What does this research mean for the field?

While approximately 40% of real-world rheumatoid arthritis patients receiving targeted therapies are ineligible for phase III trials, they achieve comparable adjusted remission rates, though the comparative effectiveness differences between drug classes are attenuated compared to trial-eligible populations. Novelty: ClaimNovelty.CONFIRMATORY. Consensus alignment: ConsensusAlignment.SUPPORTS_CONSENSUS.

What question did this study set out to answer?

The research aimed to characterize patients with rheumatoid arthritis ineligible for phase III randomized controlled trials and evaluate their outcomes with targeted therapies.

May 20, 2026Open Access

Impact of trial exclusion criteria on real-world comparative effectiveness of targeted therapies in rheumatoid arthritis: the FIRST Registry

Key Points

The research aimed to characterize patients with rheumatoid arthritis ineligible for phase III randomized controlled trials and evaluate their outcomes with targeted therapies.
Analyzed 5462 patients who initiated biological/targeted synthetic disease-modifying anti-rheumatic drugs between 2003 and 2023.
Defined RCT ineligibility using common phase III trial exclusion criteria.
Used propensity score weighting to estimate comparative effectiveness across drug classes.
39.7% of patients met at least one RCT exclusion criterion, showing higher disease activity and worse functional status.
Adjusted remission rates were similar between eligible (24.0%) and ineligible patients (23.2%; OR 0.90; 95% CI 0.78 to 1.04).
In eligible patients, remission rates with Janus kinase inhibitors were greater than those with TNF inhibitors (OR 1.39; 95% CI 1.09 to 1.76), but the effect was less pronounced in ineligible patients (OR 1.24; 95% CI 0.81 to 1.91).

Abstract

Objectives Randomised controlled trials (RCTs) use restrictive eligibility criteria, raising concerns about external validity for heterogeneous routine-care populations. We aimed to characterise real-world patients with rheumatoid arthritis who would be ineligible for phase III RCTs, to evaluate their outcomes on biological/targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs) in routine care and to assess how eligibility status influences comparative effectiveness estimates. Methods We analysed 5462 patients who initiated b/tsDMARDs between 2003 and 2023. RCT ineligibility was defined using common phase III trial exclusions (eg, renal/hepatic impairment). Outcomes were treatment persistence and Clinical Disease Activity Index remission at 26 weeks. Comparative effectiveness across drug classes was estimated using propensity score weighting, stratified by RCT eligibility. Results Overall, 39.7% (2167/5462) met at least one RCT exclusion criterion and ineligible patients had higher baseline disease activity and worse functional status. However, after propensity score adjustment for clinical characteristics, remission rates did not differ between groups (24.0% vs 23.2%; OR 0.90; 95% CI 0.78 to 1.04). The proportion ineligible differed by b/tsDMARDs, highest with interleukin 6 inhibitors (47.4%) and CTLA4-Ig (45.1%) and lowest with Janus kinase (JAK) inhibitors (31.0%). In the RCT-eligible cohort, remission with JAK inhibitors exceeded that with tumour necrosis factor inhibitors (OR 1.39; 95% CI 1.09 to 1.76), consistent with head-to-head RCTs. In the RCT-ineligible cohort, this advantage was attenuated and no longer statistically significant (OR 1.24; 95% CI 0.81 to 1.91). Conclusions Approximately 40% of routine-care patients would be RCT ineligible. Although these patients achieved comparable adjusted outcomes, between-drug differences were smaller than in trial-eligible populations. Real-world comparative analysis should therefore consider composition and calendar time when interpreting treatment effects.

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