Pathophysiology of Myopenia in rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) is a prevalent and debilitating inflammatory disease that significantly impairs functional capacity and quality of life. RA accelerates musculoskeletal aging, leading to complications such as muscle degeneration and sarcopenia. Recent research has identified myopenia as a condition of significant muscle loss associated with illness, distinct from the muscle wasting seen in other chronic diseases like cancer cachexia or heart failure. In RA, myopenia is characterized by muscle depletion without concurrent significant fat loss, and it can affect individuals of all ages. While inflammation plays a central role, it is not the sole factor contributing to the high incidence of muscle wasting in RA. In subsequent discussions, secondary sarcopenia will be considered alongside myopenia, as both involve muscle wasting decline primarily due to disease. This review summarizes recent findings on the impact of RA-related myopenia and secondary sarcopenia on functional capacity, explores its underlying mechanisms, and discusses contemporary strategies to mitigate the process of musculoskeletal aging in RA patients.

References

[1] Xu, D.F., Xu, J. & Dai, L. Myopenia and musculoskeletal aging in rheumatoid arthritis. Rheumatoid Arthritis - Other Perspectives towards a Better Practice (2020).

[2] El-LabbanAS, OmarHA, El-ShereifRR, AliF, El-MansouryTM. Pattern of young and old onset rheumatoid arthritis (YORA and EORA) among a group of egyptian patients with rheumatoid arthritis. Clin. Med. Insights Arthritis Musculoskelet. Disord., 2010, 3: 25-31

[3] RaschEK, HirschR, Paulose-RamR, HochbergMC. Prevalence of rheumatoid arthritis in persons 60 years of age and older in the United States: effect of different methods of case classification. Arthritis Rheum., 2003, 48: 917-926

[4] MaJD, et al.. Muscle wasting, a neglected complication associated with physical dysfunction in elderly patients with rheumatoid arthritis: a cross-sectional observational study. Scand. J. Rheumatol., 2021, 50: 280-289

[5] FearonK, EvansWJ, AnkerSD. Myopenia-a new universal term for muscle wasting. J. Cachexia Sarcopenia Muscle, 2011, 2: 1-3

[6] Gonzalez-PonceF, et al.. Myostatin levels and the risk of myopenia and rheumatoid cachexia in women with rheumatoid arthritis. J. Immunol. Res, 2022, 2022: 7258152

[7] CarnacG, VernusB, BonnieuA. Myostatin in the pathophysiology of skeletal muscle. Curr. Genomics, 2007, 8: 415-422

[8] WabeN, WieseMD. Treating rheumatoid arthritis to target: physician and patient adherence issues in contemporary rheumatoid arthritis therapy. J. Eval. Clin. Pr., 2017, 23: 486-493

[9] AletahaD, SmolenJS. Diagnosis and management of rheumatoid arthritis: A review. JAMA, 2018, 320: 1360-1372

[10] MitchellWK, et al.. Sarcopenia, dynapenia, and the impact of advancing age on human skeletal muscle size and strength; a quantitative review. Front Physiol., 2012, 3: 260

[11] Landers-RamosRQ, PriorSJ. The microvasculature and skeletal muscle health in aging. Exerc Sport Sci. Rev., 2018, 46: 172-179

[12] KunzHE, LanzaIR. Age-associated inflammation and implications for skeletal muscle responses to exercise. Exp. Gerontol., 2023, 177: 112177

[13] NariciMV, MaffulliN. Sarcopenia: characteristics, mechanisms and functional significance. Br. Med Bull., 2010, 95: 139-159

[14] ThomasDR. Loss of skeletal muscle mass in aging: examining the relationship of starvation, sarcopenia and cachexia. Clin. Nutr., 2007, 26: 389-399

[15] FriedLP, et al.. Frailty in older adults: Evidence for a phenotype. J. Gerontol. A Biol. Sci. Med Sci., 2001, 56: M146-M156

