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Treatment for hepatitis C virus‐associated mixed cryoglobulinaemia

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References

References to studies included in this review

Dammacco 1994 {published data only}

Dammacco F, Sansonno D, Han JH, Shyamala V, Cornacchiulo V, Iacobelli AR, et al. Natural interferon‐alpha versus its combination with 6‐methyl‐prednisolone in the therapy of type II mixed cryoglobulinemia: a long‐term, randomized, controlled study. Blood 1994;84(10):3336‐43. [MEDLINE: 7524736]CENTRAL

Dammacco 2010 {published data only}

Dammacco F, Tucci FA, Lauletta G, Gatti P, De Re V, Conteduca V, et al. Pegylated interferon‐alpha, ribavirin, and rituximab combined therapy of hepatitis C virus‐related mixed cryoglobulinemia: a long‐term study. Blood 2010;116(3):343‐53. [MEDLINE: 20308602]CENTRAL

De Vita 2012 {published data only}

De Vita S, Quartuccio L, Isola M, Masolini P, Sacco S, De Marchi G, et al. A randomized, controlled, multicenter phase III study of the efficacy and safety of rituximab (RTX) monotherapy versus the best available treatment in patients with mixed cryoglobulinemia syndrome [abstract]. Arthritis & Rheumatism 2010;62(Suppl 10):2201. [EMBASE: 70380187]CENTRAL
De Vita S, Quartuccio L, Isola M, Mazzaro C, Scaini P, Lenzi M, et al. A randomized controlled trial of rituximab for the treatment of severe cryoglobulinemic vasculitis. Arthritis & Rheumatism 2012;64(3):843‐53. [MEDLINE: 22147661]CENTRAL
De Vita S, Quartuccio L, Masolini P, Stefania S, De Marchi G, Zabotti A, et al. A randomized, controlled, multicenter phase III study of the efficacy and safety of rituximab (RTX) monotherapy versus the best available treatment (BAT) in patients with mixed cryoglobulinemia syndrome [abstract no: OP0120]. Annals of Rheumatic Diseases 2010;69(Suppl 3):93. CENTRAL
Quartuccio L, Zuliani F, Corazza L, Scaini P, Zani R, Lenzi M, et al. Retreatment regimen of rituximab monotherapy given at the relapse of severe HCV‐related cryoglobulinemic vasculitis: Long‐term follow up data of a randomized controlled multicentre study. Journal of Autoimmunity2015; Vol. 63:88‐93. [MEDLINE: 26255249]CENTRAL
Quartuccio L, Zuliani F, Corazza L, Scaini P, Zani R, Lenzi M, et al. Rituximab monotherapy of severe HCV‐related cryoglobulinemic vasculitis for more than 2 years: Follow‐up of a randomized controlled multicentre study [abstract]. Annals of the Rheumatic Diseases 2014;73(Suppl 2). [EMBASE: 71551183]CENTRAL

Ferri 1991 {published data only}

Ferri C, Marzo E, Longombardo G, La Civita L, Lombardini F, Giuggioli D, et al. Interferon alfa‐2b in mixed cryoglobulinaemia: a controlled crossover trial. Gut 1993;34(2 Suppl):S144‐5. [MEDLINE: 8314485]CENTRAL
Ferri C, Marzo E, Longombardo G, Lombardini F, Greco F, Bombardieri S. Alpha interferon in the treatment of mixed cryoglobulinaemia patients. European Journal of Cancer 1991;27 Suppl 4:S81‐2. [MEDLINE: 1799489]CENTRAL
Ferri C, Marzo E, Longombardo G, Lombardini F, La Civita L, Vanacore R, et al. Interferon‐alpha in mixed cryoglobulinemia patients: a randomized, crossover‐controlled trial. Blood 1993;81(5):1132‐6. [MEDLINE: 8382969]CENTRAL
Ferri C, Marzo E, Longombardo G, Vanacore R. Effects of alpha‐interferon on clinico‐serological parameters of mixed cryoglobulinemia [abstract]. European Journal of Clinical Investigation 1991;21(2 Pt II):66. [CENTRAL: CN‐00254102]CENTRAL

Mazzaro 1995 {published data only}

Mazzaro C, Lacchin T, Moretti M, Tulissi P, Manazzone O, Colle R, et al. Effects of two different alpha‐interferon regimens on clinical and virological findings in mixed cryoglobulinemia. Clinical & Experimental Rheumatology 1995;13 Suppl 13:S181‐5. [MEDLINE: 8730503]CENTRAL

Mazzaro 2000 {published data only}

Mazzaro C, Panarello G, Carniello S, Faelli A, Mazzi G, Crovatto M, et al. Interferon versus steroids in patients with hepatitis C virus‐associated cryoglobulinaemic glomerulonephritis. Digestive & Liver Disease 2000;32(8):708‐15. [MEDLINE: 11142582]CENTRAL
Mazzaro C, Panarello G, Faelli A, Donada C, Baracetti S, Zorat F, et al. Interferon alfa VS steroids in patients with HCV cryoglobulinemic glomerulonephritis [abstract]. Journal of Hepatology 1999;30(Suppl 1):233. [CENTRAL: CN‐00221652]CENTRAL

Misiani 1994 {published data only}

Misiani R, Bellavita P, Fenili D, Vicari O, Marchesi D, Sironi PL, et al. Interferon alfa‐2a therapy in cryoglobulinemia associated with hepatitis C virus. New England Journal of Medicine 1994;330(11):751‐6. [MEDLINE: 8107741]CENTRAL

Pioltelli 1995 {published data only}

Pioltelli P, Maldifassi P, Vacca A, Mazzaro C, Mussini C, Migliaresi S, et al. GISC protocol experience in the treatment of essential mixed cryoglobulinaemia. Clinical & Experimental Rheumatology 1995;13 Suppl 13:S187‐90. [MEDLINE: 8730504]CENTRAL

Sneller 2012 {published data only}

Sneller MC, Hu Z, Langford CA. A randomized controlled trial of rituximab following failure of antiviral therapy for hepatitis C virus‐associated cryoglobulinemic vasculitis. Arthritis & Rheumatism 2012;64(3):835‐42. [MEDLINE: 22147444]CENTRAL

Stefanutti 2009 {published data only}

Stefanutti C, Vivenzio A, Di Giacomo S, Labbadia G, Mazza F, D'Alessandri G, et al. Immunoadsorption apheresis and immunosuppressive drug therapy in the treatment of complicated HCV‐related cryoglobulinemia. Journal of Clinical Apheresis 2009;24(6):241‐6. [MEDLINE: 19927363]CENTRAL

References to studies excluded from this review

Anonymous 1989 {published data only}

Anonymous. Double‐blind study on the antiproteinuric effect of captopril versus placebo in cryoglobulinaemic glomerulonephritis: a Franco‐Hispano‐Italian study. Nephrology Dialysis Transplantation 1989;4(9):839. [MEDLINE: 2516616]CENTRAL

Candela 1994 {published data only}

Candela M, Cherubini G, Chelli F, Danieli G, Gabrielli A. Fish‐oil fatty acid supplementation in mixed cryoglobulinemia: a preliminary report. Clinical & Experimental Rheumatology 1994;12(5):509‐13. [MEDLINE: 7842531]CENTRAL

Ferri 1989 {published data only}

Ferri C, Pietrogrande M, Cecchetti R, Tavoni A, Cefalo A, Buzzetti G, et al. Low‐antigen‐content diet in the treatment of patients with mixed cryoglobulinemia. American Journal of Medicine 1989;87(5):519‐24. [MEDLINE: 2816967]CENTRAL

Lauta 1995 {published data only}

Lauta VM, De Sangro A. Long‐term results regarding the interferon alpha‐2b in the treatment essential cryoglobulinemia. Medical Oncology 1995;12(4):223‐30. [EMBASE: 26239920]CENTRAL

Vacca 1992 {published data only}

Vacca A, Dammacco F. Deflazacort versus prednisone in the treatment of essential mixed cryoglobulinemia: a between‐patient controlled clinical study. International Archives of Allergy & Immunology 1992;99(2‐4):306‐10. [EMBASE: 23075730]CENTRAL

Bartolucci 2002

Bartolucci P, Ramanoelina J, Cohen P, Mahr A, Godmer P, Le Hello C, et al. Efficacy of the anti‐TNF‐alpha antibody infliximab against refractory systemic vasculitides: an open pilot study on 10 patients. Rheumatology 2002;41(10):1126‐32. [MEDLINE: 12364631]

Cacoub 2014

Cacoub P, Terrier B, Saadoun D. Hepatitis C virus‐induced vasculitis: therapeutic options. Annals of the rheumatic diseases 2014;73(1):24‐30. [MEDLINE: 23921995]

Cacoub 2015

Cacoub P, Comarmond C, Domont F, Savey L, Saadoun D. Cryoglobulinemia vasculitis. American Journal of Medicine 2015;128(9):950‐5. [PUBMED: 25837517]

Cacoub 2017

Cacoub P, Vautier M, Desbois AC, Lafuma A, Saadoun D. Effectiveness and cost of hepatitis C virus cryoglobulinaemia vasculitis treatment: from interferon‐based to direct‐acting antivirals era. Liver International 2017;37(12):1805‐13. [MEDLINE: 28467688]

Chandesris 2004

Chandesris MO, Gayet S, Schleinitz N, Doudier B, Harle JR, Kaplanski G. Infliximab in the treatment of refractory vasculitis secondary to hepatitis C‐associated mixed cryoglobulinaemia. Rheumatology2004; Vol. 43, issue 4:532‐3. [MEDLINE: 15024144]

Charles 2009

Charles ED, Dustin LB. Hepatitis C virus‐induced cryoglobulinemia. Kidney International 2009;76(8):818‐24. [MEDLINE: 19606079]

Cohen 2012

Cohen C, Mekinian A, Saidenberg‐Kermanac'h N, Stirnemann J, Fenaux P, Gherardi R, et al. Efficacy of tocilizumab in rituximab‐refractory cryoglobulinemia vasculitis. Annals of the Rheumatic Diseases2012; Vol. 71, issue 4:628‐9. [MEDLINE: 22121135]

