Muscle loss affects up to 43% of patients with rheumatoid arthritis (RA). Given its associations with disease activity and physical function, muscle loss in RA — sometimes referred to as RA sarcopenia, cachexia, or myopenia — represents an important focus of ongoing research.
In a study published in March 2021 in Arthritis Care and Research, Baker and colleagues examined predictors of changes in muscle density and strength and function in patients with RA aged between 18 and 70 years.1
Participants completed assessments at baseline and follow-up. Lean and fat mass and muscle density were assessed with whole-body dual-energy x-ray absorptiometry and peripheral quantitative computed tomography; hand, knee, and lower leg strength were measured with dynamometry; and disability and physical function were measured with the Health Assessment Questionnaire (HAQ) and the Short Physical Performance Battery (SPPB).
Regression analyses identified female sex, smoking, higher disease activity, and lower insulin-like growth factor 1 (IGF-1) levels as predictors of reduced muscle density.
Scores on the HAQ, SPPB, and 4-meter walk time indicated that lower muscle density was linked to deteriorating physical function. Greater baseline muscle density was associated with a lower risk for clinically significant reductions in HAQ score (odds ratio [OR], 1.90; 95% CI, 1.06-3.42; P =.03) and walking speed (OR, 2.87; 95% CI, 1.05-7.89; P =.04).
In another study, patients with RA with vs without baseline myopenia had elevated rates of 1-year radiographic progression (43.4% vs 21.5%, respectively; P <.05). Baseline myopenia was identified as an independent risk factor for radiographic progression (adjusted OR [aOR], 2.5), especially among patients in remission at baseline (aOR, approximately 18.5 to 42.9-fold).2
Research also suggests that elevated levels of serum myostatin could be a biomarker for increased risk for RA cachexia; high saturated fat intake may increase the risk for muscle loss in RA; increased dietary protein may help to prevent or treat RA cachexia; and high-intensity interval training may improve muscle dysfunction affecting patients with RA.3-6
In addition, a study published in 2021 in Rheumatology indicated that “muscle damage occurs in patients with RA, irrespective of disease phenotype, and that quantitative [magnetic resonance imaging] (MRI) is sensitive enough to identify these differences,” which could have a role in monitoring muscle changes in RA.7
To get a deeper insight into the management of muscle loss in RA, we interviewed Joshua F. Baker, MD, MSCE, associate professor of rheumatology and epidemiology at the Perelman School of Medicine at the University of Pennsylvania and Philadelphia VA Medical Center; Brian Andonian, MD, MHSc, assistant professor of medicine in the division of rheumatology and immunology at the Duke University School of Medicine and member of the Duke Molecular Physiology Institute in Durham, North Carolina; and Ira Khanna, MD, rheumatology fellow at the Icahn School of Medicine at Mount Sinai in New York.
What are the factors and mechanisms that may lead to muscle loss in RA?
Dr Baker: Muscle loss in RA is probably the result of multiple factors; however, the most important factor may be the effect of inflammation on muscle. Because inflammation uses up a lot of energy, the body preserves energy by inhibiting unnecessary energy usage, such as growth of muscle tissue. Inflammatory cytokines are thought to have direct toxicity to muscle. In addition, patients with RA may be physically inactive due to joint pain, which can cause muscle atrophy.
Dr Andonian:The mechanism of sarcopenia in RA is multifactorial, and chronic inflammation is a key driver. Roubenoff et al were the first to describe the muscle wasting state in RA and coined the term “rheumatoid cachexia.”8 The researchers showed that elevated systemic inflammation, identified by increased concentrations of the proinflammatory cytokines tumor necrosis factor (TNF)-alpha and interleukin (IL)-1-beta, is associated with a hypermetabolic state and loss of body mass in RA.
The connections between inflammation, altered metabolism, and loss of muscle mass are still being studied. For example, immune cells rely on amino acids, such as glutamine, as a major energy source to sustain activation. Because skeletal muscle is a large reservoir for amino acids in the body, chronic inflammation may drive muscle tissue breakdown to fuel the immune system.9
In addition to inflammation, physical inactivity and low levels of exercise may contribute to sarcopenia in RA. Finally, certain medications, such as corticosteroids, lead to reductions in muscle protein synthesis and can further worsen RA muscle loss.10
Dr Khanna: Muscle weakness is a common symptom in patients with RA; often referred to as “rheumatoid cachexia” or “rheumatoid sarcopenia,” the condition could be due to synovial inflammation. Decreased motion of painful joints can lead to atrophy of the surrounding muscles. Other possible mechanisms include oxidative stress due to inflammatory cytokines, drug-induced effects due to steroids or hydroxychloroquine, and rarely, the effects of associated myositis or rheumatoid vasculitis.
