Muscle Pathology in Rheumatoid Arthritis: The Effects of Inflammation and Insulin Resistance
Exercise reduces insulin resistance to benefit patients with rheumatoid arthritis, but additional studies across specialties are needed.
Patients with rheumatoid arthritis (RA) typically experience reduced physical function early in the course of disease, with physical impairment accelerating over time to a greater degree than what is expected with normal aging.1 Even patients who have achieved low disease activity or remission through treat-to-target strategies have the physical function of healthy individuals 25 years older.2 Compared with the general population, individuals with RA are more sedentary and exercise less frequently.3 Although joint pain, swelling, and deformity have long been regarded as the primary contributors to functional disability in patients with RA,4,5 the downstream effect of inflammation on skeletal muscle has been implicated as another important cause.6
Unfavorable changes in body composition are common in patients with RA and believed to be mediated through metabolic perturbations.7 Rheumatoid cachexia, characterized by a decrease in lean muscle mass and an increase in total fat mass, is present in approximately 67% of individuals with stable RA, while obesity occurs in approximately 80%.2 Greater amounts of total and appendicular fat mass place patients with RA at higher risk for disability, while greater appendicular lean mass predicts lower rates of disability.5 Although there have been conflicting findings, some studies suggest that patients with RA are at an elevated risk for metabolic syndrome, a condition characterized by abdominal obesity, lipid abnormalities, hyperglycemia, and high blood pressure.8
In a recent review, Beatriz Hanaoka, MD, of the University of Alabama at Birmingham, and colleagues, discussed the mechanisms by which inflammation and insulin resistance exert deleterious effects on skeletal muscle homeostasis and function.9 Many of the proinflammatory cytokines implicated in the pathogenesis of RA, including interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α, play a role in the loss of muscle mass by accelerating proteasome-dependent proteolysis and inhibiting anabolic and/or anticatabolic signaling.9 Excessive proinflammatory cytokines such as TNF-α can reduce the storage capacity of adipocytes in primary fat depots by suppressing the recruitment and differentiation of new adipocytes, resulting in the deposition of adipocytes in non-adipose tissues, including skeletal muscle.9,10 The infiltration of fat into muscle is associated with impaired physical function and low physical activity levels in patients with RA, an effect not seen in patients with fat accumulation outside the muscle.11 Insulin resistance is highly prevalent in patients with RA and has been associated with the loss of lean muscle mass.3 Factors associated with greater rates of insulin resistance in patients with RA include:
- rheumatoid factor seropositivity
- prednisone use
- greater RA disease activity
- visceral and thigh intermuscular adiposity
While the exact relationship between insulin resistance and impaired physical function in RA is undetermined, insulin and insulin-like growth factor 1 have been shown to play a role in muscle mass regulation via the AKT signal transduction pathway, which promotes cell growth and proliferation.9 A recent study concluded that abdominal and thigh adiposity played a bigger role in skeletal muscle insulin sensitivity than disease-related factors such as cytokines or systemic inflammation.12
Reduced functional ability in RA can perpetuate a vicious cycle. Patients with reduced functionality are less likely to engage in physical activity and more likely to be sedentary; sedentary behavior in turn contributes to heightened systemic inflammation, which may further reduce functional ability and lead to worsened RA- and cardiovascular-related health outcomes.6 Intensive exercise was formerly discouraged in patients with RA based on the erroneous belief that it could exacerbate inflammation and lead to further joint damage.13 Today, there is a considerable body of evidence showing that free-living physical activity and structured exercise in patients with RA improves joint health, cardiovascular risk factors, physical function, mobility, body composition and fatigue without detrimental effects.9,13,14 Physical activity, especially activities involving high energy expenditure and high exercise intensity, is known to reduce the risk for insulin resistance and metabolic syndrome.9,15 However, these effects have not yet been specifically demonstrated in patients with RA.9 In their review, Dr Hanoaka and colleagues noted that further research is warranted regarding the interrelationships of inflammation, ectopic adipose, and muscle dysfunction, and for optimizing exercise prescriptions for RA via dose-response trials.9
Patients with RA report that impediments to physical activity and exercise can be attributed to:16
- too little time
- low motivation
- reduced mobility and functional ability
One of the strongest correlates for exercise in patients with RA is motivation and self-efficacy — the belief in one's ability to succeed.17 Support from clinicians, instructors, friends, and family has been consistently identified as a factor that can facilitate exercise participation.16 Kelly Weselman, MD, a rheumatologist with WellStar Health System in Smyrna, Georgia, advises that clinicians encourage patients with RA to exercise by providing specific advice on appropriate types of activities for their condition. “Encourage patients to make a schedule and gradually increase the duration and intensity of their exercise. Often patients are not sure what they should be doing for exercise, so some detailed guidance is helpful,” she noted. “Sometimes the barriers are overcome with simple modification suggestions, such as wearing wrist splints when performing resistance training, or doing pushups not with the wrists bent but with a device such as Perfect Pushups to keep the wrists straight. Helping patients realize that making some modifications to their exercise will make it less stressful on the joints can be the trick to overcome obstacles. Everyone is different, so exploring the barriers can help. Alternatively, enlisting the services of a physical therapist or trainer who is familiar with RA can help people get started exercising appropriately.”
