosphamide (CPA) versus RTX

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Remission Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

1.1 Complete renal response

1

19

Risk Ratio (M‐H, Random, 95% CI)

0.9 [0.16, 5.13]

1.2 Partial renal response

1

19

Risk Ratio (M‐H, Random, 95% CI)

0.75 [0.35, 1.62]

2 Infection Show forest plot

1

38

Risk Ratio (M‐H, Random, 95% CI)

0.57 [0.08, 4.20]

2.1 Major infection

1

19

Risk Ratio (M‐H, Random, 95% CI)

0.9 [0.07, 12.38]

2.2 Herpes zoster virus

1

19

Risk Ratio (M‐H, Random, 95% CI)

0.30 [0.01, 6.62]

3 Daily proteinuria Show forest plot

1

19

Mean Difference (IV, Random, 95% CI)

‐0.30 [‐2.29, 1.69]

4 Creatinine clearance Show forest plot

1

19

Mean Difference (IV, Random, 95% CI)

‐17.20 [‐50.66, 16.26]

5 Serum creatinine Show forest plot

1

19

Mean Difference (IV, Random, 95% CI)

35.00 [‐27.14, 97.14]

Figuras y tablas -
Comparison 9. Rituximab (RTX) + cyclophosphamide (CPA) versus RTX
Comparison 10. Abatacept + other immunosuppressive agent (IS) + versus placebo + other IS

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Death Show forest plot

2

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

1.1 Abatacept versus placebo

2

432

Risk Ratio (M‐H, Random, 95% CI)

0.29 [0.10, 0.91]

1.2 High dose abatacept versus placebo

1

199

Risk Ratio (M‐H, Random, 95% CI)

0.29 [0.06, 1.36]

1.3 Low dose abatacept versus placebo

1

199

Risk Ratio (M‐H, Random, 95% CI)

0.29 [0.06, 1.36]

2 Remission Show forest plot

2

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

2.1 Complete remission: abatacept versus placebo

2

432

Risk Ratio (M‐H, Random, 95% CI)

1.13 [0.74, 1.71]

2.2 Complete remission: high dose abatacept versus placebo

1

199

Risk Ratio (M‐H, Random, 95% CI)

1.14 [0.46, 2.83]

2.3 Complete remission: low dose abatacept versus placebo

1

199

Risk Ratio (M‐H, Random, 95% CI)

1.39 [0.58, 3.31]

2.4 Partial remission: abatacept versus placebo

2

432

Risk Ratio (M‐H, Random, 95% CI)

0.88 [0.58, 1.33]

2.5 Partial remission: high dose abatacept versus placebo

1

199

Risk Ratio (M‐H, Random, 95% CI)

1.01 [0.51, 2.01]

2.6 Partial remission: low dose abatacept versus placebo

1

199

Risk Ratio (M‐H, Random, 95% CI)

0.65 [0.29, 1.43]

3 Adverse renal outcomes Show forest plot

2

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

3.1 ESKD: Abatacept versus placebo

1

298

Risk Ratio (M‐H, Random, 95% CI)

0.84 [0.21, 3.45]

3.2 ESKD: high dose abatacept versus placebo

1

199

Risk Ratio (M‐H, Random, 95% CI)

1.01 [0.21, 4.88]

3.3 ESKD: low dose abatacept versus placebo

1

199

Risk Ratio (M‐H, Random, 95% CI)

0.67 [0.11, 3.94]

3.4 Renal relapse: abatacept versus placebo

1

134

Risk Ratio (M‐H, Random, 95% CI)

1.03 [0.22, 4.92]

4 Major Infection Show forest plot

2

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

4.1 Abatacept versus placebo

2

432

Risk Ratio (M‐H, Random, 95% CI)

1.29 [0.81, 2.04]

4.2 High dose abatacept versus placebo

1

199

Risk Ratio (M‐H, Random, 95% CI)

1.37 [0.78, 2.40]

4.3 Low dose abatacept versus placebo

1

199

Risk Ratio (M‐H, Random, 95% CI)

1.07 [0.59, 1.95]

5 Herpes zoster virus Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

5.1 Abatacept versus placebo

1

298

Risk Ratio (M‐H, Random, 95% CI)

9.64 [0.57, 164.02]

5.2 High dose abatacept versus placebo

1

199

Risk Ratio (M‐H, Random, 95% CI)

7.07 [0.37, 135.11]

5.3 Low dose abatacept versus placebo

1

199

Risk Ratio (M‐H, Random, 95% CI)

13.13 [0.75, 229.99]

