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American Journal of Kidney Diseases

Induction and Maintenance Immunosuppression Treatment of Proliferative Lupus Nephritis: A Network Meta-analysis of Randomized Trials

Open AccessPublished:February 21, 2017DOI:https://doi.org/10.1053/j.ajkd.2016.12.008

      Background

      Intravenous (IV) cyclophosphamide has been first-line treatment for inducing disease remission in lupus nephritis. The comparative efficacy and toxicity of newer agents such as mycophenolate mofetil (MMF) and calcineurin inhibitors are uncertain.

      Study Design

      Network meta-analysis.

      Setting & Population

      Patients with proliferative lupus nephritis.

      Selection Criteria for Studies

      Randomized trials of immunosuppression to induce or maintain disease remission.

      Interventions

      IV cyclophosphamide, oral cyclophosphamide, MMF, calcineurin inhibitor, plasma exchange, rituximab, or azathioprine, alone or in combination.

      Outcomes

      Complete remission, end-stage kidney disease, all-cause mortality, doubling of serum creatinine level, relapse, and adverse events.

      Results

      53 studies involving 4,222 participants were eligible. Induction and maintenance treatments were administered for 12 (IQR, 6-84) and 25 (IQR, 12-48) months, respectively. There was no evidence of different effects between therapies on all-cause mortality, doubling of serum creatinine level, or end-stage kidney disease. Compared to IV cyclophosphamide, the most effective treatments to induce remission in moderate- to high-quality evidence were combined MMF and calcineurin inhibitor therapy, calcineurin inhibitors, and MMF (ORs were 2.69 [95% CI, 1.74-4.16], 1.86 [95% CI, 1.05-3.30], and 1.54 [95% CI, 1.04-2.30], respectively). MMF was significantly less likely than IV cyclophosphamide to cause alopecia (OR, 0.21; 95% CI, 0.12-0.36), and MMF combined with calcineurin inhibitor therapy was less likely to cause ovarian failure (OR, 0.25; 95% CI, 0.07-0.93). Regimens generally had similar odds of major infection. MMF was the most effective strategy to maintain remission.

      Limitations

      Outcome definitions not standardized, short duration of follow-up, and possible confounding by previous or subsequent therapy.

      Conclusions

      Evidence for induction therapy for lupus nephritis is inconclusive based on treatment effects on all-cause mortality, doubling of serum creatinine level, and end-stage kidney disease. MMF, calcineurin inhibitors, or their combination were most effective for inducing remission compared to IV cyclophosphamide, while conferring similar or lower treatment toxicity. MMF was the most effective maintenance therapy.

      Index Words

      Editorial, p. 309
      Systemic lupus erythematosus principally affects women of child-bearing age. Kidney involvement affects 20% to 75% of patients in the first 10 years.
      • Cervera R.
      • Khamashta M.A.
      • Hughes G.
      The Euro-lupus project: epidemiology of systemic lupus erythematosus in Europe.
      Although 5-year survival for patients with systemic lupus erythematosus was <50% in the 1950s, this has improved to >90%, attributed to improved immunosuppression and other medical therapies. Therapies have transformed lupus nephritis from an acute to a chronic illness, in which the longer term efficacy and adverse effects of treatments may assume greater importance in medical decision making.
      Intravenous (IV) cyclophosphamide combined with corticosteroids has been first-line therapy to induce remission from lupus nephritis, but it causes considerable toxicity.
      • Flanc R.S.
      • Roberts M.A.
      • Strippoli G.F.M.
      • et al.
      Treatment for lupus nephritis.
      Existing pairwise meta-analyses suggest similar efficacy for mycophenolate mofetil (MMF) and IV cyclophosphamide with lower toxicity for MMF, but whether MMF or other drugs are equivalent or superior to IV cyclophosphamide for induction and maintenance of disease remission is uncertain.
      • Henderson L.
      • Masson P.
      • Craig J.C.
      • et al.
      Treatment for lupus nephritis.
      • Mak A.
      • Cheak A.A.
      • Tan J.Y.
      • et al.
      Mycophenolate mofetil is as efficacious as, but safer than, cyclophosphamide in the treatment of proliferative lupus nephritis: a meta-analysis and meta-regression.
      However, standard pairwise meta-analysis is only able to compare 2 drug classes that have already been evaluated in head-to-head trials. In a complex condition with several options for treatment, of which some have not been directly compared in trials, a network meta-analysis offers the potential to compare all therapeutic strategies simultaneously within a single framework and rank treatments per efficacy and safety. Network analysis has been used to evaluate induction therapy in lupus nephritis, but results have been inconclusive due to relatively few included studies
      • Tian S.Y.
      • Feldman B.M.
      • Beyene J.
      • et al.
      Immunosuppressive therapies for the induction treatment of proliferative lupus nephritis: a systematic review and network metaanalysis.
      • Lee Y.H.
      • Song G.G.
      Relative efficacy and safety of tacrolimus, mycophenolate mofetil, and cyclophosphamide as induction therapy for lupus nephritis: a Bayesian network meta-analysis of randomized controlled trials.
      or reporting of drug harms only.

      Singh J, Kotb A, Hossain A, Wells G. A systematic review and network meta-analysis of cyclophosphamide and mycophenolate mofetil in lupus nephritis. Presented at: ACR/ARHP Annual Meeting; November 14-19, 2014; Boston MA. Abstract 1660.

      Methods

      Overview

      A network meta-analysis was performed within a frequentist framework. The meta-analysis was conducted and reported according to a prespecified protocol (Item S1, available as online supplementary material) and the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) statement.
      • Hutton B.
      • Salanti G.
      • Caldwell D.M.
      • et al.
      The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations.
      Ethics committee approval was not required for this study design.

      Data Sources and Searches

      The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase were searched on July 20, 2016, using a highly sensitive search strategy without language restriction (Item S1). A Cochrane review and meta-analysis was also screened for eligible randomized trials.
      • Henderson L.
      • Masson P.
      • Craig J.C.
      • et al.
      Treatment for lupus nephritis.

      Study Selection

      Parallel-group randomized trials involving adults, adolescents, or children 10 years or older with proliferative lupus nephritis and who received immunosuppression to induce or maintain remission were included. Included trials reported comparisons between 2 immunosuppression strategies, placebo, or usual care. Two reviewers (S.C.P. and D.J.T.) independently screened titles and abstracts of retrieved search records to determine potential eligibility. Any potentially eligible citation was reviewed in full text by the same 2 reviewers, who resolved discrepancies through consensus. Potentially eligible articles published in languages other than English were translated before full-text assessment.

      Data Extraction

      Two investigators (S.C.P. and D.J.T.) abstracted data independently into an electronic database. The authors cross-checked the data and reached consensus for any discrepancies through discussion.

      Risk of Bias

      Two independent reviewers (S.C.P. and D.J.T.) assessed risks of bias using the Cochrane Collaboration assessment tool.
      • Higgins J.P.
      • Altman D.G.
      • Gotzsche P.C.
      • et al.
      The Cochrane Collaboration's tool for assessing risk of bias in randomised trials.