Cornella 2015

Cornella SL, Stine JG, Kelly V, Caldwell SH, Shah NL. Persistence of mixed cryoglobulinemia despite cure of hepatitis C with new oral antiviral therapy including direct‐acting antiviral sofosbuvir: a case series. Postgraduate Medicine 2015;127(4):413‐7. [PUBMED: 25746436]

Dammacco 2000

Dammacco F, Sansonno D, Piccoli C, Racanelli V, D'Amore FP, Lauletta G. The lymphoid system in hepatitis C virus infection: autoimmunity, mixed cryoglobulinemia, and Overt B‐cell malignancy. Seminars in Liver Disease 2000;20(2):143‐57. [MEDLINE: 10946420]

Dammacco 2013

Dammacco F, Sansonno D. Therapy for hepatitis C virus‐related cryoglobulinemic vasculitis. New England Journal of Medicine 2013;369(11):1035‐45. [PUBMED: 24024840]

Dammacco 2016

Dammacco F, Racanelli V, Russi S, Sansonno D. The expanding spectrum of HCV‐related cryoglobulinemic vasculitis: a narrative review. Clinical & Experimental Medicine 2016;16(3):233‐42. [PUBMED: 26935415]

Desbois 2017

Desbois AC, Comarmond C, Saadoun D, Cacoub P. Cryoglobulinemia vasculitis: how to handle. Current Opinion in Rheumatology 2017;29(4):343‐7. [MEDLINE: 28368978]

EASL 2011

European Association for Study of Liver. EASL Clinical Practice Guidelines: management of hepatitis C virus infection. Journal of Hepatology 2011;55(2):245‐64. [MEDLINE: 21371579]

Ferri 2004

Ferri C, Sebastiani M, Giuggioli D, Cazzato M, Longombardo G, Antonelli A, et al. Mixed cryoglobulinemia: demographic, clinical, and serologic features and survival in 231 patients. Seminars in Arthritis & Rheumatism 2004;33(6):355‐74. [MEDLINE: 15190522]

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]

Gragnani 2016

Gragnani L, Visentini M, Fognani E, Urraro T, De Santis A, Petraccia L, et al. Prospective study of guideline‐tailored therapy with direct‐acting antivirals for hepatitis C virus‐associated mixed cryoglobulinemia. Hepatology 2016;64(5):1473‐82. [MEDLINE: 27483451]

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.

Josselin 2008

Josselin L, Mahr A, Cohen P, Pagnoux C, Guaydier‐Souquieres G, Hayem G, et al. Infliximab efficacy and safety against refractory systemic necrotising vasculitides: long‐term follow‐up of 15 patients. Annals of the Rheumatic Diseases 2008;67(9):1343‐6. [MEDLINE: 18445626]

Kotter 2010

Kotter I, Hamuryudan V, Ozturk ZE, Yazici H. Interferon therapy in rheumatic diseases: state‐of‐the‐art 2010. Current Opinion in Rheumatology 2010;22(3):278‐83. [MEDLINE: 20061957]

Langhans 2017

Langhans B, Nischalke HD, Kramer B, Hausen A, Dold L, van Heteren P, et al. Increased peripheral CD4+ regulatory T cells persist after successful direct‐acting antiviral treatment of chronic hepatitis C. Journal of Hepatology 2017;66(5):888‐96. [MEDLINE: 28040549]

Latt 2012

Latt N, Alachkar N, Gurakar A. Hepatitis C virus and its renal manifestations: a review and update. Gastroenterology & Hepatology 2012;8(7):434‐45. [MEDLINE: 23293553]

Lauletta 2012

Lauletta G, Russi S, Conteduca V, Sansonno L. Hepatitis C virus infection and mixed cryoglobulinemia. Clinical & Developmental Immunology 2012;2012:502156. [MEDLINE: 22844322]

Liang 2013

Liang TJ, Ghany MG. Current and future therapies for hepatitis C virus infection. New England Journal of Medicine 2013;368(20):1907‐17. [MEDLINE: 23675659]

Lok 2012

Lok AS, Gardiner DF, Lawitz E, Martorell C, Everson GT, Ghalib R, et al. Preliminary study of two antiviral agents for hepatitis C genotype 1. New England Journal of Medicine 2012;366(3):216‐24. [MEDLINE: 22256805]

Maasoumy 2013

Maasoumy B, Port K, Markova AA, Serrano BC, Rogalska‐Taranta M, Sollik L, et al. Eligibility and safety of triple therapy for hepatitis C: lessons learned from the first experience in a real world setting. PLoS ONE [Electronic Resource] 2013;8(2):e55285. [MEDLINE: 23383319]

Martin 2017

Martin P, Fabrizi F. Editorial: Benefit of direct‐acting antiviral therapy for cryoglobulinemia due to hepatitis C infection. American Journal of Gastroenterology 2017;112(8):1309‐10. [MEDLINE: 28766566]

Matignon 2009

Matignon M, Cacoub P, Colombat M, Saadoun D, Brocheriou I, Mougenot B, et al. Clinical and morphologic spectrum of renal involvement in patients with mixed cryoglobulinemia without evidence of hepatitis C virus infection. Medicine 2009;88(6):341‐8. [MEDLINE: 19910748]

Myers 2012

Myers RP, Ramji A, Bilodeau M, Wong S, Feld JJ. An update on the management of hepatitis C: consensus guidelines from the Canadian Association for the Study of the Liver. Canadian Journal of Gastroenterology 2012;26(6):359‐75. [MEDLINE: 22720279]

Pietrogrande 2011

Pietrogrande M, De Vita S, Zignego AL, Pioltelli P, Sansonno D, Sollima S, et al. Recommendations for the management of mixed cryoglobulinemia syndrome in hepatitis C virus‐infected patients. Autoimmunity Reviews 2011;10(8):444‐54. [MEDLINE: 21303705]

Ramos‐Casals 2012

Ramos‐Casals M, Stone JH, Cid MC, Bosch X. The cryoglobulinaemias. Lancet 2012;379(9813):348‐60. [MEDLINE: 21868085]

Ramunni 2008

Ramunni A, Lauletta G, Brescia P, Saliani MT, Montrone M, Chironna M, et al. Double‐filtration plasmapheresis in the treatment of leg ulcers in cryoglobulinemia. Journal of Clinical Apheresis 2008;23(3):118‐22. [MEDLINE: 18484642]

Saadoun 2008

Saadoun D, Delluc A, Piette JC, Cacoub P. Treatment of hepatitis C‐associated mixed cryoglobulinemia vasculitis. Current Opinion in Rheumatology 2008;20(1):23‐8. [MEDLINE: 18281853]

Saadoun 2014

Saadoun D, Resche Rigon M, Thibault V, Longuet M, Pol S, Blanc F, et al. Peg‐IFNalpha/ribavirin/protease inhibitor combination in hepatitis C virus associated mixed cryoglobulinemia vasculitis: results at week 24. Annals of the Rheumatic Diseases 2014;73(5):831‐7. [MEDLINE: 23606708]

Saadoun 2016

Saadoun D, Thibault V, Si Ahmed SN, Alric L, Mallet M, Guillaud C, et al. Sofosbuvir plus ribavirin for hepatitis C virus‐associated cryoglobulinaemia vasculitis: VASCUVALDIC study. Annals of the Rheumatic Diseases 2016;75(10):1777‐82. [MEDLINE: 26567178]

Sansonno 2005

Sansonno D, Dammacco F. Hepatitis C virus, cryoglobulinaemia, and vasculitis: immune complex relations. Lancet Infectious Diseases 2005;5(4):227‐36. [MEDLINE: 15792740]

Sansonno 2007

Sansonno D, Carbone A, De Re V, Dammacco F. Hepatitis C virus infection, cryoglobulinaemia, and beyond. Rheumatology 2007;46(4):572‐8. [MEDLINE: 17317717]

Schiavinato 2017

Schiavinato A, Zanetto A, Pantano G, Tosato F, Nabergoj M, Fogar P, et al. Polyclonal and monoclonal B lymphocytes response in HCV‐infected patients treated with direct‐acting antiviral agents. Journal of Viral Hepatitis 2017;24(0):1168‐76. [MEDLINE: 28643451]

Schwartz 2013

Schwartz J, Winters JL, Padmanabhan A, Balogun RA, Delaney M, Linenberger ML, et al. Guidelines on the use of therapeutic apheresis in clinical practice‐evidence‐based approach from the Writing Committee of the American Society for Apheresis: the sixth special issue. Journal of Clinical Apheresis 2013;28(3):145‐284. [MEDLINE: 23868759]

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.

Siami 1995

Siami GA, Siami FS, Ferguson P, Stone WJ, Zborowski M. Cryofiltration apheresis for treatment of cryoglobulinemia associated with hepatitis C. ASAIO Journal 1995;41(3):M315‐8. [MEDLINE: 8573815]

Sise 2016

Sise ME, Bloom AK, Wisocky J, Lin MV, Gustafson JL, Lundquist AL, et al. Treatment of hepatitis C virus‐associated mixed cryoglobulinemia with direct‐acting antiviral agents. Hepatology 2016;63(2):408‐17. [MEDLINE: 26474537]

Suwanthawornkul 2015

Suwanthawornkul T, Anothaisintawee T, Sobhonslidsuk A, Thakkinstian A, Teerawattananon Y. Efficacy of second generation direct‐acting antiviral agents for treatment naive hepatitis C genotype 1: a systematic review and network meta‐analysis. PLoS ONE [Electronic Resource] 2015;10(12):e0145953. [MEDLINE: 26720298]

Terrier 2013

Terrier B, Cacoub P. Cryoglobulinemia vasculitis: an update. Current Opinion in Rheumatology 2013;25(1):10‐8. [MEDLINE: 23196322]

Wan 2014

Wan X, Wang W, Liu J, Tong T. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Medical Research Methodology 2014;14:135. [MEDLINE: 25524443]

References to other published versions of this review

Montero 2014

Montero N, Barrios C, Rodriguez E, Pascual J, Soler MJ. Treatment for hepatitis C virus‐associated cryoglobulinaemic vasculitis. Cochrane Database of Systematic Reviews 2014, Issue 11. [DOI: 10.1002/14651858.CD011403]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Jump to:

