Risk Factors for Rheumatoid Arthritis (RA)

Certain traits increase the risk of developing rheumatoid arthritis. Some of these traits are inherent and cannot be changed, such as genes, and others may be influenced by lifestyle changes, such as smoking.

While risk factors are known, rheumatoid arthritis is unpredictable. Having one or even several risk factors for RA does not guarantee an individual will get the disease. And while experts theorize there may be ways to prevent RA, getting RA is never an individual’s fault.

Sex and Age

Women are twice as likely to be diagnosed with rheumatoid arthritis than men. While RA can be diagnosed at any time, most people are diagnosed between 40 to 60 years of age. ¹ Riaz, S and Kontzias, A. Rheumatoid Arthritis. In: Efthimiou P, ed. Absolute Rheumatology Review. Springer Nature Switzerland AG; 2020; chap 15. Accessed September 15, 2020. https://doi.org/10.1007/978-3-030-23022-7_15

Genetic Predisposition to RA

A specific gene associated with rheumatoid arthritis, HLA-DR4, is found in 60% to 70% of Caucasians who have the disease. In contrast, it is only found in 30% of the general population. ² Assassi S. Genetics and Rheumatic Disease. American College of Rheumatology. http://www.rheumatology.org/I-Am-A/Patient-Caregiver/Diseases-Conditions/Living-Well-with-Rheumatic-Disease/Genetics-and-Rheumatic-Disease. Updated June 2015. Accessed February 22, 2016.

Genes alone are not the cause of rheumatoid arthritis. For example, studies of identical twins—who share all the same genes—have found that if one twin has RA there is only a 12% to 15% chance the other twin also has RA. ¹ Riaz, S and Kontzias, A. Rheumatoid Arthritis. In: Efthimiou P, ed. Absolute Rheumatology Review. Springer Nature Switzerland AG; 2020; chap 15. Accessed September 15, 2020. https://doi.org/10.1007/978-3-030-23022-7_15

Physicians typically do not order genetic tests when diagnosing rheumatoid arthritis.

Childhood Trauma

People who grew up with abuse, neglect, or other household dysfunction may be more likely to develop an autoimmune disease. One research study ³ Dube SR, Fairweather D, Pearson WS, Felitti VJ, Anda RF, Croft JB. Cumulative childhood stress and autoimmune diseases in adults. Psychosom Med. 2009;71(2):243-250. doi:10.1097/PSY.0b013e3181907888 found that children who experienced more than one stressful event or circumstance were twice as likely to develop rheumatoid arthritis or another rheumatologic disease.

Examples of traumatic childhood events include:

• Death of a parent or sibling
• Verbal abuse
• Sexual assault
• Parental divorce
• A parent with alcoholism

Research about this topic is ongoing. Experts suspect that stress from childhood trauma may affect either immune cell function ⁴ Fernandes SB, Patil ND, Meriaux S, et al. Unbiased Screening Identifies Functional Differences in NK Cells After Early Life Psychosocial Stress. Front Immunol. 2021;12:674532. Published 2021 Jul 30. doi:10.3389/fimmu.2021.674532 or lifestyle behaviors that affect health—or a combination of the two. ⁵ Elwenspoek MMC, Kuehn A, Muller CP, Turner JD. The effects of early life adversity on the immune system. Psychoneuroendocrinology. 2017;82:140-154. doi:10.1016/j.psyneuen.2017.05.012

Environmental and Lifestyle Factors

Day-to-day habits seem to influence people’s risk of getting rheumatoid arthritis. The most established research in this area focuses on smoking, diet, and body weight.

See Lifestyle Factors and Fatigue Associated with Rheumatoid Arthritis (RA)

Smoking and exposure to toxins

The greatest known environmental risk factor for rheumatoid arthritis is exposure to nicotine, particularly smoking. ¹ Riaz, S and Kontzias, A. Rheumatoid Arthritis. In: Efthimiou P, ed. Absolute Rheumatology Review. Springer Nature Switzerland AG; 2020; chap 15. Accessed September 15, 2020. https://doi.org/10.1007/978-3-030-23022-7_15

While the direct effect of smoking is not fully understood, it is believed that prolonged smoking plays a role in increasing the concentration of rheumatoid factor, which is an antibody (a type of protein molecule) that can be found in the blood. High levels of rheumatoid factor in the blood is one sign of RA.

