Immunosuppressive treatment for proliferative lupus nephritis

David J Tunnicliffe; Suetonia C Palmer; Lorna Henderson; Philip Masson; Jonathan C Craig; Allison Tong; Davinder Singh‐Grewal; Robert S Flanc; Matthew A Roberts; Angela C Webster; Giovanni FM Strippoli

doi:10.1002/14651858.CD002922.pub4

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Figure 1

Study flow diagram.

^*Non‐RCTs have been deleted from this update

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Figure 2

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

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Analysis 1.1

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 1 Death.

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Analysis 1.2

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 2 Remission.

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Analysis 1.3

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 3 Adverse renal outcomes.

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Analysis 1.4

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 4 Stable kidney function.

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Analysis 1.5

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 5 Ovarian failure.

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Analysis 1.6

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 6 Menstrual irregularities.

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Analysis 1.7

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 7 Infection.

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Analysis 1.8

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 8 Malignancy.

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Analysis 1.9

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 9 Leucopenia.

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Analysis 1.10

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 10 Bladder toxicity.

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Analysis 1.11

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 11 Alopecia.

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Analysis 1.12

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 12 Gastrointestinal (GI) adverse events.

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Analysis 1.13

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 13 Daily proteinuria.

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Analysis 1.14

Comparison 1 Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA), Outcome 14 Serum creatinine.

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Analysis 2.1

Comparison 2 Mycophenolate mofetil (MMF) versus oral cyclophosphamide (CPA), Outcome 1 Death.

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Analysis 2.2

Comparison 2 Mycophenolate mofetil (MMF) versus oral cyclophosphamide (CPA), Outcome 2 Remission.

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Analysis 2.3

Comparison 2 Mycophenolate mofetil (MMF) versus oral cyclophosphamide (CPA), Outcome 3 Adverse renal outcomes.

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Analysis 2.4

Comparison 2 Mycophenolate mofetil (MMF) versus oral cyclophosphamide (CPA), Outcome 4 Ovarian failure.

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Analysis 2.5

Comparison 2 Mycophenolate mofetil (MMF) versus oral cyclophosphamide (CPA), Outcome 5 Infection.

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Analysis 2.6

Comparison 2 Mycophenolate mofetil (MMF) versus oral cyclophosphamide (CPA), Outcome 6 Leucopenia.

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Analysis 2.7

Comparison 2 Mycophenolate mofetil (MMF) versus oral cyclophosphamide (CPA), Outcome 7 Bone toxicity.

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Analysis 2.8

Comparison 2 Mycophenolate mofetil (MMF) versus oral cyclophosphamide (CPA), Outcome 8 Alopecia.

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Analysis 2.9

Comparison 2 Mycophenolate mofetil (MMF) versus oral cyclophosphamide (CPA), Outcome 9 Gastrointestinal (GI) adverse events.

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Analysis 2.10

Comparison 2 Mycophenolate mofetil (MMF) versus oral cyclophosphamide (CPA), Outcome 10 Daily proteinuria.

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Analysis 3.1

Comparison 3 Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA), Outcome 1 Death.

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Analysis 3.2

Comparison 3 Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA), Outcome 2 Remission.

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Analysis 3.3

Comparison 3 Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA), Outcome 3 Adverse renal outcomes.

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Analysis 3.4

Comparison 3 Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA), Outcome 4 Stable kidney function.

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Analysis 3.5

Comparison 3 Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA), Outcome 5 Ovarian failure.

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Analysis 3.6

Comparison 3 Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA), Outcome 6 Menstrual irregularities.

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Analysis 3.7

Comparison 3 Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA), Outcome 7 Infection.

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Analysis 3.8

Comparison 3 Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA), Outcome 8 Leucopenia.

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Analysis 3.9

Comparison 3 Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA), Outcome 9 Bone toxicity.

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Analysis 3.10

Comparison 3 Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA), Outcome 10 Alopecia.

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Analysis 3.11

Comparison 3 Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA), Outcome 11 Gastrointestinal (GI) adverse events.

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Analysis 3.12

Comparison 3 Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA), Outcome 12 Daily proteinuria.

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Analysis 4.1

Comparison 4 Mycophenolate mofetil (MMF) + IV cyclophosphamide (CPA) versus IV CPA, Outcome 1 Death.