Dammacco 1994

Methods

  • Study design: parallel RCT

  • Time frame: 1989 to 1992

  • Follow‐up period: 29 months

Participants

  • Country: Italy

  • Setting: single centre

  • Inclusion criteria: patients with detectable serum cryoglobulins for at least 1 year, associated with purpura, weakness and arthralgia

  • Number: treatment group 1 (15); treatment group 2 (18); treatment group 3 (17); control group (15)

  • Mean age ± SD (years): treatment group 1 (59.2 ± 7.08); treatment group 2 (49.4 ± 16.9); treatment group 3 (56.3 ± 3.3); control group (51.4 ± 5)

  • Sex (F/M): treatment group 1 (9/6); treatment group 2 (10/8); treatment group 3 (9/8); control group (8/7)

  • Exclusion criteria: IFN or immunosuppressive therapies within the previous 6 months; pregnancy; concomitant serious illness that might preclude completion of the study; hepatic failure characterized by a history of ascites, bleeding oesophageal varices, endogenous hepatic encephalopathy, serum bilirubin level > 3 mg/dL, serum albumin level < 3 g/dL, and prothrombin time greater than 3 sec longer than that of the control; leukocyte count < 3 x 109/L and/or a platelet count < 70 x 109/L or Hb < 10 g/dL; positive test for hepatitis B surface antigen and/or antibodies to HIV; Epstein‐Barr virus or CMV acute or chronic infection; connective tissue disorders; Waldenström's macroglobulinaemia or lymphoma

Interventions

Treatment group 1

  • IFN alpha: 3 MU (IM) 3 times/week for 48 weeks

Treatment group 2

  • Prednisone: 16 mg/d for 48 weeks

Treatment group 3

  • IFN alpha: 3 MU (IM) 3 times/week for 48 weeks

  • Prednisone: 16 mg/d on non‐IFN days

Control group

  • No treatment

Outcomes

  • Response to the treatment

    • Complete response: reduction of cryocrit < 50% initial value associated with one or more of the following: disappearance of purpura, improvement of neuropathy or improvement of kidney involvement

    • Partial response: 50% to 10% reduction of cryocrit and one or more but not all clinical and laboratory signs of mixed cryoglobulinaemia.

    • Relapse: increase of > 50% cryocrit after treatment

  • HCV RNA titres

  • Drug toxicity

Notes

  • In lFN controls the activity in more than a half of patients and when it is combined with prednisone, a more prompt response and delayed relapse is found

  • Prednisone induced an increase of viraemia

  • Relapse was common after 3 months of treatment withdrawal from all treatment modalities

  • This study with multiple intervention groups has been analysed combining groups to create a single pair‐wise comparison (with IFN: Group 1 (IFN) + Group 3 (IFN+prednisone) and without: Group 2 (prednisone) + Group 4 (control)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "Randomly assigned"; method of randomisation 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 data

Selective reporting (reporting bias)

Low risk

Results are clearly stated

Other bias

Low risk

Study appears free of other biases

Dammacco 2010

Methods

  • Study design: parallel RCT

  • Time frame: January 2003 to June 2009

  • Follow‐up period: 36 months

Participants

  • Country: Italy

  • Setting: single centre

  • Inclusion criteria: detection of serum cryoglobulins associated with the triad purpura, arthralgia, and weakness; positivity for anti‐HCV antibodies and PCR–based assay to detect HCV RNA in serum; liver biopsy showing chronic hepatitis (performed within 3 months from enrolment); negativity for hepatitis B surface antigen and HIV and no previous administration of IFN or immunosuppressive drugs

  • Number: treatment group 1 (22); treatment group 2 (15)

  • Median age, range (years): treatment group 1 (63, 51 to 68); treatment group 2 (59, 50 to 66)

  • Sex (F/M): treatment group 1 (15/7); treatment group 2 (10/5)

  • Exclusion criteria: histologically proven biliary, neoplastic, and vascular liver diseases; psychiatric disorders, a history of seizures, cardiovascular diseases, poorly controlled diabetes mellitus; frank autoimmune disorders and metabolic liver disease; ingestion of more than 40 g alcohol/d; use of hepatotoxic drugs in the last 6 months; pregnancy; refuse to provide informed consent

Interventions

Treatment group 1

  • Peg‐IFN‐alpha: 180 µg or 1.5 µg/kg weekly for 48 weeks

  • Ribavirin: 1000 or 1200 mg daily for 48 weeks

  • Rituximab: 375 mg/m2 once a week for 1 month followed by two 5‐monthly infusions. Rituximab pre‐medication included 20 mg of 6‐methyl‐prednisolone.

Treatment group 2

  • Peg‐IFN‐alpha: 180 µg or 1.5 µg/kg weekly for 48 weeks

  • Ribavirin: 1000 or 1200 mg daily for 48 weeks

Outcomes

  • Proportion of complete response at any time based on disappearance or remarkable improvement of clinical features, disappearance of cryoglobulins (immunologic response), undetectably of serum HCV‐RNA (virologic response), and disappearance of B‐cell clonalities from the blood (molecular response)

  • Partial response (arbitrarily defined as the achievement of 3 of the 4 mentioned complete response criteria

  • Proportion of sustained complete response: stable at month 6 or until month 36 after completion of therapy

Notes

  • After 1 year, complete response was achieved in 54.5% in group 1 and 33.3% in group 2 (P < 0.05) and it occurred within the 10 month for both treatments

  • Of these patients with complete response, relapse occurred in 16.6% and in 60% (3/5) of group 1 and group 2, respectively

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomisation assignment was computer‐generated by an off‐site biostatistician using block sizes of 2

Allocation concealment (selection bias)

Low risk

Patient assignments were sealed in opaque envelopes that were marked on the outside with a sequence number

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

Quote: "All 37 patients completed the study".

Selective reporting (reporting bias)

Low risk

Outcomes well reported.

Other bias

Low risk

Study appears free of other biases

De Vita 2012

Methods

  • Study design: parallel RCT

  • Time frame: not reported

  • Follow‐up period: 24 months

Participants

  • Country: Italy

  • Setting: multicentre (number of centres not listed)

  • Inclusion criteria: patients with severe mixed cryoglobulinaemia who had type II cryoglobulins either HCV‐related or ‐unrelated (there were 4 patients with HCV unrelated mixed cryoglobulinaemia 1 in rituximab group and 3 in the control group), classified according to published criteria, and had serum cryoglobulins. In patients with HCV‐related cryoglobulinaemic vasculitis, study inclusion implied that therapy with antiviral agents with IFN plus ribavirin had failed, had been poorly tolerated, or was considered to be contraindicated

  • Number: treatment group (28); control group (29)

  • Mean age ± SD (years): treatment group (62.85 ± 11.36); control group (63 ± 10.6)

  • Sex (F/M): treatment group (24/4); control group (22/7),

  • HCV positive: 53/57 (93%), they were no differences between the groups in terms of disease activity

  • Exclusion criteria: presence of antibodies against human immunodeficiency virus and hepatitis B virus core antigen and surface antigen.

Interventions

Treatment group

  • Rituximab: 1 g IV at day 0 and 14 with standard premedication (100 mg IV methylprednisolone, 1000 mg oral acetaminophen, 10 mg IV chlorpheniramine maleate administered before each infusion). At the 6th month after initiation of rituximab, if no response was observed, rituximab was withdrawn

Control groups (non‐rituximab)

  • High‐doses of corticosteroids in 17/29 (58.6%): a maximum initial dosage of 1 mg/kg/d of prednisone or equivalent, with or without preceding 6 pulse doses of methylprednisolone (500 to 1000 mg/d for 3 consecutive days), and with subsequent reduction of the glucocorticoid dosage during the following months

  • Cyclophosphamide in 4/29 (13.8%) and azathioprine in 3/29 (10.3%): given orally at a dosage of 1 to 2 mg/kg/d, with or without glucocorticoids (as above)

  • Plasmapheresis in 5/29 (17.2%): at least 2 procedures/week during the first month, with subsequent reductions according to local protocols, with or without glucocorticoids (as above).

Both groups

  • If a response was observed, any of the treatments might be suspended after the end of month 6 following randomisation and then reintroduced if clinical relapse occurred

Outcomes

  • Proportion of patients who continued to take the treatment to which they were randomised at the end of month 12 (after randomisation)

  • Survival of treatment at the end of 24 month after randomizations

  • Decreasing of global disease activity (defined by BVAS)

  • Assessment of side effects

  • Response rate in rituximab‐switched group

Notes

  • Enrolment was stopped when the sample was only of 42 patients, although the sample size calculated was of 124 patients. That was because of the superiority of rituximab versus non‐rituximab for the primary end‐point (63.2% versus 4.4%, (95% CI 35.6 to 82.0); P 0.0001) during the first 12‐month interim analysis. Reasons for treatment failure up to month 24 in patients in the non‐rituximab group were: a lack of response or worsening of target organ manifestations in 86.2% of patients and side effects in 10.3%. Reasons for treatment failure during the same period in patients in the rituximab group were a lack of response or worsening of target organ manifestations in 14.3% of patients and side effects in 14.3%.

