Introduction: The Burden of Rheumatoid Cachexia
Rheumatoid arthritis (RA) is traditionally characterized by synovial inflammation and joint destruction. However, the systemic nature of the disease frequently leads to significant extra-articular manifestations, most notably rheumatoid cachexia. This condition, defined by the loss of skeletal muscle mass (sarcopenia) often accompanied by stable or increased fat mass, affects approximately two-thirds of patients with RA. Unlike age-related sarcopenia, rheumatoid cachexia is driven by chronic systemic inflammation, where pro-inflammatory cytokines such as TNF-alpha, IL-6, and IL-1 beta accelerate protein degradation via the ubiquitin-proteasome pathway and inhibit muscle protein synthesis.
The clinical consequences of muscle wasting in RA are profound, contributing to physical disability, increased fatigue, reduced quality of life, and higher metabolic risk. While traditional disease-modifying antirheumatic drugs (DMARDs) and TNF inhibitors have shown some efficacy in slowing muscle loss, the restoration of muscle volume remains a significant unmet medical need. The Janus kinase (JAK) inhibitor tofacitinib has emerged as a potent therapy for RA, but its specific impact on skeletal muscle—beyond its anti-inflammatory effects—has remained largely unexplored until the RAMUS study.
The RAMUS Study: Investigating Muscle Effects of JAK Inhibition
The Rheumatoid Arthritis and Muscle (RAMUS) study was a prospective, single-arm, experimental medicine trial conducted at the Freeman Hospital in Newcastle upon Tyne, UK. The primary objective was to determine whether tofacitinib treatment affects muscle volume, strength, and function in patients with RA.
Study Design and Population
The trial recruited 15 eligible patients (mean age 59.6 years) who were initiating tofacitinib as part of their standard clinical care. To be included, participants had to meet the 2010 ACR-EULAR classification criteria for RA and possess at least one risk factor for sarcopenia. Importantly, patients were excluded if they had previously used JAK inhibitors or had received systemic glucocorticoids within four weeks of the baseline visit to avoid confounding effects on muscle metabolism.
Methodological Rigor
The study utilized highly sensitive quantitative MRI (qMRI) to assess lower limb muscle volume at baseline, one month, and six months. This approach allowed for a precise volumetric analysis of the thigh and lower leg muscles, providing a more accurate assessment than standard dual-energy X-ray absorptiometry (DXA). Additionally, vastus lateralis biopsies were performed to investigate cellular and molecular changes, and serum creatinine was monitored to explore the previously observed rise in this biomarker during tofacitinib therapy.
Key Findings: Muscle Volume and the Creatinine Paradox
The RAMUS study yielded several significant findings that challenge current understanding of JAK inhibitor side effects and therapeutic benefits.
Significant Increase in Muscle Volume
After six months of tofacitinib treatment, participants showed a significant increase in lower limb muscle volume, with a mean increase of 242 cm3 (95% CI 44–441, p=0.017). This increase was particularly pronounced in the thigh muscles. This finding is critical because it suggests that tofacitinib may actively reverse muscle wasting in RA patients, rather than merely halting its progression.
The Rise of Serum Creatinine
A well-documented clinical observation with tofacitinib is a modest, early rise in serum creatinine levels. Historically, this has raised concerns regarding potential nephrotoxicity, although GFR measurements have generally remained stable. The RAMUS study found a significant increase in serum creatinine (p=0.0011) that correlated with the increase in muscle volume. This suggests that the creatinine rise may be a physiological reflection of increased muscle mass (the primary source of creatinine) or a direct pharmacological effect on muscle metabolism, rather than a sign of renal impairment.
Disease Activity and Functional Outcomes
Disease activity, measured by the DAS28-CRP score, showed rapid and significant improvement within the first month of treatment (p=0.0064), which was maintained through the six-month mark. Interestingly, despite the significant increase in muscle volume, the study did not observe significant improvements in muscle strength or functional performance (e.g., grip strength or chair stand tests) within the six-month study period. This suggests a potential lag between structural muscle gains and functional improvements, or perhaps a need for concurrent resistance exercise to translate volume into strength.
Expert Commentary: Mechanistic Insights
The results of the RAMUS trial suggest a dual mechanism for the muscle-sparing effects of tofacitinib. First, by potent inhibition of the JAK-STAT pathway, tofacitinib reduces the systemic inflammatory milieu (specifically IL-6 signaling) that normally drives muscle proteolysis. Second, there is emerging evidence that the JAK-STAT pathway plays a direct role in satellite cell (muscle stem cell) function and myocyte homeostasis. By modulating these pathways, tofacitinib may promote a pro-anabolic environment within the skeletal muscle tissue itself.
Furthermore, the clarification of the creatinine rise is of high clinical utility. For years, clinicians have grappled with the interpretation of rising creatinine in patients on JAK inhibitors. The RAMUS data provides a reassuring biological explanation: if muscle volume is increasing, a corresponding rise in the metabolic byproduct creatinine is to be expected. This may prevent unnecessary drug discontinuations or renal workups in patients who are otherwise responding well to therapy.
Study Limitations and Safety
As a proof-of-concept, single-arm study, RAMUS is limited by its small sample size (n=15) and the lack of a control group. While the longitudinal changes within the cohort are statistically significant, larger randomized controlled trials are required to confirm these findings and determine if they are a class effect of all JAK inhibitors or specific to tofacitinib.
Regarding safety, 28 adverse events were reported among 13 participants. Most were mild to moderate, though one severe event (COVID-19 pneumonitis) occurred prior to the initiation of the study drug. The safety profile observed was generally consistent with the known risks of tofacitinib in the RA population.
Conclusion: A New Paradigm for RA Management
The RAMUS study provides the first human evidence that tofacitinib treatment is associated with significant increases in skeletal muscle volume in patients with rheumatoid arthritis. This discovery has two-fold importance: it offers a likely non-renal explanation for the increase in serum creatinine observed in clinical trials and highlights the potential for JAK inhibitors to treat rheumatoid cachexia.
Future research should focus on whether combining JAK inhibition with targeted physical rehabilitation can translate these volumetric gains into improved physical function and strength for patients living with RA.
Funding and Registration
This study was funded by Pfizer, the BMA Foundation, the JGW Patterson Foundation, and Newcastle Hospitals Charity. ClinicalTrials.gov/ISRCTN Identifier: ISRCTN13364395.
References
1. Bennett JL, Hollingsworth KG, Pratt AG, et al. Skeletal muscle effects of Janus kinase inhibition in rheumatoid arthritis (RAMUS): a single-arm, experimental medicine study. Lancet Rheumatol. 2026;8(1):e42-e52. doi:10.1016/S2665-9913(25)00184-5.
2. Wilkinson TJ, et al. Rheumatoid cachexia: a review of mechanisms and potential therapies. Journal of Cachexia, Sarcopenia and Muscle. 2021;12(3):543-560.
3. McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med. 2011;365:2205-2219.