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Analysis 4.2

Comparison 4 Mycophenolate mofetil (MMF) + IV cyclophosphamide (CPA) versus IV CPA, Outcome 2 Remission.

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Analysis 4.3

Comparison 4 Mycophenolate mofetil (MMF) + IV cyclophosphamide (CPA) versus IV CPA, Outcome 3 Menstrual irregularities.

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Analysis 4.4

Comparison 4 Mycophenolate mofetil (MMF) + IV cyclophosphamide (CPA) versus IV CPA, Outcome 4 Infection.

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Analysis 4.5

Comparison 4 Mycophenolate mofetil (MMF) + IV cyclophosphamide (CPA) versus IV CPA, Outcome 5 Leucopenia.

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Analysis 4.6

Comparison 4 Mycophenolate mofetil (MMF) + IV cyclophosphamide (CPA) versus IV CPA, Outcome 6 Daily proteinuria.

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Analysis 5.1

Comparison 5 Mycophenolate mofetil (MMF) versus tacrolimus (TAC), Outcome 1 Death.

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Analysis 5.2

Comparison 5 Mycophenolate mofetil (MMF) versus tacrolimus (TAC), Outcome 2 Remission.

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Analysis 5.3

Comparison 5 Mycophenolate mofetil (MMF) versus tacrolimus (TAC), Outcome 3 Adverse renal outcomes.

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Analysis 5.4

Comparison 5 Mycophenolate mofetil (MMF) versus tacrolimus (TAC), Outcome 4 Stable kidney function.

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Analysis 5.5

Comparison 5 Mycophenolate mofetil (MMF) versus tacrolimus (TAC), Outcome 5 Menstrual irregularities.

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Analysis 5.6

Comparison 5 Mycophenolate mofetil (MMF) versus tacrolimus (TAC), Outcome 6 Infection.

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Analysis 5.7

Comparison 5 Mycophenolate mofetil (MMF) versus tacrolimus (TAC), Outcome 7 Leucopenia.

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Analysis 5.8

Comparison 5 Mycophenolate mofetil (MMF) versus tacrolimus (TAC), Outcome 8 Alopecia.

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Analysis 5.9

Comparison 5 Mycophenolate mofetil (MMF) versus tacrolimus (TAC), Outcome 9 Daily proteinuria (at 24 weeks).

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Analysis 5.10

Comparison 5 Mycophenolate mofetil (MMF) versus tacrolimus (TAC), Outcome 10 Disease activity.

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Analysis 5.11

Comparison 5 Mycophenolate mofetil (MMF) versus tacrolimus (TAC), Outcome 11 Serum creatinine.

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Analysis 5.12

Comparison 5 Mycophenolate mofetil (MMF) versus tacrolimus (TAC), Outcome 12 Creatinine clearance.

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Analysis 6.1

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 1 Death.

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Analysis 6.2

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 2 Remission.

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Analysis 6.3

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 3 Adverse renal outcomes.

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Analysis 6.4

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 4 Stable kidney function.

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Analysis 6.5

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 5 Ovarian failure.

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Analysis 6.6

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 6 Menstrual irregularities.

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Analysis 6.7

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 7 Infection.

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Analysis 6.8

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 8 Malignancy: extended follow‐up.

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Analysis 6.9

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 9 Leucopenia.

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Analysis 6.10

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 10 Alopecia.

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Analysis 6.11

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 11 Gastrointestinal (GI) adverse events.

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Analysis 6.12

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 12 Daily proteinuria.

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Analysis 6.13

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 13 Creatinine clearance.

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Analysis 6.14

Comparison 6 Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA), Outcome 14 Serum creatinine.

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Analysis 7.1

Comparison 7 Cyclophosphamide (CPA) versus azathioprine (AZA), Outcome 1 Death.

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Analysis 7.2

Comparison 7 Cyclophosphamide (CPA) versus azathioprine (AZA), Outcome 2 Remission in proteinuria.

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Analysis 7.3

Comparison 7 Cyclophosphamide (CPA) versus azathioprine (AZA), Outcome 3 Adverse renal outcomes.

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Analysis 7.4

Comparison 7 Cyclophosphamide (CPA) versus azathioprine (AZA), Outcome 4 Stable kidney function.