  • Three of the 28 patients in the rituximab group (all of whom had responded to the therapy), were lost to follow‐ up from month 12 of the study

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "randomised at a ratio of 1:1"; method of randomisation not reported

Allocation concealment (selection bias)

Low 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

Intention‐to‐treat analysis. 59 patients randomised. From non‐rituximab group, 23 patients were rescued with rituximab and from rituximab group, 3 patients lost to follow‐up but all data is presented

Selective reporting (reporting bias)

Low risk

All data referred in the "methods section" is presented

Other bias

Low risk

Unfunded study. Roche provided the study medication but, "Roche had no role in the study design or in the collection, analysis, or interpretation of the data"

Ferri 1991

Methods

  • Study design: cross‐over RCT

  • Time frame: not reported

  • Follow‐up period: 13 months

Participants

  • Country: Italy

  • Setting: single centre

  • Inclusion criteria: patients with at least 2 of the typical symptoms (purpura, arthralgia, or weakness), a measurable cryocrit level and liver and/or neurologic involvement

  • Number: 26

  • Median age ± SD: 54 ± 6 years

  • Sex (F/M): 15/11

  • Mean duration of disease: 11.2 ± 5.4 years

  • Exclusion criteria: kidney failure defined by SCr > 132 μmol/L

Interventions

  • Study alternated 6 months with and 6 months without IFN‐alpha therapy (2 x 106 IU/d for a month, then every other day for 5 months). For those patients who started the trial with IFN‐alpha, a 1 month wash‐out period was included before the second half of the study

Outcomes

  • Presence and extent of purpura

  • Serum glutamic pyruvic transaminase

  • Renal involvement (proteinuria and SCr)

  • Peripheral neuropathy (paraesthesia, motor disturbances, sensory‐motor conduction velocity alterations)

  • Cryocrit levels

  • Total haemolytic complement activity

  • Antinuclear, antimitochondrial, anti‐smooth muscle antibodies

  • Peripheral CD4+ and CD8+ lymphocytes

Notes

  • To be able to make the calculations, we only took into account the first period of the study before cross‐over

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

High risk

In 'Table 2', there are 5 patients that drop‐out and the authors did not present these data

Selective reporting (reporting bias)

High risk

In 'Methods Section' the authors specify that "renal and neurological involvement" and they did not report these outcomes later

Other bias

Low risk

Study appears free of other biases

Mazzaro 1995

Methods

  • Study design: parallel RCT

  • Time frame: not reported

  • Follow‐up period: 18 months

Participants

  • Country: Italy

  • Setting: multicentre

  • Inclusion criteria: patients with mixed‐cryoglobulinaemia diagnosis done by standard clinical and laboratory data and with resistance to previous treatment with corticosteroids and/or cytotoxic drugs

  • Number: treatment group 1 (18); treatment group 2 (18)

  • Mean age ± SD (years): treatment group 1 (53 ± 7); treatment group 2 (56 ± 10)

  • Sex (F/M): 26/10

  • All of the patients showed cutaneous lesions (purpura) of variable severity. Polineuropathy present in 14 (39%). Chronic liver disease in 24 (67%). All of the patients had been previously treated with corticosteroids and/or cytotoxic drugs and had become progressively resistant to such therapy.

  • Exclusion criteria: homosexual people; drug‐addiction; ethanol intake > 30 g

Interventions

Treatment group 1

  • IFN‐alpha‐2b: 3 MU 3 times/week for 6 months

Treatment group 2

  • IFN‐alpha‐2b: 3 MU 3 times/week for one year

Outcomes

  • Response to the treatment

    • Complete response: reduction of cryocrit to > 20% initial value, disappearance of all clinical manifestations of the disease (including purpura and neuropathy) and normalization of the Hb and liver function levels

    • Partial response: disappearance of all clinical manifestations of the disease (including purpura and neuropathy), normalization of the Hb and liver function levels, but a reduction of cryocrit to < 20%

    • Minor response: reduction of cryocrit < 10% initial value and disappearance of one or more (but not all) signs of vasculitis

  • ALT

  • Rheumatoid factor

  • Purpura (score)

  • HCV‐RNA

  • Adverse effects: thrombocytopenia, flu‐like syndrome, depression, hypothyroidism

Notes

  • The 2 IFN regimens have similar effect in terms of response to the treatment (group 1 versus group 2): complete response 28% versus 39%, partial response 50% both, minor response 22% versus 11%. Although differences were observed in terms of the duration of it: in group 1 89% of patients presented a relapse and only 11% maintained a long‐term response (1 year) and in group 2 only 78% relapsed and long‐term response was observed in 22%. The one‐year therapy was linked to a higher number of side‐effects (severe enough to cause the discontinuation of treatment in 2 cases) than the 6‐month schedule.

  • The IFN used was alpha 2b, new generation of IFN (PEG‐IFN‐alpha‐2a) present a different profile

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

Low risk

No exclusions or attrition reported

Selective reporting (reporting bias)

Low risk

Reported clearly the different outcomes

Other bias

Low risk

Study appears free of other biases

Mazzaro 2000

Methods

  • Study design: parallel RCT

  • Time frame: not reported

  • Follow‐up period: 18 month

Participants

  • Country: Italy

  • Setting: single centre

  • Inclusion criteria: HCV cryoglobulinaemic GN diagnosed by kidney biopsy in stationary clinical phase of the disease

  • Number: treatment group (7); control group (6)

  • Mean age ± SD (years): treatment group (64 ± 12); control group (59 ± 11)

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

  • All patients had previously been treated with corticosteroids and cyclophosphamide, and after remission of the acute phase, were randomised to one of the two treatments

  • Exclusion criteria: homosexual people; history of intravenous drug or ethanol abuse

Interventions

Treatment group

  • Lymphoblastoid IFN: 3 MU, 3 times/week for 6 months

Control group

  • Oral prednisone: 0.2 mg/kg/d for 6 months

Outcomes

  • Response to the therapy

    • Complete response: decrease and/or return to normal of SCr, return to normal of proteinuria, disappearance of the cryocrit associated with the disappearance of all clinical manifestations of the disease (including purpura)

    • Partial response: decrease of SCr and of proteinuria > 50%, disappearance of all signs of the disease, reduction of cryocrit of > 50%

    • Minimal response: decrease of SCr, decrease of proteinuria < 50%, disappearance of one or more of the signs of the disease (but not all), and a reduction of the cryocrit ˜50%

    • No response: no modification or improvement ˜10% of SCr, proteinuria, and cryocrit

  • Purpura score

  • Cryocrit level

  • SCr

  • Proteinuria

  • C4

  • Rheumatoid factor

  • HCV‐RNA

  • ALT

Notes

  • Both IFN and prednisone are associated with an improvement in clinical symptoms even in non‐responders, with minor side‐effects only in IFN group (fever, fatigue and a flu‐like syndrome in most patients during the first two weeks) with one patient withdrawal (because thrombocytopenia). Prednisone was associated with a worsening in liver function tests. Only 1 case presented complete recovery and was from IFN group, indicating that complete remission from the disease can be obtained only through eradication of the virus.

  • The type of IFN used was lymphoblastoid, new generation of IFN present a different profile.

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

Low risk

Well specified. Quote: "All patients were followed for at least 12 months after the end of treatment".

Selective reporting (reporting bias)

Low risk

All outcomes reported

Other bias

Low risk

Study appears free of other biases

Misiani 1994

Methods

  • Study design: parallel RCT

  • Time‐frame: January 1991 to February 1992

  • Follow‐up period: 24 to 48 weeks

Participants

  • Country: Italy

  • Setting: single centre

  • Inclusion criteria: HVC‐associated type II cryoglobulinaemia

  • Number: treatment group (27); control group (26)

  • Median age, range (years): treatment group (62, 30 to 70); control group (63,(47 to 70)

  • Sex (F/M): treatment group (23/4), control group (22/4)

  • Duration of disease (months: median (range): treatment group (76, 12 to 228), control group (75, 9 to 226).

  • Arthralgia: treatment group (19); control group (20)

  • Kidney disease: treatment group (20); control group (20)

  • Corticoid treatment: treatment group (22), control group (22)

  • Exclusion criteria: secondary cryoglobulinaemia; hepatic failure (bilirubin > 4 mg/dL, albumin < 3 g/dL, Prothrombin time 3 seconds longer than normal); cytopenia; serious medical illness other than liver disease

Interventions

Treatment group

  • IFN‐alpha‐2 (SC): 1.5 MU 3 times/week for a week and then 3 MU 3 times/week for 23 weeks

Control group

  • Previously prescribed treatments including: low‐dose prednisone (≤ 0.2 mg/kg/d); diuretics; antihypertensive drugs and medications to treat associated diseases. The authors present this data in the article and there were no differences between groups

Outcomes

  • Cutaneous vasculitis (using a scoring system)

  • SCr

  • Proteinuria (data available given in protein‐creatinine index (mg/mg), we estimated 24h proteinuria (mg/d)

  • HCV‐RNA

  • Serum levels of anti‐HVC antibodies

  • Cryoglobulins

  • IgM

  • Rheumatoid factor

  • Adverse events

Notes

  • The authors conclude that the beneficial effect of IFN is limited to patients in whom HCV RNA disappears from the serum (15/25 patients), whereas it worsened in those without response or in the control group

  • IFN was well tolerated except for influenza‐like illness, 2 cases discontinued because of atrial fibrillation and depression

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer generated table

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

High risk

There are also clinical variables that need blinding

Incomplete outcome data (attrition bias)
All outcomes

High risk

Missing outcome data balanced in number across intervention groups, but the authors did not impute it using appropriate methods

Selective reporting (reporting bias)

Low risk

Data well specified

Other bias

Low risk

Study appears free of other biases

Pioltelli 1995

Methods

  • Study design: parallel RCT composed of three different studies

    1. Compared the efficacy of IFN and a steroid treatment

    2. Evaluated the effect of a low‐antigen diet combined with drug treatment

    3. Estimated the need and usefulness of drug treatment in less severe stages of disease

  • Time‐frame: January 1991 to March 1993

  • Follow‐up period: not reported

Participants

  • Country: Italy

  • Setting: multicentre (number of centres not reported)

  • Inclusion criteria: type II or III cryoglobulinaemia

  • Number: treatment group 1 (28); treatment group 2 (28)

  • Median age, range (years): treatment group 1 (62, 46 to 73); treatment group 2 (58, 29 to 73)

  • Sex (F/M): treatment group 1 (20/8); treatment group 2 (21/7)

  • Exclusion criteria: asymptomatic patients, severe disease (SCr > 176 μmol/L, acute nephritic syndrome, portal hypertension, hyperviscosity syndrome, ALT level five‐fold the normal value, all patients with disorders which might be exacerbated by steroid or IFN treatment (diabetes mellitus, peptic ulcer, psychosis, congestive cardiomyopathy, coronary artery disease, malignant hypertension, glaucoma, ophthalmic herpes), lactating or pregnant women or malignancy

Interventions

Treatment group 1

  • Deflazacort: 0.1 mg/kg/d if mild disease or 0.2 mg/kg/d if moderate disease for at least 2 months and, if no improvement was obtained, was continued for a maximum of 4 months; after this time the dose was reduced to 0.1 mg/kg/d for mild disease and to 0.2 mg/kg/d for moderate disease

Treatment group 2

  • IFN‐alpha‐2b: 3MU 3 times/week

Dose changes within 25% of the dose specified in the protocol schedule were allowed

Outcomes

  • Absence of signs of disease lasting four months

  • Stage shift (from B to A, from A to B, or to stage C) and patient death.