How common is muscle loss in patients with RA, and what are some of its clinical characteristics compared with, for example, age-related muscle density loss?
Dr Baker: Because muscle loss has been defined in many different ways, the number of patients with RA who have [muscle loss in RA] is not entirely clear. It is difficult to determine in clinic whether muscle loss has occurred due to aging or due to the disease itself.
Dr Andonian:Muscle loss in RA is an important and overlooked clinical characteristic in RA that may affect all patients with RA to varying degrees. Some patients with RA can have rapid unintentional weight loss, often triggering workup for secondary causes, such as cancer. Other patients with RA have subjective and objective loss of muscle function and physical disability. Importantly, physical disability in RA occurs early on during the course of disease and remains in excess to similarly aged individuals throughout the lifespan.11
Dr Khanna: While the exact prevalence is currently unknown due to the lack of consensus on its definition or methods of assessment, findings show that muscle wasting affects at least 10% to 20% of patients with controlled RA and more than 40% of patients with active RA.12 This is characterized by a high rate of loss of muscle mass and strength, typically with preservation or slight increase in fat mass.
RA cachexia differs from other forms of cachexia such as those observed in cancer, chronic heart failure, or kidney disease, as it is rarely accompanied by a net weight loss. Muscle loss in RA also differs from age-related reduction in muscle mass observed among older adults, as it occurs at a younger age and muscle mass loss progresses at a substantially higher rate in RA.
How does muscle loss affect functioning, quality of life, and disease outcomes in patients with RA?
Dr Baker: Muscle loss is strongly correlated with poor physical functioning and lower quality of life in patients with RA. It is not possible to do a randomized trial, and it is, therefore, possible that muscle loss occurs in tandem with other health-related changes and does not causethese problems. However, the rationale that muscle loss directly contributes to poor function is strong.
Dr Andonian:Muscle loss and overall muscle dysfunction are linked to high disease activity and lead to impaired physical functioning and poor quality of life. For example, accumulation of fat within skeletal muscle in RA is comparable with that of individuals without RA who are 15 years older.13 This early aging phenotype in RA of low muscle mass and high intramuscular fat is linked to high RA disease activity and poor physical function.1
Dr Khanna: RA-related muscle loss has been shown to be associated with poorer disease outcomes, including reduced quality of life, more fatigue, and increased overall morbidity and mortality. Low muscle mass has also been linked to dysmetabolic states such as insulin resistance and type 2 diabetes and may even be partly responsible for the increased cardiovascular risk observed in RA.14
How should clinicians screen for and monitor muscle loss in patients with RA, and are effective strategies for their prevention and treatment?
Dr Baker: Recent guidelines have suggested screening for muscle loss using the “SARC-F” questionnaire.15 Further testing for muscle weakness can be performed, though it may not be necessary to initiate a treatment plan. Severity of physical limitations can be evaluated using simple tests that can be performed in clinic, such as the Timed Up and Go Test or a test of gait speed.
Increases in physical activity, including strength training, are very likely to be of value. The limitation for clinicians is the lack of resources — other than brief courses of physical therapy — to prescribe such interventions or to help patients adhere to an exercise regimen.
Dr Andonian: Patients with RA should be screened and monitored for muscle loss with proper body composition assessment.10 Body mass index is not a reliable tool for screening of muscle loss in RA because it does not differentiate between fat and lean mass. Fat and lean mass should be assessed using skinfolds, air displacement plethysmography, bioelectrical impedance (BIA), or dual-energy x-ray absorptiometry (DXA).
However, these body composition assessments can be costly, are not commonly covered by insurance providers, and are not available in most clinical settings. Regardless, assessment of muscle function can be assessed in the clinic via routine history taking, physical disability screening questionnaires, and objective measurement such as hand grip dynamometry, the 30-Second Chair Stand Test, or the 6-minute walk test.
The best strategy for preventing and treating muscle loss and muscle dysfunction in RA is to control inflammatory disease activity. However, based on available evidence, use of synthetic or biologic disease modifying antirheumatic drugs (DMARDs) does not appear to impact muscle mass in patients with RA.16 This represents an area for future research.
Further, patients with RA should try to avoid medications that can be toxic to the muscle — for example, corticosteroids.