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Analysis 7.5

Comparison 7 Cyclophosphamide (CPA) versus azathioprine (AZA), Outcome 5 Ovarian failure.

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Analysis 7.6

Comparison 7 Cyclophosphamide (CPA) versus azathioprine (AZA), Outcome 6 Menstrual irregularities.

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Analysis 7.7

Comparison 7 Cyclophosphamide (CPA) versus azathioprine (AZA), Outcome 7 Infection.

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Analysis 7.8

Comparison 7 Cyclophosphamide (CPA) versus azathioprine (AZA), Outcome 8 Malignancy.

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Analysis 7.9

Comparison 7 Cyclophosphamide (CPA) versus azathioprine (AZA), Outcome 9 Bone toxicity.

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Analysis 7.10

Comparison 7 Cyclophosphamide (CPA) versus azathioprine (AZA), Outcome 10 Bladder toxicity.

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Analysis 8.1

Comparison 8 Rituximab (RTX) + mycophenolate mofetil (MMF) versus placebo + MMF, Outcome 1 Death.

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Analysis 8.2

Comparison 8 Rituximab (RTX) + mycophenolate mofetil (MMF) versus placebo + MMF, Outcome 2 Remission.

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Analysis 8.3

Comparison 8 Rituximab (RTX) + mycophenolate mofetil (MMF) versus placebo + MMF, Outcome 3 Stable kidney function.

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Analysis 8.4

Comparison 8 Rituximab (RTX) + mycophenolate mofetil (MMF) versus placebo + MMF, Outcome 4 Infection.

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Analysis 8.5

Comparison 8 Rituximab (RTX) + mycophenolate mofetil (MMF) versus placebo + MMF, Outcome 5 Leucopenia.

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Analysis 9.1

Comparison 9 Rituximab (RTX) + cyclophosphamide (CPA) versus RTX, Outcome 1 Remission.

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Analysis 9.2

Comparison 9 Rituximab (RTX) + cyclophosphamide (CPA) versus RTX, Outcome 2 Infection.

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Analysis 9.3

Comparison 9 Rituximab (RTX) + cyclophosphamide (CPA) versus RTX, Outcome 3 Daily proteinuria.

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Analysis 9.4

Comparison 9 Rituximab (RTX) + cyclophosphamide (CPA) versus RTX, Outcome 4 Creatinine clearance.

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Analysis 9.5

Comparison 9 Rituximab (RTX) + cyclophosphamide (CPA) versus RTX, Outcome 5 Serum creatinine.

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Analysis 10.1

Comparison 10 Abatacept + other immunosuppressive agent (IS) + versus placebo + other IS, Outcome 1 Death.

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Analysis 10.2

Comparison 10 Abatacept + other immunosuppressive agent (IS) + versus placebo + other IS, Outcome 2 Remission.

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Analysis 10.3

Comparison 10 Abatacept + other immunosuppressive agent (IS) + versus placebo + other IS, Outcome 3 Adverse renal outcomes.

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Analysis 10.4

Comparison 10 Abatacept + other immunosuppressive agent (IS) + versus placebo + other IS, Outcome 4 Major Infection.

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Analysis 10.5

Comparison 10 Abatacept + other immunosuppressive agent (IS) + versus placebo + other IS, Outcome 5 Herpes zoster virus.

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Analysis 10.6

Comparison 10 Abatacept + other immunosuppressive agent (IS) + versus placebo + other IS, Outcome 6 Health‐related quality of life.

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Analysis 10.7

Comparison 10 Abatacept + other immunosuppressive agent (IS) + versus placebo + other IS, Outcome 7 Disease activity (BILAG).

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Analysis 11.1

Comparison 11 Laquinimod + other immunosuppressive agent (IS) versus placebo + other IS, Outcome 1 Death.

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Analysis 11.2

Comparison 11 Laquinimod + other immunosuppressive agent (IS) versus placebo + other IS, Outcome 2 Complete remission.

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Analysis 12.1

Comparison 12 Ocrelizumab + other immunosuppressive agent (IS) versus placebo + other IS, Outcome 1 Death.

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Analysis 12.2

Comparison 12 Ocrelizumab + other immunosuppressive agent (IS) versus placebo + other IS, Outcome 2 Remission.