    • Clinical stages: Stage A (mild disease: purpura in distal segment of the limbs, weakness and joint pain); stage B (moderate disease: purpura in whole limbs or trunk, neurological involvement, SCr > 158.5 and < 176 μmol/L, ALT above the normal range)

  • C3 or C4 levels

  • Neurological impairment

  • Kidney impairment

  • Extent of purpura

  • Liver impairment

  • Karnofsky score

  • Side effects and compliance

Notes

  • A total of 66 patients were enrolled (type II cryoglobulinaemia (51), type III cryoglobulinaemia (12)). They were stratified according to disease stage and underwent two independent randomisations

    • Intervention 1: low antigen diet versus unrestrained diet

    • Intervention 2: deflazacort versus IFN‐alpha‐2b

  • There was not available numerical data about Intervention 1 so it was not considered in the review

  • Authors did not find any difference between the effect of deflazacort and IFN, and the incidence of major toxic effects was higher in IFN group (25% of patients: ictus cerebri (1), refractory headache (1), refractory fever (1), refractory diarrhoea (1), anaphylaxis episode (1), impotentia coeundi (1), hypersomnia (1)) versus 14% in deflazacort group (femur fractures (2), diabetes mellitus (1), Cushing’s syndrome (1))

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "The randomisation were performed centrally in a 1/1 ratio within balanced blocks of 8, stratified by the centre".

Allocation concealment (selection bias)

Low risk

Central 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

Neurological impairment and extent of purpura was done by someone that is not well specified if was blinded or not.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Data well specified

Selective reporting (reporting bias)

High risk

No data at the end of the study of these items: purpura, joint pain, weakness, kidney impairment, neurological impairment,

liver impairment

Other bias

Low risk

Study appears free of other biases

Sneller 2012

Methods

  • Study design: parallel RCT

  • Time‐frame: January 1991 to March 1993

  • Follow‐up period: 12 months

Participants

  • Country: USA

  • Setting: single centre

  • Inclusion criteria: HVC‐associated mixed cryoglobulinaemia patients in whom treatment with IFN and ribavirin failed to induced response or was not tolerated and showed by one or more than: cutaneous vasculitis, peripheral neuropathy and/or GN

  • Number: treatment group (12); control group (12)

  • Median age (years): treatment group (53); control group (51)

  • Sex (F/M): treatment group (2/10); control group (4/8)

  • Baseline activity (BVAS) were similar in both groups

  • Exclusion criteria: change in immunosuppressive therapy 4 weeks of study entry; prior use of rituximab; lymphoma; severe kidney failure (CrCl < 30 mL/min); severe hepatic insufficiency (Child Pugh B or C); coinfection with VHB or HIV; liver transplantation; pregnancy; active systemic infection, or presence of potentially life‐threatening vasculitis involving the central nervous system, heart, or gastrointestinal tract

Interventions

Treatment group

  • Rituximab: 375 mg/m2 days 1, 8, 15 and 22. Patients were allowed to continue any immunosuppressive therapy they were receiving prior randomisation. Premedication include 650 mg acetaminophen, diphenhydramine 50 mg and did not include steroids

Control group

  • Patients continued to take any immunosuppressive drugs (cyclophosphamide or methotrexate) or plasma exchange

Outcomes

  • Remission (defined as a BVAS of 0) at month 6

  • Duration of remission

  • Occurrence of severe adverse effects

Notes

  • The trial was originally designed to enrol 30 patients but was stopped at a total enrolment of 24 patients when an interim analysis revealed that there was sufficient difference between groups

  • The number of patients with remission at 6 months was significantly higher with rituximab treatment (P 0.001): 83.3% in rituximab group (95% CI 51.6 to 97.9) and 8.3% in control group (95% CI 2.0 to 38.6)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "randomly assigned in a 1 to 1"; method of randomisation not reported

Allocation concealment (selection bias)

Low risk

Central allocation: NIH Clinical Center Pharmacy performed the 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

Data is detailed. It is indicated that "analyses were performed on an intention‐to‐treat basis". The authors also stated that they present a "selected adverse effects" but they refer to each outcome defined in the methods section

Selective reporting (reporting bias)

Low risk

Data well specified

Other bias

Low risk

Study appears free of other biases

Stefanutti 2009

Methods

  • Study design: parallel RCT

  • Time‐frame: not reported

  • Follow‐up period: 24 weeks

Participants

  • Country: Italy

  • Setting: single centre

  • Inclusion criteria: HVC‐associated mixed cryoglobulinaemia and at least 1 severe complication related to the pre‐existing immunologic disorder

  • Number: treatment group (9); control group (8)

  • Mean age ± SD (years): treatment group (65.5 ± 14.0); control group (64.5 ± 13.4)

  • Sex (F/M): treatment group (8/1); control group (6/2)

  • Exclusion criteria: not reported

Interventions

Patients received immunosuppressive therapy for 12 weeks, then were randomly assigned to two groups

Treatment group

  • Immunoadsorption apheresis was done using Selesorb© with a plasma volume exchange of 45 mL/kg. The number of treatments for patient was between 24 and 35

  • Immunosuppressive therapy: included pegylated IFN 3 MU 3 times/week, cyclophosphamide 7.5 to 15 mg/kg (IV), CSA 2 to 5 mg/kg/d, ribavirin 10 to 15 mg/kg/d, or melphalan 0.1 to 0.2 mg/kg/d

Control group

  • Immunosuppressive therapy: included pegylated IFN 3 MU 3 times/week, cyclophosphamide 7.5 to 15 mg/kg (IV), CSA 2 to 5 mg/kg/d, ribavirin 10 to 15 mg/kg/d, or melphalan 0.1 to 0.2 mg/kg/d

Outcomes

  • Calculated clinical score using the following: cryocrit, renal function, neurologic system, skin, vascular system, and joints related signs and symptoms) calculated at baseline, at 12 and 24 weeks

Notes

  • Clinical score changes were more favourable in combined therapy with IA plus immunosuppressants compared to immunosuppressive treatment alone. Higher remission of severe clinical complications was found with combined therapy (80% versus 33%, P 0.05). It is mentioned in the article that "no adverse reactions or complications were noted".

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: “Randomly assigned”; method of randomisation 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

Data well specified

Selective reporting (reporting bias)

Low risk

Data well specified

Other bias

Low risk

Although the immunoadsorption apheresis was interrupted before the scheduled therapy because of rapid relapse of symptomatology, the data of these patients is well reported

ALT‐ alanine aminotransferase; BVAS ‐ Birmingham Vasculitis Activity Score; CMV ‐ cytomegalovirus; CrCl ‐ creatinine clearance; CSA ‐ cyclosporine; F/M ‐ female/male; IFN ‐ interferon; IV ‐ intravenous; Hb ‐ haemoglobin; HCV ‐ hepatitis C virus; HIV ‐ human immunodeficiency virus; PCR ‐ polymerase chain reaction; RCT ‐ randomised controlled trial; SC ‐ subcutaneous; SCr ‐ serum creatinine; SD ‐ standard deviation

Characteristics of excluded studies [ordered by study ID]

Jump to:

Study

Reason for exclusion

Anonymous 1989

Protocol of a RCT; no results identified

Candela 1994

Wrong population: mixed cryoglobulinaemia including different aetiologies with and without HCV

Ferri 1989

Wrong population: II and III type mixed cryoglobulinaemia including different aetiologies with and without HCV

Lauta 1995

Wrong population: II type mixed essential cryoglobulinaemia including different aetiologies with and without HCV

Vacca 1992

Wrong population: II and III type mixed essential cryoglobulinaemia including different aetiologies with and without HCV

HCV ‐ hepatitis C virus; RCT ‐ randomised controlled trial

Data and analyses

Open in table viewer
Comparison 1. Rituximab versus no rituximab

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 1.1

Comparison 1 Rituximab versus no rituximab, Outcome 1 Death.

Comparison 1 Rituximab versus no rituximab, Outcome 1 Death.

1.1 One month

2

61

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

1.2 Six months

2

61

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

1.3 24 months

3

118

Risk Ratio (M‐H, Random, 95% CI)

0.52 [0.10, 2.61]

2 Clinical manifestations Show forest plot

2

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 1.2

Comparison 1 Rituximab versus no rituximab, Outcome 2 Clinical manifestations.

Comparison 1 Rituximab versus no rituximab, Outcome 2 Clinical manifestations.

2.1 Active urinary sediment at 1 month

1

16

Risk Ratio (M‐H, Random, 95% CI)

0.92 [0.51, 1.65]

2.2 Need for dialysis at 24 months

1

46

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2.3 Skin vasculitis (purpura, cutaneous ulcers or others) at 1 month

1

57

Risk Ratio (M‐H, Random, 95% CI)

2.59 [0.55, 12.27]

2.4 Skin vasculitis (purpura, cutaneous ulcers or others) at 18 and 24 months

2

78

Risk Ratio (M‐H, Random, 95% CI)

0.57 [0.28, 1.16]

2.5 Skin vasculitis (purpura, cutaneous ulcers or others) at 36 months

1

37

Risk Ratio (M‐H, Random, 95% CI)

0.68 [0.43, 1.08]

3 Laboratory findings Show forest plot

2

Mean Difference (IV, Random, 95% CI)

Subtotals only

Analysis 1.3

Comparison 1 Rituximab versus no rituximab, Outcome 3 Laboratory findings.

Comparison 1 Rituximab versus no rituximab, Outcome 3 Laboratory findings.

3.1 Serum creatinine at 18 months [µmol/L]

1

37

Mean Difference (IV, Random, 95% CI)

‐8.80 [‐29.27, 11.67]

3.2 Serum creatinine at 36 months [µmol/L]

1

37

Mean Difference (IV, Random, 95% CI)

17.60 [‐4.23, 39.43]

3.3 Proteinuria at 18 months [g/24 h]

1

3

Mean Difference (IV, Random, 95% CI)

‐0.5 [‐1.42, 0.42]

3.4 Proteinuria at 36 months [g/24 h]

1

3

Mean Difference (IV, Random, 95% CI)

0.24 [‐0.84, 1.32]

3.5 Cryocrit at 12 months [%]

2

41

Mean Difference (IV, Random, 95% CI)

‐2.01 [‐10.29, 6.27]

3.6 Serum HCV‐RNA at 12 months [IU/mL]

1

17

Mean Difference (IV, Random, 95% CI)

‐435182.0 [‐1051224.79, 180860.79]

4 Adverse effects of the medication Show forest plot

3

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 1.4

Comparison 1 Rituximab versus no rituximab, Outcome 4 Adverse effects of the medication.

