Skeletal muscle effects of Janus kinase inhibition in rheumatoid arthritis (RAMUS): a single-arm, experimental medicine study

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BACKGROUND: Rheumatoid arthritis increases the risk of generalised muscle wasting, with chronic inflammation contributing to the loss of muscle mass and strength. Tofacitinib, a Janus kinase (JAK) inhibitor used to treat rheumatoid arthritis, increases serum creatinine concentrations without conclusive evidence of nephrotoxicity. In the Rheumatoid Arthritis and Muscle (RAMUS) study, we investigated whether tofacitinib affects muscle volume, strength, and function. METHODS: RAMUS was a prospective, single-arm, single-centre, proof of concept experimental study, done at Freeman Hospital, Newcastle upon Tyne, UK. Patients aged older than 18 years, with rheumatoid arthritis (according to the 2010 American College of Rheumatology and European Alliance of Associations for Rheumatology [ACR-EULAR] classification criteria for rheumatoid arthritis) initiating tofacitinib as standard care were recruited. Additional inclusion criteria were at least one sarcopenia risk factor, no previous treatment with JAK inhibitors, no systemic glucocorticoid treatment for at least 4 weeks before the baseline visit, and serum creatinine 1·5 times the upper limit of normal or less. Participants provided blood samples at baseline, 1 month, and 6 months; vastus lateralis biopsies were performed at baseline and 6 months. The primary outcome was change in lower limb muscle volume, assessed by quantitative MRI at baseline and after 1 and 6 months of tofacitinib treatment, and was assessed in all participants who completed the study. Secondary outcomes included changes in serum creatinine, appendicular lean mass index, muscle strength, muscle function, and disease activity (Disease Activity Score 28-C-reactive Protein [DAS28-CRP] score). Adverse events were recorded. People with lived experience with rheumatoid arthritis were involved in the design and set-up phases of this study. RAMUS was registered with ISRCTN (ISRCTN13364395). FINDINGS: [95% CI 44-441], p=0·017), particularly in the thigh, and significant increases in serum creatinine (p=0·0011). Disease activity (DAS28-CRP) was significantly reduced after 1 month of tofacitinib treatment (p=0·0064) with no further changes at 6 months. No significant changes in appendicular lean mass index, muscle strength, or muscle function were observed. 28 adverse events were recorded in 13 (87%) of 15 participants; one event was classified as severe and serious, and concerned a participant being hospitalised with COVID-19 pneumonitis before commencing tofacitinib. INTERPRETATION: Tofacitinib treatment in patients with rheumatoid arthritis was associated with increased muscle volume after 6 months. The increase in serum creatinine associated with tofacitinib treatment might reflect increased muscle volume via a direct pharmacological effect on skeletal muscle or via reduced inflammation, or a combination. Larger studies are needed to verify our findings, demonstrate functional benefit, and determine whether they are unique to tofacitinib. FUNDING: Pfizer, BMA Foundation, JGW Patterson Foundation and Newcastle Hospitals Charity.

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