[16] BauerJ, et al.. Sarcopenia: A time for action. An SCWD position paper. J. Cachexia Sarcopenia Muscle, 2019, 10: 956-961

[17] LarssonL, et al.. Sarcopenia: aging-related loss of muscle mass and function. Physiol. Rev., 2019, 99: 427-511

[18] RoubenoffR, et al.. Rheumatoid cachexia: cytokine-driven hypermetabolism accompanying reduced body cell mass in chronic inflammation. J. Clin. Invest, 1994, 93: 2379-2386

[19] RajbhandaryR, KhezriA, PanushRS. Rheumatoid cachexia: What is it and why is it important?. J. Rheumatol., 2011, 38: 406-408

[20] RoubenoffR. Rheumatoid cachexia: a complication of rheumatoid arthritis moves into the 21st century. Arthritis Res Ther., 2009, 11: 108

[21] GregersenPK, SilverJ, WinchesterRJ. The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum., 1987, 30: 1205-1213

[22] MatteyDL, et al.. Independent association of rheumatoid factor and the HLA-DRB1 shared epitope with radiographic outcome in rheumatoid arthritis. Arthritis Rheum., 2001, 44: 1529-1533

[23] WeyandCM, HicokKC, ConnDL, GoronzyJJ. The influence of HLA-DRB1 genes on disease severity in rheumatoid arthritis. Ann. Intern Med, 1992, 117: 801-806

[24] Gonzalez-GayMA, et al.. Seronegative rheumatoid arthritis in elderly and polymyalgia rheumatica have similar patterns of HLA association. J. Rheumatol., 2001, 28: 122-125

[25] KimEJ, et al.. Shared epitope and radiologic progression are less prominent in elderly onset RA than young onset RA. Rheumatol. Int, 2013, 33: 2135-2140

[26] HellierJP, EliaouJF, DaurèsJP, SanyJ, CombeB. HLA-DRB1 genes and patients with late onset rheumatoid arthritis. Ann. Rheum. Dis., 2001, 60: 531-533

[27] WuH, et al.. Interaction between RANKL and HLA-DRB1 genotypes may contribute to younger age at onset of seropositive rheumatoid arthritis in an inception cohort. Arthritis Rheum., 2004, 50: 3093-3103

[28] ZhangTP, et al.. The contribution of genetic variation and aberrant methylation of aryl hydrocarbon receptor signaling pathway genes to rheumatoid arthritis. Front Immunol., 2022, 13: 823863

[29] HuangH, et al.. Identification of key candidate genes and pathways in rheumatoid arthritis and osteoarthritis by integrated bioinformatical analysis. Front Genet, 2023, 14: 1083615

[30] GaratacheaN, LucíaA. Genes and the ageing muscle: A review on genetic association studies. Age (Dordr.), 2013, 35: 207-233

[31] WenYP, YuZG. Identifying shared genetic loci and common risk genes of rheumatoid arthritis associated with three autoimmune diseases based on large-scale cross-trait genome-wide association studies. Front Immunol., 2023, 14: 1160397

[32] ShaoM, et al.. Association of interleukin-6 promoter polymorphism with rheumatoid arthritis: a meta-analysis with trial sequential analysis. Clin. Rheumatol., 2022, 41: 411-419

[33] PunziL, et al.. Synovial fluid levels of proinflammatory interleukins and their inter-relationships in elderly vs younger onset rheumatoid arthritis. Aging (Milano), 1996, 8: 277-281

[34] Miesel, R., Murphy, M. P. & Kröger, H. Enhanced mitochondrial radical production in patients with rheumatoid arthritis correlates with elevated levels of tumor necrosis factor alpha in plasma. Free Radic. Res. 25, 161–169 (1996).

[35] Dodd, S. L., Gagnon, B. J., Senf, S. M., Hain, B. A. & Judge, A. R. ROS-mediated activation of NF-κB and Foxo during muscle disuse. Muscle Nerve 41, 110–113 (2010).

