Iguratimod Combined With Methotrexate For Rheumatoid Arthritis: A Systematic Review

Objective. To evaluate the efficacy and safety of the combination of iguratimod and methotrexate(MTX) in the treatment of rheumatoid arthritis(RA).Methods. A systematic literature search was performed, using Pubmed, Cochrane Library, Embase, CINAHL, CBM, CNKI, Weipu database, Wangfang database(until November 2015), to search randomized controlled trials(RCT) about the combination of iguratimod and MTX for RA in any language. Two reviewers independently identified the eligible studies, assessed their risk of bias and extracted data. The Cochrance Collaboration's Review Manager software 5.3 was used for meta-analysis.The primary outcomes were ACR20/50/70. There were 12 secondary outcomes,including tender joint count, swollen joint count, Health Assessment Questionnaire(HAQ), etc. The safety outcomes were adverse events, serious adverse events,toxicity-related withdrawals and total withdrawals and drop-outs.Results. 7 RCTs met the inclusion criteria. The dosage of iguratimod was 25 mg/d or 50mg/d with the duration of treatment ranged from 12 weeks to 12 months. These RCTs compared the combination of iguratimod and MTX with MTX monotherapy, placebo plus MTX or MTX plus hydroxychloroquine(HCQ) and sulfasalazine(SSZ). The quality of all RCTs were poor. Among them, 4, 7, 5, 3 and 2 RCTs did not offer detail information in randomization, allocation concealment, blinding, complete outcome report and whether or not selective reporting, respectively. In addition, 2 RCTs didnot use double blind and 1 RCT did not use intention to treat(ITT) analysis. 6 RCTs compared the combination of iguratimod and MTX with MTX(monotherapy or plus placebo) for active RA patients, either DMARD-naive or DMARD-experienced. The results showed that the combination was superior to MTX in all primary outcomes and secondary outcomes except RF. The RRs of ACR20, ACR50 and ACR70 were1.51(1.08,2.10), 2.11(1.63,2.73)and2.44(1.51,3.93), respectively. NNTs were 3.91,4.38 and 8.33, respectively. There was no statistical difference in adverse events and toxicity-related withdrawals. Total withdrawals and drop-outs was significantly fewer in the combination of iguratimod and MTX group. 1 RCT compared iguratimod plus MTX with MTX plus SSZ and HCQ. The comparison enrolled the refractory RA patients who had an inadequate response to MTX. The RRs of ACR20 and ACR50 were 1.41(1.00,1.98) and 1.33(0.86, 2.07), respectively, showing that iguratimod plus MTX group was higher than MTX plus SSZ and HCQ group, but the different was not statistically significant. ACR70 was not reported in this trial. In terms of the secondary outcomes,iguratimod plus MTX was better than control group. There was no statistical difference in safety outcomes between these two groups.Conclusion. In comparison with MTX monotherapy, the combination of iguratimod and MTX might increase the ACR20/50/70 response rate and benefit them in secondary outcomes but not increase the adverse events for active RA patients, either DMARD-na?ve or DMARD-experienced. Compared to MTX plus SSZ and HCQ combination, iguratimod plus MTX might have higher ACR20/50 in refractory RA patients. More RCTs of high quality and larger sample size are needed to confirm the efficacy of iguratimod and MTX combination in RA.