Finally, patients with RA should be prescribed muscle strengthening exercises 2 to 3 days per week involving all major muscle groups. Exercise therapy, in particular resistance training exercise, has the greatest available evidence for improving muscle mass, quality, and function.17
Dr Khanna: We can screen for rheumatoid sarcopenia by monitoring patients’ disease activity, muscle strength, and body weight. However, more objective ways to measure muscle mass could include BIA to measure fat free mass and DXA to measure lean body mass.
There are no established guidelines regarding prevention and treatment of muscle loss in RA, but general strategies include controlling RA disease activity to decrease systemic inflammation and pursuing an adequate exercise program. The latter could include aerobic exercise like cycling — which may need to be modified for patients with severe joint damage — or resistance training. Multiple studies have shown that exercise is a safe intervention for patients with RA that can reverse muscle wasting and increase muscle mass, and hence, should be encouraged.
- Association of low muscle density with deteriorations in muscle strength and physical functioning in rheumatoid arthritis. Arthritis Care Res (Hoboken). 2021;73(3):355-363. doi:10.1002/acr.24126
- Reduced skeletal muscle independently predicts 1-year aggravated joint destruction in patients with rheumatoid arthritis. Ther Adv Musculoskelet Dis. 2020;12:1759720X20946220. doi:10.1177/1759720X20946220
- Levels and the risk of myopenia and rheumatoid cachexia in women with rheumatoid arthritis. J Immunol Res. 2022;2022:7258152. doi:10.1155/2022/7258152
- , Tsutsumi R, Senoura S, et al. Saturated fatty acids intake is associated with muscle atrophy in rheumatoid arthritis. JCSM Rapid Communications. 2022;5:86-101. doi:10.1002/rco2.53
- , Zhao J, Heitman K, et al. Interaction effect of systemic inflammation and modifiable rheumatoid cachexia risk factors on resting energy expenditure in patients with rheumatoid arthritis. JCSM Clinical Reports. 2022;7:12–23. doi:10.1002/crt2.45.
- Rheumatoid arthritis T cell and muscle oxidative metabolism associate with exercise-induced changes in cardiorespiratory fitness. Sci Rep. 2022;12(1):7450. doi:10.1038/s41598-022-11458-4
- Muscle deterioration due to rheumatoid arthritis: assessment by quantitative MRI and strength testing. Rheumatology (Oxford). 2021;60(3):1216-1225. doi:10.1093/rheumatology/keaa364
- Rheumatoid cachexia: cytokine-driven hypermetabolism accompanying reduced body cell mass in chronic inflammation. J Clin Invest. 1994;93(6):2379-2386. doi:10.1172/JCI117244
- Altered skeletal muscle metabolic pathways, age, systemic inflammation, and low cardiorespiratory fitness associate with improvements in disease activity following high-intensity interval training in persons with rheumatoid arthritis. Arthritis Res Ther. 2021;23(1):187. doi:10.1186/s13075-021-02570-3
- Skeletal muscle disease in rheumatoid arthritis: the center of cardiometabolic comorbidities? Curr Opin Rheumatol. 2020;32(3):297-306. doi:10.1097/BOR.0000000000000697
- Trends in prevalence of functional disability in rheumatoid arthritis compared with the general population. Mayo Clin Proc. 2019;94(6):1035-1039. doi:10.1016/j.mayocp.2019.01.002
- Muscle wasting in rheumatoid arthritis: the role of oxidative stress. World J Rheumatol. 2014;4(3):44-53. doi:10.5499/wjr.v4.i3.44
- Skeletal muscle fat in individuals with rheumatoid arthritis compared to healthy adults. Exp Gerontol. 2020;129:110768. doi:10.1016/j.exger.2019.110768
- Relationship between low relative muscle mass and coronary artery calcification in healthy adults. Arterioscler Thromb Vasc Biol. 2016;36(5):1016-1021. doi:10.1161/ATVBAHA.116.307156
- The assessment of muscle mass and function in patients with long-standing rheumatoid arthritis. J Clin Med. 2021;10(16):3458. doi:10.3390/jcm10163458
- The effect of disease-modifying anti-rheumatic drugs on skeletal muscle mass in rheumatoid arthritis patients: a systematic review with meta-analysis. Arthritis Res Ther. 2022;24(1):171. doi:10.1186/s13075-022-02858-y
- Exercise therapy for sarcopenia in rheumatoid arthritis: a meta-analysis and meta-regression of randomized controlled trials. Clin Rehabil. 2022;36(2):145-157. doi:10.1177/02692155211035539