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Analysis 12.3

Comparison 12 Ocrelizumab + other immunosuppressive agent (IS) versus placebo + other IS, Outcome 3 Major Infection.

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Analysis 13.1

Comparison 13 Sirukumab + other immunosuppressive agent (IS) versus placebo + other IS, Outcome 1 Death.

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Analysis 13.2

Comparison 13 Sirukumab + other immunosuppressive agent (IS) versus placebo + other IS, Outcome 2 Infection.

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Analysis 13.3

Comparison 13 Sirukumab + other immunosuppressive agent (IS) versus placebo + other IS, Outcome 3 Malignancy.

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Analysis 13.4

Comparison 13 Sirukumab + other immunosuppressive agent (IS) versus placebo + other IS, Outcome 4 Gastrointestinal (GI) adverse events.

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Analysis 14.1

Comparison 14 IV versus oral cyclophosphamide (CPA), Outcome 1 Death.

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Analysis 14.2

Comparison 14 IV versus oral cyclophosphamide (CPA), Outcome 2 Adverse renal outcomes.

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Analysis 14.3

Comparison 14 IV versus oral cyclophosphamide (CPA), Outcome 3 Stable kidney function.

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Analysis 14.4

Comparison 14 IV versus oral cyclophosphamide (CPA), Outcome 4 Ovarian failure.

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Analysis 14.5

Comparison 14 IV versus oral cyclophosphamide (CPA), Outcome 5 Infection.

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Analysis 14.6

Comparison 14 IV versus oral cyclophosphamide (CPA), Outcome 6 Malignancy.

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Analysis 14.7

Comparison 14 IV versus oral cyclophosphamide (CPA), Outcome 7 Bladder toxicity.

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Analysis 14.8

Comparison 14 IV versus oral cyclophosphamide (CPA), Outcome 8 Gastrointestinal (GI) adverse events.

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Analysis 15.1

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 1 Death.

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Analysis 15.2

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 2 Remission.

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Analysis 15.3

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 3 Adverse renal outcomes.

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Analysis 15.4

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 4 Stable kidney function.

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Analysis 15.5

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 5 Ovarian failure.

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Analysis 15.6

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 6 Infection.

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Analysis 15.7

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 7 Malignancy.

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Analysis 15.8

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 8 Leucopenia.

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Analysis 15.9

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 9 Bone toxicity.

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Analysis 15.10

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 10 Alopecia.

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Analysis 15.11

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 11 Gastrointestinal (GI) adverse events.

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Analysis 15.12

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 12 Daily proteinuria.

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Analysis 15.13

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 13 Creatinine clearance.

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Analysis 15.14

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 14 Serum creatinine.

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Analysis 15.15

Comparison 15 Low versus high dose cyclophosphamide (CPA), Outcome 15 Disease activity (SLEDAI).

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Analysis 16.1

Comparison 16 Standard versus reduced dose oral corticosteroids, Outcome 1 Death.

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Analysis 16.2

Comparison 16 Standard versus reduced dose oral corticosteroids, Outcome 2 Remission.

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Analysis 16.3

Comparison 16 Standard versus reduced dose oral corticosteroids, Outcome 3 Relapse.

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Analysis 16.4

Comparison 16 Standard versus reduced dose oral corticosteroids, Outcome 4 Infection.

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Analysis 16.5

Comparison 16 Standard versus reduced dose oral corticosteroids, Outcome 5 Gastrointestinal (GI) adverse events.

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Analysis 16.6

Comparison 16 Standard versus reduced dose oral corticosteroids, Outcome 6 Creatinine clearance.

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Analysis 16.7

Comparison 16 Standard versus reduced dose oral corticosteroids, Outcome 7 Serum creatinine.

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Analysis 17.1

Comparison 17 IV versus oral corticosteroids, Outcome 1 Death.

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Analysis 17.2

Comparison 17 IV versus oral corticosteroids, Outcome 2 Adverse renal outcomes.

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Analysis 18.1

Comparison 18 Cyclophosphamide (CPA) + corticosteroids versus corticosteroids, Outcome 1 Death.

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Analysis 18.2

Comparison 18 Cyclophosphamide (CPA) + corticosteroids versus corticosteroids, Outcome 2 Complete remission of proteinuria.