- Norton S, Sacker A, Dixey J, et al. Trajectories of functional limitation in early rheumatoid arthritis and their association with mortality. Rheumatology (Oxford). 2013;52(11):2016-2024.
- Lemmey AB, Wilkinson TJ, Clayton RJ, et al. Tight control of disease activity fails to improve body composition or physical function in rheumatoid arthritis patients. Rheumatology (Oxford). 2016;55(10):1736-1745.
- Hugo M, Mehsen-Cetre N, Pierreisnard A, Schaeverbeke T, Gin H, Rigalleau V. Energy expenditure and nutritional complications of metabolic syndrome and rheumatoid cachexia in rheumatoid arthritis: an observational study using calorimetry and actimetry. Rheumatology (Oxford). 2016;55(7):1202-1209.
- Scott DL, Pugner K, Kaarela K, et al. The links between joint damage and disability in rheumatoid arthritis. Rheumatology (Oxford). 2000;39(2):122-132.
- Giles JT, Bartlett SJ, Andersen RE, Fontaine KR, Bathon JM. Association of body composition with disability in rheumatoid arthritis: impact of appendicular fat and lean tissue mass. Arthritis Rheum. 2008;59(10):1407-1415.
- Fenton SAM, Veldhuijzen van Zanten JJCS, Duda JL, Metsios GS, Kitas GD. Sedentary behaviour in rheumatoid arthritis: definition, measurement and implications for health. Rheumatology (Oxford). 2018;57(2):213-226.
- Dessein PH, Solomon A, Hollan I. Metabolic abnormalities in patients with inflammatory rheumatic diseases. Best Pract Res Clin Rheumatol. 2016;30(5):901-915.
- Hallajzadeh J, Safiri S, Mansournia MA, et al. Metabolic syndrome and its components among rheumatoid arthritis patients: a comprehensive updated systematic review and meta-analysis. PLoS One. 2017;12(3):e0170361.
- Hanaoka BY, Ithurburn MP, Rigsbee CA, et al. Chronic inflammation in rheumatoid arthritis and mediators of skeletal muscle pathology and physical impairment: a review [published online October 8, 2018]. Arthritis Care Res (Hoboken). doi:10.1002/acr.23775
- Cawthorn WP, Sethi JK. TNF-α and adipocyte biology. FEBS Lett. 2008;582(1):117-131.
- Khoja SS, Moore CG, Goodpaster BH, Delitto A, Piva SR. Skeletal muscle fat and its association with physical function in rheumatoid arthritis. Arthritis Care Res (Hoboken). 2018;70(3):333-342.
- AbouAssi H, Tune KN, Gilmore B, et al. Adipose depots, not disease-related factors, account for skeletal muscle insulin sensitivity in established and treated rheumatoid arthritis. J Rheumatol. 2014;41(10):1974-1979.
- de Jong Z, Munneke M, Zwinderman AH, et al. Is a long-term high-intensity exercise program effective and safe in patients with rheumatoid arthritis? Results of a randomized controlled trial. Arthritis Rheum. 2003;48(9):2415-2424.
- Rausch Osthoff A-K, Juhl CB, Knittle K, et al. Effects of exercise and physical activity promotion: meta-analysis informing the 2018 EULAR recommendations for physical activity in people with rheumatoid arthritis, spondyloarthritis and hip/knee osteoarthritis. RMD Open. 2018;4(2): e000713.
- Bird SR, Hawley JA. Update on the effects of physical activity on insulin sensitivity in humans. BMJ Open Sport Exerc Med. 2016;2(1):e000143.
- Veldhuijzen van Zanten JJCS, Rouse PC, Hale ED, et al. Perceived barriers, facilitators and benefits for regular physical activity and exercise in patients with rheumatoid arthritis: a review of the literature. Sports Med. 2015;45(10):1401-1412.
- Huffman KM, Pieper CF, Hall KS, St Clair EW, Kraus WE. Self-efficacy for exercise, more than disease-related factors, is associated with objectively assessed exercise time and sedentary behaviour in rheumatoid arthritis. Scand J Rheumatol. 2015;44(2):106-110.