JAK inhibition with tofacitinib increased lower limb muscle volume; strength and function did not improve in rheumatoid arthritis.
Experimental Medicine Design and Primary Outcome
In the prospective, single-arm RAMUS study, adults with rheumatoid arthritis at risk for sarcopenia initiated tofacitinib as standard care and underwent quantitative MRI at baseline, one month, and six months. Among fifteen completers, lower limb muscle volume rose significantly after six months, with a mean increase of 242 cm³ and a 95% confidence interval of 44 to 441. Gains were most pronounced in the thigh, aligning with the protocol’s focus on vastus lateralis biopsy to explore mechanistic signals in skeletal muscle.
Disease Control, Muscle Function, and Safety
Inflammation improved promptly. Disease Activity Score 28 using C-reactive protein decreased at one month with a reported p value of 0.0064 and showed no further change by six months. Despite increased muscle volume, appendicular lean mass index, measured strength, and functional performance did not show significant differences over six months, indicating structural changes may precede measurable functional benefit. Serum creatinine increased significantly with a reported p value of 0.0011, consistent with either increased muscle mass or a pharmacologic effect on skeletal muscle. Twenty-eight adverse events were recorded in thirteen participants; one serious event involved hospitalization for COVID-19 pneumonitis before tofacitinib initiation.
JAK Inhibition in Rheumatoid Arthritis: Clinical Takeaways
These experimental medicine data suggest JAK inhibition in rheumatoid arthritis can increase skeletal muscle volume over six months without parallel strength gains. The observed creatinine rise may reflect greater muscle mass or reduced inflammation rather than nephrotoxicity, although this requires confirmation. The single-center, single-arm design and small sample emphasize the need for larger, controlled studies to verify efficacy, delineate mechanism, and clarify whether effects are specific to tofacitinib. Until then, clinicians should view the MRI muscle signal as hypothesis-generating while continuing to center decisions on established outcomes, safety monitoring, and individualized risk–benefit discussions.
Reference: Bennett JL et al. Skeletal muscle effects of Janus kinase inhibition in rheumatoid arthritis (RAMUS): a single-arm, experimental medicine study. Lancet Rheumatol. 2025. doi: 10.1016/S2665-9913(25)00184-5.
