Tofacitinib‐Induced Weight Gain in Context: comment on the article by Wollenhaupt et al.

We read the article “Analysis of the impact of tofacitinib treatment on weight and body mass index in patients with rheumatoid arthritis” by Wollenhaupt et al with great interest.1 In this letter, we want to put their main findings into context and raise questions for further research. In the article at hand, several randomized trials in patients with active rheumatoid arthritis (RA) were pooled to assess weight trajectories in patients receiving either tofacitinib (various dosing regimens) or placebo, alone or in combination with conventional synthetic disease-modifying antirheumatic drugs (DMARDs). The main finding was that patients receiving tofacitinib gained more weight than patients receiving placebo. Weight increased in all groups over time, but after six months, there was an additional increase in body weight of about 1.5 kg with tofacitinib 10 mg twice daily and about 0.8 kg with tofacitinib 11 mg once daily compared to placebo. After 12 months, there were no more data from a placebo group, but weight within the tofacitinib groups had continued to increase. First, we wondered about weight trajectories after 12 months. Treatment with DMARDs is chronic, sometimes lifelong. For example, if weight continued to increase linearly, patients with RA would on average gain additional ~16 kg after 10 years with tofacitinib 11 mg once daily. However, weight gain could also be the consequence of good disease control and might be limited to the first months or year(s) of treatment. As the authors had access to a variety of trials belonging to the ORAL (Oral Rheumatoid Arthritis triaL) trial series, it would be especially interesting if the authors could leverage data that the ORAL Surveillance trial.2 ORAL Surveillance was a large safety-endpoint trial that compared tofacitinib to tumor necrosis factor α inhibitors and went on for several years. Second, we want to point out that the mean weight gain seen with any tofacitinib dose exceeds the weight gain observed with low-dose glucocorticoids (GCs) in RA.3 In a pooled analysis of trials comparing GCs at a dose of ≤7.5 mg/day prednisone equivalent to placebo (all patients had a background therapy with DMARDs), there was an additional weight gain of 1.1 kg after two years, most pronounced in the first year of treatment.4 However, a main weakness of this study was that body composition was not investigated: GC might lead to muscle wasting and a more pronounced gain in body fat. This leads us to our next question: Do Wollenhaupt et al have any data available on changes in body composition over time with tofacitinib? Last, it is unclear whether other JAK inhibitors would result in similar weight gain or perhaps offer an advantage over tofacitinib in this regard. JAK inhibitors exhibit different specificity or preference toward combinations of the four members of the JAK family: JAK1, 2, and 3 and tyrosine kinase 2, which play synergistic and multifarious roles in the signaling of different cytokines and hormones.5 Among JAK inhibitors approved for the treatment of RA, tofacitinib and baricitinib are considered less selective than upadacitinib (JAK1-preferential) and filgotinib (JAK1-preferential).5 Even inhibition of a single JAK member results in a pattern of disrupted cytokine pathways, which are mechanistically tied to the complex mode-of-action and potential side effects of the inhibitor. If weight gain were not solely mediated by improved disease control, mechanistic links to weight gain could be JAK2 signaling by leptin,6, 7 a mediator of satiety that prevents hyperphagia and weight gain, or by growth hormone,8 the disruption of which could result in increased fat mass and a relative decrease in muscle mass, mimicking adult growth hormone deficiency.9 It would be interesting to analyze whether different selectivity toward JAK2 results in distinct effects on body weight, and—perhaps more importantly—composition. Indeed, an analysis of filgotinib trials found no effect on body mass index,10 whereas substantial weight gain has been reported in baricitinib trials.11 In an observational study of patients treated for dermatological indications, patients receiving a JAK1-preferential inhibitor showed less weight gain than patients treated with unselective agents.12 In the treatment of myelofibrosis, ruxolitinib (unselective), but surprisingly not fedratinib (JAK2-preferential), has resulted in weight gain.13 In a systematic review and meta-analysis from 2023, ruxolitinib led to more weight gain compared to other JAK inhibitors, but these results must be interpreted with caution as trials across several diseases were pooled.14 In summary, the study by Wollenhaupt et al provides great insights into weight gain associated with tofacitinib. It calls for longer-term investigations, assessments of body composition and analyses of a potential interaction with disease activity. Finally, we think that a systematic comparison of different JAK inhibitors in rheumatology regarding changes in body weight and composition could provide clinicians with useful information when choosing a JAK inhibitor as a long-term treatment for RA. Disclosure form. Appendix S1: Supplementary Information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.