      Data Synthesis and Analysis

      The primary outcomes of interest for induction therapy were complete remission and all-cause mortality. Other outcomes were end-stage kidney disease, doubling of serum creatinine level, failure to induce remission, major infection, alopecia, ovarian failure, malignancy, nausea, vomiting, bone toxicity, bladder toxicity, leukopenia, and herpes infection. In maintenance therapy trials, relapse after remission was the primary outcome. Studies reporting zero events in all arms were excluded from analyses. Data from trials principally evaluating induction treatment were analyzed separately from trials evaluating maintenance treatment.
      The clinical setting and participant characteristics were evaluated to consider whether the trials were sufficiently similar that a network meta-analysis approach was appropriate.
      • Salanti G.
      Indirect and mixed-treatment comparison, network, or multiple-treatments meta-analysis: many names, many benefits, many concerns for the next generation evidence synthesis tool.
      Box plots were generated according to treatment class to explore distributions of key effect modifiers, including age, sex, serum creatinine level, and date of publication. We intended to explore distributions of treatment classes by ethnicity or race, but these assessments were precluded by insufficient data observations.
      Random-effects pairwise meta-analysis was then conducted. Heterogeneity of treatment estimates between trials in pairwise meta-analysis was assessed using χ2 test and the corresponding I2 statistic. I2 thresholds of 0% to 40%, 30% to 60%, 50% to 90%, and 75% to 100% were considered to represent heterogeneity that might not be important, that is moderate, that is substantial, and that is considerable, respectively, considering also the magnitude and direction of treatment effects.
      • Higgins J.P.
      • Thompson S.G.
      • Deeks J.J.
      • Altman D.G.
      Measuring inconsistency in meta-analyses.
      Finally, using a frequentist framework, random-effects network meta-analysis was used to compare all classes of immunosuppression for each prespecified outcome.
      • Salanti G.
      Indirect and mixed-treatment comparison, network, or multiple-treatments meta-analysis: many names, many benefits, many concerns for the next generation evidence synthesis tool.
      • Caldwell D.M.
      • Ades A.E.
      • Higgins J.P.
      Simultaneous comparison of multiple treatments: combining direct and indirect evidence.
      We assumed a random-effects model to describe the effects of the base treatment in each study in each network, with the conventional assumption of a normal distribution for random effects. Comparative treatment effects were calculated as odds ratios (ORs) and 95% confidence intervals (CIs). The extent of heterogeneity in each network analysis was evaluated using the restricted maximum likelihood method to generate a common heterogeneity variance (tau [τ]), which was then compared with an empirical distribution of heterogeneity variances, considering the range of ORs expected. Values of 0.1 to 0.5 were considered low, those >0.5 to 1.0 were considered fairly high, and those >1.0 represented fairly extreme heterogeneity.
      • Turner R.M.
      • Davey J.
      • Clarke M.J.
      • Thompson S.G.
      • Higgins J.P.
      Predicting the extent of heterogeneity in meta-analysis, using empirical data from the Cochrane Database of Systematic Reviews.
      To explore for network inconsistency, a loop-specific approach was used that compares the estimated treatment effects derived from direct and indirect evidence in all triangular and quadratic loops in a network. To check the assumption of consistency in the entire analytical network, the design-by-treatment interaction approach was used.
      • Higgins J.P.T.
      • Jackson D.
      • Barrett J.K.
      • et al.
      Consistency and inconsistency in network meta-analysis: concepts and models for multi-arm studies.
      Drug classes were ranked to generate a hierarchy of treatments for a given clinical end point. The relative ranking probability of each treatment being among the “best” treatment was obtained using surface under the cumulative ranking (SUCRA) curves and displayed using rankograms. The GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach to assess confidence in estimates of effect associated with specific drug comparisons in network analyses was used to determine confidence in the evidence for all-cause mortality, end-stage kidney disease, and complete remission.
      • Salanti G.
      • Del Giovane C.
      • Chaimani A.
      • Caldwell D.M.
      • Higgins J.P.
      Evaluating the quality of evidence from a network meta-analysis.
      We considered risk of bias, consistency, imprecision, indirectness, and publication bias. Pairwise and network meta-analyses were done in Stata, version 13 (StataCorp LP) using the network command
      • White I.R.
      Network meta-analysis.
      and self-programmed Stata routines.
      • Chaimani A.
      • Higgins J.P.
      • Mavridis D.
      • Spyridonos P.
      • Salanti G.
      Graphical tools for network meta-analysis in STATA.
      We planned metaregression analyses to explore associations of year of publication, race or ethnicity, outcome definition, or age with treatment estimates.

