Induction maintenance with tumour necrosis factor-inhibitor combination therapy with discontinuation versus methotrexate monotherapy in early rheumatoid arthritis: a systematic review and meta-analysis of efficacy in randomised controlled trials

Abstract

Objective: To determine whether an induction-maintenance strategy of combined therapy (methotrexate (MTX)+tumour necrosis factor (TNF) inhibitor (TNFi)) followed by withdrawal of TNFi could yield better long-term results than a strategy with MTX monotherapy, since it is unclear if the benefits from an induction phase with combined therapy are sustained if TNFi is withdrawn.

Methods: We performed a meta-analysis of trials using the initial combination of MTX+TNFi in conventional synthetic disease-modifying antirheumatic drug-naïve patients with early rheumatoid arthritis (RA). A systematic literature search was performed for induction-maintenance randomised controlled trials (RCTs) where initial combination therapy was compared with MTX monotherapy in patients with clinically active early RA. Our primary outcome was the proportion of patients who achieved low disease activity (LDA; Disease Activity Score (DAS)28<3.2) and/or remission (DAS28<2.6) at 12-76 weeks of follow-up. A random-effects model was used to pool the risk ratio (RR) for LDA and remission and heterogeneity was explored by subgroup analyses.

Results: We identified 6 published RCTs, 4 of them where MTX+adalimumab was given as initial therapy and where adalimumab was withdrawn in a subset of patients after LDA/remission had been achieved. 2 additional trials used MTX+infliximab as combination therapy. The pooled RRs for achieving LDA and clinical remission at follow-up after withdrawal of TNFi were 1.41 (95% CI 1.05 to 1.89) and 1.34 (95% CI 0.95 to 1.89), respectively. There was significant heterogeneity between trials due to different treatment strategies, which was a limitation to this study.

Conclusions: Initial therapy with MTX+TNFi is associated with a higher chance of retaining LDA and/or remission even after discontinuation of TNFi.

Keywords: Anti-TNF; Disease Activity; Early Rheumatoid Arthritis; Methotrexate; Treatment.

Figure 1

Flow chart of study selection. ERA, early rheumatoid arthritis; MA, meta-analysis; MTX, methotrexate; RCT, randomised controlled trial; TNFi, tumour necrosis factor inhibitor; SR, systematic review.

Figure 2

Forest plot of the risk ratio of attaining LDA or remission using combination therapy versus monotherapy at induction. The I² and p values for heterogeneity are shown (remission=DAS28<2.6; LDA=DAS28<3.2). DAS28, disease activity score by 28 joints; LDA, low disease activity; MTX, methotrexate; TNFi, tumour necrosis factor inhibitor.

Figure 3

Forest plot of the risk ratio of attaining LDA or remission using combination therapy versus monotherapy during maintenance. The I² and p values for heterogeneity are shown (remission=DAS28<2.6; LDA=DAS28<3.2). Note: for BeST, only LDA could be assessed. DAS28, disease activity score by 28 joints; LDA, low disease activity; MTX, methotrexate; TNFi, tumour necrosis factor inhibitor.