Abstract
Both cachexia and cardiovascular disease are strongly associated with rheumatoid arthritis (RA) and linked to the chronic inflammatory process. Typically, rheumatoid cachexia occurs in individuals with normal or increased BMI (reduced muscle mass and increased fat mass). Classic cachexia (reduced muscle mass and reduced fat mass) is rare in RA but is associated with high inflammatory activity and aggressive joint destruction in patients with a poor cardiovascular prognosis. Conversely, obesity is linked to hypertension and dyslipidemia but, paradoxically, lower RA disease activity and less cardiovascular disease-related mortality. Rheumatoid cachexia might represent the 'worst of both worlds' with respect to cardiovascular outcome, but until diagnostic criteria for this condition are agreed upon, its effect on cardiovascular disease risk remains controversial.
Key Points
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Two forms of cachexia occur in rheumatoid arthritis (RA): rheumatoid cachexia with normal BMI (low muscle mass and increased fat mass) and classic cachexia with low BMI (low muscle mass and low fat mass)
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Classic cachexia is rarely seen in RA but is associated with severe systemic inflammation, increased cardiovascular disease (CVD) risk and poor RA outcome
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Within the RA population, increasing fat mass is linked to increasing prevalence of traditional CVD risk factors but, paradoxically, less-severe joint destruction and lower CVD-related mortality
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Rheumatoid cachexia has features of both classic cachexia and obesity and might represent the 'worst of both worlds' with respect to cardiovascular outcomes but current data is inconclusive
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There is a lack of agreed diagnostic criteria for rheumatoid cachexia and this hampers research into the prevalence and importance of this condition
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Treatment with methotrexate or tumor necrosis factor inhibitors has not yet been shown to reverse rheumatoid cachexia, although exercise therapy is likely to be beneficial
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References
Pincus, T., Sokka, T., & Wolfe, F. Premature mortality in patients with rheumatoid arthritis: evolving concepts. Arthritis Rheum. 44, 1234–1236 (2001).
Gonzalez, A. et al. Mortality trends in rheumatoid arthritis: the role of rheumatoid factor. J. Rheumatol. 35, 1009–1014 (2008).
Kitas, G. D. & Erb, N. Tackling ischaemic heart disease in rheumatoid arthritis. Rheumatology (Oxford) 42, 607–613 (2003).
Solomon, D. H. et al. Cardiovascular morbidity and mortality in women diagnosed with rheumatoid arthritis. Circulation 107, 1303–1307 (2003).
Bacon, P. A., Stevens, R. J., Carruthers, D. M., Young, S. P. & Kitas, G. D. Accelerated atherogenesis in autoimmune rheumatic diseases. Autoimmun. Rev. 1, 338–347 (2002).
Douglas, K. M. et al. Excess recurrent cardiac events in rheumatoid arthritis patients with acute coronary syndrome. Ann. Rheum. Dis. 65, 348–353 (2006).
Panoulas, V. F. et al. Prevalence and associations of hypertension and its control in patients with rheumatoid arthritis. Rheumatology (Oxford) 46, 1477–1482 (2007).
Panoulas, V. F. et al. Hypertension in rheumatoid arthritis. Rheumatology (Oxford) 47, 1286–1298 (2008).
Stavropoulos-Kalinoglou, A. et al. Associations of obesity with modifiable risk factors for the development of cardiovascular disease in patients with rheumatoid arthritis. Ann. Rheum. Dis. 68, 242–245 (2009).
Metsios, G. S. et al. Association of physical inactivity with increased cardiovascular risk in patients with rheumatoid arthritis. Eur. J. Cardiovasc. Prev. Rehabil. 16, 188–194 (2009).
del Rincón, I., Freeman, G. L., Haas, R. W., O'Leary, D. H. & Escalante, A. Relative contribution of cardiovascular risk factors and rheumatoid arthritis clinical manifestations to atherosclerosis. Arthritis Rheum. 52, 3413–3423 (2005).
Sattar, N., McCarey, D. W., Capell, H. & McInnes, I. B. Explaining how “high-grade” systemic inflammation accelerates vascular risk in rheumatoid arthritis. Circulation 108, 2957–2963 (2003).
Stevens, R. J., Douglas, K. M., Saratzis, A. N. & Kitas, G. D. Inflammation and atherosclerosis in rheumatoid arthritis. Expert Rev. Mol. Med. 7, 1–24 (2005).
Metsios, G. S. et al. Vascular function and inflammation in rheumatoid arthritis: the role of physical activity. Open Cardiovasc. Med. J. 23, 89–96 (2010).
