Functional Medicine News March 2019


Institute for Functional Medicine – Insights

Who Is at Risk for Rheumatoid Arthritis?

Rheumatoid arthritis (RA) affects more than 1.5% of the worlds’ population.1 Genetic and environmental factors play a role in the beginning and the progression of the disease. Before the condition emerges, patients enter a pro-inflammatory state. What factors can tip the scale to cause RA?

Genetics play a large role in the emergence of RA. Heritability estimates for RA range from 53-65%.2,3 There are close to 60 loci associated with susceptibility to RA across multiple populations.4 These loci are at least partially shared across ethnicities.3 In an RA patient, enzymes that promote methylation increase in response to stimuli, resulting in both hypo- and hypermethylation in synovial cells.5 Upregulation of histone phosphorylation increases cytokines and leads to a pro-inflammatory state.5

This may explain the increased production of autoantibodies, which are detectable more than 10 years before RA can be diagnosed.6,7,11 Environmental factors may exacerbate this pro-inflammatory state, acting as a mediator that can speed up development of RA. What lifestyle factors contribute to this epigenetic process?

Increased urbanization has been associated with an increased prevalence of RA. For example, rural populations have significantly lower rates of RA than urban populations.8,9 This could partly be attributed to the hygiene hypothesis.10 An urban environment may reduce exposure to allergens, particularly in early life. Prenatal and early life environment play an important role in autoimmune conditions like RA.11

No contributing environmental factor is quite as established as smoking to predispose an individual to autoimmune conditions.12-14 The increased likelihood of P. gingivalis infection in smokers may explain some of that association.3,15 Underlying bacterial infections and lipopolysaccharides (LPS) are suspected to play a role in RA.16 On the other hand, like for many other chronic conditions, a diet rich in fruits and vegetables may be protective—especially if it includes mushrooms and citrus and reduces red meat.17 Further study is needed to understand more of the epigenetic factors in RA.18


Verma MK, Sobha K. Understanding the major risk factors in the beginning and the progression of rheumatoid arthritis: current scenario and future prospects. Inflamm Res. 2015;64(9):647-659. doi:10.1007/s00011-015-0843-8.

MacGregor AJ, Snieder H, Rigby AS, et al. Characterizing the quantitative genetic contribution to rheumatoid arthritis using data from twins. Arthritis Rheum. 2000;43(1):30-37. doi:10.1002/1529-0131(200001)43:1<30::AID-ANR5>3.0.CO;2-B.

Araki Y, Mimura T. The mechanisms underlying chronic inflammation in rheumatoid arthritis from the perspective of the epigenetic landscape. J Immunol Res. 2016;2016:6290682. doi:10.1155/2016/6290682.

Viatte S, Plant D, Raychaudhuri S. Genetics and epigenetics of rheumatoid arthritis. Nat Rev Rheumatol. 2013;9(3):141-153. doi:10.1038/nrrheum.2012.237.

Glant TT, Mikecz K, Rauch TA. Epigenetics in the pathogenesis of rheumatoid arthritis. BMC Med. 2014;12:35. doi:10.1186/1741-7015-12-35.

Nielen MM, van Schaardenburg D, Reesink HW, et al. Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors. Arthritis Rheum. 2004;50(2):380-386. doi:10.1002/art.20018.

Tracy A, Buckley CD, Raza K. Pre-symptomatic autoimmunity in rheumatoid arthritis: when does the disease start? Semin Immunopathol. 2017;39(4):423-435. doi:10.1007/s00281-017-0620-6.

Solomon L, Robin G, Valkenburg HA. Rheumatoid arthritis in an urban South African Negro population. Ann Rheum Dis. 1975;34(2):128-35.

Chou CT, Pei L, Chang DM, Lee CF, Schumacher HR, Liang MH. Prevalence of rheumatic diseases in Taiwan: a population study of urban, suburban, rural differences. J Rheumatol. 1994;21(2):302-306.

Okada H, Kuhn C, Feillet H, Bach J-F. The “hygiene hypothesis” for autoimmune and allergic diseases: an update. Clin Exp Immunol. 2010;160(1):1-9. doi:10.1111/j.1365-2249.2010.04139.x.

Edwards CJ, Cooper C. Early environmental factors and rheumatoid arthritis. Clin Exp Immunol. 2006;143(1):1-5. doi:10.1111/j.1365-2249.2005.02940.x.

Silman AJ, Newman J, MacGregor AJ. Cigarette smoking increases the risk of rheumatoid arthritis. Results from a nationwide study of disease-discordant twins. Arthritis Rheum. 1996;39(5):732-735.

Stolt P, Bengtsson C, Nordmark B, et al. Quantification of the influence of cigarette smoking on rheumatoid arthritis: results from a population based case-control study, using incident cases. Ann Rheum Dis. 2003;62(9):835-841.

Hutchinson D, Shepstone L, Moots R, Lear J, Lynch M. Heavy cigarette smoking is strongly associated with rheumatoid arthritis (RA), particularly in patients without a family history of RA. Ann Rheum Dis. 2001;60(3):223-227. doi:10.1136/ard.60.3.223.

Bingham CO, Moni M. Periodontal disease and rheumatoid arthritis: the evidence accumulates for complex pathobiologic interactions. Curr Opin Rheumatol. 2013;25(3):345-353. doi:10.1097/BOR.0b013e32835fb8ec.

Pretorius E, Akeredolu OO, Soma P, Kell DB. Major involvement of bacterial components in rheumatoid arthritis and its accompanying oxidative stress, systemic inflammation and hypercoagulability. Exp Biol Med (Maywood). 2017;242(4):355-373. doi:10.1177/1535370216681549.

He J, Wang Y, Feng M, et al. Dietary intake and risk of rheumatoid arthritis—a cross section multicenter study. Clin Rheumatol. 2016;35(12):2901-2908. doi:10.1007/s10067-016-3383-x.

Araki Y, Mimura T. The mechanisms underlying chronic inflammation in rheumatoid arthritis from the perspective of the epigenetic landscape. J Immunol Res. 2016;2016:6290682. doi:10.1155/2016/6290682.

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