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Analysis 18.3

Comparison 18 Cyclophosphamide (CPA) + corticosteroids versus corticosteroids, Outcome 3 Adverse renal outcomes.

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Analysis 18.4

Comparison 18 Cyclophosphamide (CPA) + corticosteroids versus corticosteroids, Outcome 4 Deterioration of kidney function.

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Analysis 18.5

Comparison 18 Cyclophosphamide (CPA) + corticosteroids versus corticosteroids, Outcome 5 Stable kidney function.

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Analysis 18.6

Comparison 18 Cyclophosphamide (CPA) + corticosteroids versus corticosteroids, Outcome 6 Ovarian failure.

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Analysis 18.7

Comparison 18 Cyclophosphamide (CPA) + corticosteroids versus corticosteroids, Outcome 7 Infection.

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Analysis 18.8

Comparison 18 Cyclophosphamide (CPA) + corticosteroids versus corticosteroids, Outcome 8 Malignancy.

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Analysis 18.9

Comparison 18 Cyclophosphamide (CPA) + corticosteroids versus corticosteroids, Outcome 9 Bone toxicity.

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Analysis 18.10

Comparison 18 Cyclophosphamide (CPA) + corticosteroids versus corticosteroids, Outcome 10 Bladder toxicity.

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Analysis 18.11

Comparison 18 Cyclophosphamide (CPA) + corticosteroids versus corticosteroids, Outcome 11 Daily proteinuria.

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Analysis 18.12

Comparison 18 Cyclophosphamide (CPA) + corticosteroids versus corticosteroids, Outcome 12 Serum creatinine.

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Analysis 18.13

Comparison 18 Cyclophosphamide (CPA) + corticosteroids versus corticosteroids, Outcome 13 Creatinine clearance.

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Analysis 19.1

Comparison 19 Cyclophosphamide (CPA) + azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 1 Death.

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Analysis 19.2

Comparison 19 Cyclophosphamide (CPA) + azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 2 Adverse renal outcomes.

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Analysis 19.3

Comparison 19 Cyclophosphamide (CPA) + azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 3 Stable kidney function.

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Analysis 19.4

Comparison 19 Cyclophosphamide (CPA) + azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 4 Ovarian failure.

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Analysis 19.5

Comparison 19 Cyclophosphamide (CPA) + azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 5 Infection.

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Analysis 19.6

Comparison 19 Cyclophosphamide (CPA) + azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 6 Bladder toxicity.

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Analysis 20.1

Comparison 20 Azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 1 Death.

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Analysis 20.2

Comparison 20 Azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 2 Complete remission of proteinuria.

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Analysis 20.3

Comparison 20 Azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 3 Adverse renal outcomes.

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Analysis 20.4

Comparison 20 Azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 4 Stable kidney function.

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Analysis 20.5

Comparison 20 Azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 5 Ovarian failure.

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Analysis 20.6

Comparison 20 Azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 6 Infection.

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Analysis 20.7

Comparison 20 Azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 7 Malignancy.

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Analysis 20.8

Comparison 20 Azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 8 Bone toxicity.

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Analysis 20.9

Comparison 20 Azathioprine (AZA) + corticosteroids versus corticosteroids alone, Outcome 9 Creatinine clearance.

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Analysis 21.1

Comparison 21 Cyclosporin (CSA) + corticosteroids versus corticosteroids alone, Outcome 1 Daily proteinuria.

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Analysis 21.2

Comparison 21 Cyclosporin (CSA) + corticosteroids versus corticosteroids alone, Outcome 2 Serum creatinine.

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Analysis 21.3

Comparison 21 Cyclosporin (CSA) + corticosteroids versus corticosteroids alone, Outcome 3 Creatinine clearance.

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Analysis 22.1

Comparison 22 Misoprostol + corticosteroids versus corticosteroids alone, Outcome 1 Adverse renal outcomes.

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Analysis 23.1

Comparison 23 Plasma exchange (PE) + immunosuppression (IS) versus IS alone, Outcome 1 Death.

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Analysis 23.2

Comparison 23 Plasma exchange (PE) + immunosuppression (IS) versus IS alone, Outcome 2 Adverse renal outcomes.

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Analysis 23.3

Comparison 23 Plasma exchange (PE) + immunosuppression (IS) versus IS alone, Outcome 3 Stable kidney function.