6 Health‐related quality of life Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

6.1 Physical component

1

134

Mean Difference (IV, Random, 95% CI)

0.0 [‐3.73, 3.73]

6.2 Mental component

1

134

Mean Difference (IV, Random, 95% CI)

‐0.60 [‐4.50, 3.30]

7 Disease activity (BILAG) Show forest plot

1

134

Mean Difference (IV, Random, 95% CI)

‐0.40 [‐1.23, 0.43]

Figuras y tablas -
Comparison 10. Abatacept + other immunosuppressive agent (IS) + versus placebo + other IS
Comparison 11. Laquinimod + other immunosuppressive agent (IS) versus placebo + other IS

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Death Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

1.1 Laquinimod versus placebo

1

46

Risk Ratio (M‐H, Random, 95% CI)

1.5 [0.06, 34.79]

1.2 High dose laquinimod versus placebo

1

30

Risk Ratio (M‐H, Random, 95% CI)

3.0 [0.13, 68.26]

1.3 Low dose laquinimod versus placebo

1

31

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2 Complete remission Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

2.1 Complete remission: laquinimod versus placebo

1

46

Risk Ratio (M‐H, Random, 95% CI)

1.55 [0.70, 3.42]

2.2 Complete remission: high dose laquinimod versus placebo

1

30

Risk Ratio (M‐H, Random, 95% CI)

1.2 [0.47, 3.09]

2.3 Complete remission: low dose laquinimod versus placebo

1

31

Risk Ratio (M‐H, Random, 95% CI)

1.88 [0.83, 4.22]

Figuras y tablas -
Comparison 11. Laquinimod + other immunosuppressive agent (IS) versus placebo + other IS
Comparison 12. Ocrelizumab + other immunosuppressive agent (IS) versus placebo + other IS

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Death Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

1.1 Ocrelizumab versus placebo

1

379

Risk Ratio (M‐H, Random, 95% CI)

0.66 [0.23, 1.85]

1.2 High dose ocrelizumab versus placebo

1

253

Risk Ratio (M‐H, Random, 95% CI)

0.81 [0.25, 2.60]

1.3 Low dose ocrelizumab versus placebo

1

251

Risk Ratio (M‐H, Random, 95% CI)

0.50 [0.13, 1.94]

2 Remission Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

2.1 Complete remission: ocrelizumab versus placebo

1

223

Risk Ratio (M‐H, Random, 95% CI)

1.07 [0.74, 1.56]

2.2 Complete remission: high dose ocrelizumab versus placebo

1

148

Risk Ratio (M‐H, Random, 95% CI)

0.91 [0.57, 1.44]

2.3 Complete remission: low dose ocrelizumab versus placebo

1

150

Risk Ratio (M‐H, Random, 95% CI)

1.23 [0.82, 1.85]

2.4 Partial remission: ocrelizumab versus placebo

1

223

Risk Ratio (M‐H, Random, 95% CI)

1.49 [0.89, 2.49]

2.5 Partial remission: high dose ocrelizumab versus placebo

1

148

Risk Ratio (M‐H, Random, 95% CI)

1.78 [1.03, 3.08]

2.6 Partial remission: low dose ocrelizumab versus placebo

1

150

Risk Ratio (M‐H, Random, 95% CI)

1.2 [0.65, 2.20]

3 Major Infection Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

3.1 Ocrelizumab versus placebo

1

378

Risk Ratio (M‐H, Random, 95% CI)

1.14 [0.95, 1.36]

3.2 High dose ocrelizumab versus placebo

1

252

Risk Ratio (M‐H, Random, 95% CI)

1.05 [0.85, 1.30]

3.3 Low dose ocrelizumab versus placebo

1

251

Risk Ratio (M‐H, Random, 95% CI)

1.22 [1.00, 1.48]

Figuras y tablas -
Comparison 12. Ocrelizumab + other immunosuppressive agent (IS) versus placebo + other IS
Comparison 13. Sirukumab + other immunosuppressive agent (IS) versus placebo + other IS

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Death Show forest plot

1

25

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2 Infection Show forest plot

1

25

Risk Ratio (M‐H, Random, 95% CI)

0.93 [0.66, 1.32]

2.1 Major infection

1

25

Risk Ratio (M‐H, Random, 95% CI)

0.93 [0.66, 1.32]

3 Malignancy Show forest plot

1

25

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

4 Gastrointestinal (GI) adverse events Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

4.1 Diarrhoea

1

25

Risk Ratio (M‐H, Random, 95% CI)

1.59 [0.10, 26.15]