Metsios, G. S. et al. New resting energy expenditure prediction equations for patients with rheumatoid arthritis. Rheumatology (Oxford) 47, 500–506 (2008).
Metsios, G. S., Stavropoulos-Kalinoglou, A., Koutedakis, Y. & Kitas, G. D. Rheumatoid cachexia: causes, significance and possible interventions. Hosp. Chronicles 1, 20–26 (2006).
Roubenoff, R. et al. Rheumatoid cachexia: cytokine-driven hypermetabolism accompanying reduced body cell mass in chronic inflammation. J. Clin. Invest. 93, 2379–2386 (1994).
Evans, W. J. et al. Cachexia: a new definition. Clin. Nutr. 27, 793–799 (2008).
Summers, G. D., Deighton, C. M., Rennie, M. J. & Booth, A. H. Rheumatoid cachexia: a clinical perspective. Rheumatology (Oxford) 47, 1124–1131 (2008).
Kremers, H. M., Nicola, P. J., Crowson, C. S., Ballman, K. V. & Gabriel, S. E. Prognostic importance of low body mass index in relation to cardiovascular mortality in rheumatoid arthritis. Arthritis Rheum. 50, 3450–3457 (2004).
Morley, J. E., Thomas, D. R. & Wilson, M. M. Cachexia: pathophysiology and clinical relevance. Am. J. Clin. Nutr. 83, 735–743 (2006).
Elkan, A. C., Engvall, I. L., Cederholm, T. & Hafström, I. Rheumatoid cachexia, central obesity and malnutrition in patients with low-active rheumatoid arthritis: feasibility of anthropometry, Mini Nutritional Assessment and body composition techniques. Eur. J. Nutr. 48, 315–322 (2009).
Engvall, I. L. et al. Cachexia in rheumatoid arthritis is associated with inflammatory activity, physical disability, and low bioavailable insulin-like growth factor. Scand. J. Rheumatol. 37, 321–328 (2008).
Elkan, A. C., Håkansson, N., Frostegård, J., Cederholm, T. & Hafström, I. Rheumatoid cachexia is associated with dyslipidemia and low levels of atheroprotective natural antibodies against phosphorylcholine but not with dietary fat in patients with rheumatoid arthritis: a cross-sectional study. Arthritis Res. Ther. 11, R37 (2009).
Morgan, S. L. et al. Nutrient intake patterns, body mass index, and vitamin levels in patients with rheumatoid arthritis. Arthritis Care Res. 10, 9–17 (1997).
Munro, R. & Capell, H. Prevalence of low body mass in rheumatoid arthritis: association with the acute phase response. Ann. Rheum. Dis. 56, 326–329 (1997).
Escalante, A., Haas, R. W. & del Rincón, I. Paradoxical effect of body mass index on survival in rheumatoid arthritis: role of comorbidity and systemic inflammation. Arch. Intern. Med. 165, 1624–1629 (2005).
Westhoff, G., Rau, R. & Zink, A. Radiographic joint damage in early rheumatoid arthritis is highly dependent on body mass index. Arthritis Rheum. 56, 3575–3582 (2007).
Metsios, G. S. et al. Rheumatoid cachexia and cardiovascular disease. Clin. Exp. Rheumatol. 27, 985–988 (2009).
Giles, J. T. et al. Abnormal body composition phenotypes in older rheumatoid arthritis patients: association with disease characteristics and pharmacotherapies. Arthritis Rheum. 59, 807–815 (2008).
Mitch, W. E. & Goldberg, A. L. Mechanisms of muscle wasting. The role of the ubiquitin-proteasome pathway. N. Engl. J. Med. 335, 1897–1905 (1996).
Li, Y. P. et al. TNF-alpha increases ubiquitin-conjugating activity in skeletal muscle by up-regulating UbcH2/E220k. FASEB J. 17, 1048–1057 (2003).
Kotler, D. P. Cachexia. Ann. Intern. Med. 133, 622–634 (2000).
Rennie, K. L., Hughes, J., Lang, R. & Jebb, S. A. Nutritional management of rheumatoid arthritis: a review of the evidence. J. Hum. Nutr. Diet 16, 97–109 (2003).
Metsios, G. S. et al. Smoking significantly increases basal metabolic rate in patients with rheumatoid arthritis. Ann. Rheum. Dis. 67, 70–73 (2007).
Stavropoulos-Kalinoglou, A. et al. Cigarette smoking associates with body weight and muscle mass of patients with rheumatoid arthritis: a cross-sectional, observational study. Arthritis Res. Ther. 10, R59 (2008).