[36] Stavropoulos-Kalinoglou, A. Muscle wasting in rheumatoid arthritis: The role of oxidative stress. World J. Rheumatol. 4, 44–53 (2014).

[37] Poniewierska-Baran, A., Bochniak, O., Warias, P. & Pawlik, A. Role of sirtuins in the pathogenesis of rheumatoid arthritis. Int. J. Mol. Sci. 24, 1532 (2023).

[38] FouaniM, et al.. Heat shock proteins alterations in rheumatoid arthritis. Int. J. Mol. Sci., 2022, 23: 5828

[39] Gyebrovszki, B. et al. The role of IgG Fc region N-glycosylation in the pathomechanism of rheumatoid arthritis. Int. J. Mol. Sci. 23, 5828 (2022).

[40] NishimuraK, et al.. Meta-analysis: Diagnostic accuracy of anti-cyclic citrullinated peptide antibody and rheumatoid factor for rheumatoid arthritis. Ann. Intern Med., 2007, 146: 797-808

[41] BizzaroN, et al.. Anti-cyclic citrullinated peptide antibody titer predicts time to rheumatoid arthritis onset in patients with undifferentiated arthritis: Results from a 2-year prospective study. Arthritis Res Ther., 2013, 15: R16

[42] MalmströmV, CatrinaAI, KlareskogL. The immunopathogenesis of seropositive rheumatoid arthritis: from triggering to targeting. Nat. Rev. Immunol., 2017, 17: 60-75

[43] PadyukovL, et al.. A genome-wide association study suggests contrasting associations in ACPA-positive versus ACPA-negative rheumatoid arthritis. Ann. Rheum. Dis., 2011, 70: 259-265

[44] SchuerweghAJ, et al.. Evidence for a functional role of IgE anticitrullinated protein antibodies in rheumatoid arthritis. Proc. Natl. Acad. Sci. USA, 2010, 107: 2586-2591

[45] van DongenH, et al.. Efficacy of methotrexate treatment in patients with probable rheumatoid arthritis: A double-blind, randomized, placebo-controlled trial. Arthritis Rheum., 2007, 56: 1424-1432

[46] SellamJ, et al.. B cell activation biomarkers as predictive factors for the response to rituximab in rheumatoid arthritis: a six-month, national, multicenter, open-label study. Arthritis Rheum., 2011, 63: 933-938

[47] Straub, R. H., Lehle, K., Herfarth, H., Weber, M., Falk, W., Preuner, J. & Schölmerich, J. Dehydroepiandrosterone in relation to other adrenal hormones during an acute inflammatory stressful disease state compared with chronic inflammatory disease: role of interleukin-6 and tumour necrosis factor. Eur. J. Endocrinol. 146, 365–374 (2002).

[48] BennettJL, PrattAG, DoddsR, SayerAA, IsaacsJD. Rheumatoid sarcopenia: loss of skeletal muscle strength and mass in rheumatoid arthritis. Nat. Rev. Rheumatol., 2023, 19: 239-251

[49] ZandersL, et al.. Sepsis induces interleukin 6, gp130/JAK2/STAT3, and muscle wasting. J. Cachexia Sarcopenia Muscle, 2022, 13: 713-727

[50] GamerithF, et al.. Differences in anti-Fab antibodies in adult and late onset rheumatoid arthritis. Rheumatol. Int, 1993, 13: 107-112

[51] MitraA, QaisarR, BoseB, SudheerSP. The elusive role of myostatin signaling for muscle regeneration and maintenance of muscle and bone homeostasis. Osteoporos. Sarcopenia, 2023, 9: 1-7

[52] LinJZ, et al.. Myokine myostatin is a novel predictor of one-year radiographic progression in patients with rheumatoid arthritis: A prospective cohort study. Front Immunol., 2022, 13: 1005161

[53] ItohY, SaitohM, MiyazawaK. Smad3–STAT3 crosstalk in pathophysiological contexts. Acta Biochimica et. Biophysica Sin., 2018, 50: 82-90