Comparison 1 Rituximab versus no rituximab, Outcome 4 Adverse effects of the medication.

4.1 Infusion reactions

3

118

Risk Ratio (M‐H, Random, 95% CI)

4.33 [0.76, 24.75]

4.2 Discontinuation of the treatment due to adverse drug reactions

3

118

Risk Ratio (M‐H, Random, 95% CI)

0.97 [0.22, 4.36]

4.3 Infection (pneumonia, urosepsis) at 6 months

1

24

Risk Ratio (M‐H, Random, 95% CI)

0.50 [0.05, 4.81]

4.4 Infection (pneumonia, urosepsis) at 24 months

1

57

Risk Ratio (M‐H, Random, 95% CI)

0.35 [0.04, 3.12]

4.5 Cardiovascular events (angina, myocardial infarction, heart failure) at 24 months

1

57

Risk Ratio (M‐H, Random, 95% CI)

0.52 [0.10, 2.61]

4.6 Gastrointestinal bleeding

1

57

Risk Ratio (M‐H, Random, 95% CI)

3.10 [0.13, 73.12]

4.7 Haemorrhagic alveolitis

1

57

Risk Ratio (M‐H, Random, 95% CI)

0.34 [0.01, 8.12]

4.8 Leukopenia at 6 months

1

24

Risk Ratio (M‐H, Random, 95% CI)

0.50 [0.05, 4.81]

4.9 Thrombocytopenia at 6 months

1

24

Risk Ratio (M‐H, Random, 95% CI)

1.0 [0.07, 14.21]

5 Antiviral therapy failure or not indicated Show forest plot

3

118

Risk Ratio (M‐H, Random, 95% CI)

1.21 [0.77, 1.90]

Analysis 1.5

Comparison 1 Rituximab versus no rituximab, Outcome 5 Antiviral therapy failure or not indicated.

Comparison 1 Rituximab versus no rituximab, Outcome 5 Antiviral therapy failure or not indicated.

Open in table viewer
Comparison 2. Interferon versus control

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 2.1

Comparison 2 Interferon versus control, Outcome 1 Death.

Comparison 2 Interferon versus control, Outcome 1 Death.

1.1 12 months

4

160

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

1.2 24 months

2

91

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2 Clinical manifestations Show forest plot

3

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 2.2

Comparison 2 Interferon versus control, Outcome 2 Clinical manifestations.

Comparison 2 Interferon versus control, Outcome 2 Clinical manifestations.

2.1 Skin vasculitis (purpura, cutaneous ulcers or others) at 12 months

3

95

Risk Ratio (M‐H, Random, 95% CI)

0.60 [0.36, 1.00]

3 Laboratory findings Show forest plot

4

Mean Difference (IV, Random, 95% CI)

Subtotals only

Analysis 2.3

Comparison 2 Interferon versus control, Outcome 3 Laboratory findings.

Comparison 2 Interferon versus control, Outcome 3 Laboratory findings.

3.1 Serum creatinine at 18 months [µmol/L]

2

49

Mean Difference (IV, Random, 95% CI)

‐30.32 [‐80.59, 19.95]

3.2 Proteinuria at 18 months [g/24h]

2

49

Mean Difference (IV, Random, 95% CI)

‐1.98 [‐2.89, ‐1.07]

3.3 ALT or GPT at 6 months [UI/L]

2

39

Mean Difference (IV, Random, 95% CI)

‐5.89 [‐55.77, 43.99]

3.4 ALT or GPT at 18 months [UI/L]

2

49

Mean Difference (IV, Random, 95% CI)

‐28.28 [‐48.03, ‐8.54]

3.5 Rheumatoid factor activity at 6 months [UI/mL]

1

13

Mean Difference (IV, Random, 95% CI)

97.0 [‐187.37, 381.37]

3.6 C4 at 18 months [mg/dL]

2

49

Mean Difference (IV, Random, 95% CI)

‐0.04 [‐2.74, 2.67]

3.7 IgM at 18 months [mg/dL]

2

52

Mean Difference (IV, Random, 95% CI)

‐595.75 [‐877.20, ‐314.30]

3.8 Cryocrit at 6 months [%]

2

39

Mean Difference (IV, Random, 95% CI)

‐1.38 [‐2.38, ‐0.38]

4 Adverse effects of the medication Show forest plot

5

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 2.4

Comparison 2 Interferon versus control, Outcome 4 Adverse effects of the medication.

Comparison 2 Interferon versus control, Outcome 4 Adverse effects of the medication.

4.1 Infusion reactions

1

65

Risk Ratio (M‐H, Random, 95% CI)

27.82 [1.72, 449.18]

4.2 Discontinuations of the treatment due to adverse drug reactions

4

148

Risk Ratio (M‐H, Random, 95% CI)

2.32 [0.91, 5.90]

5 Antiviral therapy failure or not indicated Show forest plot

2

78

Risk Ratio (M‐H, Random, 95% CI)

0.59 [0.21, 1.64]

Analysis 2.5

Comparison 2 Interferon versus control, Outcome 5 Antiviral therapy failure or not indicated.

Comparison 2 Interferon versus control, Outcome 5 Antiviral therapy failure or not indicated.

Open in table viewer
Comparison 3. Interferon for 6 months versus 1 year

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Death at 24 months Show forest plot

1

36

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

Analysis 3.1

Comparison 3 Interferon for 6 months versus 1 year, Outcome 1 Death at 24 months.

Comparison 3 Interferon for 6 months versus 1 year, Outcome 1 Death at 24 months.

Open in table viewer
Comparison 4. Immunoadsorption apheresis versus immunosuppressive drug therapy

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Death at 24 months Show forest plot

1

17

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

Analysis 4.1

Comparison 4 Immunoadsorption apheresis versus immunosuppressive drug therapy, Outcome 1 Death at 24 months.

Comparison 4 Immunoadsorption apheresis versus immunosuppressive drug therapy, Outcome 1 Death at 24 months.

2 Clinical manifestations Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

Analysis 4.2

Comparison 4 Immunoadsorption apheresis versus immunosuppressive drug therapy, Outcome 2 Clinical manifestations.

Comparison 4 Immunoadsorption apheresis versus immunosuppressive drug therapy, Outcome 2 Clinical manifestations.

2.1 Skin vasculitis (purpura, cutaneous ulcers or others) at 6 months

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2.2 Peripheral neuropathies at 6 months

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2.3 Peripheral joint arthralgia at 6 months

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

3 Laboratory findings Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

Analysis 4.3

Comparison 4 Immunoadsorption apheresis versus immunosuppressive drug therapy, Outcome 3 Laboratory findings.

Comparison 4 Immunoadsorption apheresis versus immunosuppressive drug therapy, Outcome 3 Laboratory findings.

3.1 Cryocrit [%]

1

Mean Difference (IV, Random, 95% CI)

0.0 [0.0, 0.0]

4 Adverse effects of the medication Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 4.4

Comparison 4 Immunoadsorption apheresis versus immunosuppressive drug therapy, Outcome 4 Adverse effects of the medication.

Comparison 4 Immunoadsorption apheresis versus immunosuppressive drug therapy, Outcome 4 Adverse effects of the medication.

4.1 Infusion reactions

1

17

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

Flow chart showing source and identification of studies for inclusion.
Figures and Tables -
Figure 1

Flow chart showing source and identification of studies for inclusion.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Figures and Tables -
Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Figures and Tables -
Figure 3

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Comparison 1 Rituximab versus no rituximab, Outcome 1 Death.
Figures and Tables -
Analysis 1.1

Comparison 1 Rituximab versus no rituximab, Outcome 1 Death.

Comparison 1 Rituximab versus no rituximab, Outcome 2 Clinical manifestations.
Figures and Tables -
Analysis 1.2

Comparison 1 Rituximab versus no rituximab, Outcome 2 Clinical manifestations.

Comparison 1 Rituximab versus no rituximab, Outcome 3 Laboratory findings.
Figures and Tables -
Analysis 1.3

Comparison 1 Rituximab versus no rituximab, Outcome 3 Laboratory findings.

Comparison 1 Rituximab versus no rituximab, Outcome 4 Adverse effects of the medication.
Figures and Tables -
Analysis 1.4

Comparison 1 Rituximab versus no rituximab, Outcome 4 Adverse effects of the medication.

Comparison 1 Rituximab versus no rituximab, Outcome 5 Antiviral therapy failure or not indicated.
Figures and Tables -
Analysis 1.5

Comparison 1 Rituximab versus no rituximab, Outcome 5 Antiviral therapy failure or not indicated.

Comparison 2 Interferon versus control, Outcome 1 Death.
Figures and Tables -
Analysis 2.1

Comparison 2 Interferon versus control, Outcome 1 Death.

Comparison 2 Interferon versus control, Outcome 2 Clinical manifestations.
Figures and Tables -
Analysis 2.2

Comparison 2 Interferon versus control, Outcome 2 Clinical manifestations.

Comparison 2 Interferon versus control, Outcome 3 Laboratory findings.
Figures and Tables -
Analysis 2.3

Comparison 2 Interferon versus control, Outcome 3 Laboratory findings.

Comparison 2 Interferon versus control, Outcome 4 Adverse effects of the medication.
Figures and Tables -
Analysis 2.4

Comparison 2 Interferon versus control, Outcome 4 Adverse effects of the medication.

Comparison 2 Interferon versus control, Outcome 5 Antiviral therapy failure or not indicated.
Figures and Tables -
Analysis 2.5

Comparison 2 Interferon versus control, Outcome 5 Antiviral therapy failure or not indicated.

Comparison 3 Interferon for 6 months versus 1 year, Outcome 1 Death at 24 months.
Figures and Tables -
Analysis 3.1

Comparison 3 Interferon for 6 months versus 1 year, Outcome 1 Death at 24 months.

