- Design
- Systematic review with pairwise and network meta-analysis of randomised controlled trials
- Population
- 13,387 methotrexate-naive adults with early rheumatoid arthritis across 29 trials
- Primary outcome
- DAS28 remission at 6 months, with secondary analyses at 3 and 12 months
- Effect
- b/tsDMARD plus methotrexate versus methotrexate: RR 1.62 (95% CI 1.39-1.89) at 6 months, 1.95 (1.47-2.57) at 3 months, 1.54 (1.39-1.71) at 12 months. Monotherapy RR 1.81 (1.42-2.31) at 6 months
Treatment guidelines put methotrexate first in early rheumatoid arthritis and add a biologic or targeted synthetic DMARD when it fails. This meta-analysis asks what is lost by that sequence.
Twenty-nine randomised trials and 13,387 methotrexate-naive adults with early RA were pooled, comparing initial b/tsDMARDs — either with methotrexate or as monotherapy — against methotrexate alone, with DAS28 remission at six months as the primary outcome and pairwise plus network analysis.
Starting a b/tsDMARD alongside methotrexate raised DAS28 remission at six months (RR 1.62, 95% CI 1.39-1.89), at three months (RR 1.95, 1.47-2.57) and at twelve (RR 1.54, 1.39-1.71), with the same direction for CDAI remission and ACR50. Every b/tsDMARD class did better than methotrexate alone in the network analysis. The benefit was larger in trials with higher baseline disease activity and more rheumatoid factor-positive participants.
As monotherapy the pooled effect was similar (RR 1.81 at six months, 1.42-2.31), but at class level only tocilizumab and JAK inhibitors reached significance — consistent with what is already known about which agents work without methotrexate.
The practical question this raises is not whether combination works, which was never really in doubt, but whether the benefit survives the cost. In Indian practice, where most of these agents are paid for out of pocket, the enrichment signal matters more than the average: high disease activity and rheumatoid factor positivity identify who gains most, which is the group for whom the expenditure is easiest to justify.
- Higher baseline disease activity and RF positivity marked the patients who gained most
- For monotherapy, only tocilizumab and JAK inhibitors held up at class level
- DAS28 remission is a disease activity endpoint, not a structural or functional one
- The comparison is against methotrexate alone, not against treat-to-target escalation
- Cost decides most of these conversations; the enrichment finding is what makes them tractable
Why it matters
It quantifies what the methotrexate-first sequence costs in remission, in a form that can be weighed against price.
Don't overread it
The comparator was methotrexate alone; this does not show superiority over a treat-to-target strategy that escalates on failure.
The statistics, in plain English
A risk ratio of 1.62 for remission means about 62% more patients reached DAS28 remission than on methotrexate alone — proportionally large, though how many extra patients that is depends on the baseline remission rate, which varied across trials. The subgroup enrichment finding comes from study-level meta-regression, which correlates trial averages rather than individual patients, and is weaker evidence than it sounds. These trials also compared against methotrexate alone rather than against a treat-to-target strategy that escalates, which is what most guidelines actually recommend.
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