induction and maintenance immunosuppression treatment of proliferative lupus nephritis a network meta analysis of randomized trials

Original Investigation Induction and Maintenance Immunosuppression Treatment of Proliferative Lupus Nephritis: A Network Meta-analysis of Randomized Trials Suetonia C Palmer, MBChB, PhD,1,* David J Tunnicliffe, MIPH,2,3,* Davinder Singh-Grewal, MBBS, PhD,4,5 Dimitris Mavridis, PhD,6,7 Marcello Tonelli, MD,8 David W Johnson, MBBS (Hons), PhD,9,10 Jonathan C Craig, MBChB, PhD,2,3 Allison Tong, PhD,2,3 and Giovanni F.M Strippoli, MD, PhD 2,11,12 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 moderateto 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 Am J Kidney Dis -(-): - ª 2017 The Authors Published by Elsevier Inc on behalf of the National Kidney Foundation, Inc This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/) INDEX WORDS: Lupus nephritis; immunosuppression; remission; induction therapy; maintenance therapy; mycophenolate mofetil (MMF); intravenous cyclophosphamide; calcineurin inhibitor; end-stage kidney disease (ESKD); dialysis; renal failure; toxicity; adverse events; meta-analysis From the 1Department of Medicine, University of Otago Christchurch, Christchurch, New Zealand; 2Sydney School of Public Health, University of Sydney, Sydney, NSW, Australia; 3Centre for Kidney Research, The Children’s Hospital at Westmead, Westmead, NSW, Australia; 4School of Paediatrics and Child Health, The University of Sydney, Sydney, NSW, Australia; 5Department of Rheumatology, The Sydney Children’s Hospitals Network Westmead and Randwick, NSW, Australia; 6Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece; Department of Primary Education, University of Ioannina, Ioannina, Greece; 8Cumming School of Medicine, University of Calgary, Calgary, Canada; 9Division of Medicine, Department of Nephrology, University of Queensland at the Princess Alexandra Hospital, Brisbane, QLD, Australia; 10Translational Research Institute, Brisbane, QLD, Australia; 11Diaverum Medical Scientific Office and Diaverum Am J Kidney Dis 2017;-(-): - Academy, Lund, Sweden; and 12Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy * S.C.P and D.J.T contributed equally to this work Received May 16, 2016 Accepted in revised form December 1, 2016 Address correspondence to Giovanni Strippoli, MD, PhD, Department of Emergency and Organ Transplantation, University of Bari, Piazza Giulio Cesare, 70124 Bari, Italy E-mail: gfmstrippoli@gmail.com Ó 2017 The Authors Published by Elsevier Inc on behalf of the National Kidney Foundation, Inc This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/) 0272-6386 http://dx.doi.org/10.1053/j.ajkd.2016.12.008 Palmer et al S ystemic lupus erythematosus principally affects women of child-bearing age Kidney involvement affects 20% to 75% of patients in the first 10 years.1 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.2 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.3,4 However, standard pairwise metaanalysis is only able to compare 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 studies5,6 or reporting of drug harms only.7 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.8 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.3 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 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 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.9 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.10 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 c2 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.11 Finally, using a frequentist framework, random-effects network meta-analysis was used to compare all classes of immunosuppression for each prespecified outcome.10,12 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 [s]), 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.13 To explore for network inconsistency, a loopspecific 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.14 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 Am J Kidney Dis 2017;-(-): - Immunosuppression for Lupus Nephritis 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.15 