      Results

      Description of Included Studies

      Thirty-eight trials were included from a Cochrane review
      • Henderson L.
      • Masson P.
      • Craig J.C.
      • et al.
      Treatment for lupus nephritis.
      and 15 additional trials were identified through electronic database searching (Fig 1). Fifty-three randomized trials were eligible involving 4,222 participants (aged ≥ 10 years; Table S1).
      The ACCESS Trial Group
      Treatment of lupus nephritis with abatacept: the Abatacept and Cyclophosphamide Combination Efficacy and Safety Study.
      • El-Sehemy M.S.
      • Al-Saaran A.M.
      • Baddour N.M.
      • Adam A.G.
      • Moez P.E.
      Comparative clinical prospective therapeutic study between cyclophosphamide, cyclosporine and azathioprine in the treatment of lupus nephritis.
      • Aranow C.
      • Van Vollenhoven R.
      • Rovin B.H.
      • et al.
      A phase 2, multicenter, randomized, double-blind, placebo-controlled, proof-of-concept study to evaluate the efficacy and safety of sirukumab in patients with active lupus nephritis [abstract].
      • Appel G.B.
      • Contreras G.
      • Dooley M.A.
      • et al.
      Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis.
      • Dooley M.A.
      • Jayne D.
      • Ginzler E.M.
      • et al.
      Mycophenolate versus azathioprine as maintenance therapy for lupus nephritis.
      • Austin 3rd, H.A.
      • Klippel J.H.
      • Balow J.E.
      • et al.
      Therapy of lupus nephritis. Controlled trial of prednisone and cytotoxic drugs.
      • Balletta M.
      • Sabella D.
      • Magri P.
      • Sepe V.
      • Stanziale P.
      • Di Luccio R.
      • et al.
      Cyclosporin plus steroids versus steroids alone in the treatment of lupus nephritis.
      • Bao H.
      • Liu Z.H.
      • Xie H.L.
      • et al.
      Successful treatment of class V+IV lupus nephritis with multitarget therapy.
      • Belmont H.M.
      • Kitsis E.
      • Skovron M.L.
      • et al.
      Misoprostol and prednisone treatment of lupus nephritis.
      • Mysler E.F.
      • Spindler A.J.
      • Guzman R.
      • et al.
      Efficacy and safety of ocrelizumab in active proliferative lupus nephritis: results from a randomized, double-blind, phase III study.
      • Boletis J.N.
      • Ioannidis J.P.A.
      • Boki K.A.
      • Moutsopoulos H.M.
      Intravenous immunoglobulin compared with cyclophosphamide for proliferative lupus nephritis.
      • Boumpas D.T.
      • Austin H.
      • Vaughn E.M.
      • et al.
      Controlled trial of pulse methylprednisolone versus two regimens of pulse cyclophosphamide in severe lupus nephritis.
      • Cade R.
      • Spooner G.
      • Schlein E.
      • et al.
      Comparison of azathioprine, prednisone, and heparin alone or combined in treating lupus nephritis.
      • Chan T.M.
      • Li F.K.
      • Tang C.S.
      • et al.
      Efficacy of mycophenolate mofetil in patients with diffuse proliferative lupus nephritis. Hong Kong-Guangzhou Nephrology Study Group.
      • Chen W.
      • Tang X.
      • Liu Q.
      • et al.
      Short-term outcomes of induction therapy with tacrolimus versus cyclophosphamide for active lupus nephritis: a multicenter randomized clinical trial.
      • Chen W.
      • Liu Q.
      • Chen W.
      • et al.
      Outcomes of maintenance therapy with tacrolimus versus azathioprine for active lupus nephritis: a multicenter randomized clinical trial.
      • Clark W.F.
      • Lindsay R.M.
      • Cattran D.C.
      • et al.
      Monthly plasmapheresis for systemic lupus erythematosus with diffuse proliferative glomerulonephritis: a pilot study.
      • Clark W.
      • Williams W.
      • Cattran D.
      • et al.
      A controlled trial of chronic plasma exchange therapy in S.L.E. nephritis.
      • Contreras G.
      • Pardo V.
      • Leclercq B.
      • et al.
      Maintenance therapy for proliferative forms of lupus nephritis: a randomized clinical trial comparing quarterly intravenous cyclophosphamide (IVCY) versus oral mycophenolate mofetil (MMF) or azathioprine (AZA).
      • Zavada J.
      • Pesickova S.
      • Rysava R.
      • et al.
      Cyclosporine A or intravenous cyclophosphamide for lupus nephritis: the Cyclofa-Lune study.
      • Donadio Jr., J.V.
      • Holley K.E.
      • Wagoner R.D.
      • Ferguson R.H.
      • McDuffie F.C.
      Treatment of lupus nephritis with prednisone and combined prednisone and azathioprine.
      • Donadio Jr., J.V.
      • Holley K.E.
      • Ferguson R.H.
      • Ilstrup D.M.
      Treatment of diffuse proliferative lupus nephritis with prednisone and combined prednisone and cyclophosphamide.
      • Doria A.
      • Piccoli A.
      • Vesco P.
      • et al.
      Therapy of lupus nephritis. A two-year prospective study.
      • Dyadyk A.
      • Vasilenko I.
      • Bagriy A.
      • et al.
      Azathioprine and cyclophosphamide in treatment of patients with diffuse proliferative lupus nephritis - a randomized controlled study.
      • El-Shafey E.M.
      • Abdou S.H.
      • Shareef M.M.
      Is mycophenolate mofetil superior to pulse intravenous cyclophosphamide for induction therapy of proliferative lupus nephritis in Egyptian patients?.
      • Feng X.B.
      • Gu F.
      • Chen W.W.
      • et al.
      Mizoribine versus mycophenolate mofetil or intravenous cyclophosphamide for induction treatment of active lupus nephritis.
      • Fries J.F.
      • Sharp G.C.
      • McDevitt H.O.
      • Holman H.R.
      Cyclophosphamide therapy in systemic lupus erythematosus and polymyositis.
      • Fu L.W.
      • Yang L.Y.
      • Chen W.P.
      • Lin C.Y.
      Clinical efficacy of cyclosporin A neoral in the treatment of paediatric lupus nephritis with heavy proteinuria.
      • Furie R.
      • Nicholls K.
      • Cheng T.T.
      • et al.
      Efficacy and safety of abatacept in lupus nephritis: a twelve-month, randomized, double-blind study.
      • Ginzler E.M.
      • Dooley M.A.
      • Aranow C.
      • et al.
      Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis.
      • Ginzler E.M.
      • Wax S.
      • Rajeswaran A.
      • et al.
      Atacicept in combination with MMF and corticosteroids in lupus nephritis: results of a prematurely terminated trial.
      • Gourley M.F.
      • Austin 3rd, H.A.
      • Scott D.
      • et al.
      Methylprednisolone and cyclophosphamide, alone or in combination, in patients with lupus nephritis. A randomized, controlled trial.
      • Grootscholten C.
      • Ligtenberg G.
      • Hagen E.C.
      • et al.
      Azathioprine/methylprednisolone versus cyclophosphamide in proliferative lupus nephritis. A randomized controlled trial.
      • Hahn B.H.
      • Kantor O.S.
      • Osterland C.K.
      Azathioprine plus prednisone compared with prednisone alone in the treatment of systemic lupus erythematosus. Report of a prospective controlled trial in 24 patients.
      • Hong R.
      • Haijin Y.
      • Xianglin W.
      • Cuilan H.
      • Nan C.
      A preliminary study of tacrolimus versus cyclophosphamide in patients with diffuse proliferative lupus nephritis.
      • Jayne D.
      • Appel G.
      • Chan T.M.
      • et al.
      A randomized controlled study of laquinimod in active lupus nephritis patients in combination with standard of care.
      • Lewis E.J.
      • Hunsicker L.G.
      • Lan S.P.
      • Rohde R.D.
      • Lachin J.M.
      A controlled trial of plasmapheresis therapy in severe lupus nephritis. The Lupus Nephritis Collaborative Study Group.
      • Li E.K.
      • Tam L.S.
      • Zhu T.Y.
      • et al.
      Is combination rituximab with cyclophosphamide better than rituximab alone in the treatment of lupus nephritis?.
      • Li X.
      • Ren H.
      • Zhang Q.
      • et al.
      Mycophenolate mofetil or tacrolimus compared with intravenous cyclophosphamide in the induction treatment for active lupus nephritis.
      • Liu Z.
      • Zhang H.
      • Xing C.
      • et al.
      Multitarget therapy for induction treatment of lupus nephritis: a randomized trial.
      • Lui S.
      • Cheng I.
      • Tong K.
      • et al.
      Treatment of type IV lupus nephritis (LN) - comparison of 2 triple therapy regimens: cyclosporin A (CSA), prednisolone (PRED), azathioprine (AZA) vs. oral cyclophosphamide (POCP), prednisolone, azathioprine.
      • Rovin B.H.
      • Furie R.
      • Latinis K.
      • et al.
      Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the Lupus Nephritis Assessment with Rituximab study.
      • Houssiau F.A.
      • D'Cruz D.
      • Sangle S.
      • et al.
      Azathioprine versus mycophenolate mofetil for long-term immunosuppression in lupus nephritis: results from the MAINTAIN Nephritis Trial.
      • Mok C.C.
      • Ying K.Y.
      • Yim C.W.
      • et al.
      Tacrolimus versus mycophenolate mofetil for induction therapy of lupus nephritis: a randomised controlled trial and long-term follow-up.
      • Moroni G.
      • Doria A.
      • Mosca M.
      • et al.
      A randomized pilot trial comparing cyclosporine and azathioprine for maintenance therapy in diffuse lupus nephritis over four years.
      • Mulic-Bacic S.
      • Antic D.
      • Krizic M.
      • Hajdarovic A.
      • Mulic E.
      Mycophenolate mofetil or intravenous cyclophosphamide in treatment of lupus nephritis.
      • Nakamura T.
      • Ushiyama C.
      • Hara M.
      • et al.
      Comparative effects of plasmapheresis and intravenous cyclophosphamide on urinary podocyte excretion in patients with proliferative lupus nephritis.
      • Ong L.M.
      • Hooi L.S.
      • Lim T.O.
      • et al.
      Randomized controlled trial of pulse intravenous cyclophosphamide versus mycophenolate mofetil in the induction therapy of proliferative lupus nephritis.
      • Rathi M.
      • Goyal A.
      • Jaryal A.
      • et al.
      Comparison of low-dose intravenous cyclophosphamide with oral mycophenolate mofetil in the treatment of lupus nephritis.
      • Sesso R.
      • Monteiro M.
      • Sato E.
      • et al.
      A controlled trial of pulse cyclophosphamide versus pulse methylprednisolone in severe lupus nephritis.
      • Galbraith L.
      • Manns B.
      • Hemmelgarn B.
      • Walsh M.
      The Steroids In the Maintenance of remission of Proliferative Lupus nephritis (SIMPL) pilot trial.
      • Sun J.
      • Zhang H.
      • Ji Y.
      • et al.
      Efficacy and safety of cyclophosphamide combined with mycophenolate mofetil for induction treatment of class IV lupus nephritis.
      • Wallace D.J.
      • Goldfinger D.
      • Pepkowitz S.H.
      • et al.
      Randomized controlled trial of pulse/synchronization cyclophosphamide/apheresis for proliferative lupus nephritis.
      Participants with active nephritis were randomly allocated to therapy to induce remission in 45 trials (n = 3,623), whereas participants who had previously achieved disease remission were randomly allocated to therapeutic strategies to maintain remission in 8 trials (n = 599; Table S2). Of the included trials, 2 reported outcomes in participants randomly allocated to induction and then subsequently to maintenance therapy in separate trials within a single cohort.
      • Appel G.B.
      • Contreras G.
      • Dooley M.A.
      • et al.
      Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis.
      • Dooley M.A.
      • Jayne D.
      • Ginzler E.M.
      • et al.
      Mycophenolate versus azathioprine as maintenance therapy for lupus nephritis.
      • Chen W.
      • Tang X.
      • Liu Q.
      • et al.
      Short-term outcomes of induction therapy with tacrolimus versus cyclophosphamide for active lupus nephritis: a multicenter randomized clinical trial.
      • Chen W.
      • Liu Q.
      • Chen W.
      • et al.
      Outcomes of maintenance therapy with tacrolimus versus azathioprine for active lupus nephritis: a multicenter randomized clinical trial.
      Figure thumbnail gr1
      Figure 1Summary of evidence search and selection.
      The median number of study participants was 47 (range, 6-378), while the mean age of study participants was 30.2 ± 4.9 (standard deviation; range, 10.2-40.3) years. Induction treatment was continued for a median follow-up of 12 (range, 5.5-84) months, while the median duration of follow-up of maintenance therapy was 24 (range, 6-110) months.
