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Patients with rheumatoid arthritis (RA) treated with leflunomide (Arava) experienced modest but significant weight loss not seen with other RA therapies, a large Veterans Administration study found.

Data from large national databases of patients with RA revealed a 73% greater risk of weight loss with leflunomide compared with methotrexate after multivariable adjustment (OR 1.73, 95% CI 1.55-1.79, P<0.001), according to , from the Philadelphia VA Medical Center and the Perelman School of Medicine at the University of Pennsylvania, and colleagues.

"While there were significant differences in the change in body mass index (BMI) among leflunomide users, the changes were modest on average, with a less than two-fold increase in odds of losing more than 1 kg/m² at 6 months," they wrote online in .

However, as observed in other studies, weight loss in RA patients was associated with higher 3-year mortality, they noted.

"Low body mass index is associated with adverse long-term outcomes in rheumatoid arthritis," which may be influenced by disease-related weight loss and drug therapies.

There have been reports for more than a decade of treatment-related weight loss among patients treated with leflunomide, although explanations for this have been unclear.

"Anecdotal observations of greater weight loss among patients treated with leflunomide may be confounded by the use of the drug as a salvage therapy, particularly among patients with comorbid conditions such as chronic lung disease," Baker and colleagues wrote.

In contrast, prednisone has long been linked with weight gain, while information about weight changes with tumor necrosis factor inhibitors has been uncertain.

To further explore concerns about weight changes with RA treatment, the researchers used three national administrative VA databases to identify 32,859 RA patients treated with a total of 52,662 courses of anti-RA therapies. The primary outcome was the change in BMI at 6 months from the date the first prescription was filled.

In unadjusted analyses, significant increases in BMI at months 3, 6, and 12 with the use of methotrexate (P< 0.001), prednisone (P< 0.001) and TNF inhibitors (P<0.01), and weight gain was greater at 6 months among patients who initiated prednisone compared with those receiving methotrexate (P<0.001).

Among patients who began treatment with leflunomide, 30% lost more than 1 kg/m² of BMI compared with 19% taking methotrexate (P<0.001).

In unadjusted models, leflunomide was associated with greater loss of BMI (-0.47, 95% CI -0.53 to -0.42, P<0.001) and a greater risk of weight loss (OR 1.86 (95% CI 1.71-1.97, P<0.001) compared with methotrexate.

For prednisone, there was a modestly higher gain in BMI at 6 months compared with methotrexate (β=0.078 kg/m², 95% CI0.048-0.11, P<0.001) in unadjusted analyses, and the association remained in a multivariable analysis.

The weight gain with prednisone was independent of improvements in C-reactive protein, the researchers noted. "However, compared to methotrexate, prednisone-related weight gain was most pronounced among patients with the greatest improvements in systemic inflammation, suggesting that influence of prednisone may be most notable in this group," they wrote.

Use of a TNF inhibitor was not associated with weight change in multivariable models. In unadjusted analyses, TNF inhibitor use was associated with weight change similar to that with methotrexate (considered the reference), an observation that was consistent after propensity adjustment and in sensitivity analyses.

Weight loss at 6 months was independently associated with an increased mortality risk at 3 years (OR 1.56, 95% CI 1.45-1.67, P<0.001), regardless of study drug.

In a multivariable analysis comparing other agents with methotrexate, 3-year mortality was higher among patients receiving prednisone (OR 1.10, 95% CI 1.05-1.15, P<0.001) or leflunomide (OR 1.23, 95% CI 1.14-1.33, P<0.001), but was similar for those being treated with a TNF inhibitor (OR 1.06, 95% CI 0.99-1.12, P=0.09).

"I personally would not recommend making initial treatment choices based on the modest weight changes observed here," Baker commented to MedPage Today. "In the case of an individual who appears to be doing well on leflunomide but is losing weight, I do not think there is evidence here to suggest a need to discontinue the drug."

"However, there was also no evidence that weight loss in the setting of leflunomide was of less risk in terms of 3-year mortality," he added. "Therefore, I think weight loss in the setting of leflunomide should still be a warning to the treating physician even if not an absolute reason to discontinue the treatment."

The high proportion of men in the study, as expected with a VA setting, was a limitation to the study, but the authors pointed out that no interactions with gender or race were found in primary analyses. Also, selection of participants on the basis of the availability of weight measurements could have resulted in bias.

"Finally, BMI may not be an ideal metabolic indicator in disease states associated with changes in body composition such as in RA," the authors wrote.

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