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 command16 and selfprogrammed Stata routines.17 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 review3 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).18-70 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 trials (n 599; Table S2) Of the included trials, reported outcomes in participants randomly allocated to induction and then subsequently to maintenance therapy in separate trials within a single cohort.21,22,32,33 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),19,21,23,25,29,32,37,42,43,48-50,52,56,57,63-67,69 10 trials (516 participants) evaluated MMF (2,0003,000 mg daily),21,31,42,43,47,56,61,63,65,66 trials (123 participants) evaluated oral cyclophosphamide (1.54 mg/kg daily),23,31,39,41,44,58 trials (231 participants) evaluated calcineurin inhibitors (cyclosporine, Unique records identified through updated database searching of MEDLINE, Embase and Cochrane databases through July 20, 2016 (n = 416) Duplicate records from previous Cochrane review excluded (n = 5) Records evaluated in title and abstract (n = 411) Records excluded on title and abstract (n=360) Not people with lupus nephritis Not immunosuppression therapy Not randomized controlled trial Records evaluated in full text detail (n = 51) Records excluded on full text analysis (n=11) Not people with lupus nephritis Not immunosuppression therapy Not randomized controlled trial Ongoing study (n=1) (n=2) (n=6) (n=2) Randomized trials included in updated review (n=15 studies in 40 publications) (n=226) (n=24) (n=110) Records identified through existing Cochrane review current to April 2012 (n=50 studies in 168 publications) Records excluded as ineligible for network meta-analysis (n=22) Not comparing two different drug classes (n=20) Full study publication identified in search update (n=2) Randomized trials obtained from Cochrane review (n=38 studies in 146 publications) 53 unique randomized trials in 186 publications included in network meta-analysis (involving 4,222 adults, adolescents, and children) Induction therapy n=45 studies (3623 adults and children) Maintenance therapy n=8 studies (599 adults and children) Figure Summary of evidence search and selection Am J Kidney Dis 2017;-(-): - Palmer et al 1-5 mg/kg, daily or tacrolimus, 0.05-0.1 mg/kg, daily),19,24,32,37,52,56,58,61 trials (201 participants) evaluated MMF (1,000 mg daily) combined with tacrolimus (4-8 mg daily),25,57 trials (90 participants) evaluated plasma exchange,34,35,40,54,64,70 trial (40 participants) evaluated MMF (1,000 mg daily) combined with IV cyclophosphamide (400 mg/ m2/body surface area monthly),69 and trials (81 participants) evaluated rituximab (commencing at 1,000 mg on days and 15).55,59 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 (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 s , 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 Table Network Treatment Estimates for Efficacy of Induction Therapies for Disease Remission in Proliferative Lupus Nephritis Treatment Strategy MMF calcineurin inhibitor Calcineurin inhibitor IV cyclophosphamide MMF MMF Oral cyclophosphamide Prednisone Mizoribine Azathioprine Plasma exchange Rituximab No of studies; no of participants in network Complete Remissiona 2.69 1.74 1.48 1.44 0.57 0.57 0.29 (1.74-4.16)c (1.09-2.79)c (0.62-3.53) (1.00-2.06)c (0.23-1.40) (0.23-1.40) (0.08-1.11) All-Cause Mortality b 1.00 0.83 0.92 1.20 2.86 2.03 ESKD b — Doubling Scr b Treatment Failure b — (0.02-52.8) (0.27-2.56) (0.06-15.3) (0.59-2.44) (0.82-10.0) (0.72-5.77) 2.08 (0.23-18.9) 3.02 (0.12-74.5) 3.26 (0.25-42.0) 0.28 (0.12-0.65)c 2.60 (0.36-18.7) 1.34 (0.31-5.88) 2.40 (1.05-5.48) 1.51 (0.12-19.3) 1.85 (0.48-7.22) 2.95 (1.45-6.01)c 0.51 (0.29-0.90)c 1.70 (0.24-12.5) 4.03 (1.30-12.6)c — — — 1.52 (0.52-4.46) 8.21 (0.22-304) 1.79 (0.56-5.70) 2.92 (0.31-27.8) 3.39 (1.18-9.71)c — — — 4.15 (0.16-105) 19; 1,862 21; 1,694 12; 819 9; 984 — — — — — — — — — — 10; 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 favors active drug class b Odds ratio , 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 (s) values in the