[54] ShawCS, ClarkJ, WagenmakersAJM. The effect of exercise and nutrition on intramuscular fat metabolism and insulin sensitivity. Annu. Rev. Nutr., 2010, 30: 13-34

[55] DuH, et al.. Advanced glycation end products induce skeletal muscle atrophy and insulin resistance via activating ROS-mediated ER stress PERK/FOXO1 signaling. Am. J. Physiol. Endocrinol. Metab., 2023, 324: E279-E287

[56] JohnsonDE, O'KeefeRA, GrandisJR. Targeting the IL-6/JAK/STAT3 signalling axis in cancer.. Nat. Rev. Clin. Oncol., 2018, 15: 234-248

[57] EskilerGG, et al.. IL-6 mediated JAK/STAT3 signaling pathway in cancer patients with cachexia. Bratisl. Lek. Listy, 2019, 66: 819-826

[58] HuffmanKM, et al.. Molecular alterations in skeletal muscle in rheumatoid arthritis are related to disease activity, physical inactivity, and disability. Arthritis Res Ther., 2017, 19: 12

[59] HealeyLA. Subsets of rheumatoid arthritis in the aged. Arthritis Rheum., 1986, 29: 149

[60] HealeyLA, SheetsPK. The relation of polymyalgia rheumatica to rheumatoid arthritis. J. Rheumatol., 1988, 15: 750-752

[61] McCartyDJ, O’DuffyJD, PearsonL, HunterJB. Remitting seronegative symmetrical synovitis with pitting edema. RS3PE syndrome. Jama, 1985, 254: 2763-2767

[62] InoueK, ShichikawaK, NishiokaJ, HirotaS. Older age onset rheumatoid arthritis with or without osteoarthritis. Ann. Rheum. Dis., 1987, 46: 908-911

[63] GoemaereS, et al.. Onset of symptoms of rheumatoid arthritis in relation to age, sex and menopausal transition. J. Rheumatol., 1990, 17: 1620-1622

[64] FerraccioliGF, et al.. Clinical features, scintiscan characteristics and X-ray progression of late onset rheumatoid arthritis. Clin. Exp. Rheumatol., 1984, 2: 157-161

[65] TurkcaparN, et al.. Late onset rheumatoid arthritis: clinical and laboratory comparisons with younger onset patients. Arch. Gerontol. Geriatr., 2006, 42: 225-231

[66] van der HeijdeDM, et al.. Older versus younger onset rheumatoid arthritis: results at onset and after 2 years of a prospective followup study of early rheumatoid arthritis. J. Rheumatol., 1991, 18: 1285-1289

[67] ChenDY, et al.. Proinflammatory cytokine profiles of patients with elderly-onset rheumatoid arthritis: a comparison with younger-onset disease. Gerontology, 2009, 55: 250-258

[68] LanceNJ, CurranJJ. Late-onset, seropositive, erosive rheumatoid arthritis. Semin Arthritis Rheum., 1993, 23: 177-182

[69] LinJZ, et al.. Myopenia is associated with joint damage in rheumatoid arthritis: a cross-sectional study. J. Cachexia Sarcopenia Muscle, 2019, 10: 355-367

[70] van SchaardenburgD, et al.. Outcome of rheumatoid arthritis in relation to age and rheumatoid factor at diagnosis. J. Rheumatol., 1993, 20: 45-52

[71] ChoSK, et al.. Do patients with elderly-onset rheumatoid arthritis have severe functional disability?. Semin Arthritis Rheum., 2012, 42: 23-31

[72] SerhalL, LwinMN, HolroydC, EdwardsCJ. Rheumatoid arthritis in the elderly: Characteristics and treatment considerations. Autoimmun. Rev., 2020, 19: 102528

[73] PanJ, et al.. Muscle mass loss is associated with physical dysfunction in patients with early rheumatoid arthritis. Front Nutr., 2022, 9: 1007184

