Skeletal Muscle Disease and Cardiometabolic Dysfunction in Rheumatoid Arthritis

skeletal muscle
skeletal muscle
Skeletal muscle alterations in rheumatoid arthritis are often overlooked despite their important role in disability and cardiometabolic disease development.

Skeletal muscle disease in patients with rheumatoid arthritis (RA) may contribute to disability and cardiometabolic disease. In a review published in Current Opinion in Rheumatology, changes in RA skeletal muscle phenotypes after the introduction of biologic disease-modifying antirheumatic drugs (bDMARDs) and recommended management strategies to improve RA skeletal muscle function were discussed.

While bDMARDs have had a significant effect on care for patients with RA, the insidious pathogenesis of the disease leads to high risks for disability, cardiometabolic disease, and early mortality in patients with RA.

Skeletal muscle is important for body structure, movement, and metabolism. Skeletal muscle impairment in RA can result from 3 factors: inflammation, physical inactivity, and medication toxicity. Significant fatigue, joint swelling, and joint damage with pain are common in RA and result in physical inactivity and poor aerobic capacity. Inflammation is another important factor in RA skeletal muscle disease, although there is usually no infiltration of immune cells into the muscle. Medications may also play a significant role; for example, chronic corticosteroid treatment is associated with reduced muscle synthesis.

The clinical features of RA skeletal disease may include reduced strength and muscle mass and impaired endurance or oxidative metabolism.

Prior to the introduction of bDMARDs, RA skeletal disease was mainly driven by cachexia, wasting state with reduced body cell mass, and chronic systemic inflammation, referred to as a hypermetabolic state. However, at present, RA skeletal disease is generally characterized by a hypometabolic state with decreased skeletal muscle mass, increased fat mass, and intramuscular adiposity. Thus, the current DMARD era is characterized by sarcopenic obesity, as excessive body fat mass and intramuscular fat accumulation contribute to functional impairment.

Cardiovascular Disease in RA

Inflammation, altered lipid profile, and altered body composition are RA-specific risk factors for cardiovascular disease (CVD) that are largely the result of disease-associated chronic inflammation. Impaired glucose tolerance and skeletal muscle insulin resistance are common in patients with RA and result from inflammation, chronic corticosteroid use, and intramuscular adiposity. Alterations in lipoprotein particle size also contribute to increased CVD risk among patients with RA, despite a unique lipid profile characterized by low concentrations of total and low-density lipoprotein cholesterol in these patients.

These disease-specific risk factors may be present alongside traditional risk factors, such as physical inactivity, smoking, and insulin resistance/type 2 diabetes. Risk factors for CVD have bidirectional interactions with muscle disease; for instance, physical inactivity contributes to muscle disease, which in turn contributes to inactivity.

Medications Effects on Skeletal Muscle

Medications used to treat RA may also have a significant effect on skeletal muscle and cardiometabolic disease in patients with RA. However, the exact mechanisms responsible for the effects of RA pharmacotherapy on muscle function, body composition, and cardiometabolic risk remain unclear.

Corticosteroid use is associated with reduced skeletal muscle function and mass, along with increased fat mass and increased CVD risk, particularly at dose equivalents of prednisone 7.5 mg daily or greater.

There are limited data on the effects of other RA medications on the skeletal muscle and more studies are required. Nonsteroidal anti-inflammatory drugs (NSAIDs), antimalarials, and methotrexate have mixed effects on skeletal muscle mass or fat mass, but while NSAID use is associated with increased CVD risk, the other medications may have an advantageous effect on CVD risk.

Tumor necrosis factor (TNF) inhibitors can increase fat mass but no effect on skeletal muscle function or mass has been seen. These agents may also decrease CVD risk. Interleukin-6 or janus kinase/signal transducer activator of transcription (JAK-STAT) inhibition is also reported to improve CVD risk in patients with RA.

Statins have a beneficial effect on CVD risk in both the general population and in patients with RA, and they also have important anti-inflammatory properties. There are reports that statins may reduce skeletal muscle function, but based on current evidence, they have no apparent effect on fat or skeletal muscle mass.

Management of Skeletal Muscle Disease in RA

After assessment of baseline skeletal muscle health, including assessment of body composition and muscle function, it is recommended to start with synthetic DMARD treatment, such as methotrexate, or to add a bDMARD to control disease activity. Avoiding continuous use of systemic corticosteroids and reviewing the potential risk for muscle toxicity with other medications are important steps in minimizing the risk for medication toxicity.

Exercise training may improve skeletal muscle mass and function and reduce fat mass and CVD risk. The recommended regimen includes strength/resistance training exercises 2 to 3 days per week and endurance/aerobic exercise building up to 150 minutes per week, along with ongoing range-of-motion and light exercise during periods of active disease.

Medication change should be considered when skeletal muscle disease persists, including discontinuation of statins or antimalarials medication and switching from a TNF inhibitor to another bDMARD, such as an interleukin-6/JAK inhibitor.


Brian Andonian, MD, of the division of rheumatology at Duke University School of Medicine in Durham, North Carolina, first author of the review published in Current Opinion in Rheumatology, summarized his main conclusions for clinicians.

“My biggest takeaways from this review are: 1) the skeletal muscle abnormalities seen in RA have changed over time from the wasting state of rheumatoid cachexia to sarcopenic obesity in the current era of widespread biologic DMARD use; 2) it is important for clinicians to recognize sarcopenic obesity in RA because this disease-associated muscle phenotype is linked to functional deficits, disability, and cardiometabolic risk; 3) some of the most common drugs rheumatologists use to treat RA (especially corticosteroids, but also NSAIDS, TNF inhibitors, and hydroxychloroquine to a lesser extent) may contribute adversely to sarcopenic obesity and muscle disease in RA; and 4) the most evidence-based therapy option for management of RA skeletal muscle disease and sarcopenic obesity is combined aerobic and resistance training,” stated Dr Andonian.

“Ultimately, it is my hope that by reading this review, clinicians will be more aware of skeletal muscle disease as a neglected organ system that is severely impacted by RA and prescribe exercise training as part of routine care for RA for this reason,” Dr Andonian concluded.


Andonian BJ, Huffman KM. Skeletal muscle disease in rheumatoid arthritis: the center of cardiometabolic comorbidities? Curr Opin Rheumatol. 2020;32(3):297‐306.