Tengstrand, B., Carlström, K. & Hafström, I. Gonadal hormones in men with rheumatoid arthritis--from onset through 2 years. J. Rheumatol. 36, 887–892 (2009).
Straub, R. H. et al. Sex hormone concentrations in patients with rheumatoid arthritis are not normalized during 12 weeks of anti-tumor necrosis factor therapy. J. Rheumatol. 32, 1253–1258 (2005).
Haren, M. T., Kim, M. J., Tariq, S. H., Wittert, G. A. & Morley, J. E. Andropause: a quality-of-life issue in older males. Med. Clin. North Am. 90, 1005–1023 (2006).
Metsios, G. S. et al. Rheumatoid arthritis, cardiovascular disease and physical exercise: a systematic review. Rheumatology (Oxford) 47, 239–248 (2008).
Munneke, M. et al. High intensity exercise or conventional exercise for patients with rheumatoid arthritis? Outcome expectations of patients, rheumatologists, and physiotherapists. Ann. Rheum. Dis. 63, 804–808 (2004).
Stavropoulos-Kalinoglou, A. et al. Underweight and obese states both associate with worse disease activity and physical function in patients with established rheumatoid arthritis. Clin. Rheumatol. 28, 439–444 (2009).
Kaufmann, J., Kielstein, V., Kilian, S., Stein, G. & Hein, G. Relation between body mass index and radiological progression in patients with rheumatoid arthritis. J. Rheumatol. 30, 2350–2355 (2003).
Fleming, A., Crown, J. M. & Corbett, M. Prognostic value of early features in rheumatoid disease. Br. Med. J. 1, 1243–1245 (1976).
Roubenoff, R. & Rall, L. C. Humoral mediation of changing body composition during aging and chronic inflammation. Nutr. Rev. 51, 1–11 (1993).
Pierson, R. N. Jr. Body composition in aging: a biological perspective. Curr. Opin. Clin. Nutr. Metab. Care 6, 15–20 (2003).
Navarro-Cano, G., Del Rincón, I., Pogosian, S., Roldán, J. F. & Escalante, A. Association of mortality with disease severity in rheumatoid arthritis, independent of comorbidity. Arthritis Rheum. 48, 2425–2433 (2003).
Roubenoff, R., Roubenoff, R. A., Ward, L. M., Holland, S. M. & Hellmann, D. B. Rheumatoid cachexia: depletion of lean body mass in rheumatoid arthritis. Possible association with tumor necrosis factor. J. Rheumatol. 19, 1505–1510 (1992).
Arshad, A., Rashid, R. & Benjamin, K. The effect of disease activity on fat-free mass and resting energy expenditure in patients with rheumatoid arthritis versus noninflammatory arthropathies/soft tissue rheumatism. Mod. Rheumatol. 17, 470–475 (2007).
Hernandez-Beriain, J. A. et al. Undernutrition in rheumatoid arthritis patients with disability. Scand. J. Rheumatol. 25, 383–387 (1996).
Florea, V. G. et al. Wasting of the left ventricle in patients with cardiac cachexia: a cardiovascular magnetic resonance study. Int. J. Cardiol. 97, 15–20 (2004).
Stavropoulos-Kalinoglou, A. et al. Redefining overweight and obesity in rheumatoid arthritis patients. Ann. Rheum. Dis. 66, 1316–1321 (2007).
Armstrong, D. J., McCausland, E. M., Quinn, A. D. & Wright, G. D. Obesity and cardiovascular risk factors in rheumatoid arthritis. Rheumatology (Oxford) 45, 782 (2006).
Dessein, P. H., Norton, G. R., Woodiwiss, A. J., Joffe, B. I. & Solomon, A. Independent role of conventional cardiovascular risk factors as predictors of C-reactive protein concentrations in rheumatoid arthritis. J. Rheumatol. 34, 681–688 (2007).
Goodson, N. J. et al. Baseline levels of C-reactive protein and prediction of death from cardiovascular disease in patients with inflammatory polyarthritis: a ten-year followup study of a primary care-based inception cohort. Arthritis Rheum. 52, 2293–2299 (2005).
Naranjo, A. et al. Cardiovascular disease in patients with rheumatoid arthritis: results from the QUEST-RA study. Arthritis Res. Ther. 10, R30 (2008).
van der Helm-van Mil, A. H., van der Kooij, S. M., Allaart, C. F., Toes, R. E. & Huizinga, T. W. A high body mass index has a protective effect on the amount of joint destruction in small joints in early rheumatoid arthritis. Ann. Rheum. Dis. 67, 769–774 (2008).