Comparison 4 Immunoadsorption apheresis versus immunosuppressive drug therapy, Outcome 1 Death at 24 months.
Figures and Tables -
Analysis 4.1

Comparison 4 Immunoadsorption apheresis versus immunosuppressive drug therapy, Outcome 1 Death at 24 months.

Comparison 4 Immunoadsorption apheresis versus immunosuppressive drug therapy, Outcome 2 Clinical manifestations.
Figures and Tables -
Analysis 4.2

Comparison 4 Immunoadsorption apheresis versus immunosuppressive drug therapy, Outcome 2 Clinical manifestations.

Comparison 4 Immunoadsorption apheresis versus immunosuppressive drug therapy, Outcome 3 Laboratory findings.
Figures and Tables -
Analysis 4.3

Comparison 4 Immunoadsorption apheresis versus immunosuppressive drug therapy, Outcome 3 Laboratory findings.

Comparison 4 Immunoadsorption apheresis versus immunosuppressive drug therapy, Outcome 4 Adverse effects of the medication.
Figures and Tables -
Analysis 4.4

Comparison 4 Immunoadsorption apheresis versus immunosuppressive drug therapy, Outcome 4 Adverse effects of the medication.

Summary of findings for the main comparison. Rituximab compared to no rituximab for hepatitis C virus‐associated mixed cryoglobulinaemia

Rituximab compared to no rituximab for hepatitis C virus‐associated mixed cryoglobulinaemia

Patient or population: hepatitis C virus‐associated mixed cryoglobulinaemia
Setting: USA and Italy
Intervention: rituximab
Comparison: no rituximab

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No. of participants
(studies)

Quality of the evidence
(GRADE)

Risk with no rituximab

Risk with rituximab

Skin vasculitis (purpura, cutaneous ulcers or others) at 18 and 24 months: number of affected patients

Study population

RR 0.57
(0.28 to 1.16)

78 (2)

⊕⊕⊕⊝
MODERATE 1

26 per 100

15 per 100
(7 to 30)

SCr at 18 months

The mean SCr at 18 months was 194.3 μmol/L

MD was 8.8 μmol/L lower
(29.27 lower to 11.67 higher)

37 (1)

⊕⊕⊕⊝
MODERATE 1

Cryocrit at 12 months
assessed with: %

The mean cryocrit at 12 months was 6.55%

MD was 2.01% lower
(10.29% lower to 6.27% higher)

41 (2)

⊕⊕⊝⊝
LOW 1 2

Adverse effects ‐ infusion reactions: number of events

Study population

RR 4.33
(0.76 to 24.75)

118 (3)

⊕⊕⊕⊝
MODERATE 1

0 per 100

0 per 100
(0 to 0)

Activity outcomes
BVAS: from 0 to 63

De Vita 2012 found a significant reduction in the BVAS at 2 months in the rituximab group (from mean ± SD: 11.9 ± 5.4 to 7.1 ± 5.7; P < 0.001), and this difference persisted at 6 months (6.9 ± 6.8; P < 0.001), 12 months (5.4 ± 6.2; P 0.0001), and 24 months (4.4 ± 4.6; P < 0.0001). Without differences in the control group.

Sneller 2012 BVAS scores became significantly lower in the rituximab group at month 4 (from 10.2 ± 8.4, at 6 months: 0 ± 0; P < 0.02). Without differences in control group.

81 (2)

⊕⊕⊕⊝
MODERATE 3

*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

BVAS: Birmingham vasculitis activity score; CI: confidence interval; RR: risk ratio; SCr: serum creatinine

GRADE Working Group grades of evidence
High quality: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

1 95% CI overlaps no effect, and the CI fails to exclude important benefit or important harm

2 Base on tests of heterogeneity which test the null hypothesis that all studies have the same underlying magnitude of effect, have a low P‐value (P = 0.00001), indicating to reject the null hypothesis I2 statistic, which quantifies the proportion of the variation in point estimates due to among‐study differences, is large (97%)

3 High risk of performance bias: non‐blinded participants and personnel

Figures and Tables -
Summary of findings for the main comparison. Rituximab compared to no rituximab for hepatitis C virus‐associated mixed cryoglobulinaemia
Table 1. Studies including new antiviral treatments for HCV‐related mixed cryoglobulinaemia

Study ID

Study design

Patient profile

Objective

No. of patients

Treatment

Results

Adverse effects

Gragnani 2016

Non‐randomised, non‐controlled prospective study

HCV RNA (+) + cryoglobulinaemic syndrome with organ damage and B‐cell lymphoproliferative syndrome

To assess the hepatovirological response, the clinical and immunological efficacy and the safety of using sofosbuvir‐based direct‐acting antiviral therapy in patients with HCV‐associated mixed cryoglobulinaemia(according to the latest guidelines)

44

1) Sofosbuvir+ribavirin (18)

2) Sofosbuvir+simeprevir (12) ± ribavirin (6 of 12 patients)

3) Sofosbuvir+daclatasvir (4) ± ribavirin (1 patient)

4) Sofosbuvir+ledipasvir (10) ± ribavirin (3 patients)

Hepatovirological response

‐ Undetectable HCV RNA negative rate 100% at week 4; 12SVR and 24SVR remained 100% negative

‐ Decrease of ALT from 77.7 ± 10.3 IU/L at baseline to 27.3 ± 10.3 IU/L at 24SVR

‐ Decrease of AST from 55.2 ± 60.4 IU/L at baseline to 22.6 ± 8.3 IU/L at 24SVR (P < 0.001)

Clinical efficacy

‐ Decrease of BVAS from 5.41 ± 3.53 at baseline to 1.27 ± 1.68 at 24SVR (P < 0.001)

Immunological efficacy

‐ Decrease of cryocrit level from 7.2 ± 15.4% at baseline to 1.8 ± 5.1% at 24SVR (P < 0.001)

Total: 26/44 (59%)

Withdrawals: 1 patient withdrew ribavirin while continuing sofosbuvir+simeprevir

Death: none

Relapse: none

Most frequent AE:

Anaemia (13, all receiving ribavirin); fatigue (15); nausea (7)

Cornella 2015

Case series

Five patients with HVC RNA + with detectable cryoglobulins in plasma and symptomatic mixed cryoglobulinaemia

Patient 1: bilateral foot neuropathy and purpura

Patient 2: painful left foot drop and purpura

Patient 3: purpura and MPGN

Patient 4: MPGN

Patient 5: MPGN + low grade lymphoma

Review of one centre's experience in treating patients with mixed cryoglobulinaemia with new oral antiviral agents and to assess common factors associated with persistence of mixed cryoglobulinaemia despite SVR

5

Patient 1: PEG‐IFN+ribavirin+boceprevir

Patient 2: Firstly with rituximab (5 weeks); later with: PEG‐IFN+ribavirin+telaprevir for 4 weeks; PEG‐IFN+ribavirin for 12 weeks; and PEG‐IFN+ribavirin+sofosbuvir for 15 weeks (telaprevir discontinued for persistent viral load > 1000 IU/mL)

Patient 3: PEG‐IFN+ribavirin+telaprevir for 47 weeks

Patient 4: PEG‐IFN+ribavirin for 24 weeks; afterwards adding sofosbuvir until completing 12 weeks of triple therapy (total 36 weeks)

Patient 5: 2 cycles of rituximab: weekly infusions 375mg/m2 during 4 weeks in 2010 then two extra doses of rituximab in 2013

‐PEG‐IFN+ribavirin+sofosbuvir for 8 weeks in 2014

Patient 1: complete clearance of virus at week 8; complete clearance of cryoglobulins at week 28. Persistence of neuropathy

Patient 2: SVR and no detectable cryoglobulins at month 6 after last triple therapy. Persistence of neuropathy.

Patient 3: clearance of HCV at week 4 after PEG‐IFN+ribavirin+telaprevir, with persistent cryoglobulins.

Active MPGN and vasculitis after ending of previous treatment (responding to steroid therapy).

Patient 4: SVR with persistence of cryoglobulinaemia. Kidney function remained stable.
Patient 5: SVR 6 months after treatment without cryoglobulins. Rituximab at maintenance dose for lymphoma treatment

Sise 2016

Retrospective case series

HCV RNA > 1000 IU/mL + circulating purpura + cutaneous ulcers, Raynaud’s phenomenon, arthralgia, sicca syndrome, gastrointestinal vasculitis, neurologic involvement or renal involvement

Comparison of 2 historical cohorts: one treated with PEG‐IFN and ribavirin and the other sofosbuvir+simeprevir (8/12) or sofosbuvir+ribavirin (4/12). Evaluation of 12SVR, relapses, clinical, immunological (cryoglobulins) and biochemical (AST, Hb) response and adverse effects; without statistical comparison between them

22

1) PEG‐IFN+ribavirin

2) IFN‐free regimens

2a) Sofosbuvir 400 mg/24 h + simeprevir 150 mg/24h

2b) Sofosbuvir 400 mg/24 h + ribavirin (adjusted to kidney function)

PEG‐IFN+ribavirin

‐ SVR12: 1/10

IFN‐free regimens

‐ SVR12: 10/12 (95%)

‐ ALT decreased from 42 U/L at baseline to 20 U/L after treatment

‐ Cryoglobulin levels decreased from 1.5% (0.5% to 4%) at baseline to 0.5% (0% to 2%) after treatment

‐ Decrease of proteinuria in all cases of kidney involvement (table IV)

Total

PEG‐IFN+ribavirin: 10/10

IFN‐free regimens: 8/12

Withdrawals

PEG‐IFN+ribavirin: 5/10

IFN‐free regimens: 1/12 (anxiety and insomnia)

Deaths: none

Relapses
PEG‐IFN+ribavirin: not specified

IFN‐free regimens: 2 (genotype 1

sofosbuvir+simeprevir; genotype 4 sofosbuvir+ribavirin)

Saadoun 2014

Open‐label, non‐controlled, prospective cohort study

Chronic active HCV infection with signs of mixed cryoglobulinaemia. All 23 patients had positive cryoglobulins in plasma at baseline or earlier

To analyse the safety and efficacy of Peg‐IFN‐alpha/ribavirin/protease inhibitor combination in HCV‐mixed cryoglobulinaemia

23

Peg‐IFN‐alpha+ribavirin

a) + telaprevir (375 mg, 3 times/d for 12 weeks) for 48 weeks (15 patients)

b) + boceprevir (800 mg, 3 times/d for 44 weeks) for 48 weeks (8 patients)

Complete clinical responders (improvement in all baseline clinical manifestations): 13 patients (56.5%) at week 24

Virological response (i.e., HCV RNA negative) was of 69.6% at week 24 (P = 0.005).

