Weight change patterns in rheumatoid arthritis patients treated with leflunomide: A real-world comparative study

Leflunomide is a widely used conventional synthetic disease-modifying antirheumatic drug (csDMARD) in rheumatoid arthritis (RA), particularly in low- and middle-income countries where biologics are cost-prohibitive. Weight loss is a recognised but understudied adverse effect. This study aimed to characterise the prevalence, magnitude, and temporal patterns of leflunomide-associated weight change in a real-world RA cohort.

This prospective longitudinal observational study was conducted at a rheumatology department using an exposure-defined prospective comparative cohort design. Patients newly initiated on leflunomide 20mg/day at enrollment (cases, n=206) were compared with RA patients not receiving leflunomide (controls, n=92) over 12 months. Body weight was recorded in the morning on a standardised scale by the same nurse at baseline and at 3, 6, 9, and 12 months. Primary outcomes included any weight loss, clinically significant weight loss (≥5%), severe weight loss (≥10%), and rapid weight loss (≥5% by 3 months). Multivariable logistic regression was performed, adjusting for age, gender, baseline weight, disease activity, and disease duration.

At 6 months, 56.8% of leflunomide-treated patients experienced any weight loss, with clinically significant weight loss (≥5%) in 31.1% and severe weight loss (≥10%) in 8.3%. Rapid weight loss occurred in 17.0% of cases. Leflunomide-exposed patients showed a progressive, stepwise mean weight decline (-0.94kg at 3 months, -1.44kg at 6 months, -2.23kg at 9 months), while controls remained stable. At 12 months, severe weight loss was significantly more frequent in cases than controls (19.6% vs 8.8%; p=0.042). Sustained clinically significant weight loss was observed in 21.7% of cases. On multivariable analysis, leflunomide exposure was independently associated with more than twofold higher odds of ≥5% weight loss (OR 2.46, 95% CI 1.21-5.03).

Leflunomide is independently associated with clinically meaningful and often progressive weight loss in patients with RA. These findings support routine weight monitoring in leflunomide-treated patients and underscore the importance of distinguishing drug-related weight reduction from other causes to avoid unnecessary diagnostic investigations and optimise patient counselling.