Tofacitinib may increase skeletal muscle mass in rheumatoid arthritis

medwireNews: The Janus kinase (JAK) inhibitor tofacitinib may increase skeletal muscle mass in patients with rheumatoid arthritis (RA), suggests a small, proof-of-concept study.

The effect of tofacitinib “might represent reversal of inflammation by JAK inhibition although similar changes have not been observed with other potent anti-inflammatory DMARDs [disease-modifying anti-rheumatic drugs],” say John Isaacs (Newcastle University, UK) and colleagues in The Lancet Rheumatology.

Other possible explanations for the findings include a “direct pharmacological effect on muscle metabolism or physiology,” the researchers suggest, or an increase in the patients’ physical activity, although no significant changes in self-reported activity were recorded.

“Ultimately, improved knowledge of the effects of JAK inhibition on muscle health could contribute to a more personalised medicine approach for patients with rheumatoid arthritis in which therapeutic choices are influenced by the anti-sarcopenic effect of DMARDs,” the team highlights.

In an accompanying comment, Jin Kyun Park and Eun Bong Lee, both from Seoul National University in the Republic of Korea, write: “This study suggests a novel role for tofacitinib in the treatment of sarcopenia. If confirmed, further studies are needed to compare efficacy of different DMARDs for sarcopenia management.

“Furthermore, it remains to be determined whether JAK inhibitors can prevent sarcopenia in other inflammatory diseases including idiopathic inflammatory myopathies.”

Increased skeletal muscle volume after 6 months

Tofacitinib is associated with small increases in serum creatinine, but “without conclusive evidence of renal impairment,” the researchers explain. As serum creatinine levels are also determined by skeletal muscle mass, they investigated the effect of tofacitinib on skeletal muscle metabolism in the single-arm RAMUS study.

The 15 adults initiated tofacitinib as standard care for RA. They had at least one sarcopenia risk factor, serum creatinine levels no greater than 1.5 times the upper limit of normal and had not received prior treatment with JAK inhibitors, or systemic glucocorticoid treatment for at least 4 weeks prior to the baseline visit.

The average age of the participants was 60 years, 87% were women, and the majority (80%) were White. Low muscle strength, defined as low grip strength and/or prolonged five times sit-to-stand test time, was recorded in 86%, and the average tender joint count was 34 out of 68.

Between baseline and the 6-month follow-up, mean lower limb muscle volume, measured by magnetic resonance imaging, increased by a significant 242 cm³, equivalent to a 4% increase. This increase was due primarily to a significant 200 cm³ increase in mean thigh muscle volume (5% increase), while the increase in lower leg muscle volume was a nonsignificant 52 cm³ (2% increase). 

Muscle composition and metabolism measured via vastus lateralis biopsies remained otherwise stable, the investigators observe, with no evidence of muscle inflammation.

“This suggests that tofacitinib therapy might counteract the natural tendency for muscle loss that is accelerated in rheumatoid arthritis,” they say.

Are there underlying factors?

There was an accompanying significant 5.6 μmol/L increase in mean serum creatinine levels at 6 months. However, assessment of other biomarkers, such as lactate dehydrogenase, aspartate aminotransferase, and myoglobin, showed no changes, indicating that there was “no muscle damage in association with tofacitinib treatment,” the investigators comment.

There were no significant changes in muscle strength or function, although a nonsignificant increase in mean grip strength was recorded during the study, from 12.6 kg at baseline to 15.8 kg at 6 months.

After 1 month, the Disease Activity Score in 28 joints using CRP (DAS28-CRP) was significantly reduced from 5.14 points to 4.09 points, with no further changes at 6 months.

“Changes in DAS28-CRP did not predict changes in thigh muscle volume, suggesting that these changes could not be attributed solely to improved disease activity,” Isaacs et al point out.

There were 28 adverse events recorded in 87% of participants during tofacitinb treatment, of which 54% were considered mild and 43% moderate, and there were no on-treatment serious adverse events.

The team acknowledges that “[t]he small sample size, absence of a control group, and high tender joint count limited the power to detect changes in muscle strength and function, while similarly limiting generalisation to the wider rheumatoid arthritis population.”

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Lancet Rheumatol 2025; doi:10.1016/S2665-9913(25)00184-5
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