network analyses were: complete remission, s , 0.001 (low heterogeneity); all-cause mortality, s50.18 (low heterogeneity); end-stage kidney disease, s , 0.001 (low heterogeneity); doubling of Scr level, s , 0.001 (low heterogeneity); and treatment failure, s , 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 Am J Kidney Dis 2017;-(-): - 2; 508 3; 259 14; 1,096 8; 1,171 20; 1,705 — — — Am J Kidney Dis 2017;-(-): - 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 , 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 (s) values in the network analyses were all s , 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 3.16 (0.12-83.7) 16; 1584 11; 919 — — — — — — — — — — — — — 2.32 (0.11-48.4) 0.21 (0.12-0.36)a 0.54 (0.21-1.40) — 1; 364 — — (0.08-2.51) (0.17-1.60) (0.17-1.60) (0.63-6.66) (0.92-3.15) (0.19-3.44) — 0.44 0.38 (0.11-1.33) 0.53 — 0.52 2.06 0.76 (0.31-1.86) 1.70 8.02 (0.82-78.2) 0.80 1.42 (0.22-9.01) (0.11-1.80) 4.76 (0.61-37.7) — — (0.08-1.11) — 0.14 (0.02-0.92)a — (0.03-0.44)a 0.56 (0.05-6.18) — — — — (0.70-86.3) 7.77 (0.81-74.9) (0.20-2.45) — 0.21 (0.12-0.34)a 0.26 (0.15-0.44)a (0.07-0.93)a — — — (0.11-1.47) — — — 0.44 0.31 0.11 7.79 0.71 0.25 0.40 — 0.53 (0.09-3.09) (0.10-1.13) (0.28-1.16) (0.34-1.94) (0.43-2.94) (0.84-1.77) (0.66-19.5) 0.34 0.57 0.81 1.12 1.23 3.59 Azathioprine Calcineurin inhibitor Prednisone Oral cyclophosphamide MMF MMF calcineurin inhibitor IV cyclophosphamide MMF Rituximab Plasma exchange No of studies; no of participants in network Leukopenia Vomiting Nausea Malignancy Ovarian Failure Alopecia Major Infection Drug Class Table Network Treatment Estimates for Adverse Effects of Induction Therapies for Disease Remission in Proliferative Lupus Nephritis Herpes Infection Immunosuppression for Lupus Nephritis investigators are described in Table S9 Network analysis results are summarized in Tables and and figs a-p of Item S2 GRADE assessments for all-cause mortality, complete remission, and end-stage kidney failure are provided in Table Treatment networks for primary outcomes are shown in Fig 2, and for other outcomes are shown in figures a-c of Item S3 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) 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 Palmer et al Table Summary of Confidence in Network Treatment Estimates for Complete Disease Remission, All-Cause Mortality, and EndStage Kidney Disease Associated With Immunosuppression Treatment to Induce Disease Remission in Lupus Nephritis Outcome & Treatment Strategy Complete Remission MMF calcineurin inhibitor Confidence in Evidence High CCCC Calcineurin inhibitor High CCCC IV cyclophosphamide MMF Low CCBB MMF Moderate CCCB Oral cyclophosphamide Low CCBB Prednisone Low CCBB Mizoribine Very low CBBB All-cause mortality MMF Moderate CCCB Oral cyclophosphamide Low CCBB Calcineurin inhibitor Moderate CCCB Azathioprine Low CCBB MMF calcineurin inhibitor Moderate CCCB IV cyclophosphamide MMF Moderate CCCB Plasma exchange Very low CBBB Prednisone Moderate CCCB End-Stage Kidney Disease Oral cyclophosphamide Low CCBB Azathioprine Very low CBBB Calcineurin inhibitor Very low CBBB Prednisone High CCCC MMF Low CCBB Plasma exchange Low CCBB Network Treatment Estimate vs IV Cyclophosphamidec Reasons for Downgrading Confidence in Evidencea,b No downgrades in confidence 2.69 (1.74-4.16)d No downgrades in confidence 1.74 (1.09-2.79)d Downgrade levels in confidence based on study limitations (21) and imprecision (21) Downgrade level in confidence based on study limitations (21) Downgrade levels in confidence based on study limitations (21) and imprecision (21) Downgrade levels in confidence based on study limitations (21) and imprecision (21) Downgrade levels in confidence based on study limitations (22) and imprecision (21) 1.48 (0.62-3.53) Downgrade level in confidence based on imprecision (21) Downgrade levels in confidence based on study limitations (21) and imprecision (21) Downgrade level in confidence based on imprecision (21) Downgrade levels in confidence based on study limitations (21) and imprecision (21) Downgrade level in confidence based on imprecision (21) Downgrade level in