Figuras y tablas -
Comparison 13. Sirukumab + other immunosuppressive agent (IS) versus placebo + other IS
Comparison 14. IV versus oral cyclophosphamide (CPA)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Death Show forest plot

2

67

Risk Ratio (M‐H, Random, 95% CI)

0.80 [0.20, 3.24]

2 Adverse renal outcomes Show forest plot

2

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

2.1 ESKD

2

67

Risk Ratio (M‐H, Random, 95% CI)

0.23 [0.04, 1.28]

2.2 Doubling of serum creatinine

2

67

Risk Ratio (M‐H, Random, 95% CI)

0.67 [0.23, 1.98]

2.3 Deterioration of kidney function

1

38

Risk Ratio (M‐H, Random, 95% CI)

0.72 [0.23, 2.27]

3 Stable kidney function Show forest plot

1

38

Risk Ratio (M‐H, Random, 95% CI)

1.11 [0.77, 1.59]

4 Ovarian failure Show forest plot

2

56

Risk Ratio (M‐H, Random, 95% CI)

0.70 [0.37, 1.30]

5 Infection Show forest plot

2

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

5.1 Major infection

2

67

Risk Ratio (M‐H, Random, 95% CI)

1.16 [0.47, 2.90]

5.2 Herpes zoster virus

1

38

Risk Ratio (M‐H, Random, 95% CI)

0.75 [0.28, 2.04]

6 Malignancy Show forest plot

2

67

Risk Ratio (M‐H, Random, 95% CI)

1.43 [0.41, 4.96]

7 Bladder toxicity Show forest plot

2

67

Risk Ratio (M‐H, Random, 95% CI)

0.22 [0.03, 1.83]

8 Gastrointestinal (GI) adverse events Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

8.1 GI upset

1

29

Risk Ratio (M‐H, Random, 95% CI)

3.69 [0.43, 31.43]

Figuras y tablas -
Comparison 14. IV versus oral cyclophosphamide (CPA)
Comparison 15. Low versus high dose cyclophosphamide (CPA)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Death Show forest plot

4

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

1.1 At 6 months

1

117

Risk Ratio (M‐H, Random, 95% CI)

1.81 [0.19, 16.85]

1.2 At 12 months

2

121

Risk Ratio (M‐H, Random, 95% CI)

0.97 [0.14, 6.56]

1.3 At 5 years

1

85

Risk Ratio (M‐H, Random, 95% CI)

0.13 [0.01, 2.51]

1.4 At 10 years

1

90

Risk Ratio (M‐H, Random, 95% CI)

0.38 [0.08, 1.87]

2 Remission Show forest plot

3

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

2.1 Complete renal remission

3

267

Risk Ratio (M‐H, Random, 95% CI)

1.09 [0.63, 1.86]

2.2 Partial renal remission

3

267

Risk Ratio (M‐H, Random, 95% CI)

0.88 [0.69, 1.14]

3 Adverse renal outcomes Show forest plot

3

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

3.1 ESKD

2

135

Risk Ratio (M‐H, Random, 95% CI)

0.49 [0.05, 5.20]

3.2 ESKD at 5 years

1

85

Risk Ratio (M‐H, Random, 95% CI)

2.80 [0.30, 25.81]

3.3 ESKD at 10 years

1

90

Risk Ratio (M‐H, Random, 95% CI)

1.91 [0.37, 9.92]

3.4 Renal relapse

3

211

Risk Ratio (M‐H, Random, 95% CI)

2.75 [0.47, 15.98]

3.5 Doubling of serum creatinine

2

135

Risk Ratio (M‐H, Random, 95% CI)

0.33 [0.04, 3.02]

3.6 Doubling of serum creatinine at 5 years

1

85

Risk Ratio (M‐H, Random, 95% CI)

0.13 [0.02, 1.04]

3.7 Doubling of serum creatinine at 10 years

1

90

Risk Ratio (M‐H, Random, 95% CI)

0.80 [0.26, 2.42]

4 Stable kidney function Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

4.1 At 3 years

1

89

Risk Ratio (M‐H, Random, 95% CI)

0.72 [0.50, 1.03]

4.2 At 5 years

1

85

Risk Ratio (M‐H, Random, 95% CI)

0.96 [0.77, 1.20]

5 Ovarian failure Show forest plot

4

299

Risk Ratio (M‐H, Random, 95% CI)

1.73 [0.70, 4.31]

6 Infection Show forest plot

4

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

6.1 Major infection

4

327

Risk Ratio (M‐H, Random, 95% CI)

1.44 [0.83, 2.49]

6.2 Herpes zoster virus

3

281

Risk Ratio (M‐H, Random, 95% CI)