      In the early trials (1972-1984), interventions were oral azathioprine, oral cyclophosphamide, prednisone alone, or plasma exchange. The first trial of IV cyclophosphamide was reported in 1986, and trials evaluating calcineurin inhibitors emerged in 1992. The earliest study assessing MMF appeared in 2005, and rituximab has been evaluated in trials since 2009. From 2012 onward, a range of other immunomodulatory drugs including atacicept, abatacept, laquinimod, sirukumab, and mizoribine have been evaluated as induction therapies. Twenty-one induction therapy trials (905 participants) evaluated IV cyclophosphamide (500-1,000 mg/m2 body surface area monthly),
      • El-Sehemy M.S.
      • Al-Saaran A.M.
      • Baddour N.M.
      • Adam A.G.
      • Moez P.E.
      Comparative clinical prospective therapeutic study between cyclophosphamide, cyclosporine and azathioprine in the treatment of lupus nephritis.
      • Appel G.B.
      • Contreras G.
      • Dooley M.A.
      • et al.
      Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis.
      • Austin 3rd, H.A.
      • Klippel J.H.
      • Balow J.E.
      • et al.
      Therapy of lupus nephritis. Controlled trial of prednisone and cytotoxic drugs.
      • Bao H.
      • Liu Z.H.
      • Xie H.L.
      • et al.
      Successful treatment of class V+IV lupus nephritis with multitarget therapy.
      • Boumpas D.T.
      • Austin H.
      • Vaughn E.M.
      • et al.
      Controlled trial of pulse methylprednisolone versus two regimens of pulse cyclophosphamide in severe lupus nephritis.
      • Chen W.
      • Tang X.
      • Liu Q.
      • et al.
      Short-term outcomes of induction therapy with tacrolimus versus cyclophosphamide for active lupus nephritis: a multicenter randomized clinical trial.
      • Zavada J.
      • Pesickova S.
      • Rysava R.
      • et al.
      Cyclosporine A or intravenous cyclophosphamide for lupus nephritis: the Cyclofa-Lune study.
      • El-Shafey E.M.
      • Abdou S.H.
      • Shareef M.M.
      Is mycophenolate mofetil superior to pulse intravenous cyclophosphamide for induction therapy of proliferative lupus nephritis in Egyptian patients?.
      • Feng X.B.
      • Gu F.
      • Chen W.W.
      • et al.
      Mizoribine versus mycophenolate mofetil or intravenous cyclophosphamide for induction treatment of active lupus nephritis.
      • Ginzler E.M.
      • Wax S.
      • Rajeswaran A.
      • et al.
      Atacicept in combination with MMF and corticosteroids in lupus nephritis: results of a prematurely terminated trial.
      • Gourley M.F.
      • Austin 3rd, H.A.
      • Scott D.
      • et al.
      Methylprednisolone and cyclophosphamide, alone or in combination, in patients with lupus nephritis. A randomized, controlled trial.
      • Grootscholten C.
      • Ligtenberg G.
      • Hagen E.C.
      • et al.
      Azathioprine/methylprednisolone versus cyclophosphamide in proliferative lupus nephritis. A randomized controlled trial.
      • Hong R.
      • Haijin Y.
      • Xianglin W.
      • Cuilan H.
      • Nan C.
      A preliminary study of tacrolimus versus cyclophosphamide in patients with diffuse proliferative lupus nephritis.
      • Li X.
      • Ren H.
      • Zhang Q.
      • et al.
      Mycophenolate mofetil or tacrolimus compared with intravenous cyclophosphamide in the induction treatment for active lupus nephritis.
      • Liu Z.
      • Zhang H.
      • Xing C.
      • et al.
      Multitarget therapy for induction treatment of lupus nephritis: a randomized trial.
      • Mulic-Bacic S.
      • Antic D.
      • Krizic M.
      • Hajdarovic A.
      • Mulic E.
      Mycophenolate mofetil or intravenous cyclophosphamide in treatment of lupus nephritis.
      • Nakamura T.
      • Ushiyama C.
      • Hara M.
      • et al.
      Comparative effects of plasmapheresis and intravenous cyclophosphamide on urinary podocyte excretion in patients with proliferative lupus nephritis.
      • Ong L.M.
      • Hooi L.S.
      • Lim T.O.
      • et al.
      Randomized controlled trial of pulse intravenous cyclophosphamide versus mycophenolate mofetil in the induction therapy of proliferative lupus nephritis.
      • Rathi M.
      • Goyal A.
      • Jaryal A.
      • et al.
      Comparison of low-dose intravenous cyclophosphamide with oral mycophenolate mofetil in the treatment of lupus nephritis.
      • Sesso R.
      • Monteiro M.
      • Sato E.
      • et al.
      A controlled trial of pulse cyclophosphamide versus pulse methylprednisolone in severe lupus nephritis.
      • Sun J.
      • Zhang H.
      • Ji Y.
      • et al.
      Efficacy and safety of cyclophosphamide combined with mycophenolate mofetil for induction treatment of class IV lupus nephritis.
      10 trials (516 participants) evaluated MMF (2,000-3,000 mg daily),
      • Appel G.B.
      • Contreras G.
      • Dooley M.A.
      • et al.
      Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis.
      • Chan T.M.
      • Li F.K.
      • Tang C.S.
      • et al.
      Efficacy of mycophenolate mofetil in patients with diffuse proliferative lupus nephritis. Hong Kong-Guangzhou Nephrology Study Group.
      • El-Shafey E.M.
      • Abdou S.H.
      • Shareef M.M.
      Is mycophenolate mofetil superior to pulse intravenous cyclophosphamide for induction therapy of proliferative lupus nephritis in Egyptian patients?.
      • Feng X.B.
      • Gu F.
      • Chen W.W.
      • et al.
      Mizoribine versus mycophenolate mofetil or intravenous cyclophosphamide for induction treatment of active lupus nephritis.
      • Ginzler E.M.
      • Dooley M.A.
      • Aranow C.
      • et al.
      Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis.
      • Li X.
      • Ren H.
      • Zhang Q.
      • et al.
      Mycophenolate mofetil or tacrolimus compared with intravenous cyclophosphamide in the induction treatment for active lupus nephritis.
      • Mok C.C.
      • Ying K.Y.
      • Yim C.W.
      • et al.
      Tacrolimus versus mycophenolate mofetil for induction therapy of lupus nephritis: a randomised controlled trial and long-term follow-up.
      • Mulic-Bacic S.
      • Antic D.
      • Krizic M.
      • Hajdarovic A.
      • Mulic E.
      Mycophenolate mofetil or intravenous cyclophosphamide in treatment of lupus nephritis.
      • Ong L.M.
      • Hooi L.S.
      • Lim T.O.
      • et al.
      Randomized controlled trial of pulse intravenous cyclophosphamide versus mycophenolate mofetil in the induction therapy of proliferative lupus nephritis.
      • Rathi M.
      • Goyal A.
      • Jaryal A.
      • et al.
      Comparison of low-dose intravenous cyclophosphamide with oral mycophenolate mofetil in the treatment of lupus nephritis.
      6 trials (123 participants) evaluated oral cyclophosphamide (1.5-4 mg/kg daily),
      • Austin 3rd, H.A.
      • Klippel J.H.
      • Balow J.E.
      • et al.
      Therapy of lupus nephritis. Controlled trial of prednisone and cytotoxic drugs.
      • Chan T.M.
      • Li F.K.
      • Tang C.S.
      • et al.
      Efficacy of mycophenolate mofetil in patients with diffuse proliferative lupus nephritis. Hong Kong-Guangzhou Nephrology Study Group.
      • Donadio Jr., J.V.
      • Holley K.E.
      • Ferguson R.H.
      • Ilstrup D.M.
      Treatment of diffuse proliferative lupus nephritis with prednisone and combined prednisone and cyclophosphamide.
      • Dyadyk A.
      • Vasilenko I.
      • Bagriy A.
      • et al.
      Azathioprine and cyclophosphamide in treatment of patients with diffuse proliferative lupus nephritis - a randomized controlled study.
      • Fries J.F.
      • Sharp G.C.
      • McDevitt H.O.
      • Holman H.R.
      Cyclophosphamide therapy in systemic lupus erythematosus and polymyositis.
      • Lui S.
      • Cheng I.
      • Tong K.
      • et al.
      Treatment of type IV lupus nephritis (LN) - comparison of 2 triple therapy regimens: cyclosporin A (CSA), prednisolone (PRED), azathioprine (AZA) vs. oral cyclophosphamide (POCP), prednisolone, azathioprine.
      8 trials (231 participants) evaluated calcineurin inhibitors (cyclosporine, 1-5 mg/kg, daily or tacrolimus, 0.05-0.1 mg/kg, daily),
      • El-Sehemy M.S.
      • Al-Saaran A.M.
      • Baddour N.M.
      • Adam A.G.
      • Moez P.E.
      Comparative clinical prospective therapeutic study between cyclophosphamide, cyclosporine and azathioprine in the treatment of lupus nephritis.
      • Balletta M.
      • Sabella D.
      • Magri P.
      • Sepe V.
      • Stanziale P.
      • Di Luccio R.
      • et al.
      Cyclosporin plus steroids versus steroids alone in the treatment of lupus nephritis.
      • Chen W.
      • Tang X.
      • Liu Q.
      • et al.
      Short-term outcomes of induction therapy with tacrolimus versus cyclophosphamide for active lupus nephritis: a multicenter randomized clinical trial.
      • Zavada J.
      • Pesickova S.
      • Rysava R.
      • et al.
      Cyclosporine A or intravenous cyclophosphamide for lupus nephritis: the Cyclofa-Lune study.
      • Hong R.
      • Haijin Y.
      • Xianglin W.
      • Cuilan H.
      • Nan C.
      A preliminary study of tacrolimus versus cyclophosphamide in patients with diffuse proliferative lupus nephritis.
      • Li X.
      • Ren H.
      • Zhang Q.
      • et al.
      Mycophenolate mofetil or tacrolimus compared with intravenous cyclophosphamide in the induction treatment for active lupus nephritis.
      • Lui S.
      • Cheng I.
      • Tong K.
      • et al.
      Treatment of type IV lupus nephritis (LN) - comparison of 2 triple therapy regimens: cyclosporin A (CSA), prednisolone (PRED), azathioprine (AZA) vs. oral cyclophosphamide (POCP), prednisolone, azathioprine.
      • Mok C.C.
      • Ying K.Y.
      • Yim C.W.
      • et al.
      Tacrolimus versus mycophenolate mofetil for induction therapy of lupus nephritis: a randomised controlled trial and long-term follow-up.
      2 trials (201 participants) evaluated MMF (1,000 mg daily) combined with tacrolimus (4-8 mg daily),
      • Bao H.
      • Liu Z.H.
      • Xie H.L.
      • et al.
      Successful treatment of class V+IV lupus nephritis with multitarget therapy.
      • Liu Z.
      • Zhang H.
      • Xing C.
      • et al.
      Multitarget therapy for induction treatment of lupus nephritis: a randomized trial.
      6 trials (90 participants) evaluated plasma exchange,
      • Clark W.F.
      • Lindsay R.M.
      • Cattran D.C.
      • et al.
      Monthly plasmapheresis for systemic lupus erythematosus with diffuse proliferative glomerulonephritis: a pilot study.
      • Clark W.
      • Williams W.
      • Cattran D.
      • et al.
      A controlled trial of chronic plasma exchange therapy in S.L.E. nephritis.
      • Doria A.
      • Piccoli A.
      • Vesco P.
      • et al.
      Therapy of lupus nephritis. A two-year prospective study.
      • Lewis E.J.
      • Hunsicker L.G.
      • Lan S.P.
      • Rohde R.D.
      • Lachin J.M.
      A controlled trial of plasmapheresis therapy in severe lupus nephritis. The Lupus Nephritis Collaborative Study Group.
      • Nakamura T.
      • Ushiyama C.
      • Hara M.
      • et al.
      Comparative effects of plasmapheresis and intravenous cyclophosphamide on urinary podocyte excretion in patients with proliferative lupus nephritis.
      • Wallace D.J.
      • Goldfinger D.
      • Pepkowitz S.H.
      • et al.
      Randomized controlled trial of pulse/synchronization cyclophosphamide/apheresis for proliferative lupus nephritis.
      1 trial (40 participants) evaluated MMF (1,000 mg daily) combined with IV cyclophosphamide (400 mg/m2/body surface area monthly),
      • Sun J.
      • Zhang H.
      • Ji Y.
      • et al.
      Efficacy and safety of cyclophosphamide combined with mycophenolate mofetil for induction treatment of class IV lupus nephritis.
      and 2 trials (81 participants) evaluated rituximab (commencing at 1,000 mg on days 1 and 15).
      • Li E.K.
      • Tam L.S.
      • Zhu T.Y.
      • et al.
      Is combination rituximab with cyclophosphamide better than rituximab alone in the treatment of lupus nephritis?.
      • Rovin B.H.
      • Furie R.
      • Latinis K.
      • et al.
      Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the Lupus Nephritis Assessment with Rituximab study.

