Sex-Based Differences in Rheumatoid Arthritis: Clinical Implications and Patient Management

Rheumatoid arthritis (RA) and other autoimmune diseases have a well-known female preponderance. Approximately 78% of patients affected by autoimmune diseases such as multiple sclerosis, scleroderma, systemic lupus erythematosus, Sjogren syndrome, and RA are women.¹ RA is twice as common in women, with a peak incidence between the ages of 45 and 55 years, and the incidence of RA in women appears to be increasing.^1-3 According to an analysis of the Olmstead, Minnesota, incidence cohort involving 466 patients with RA, the incidence rate of RA increased by 2.5% per year among women between 1995 and 2007. No corresponding increase was seen among men.³ 

Namrata Singh, MD, MSCI, FACP, a rheumatologist affiliated with the University of Iowa Hospitals and Clinics and Iowa City VA Medical Center, told Rheumatology Advisor, “Sex contributes to several differences in RA disease aspects like epidemiology, disease course, and management, making the experience different for affected males and females. This should be taken into account while personalizing management of RA to a specific patient.”

The exact mechanisms responsible for sex-based differences in RA are still being elucidated. Differences between men and women in hormone production, physiologic characteristics, chromosome complement, gender-based roles, and behavioral expectations have all been proposed as contributing factors.⁴ Researchers have implicated gonad-specific hormones as a factor influencing RA severity since the 1930s, when it was first noted in the medical literature that disease activity in RA tends to enter into temporary remission during pregnancy.⁴ However, sex-based treatment disparities do not appear to be a major factor in RA outcomes, despite concerns at the beginning of the millennium that women might receive less intensive treatment.^5,6 Those concerns were dispelled by an analysis of the large international cohort of patients with RA known as Quantitative Standard Monitoring of Patients with RA (QUEST-RA), which indicated that similar proportions of men and women were receiving prednisone, methotrexate, or biologic agents.⁵

“We do tend to see that disease activity and disability scores are higher in women compared to men,” noted Ruchi Jain, MD, a rheumatologist in Montefiore Health System in New York, in an interview with Rheumatology Advisor. “This may be related to the fact that women may generally be open to report more symptoms and poorer scores on questionnaires, which can potentially affect disease activity measures overall.” Better disease activity scores in men may also be partially attributable to phenotypic attributes such as greater muscle strength and bone density, which may allow men to compensate more successfully than women for losses in functional capacity.^7,8

The QUEST-RA study revealed that men and women did not differ significantly in RA disease activity, as determined by Disease Activity Score for 28 joints (DAS28) and Health Assessment Questionnaire scores. However, more men than women met criteria for DAS28 remission.⁵ Another observational study involving 1912 patients with RA treated with biologic therapies found that compared with men, women with RA scored significantly higher in subjective, but not objective, measures of disease activity.⁹ Studies involving several cohorts of patients with RA demonstrated no evidence of any difference between men and women in long-term radiographic joint damage, which is the most objective measure available for assessing disease activity in RA.^10,11 This has led some researchers to conclude that a differentiation in the treatment of RA based on sex is not warranted.¹⁰

However, Dr Singh pointed out that there are instances where sex-based treatment differentiation is essential. “Gender plays a big role as a determinant of treatment choice during plans to conceive, pregnancy, or lactation as some of the RA drugs can be teratogenic and potentially be absorbed by the baby from breast milk,” she stated. In particular, methotrexate, widely considered to be the cornerstone of treatment in RA, is a known teratogen and abortifacient with no definite safe dosage in pregnant women.”¹²

The patient’s sex should also be taken into account when managing extra-articular manifestations and comorbidities. Fibromyalgia, a disease that is 9 times more common in women than men, occurs in 10% to 20% of all patients with RA.^13,14 Patients with RA and concomitant fibromyalgia frequently have self-reported disease activity ratings that are higher than their counterparts without fibromyalgia, and thus they may fail to meet the criteria for RA remission. Because this can lead to the inappropriate escalation of RA treatment, a diagnosis of fibromyalgia should be considered in women who do not respond to RA therapy.¹³ Depression is more common in women than in men and can similarly lead to worse self-reported RA disease scores and assessments of functional status.⁶ Clinicians frequently underrecognize and undertreat heart disease in women because of the belief that female sex provides some protection against heart disease.¹⁵ However, RA confers an equally high risk for heart disease in women and men because of the effects of systemic inflammation.⁶ 