1.58 [0.41, 6.05]

7 Malignancy Show forest plot

2

206

Risk Ratio (M‐H, Random, 95% CI)

1.44 [0.09, 23.31]

8 Leucopenia Show forest plot

3

281

Risk Ratio (M‐H, Random, 95% CI)

0.82 [0.13, 5.15]

9 Bone toxicity Show forest plot

2

164

Risk Ratio (M‐H, Random, 95% CI)

2.93 [0.48, 18.02]

10 Alopecia Show forest plot

1

75

Risk Ratio (M‐H, Random, 95% CI)

0.28 [0.06, 1.25]

11 Gastrointestinal (GI) adverse events Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

11.1 GI disturbance

1

75

Risk Ratio (M‐H, Random, 95% CI)

0.11 [0.01, 1.94]

12 Daily proteinuria Show forest plot

3

242

Mean Difference (IV, Random, 95% CI)

‐0.10 [‐0.65, 0.46]

13 Creatinine clearance Show forest plot

1

117

Mean Difference (IV, Random, 95% CI)

‐12.60 [‐23.63, ‐1.57]

14 Serum creatinine Show forest plot

3

247

Mean Difference (IV, Random, 95% CI)

2.85 [‐7.61, 13.31]

15 Disease activity (SLEDAI) Show forest plot

1

75

Mean Difference (IV, Random, 95% CI)

‐1.50 [‐3.04, 0.04]

Figuras y tablas -
Comparison 15. Low versus high dose cyclophosphamide (CPA)
Comparison 16. Standard versus reduced dose oral corticosteroids

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Death Show forest plot

1

81

Risk Ratio (M‐H, Random, 95% CI)

4.65 [0.23, 93.95]

2 Remission Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

2.1 Complete renal remission

1

81

Risk Ratio (M‐H, Random, 95% CI)

0.93 [0.39, 2.23]

2.2 Partial renal remission

1

81

Risk Ratio (M‐H, Random, 95% CI)

1.33 [0.78, 2.24]

3 Relapse Show forest plot

1

50

Risk Ratio (M‐H, Random, 95% CI)

2.38 [0.10, 55.72]

4 Infection Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

4.1 Major infection

1

81

Risk Ratio (M‐H, Random, 95% CI)

4.64 [0.57, 38.00]

4.2 Herpes zoster virus

1

81

Risk Ratio (M‐H, Random, 95% CI)

13.95 [0.82, 236.48]

5 Gastrointestinal (GI) adverse events Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

5.1 Diarrhoea

1

81

Risk Ratio (M‐H, Random, 95% CI)

1.16 [0.51, 2.64]

5.2 Vomiting

1

81

Risk Ratio (M‐H, Random, 95% CI)

0.93 [0.25, 3.46]

5.3 Nausea

1

81

Risk Ratio (M‐H, Random, 95% CI)

2.79 [0.30, 25.67]

6 Creatinine clearance Show forest plot

1

74

Mean Difference (IV, Random, 95% CI)

‐5.80 [‐21.08, 9.48]

7 Serum creatinine Show forest plot

1

81

Mean Difference (IV, Random, 95% CI)

‐2.40 [‐15.98, 11.18]

Figuras y tablas -
Comparison 16. Standard versus reduced dose oral corticosteroids
Comparison 17. IV versus oral corticosteroids

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Death Show forest plot

1

22

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2 Adverse renal outcomes Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

2.1 Renal relapse

1

22

Risk Ratio (M‐H, Random, 95% CI)

0.95 [0.44, 2.04]

Figuras y tablas -
Comparison 17. IV versus oral corticosteroids
Comparison 18. Cyclophosphamide (CPA) + corticosteroids versus corticosteroids

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Death Show forest plot

5

226

Risk Ratio (M‐H, Random, 95% CI)

0.98 [0.53, 1.82]

2 Complete remission of proteinuria Show forest plot

1

13

Risk Ratio (M‐H, Random, 95% CI)

2.63 [0.13, 54.64]

3 Adverse renal outcomes Show forest plot

5

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

3.1 ESKD

5

278

Risk Ratio (M‐H, Random, 95% CI)

0.63 [0.39, 1.03]

3.2 Renal relapse

2

84

Risk Ratio (M‐H, Random, 95% CI)

0.23 [0.08, 0.62]

3.3 Doubling serum creatinine

4

228

Risk Ratio (M‐H, Random, 95% CI)

0.59 [0.40, 0.88]

4 Deterioration of kidney function Show forest plot

5

179

Risk Ratio (M‐H, Random, 95% CI)

