Leflunomide Combined With Mycophenolate Mofetil For Lupus Nephritis: A Systematic Review

Objective.To evaluate the efficacy and safety of the combination of mycophenolate mofetil(MMF)and leflunomide(LEF)in the treatment of lupus nephritis(LN).Methods.A systematic literature search was performed,using Pubmed,Cochrane Library,Embase,CINAHL,CBM,CNKI,Weipu database,Wangfang database(up to Nov,2016),to search randomized controlled trials(RCT)about the combination of MMF and LEF for LN.All the patients fulfilled the 1997 or 2009 American College of Rheumatology SLE classification criteria,and they had evidence of renal involvement and / or biopsy proved LN.The primary outcomes were the complete response rate(CR),partial response rate(PR),total response rate(TR)The secondary outcomes were systemic lupus erythematosus disease activity index(SLEDAI),24-hour urine protein quantity and the level of serum C3 and C4.Two reviewers independently identified literature,extracted data,assessed risk of bias of included studies.Meta-analysis was then conducted using RevMan 5.3 software.Results.Six RCTs met the inclusion criteria.3 RCTs compared the combination of LEF(10-20 mg PO,qd)and MMF(500mg-2000 mg PO,qd)with CTX(0.8-1.0 g IV drip twice/once a month).The other 3 RCTs compared the combination of LEF(10-50 mg oral qd)and MMF(500mg-1500 mg PO,qd)with MMF monotherapy.All the included RCTs showed high risk of bias.3 RCTs(n=234)compared the combination of MMF and LEF with CTX monotherapy for active LN patients.The results showed that the combination of LEF and MMF was superior to CTX in CR and TR.The RRs were1.81(1.32,2.48)and 1.28(1.11,1.48),respectively.Moreover,the combination therapy group were advantageous in reducing SLEDAI,24-hour urine protein and increasing the levels of C4.The MDs were-1.78(-3.19,-0.37),-0.31(-0.61,-0.00)g/24 h and 0.07(0.02,0.11)g/L,respectively.No difference was found in adverse events,toxicity-related withdrawals.And withdraws with any reason.3 RCTs(n=280) compared MMF plus LEF with MMF.Pooled results showed that the combination of LEF + MMF got higher rates of CR and TR.The RRs were 1.59(1.18,2.15)and 1.24(1.11,1.38),respectively.2 RCTs(n=118)report 24-hour urine protein and the level of C3 and C4.Pooled result showed that the combination therapy group had decreased urine protein and higher C3 and C4.The MDs were-1.53(-2.01,-1.05)g/24 h,0.07(0.04,0.10)g/L and 0.15(0.13,0.18)g/L,respectively.None of these RCTs reported more AEs and withdrawals in the combination therapy group than in MMF monotherapy.Conclusion.In comparison with CTX or MMF monotherapy,the combination of MMF and LEF could have higher TR and CR for LN patients,Moreover,the combination was advantageous in reduction of SLEDAI and 24-hour urine protein.Because of the high risk of bias and small sample size included in this systematic review,more high quality studies were needed to verify the efficacy of combination of LEF + MMF.