Skeletal Muscle Alterations Found to be Related to Disease Activity in Patients with RA

Nancy E. Lane, MD

Rheumatoid arthritis is a chronic systemic inflammatory disease in which the major clinical manifestations are pain and swelling in the synovial lined joints. However, the other organs of the body are also affected from the systemic inflammatory state, and muscle is no exception.

While rheumatologists have long known that patients with active rheumatoid arthritis (RA) have muscle weakness, the field has been slow to investigate the changes in muscle with both the systemic inflammation and response to effective therapies. However, most rheumatologists acknowledge there is probably a low correlation between the reduction in joint swelling and muscle function.

Huffman and colleagues performed a detailed evaluation molecular evaluation of muscle tissue including pro-inflammatory cytokines, transcriptomes and metabolic profiling in RA patients and controls. Compared to controls, RA patients had higher muscle concentrations of inflammatory cytokines, including IL-6, more skeletal muscle repair processes, glycolic metabolism, pyruvate and amino acids associated with fibrosis. In addition, muscle molecular muscle markers were correlated with active disease but not with circulating inflammatory cytokines.

These results support our clinical observation that muscle changes accompany the systemic inflammation of RA and our standard serum assessments of inflammation does not appear to reflect the degree of muscle tissue inflammation. Therefore, research now should be directed to determine inflammatory biomarkers that are sensitive and specific to muscle tissue.

While both clinical and tissue evidence now exists that shows that muscle tissue changes are present in an inflammatory state, including elevated IL-6 concentrations, we should be careful to not too quickly extrapolate that systemic treatment with an IL-6 inhibitor will reduce the muscle inflammation observed in active RA. Muscle needs IL-6 to regenerate, it is often referred to as a muscle growth factor and inhibition may reduce the ability of muscle to remodel tissue. Also, bone and muscle metabolism are linked through crosstalk and changes in these tissues in the presence of inflammation occur simultaneously, and therefore need to be investigated together.

This cross-sectional study clearly demonstrates that the systemic inflammation of RA affects the muscle, and the clinical observation of muscle weakness in our patients is most likely the result of muscle inflammation that then reduces muscle function. We now need to perform longitudinal studies that assess muscle biology, metabolism and function at the time of an RA diagnosis, the changes that occur over time when the disease transitions from early to later stages and how muscle biology responses to biologic therapies reduce the joint inflammation. A more comprehensive understanding of muscle biology in the presence of the systemic inflammation in RA will allow clinicians to improve treatments such that we reduce the musculoskeletal disabilities that accompany RA.