Higher BMI modifies treatment response in rheumatoid arthritis (RA) patients receiving JAK inhibitors, such that the benefit conferred by JAK inhibitors decreases progressively with increasing BMI, according to a meta-analysis.
Pooled individual patient data from 16 phase III trials showed a “clear and consistent association between higher BMI and reduced efficacy of JAK inhibitors,” reported first author Dr Katie Bechman and colleagues from King’s College London, London, UK. “Although participants with healthy weight showed the greatest improvement, those with class 1–3 obesity derived a smaller incremental benefit.”
The likelihood of achieving a 20-percent improvement based on American College of Rheumatology (ACR) core set variables (ACR20) was reduced by 6 percent among patients who were overweight (25 to <30 kg/m2: adjusted relative risk [aRR], 0.94, 95 percent confidence interval [CI], 0.91–0.98), by 8 percent among those with class 1 obesity (30 to <35 kg/m2: aRR, 0.92, 95 percent CI, 0.89–0.96), by 12 percent among those with class 2 obesity (35 to <40 kg/m2: aRR, 0.88, 95 percent CI, 0.81–0.96), and by 22 percent among those with class 3 obesity (≥40 kg/m2: aRR, 0.78, 95 percent CI, 0.71–0.85) compared with patients with healthy weight. [Lancet Rheumatol 2026;8:e691-e703]
Results for Disease Activity Score based on the evaluation of 28 joints and C-reactive protein (DAS28-CRP) were similar, with the likelihood of achieving this endpoint decreasing by 6 percent among patients who were overweight (aRR, 0.94, 95 percent CI, 0.90–0.97), by 8 percent among those with class 1 obesity (aRR, 0.92, 95 percent CI, 0.88–0.96), by 10 percent among those with class 2 obesity (aRR, 0.90, 95 percent CI, 0.84–0.96), and by 19 percent among those with class 3 obesity (aRR, 0.81, 95 percent CI, 0.75–0.88).
“This BMI–treatment interaction indicates that obesity acts as a true effect modifier of JAK inhibitor efficacy rather than a prognostic marker of poorer outcomes,” Bechman and colleagues said.
The diminishing treatment efficacy at higher BMI levels was specific in the JAK inhibitor group and not observed in the placebo group, “supporting the interpretation that this change reflects reduced pharmacological response rather than differences in baseline disease trajectory,” they added.
Clinical takeaways
For clinicians managing patients with RA, these findings carry several practice implications.
First, clinicians must counsel patients regarding the potential influence of BMI on treatment response to establish clear expectations before starting JAK inhibitor therapy, as well as to consider medications with alternative mechanisms of action for JAK inhibitor-treated patients who show no or inadequate response, according to Bechman and colleagues.
“Increasing JAK inhibitor dose is unlikely to be a viable strategy [to induce response] given established safety concerns and the dose-dependent risks highlighted in regulatory guidance. Adding further complexity, JAK inhibitors have been associated with weight gain, which might reflect improvement in inflammatory burden and reversal of rheumatoid cachexia,” they said.
For clinicians seeing patients with high BMI, Bechman and colleagues recommended that weight be managed through lifestyle approaches and emerging options such as GLP-1 receptor agonists, which could reduce inflammatory burden and improve treatment responsiveness.
“However, current evidence does not establish whether GLP-1 receptor agonists exert immunomodulatory effects independent of weight loss, and whether weight loss attained with these agents enhances JAK inhibitor response remains a testable hypothesis and an important area for future research,” they added.
A gap addressed
This meta-analysis succeeds in “disentangling the prognostic effect of BMI from its potential role as a modifier of JAK inhibitor efficacy in patients with RA,” wrote Drs Chary Lopez Pedrera and Carlos Perez Sanchez from the University of Córdoba, Córdoba, Spain, in a linked editorial. [Lancet Rheumatol 2026;8:e676-e677]
The findings “provide a more rigorous basis for interpreting excess weight as clinically relevant to therapeutic response rather than to baseline disease severity or symptom burden… [and support] embedding BMI into therapeutic decision making,” Pedrera and Sanchez added.
Looking ahead, Pedrera and Sanchez emphasized the need to translate the findings into practice by conducting prospective studies that directly measure body composition, given that “BMI remains an imperfect surrogate of adiposity and does not fully capture body composition, visceral fat accumulation, sarcopenic obesity, or metabolic dysfunction, all of which might be directly linked to inflammatory tone and drug response.”
Additionally, RA care should adopt a dual-target approach that pairs targeted therapy with metabolic health management, they said.
The meta-analysis included 16 phase III randomized controlled trials of tofacitinib, baricitinib, upadacitinib, and filgotinib. Trial durations ranged from 12 weeks to 104 weeks.
The total population comprised 11,883 adults (mean age 52.9 years, 80.7 percent female, 71.5 percent White participants) with RA. Of the patients, 65.3 percent received a JAK inhibitor (tofacitinib, upadacitinib, or baricitinib), 7.8 percent received methotrexate, 16.5 percent received placebo, and 10.3 percent received a biologic comparator (adalimumab or abatacept).
Median BMI at baseline was 26.8 kg/m2. Of the patients, 31.2 percent were overweight, 17.4 percent had class 1 obesity, 8 percent had class 2 obesity, and 5.6 percent had class 3 obesity.
The primary outcomes were ACR20 and DAS28-CRP.