See Blood Tests to Help Diagnose Rheumatoid Arthritis (RA)

Poor air quality at home, work, or in the environment seems to also have an impact on the development of rheumatoid arthritis. ⁶ Adami G, Viapiana O, Rossini M, et al. Association between environmental air pollution and rheumatoid arthritis flares. Rheumatology (Oxford). 2021;60(10):4591-4597. doi:10.1093/rheumatology/keab049 ^{, 7} Ilar A, Alfredsson L, Wiebert P, Klareskog L, Bengtsson C. Occupation and Risk of Developing Rheumatoid Arthritis: Results From a Population-Based Case-Control Study. Arthritis Care Res (Hoboken). 2018;70(4):499-509. doi:10.1002/acr.23321 Exposure to heavy metals may also play a role. ⁸ Irfan S, Rani A, Riaz N, Arshad M, Kashif Nawaz S. Comparative Evaluation of Heavy Metals in Patients with Rheumatoid Arthritis and Healthy Control in Pakistani Population. Iran J Public Health. 2017;46(5):626-633. ^{, 9} Joo SH, Lee J, Hutchinson D, Song YW. Prevalence of rheumatoid arthritis in relation to serum cadmium concentrations: cross-sectional study using Korean National Health and Nutrition Examination Survey (KNHANES) data. BMJ Open. 2019;9(1):e023233. Published 2019 Jan 3. doi:10.1136/bmjopen-2018-023233

Diet

The development of rheumatoid arthritis has been linked to drinking sugary sodas, ¹⁰ Hu Y, Costenbader KH, Gao X, Al-Daabil M, Sparks JA, Solomon DH, Hu FB, Karlson EW, Lu B. Sugar-sweetened soda consumption and risk of developing rheumatoid arthritis in women. Am J Clin Nutr. 2014 Sep;100(3):959-67. doi: 10.3945/ajcn.114.086918. Epub 2014 Jul 16. PubMed PMID: 25030783; PubMed Central PMCID: PMC4135503. and possibly to foods high in sugar and trans fats.

While there is a connection between diet and rheumatoid arthritis, scientists are still learning about the details. Diet may influence RA development and symptoms in one or more ways. For example, diet has the potential to affect:

• The gut microbiome, which influences immune system function and susceptibility to autoimmune disease ¹¹ Alpízar-Rodríguez D, Finckh A, Gilbert B. The Role of Nutritional Factors and Intestinal Microbiota in Rheumatoid Arthritis Development. Nutrients. 2020;13(1):96. Published 2020 Dec 30. doi:10.3390/nu13010096
• The cells of the immune system, which can release protein molecules that promote inflammation, called pro-inflammatory cytokines ¹² Giugliano D, Ceriello A, Esposito K. The effects of diet on inflammation: emphasis on the metabolic syndrome. J Am Coll Cardiol. 2006;48(4):677-685. doi:10.1016/j.jacc.2006.03.052 ^{, 13} Okada Y, Tsuzuki Y, Sato H, et al. Trans fatty acids exacerbate dextran sodium sulphate-induced colitis by promoting the up-regulation of macrophage-derived proinflammatory cytokines involved in T helper 17 cell polarization. Clin Exp Immunol. 2013;174(3):459-471. doi:10.1111/cei.12200 ^{, 14} Khanna S, Jaiswal KS, Gupta B. Managing Rheumatoid Arthritis with Dietary Interventions. Front Nutr. 2017;4:52. Published 2017 Nov 8. doi:10.3389/fnut.2017.00052
• The presence of excess fat tissue, which can contribute to inflammation and the development of autoimmune disease ¹⁵ Taylor EB. The complex role of adipokines in obesity, inflammation, and autoimmunity. Clin Sci (Lond). 2021;135(6):731-752. doi:10.1042/CS20200895

See An Anti-Inflammatory Diet for Arthritis

Using diet to decrease the risk of rheumatoid arthritis or reduce symptoms is becoming more common but remains an unproven strategy. In general, studies suggest that:

