Systematic review and network meta-analysis of the efficacy and safety of tumour necrosis factor inhibitor–methotrexate combination therapy versus triple therapy in rheumatoid arthritis

Abstract

ObjectiveClinical trials have not consistently demonstrated differences between tumour necrosis factor inhibitor (TNFi) plus methotrexate and triple therapy (methotrexate plus hydroxychloroquine plus sulfasalazine) in rheumatoid arthritis (RA). The study objective was to estimate the efficacy, radiographic benefits, safety and patient-reported outcomes of TNFi–methotrexate versus triple therapy in patients with RA.MethodsA systematic review and network meta-analysis (NMA) of randomised controlled trials of TNFi–methotrexate or triple therapy as one of the treatment arms in patients with an inadequate response to or who were naive to methotrexate was conducted. American College of Rheumatology 70% response criteria (ACR70) at 6 months was the prespecified primary endpoint to evaluate depth of response. Data from direct and indirect comparisons between TNFi–methotrexate and triple therapy were pooled and quantitatively analysed using fixed-effects and random-effects Bayesian models.ResultsWe analysed 33 studies in patients with inadequate response to methotrexate and 19 in patients naive to methotrexate. In inadequate responders, triple therapy was associated with lower odds of achieving ACR70 at 6 months compared with TNFi–methotrexate (OR 0.35, 95% credible interval (CrI) 0.19 to 0.64). Most secondary endpoints tended to favour TNFi–methotrexate in terms of OR direction; however, no clear increased likelihood of achieving these endpoints was observed for either therapy. The odds of infection were lower with triple therapy than with TNFi−methotrexate (OR 0.08, 95% CrI 0.00 to 0.57). There were no differences observed between the two regimens in patients naive to methotrexate.ConclusionsIn this NMA, triple therapy was associated with 65% lower odds of achieving ACR70 at 6 months compared with TNFi–methotrexate in patients with inadequate response to methotrexate. Although secondary endpoints numerically favoured TNFi–methotrexate, no clear differences were observed. The odds of infection were greater with TNFi–methotrexate. No differences were observed for patients naive to methotrexate. These results may help inform care of patients who fail methotrexate first-line therapy.

Risk of Serious Infection Among Initiators of Tumor Necrosis Factor Inhibitors Plus Methotrexate Versus Triple Therapy for Rheumatoid Arthritis: A Cohort Study

“…Based on these previous results, one could hypothesize that the risk of infection would be less with triple therapy compared to TNFi plus MTX treatment. A recent network meta‐analysis of 33 RCTs on MTX‐inadequate responders showed a strikingly low odds ratio (OR) of overall infection in the triple therapy group compared with TNFi plus MTX treatment (OR 0.08 [95% credible interval 0.00–0.57]) (7). However, this estimate may have been exaggerated due to indirect comparisons of the included RCTs and/or small sample sizes and low event numbers in trials.…”

“…A systematic literature review on observational studies has suggested an increased risk of serious infections associated with bDMARDs compared to cDMARDs (6). A recent network meta‐analysis of RCTs reported an exceptionally greater risk of infection in the TNFi plus MTX group compared to the triple therapy group (7), but this study is likely limited by relying mostly on indirect comparisons of the 2 groups in RCTs.…”

Metering the METEOR in methotrexate failure: is propensity score a falling star?

“…There is already plenty of evidence that addition of a bDMARD to MTX (on failure of monotherapy) is better in the short term than addition of a cs-DMARD. A network meta-analysis of 33 trials has shown the superiority of b-DMARDs at 6 months in achieving higher disease control, that is, in the American College of Rheumatology 70% response criteria (ACR70) 2. Similarly, a meta-analysis of eight such trials demonstrated similar benefits with bDMARDs at 6 months, but the differences disappeared at 24 months 3.…”

Response to: ‘Metering the METEOR in methotrexate failure: is propensity score a falling star?’ by Ahmed et al

“…As Dr Ahmed mentioned, previous research has been performed into treatment options after MTX failure, including the mentioned network meta-analysis based on clinical trials 2. These trials mostly included a selected population and reported response to one or at most two treatment options, either including a biologic disease modifying anti-rheumatic drug (bDMARD) or conventional synthetic (cs) DMARD triple therapy.…”