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Analysis 23.4

Comparison 23 Plasma exchange (PE) + immunosuppression (IS) versus IS alone, Outcome 4 Infection.

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Analysis 23.5

Comparison 23 Plasma exchange (PE) + immunosuppression (IS) versus IS alone, Outcome 5 Leucopenia.

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Analysis 23.6

Comparison 23 Plasma exchange (PE) + immunosuppression (IS) versus IS alone, Outcome 6 Daily proteinuria.

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Analysis 23.7

Comparison 23 Plasma exchange (PE) + immunosuppression (IS) versus IS alone, Outcome 7 Serum creatinine.

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Analysis 23.8

Comparison 23 Plasma exchange (PE) + immunosuppression (IS) versus IS alone, Outcome 8 Creatinine clearance.

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Analysis 23.9

Comparison 23 Plasma exchange (PE) + immunosuppression (IS) versus IS alone, Outcome 9 Disease activity (SLAM).

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Analysis 24.1

Comparison 24 Plasma exchange (PE) versus immunosuppression (IS), Outcome 1 Adverse renal outcomes.

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Analysis 24.2

Comparison 24 Plasma exchange (PE) versus immunosuppression (IS), Outcome 2 Infection.

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Analysis 24.3

Comparison 24 Plasma exchange (PE) versus immunosuppression (IS), Outcome 3 Leucopenia.

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Analysis 24.4

Comparison 24 Plasma exchange (PE) versus immunosuppression (IS), Outcome 4 Alopecia.

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Analysis 24.5

Comparison 24 Plasma exchange (PE) versus immunosuppression (IS), Outcome 5 Daily proteinuria.

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Analysis 24.6

Comparison 24 Plasma exchange (PE) versus immunosuppression (IS), Outcome 6 Creatinine clearance.

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Analysis 25.1

Comparison 25 Long versus short duration cyclophosphamide (CPA), Outcome 1 Adverse renal outcomes.

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Analysis 25.2

Comparison 25 Long versus short duration cyclophosphamide (CPA), Outcome 2 Stable kidney function.

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Analysis 25.3

Comparison 25 Long versus short duration cyclophosphamide (CPA), Outcome 3 Ovarian failure.

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Analysis 25.4

Comparison 25 Long versus short duration cyclophosphamide (CPA), Outcome 4 Infection.

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Analysis 25.5

Comparison 25 Long versus short duration cyclophosphamide (CPA), Outcome 5 Malignancy.

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Analysis 25.6

Comparison 25 Long versus short duration cyclophosphamide (CPA), Outcome 6 Bone toxicity.

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Analysis 25.7

Comparison 25 Long versus short duration cyclophosphamide (CPA), Outcome 7 Bladder toxicity.

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Analysis 26.1

Comparison 26 Maintenance: azathioprine (AZA) versus mycophenolate mofetil (MMF), Outcome 1 Death.

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Analysis 26.2

Comparison 26 Maintenance: azathioprine (AZA) versus mycophenolate mofetil (MMF), Outcome 2 Renal relapse.

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Analysis 26.3

Comparison 26 Maintenance: azathioprine (AZA) versus mycophenolate mofetil (MMF), Outcome 3 End‐stage kidney disease.

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Analysis 26.4

Comparison 26 Maintenance: azathioprine (AZA) versus mycophenolate mofetil (MMF), Outcome 4 Doubling of serum creatinine.

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Analysis 26.5

Comparison 26 Maintenance: azathioprine (AZA) versus mycophenolate mofetil (MMF), Outcome 5 Ovarian failure.

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Analysis 26.6

Comparison 26 Maintenance: azathioprine (AZA) versus mycophenolate mofetil (MMF), Outcome 6 Infection.

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Analysis 26.7

Comparison 26 Maintenance: azathioprine (AZA) versus mycophenolate mofetil (MMF), Outcome 7 Malignancy.

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Analysis 26.8

Comparison 26 Maintenance: azathioprine (AZA) versus mycophenolate mofetil (MMF), Outcome 8 Leucopenia.

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Analysis 26.9

Comparison 26 Maintenance: azathioprine (AZA) versus mycophenolate mofetil (MMF), Outcome 9 Bone toxicity.

