In a first of its kind investigation using MRI based muscle assessment, researchers have reported that tofacitinib, a Janus kinase (JAK) inhibitor used in rheumatoid arthritis (RA), may promote muscle growth alongside its anti-inflammatory benefits.
The recent study published in The Lancet Rheumatology revealed that patients with RA treated with tofacitinib experienced significant gains in lower limb muscle volume after six months of therapy. The increase in serum creatinine observed during treatment, typically considered a potential marker of kidney dysfunction, may instead indicate enhanced muscle mass.
The RAMUS (Rheumatoid Arthritis and Muscle) study was a prospective, single arm, proof of concept trial conducted at a single centre, involving 15 RA patients who were initiating tofacitinib as part of standard care. Researchers used quantitative MRI to measure changes in lower limb muscle volume at baseline, one month, and six months. After six months of treatment, participants showed a mean increase of 242 cm³ in lower limb muscle volume (95% CI 44–441, P=0.017), particularly in the thigh region. Serum creatinine concentrations increased significantly (P=0.0011), while disease activity measured using DAS28 CRP declined sharply after one month (P=0.0064) and remained stable thereafter. However, the study found no significant improvement in muscle strength, function, or appendicular lean mass index.
Gene expression analysis of skeletal muscle tissue revealed transcriptional changes opposite to those seen in age related sarcopenia, suggesting potential restoration of muscle health at a molecular level. Over the course of the study, 28 adverse events were reported among 13 participants, though only one was severe, involving hospitalization for COVID 19 pneumonitis that occurred prior to tofacitinib initiation.
The findings align with earlier work by Chikugo et al., which assessed body composition changes in women with RA treated with tofacitinib for three months. The study found that patients maintained muscle mass while gaining fat mass, a pattern not observed in those receiving biological DMARDs.
Researchers proposed three possible mechanisms for tofacitinib’s observed effects on muscle. These include reversal of chronic inflammation through JAK pathway inhibition, a direct pharmacological action on muscle metabolism or physiology, and increased physical activity, though the latter was considered less likely as self-reported activity levels did not significantly change. The concurrent rise in serum creatinine, also noted with other JAK inhibitors, may represent a class effect reflecting increased muscle mass rather than kidney damage.
This study marks the first MRI based assessment of JAK inhibition on skeletal muscle in RA. The authors concluded that larger, controlled trials are warranted to confirm these findings, assess functional outcomes, and determine whether the effects are specific to tofacitinib or extend across the broader JAK inhibitor class. If confirmed, these results may reshape understanding of JAK inhibitors’ impact on muscle physiology in inflammatory diseases, offering new insights into managing sarcopenia risk in RA.
References
- Bennett JL, Hollingsworth KG, Pratt AG, Degnan AEA, Gorman GS, Feeney C, Naamane N, Nsengimana J, Sayer AA, Anderson AE, Isaacs JD. Skeletal muscle effects of Janus kinase inhibition in rheumatoid arthritis (RAMUS): a single-arm, experimental medicine study. Lancet Rheumatol. 2025 Oct 15:S2665-9913(25)00184-5.
- Chikugo M, Sebe M, Tsutsumi R, Iuchi M, KIshi J, Kuroda M, Harada N, Nishioka Y, Sakaue H. Effect of Janus kinase inhibition by tofacitinib on body composition and glucose metabolism. J Med Invest. 2018;65(3.4):166-170.