Rimm, E. B. et al. Body size and fat distribution as predictors of coronary heart disease among middle-aged and older US men. Am. J. Epidemiol. 141, 1117–1127 (1995).
DeNino, W. F. et al. Contribution of abdominal adiposity to age-related differences in insulin sensitivity and plasma lipids in healthy nonobese women. Diabetes Care 24, 925–932 (2001).
Dessein, P. H., Joffe, B. I. & Stanwix, A. E. Inflammation, insulin resistance, and aberrant lipid metabolism as cardiovascular risk factors in rheumatoid arthritis. J. Rheumatol. 30, 1403–1405 (2003).
Inaba, M. et al. Independent association of increased trunk fat with increased arterial stiffening in postmenopausal patients with rheumatoid arthritis. J. Rheumatol. 34, 290–295 (2007).
Westhovens, R., Nijs, J., Taelman, V. & Dequeker, J. Body composition in rheumatoid arthritis. Br. J. Rheumatol. 36, 444–448 (1997).
Otero, M. et al. Changes in plasma levels of fat-derived hormones adiponectin, leptin, resistin and visfatin in patients with rheumatoid arthritis. Ann. Rheum. Dis. 65, 1198–1201 (2006).
Gonzalez-Gay, M. A. et al. High-grade inflammation, circulating adiponectin concentrations and cardiovascular risk factors in severe rheumatoid arthritis. Clin. Exp. Rheumatol. 26, 596–603 (2008).
Marcora, S. M., Chester, K. R., Mittal, G., Lemmey, A. B. & Maddison, P. J. Randomized phase 2 trial of anti-tumor necrosis factor therapy for cachexia in patients with early rheumatoid arthritis. Am. J. Clin. Nutr. 84, 1463–1472 (2006).
Metsios, G. S. et al. Blockade of tumour necrosis factor-alpha in rheumatoid arthritis: effects on components of rheumatoid cachexia. Rheumatology (Oxford) 46, 1824–1827 (2007).
Nishida, K., Okada, Y., Nawata, M., Saito, K. & Tanaka, Y. Induction of hyperadiponectinemia following long-term treatment of patients with rheumatoid arthritis with infliximab (IFX), an anti-TNF-alpha antibody. Endocr. J. 55, 213–216 (2008).
Nagashima, T. et al. Increase in plasma levels of adiponectin after administration of anti-tumor necrosis factor agents in patients with rheumatoid arthritis. J. Rheumatol. 35, 936–938 (2008).
Komai, N., Morita, Y., Sakuta, T., Kuwabara, A. & Kashihara, N. Anti-tumor necrosis factor therapy increases serum adiponectin levels with the improvement of endothelial dysfunction in patients with rheumatoid arthritis. Mod. Rheumatol. 17, 385–390 (2007).
Härle, P., Sarzi-Puttini, P., Cutolo, M. & Straub, R. H. No change of serum levels of leptin and adiponectin during anti-tumour necrosis factor antibody treatment with adalimumab in patients with rheumatoid arthritis. Ann. Rheum. Dis. 65, 970–971 (2006).
Gonzalez-Gay, M. A. et al. Anti-TNF-alpha therapy does not modulate leptin in patients with severe rheumatoid arthritis. Clin. Exp. Rheumatol. 27, 222–228 (2009).
Rosenvinge, A., Krogh-Madsen, R., Baslund, B. & Pedersen, B. K. Insulin resistance in patients with rheumatoid arthritis: effect of anti-TNFalpha therapy. Scand. J. Rheumatol. 36, 91–96 (2007).
Kiortsis, D. N., Mavridis, A. K., Vasakos, S., Nikas, S. N. & Drosos, A. A. Effects of infliximab treatment on insulin resistance in patients with rheumatoid arthritis and ankylosing spondylitis. Ann. Rheum. Dis. 64, 765–766 (2005).
Morley, J. E. Weight loss in older persons: new therapeutic approaches. Curr. Pharm. Des. 13, 3637–3647 (2007).
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Charles P. Vega, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the MedscapeCME-accredited continuing medical education activity associated with this article.
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Summers, G., Metsios, G., Stavropoulos-Kalinoglou, A. et al. Rheumatoid cachexia and cardiovascular disease. Nat Rev Rheumatol 6, 445–451 (2010). https://doi.org/10.1038/nrrheum.2010.105
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DOI: https://doi.org/10.1038/nrrheum.2010.105
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