      Risks of Bias

      Risks of bias are shown in Figs S1 and S2. Specifically, 15 (28%) studies were at low risk of bias in generation of the random sequence, whereas 16 (30%) studies were at low risk of bias for allocation concealment. Nine (17%) studies reported blinding of participants and investigators to allocated treatment and 5 (9%) reported blinded outcome assessment. Forty-five (85%) studies were at low risk of incomplete outcome reporting, whereas 31 (58%) were at low risk of selective outcome reporting. Overall, 36 (68%) studies were at low risk of other sources of bias. Risks of bias in treatment estimates for complete remission, all-cause mortality, and end-stage kidney disease proportional to contributions of head-to-head trials to the network estimates are summarized in Fig S3. Funding sources in trials are described in Table S3.

      Exploration of Network Structure, Heterogeneity, and Consistency

      When participant characteristics (age, sex, kidney function, disease definition, and racial origin), interventions (doses and duration), and study design (duration of follow-up) in the included trials were evaluated per treatment class, the trials were deemed sufficiently similar for the key interventions that a network analysis was reasonable (Fig S4). There was evidence of different publication eras for therapies: trials evaluating IV cyclophosphamide, MMF, and calcineurin inhibitors tended to be published more recently than those evaluating corticosteroids alone, oral cyclophosphamide, and azathioprine. Network heterogeneity was frequently very low (heterogeneity τ < 0.001 for most networks) consistent with low statistical power in the networks to detect heterogeneity (figs a-p of Item S2).
      Pairwise and network meta-analysis estimates were similar in magnitude (Tables S4 and S5) and testing did not reveal evidence of inconsistency between direct and indirect treatment effects, although CIs were frequently wide (Table S6). There was no evidence of global inconsistency in any network (Table S7).

      Outcomes

      Overview

      The raw event data for each outcome per trial are shown in Table S8. Trial end points defined by investigators are described in Table S9. Network analysis results are summarized in Tables 1 and 2 and figs a-p of Item S2. GRADE assessments for all-cause mortality, complete remission, and end-stage kidney failure are provided in Table 3. Treatment networks for primary outcomes are shown in Fig 2, and for other outcomes are shown in figures a-c of Item S3.
      Table 1Network Treatment Estimates for Efficacy of Induction Therapies for Disease Remission in Proliferative Lupus Nephritis
      Treatment StrategyComplete Remission
      Odds ratio > 1 favors active drug class.
      All-Cause Mortality
      Odds ratio < 1 favors active drug class. There were insufficient observations to calculate estimated treatment effects from network analysis for rituximab for any efficacy outcome. The heterogeneity tau (τ) values in the network analyses were: complete remission, τ<0.001 (low heterogeneity); all-cause mortality, τ=0.18 (low heterogeneity); end-stage kidney disease, τ<0.001 (low heterogeneity); doubling of Scr level, τ<0.001 (low heterogeneity); and treatment failure, τ<0.001 (low heterogeneity). Extreme low P values for network heterogeneity were consistent with low statistical power in the networks to detect heterogeneity.
      ESKD
      Odds ratio < 1 favors active drug class. There were insufficient observations to calculate estimated treatment effects from network analysis for rituximab for any efficacy outcome. The heterogeneity tau (τ) values in the network analyses were: complete remission, τ<0.001 (low heterogeneity); all-cause mortality, τ=0.18 (low heterogeneity); end-stage kidney disease, τ<0.001 (low heterogeneity); doubling of Scr level, τ<0.001 (low heterogeneity); and treatment failure, τ<0.001 (low heterogeneity). Extreme low P values for network heterogeneity were consistent with low statistical power in the networks to detect heterogeneity.
      Doubling Scr
      Odds ratio < 1 favors active drug class. There were insufficient observations to calculate estimated treatment effects from network analysis for rituximab for any efficacy outcome. The heterogeneity tau (τ) values in the network analyses were: complete remission, τ<0.001 (low heterogeneity); all-cause mortality, τ=0.18 (low heterogeneity); end-stage kidney disease, τ<0.001 (low heterogeneity); doubling of Scr level, τ<0.001 (low heterogeneity); and treatment failure, τ<0.001 (low heterogeneity). Extreme low P values for network heterogeneity were consistent with low statistical power in the networks to detect heterogeneity.
      Treatment Failure
      Odds ratio < 1 favors active drug class. There were insufficient observations to calculate estimated treatment effects from network analysis for rituximab for any efficacy outcome. The heterogeneity tau (τ) values in the network analyses were: complete remission, τ<0.001 (low heterogeneity); all-cause mortality, τ=0.18 (low heterogeneity); end-stage kidney disease, τ<0.001 (low heterogeneity); doubling of Scr level, τ<0.001 (low heterogeneity); and treatment failure, τ<0.001 (low heterogeneity). Extreme low P values for network heterogeneity were consistent with low statistical power in the networks to detect heterogeneity.
      MMF + calcineurin inhibitor2.69 (1.74-4.16)
      Statistically significant.
      1.00 (0.02-52.8)3.02 (0.12-74.5)
      Calcineurin inhibitor1.74 (1.09-2.79)
      Statistically significant.
      0.83 (0.27-2.56)2.08 (0.23-18.9)3.26 (0.25-42.0)0.28 (0.12-0.65)
      Statistically significant.
      IV cyclophosphamide + MMF1.48 (0.62-3.53)0.92 (0.06-15.3)
      MMF1.44 (1.00-2.06)
      Statistically significant.
      1.20 (0.59-2.44)2.60 (0.36-18.7)1.51 (0.12-19.3)0.51 (0.29-0.90)
      Statistically significant.
      Oral cyclophosphamide0.57 (0.23-1.40)2.86 (0.82-10.0)1.34 (0.31-5.88)1.85 (0.48-7.22)1.70 (0.24-12.5)
      Prednisone0.57 (0.23-1.40)2.03 (0.72-5.77)2.40 (1.05-5.48)2.95 (1.45-6.01)
      Statistically significant.
      4.03 (1.30-12.6)
      Statistically significant.
      Mizoribine0.29 (0.08-1.11)
      Azathioprine1.52 (0.52-4.46)1.79 (0.56-5.70)3.39 (1.18-9.71)
      Statistically significant.
      4.15 (0.16-105)
      Plasma exchange8.21 (0.22-304)2.92 (0.31-27.8)
      Rituximab
      No. of studies; no. of participants in network19; 1,86221; 1,69412; 8199; 98410; 753
      Note: Treatment estimates are shown as odds ratio (95% confidence interval) derived from network meta-analysis for all treatments compared with IV cyclophosphamide (reference). Data are shown in order of efficacy surface under the cumulative ranking (SUCRA) curve for induction of complete disease remission.
      Abbreviations: ESKD, end-stage kidney disease; IV, intravenous; MMF, mycophenolate mofetil; Scr, serum creatinine.
      a Odds ratio > 1 favors active drug class.
      b Odds ratio < 1 favors active drug class. There were insufficient observations to calculate estimated treatment effects from network analysis for rituximab for any efficacy outcome. The heterogeneity tau (τ) values in the network analyses were: complete remission, τ < 0.001 (low heterogeneity); all-cause mortality, τ=0.18 (low heterogeneity); end-stage kidney disease, τ < 0.001 (low heterogeneity); doubling of Scr level, τ < 0.001 (low heterogeneity); and treatment failure, τ < 0.001 (low heterogeneity). Extreme low P values for network heterogeneity were consistent with low statistical power in the networks to detect heterogeneity.
      c Statistically significant.
      Table 2Network Treatment Estimates for Adverse Effects of Induction Therapies for Disease Remission in Proliferative Lupus Nephritis
      Drug ClassMajor InfectionAlopeciaOvarian FailureMalignancyNauseaVomitingLeukopeniaHerpes Infection
      Azathioprine0.34 (0.10-1.13)0.44 (0.11-1.80)4.76 (0.61-37.7)0.44 (0.08-2.51)
      Calcineurin inhibitor0.57 (0.28-1.16)0.53 (0.09-3.09)0.31 (0.08-1.11)0.14 (0.02-0.92)
      Statistically significant.
      0.38 (0.11-1.33)0.53 (0.17-1.60)
      Prednisone0.81 (0.34-1.94)0.11 (0.03-0.44)
      Statistically significant.
      0.56 (0.05-6.18)0.52 (0.17-1.60)
      Oral cyclophosphamide1.12 (0.43-2.94)2.32 (0.11-48.4)7.79 (0.70-86.3)7.77 (0.81-74.9)2.06 (0.63-6.66)
      MMF1.23 (0.84-1.77)0.21 (0.12-0.36)
      Statistically significant.
      0.71 (0.20-2.45)0.21 (0.12-0.34)
      Statistically significant.
      0.26 (0.15-0.44)
      Statistically significant.
      0.76 (0.31-1.86)1.70 (0.92-3.15)
      MMF + calcineurin inhibitor3.59 (0.66-19.5)0.54 (0.21-1.40)0.25 (0.07-0.93)
      Statistically significant.
      8.02 (0.82-78.2)0.80 (0.19-3.44)
      IV cyclophosphamide + MMF0.40 (0.11-1.47)1.42 (0.22-9.01)
      Rituximab
      Plasma exchange3.16 (0.12-83.7)
      No. of studies; no. of participants in network20; 1,7058; 1,17114; 1,0963; 2592; 5081; 36411; 91916; 1584
      Note: Treatment estimates are shown as odds ratio (95% confidence interval) derived from network meta-analysis for all treatments compared to IV cyclophosphamide (reference). Odds ratio < 1 favors active drug class. There were insufficient observations to calculate estimated treatment effects from network analysis for rituximab for any adverse outcome. The heterogeneity tau (τ) values in the network analyses were all τ < 0.001 (low heterogeneity, was not estimable for the networks estimating odds of malignancy, nausea, or bone toxicity). There was no evidence of network heterogeneity in the network for bladder toxicity. Extreme low P values for network heterogeneity were consistent with low statistical power in the networks to detect heterogeneity. Data are shown in order of efficacy surface under the cumulative ranking (SUCRA) curve for major infection.
      Abbreviations: IV, intravenous; MMF, mycophenolate mofetil.
      a Statistically significant.
      Table 3Summary of Confidence in Network Treatment Estimates for Complete Disease Remission, All-Cause Mortality, and End-Stage Kidney Disease Associated With Immunosuppression Treatment to Induce Disease Remission in Lupus Nephritis
      Outcome & Treatment StrategyConfidence in EvidenceReasons for Downgrading Confidence in Evidence
      The confidence in the evidence was adjudicated according to GRADE (Grading of Recommendations Assessment, Development and Evaluation) criteria15 based on study limitations (risks of bias including sequence generation, allocation concealment, blinding, attrition from follow-up, selective reporting of outcomes, and other sources of bias), consistency in treatment effects between studies, directness of the evidence to likely clinical setting, evidence of small study effects (smaller studies with systematically different results from larger studies), and precision of the estimate (imprecision was considered to be present when the confidence interval favored either of the compared treatments). Study limitations were calculated as proportional to the risks of bias from the contributions of direct (head-to-head) evidence to each network estimate for complete remission, all-cause mortality, and end-stage kidney disease. The risks of bias proportional to the contributions of head-to-head trials evidence in each network estimate are shown in Fig S3.
      ,
      High confidence in the overall evidence meant that additional studies were not likely to have an impact on our confidence in the treatment effects and moderate confidence in the overall evidence meant that additional studies were likely to have an important impact on our confidence in treatment effects and may change the estimate. Low confidence means that additional studies are very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
      Network Treatment Estimate vs IV Cyclophosphamide
      Values given as odds ratio (95% confidence interval).
      Complete Remission
      MMF + calcineurin inhibitorHigh