[74] SiparskyPN, KirkendallDT, GarrettWE Jr.. Muscle changes in aging: understanding sarcopenia. Sports Health, 2014, 6: 36-40

[75] KellerK, EngelhardtM. Strength and muscle mass loss with aging process. Age and strength loss. Muscles Ligaments Tendons J., 2013, 3: 346-350

[76] MolinoS, DossenaM, BuonocoreD, VerriM. Sarcopenic obesity: An appraisal of the current status of knowledge and management in elderly people. J. Nutr. Health Aging, 2016, 20: 780-788

[77] ZamboniM, MazzaliG, FantinF, RossiA, Di FrancescoV. Sarcopenic obesity: a new category of obesity in the elderly. Nutr. Metab. Cardiovasc Dis., 2008, 18: 388-395

[78] LinJZ, et al.. Neglected extra-articular manifestations in rheumatoid arthritis patients with normal body mass index: reduced skeletal muscle overlapping overfat. Ther. Adv. Chronic Dis., 2020, 11: 2040622320975241

[79] KerekesG, et al.. Rheumatoid arthritis and metabolic syndrome. Nat. Rev. Rheumatol., 2014, 10: 691-696

[80] BakerJF, et al.. Muscle deficits in rheumatoid arthritis contribute to inferior cortical bone structure and trabecular bone mineral density. J. Rheumatol., 2017, 44: 1777-1785

[81] ChengKY, et al.. Diagnosis of sarcopenia by evaluating skeletal muscle mass by adjusted bioimpedance analysis validated with dual-energy X-ray absorptiometry. J. Cachexia Sarcopenia Muscle, 2021, 12: 2163-2173

[82] LiJ, SheB, HeM, YuanC, LiN. Advances in imaging examination of bone density and bone quality. Endokrynol. Pol., 2025, 76: 29-39

[83] Lin, J.Z. et al. Reduced skeletal muscle independently predicts 1-year aggravated joint destruction in patients with rheumatoid arthritis. Ther. Adv. Musculoskelet Dis. 12, 1759720×20946220 (2020).

[84] PeaseCT, BhaktaBB, DevlinJ, EmeryP. Does the age of onset of rheumatoid arthritis influence phenotype?: a prospective study of outcome and prognostic factors. Rheumatol. (Oxf.), 1999, 38: 228-234

[85] Calvo-AlénJ, et al.. Outcome of late-onset rheumatoid arthritis. Clin. Rheumatol., 2005, 24: 485-489

[86] KramsT, et al.. Effect of age at rheumatoid arthritis onset on clinical, radiographic, and functional outcomes: The ESPOIR cohort. Jt. Bone Spine, 2016, 83: 511-515

[87] MetsiosGS, et al.. Rheumatoid arthritis, cardiovascular disease and physical exercise: a systematic review. Rheumatol. (Oxf.), 2008, 47: 239-248

[88] LeeDM, WeinblattME. Rheumatoid arthritis. Lancet, 2001, 358: 903-911

[89] EkdahlC, BromanG. Muscle strength, endurance, and aerobic capacity in rheumatoid arthritis: a comparative study with healthy subjects. Ann. Rheum. Dis., 1992, 51: 35-40

[90] LiZ, WangXQ. Clinical effect and biological mechanism of exercise for rheumatoid arthritis: A mini review. Front Immunol., 2022, 13: 1089621

[91] de JongZ, 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: 2415-2424

[92] HäkkinenA. Effectiveness and safety of strength training in rheumatoid arthritis. Curr. Opin. Rheumatol., 2004, 16: 132-137

[93] Stavropoulos-KalinoglouA, et al.. Individualised aerobic and resistance exercise training improves cardiorespiratory fitness and reduces cardiovascular risk in patients with rheumatoid arthritis. Ann. Rheum. Dis., 2013, 72: 1819-1825

[94] CooneyJK, et al.. Benefits of exercise in rheumatoid arthritis. J. Aging Res., 2011, 2011: 681640

[95] PeresD, et al.. Effects of an exercise program and cold-water immersion recovery in patients with rheumatoid arthritis (RA): feasibility study. Int. J. Environ. Res. Public Health, 2023, 20: 6128

[96] Pedersen, B.K. Muscle as a secretory organ. in Comprehensive Physiology 1337-1362 (2013).