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Analysis 26.10

Comparison 26 Maintenance: azathioprine (AZA) versus mycophenolate mofetil (MMF), Outcome 10 Alopecia.

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Analysis 26.11

Comparison 26 Maintenance: azathioprine (AZA) versus mycophenolate mofetil (MMF), Outcome 11 Gastrointestinal (GI) adverse events.

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Analysis 26.12

Comparison 26 Maintenance: azathioprine (AZA) versus mycophenolate mofetil (MMF), Outcome 12 Daily proteinuria.

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Analysis 27.1

Comparison 27 Maintenance: azathioprine (AZA) versus cyclosporin (CSA), Outcome 1 Death.

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Analysis 27.2

Comparison 27 Maintenance: azathioprine (AZA) versus cyclosporin (CSA), Outcome 2 Adverse renal outcomes.

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Analysis 27.3

Comparison 27 Maintenance: azathioprine (AZA) versus cyclosporin (CSA), Outcome 3 Infection.

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Analysis 27.4

Comparison 27 Maintenance: azathioprine (AZA) versus cyclosporin (CSA), Outcome 4 Leucopenia.

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Analysis 27.5

Comparison 27 Maintenance: azathioprine (AZA) versus cyclosporin (CSA), Outcome 5 Gastrointestinal (GI) adverse events.

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Analysis 27.6

Comparison 27 Maintenance: azathioprine (AZA) versus cyclosporin (CSA), Outcome 6 Daily proteinuria.

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Analysis 27.7

Comparison 27 Maintenance: azathioprine (AZA) versus cyclosporin (CSA), Outcome 7 Disease activity (SLEDAI).

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Analysis 28.1

Comparison 28 Maintenance: azathioprine (AZA) versus cyclophosphamide (CPA), Outcome 1 Death.

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Analysis 28.2

Comparison 28 Maintenance: azathioprine (AZA) versus cyclophosphamide (CPA), Outcome 2 Adverse renal outcomes.

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Analysis 28.3

Comparison 28 Maintenance: azathioprine (AZA) versus cyclophosphamide (CPA), Outcome 3 Bladder toxicity.

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Analysis 28.4

Comparison 28 Maintenance: azathioprine (AZA) versus cyclophosphamide (CPA), Outcome 4 Creatinine clearance.

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Analysis 29.1

Comparison 29 Maintenance: azathioprine (AZA) versus tacrolimus (TAC), Outcome 1 Adverse renal outcomes.

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Analysis 29.2

Comparison 29 Maintenance: azathioprine (AZA) versus tacrolimus (TAC), Outcome 2 Infection.

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Analysis 29.3

Comparison 29 Maintenance: azathioprine (AZA) versus tacrolimus (TAC), Outcome 3 Gastrointestinal (GI) adverse events.

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Analysis 30.1

Comparison 30 Maintenance: prednisone withdrawal versus prednisone continuation, Outcome 1 Relapse.

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Analysis 30.2

Comparison 30 Maintenance: prednisone withdrawal versus prednisone continuation, Outcome 2 Major infection.

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Analysis 31.1

Comparison 31 Maintenance: intravenous immunoglobulin (IVIG) versus intravenous cyclophosphamide (IV CPA), Outcome 1 Creatinine clearance.

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Analysis 31.2

Comparison 31 Maintenance: intravenous immunoglobulin (IVIG) versus intravenous cyclophosphamide (IV CPA), Outcome 2 Daily proteinuria.

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Analysis 31.3

Comparison 31 Maintenance: intravenous immunoglobulin (IVIG) versus intravenous cyclophosphamide (IV CPA), Outcome 3 Serum creatinine.

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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 low^1,2,3	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 low^1,2,3	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)	⊕⊕⊝⊝ low^1,2,3	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)	⊕⊕⊝⊝ low^1,2	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 low^1,2,3	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)	⊕⊕⊝⊝ low^1,2	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)	⊕⊕⊕⊝ moderate^1,2,3	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)	⊕⊕⊕⊝ moderate^1,2,3	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

Summary of findings for the main comparison. Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA) for induction therapy

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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)	⊕⊕⊝⊝ low^1,2,3,4	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)	⊕⊕⊝⊝ low^1,2	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)	⊕⊕⊝⊝ low^1,2,3,4	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.