      ●●●●
      No downgrades in confidence2.69 (1.74-4.16)
      Statistically significant.
      Calcineurin inhibitorHigh

      ●●●●
      No downgrades in confidence1.74 (1.09-2.79)
      Statistically significant.
      IV cyclophosphamide + MMFLow

      ●●○○
      Downgrade 2 levels in confidence based on study limitations (−1) and imprecision (−1)1.48 (0.62-3.53)
      MMFModerate

      ●●●○
      Downgrade 1 level in confidence based on study limitations (−1)1.44 (1.00-2.06)
      Statistically significant.
      Oral cyclophosphamideLow

      ●●○○
      Downgrade 2 levels in confidence based on study limitations (−1) and imprecision (−1)0.57 (0.23-1.40)
      PrednisoneLow

      ●●○○
      Downgrade 2 levels in confidence based on study limitations (−1) and imprecision (−1)0.57 (0.23-1.40)
      MizoribineVery low

      ●○○○
      Downgrade 3 levels in confidence based on study limitations (−2) and imprecision (−1)0.29 (0.08-1.11)
      All-cause mortality
      MMFModerate

      ●●●○
      Downgrade 1 level in confidence based on imprecision (−1)1.20 (0.59-2.44)
      Oral cyclophosphamideLow

      ●●○○
      Downgrade 2 levels in confidence based on study limitations (−1) and imprecision (−1)2.86 (0.82-10.0)
      Calcineurin inhibitorModerate

      ●●●○
      Downgrade 1 level in confidence based on imprecision (−1)0.83 (0.27-2.56)
      AzathioprineLow

      ●●○○
      Downgrade 2 levels in confidence based on study limitations (−1) and imprecision (−1)1.52 (0.52-4.46)
      MMF + calcineurin inhibitorModerate

      ●●●○
      Downgrade 1 level in confidence based on imprecision (−1)1.00 (0.02-52.8)
      IV cyclophosphamide + MMFModerate

      ●●●○
      Downgrade 1 level in confidence based on imprecision (−1)0.92 (0.06-15.3)
      Plasma exchangeVery low

      ●○○○
      Downgrade 3 levels in confidence based on study limitations (−2) and imprecision8.21 (0.22-304)
      PrednisoneModerate

      ●●●○
      Downgrade 1 level in confidence based on imprecision (−1)2.01 (0.69-5.86)
      End-Stage Kidney Disease
      Oral cyclophosphamideLow

      ●●○○
      Downgrade 2 levels in confidence based on study limitations (−1) and imprecision (−1)1.34 (0.31-5.88)
      AzathioprineVery low

      ●○○○
      Downgrade 3 levels in confidence based on study limitations (−2) and imprecision (−1)1.79 (0.56-5.70)
      Calcineurin inhibitorVery low

      ●○○○
      Downgrade 3 levels in confidence based on study limitations (−2) and imprecision (−1)2.08 (0.23-18.9)
      PrednisoneHigh

      ●●●●
      No downgrades in confidence2.40 (1.05-5.48)
      Statistically significant.
      MMFLow

      ●●○○
      Downgrade 2 levels in confidence based on study limitations (−1) and imprecision (−1)2.60 (0.36-18.7)
      Plasma exchangeLow

      ●●○○
      Downgrade 2 levels in confidence based on study limitations (−1) and imprecision (−1)2.92 (0.31-27.8)
      Abbreviations: IV, intravenous; MMF, mycophenolate mofetil.
      a The confidence in the evidence was adjudicated according to GRADE (Grading of Recommendations Assessment, Development and Evaluation) criteria
      • Salanti G.
      • Del Giovane C.
      • Chaimani A.
      • Caldwell D.M.
      • Higgins J.P.
      Evaluating the quality of evidence from a network meta-analysis.
      based on study limitations (risks of bias including sequence generation, allocation concealment, blinding, attrition from follow-up, selective reporting of outcomes, and other sources of bias), consistency in treatment effects between studies, directness of the evidence to likely clinical setting, evidence of small study effects (smaller studies with systematically different results from larger studies), and precision of the estimate (imprecision was considered to be present when the confidence interval favored either of the compared treatments). Study limitations were calculated as proportional to the risks of bias from the contributions of direct (head-to-head) evidence to each network estimate for complete remission, all-cause mortality, and end-stage kidney disease. The risks of bias proportional to the contributions of head-to-head trials evidence in each network estimate are shown in Fig S3.
      b High confidence in the overall evidence meant that additional studies were not likely to have an impact on our confidence in the treatment effects and moderate confidence in the overall evidence meant that additional studies were likely to have an important impact on our confidence in treatment effects and may change the estimate. Low confidence means that additional studies are very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
      c Values given as odds ratio (95% confidence interval).
      d Statistically significant.
      Figure thumbnail gr2
      Figure 2Graphic representation of treatment comparisons for efficacy and safety of induction immunosuppression treatment for proliferative lupus nephritis. Lines represent trials comparing 2 classes of drug or drugs for (A) complete remission of lupus nephritis, (B) all-cause mortality, and (C) end-stage kidney disease. Numbers on connecting lines represent the number of studies/number of participants in trials directly comparing the two treatments. The nodes indicate the drug treatments assessed in existing trials. The size of the node is proportional to the number of studies evaluating the treatment. For example, the most commonly evaluated treatment for complete remission of lupus nephritis is intravenous cyclophosphamide. Abbreviation: MMF, mycophenolate mofetil.