0.78 [0.52, 1.18]

5 Stable kidney function Show forest plot

5

278

Risk Ratio (M‐H, Random, 95% CI)

1.20 [1.00, 1.45]

6 Ovarian failure Show forest plot

3

147

Risk Ratio (M‐H, Random, 95% CI)

2.18 [1.10, 4.34]

7 Infection Show forest plot

6

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

7.1 Major infection

6

291

Risk Ratio (M‐H, Random, 95% CI)

0.87 [0.50, 1.51]

7.2 Herpes zoster virus

3

199

Risk Ratio (M‐H, Random, 95% CI)

1.77 [0.63, 4.99]

8 Malignancy Show forest plot

2

117

Risk Ratio (M‐H, Random, 95% CI)

0.82 [0.07, 9.90]

9 Bone toxicity Show forest plot

3

197

Risk Ratio (M‐H, Random, 95% CI)

0.84 [0.40, 1.75]

10 Bladder toxicity Show forest plot

2

65

Risk Ratio (M‐H, Random, 95% CI)

2.66 [0.33, 21.68]

11 Daily proteinuria Show forest plot

3

92

Mean Difference (IV, Random, 95% CI)

0.15 [‐0.23, 0.54]

12 Serum creatinine Show forest plot

1

29

Mean Difference (IV, Random, 95% CI)

‐52.0 [‐111.39, 7.39]

13 Creatinine clearance Show forest plot

2

63

Mean Difference (IV, Random, 95% CI)

12.23 [‐0.13, 24.58]

Figuras y tablas -
Comparison 18. Cyclophosphamide (CPA) + corticosteroids versus corticosteroids
Comparison 19. Cyclophosphamide (CPA) + azathioprine (AZA) + corticosteroids versus corticosteroids alone

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Death Show forest plot

1

29

Risk Ratio (M‐H, Random, 95% CI)

0.53 [0.17, 1.68]

2 Adverse renal outcomes Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

2.1 ESKD

1

29

Risk Ratio (M‐H, Random, 95% CI)

0.21 [0.04, 1.02]

2.2 Doubling of serum creatinine

1

29

Risk Ratio (M‐H, Random, 95% CI)

0.16 [0.04, 0.69]

3 Stable kidney function Show forest plot

1

29

Risk Ratio (M‐H, Random, 95% CI)

1.59 [0.83, 3.06]

4 Ovarian failure Show forest plot

1

27

Risk Ratio (M‐H, Random, 95% CI)

7.32 [0.49, 108.96]

5 Infection Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

5.1 Major infection

1

29

Risk Ratio (M‐H, Random, 95% CI)

0.48 [0.10, 2.30]

5.2 Herpes zoster virus

1

29

Risk Ratio (M‐H, Random, 95% CI)

5.22 [0.33, 81.40]

6 Bladder toxicity Show forest plot

1

29

Risk Ratio (M‐H, Random, 95% CI)

2.43 [0.14, 42.17]

Figuras y tablas -
Comparison 19. Cyclophosphamide (CPA) + azathioprine (AZA) + corticosteroids versus corticosteroids alone
Comparison 20. Azathioprine (AZA) + corticosteroids versus corticosteroids alone

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Death Show forest plot

3

78

Risk Ratio (M‐H, Random, 95% CI)

0.60 [0.36, 0.99]

2 Complete remission of proteinuria Show forest plot

2

37

Risk Ratio (M‐H, Random, 95% CI)

0.95 [0.54, 1.69]

3 Adverse renal outcomes Show forest plot

3

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

3.1 ESKD

2

54

Risk Ratio (M‐H, Random, 95% CI)

0.66 [0.17, 2.55]

3.2 Renal relapse

1

16

Risk Ratio (M‐H, Random, 95% CI)

0.78 [0.22, 2.74]

3.3 Doubling of serum creatinine

1

26

Risk Ratio (M‐H, Random, 95% CI)

0.98 [0.36, 2.68]

4 Stable kidney function Show forest plot

1

26

Risk Ratio (M‐H, Random, 95% CI)

1.01 [0.48, 2.14]

5 Ovarian failure Show forest plot

1

24

Risk Ratio (M‐H, Random, 95% CI)

2.58 [0.15, 43.86]

6 Infection Show forest plot

2

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

6.1 Herpes zoster virus

2

42

Risk Ratio (M‐H, Random, 95% CI)

3.56 [0.46, 27.79]

7 Malignancy Show forest plot

1

26

Risk Ratio (M‐H, Random, 95% CI)

2.0 [0.11, 37.22]

