In a large-scale observational study of patients from the US Department of Veterans Affairs pharmacy databases, researchers found that rheumatoid arthritis (RA) treatment with leflunomide was associated with significantly increased, but modest, unintentional weight loss compared with other therapies, while prednisone was associated with greater weight gain. These results were recently published in Arthritis & Rheumatology.1

“Low body mass index (BMI) is associated with adverse long-term outcomes in patients with RA.2–7 Associations between BMI and long-term risks may be partially explained by disease related changes in weight over time among patients with severe RA,” 7,8 wrote Joshua F. Baker, MD, MSCE, from the Philadelphia VA Medical Center and University of Pennsylvania, Philadelphia and colleagues. “Disease-modifying antirheumatic drugs (DMARDs) utilized for the treatment of RA might also influence changes in weight.”

High Yield Data Summary

  • Leflunomide was associated with modest weight loss compared to other therapies for RA
  • Predisone was associated with greater weight gain compared to other therapies for RA

While the possibility that leflunomide might cause weight loss in RA has been debated for over a decade,9-12 no previous studies have examined weight changes as a continuous outcome in a large, real-world setting. And while high-dose prednisone has been widely accepted as a cause of weight gain, there is very little evidence to support the possibility of weight gain compared with other therapies.


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Previous studies have also not compared weight change observed with tumor necrosis factor inhibitors (TNFi), nor have they considered how other elements such as simultaneous treatments or disease activity may have impacted weight change.

To attempt to fill some of these gaps in knowledge, the researchers used data from the US Department of Veterans Affairs (VA) health system and evaluated weight change over 3, 6, and 12 months among patients with RA who were initiating treatment with leflunomide, prednisone, or TNFi compared with patients initiating treatment with methotrexate.

Researchers hoped to gain insight into which RA pharmacotherapies were persistently associated with changes in weight despite adjustment for various confounders. 

Out of 52 662 treatment courses in 32 859 patients with RA, weight gain was seen at 6 months in those taking methotrexate, prednisone, and TNFi. Patients taking prednisone had more weight gain on average (β =0.072 kg/m2, 95% confidence interval [CI] 0.042, 0.10; P<.001) than those taking methotrexate.

Patients taking leflunomide had more weight loss (β =-0.41 kg/m2, 95% confidence interval [CI] 20.46, 20.36; P< .001) and a greater risk of weight loss (odds ratio 1.73, 95% CI 1.55, 1.79; P< .001); although the weight loss were “modest,” with a <2-fold increase in the likelihood of losing more than 1 kg/m2 at 6 months.

These associations remained when adjusted for propensity scores and in sensitivity analyses.

“The strength of this association, lack of attenuation of the association after adjustment for multiple variables and propensity scores, and the biologic plausibility of this finding all suggest that this observation is not likely to be fully explained by confounding by indication and channeling bias,” the authors wrote. “The sensitivity analyses performed herein suggest that the association was even more robust when excluding those who discontinued the drug early, suggesting that the observed association is not simply attributable to poor response and resulting treatment failure.”

Summary & Clinical Applicability

Researchers of this large-scale observational study found that compared with methotrexate, treating RA with leflunomide was associated with weight loss at 6 months, whereas treating RA with prednisone was associated with weight gain.

Factors that were independently associated with a greater risk of weight loss included older age, baseline C-reactive protein (CRP) level, less improvement in CRP level, greater baseline BMI, a status of active smoking, anti-cyclic citrullinated peptide (CCP) seropositivity, longer disease duration, a history of lung disease, malignancy, or congestive heart failure, and greater extent of overall comorbidity.

Limitations & Disclosures

  • The US Department of Veterans Affairs (VA) health system had a high proportion of men, which may not be generalizable to other populations. While sex and race were not found to interact with the primary analyses, these findings should be confirmed in other populations.
  • BMI may not be an ideal indicator of RA disease changes that occur because of body composition.

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References

1. Baker JF, Sauer BC, Cannon GW, et al. Changes in Body Mass Related to the Initiation of Disease-Modifying Therapies in Rheumatoid Arthritis. Arthritis Rheumatol. 2016;68(8):1818-27. doi: 10.1002/art.39647.

2. Mikuls TR, Fay BT, Michaud K, Sayles H, Thiele GM, CaplanL, et al. Associations of disease activity and treatments with mortality in men with rheumatoid arthritis: results from the VARA registry. Rheumatology (Oxford). 2011;50:101–9.

3. Kaufmann J, Kielstein V, Kilian S, Stein G, Hein G. Relation between body mass index and radiological progression in patients with rheumatoid arthritis. J Rheumatol. 2003;30:2350–5.

4. Van der Helm-van Mil AH, van der Kooij SM, Allaart CF, Toes RE, Huizinga TW. A high body mass index has a protective effect on the amount of joint destruction in small joints in early rheumatoid arthritis. Ann Rheum Dis. 2008;67:769–74.

5. Westhoff G, Rau R, Zink A. Radiographic joint damage in early rheumatoid arthritis is highly dependent on body mass index. Arthritis Rheum. 2007;56:3575–82.

6. Escalante A, Haas RW, del Rincon I. Paradoxical effect of body mass index on survival in rheumatoid arthritis: role of comorbidity and systemic inflammation. Arch Intern Med. 2005;165:1624–9.

7. Myrskyla M, Chang VW. Weight change, initial BMI, and mortality among middle- and older-aged adults. Epidemiology. 2009; 20:840–8.

8. Baker JF, Billig E, Michaud K, Ibrahim S, Caplan L, Cannon GW, et al. Weight loss, the obesity paradox, and the risk of death in rheumatoid arthritis. Arthritis Rheumatol. 2015;67: 1711–7.

9. Osiri M, Shea B, Robinson V, Suarez-Almazor M, Strand V, Tugwell P, et al. Leflunomide for the treatment of rheumatoid arthritis: a systematic review and metaanalysis. J Rheumatol. 2003;30:1182–90.

10. Osiri M, Shea B, Robinson V, Suarez-Almazor M, Strand V, Tugwell P, et al. Leflunomide for treating rheumatoid arthritis. Cochrane Database Syst Rev. 2003:CD002047.

11. Alcorn N, Saunders S, Madhok R. Benefit-risk assessment of leflunomide: an appraisal of leflunomide in rheumatoid arthritis 10 years after licensing. Drug Saf. 2009;32:1123–34.

12. Coblyn JS, Shadick N, Helfgott S. Leflunomide-associated weight loss in rheumatoid arthritis. Arthritis Rheum. 2001;44:1048–51.

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