[97] MudanoAS, TugwellP, WellsGA, SinghJA. Tai Chi for rheumatoid arthritis. Cochrane Database Syst. Rev., 2019, 9: Cd004849

[98] ImotoAM, et al.. Evidence for the efficacy of Tai Chi for treating rheumatoid arthritis: an overview of systematic reviews. Sao Paulo Med J., 2021, 139: 91-97

[99] Han, A. et al. Tai chi for treating rheumatoid arthritis. Cochrane Database Syst. Rev. 3, CD004849 (2004).

[100] SagtaganovZ, YessirkepovM, BekaryssovaD. Yoga as a complementary therapy for rheumatoid arthritis: A case-based review. Rheumatol. Int, 2024, 44: 1575-1579

[101] Sagtaganov, Z., Yessirkepov, M., Bekaryssova, D. & Suigenbayev, D. Managing rheumatoid arthritis and cardiovascular disease: the role of physical medicine and rehabilitation. Rheumatol. Int. 44, 1749–1756 (2024).

[102] Al-QubaeissyKY, FatoyeFA, GoodwinPC, YohannesAM. The effectiveness of hydrotherapy in the management of rheumatoid arthritis: a systematic review. Musculoskelet. Care, 2013, 11: 3-18

[103] Gioia, C., Lucchino, B., Tarsitano, M. G., Iannuccelli, C. & Di Franco, M. Dietary habits and nutrition in rheumatoid arthritis: can diet influence disease development and clinical manifestations? Nutrients 12, 1456 (2020).

[104] YaoX, LiH, LengSX. Inflammation and immune system alterations in frailty. Clin. Geriatr. Med, 2011, 27: 79-87

[105] DentE, KowalP, HoogendijkEO. Frailty measurement in research and clinical practice: A review. Eur. J. Intern Med, 2016, 31: 3-10

[106] de VriesNM, et al.. Outcome instruments to measure frailty: A systematic review. Ageing Res. Rev., 2011, 10: 104-114

[107] HaiderS, et al.. Frailty in seropositive rheumatoid arthritis patients of working age: A cross-sectional study. Clin. Exp. Rheumatol., 2019, 37: 585-592

[108] ArmstrongEJ, HarskampCT, ArmstrongAW. Psoriasis and major adverse cardiovascular events: a systematic review and meta-analysis of observational studies. J. Am. Heart Assoc., 2013, 2: e000062

[109] Avina-ZubietaJA, ThomasJ, SadatsafaviM, LehmanAJ, LacailleD. Risk of incident cardiovascular events in patients with rheumatoid arthritis: a meta-analysis of observational studies. Ann. Rheum. Dis., 2012, 71: 1524-1529

[110] FilimonAM, et al.. Cardiovascular involvement in inflammatory bowel disease: Dangerous liaisons. World J. Gastroenterol., 2015, 21: 9688-9692

[111] SoubrierM, et al.. Cardiovascular risk in rheumatoid arthritis. Jt. Bone Spine, 2014, 81: 298-302

[112] AhlehoffO, et al.. Psoriasis is associated with clinically significant cardiovascular risk: a Danish nationwide cohort study. J. Intern Med, 2011, 270: 147-157

[113] BradySR, et al.. The role of traditional cardiovascular risk factors among patients with rheumatoid arthritis. J. Rheumatol., 2009, 36: 34-40

[114] LindhardsenJ, et al.. The risk of myocardial infarction in rheumatoid arthritis and diabetes mellitus: a Danish nationwide cohort study. Ann. Rheum. Dis., 2011, 70: 929-934