confidence based on imprecision (21) Downgrade levels in confidence based on study limitations (22) and imprecision Downgrade level in confidence based on imprecision (21) 1.20 (0.59-2.44) Downgrade levels in confidence based on study limitations (21) and imprecision (21) Downgrade levels in confidence based on study limitations (22) and imprecision (21) Downgrade levels in confidence based on study limitations (22) and imprecision (21) No downgrades in confidence 1.34 (0.31-5.88) Downgrade levels in confidence based on study limitations (21) and imprecision (21) Downgrade levels in confidence based on study limitations (21) and imprecision (21) 1.44 (1.00-2.06)d 0.57 (0.23-1.40) 0.57 (0.23-1.40) 0.29 (0.08-1.11) 2.86 (0.82-10.0) 0.83 (0.27-2.56) 1.52 (0.52-4.46) 1.00 (0.02-52.8) 0.92 (0.06-15.3) 8.21 (0.22-304) 2.01 (0.69-5.86) 1.79 (0.56-5.70) 2.08 (0.23-18.9) 2.40 (1.05-5.48)d 2.60 (0.36-18.7) 2.92 (0.31-27.8) Abbreviations: IV, intravenous; MMF, mycophenolate mofetil 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 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 a Am J Kidney Dis 2017;-(-): - Immunosuppression for Lupus Nephritis A Complete disease remission MMF Prednisone Oral cyclophosphamide Calcineurin inhibitor 1/55 Intravenous cyclophosphamide 1/60 MMF + calcineurin inhibitor IV cyclophosphamide + MMF Oral cyclophosphamide + prednisone Mizoribine B All-cause mortality Oral cyclophosphamide MMF Intravenous cyclophosphamide Plasma exchange Standard therapy Prednisone Calcineurin inhibitor Azathioprine 1/50 IV cyclophosphamide + MMF 1/55 Oral cyclophosphamide + azathioprine MMF + calcineurin inhibitor Oral cyclophosphamide + prednisone 1/26 Azathioprine + prednisone Azathioprine + heparin Oral cyclophosphamide Plasma exchange 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 C End-stage kidney disease MMF 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 Sensitivity Analysis Intravenous cyclophosphamide 2/91 2/104 Standard therapy Prednisone 2/75 Azathioprine Oral cyclophosphamide + prednisone Calcineurin inhibitors Oral cyclophosphamide + azathioprine Azathioprine + prednisone Azathioprine + heparin Figure Graphic representation of treatment comparisons for efficacy and safety of induction immunosuppression treatment for proliferative lupus nephritis Lines represent trials comparing 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 Am J Kidney Dis 2017;-(-): - 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 Palmer et al Efficacy Intravenous cyclophosphamide B Oral cyclophosphamide MMF Oral cyclophosphamide 0 Worst Best Worst Calcineurin inhibitor Best Worst Prednisone Best Worst Best Best Worst Calcineurin inhibitor Azathioprine Worst Prednisone 0 50 50 Azathioprine 100 100 Best Best Worst MMF + calcineurin inhibitor Best Worst Intravenous cyclophosphamide + MMF Worst Plasma exchange Best Worst Best MMF + calcineurin inhibitor Worst Intravenous cyclophosphamide + MMF 0 Best Best 100 Worst Plasma exchange 50 100 Best 50 Probability (%) Intravenous cyclophosphamide 50 50 MMF Major infection Alopecia Ovarian failure Adverse effects 100 100 A Complete disease remission All-cause mortality End-stage kidney disease Worst Best Worst Best Worst Best Worst Best Worst Best Worst Figure Rankings 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) contrasts with a 2012 updated Cochrane review that found no differences between these treatments for complete remission of proteinuria,3 although it Intravenous cyclophosphamide 100 MMF MMF Calcineurin inhibitor Azathioprine IV cyclophosphamide 0.53 0.64 1.00 1.68 (0.31-0.90)a (0.22-1.88) (reference) (0.51-5.51) Note: Based on studies (570 participants) in network Values are given as odds ratio (95% confidence interval) derived from network meta-analysis Odds ratio , favors active drug class The heterogeneity tau (s) value in the network analysis for treatment relapse was s , 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 Calcineurin inhibitor Best Worst Azathioprine 100 Network Meta-analysis Estimate vs Azathioprine Worst 50 Drug(s) Comparison for Relapse Best Table Summary Network Estimates of Drug Regimens