8 Bone toxicity Show forest plot

1

24

Risk Ratio (M‐H, Random, 95% CI)

3.55 [0.43, 29.42]

9 Creatinine clearance Show forest plot

1

24

Mean Difference (IV, Random, 95% CI)

5.0 [‐3.14, 13.14]

Figuras y tablas -
Comparison 20. Azathioprine (AZA) + corticosteroids versus corticosteroids alone
Comparison 21. Cyclosporin (CSA) + corticosteroids versus corticosteroids alone

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Daily proteinuria Show forest plot

1

10

Mean Difference (IV, Random, 95% CI)

‐1.8 [‐2.59, ‐1.01]

2 Serum creatinine Show forest plot

1

10

Mean Difference (IV, Random, 95% CI)

‐31.90 [‐73.63, 9.83]

3 Creatinine clearance Show forest plot

1

10

Mean Difference (IV, Random, 95% CI)

‐42.5 [‐85.02, 0.02]

Figuras y tablas -
Comparison 21. Cyclosporin (CSA) + corticosteroids versus corticosteroids alone
Comparison 22. Misoprostol + corticosteroids versus corticosteroids alone

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Adverse renal outcomes Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

1.1 Doubling of serum creatinine

1

14

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

Figuras y tablas -
Comparison 22. Misoprostol + corticosteroids versus corticosteroids alone
Comparison 23. Plasma exchange (PE) + immunosuppression (IS) versus IS alone

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Death Show forest plot

2

125

Risk Ratio (M‐H, Random, 95% CI)

1.62 [0.64, 4.09]

2 Adverse renal outcomes Show forest plot

4

251

Risk Ratio (M‐H, Random, 95% CI)

0.89 [0.51, 1.55]

2.1 ESKD

3

143

Risk Ratio (M‐H, Random, 95% CI)

1.24 [0.60, 2.57]

2.2 Doubling of serum creatinine

2

51

Risk Ratio (M‐H, Random, 95% CI)

0.17 [0.02, 1.26]

2.3 Deterioration of kidney function

2

57

Risk Ratio (M‐H, Random, 95% CI)

0.53 [0.06, 4.83]

3 Stable kidney function Show forest plot

3

75

Risk Ratio (M‐H, Random, 95% CI)

1.10 [0.94, 1.30]

4 Infection Show forest plot

3

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

4.1 Major infection

2

125

Risk Ratio (M‐H, Random, 95% CI)

0.69 [0.35, 1.37]

4.2 Herpes zoster virus

2

104

Risk Ratio (M‐H, Random, 95% CI)

1.69 [0.10, 29.42]

5 Leucopenia Show forest plot

1

18

Risk Ratio (M‐H, Random, 95% CI)

2.60 [0.20, 34.07]

6 Daily proteinuria Show forest plot

2

30

Mean Difference (IV, Random, 95% CI)

‐0.56 [‐5.23, 4.11]

7 Serum creatinine Show forest plot

3

69

Mean Difference (IV, Random, 95% CI)

‐17.90 [‐23.41, ‐12.39]

8 Creatinine clearance Show forest plot

1

12

Mean Difference (IV, Random, 95% CI)

26.0 [‐17.60, 69.60]

9 Disease activity (SLAM) Show forest plot

1

18

Mean Difference (IV, Random, 95% CI)

0.67 [‐3.47, 4.81]

Figuras y tablas -
Comparison 23. Plasma exchange (PE) + immunosuppression (IS) versus IS alone
Comparison 24. Plasma exchange (PE) versus immunosuppression (IS)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Adverse renal outcomes Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

1.1 ESKD

1

20

Risk Ratio (M‐H, Random, 95% CI)

0.24 [0.01, 4.44]

2 Infection Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

2.1 Major infection

1

20

Risk Ratio (M‐H, Random, 95% CI)

0.4 [0.02, 8.78]

2.2 Herpes zoster virus

1

20

Risk Ratio (M‐H, Random, 95% CI)

0.24 [0.01, 4.44]

3 Leucopenia Show forest plot

1

20

Risk Ratio (M‐H, Random, 95% CI)

0.24 [0.01, 4.44]

4 Alopecia Show forest plot

1

20

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

5 Daily proteinuria Show forest plot

1

20

Mean Difference (IV, Random, 95% CI)

‐0.10 [‐0.45, 0.25]

6 Creatinine clearance Show forest plot

1

20

Mean Difference (IV, Random, 95% CI)

15.30 [‐5.40, 36.00]

Figuras y tablas -
Comparison 24. Plasma exchange (PE) versus immunosuppression (IS)
Comparison 25. Long versus short duration cyclophosphamide (CPA)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Adverse renal outcomes Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