[115] del RincónI, et al.. Systemic inflammation and cardiovascular risk factors predict rapid progression of atherosclerosis in rheumatoid arthritis. Ann. Rheum. Dis., 2015, 74: 1118-1123

[116] ZouYW, et al.. Association between metabolic dysfunction-associated fatty liver disease and cardiovascular risk in patients with rheumatoid arthritis: A cross-sectional study of Chinese cohort. Front Cardiovasc Med, 2022, 9: 884636

[117] ZouYW, et al.. Prevalence and influence of hypouricemia on cardiovascular diseases in patients with rheumatoid arthritis. Eur. J. Med Res, 2022, 27 ArticleID: 260

[118] GoAS, et al.. Heart disease and stroke statistics-2014 update: A report from the American Heart Association. Circulation, 2014, 129: e28-e292

[119] KalogeropoulosA, et al.. Inflammatory markers and incident heart failure risk in older adults: The Health ABC (Health, Aging, and Body Composition) study. J. Am. Coll. Cardiol., 2010, 55: 2129-2137

[120] AslamF, BandealiSJ, KhanNA, AlamM. Diastolic dysfunction in rheumatoid arthritis: a meta-analysis and systematic review. Arthritis Care Res. (Hoboken), 2013, 65: 534-543

[121] CioffiG, et al.. Prognostic role of subclinical left ventricular systolic dysfunction evaluated by speckle-tracking echocardiography in rheumatoid arthritis. J. Am. Soc. Echocardiogr., 2017, 30: 602-611

[122] FosterW, CarruthersD, LipGY, BlannAD. Inflammation and microvascular and macrovascular endothelial dysfunction in rheumatoid arthritis: effect of treatment. J. Rheumatol., 2010, 37: 711-716

[123] MartiCN, et al.. Endothelial dysfunction, arterial stiffness, and heart failure. J. Am. Coll. Cardiol., 2012, 60: 1455-1469

[124] MidtbøH, SembAG, MatreK, KvienTK, GerdtsE. Disease activity is associated with reduced left ventricular systolic myocardial function in patients with rheumatoid arthritis. Ann. Rheum. Dis., 2017, 76: 371-376

[125] PaulusWJ, TschöpeC. A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. J. Am. Coll. Cardiol., 2013, 62: 263-271

[126] FanF, et al.. Comparison of inflammation, arterial stiffness and traditional cardiovascular risk factors between rheumatoid arthritis and inflammatory bowel disease. J. Inflamm. (Lond.), 2014, 11: 29

[127] MantelÄ, HolmqvistM, AnderssonDC, LundLH, AsklingJ. Association between rheumatoid arthritis and risk of ischemic and nonischemic heart failure. J. Am. Coll. Cardiol., 2017, 69: 1275-1285

[128] NicolaPJ, et al.. The risk of congestive heart failure in rheumatoid arthritis: a population-based study over 46 years. Arthritis Rheum., 2005, 52: 412-420

[129] Khalid, U. et al. Incident heart failure in patients with rheumatoid arthritis: a nationwide cohort study. J. Am. Heart Assoc. 7, e007227 (2018).

[130] AvouacJ, et al.. Inflammation and disease activity are associated with high circulating cardiac markers in rheumatoid arthritis independently of traditional cardiovascular risk factors. J. Rheumatol., 2014, 41: 248-255

[131] MasoudS, LimPB, KitasGD, PanoulasV. Sudden cardiac death in patients with rheumatoid arthritis. World J. Cardiol., 2017, 9: 562-573

[132] PetersMJ, et al.. EULAR evidence-based recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthritis. Ann. Rheum. Dis., 2010, 69: 325-331

[133] FinckhA, LiangMH, van HerckenrodeCM, de PabloP. Long-term impact of early treatment on radiographic progression in rheumatoid arthritis: A meta-analysis. Arthritis Rheum., 2006, 55: 864-872

[134] WuD, et al.. Systemic complications of rheumatoid arthritis: Focus on pathogenesis and treatment. Front Immunol., 2022, 13: 1051082