• Inflammation is triggered by consuming drinks and packaged foods that are high in sugar and trans fats ¹⁰ Hu Y, Costenbader KH, Gao X, Al-Daabil M, Sparks JA, Solomon DH, Hu FB, Karlson EW, Lu B. Sugar-sweetened soda consumption and risk of developing rheumatoid arthritis in women. Am J Clin Nutr. 2014 Sep;100(3):959-67. doi: 10.3945/ajcn.114.086918. Epub 2014 Jul 16. PubMed PMID: 25030783; PubMed Central PMCID: PMC4135503.
• Inflammation may be decreased by a whole-foods, plant-based diet that emphasizes fruits, vegetables, and foods that are high in fiber and omega-3 fatty acids

Recommendations regarding specific foods can be conflicting and confusing. Certain foods affect people differently. For example, dairy foods may trigger RA inflammation in one person but not another.

See Foods for a Healthier Gut and Less Arthritis Pain

Body weight

In general, researchers have found that people who carry excess weight have a greater risk of developing rheumatoid arthritis. ¹⁶ Sparks JA, Chen C-Y, Hiraki LT, Malspeis S, Costenbader KH, Karlson EW. Contributions of Familial Rheumatoid Arthritis or Lupus and Environmental Factors to Risk of Rheumatoid Arthritis in Women: a Prospective Cohort Study. Arthritis care & research. 2014;66(10):1438-1446. doi:10.1002/acr.22366. ^{, 17} Lu B, Hiraki L, Sparks JA, et al. Being overweight or obese and risk of developing rheumatoid arthritis among women: a prospective cohort study. Annals of the rheumatic diseases. 2014;73(11):1914-1922. doi:10.1136/annrheumdis-2014-205459. ^{, 18} Versini M, Jeandel PY, Rosenthal E, Shoenfeld Y. Obesity in autoimmune diseases: not a passive bystander. Autoimmun Rev. 2014 Sep;13(9):981-1000. doi: 10.1016/j.autrev.2014.07.001. Epub 2014 Aug 2. Review. PubMed PMID: 25092612. However, the results of one large study suggest that while excess weight increases the risk of developing RA for women, it may decrease the risk for men. ¹⁹ Turesson C, Bergström U, Pikwer M, Nilsson JÅ, Jacobsson LT. A high body mass index is associated with reduced risk of rheumatoid arthritis in men, but not in women. Rheumatology (Oxford). 2016 Feb;55(2):307-14. doi: 10.1093/rheumatology/kev313. Epub 2015 Sep 8. PubMed PMID: 26350488. More research is needed in this area.

Although environmental and lifestyle factors can influence the risk of getting RA, there is not a direct link. Most people who smoke, are overweight, and eat food high in sugar and trans fats will not get rheumatoid arthritis.

Disruption in Hormone Balance

Fluctuations in hormones may play a role in the development of rheumatoid arthritis and symptom severity. Researchers have found:

• RA symptoms subside in women during pregnancy, only to flare up again after the birth
• Women who enter menopause early (before age 40) may have an increased risk of developing seronegative RA ²⁰ Bengtsson C, Malspeis S, Orellana C, Sparks JA, Costenbader KH, Karlson EW. Association Between Menopausal Factors and the Risk of Seronegative and Seropositive Rheumatoid Arthritis: Results From the Nurses' Health Studies. Arthritis Care Res (Hoboken). 2017;69(11):1676-1684. doi:10.1002/acr.23194

Oral contraceptives, which contain progestin and/or estrogen, may decrease the likelihood of developing RA. ²¹ Orellana C, Saevarsdottir S, Klareskog L, Karlson EW, Alfredsson L, Bengtsson C. Oral contraceptives, breastfeeding and the risk of developing rheumatoid arthritis: results from the Swedish EIRA study. Ann Rheum Dis. 2017;76(11):1845-1852. doi:10.1136/annrheumdis-2017-211620 This topic is controversial and more research is needed. ²² Benagiano G, Benagiano M, Bianchi P, D'Elios MM, Brosens I. Contraception in autoimmune diseases. Best Pract Res Clin Obstet Gynaecol. 2019;60:111-123. doi:10.1016/j.bpobgyn.2019.05.003