1.1 ESKD

1

40

Risk Ratio (M‐H, Random, 95% CI)

0.4 [0.09, 1.83]

1.2 Doubling of serum creatinine

1

40

Risk Ratio (M‐H, Random, 95% CI)

0.43 [0.13, 1.43]

1.3 Deterioration of kidney function

1

40

Risk Ratio (M‐H, Random, 95% CI)

0.43 [0.13, 1.43]

2 Stable kidney function Show forest plot

1

40

Risk Ratio (M‐H, Random, 95% CI)

1.31 [0.90, 1.89]

3 Ovarian failure Show forest plot

1

29

Risk Ratio (M‐H, Random, 95% CI)

2.05 [0.60, 7.02]

4 Infection Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

4.1 Major infection

1

40

Risk Ratio (M‐H, Random, 95% CI)

1.0 [0.07, 14.90]

4.2 Herpes zoster virus

1

40

Risk Ratio (M‐H, Random, 95% CI)

0.5 [0.05, 5.08]

5 Malignancy Show forest plot

1

40

Risk Ratio (M‐H, Random, 95% CI)

3.0 [0.13, 69.52]

6 Bone toxicity Show forest plot

1

40

Risk Ratio (M‐H, Random, 95% CI)

1.33 [0.34, 5.21]

7 Bladder toxicity Show forest plot

1

40

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

Figuras y tablas -
Comparison 25. Long versus short duration cyclophosphamide (CPA)
Comparison 26. Maintenance: azathioprine (AZA) versus mycophenolate mofetil (MMF)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Death Show forest plot

4

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

1.1 At end of treatment duration or follow‐up

4

451

Risk Ratio (M‐H, Random, 95% CI)

1.15 [0.34, 3.87]

1.2 At 10 years

1

87

Risk Ratio (M‐H, Random, 95% CI)

0.62 [0.11, 3.54]

2 Renal relapse Show forest plot

4

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

2.1 At end of treatment duration or follow‐up

4

452

Risk Ratio (M‐H, Random, 95% CI)

1.75 [1.20, 2.55]

2.2 At 10 years

1

87

Risk Ratio (M‐H, Random, 95% CI)

1.08 [0.69, 1.69]

3 End‐stage kidney disease Show forest plot

4

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

3.1 At end of treatment duration or follow‐up

4

452

Risk Ratio (M‐H, Random, 95% CI)

1.70 [0.52, 5.54]

3.2 At 10 years

1

87

Risk Ratio (M‐H, Random, 95% CI)

0.31 [0.03, 2.88]

4 Doubling of serum creatinine Show forest plot

4

452

Risk Ratio (M‐H, Random, 95% CI)

2.19 [1.03, 4.66]

5 Ovarian failure Show forest plot

2

177

Risk Ratio (M‐H, Random, 95% CI)

0.77 [0.17, 3.42]

6 Infection Show forest plot

3

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

6.1 Major infection

3

412

Risk Ratio (M‐H, Random, 95% CI)

1.08 [0.60, 1.96]

6.2 Herpes zoster virus

1

105

Risk Ratio (M‐H, Random, 95% CI)

1.27 [0.36, 4.48]

7 Malignancy Show forest plot

3

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

7.1 At end of treatment duration or follow‐up

3

370

Risk Ratio (M‐H, Random, 95% CI)

4.04 [0.45, 36.07]

7.2 At 10 years

1

87

Risk Ratio (M‐H, Random, 95% CI)

1.87 [0.18, 19.84]

8 Leucopenia Show forest plot

3

412

Risk Ratio (M‐H, Random, 95% CI)

5.61 [1.68, 18.72]

9 Bone toxicity Show forest plot

1

105

Risk Ratio (M‐H, Random, 95% CI)

3.06 [0.13, 73.36]

10 Alopecia Show forest plot

3

412

Risk Ratio (M‐H, Random, 95% CI)

0.95 [0.46, 1.95]

11 Gastrointestinal (GI) adverse events Show forest plot

3

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

11.1 GI symptoms

1

105

Risk Ratio (M‐H, Random, 95% CI)

1.02 [0.41, 2.51]

11.2 Nausea

2

307

Risk Ratio (M‐H, Random, 95% CI)

1.08 [0.65, 1.80]

11.3 Diarrhoea

2

307

Risk Ratio (M‐H, Random, 95% CI)

0.74 [0.31, 1.73]

11.4 Vomiting

2

307

Risk Ratio (M‐H, Random, 95% CI)

0.81 [0.18, 3.62]