as Maintenance Treatment on Disease Relapse Compared to Azathioprine Probability of relapse (%) 50 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 Best Worst Best Worst Figure Rankings 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 Am J Kidney Dis 2017;-(-): - Immunosuppression for Lupus Nephritis concluded that there was similar uncertainty, as observed in the current analysis for treatment odds of death and kidney function Similarly, a 2009 metaanalysis observed similar efficacy between MMF and IV cyclophosphamide for inducing kidney disease remission, with comparable risks for death and end-stage kidney disease.4 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 months.5 A network analysis involving 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.6 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 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.57 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 trials25,57 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.71 In that meta-analysis, MMF was ranked as the best therapy for preventing kidney Am J Kidney Dis 2017;-(-): - 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 endstage 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 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 Palmer et al 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 trials72) 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.73 Based on the potential benefits of calcineurin inhibitors and MMF on shortterm 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 10 received research funding from Amgen Dompé Dr Johnson has received consultancy fees from Baxter, Fresenius, Gambro, Amgen, Janssen-Cilag, Roche, Genzyme, Shire, Sigma, SanofiAventis, 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, JanssenCilag, 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 external peer reviewers, a Statistical Editor, a Co-Editor, and Editor-in-Chief Levey SUPPLEMENTARY MATERIAL Table S1: Characteristics of included studies Table S2: Description of randomized treatment strategies for induction or maintenance of remission and nonrandomized treatment to maintain remission Table S3: Funding sources in included trials Table S4: Pairwise and network estimates of efficacy end points associated with immunosuppression for induction treatment of proliferative lupus nephritis Table S5: Summary pairwise and network estimates of safety end points associated with immunosuppression for induction treatment of proliferative lupus nephritis Table S6: Evaluation of loop-specific consistency in triangular and quadrilateral treatment loops for each binary outcome network Table S7: Evidence of global heterogeneity within analyses Table S8: Summary raw data for duration of follow up, no of events, and no of participants at risk for each outcome reported in network Table S9: Definitions of primary and secondary end points in trials Table S10: Pre-specified sensitivity analyses for primary outcome of complete disease remission Figure S1: Risk of bias summary: judgments about each bias item for each study Figure S2: Risk of bias summary graph Figure S3: Study limitations for each network estimate for immunosuppressive strategies vs IV cyclophosphamide Figure S4: Summary study-level characteristics according to drug class Item S1: Study protocol Item S2: Network treatment estimates Item S3: Networks of treatment comparisons for other outcomes Am J Kidney Dis 2017;-(-): - Immunosuppression for Lupus Nephritis Note: The supplementary material accompanying this article (http://dx.doi.org/10.1053/j.ajkd.2016.12.008) is available at 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Relative efficacy and safety of tacrolimus, mycophenolate mofetil, and cyclophosphamide as induction therapy for lupus nephritis: a Bayesian network metaanalysis of randomized controlled trials Lupus. .. 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... Mycophenolate mofetil is as efficacious as, but safer than, cyclophosphamide in the treatment of proliferative lupus nephritis: a meta- analysis and metaregression Rheumatology 2009;48(8):944-952 Tian