      Primary Outcomes

      Disease remission

      Compared to IV cyclophosphamide, the most effective treatments to induce remission in moderate- to high-quality evidence were MMF combined with a calcineurin inhibitor, calcineurin inhibitor alone, or MMF alone (ORs of 2.69 [95% CI, 1.74-4.16], 1.74 [95% CI, 1.09-2.79], and 1.44 [95% CI, 1.00-2.06], respectively). The combination of MMF plus calcineurin inhibitor ranked as the best treatment to induce remission (Fig 3).
      Figure thumbnail gr3
      Figure 3Rankings for efficacy and safety of immunosuppression treatment to induce disease remission in lupus nephritis. The graphs display the distribution of probabilities of treatment ranking from best through worst for each outcome. Ranking indicates the probability that drug class is first “best,” second “best,” etc. For example, the ranking suggests that oral cyclophosphamide treatment posed the highest risk for incurring ovarian failure (worst), while prednisone incurred the lowest probability of ovarian failure (best). Mycophenolate mofetil (MMF) and calcineurin inhibitors were among the best treatments for inducing disease remission, while intravenous cyclophosphamide and prednisone alone provided the lowest probability of disease remission (worst).

      All-cause mortality

      There was no evidence of different effects between immunosuppression strategies on all-cause mortality in generally moderate- to low-quality evidence (Table 1), and treatment rankings were uncertain (Fig 3).

      Secondary Outcomes

      End-stage kidney disease and doubling of serum creatinine level

      There was no evidence that MMF or calcineurin inhibitors, alone or in combination, had different effects on end-stage kidney disease or doubling of serum creatinine level compared to IV cyclophosphamide or each other (Table 1; Item S2) in low-quality evidence. Ranking of treatments by efficacy for kidney outcomes was not informative because drug strategies had similar ranking probabilities (Fig 3).

      Treatment failure

      Compared to IV cyclophosphamide, calcineurin inhibitors and MMF had lower risks for treatment failure (ORs of 0.28 [95% CI, 0.12-0.65] and 0.51 [95% CI, 0.29-0.90], respectively) and were ranked the best treatments (Table 1).

      Adverse events

      Compared with calcineurin inhibitors, MMF had higher odds of major infection (OR, 2.16; 95% CI, 1.05-4.44), although neither drug class had significantly different odds of major infection compared to IV cyclophosphamide (Table 2). Compared to IV cyclophosphamide, MMF had lower odds of alopecia (OR, 0.21; 95% CI, 0.12-0.36), whereas the odds with calcineurin inhibitors were not significantly different; calcineurin inhibitors were ranked similarly to MMF.
      Compared to oral cyclophosphamide, IV cyclophosphamide, MMF, and calcineurin inhibitors conferred similarly lower odds of ovarian failure (ORs of 0.13 [95% CI, 0.01-1.42], 0.09 [95% CI, 0.01-0.99], and 0.04 [95% CI, 0.00-0.40], respectively), although the result for IV cyclophosphamide was not significant.
      There was no evidence that MMF, calcineurin inhibitors, or IV cyclophosphamide had significantly different odds of leukopenia and herpes infection (Table 2; Item S2). Compared to IV cyclophosphamide, MMF was more likely to cause diarrhea (OR, 2.70; 95% CI, 1.61-4.53). Compared to IV cyclophosphamide, MMF and calcineurin inhibitor therapy incurred lower odds of nausea (ORs of 0.21 [95% CI, 0.12-0.34] and 0.14 [95% CI, 0.02-0.92], respectively). There was no evidence of different odds of bladder toxicity between oral and IV cyclophosphamide (OR, 0.11; 95% CI, 0.01-2.25]).

      Disease relapse

      When considering maintenance therapy to prevent disease relapse, MMF was superior to azathioprine (OR, 0.57; 95% CI, 0.35-0.93), whereas the treatment effects of calcineurin inhibitors did not differ significantly from MMF (OR, 1.13; 95% CI, 0.35-3.69) and were not significantly better than azathioprine (OR, 0.64; 95% CI, 0.22-1.88; Table 4; Fig 4). Comparative adverse effects of maintenance therapy were not estimated due to the relatively few studies reporting these treatment strategies.
      Table 4Summary Network Estimates of Drug Regimens as Maintenance Treatment on Disease Relapse Compared to Azathioprine
      Drug(s) Comparison for RelapseNetwork Meta-analysis Estimate vs Azathioprine
      MMF0.53 (0.31-0.90)
      Statistically significant.
      Calcineurin inhibitor0.64 (0.22-1.88)
      Azathioprine1.00 (reference)
      IV cyclophosphamide1.68 (0.51-5.51)
      Note: Based on 6 studies (570 participants) in network. Values are given as odds ratio (95% confidence interval) derived from network meta-analysis. Odds ratio < 1 favors active drug class. The heterogeneity tau (τ) value in the network analysis for treatment relapse was τ < 0.001 (low heterogeneity), consistent with the possibility there was insufficient statistical power in the network to detect heterogeneity. Treatment estimates are shown in order of efficacy per the surface under the cumulative ranking (SUCRA) curve.
      Abbreviations: IV, intravenous; MMF, mycophenolate mofetil.
      a Statistically significant.
      Figure thumbnail gr4
      Figure 4Rankings for efficacy of immunosuppression as maintenance therapy to prevent disease relapse in lupus nephritis. Graph displays distribution of probabilities for each outcome. Ranking indicates probability that drug class is first “best,” second best, etc. For example, mycophenolate mofetil (MMF) is among the best for preventing disease relapse during maintenance therapy, while intravenous cyclophosphamide is among the worst.

      Sensitivity Analysis

      Treatment effects were imprecise in sensitivity analyses restricted to trials with follow-up of 24 months or longer and in trials in which allocation was adequately concealed (Table S10). There were insufficient observations to perform reliable metaregression analyses accounting for year of publication, race or ethnicity, outcome definition, or age.