12 Daily proteinuria Show forest plot

1

81

Mean Difference (IV, Random, 95% CI)

0.40 [‐0.53, 1.33]

Figuras y tablas -
Comparison 26. Maintenance: azathioprine (AZA) versus mycophenolate mofetil (MMF)
Comparison 27. Maintenance: azathioprine (AZA) versus cyclosporin (CSA)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Death Show forest plot

1

69

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2 Adverse renal outcomes Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

2.1 ESKD

1

69

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2.2 Renal relapse

1

69

Risk Ratio (M‐H, Random, 95% CI)

1.25 [0.51, 3.06]

3 Infection Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

3.1 Major infection

1

69

Risk Ratio (M‐H, Random, 95% CI)

2.18 [1.01, 4.73]

4 Leucopenia Show forest plot

1

69

Risk Ratio (M‐H, Random, 95% CI)

2.73 [0.95, 7.86]

5 Gastrointestinal (GI) adverse events Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

5.1 GI disturbance

1

69

Risk Ratio (M‐H, Random, 95% CI)

0.30 [0.09, 0.97]

6 Daily proteinuria Show forest plot

1

69

Mean Difference (IV, Random, 95% CI)

0.15 [‐0.23, 0.53]

7 Disease activity (SLEDAI) Show forest plot

1

69

Mean Difference (IV, Random, 95% CI)

‐3.20 [‐5.77, ‐0.63]

Figuras y tablas -
Comparison 27. Maintenance: azathioprine (AZA) versus cyclosporin (CSA)
Comparison 28. Maintenance: azathioprine (AZA) versus cyclophosphamide (CPA)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Death Show forest plot

1

39

Risk Ratio (M‐H, Random, 95% CI)

0.12 [0.01, 2.03]

2 Adverse renal outcomes Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

2.1 ESKD

1

39

Risk Ratio (M‐H, Random, 95% CI)

0.35 [0.04, 3.09]

2.2 Renal relapse

1

39

Risk Ratio (M‐H, Random, 95% CI)

0.79 [0.34, 1.85]

2.3 Doubling of serum creatinine

1

39

Risk Ratio (M‐H, Random, 95% CI)

0.79 [0.34, 1.85]

3 Bladder toxicity Show forest plot

1

39

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

4 Creatinine clearance Show forest plot

1

38

Mean Difference (IV, Random, 95% CI)

‐15.70 [‐23.71, ‐7.69]

Figuras y tablas -
Comparison 28. Maintenance: azathioprine (AZA) versus cyclophosphamide (CPA)
Comparison 29. Maintenance: azathioprine (AZA) versus tacrolimus (TAC)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Adverse renal outcomes Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

1.1 Renal relapse

1

70

Risk Ratio (M‐H, Random, 95% CI)

6.62 [0.35, 123.63]

2 Infection Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

2.1 Major infection

1

70

Risk Ratio (M‐H, Random, 95% CI)

1.26 [0.30, 5.22]

3 Gastrointestinal (GI) adverse events Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

3.1 GI disturbance

1

70

Risk Ratio (M‐H, Random, 95% CI)

1.89 [0.18, 19.89]

Figuras y tablas -
Comparison 29. Maintenance: azathioprine (AZA) versus tacrolimus (TAC)
Comparison 30. Maintenance: prednisone withdrawal versus prednisone continuation

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Relapse Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

1.1 Renal relapse

1

15

Risk Ratio (M‐H, Random, 95% CI)

0.38 [0.05, 2.88]

1.2 Non‐renal relapse

1

15

Risk Ratio (M‐H, Random, 95% CI)

0.38 [0.02, 7.96]

2 Major infection Show forest plot

1

15

Risk Ratio (M‐H, Random, 95% CI)

0.57 [0.06, 5.03]

Figuras y tablas -
Comparison 30. Maintenance: prednisone withdrawal versus prednisone continuation
Comparison 31. Maintenance: intravenous immunoglobulin (IVIG) versus intravenous cyclophosphamide (IV CPA)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Creatinine clearance Show forest plot

1

13

Mean Difference (IV, Random, 95% CI)

2.20 [‐37.85, 42.25]

2 Daily proteinuria Show forest plot

1

13

Mean Difference (IV, Random, 95% CI)

‐0.08 [‐0.95, 0.79]

3 Serum creatinine Show forest plot

1

14

Mean Difference (IV, Random, 95% CI)

‐35.40 [‐128.90, 58.10]

Figuras y tablas -
Comparison 31. Maintenance: intravenous immunoglobulin (IVIG) versus intravenous cyclophosphamide (IV CPA)