Summary of findings 2. Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA) for induction therapy

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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 low^1,2,3	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 low^1,2,3	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)	⊕⊕⊝⊝ low^1,2	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)	⊕⊕⊝⊝ low^1,2	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)	⊕⊕⊝⊝ low^1,2	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)	⊕⊕⊝⊝ low^1,2	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

Summary of findings 3. Azathioprine (AZA) versus mycophenolate mofetil (MMF) for maintenance therapy

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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

Table 1. Description of health‐related quality of life outcomes

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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

Table 2. Description of fatigue outcomes

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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
Mok 2016	MMF versus TAC	Extrarenal SLEDAI (mean ± SD)	6 months	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)
MyLupus 2011	Standard dose PRED versus reduced dose PRED	SLEDAI (mean ± SD)	6 months	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.”
Rovin 2016	Sirukumab versus placebo	Physician's and patients global assessment of disease activity	6 months	“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"
MAINTAIN Nephritis 2010	AZA versus MMF	ECLAM	36 months
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

Table 3. Description of disease activity outcomes

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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]

Comparison 1. Mycophenolate mofetil (MMF) versus IV cyclophosphamide (CPA)

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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]

Comparison 2. Mycophenolate mofetil (MMF) versus oral cyclophosphamide (CPA)

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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]

Comparison 3. Mycophenolate mofetil (MMF) + tacrolimus (TAC) versus IV cyclophosphamide (CPA)

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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]

Comparison 4. Mycophenolate mofetil (MMF) + IV cyclophosphamide (CPA) versus IV CPA

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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]

Comparison 5. Mycophenolate mofetil (MMF) versus tacrolimus (TAC)

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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]

Comparison 6. Calcineurin inhibitors (CNI) versus IV cyclophosphamide (CPA)

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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]

Comparison 7. Cyclophosphamide (CPA) versus azathioprine (AZA)

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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]

Comparison 8. Rituximab (RTX) + mycophenolate mofetil (MMF) versus placebo + MMF

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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]

Comparison 9. Rituximab (RTX) + cyclophosphamide (CPA) versus RTX

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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]

Comparison 10. Abatacept + other immunosuppressive agent (IS) + versus placebo + other IS

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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]

Comparison 11. Laquinimod + other immunosuppressive agent (IS) versus placebo + other IS

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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]

Comparison 12. Ocrelizumab + other immunosuppressive agent (IS) versus placebo + other IS

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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]

Comparison 13. Sirukumab + other immunosuppressive agent (IS) versus placebo + other IS

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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]

Comparison 14. IV versus oral cyclophosphamide (CPA)

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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]

Comparison 15. Low versus high dose cyclophosphamide (CPA)

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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]

Comparison 16. Standard versus reduced dose oral corticosteroids

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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]

Comparison 17. IV versus oral corticosteroids

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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]

Comparison 18. Cyclophosphamide (CPA) + corticosteroids versus corticosteroids

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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]

Comparison 19. Cyclophosphamide (CPA) + azathioprine (AZA) + corticosteroids versus corticosteroids alone

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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]

Comparison 20. Azathioprine (AZA) + corticosteroids versus corticosteroids alone

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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]

Comparison 21. Cyclosporin (CSA) + corticosteroids versus corticosteroids alone

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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]

Comparison 22. Misoprostol + corticosteroids versus corticosteroids alone

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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]

Comparison 23. Plasma exchange (PE) + immunosuppression (IS) versus IS alone

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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]

Comparison 24. Plasma exchange (PE) versus immunosuppression (IS)

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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]

Comparison 25. Long versus short duration cyclophosphamide (CPA)

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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]

Comparison 26. Maintenance: azathioprine (AZA) versus mycophenolate mofetil (MMF)

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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]

Comparison 27. Maintenance: azathioprine (AZA) versus cyclosporin (CSA)

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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]

Comparison 28. Maintenance: azathioprine (AZA) versus cyclophosphamide (CPA)

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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]

Comparison 29. Maintenance: azathioprine (AZA) versus tacrolimus (TAC)

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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]

Comparison 30. Maintenance: prednisone withdrawal versus prednisone continuation

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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]

Comparison 31. Maintenance: intravenous immunoglobulin (IVIG) versus intravenous cyclophosphamide (IV CPA)

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