      Discussion

      Considering benefits and harms of therapy, this network meta-analysis indicated that when added to corticosteroids, MMF or calcineurin inhibitors or their combination were superior to IV cyclophosphamide for inducing remission. However, despite 53 trials, the longer term effects of immunosuppression on risks for mortality or end-stage kidney disease remain uncertain, in part due to the relative rarity of these events and the short duration of existing studies. Compared to IV cyclophosphamide, MMF incurred lower risks for alopecia, nausea, and vomiting, whereas calcineurin inhibitors incurred lower risks for nausea. Combined MMF and calcineurin inhibitor therapy had considerably lower average odds of ovarian failure than IV cyclophosphamide, but this did not reach statistical significance for either therapy alone. MMF was the best treatment to maintain disease remission and was superior to azathioprine.
      Based on these results and weighing the balance of benefits and harms, no treatment approach demonstrably lowers long-term risks for end-stage kidney failure or death. Based on surrogate outcomes, MMF with or without calcineurin inhibitor treatment would be a reasonable first-line agent for inducing and maintaining complete remission in patients with proliferative lupus nephritis. However, patients should be made aware of the lack of long-term data for treatment effects on kidney function and longer term toxicity.
      The finding that MMF and calcineurin inhibitors alone or in combination have a higher probability of inducing remission than IV cyclophosphamide contrasts with a 2012 updated Cochrane review that found no differences between these 2 treatments for complete remission of proteinuria,
      • Henderson L.
      • Masson P.
      • Craig J.C.
      • et al.
      Treatment for lupus nephritis.
      although it concluded that there was similar uncertainty, as observed in the current analysis for treatment odds of death and kidney function. Similarly, a 2009 meta-analysis observed similar efficacy between MMF and IV cyclophosphamide for inducing kidney disease remission, with comparable risks for death and end-stage kidney disease.
      • Mak A.
      • Cheak A.A.
      • Tan J.Y.
      • et al.
      Mycophenolate mofetil is as efficacious as, but safer than, cyclophosphamide in the treatment of proliferative lupus nephritis: a meta-analysis and meta-regression.
      A Bayesian network meta-analysis published in 2014 concluded that there was insufficient evidence to determine whether mycophenolate or tacrolimus was superior to cyclophosphamide for inducing proteinuric remission or normal serum creatinine levels at 6 months.
      • Tian S.Y.
      • Feldman B.M.
      • Beyene J.
      • et al.
      Immunosuppressive therapies for the induction treatment of proliferative lupus nephritis: a systematic review and network metaanalysis.
      A network analysis involving 9 trials in 972 patients concluded that tacrolimus was superior to cyclophosphamide for inducing complete or partial disease remission, whereas MMF was comparable to cyclophosphamide treatment.
      • Lee Y.H.
      • Song G.G.
      Relative efficacy and safety of tacrolimus, mycophenolate mofetil, and cyclophosphamide as induction therapy for lupus nephritis: a Bayesian network meta-analysis of randomized controlled trials.
      The different conclusions drawn by these meta-analyses and the present study are likely due to the larger amount of information available in the present review to permit more precise inferences about competing treatments for lupus nephritis.
      The findings of this network meta-analysis were consistent with those of a recent randomized trial comparing combined tacrolimus and MMF therapy versus IV cyclophosphamide in biopsy-proven lupus nephritis, which showed that patients who received combined therapy had a higher probability of complete or partial disease remission at 6 months (hazard ratio [HR], 1.72; 95% CI, 1.34-2.21), although there were more serious adverse events and greater withdrawal with tacrolimus plus MMF therapy, driven primarily by infection-related events.
      • Liu Z.
      • Zhang H.
      • Xing C.
      • et al.
      Multitarget therapy for induction treatment of lupus nephritis: a randomized trial.
      This raises the possibility that dual therapy might incur greater toxicity than each individual treatment class alone. Although there have been no previous head-to-head trials of dual versus monotherapy, when the 2 trials
      • Bao H.
      • Liu Z.H.
      • Xie H.L.
      • et al.
      Successful treatment of class V+IV lupus nephritis with multitarget therapy.
      • Liu Z.
      • Zhang H.
      • Xing C.
      • et al.
      Multitarget therapy for induction treatment of lupus nephritis: a randomized trial.
      evaluating combined MMF plus tacrolimus versus cyclophosphamide as induction therapy were included in the network for complete remission in this meta-analysis, dual MMF plus tacrolimus therapy was significantly better than MMF alone (OR,1.87; 95% CI, 1.06-3.29) but was not superior to tacrolimus alone (OR, 1.54; 95% CI, 0.81-2.94). Based on these promising results and to test the balance of benefits and harms of dual therapy further, a trial comparing tacrolimus monotherapy against combined MMF plus tacrolimus might be considered a priority, including careful documentation of long-term patient-centered treatment efficacy and harms.
      The findings of this network analysis were consistent with a 2015 study evaluating comparative effects of cyclophosphamide, azathioprine, MMF, and prednisone alone on maintenance of disease remission in lupus nephritis.
      • Tian S.Y.
      • Feldman B.M.
      • Beyene J.
      • et al.
      Immunosuppressive therapies for the maintenance treatment of proliferative lupus nephritis: a systematic review and network metaanalysis.
      In that meta-analysis, MMF was ranked as the best therapy for preventing kidney failure during maintenance treatment, although due to a small number of events, the estimated treatment effects were very imprecise. The similar findings between that previous review and the present study despite differing statistical approaches and end points strengthen the conclusions of both studies that MMF might be the best treatment for maintaining remission of lupus nephritis.
      Although the strengths of this systematic review included a comprehensive literature search without language or date restriction, evaluation of the assumptions of consistency among included trials before generating treatment estimates, and including standardized approaches to assess the confidence that might be held in the results, the meta-analysis has limitations that might be considered. First, the analysis was limited by the data in the primary trials and the methods of reporting data. For example, complete remission was a heterogeneous outcome with variable definitions in existing studies. Notwithstanding the differences in end point definitions among trials, there was evidence of low heterogeneity in the pooled analysis, indicating that a network meta-analysis was appropriate, although the statistical power within networks to detect heterogeneity was likely to be low. Second, there were few deaths (n = 235) and patients progressing to end-stage kidney disease (n = 164) during trial follow-up. Nearly 40% of studies did not report clinically relevant outcomes, especially end-stage kidney failure, because these were only likely to have accrued over several years of treatment and specific outcomes for trials have not been mandated. This has led to considerable uncertainty in treatment effects on these patient-relevant outcomes and has resulted in an inability of patients and clinicians to weigh the relative balance of benefits and harms of treatments. It remains uncertain whether biochemical remission of disease based on proteinuria and/or serum creatinine level is a valid predictor of end-stage kidney disease because existing trials generally do not follow up patients long enough. Similarly, there was insufficient precision in treatment effects on doubling of serum creatinine level, although azathioprine or corticosteroids alone were clearly inferior to IV cyclophosphamide. Third, although treatment classes were derived from similar study populations (age, sex, and serum creatinine level), there were secular trends in the publication era for differing treatments. As expected, azathioprine, oral cyclophosphamide, and prednisone alone were principally evaluated in earlier decades, whereas IV cyclophosphamide, MMF, and calcineurin inhibitors were assessed in more recent trials. Although this difference might threaten the assumed consistency required to generate a single analytical network and confound treatment comparisons due to differing epidemiologic patterns of disease and treatments over time, notably there was low heterogeneity observed in networks for the primary outcomes, and the key treatment comparisons (cyclophosphamide, MMF, and calcineurin inhibitors) were drawn from trials published more recently. Fourth, different outcomes and responses to treatment were observed among people of different racial origins in lupus nephritis, and therefore it might be hypothesized that treatment effects might be different based on ethnicity. However, there were insufficient data for race or ethnicity in the original trial reports to perform metaregression analyses to explore this possibility. Fifth, we did not include trials with zero events. This approach may have resulted in effect estimates moving toward the null, although for all clinical efficacy end points including mortality and end-stage kidney disease, this approach likely overestimated the magnitude of effect. Finally, the inconsistent end point definitions and imprecision in treatment estimates for mortality and end-stage kidney disease have implications for future trial design. In future studies, longer term end points and larger study populations might be achieved through more efficient study design (eg, registry-based randomized trials
      • Frobert O.
      • Lagerqvist B.
      • Olivecrona G.K.
      • et al.
      Thrombus aspiration during ST-segment elevation myocardial infarction.
      ) in which important patient-centered outcomes such as death and end-stage kidney disease are captured automatically during long-term routine follow-up within registry databases. Standardization of both safety and short- and long-term efficacy outcomes in trials evaluating therapies for lupus nephritis, as has been generated in rheumatology, might facilitate better understanding about the benefits and harms of therapy.
      • Tugwell P.
      • Boers M.
      • Brooks P.
      • et al.
      OMERACT: an international initiative to improve outcome measurement in rheumatology.
      Based on the potential benefits of calcineurin inhibitors and MMF on short-term outcomes in this analysis, future head-to-head trials comparing the benefits and harms of these treatments alone or in combination might be prioritized.
      In conclusion, evidence for induction therapy for lupus nephritis is inconclusive based on treatment effects on all-cause mortality, doubling of serum creatinine level, and end-stage kidney disease. Compared to IV cyclophosphamide, the most effective therapies for inducing remission were MMF, calcineurin inhibitors, or their combination while conferring similar or lower treatment toxicity. The most effective maintenance therapy was MMF.

      Acknowledgements

      Support: There were no specific funders of this study. Dr Palmer is supported by a Rutherford Discovery Fellowship. Mr Tunnicliffe is funded by a postgraduate scholarship from the Sydney Medical School, The University of Sydney. Dr Mavridis is supported by the European Research Council ( IMMA 260559 ). Dr Tonelli received funding from Alberta Innovates Health Solutions.
      Financial Disclosure: Dr Palmer received a research grant from the Royal Society of New Zealand during the study and has received research funding from Amgen Dompé. Dr Johnson has received consultancy fees from Baxter, Fresenius, Gambro, Amgen, Janssen-Cilag, Roche, Genzyme, Shire, Sigma, Sanofi-Aventis, Boehringer-Ingelheim, Lilley, Merck Sharpe & Dohme, Bristol-Myers Squibb, and Novartis; speaker’s honoraria from Baxter, Fresenius, Gambro, Amgen, Janssen-Cilag, Roche, Servier, Shire, Merck Sharpe & Dohme, Boehringer-Ingelheim, and Bristol Myers Squibb; research grants from Baxter Extramural, Fresenius, Roche Foundation for Anaemia Research (RoFar), Amgen, Janssen-Cilaz, Pfizer, and Abbott; and travel sponsorships from Baxter, Fresenius, Gambro, Amgen, Janssen-Cilag, Roche, and Shire. Dr Tonelli has received honoraria for a lecture series on management of dyslipidemia of chronic kidney disease from Merck; all honoraria were donated to charity. Dr Strippoli received a research grant from Agenzia Italiana del Farmaco during the study and has received personal fees for consultancy from Servier Laboratories.
      Contributions: Research idea and study design: SCP, GFMS; data acquisition: DJT, SCP; data interpretation: DJT, DS-G, DM, MT, DWJ, JCC, AT, GFMS; statistical analysis: SCP; supervision or mentorship: DM, GFMS.Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved. GFMS takes responsibility that this study has been reported honestly, accurately, and transparently; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained.
      Peer Review: Evaluated by 2 external peer reviewers, a Statistical Editor, a Co-Editor, and Editor-in-Chief Levey.

      Supplementary Material

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