The Gut Microbiome and Infection History

A body’s microbiome is a collection of microbes, such as bacteria and fungi, that live in the mouth, digestive tract, airway, and elsewhere. The body’s microbiome, particularly in the intestines or gut, can influence the development of RA. ²³ Brusca SB, Abramson SB, Scher JU. Microbiome and mucosal inflammation as extra-articular triggers for rheumatoid arthritis and autoimmunity. Curr Opin Rheumatol. 2014;26(1):101-107. doi:10.1097/BOR.0000000000000008 ^{, 24} Scher JU, Abramson SB. The microbiome and rheumatoid arthritis. Nat Rev Rheumatol. 2011 Aug 23;7(10):569-78. doi: 10.1038/nrrheum.2011.121. ^{, 25} Catrina AI, Deane KD, Scher JU. Gene, environment, microbiome and mucosal immune tolerance in rheumatoid arthritis. Rheumatology (Oxford). 2016 Mar;55(3):391-402. doi: 10.1093/rheumatology/keu469. Epub 2014 Dec 23. PubMed PMID: 25539828; PubMed Central PMCID: PMC4746430. ^{, 26} Chen J, Wright K, Davis JM, Jeraldo P, Marietta EV, Murray J, Nelson H, Matteson EL, Taneja V. An expansion of rare lineage intestinal microbes characterizes rheumatoid arthritis. Genome Med. 2016 Apr 21;8(1):43. doi: 10.1186/s13073-016-0299-7. PubMed PMID: 27102666; PubMed Central PMCID: PMC4840970. ^{, 27} Li M, Wang F. Role of Intestinal Microbiota on Gut Homeostasis and Rheumatoid Arthritis. J Immunol Res. 2021;2021:8167283. Published 2021 Jun 4. doi:10.1155/2021/8167283

Current research shows:

• The gut microbiome affects overall health, including metabolism and immune system function
• The gut microbiome is seeded at birth, develops in early childhood, and is influenced throughout life by things like environment, diet, stress, exercise, and medications, particularly antibiotics
• A healthy gut microbiome includes a balanced, diverse array of thousands of microbiota species
• When gut microbiota species are out of balance (there are too much or too few of certain species), the risk for developing an autoimmune disease, such as RA, may increase

Learn how to Reduce the Risk of Arthritis by Improving the Microbiome

In addition, ongoing research is examining the link between bacterial and viral infections and the development of rheumatoid arthritis. Clinical research suggests there may be associations between RA and certain infections, such as gingivitis, the Epstein-Barr virus, and chronic hepatitis C. ²⁸ Kharlamova N, Jiang X, Sherina N, Potempa B, Israelsson L, Quirke AM, Eriksson K, Yucel-Lindberg T, Venables PJ, Potempa J, Alfredsson L, Lundberg K. Antibodies to Porphyromonas gingivalis indicate interaction between oral infection, smoking and risk genes in rheumatoid arthritis etiology. Abstract only. Arthritis Rheumatol. 2015 Nov 10. doi: 10.1002/art.39491. [Epub ahead of print] PubMed PMID: 26554752. ^{, 29} Berthelot JM, Sibilia J. Rampant infections of bone marrow stem cell niches as triggers for spondyloarthropathies and rheumatoid arthritis. Abstract only. Clin Exp Rheumatol. 2016 Feb 9. [Epub ahead of print] Review. PubMed PMID: 26886813. ^{, 30} Kuwana Y, Takei M, Yajima M, Imadome K-I, Inomata H, Shiozaki M, et al. (2011) Epstein-Barr Virus Induces Erosive Arthritis in Humanized Mice. PLoS ONE 6(10): e26630. doi:10.1371/journal.pone.0026630 ^{, 31} Su F-H, Wu C-S, Sung F-C, Chang S-N, Su C-T, Shieh Y-H, et al. (2014) Chronic Hepatitis C Virus Infection Is Associated with the Development of Rheumatoid Arthritis: A Nationwide Population-Based Study in Taiwan. PLoS ONE 9(11): e113579. doi:10.1371/journal.pone.0113579

Although experts have identified possible links between microbes and RA, there is not enough evidence to point to clear cause and effect. More research is needed.