[135] FuchsHA, KayeJJ, CallahanLF, NanceEP, PincusT. Evidence of significant radiographic damage in rheumatoid arthritis within the first 2 years of disease. J. Rheumatol., 1989, 16: 585-591

[136] CohenS, EmeryP. The American college of rheumatology/european league against rheumatism criteria for the classification of rheumatoid arthritis: a game changer. Ann. Rheum. Dis., 2010, 69: 1575-1576

[137] GuoQ, et al.. Rheumatoid arthritis: pathological mechanisms and modern pharmacologic therapies. Bone Res, 2018, 6: 15

[138] Ben MridR, et al.. Anti-rheumatoid drugs advancements: New insights into the molecular treatment of rheumatoid arthritis. Biomed. Pharmacother., 2022, 151: 113126

[139] FraenkelL, et al.. American college of rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Care Res. (Hoboken), 2021, 73: 924-939

[140] SmolenJS, et al.. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2022 update. Ann. Rheum. Dis., 2023, 82: 3-18

[141] TutuncuZ, ReedG, KremerJ, KavanaughA. Do patients with older-onset rheumatoid arthritis receive less aggressive treatment?. Ann. Rheum. Dis., 2006, 65: 1226-1229

[142] WalkerJ, WynneH. Review: the frequency and severity of adverse drug reactions in elderly people. Age Ageing, 1994, 23: 255-259

[143] MuellerRB, et al.. Does addition of glucocorticoids to the initial therapy influence the later course of the disease in patients with early RA? Results from the Swiss prospective observational registry (SCQM). Clin. Rheumatol., 2017, 36: 59-66

[144] GenevayS, et al.. Tolerance and effectiveness of anti-tumor necrosis factor alpha therapies in elderly patients with rheumatoid arthritis: a population-based cohort study. Arthritis Rheum., 2007, 57: 679-685

[145] BathonJM, et al.. Safety and efficacy of etanercept treatment in elderly subjects with rheumatoid arthritis. J. Rheumatol., 2006, 33: 234-243

[146] PersYM, et al.. Efficacy and safety of tocilizumab in elderly patients with rheumatoid arthritis. Jt. Bone Spine, 2015, 82: 25-30

[147] CurtisJR, et al.. Efficacy and safety of tofacitinib in older and younger patients with rheumatoid arthritis. Clin. Exp. Rheumatol., 2017, 35: 390-400

[148] KobakS, BesC. An autumn tale: geriatric rheumatoid arthritis. Ther. Adv. Musculoskelet. Dis., 2018, 10: 3-11

[149] Bermejo-Álvarez, I. et al. Effects of tofacitinib on muscle remodeling in experimental rheumatoid sarcopenia. Int. J. Mol. Sci. 24, 13181 (2023).

[150] Rolland, Y., Dray, C., Vellas, B. & Barreto, P. S. Current and investigational medications for the treatment of sarcopenia. Metabolism 149, 155597 (2023).

[151] Liu, H. et al. Associations between sarcopenia and circulating branched-chain amino acids: a cross-sectional study over 100,000 participants. BMC Geriatr. 24, 541 (2024).

[152] Minamino, H. et al. Serum vitamin D status inversely associates with a prevalence of severe sarcopenia among female patients with rheumatoid arthritis. Sci. Rep. 11, 20485 (2021).

[153] Gwinnutt, J. M. et al. Effects of diet on the outcomes of rheumatic and musculoskeletal diseases (RMDs): systematic review and meta-analyses informing the 2021 EULAR recommendations for lifestyle improvements in people with RMDs. RMD Open 8, e002167 (2022).

[154] Lanchais, K., Capel, F. & Tournadre, A. Could omega-3 fatty acids preserve muscle health in rheumatoid arthritis? Nutrients 12, 223 (2020).

[155] Pope, J. E. Management of fatigue in rheumatoid arthritis. RMD Open 6, e001084 (2020).

RIGHTS & PERMISSIONS

The Author(s)