Cryoglobulin level: decreased from 0.44 to 0.06 g/L(P = 0.0006)

C4 level: increased from 0.09 to 0.15 g/L (P = 0.045)

No significant difference was found between the two treatment regiments

Total: 105

Withdrawals: 8 patients (34.7%) ( virological non‐response (5); virological relapse (2); depression (1))

Death: none

Relapse: 1

Most frequent AE:

fatigue (87%); neutropenia (78.3%);

thrombocytopenia (65.2%); infection (47.8%); pruritus (39.1%); depression (21.7%); nausea (21.7%)

Saadoun 2016

Open‐label, non‐controlled, prospective cohort study

Active HCV infection and active mixed cryoglobulinaemia. Excluded non‐active mixed cryoglobulinaemia, HIV or HBV active infection and current decompensated cirrhosis

To evaluate safety and efficacy of an oral IFN‐free regimen, sofosbuvir+ribavirin, in HCV‐mixed cryoglobulinaemia

24

Sofosbuvir (400 mg/d) + ribavirin (200 to 1400 mg/d) for 24 weeks

“Rituximab was used in four cases, in addition to prednisone and plasmapheresis in two patients”

Complete response (improvement of ALL the affected organs involved at baseline) at week 24: 21 (87.5%)

HCV RNA clearance at week 24: 22/24 (91.7%)

SVR12: 74%

Cryocrit: decrease from 0.35 g/L at baseline to 0 at 12 weeks after end‐of‐treatment.

C4: increase from 0.1 g/L at baseline to 0.22 g/L at 12 week after end‐of treatment

“No difference of outcome was found in patients who received immunosuppressive treatment or not”

Total: 14/24 (54%)

Withdrawals: 2 (8%)

(hallucination and irritability (1); grade 4 anaemia (1))

Death: 2 (severe pneumonia in the context of B cell lymphoma; pulmonary embolism in the context of hepatocellular carcinoma)

Relapses: none

Most frequent AE: (fatigue (25%); anaemia (25%); insomnia (21%); infection (17%); alopecia (8%))

12SVR ‐ 12 week SVR; 24SVR ‐ 24 week SVR; AE ‐ adverse event; ALT ‐ alanine aminotransferase; AST‐ aspartate aminotransferase; BVAS ‐ Birmingham Vasculitis Activity Score; Hb ‐ haemoglobin; HBV ‐ hepatitis B virus; HCV ‐ hepatitis C virus; HIV ‐ human immunodeficiency virus; IFN ‐ interferon; MPGN ‐ membranoproliferative glomerulonephritis; PEG ‐ pegylated; SVR ‐ sustained viral response

Figures and Tables -
Table 1. Studies including new antiviral treatments for HCV‐related mixed cryoglobulinaemia
Comparison 1. Rituximab versus no rituximab

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 One month

2

61

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

1.2 Six months

2

61

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

1.3 24 months

3

118

Risk Ratio (M‐H, Random, 95% CI)

0.52 [0.10, 2.61]

2 Clinical manifestations Show forest plot

2

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

2.1 Active urinary sediment at 1 month

1

16

Risk Ratio (M‐H, Random, 95% CI)

0.92 [0.51, 1.65]

2.2 Need for dialysis at 24 months

1

46

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2.3 Skin vasculitis (purpura, cutaneous ulcers or others) at 1 month

1

57

Risk Ratio (M‐H, Random, 95% CI)

2.59 [0.55, 12.27]

2.4 Skin vasculitis (purpura, cutaneous ulcers or others) at 18 and 24 months

2

78

Risk Ratio (M‐H, Random, 95% CI)

0.57 [0.28, 1.16]

2.5 Skin vasculitis (purpura, cutaneous ulcers or others) at 36 months

1

37

Risk Ratio (M‐H, Random, 95% CI)

0.68 [0.43, 1.08]

3 Laboratory findings Show forest plot

2

Mean Difference (IV, Random, 95% CI)

Subtotals only

3.1 Serum creatinine at 18 months [µmol/L]

1

37

Mean Difference (IV, Random, 95% CI)

‐8.80 [‐29.27, 11.67]

3.2 Serum creatinine at 36 months [µmol/L]

1

37

Mean Difference (IV, Random, 95% CI)

17.60 [‐4.23, 39.43]

3.3 Proteinuria at 18 months [g/24 h]

1

3

Mean Difference (IV, Random, 95% CI)

‐0.5 [‐1.42, 0.42]

3.4 Proteinuria at 36 months [g/24 h]

1

3

Mean Difference (IV, Random, 95% CI)

0.24 [‐0.84, 1.32]

3.5 Cryocrit at 12 months [%]

2

41

Mean Difference (IV, Random, 95% CI)

‐2.01 [‐10.29, 6.27]

3.6 Serum HCV‐RNA at 12 months [IU/mL]

1

17

Mean Difference (IV, Random, 95% CI)

‐435182.0 [‐1051224.79, 180860.79]

4 Adverse effects of the medication Show forest plot

3

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

4.1 Infusion reactions

3

118

Risk Ratio (M‐H, Random, 95% CI)

4.33 [0.76, 24.75]

4.2 Discontinuation of the treatment due to adverse drug reactions

3

118

Risk Ratio (M‐H, Random, 95% CI)

0.97 [0.22, 4.36]

4.3 Infection (pneumonia, urosepsis) at 6 months

1

24

Risk Ratio (M‐H, Random, 95% CI)

0.50 [0.05, 4.81]

4.4 Infection (pneumonia, urosepsis) at 24 months

1

57

Risk Ratio (M‐H, Random, 95% CI)

0.35 [0.04, 3.12]

4.5 Cardiovascular events (angina, myocardial infarction, heart failure) at 24 months

1

57

Risk Ratio (M‐H, Random, 95% CI)

0.52 [0.10, 2.61]

4.6 Gastrointestinal bleeding

1

57

Risk Ratio (M‐H, Random, 95% CI)

3.10 [0.13, 73.12]

4.7 Haemorrhagic alveolitis

1

57

Risk Ratio (M‐H, Random, 95% CI)

0.34 [0.01, 8.12]

4.8 Leukopenia at 6 months

1

24

Risk Ratio (M‐H, Random, 95% CI)

0.50 [0.05, 4.81]

4.9 Thrombocytopenia at 6 months

1

24

Risk Ratio (M‐H, Random, 95% CI)

1.0 [0.07, 14.21]

5 Antiviral therapy failure or not indicated Show forest plot

3

118

Risk Ratio (M‐H, Random, 95% CI)

1.21 [0.77, 1.90]

Figures and Tables -
Comparison 1. Rituximab versus no rituximab
Comparison 2. Interferon versus control

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 12 months

4

160

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

1.2 24 months

2

91

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2 Clinical manifestations Show forest plot

3

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

2.1 Skin vasculitis (purpura, cutaneous ulcers or others) at 12 months

3

95

Risk Ratio (M‐H, Random, 95% CI)

0.60 [0.36, 1.00]

3 Laboratory findings Show forest plot

4

Mean Difference (IV, Random, 95% CI)

Subtotals only

3.1 Serum creatinine at 18 months [µmol/L]

2

49

Mean Difference (IV, Random, 95% CI)

‐30.32 [‐80.59, 19.95]

3.2 Proteinuria at 18 months [g/24h]

2

49

Mean Difference (IV, Random, 95% CI)

‐1.98 [‐2.89, ‐1.07]

3.3 ALT or GPT at 6 months [UI/L]

2

39

Mean Difference (IV, Random, 95% CI)

‐5.89 [‐55.77, 43.99]

3.4 ALT or GPT at 18 months [UI/L]

2

49

Mean Difference (IV, Random, 95% CI)

‐28.28 [‐48.03, ‐8.54]

3.5 Rheumatoid factor activity at 6 months [UI/mL]

1

13

Mean Difference (IV, Random, 95% CI)

97.0 [‐187.37, 381.37]

3.6 C4 at 18 months [mg/dL]

2

49

Mean Difference (IV, Random, 95% CI)

‐0.04 [‐2.74, 2.67]

3.7 IgM at 18 months [mg/dL]

2

52

Mean Difference (IV, Random, 95% CI)

‐595.75 [‐877.20, ‐314.30]

3.8 Cryocrit at 6 months [%]

2

39

Mean Difference (IV, Random, 95% CI)

‐1.38 [‐2.38, ‐0.38]

4 Adverse effects of the medication Show forest plot

5

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

4.1 Infusion reactions

1

65

Risk Ratio (M‐H, Random, 95% CI)

27.82 [1.72, 449.18]

4.2 Discontinuations of the treatment due to adverse drug reactions

4

148

Risk Ratio (M‐H, Random, 95% CI)

2.32 [0.91, 5.90]

5 Antiviral therapy failure or not indicated Show forest plot

2

78

Risk Ratio (M‐H, Random, 95% CI)

0.59 [0.21, 1.64]

Figures and Tables -
Comparison 2. Interferon versus control
Comparison 3. Interferon for 6 months versus 1 year

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Death at 24 months Show forest plot

1

36

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

Figures and Tables -
Comparison 3. Interferon for 6 months versus 1 year
Comparison 4. Immunoadsorption apheresis versus immunosuppressive drug therapy

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Death at 24 months Show forest plot

1

17

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2 Clinical manifestations Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

2.1 Skin vasculitis (purpura, cutaneous ulcers or others) at 6 months

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2.2 Peripheral neuropathies at 6 months

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2.3 Peripheral joint arthralgia at 6 months

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

3 Laboratory findings Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

3.1 Cryocrit [%]

1

Mean Difference (IV, Random, 95% CI)

0.0 [0.0, 0.0]

4 Adverse effects of the medication Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

4.1 Infusion reactions

1

17

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

Figures and Tables -
Comparison 4. Immunoadsorption apheresis versus immunosuppressive drug therapy