Coping strategies among men and women with RA may differ because of gender-specific social factors. Some research has shown that compared with women, men with RA have a greater preference for one-to-one support from a clinician, with an emphasis on information exchange, whereas women with RA have a greater preference than men for interaction with other patients.¹⁶ “Since autoimmune diseases tend to occur more commonly in women, the men who have the disease may not be as outspoken or willing to share their diagnosis as readily as women may,” Dr Jain stated, noting also that the preponderance of female patients with RA may lead online support groups and real-life support groups to cater more to women than to men. “However, many of the men who have RA have had family members such as their mothers, aunts, or sisters with the disease and may understand the genetic link and have family member support.”

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References 

1. Fairweather D, Frisancho-Kiss S, Rose NR. Sex differences in autoimmune disease from a pathological perspective.  Am J Pathol. 2008;173(3):600-609.
2. Tedeschi SK, Bermas B, Costenbader KH. Sexual disparities in the incidence and course of SLE and RA. Clin Immunol. 2013;149(2):211-218.
3. Myasoedova E, Crowson CS, Kremers HM, Therneau TM, Gabriel SE. Is the incidence of rheumatoid arthritis rising?: results from Olmsted County, Minnesota, 1955-2007.  Arthritis Rheum. 2010;62(6):1576-1582.
4. Kovacs WJ, Olsen NJ. Sexual dimorphism of RA manifestations: genes, hormones and behavior. Nat Rev Rheumatol. 2011;7(5):307-310.
5. Sokka T, Toloza S, Cutolo M, et al. Women, men, and rheumatoid arthritis: analyses of disease activity, disease characteristics, and treatments in the QUEST-RA study. Arthritis Res Ther. 2009;11(1):R7.
6. Favalli EG, Biggioggero M, Crotti C, Becciolini A, Raimondo MG, Meroni PL. Sex and Management of Rheumatoid Arthritis [published online January 26, 2018].  Clin Rev Allergy Immunol. doi:10.1007/s12016-018-8672-5
7. Häkkinen A, Kautiainen H, Hannonen P, Ylinen J, Mäkinen H, Sokka T. Muscle strength, pain, and disease activity explain individual subdimensions of the Health Assessment Questionnaire disability index, especially in women with rheumatoid arthritis. Ann Rheum Dis. 2006;65(1):30-34.
8. van Vollenhoven RF. Sex differences in rheumatoid arthritis: more than meets the eye…  BMC Med. 2009;7:12.
9. Lesuis N, Befrits R, Nyberg F, van Vollenhoven RF. Gender and the treatment of immune-mediated chronic inflammatory diseases: rheumatoid arthritis, inflammatory bowel disease and psoriasis: an observational study. BMC Med. 2012;10:82.
10. Asikainen J, Nikiphorou E, Kaarela K, et al. Is long-term radiographic joint damage different between men and women? Prospective longitudinal data analysis of four early RA cohorts with greater than 15 years follow-up. Clin Exp Rheumatol. 2016;34(4):641-645.
11. Asikainen J, Rannio T, Kautiainen H, Hannonen P, Sokka T. THU0056 women, men, and rheumatoid arthritis: radiographic progression over ten years in the current millennium. Ann Rheum Dis. 2016;75(Suppl 2):198-198.
12. Ince-Askan H, Dolhain RJEM. Pregnancy and rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2015;29(4-5):580-596.
13. Salaffi F, Gerardi MC, Atzeni F, et al. The influence of fibromyalgia on achieving remission in patients with long-standing rheumatoid arthritis. Rheumatol Int. 2017;37(12):2035-2042.
14. Yunus MB. Gender differences in fibromyalgia and other related syndromes.  J Gend-Specif Med. 2002;5(2):42-47.
15. Maas AH, Appelman YE. Gender differences in coronary heart disease.  Neth Heart J. 2010;18(12):598-602.
16. Flurey CA, Hewlett S, Rodham K, White A, Noddings R, Kirwan JR. Coping strategies, psychological impact, and support preferences of men with rheumatoid arthritis: a multicenter survey [published online September 21, 2017].  Arthritis Care Res (Hoboken). doi:10.1002/acr.23422