Look Beyond Hormones to Explain RA Gender Gap

Women are at two to three times greater risk for rheumatoid arthritis (RA) than men, a tendency once [[{"type":"media","view_mode":"media_crop","fid":"23604","attributes":{"alt":"","class":"media-image media-image-right","id":"media_crop_6356546094658","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"1901","media_crop_rotate":"0","media_crop_scale_h":"0","media_crop_scale_w":"0","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"width: 118px; height: 180px; margin: 5px; float: right;","title":" ","typeof":"foaf:Image"}}]]mainly attributed to female hormones.

This theory stems from the observations that RA often gets better during pregnancy, when estrogen is high, and that peak incidence rises after menopause, when hormone levels drop. Estrogen is known to stimulate some immune responses, while progesterone inhibits others.¹

But it’s more complicated than that. For example, among newfound genes linked to RA are a group on the X chromosome, giving XX women a double dose compared to XY men.² Also, some recent studies hint at gender-specific environmental factors that may boost women's risk of RA.³

"Weaker Sex?" Not in Immune Response

Females are born with stronger immune systems than males and more active thymus glands. Their inflammatory and cytotoxic T-cell responses are more robust than men's, and they are more likely to survive infections.¹

These stronger immune responses lead to overexpression of certain immune system genes and to a preponderance of many autoimmune diseases like RA among women¸ noted immunologist Eric Gershwin MD, chief of the division of Rheumatology, Allergy and Clinical Immunology at the University of California, Davis.⁴

Women also have higher background levels of autoimmune antibodies than men, Gershwin told a special session on sex, autoimmunity and hormones at the 2013 meeting of the American College of Rheumatology (ACR).⁴

Estrogens stimulate the immune system, favoring Th2 and B cells and increased antibody production, promoting B-cell mediated autoimmune diseases like RA, he said. In contrast, androgens act as natural immunosuppressants, favoring Th1 responses.⁴

One mechanism by which high estrogen levels during pregnancy improve disease may be through decreased T-cell mediated immune responses, he suggests.⁴ At the same time, less human leukocyte antigen (HLA) similarity between a mother and fetus increases the likelihood of remission during pregnancy, he added.

Beyond Hormones

Even pregnancy outcomes may affect RA risk.

A recent study from the University of Washington at Seattle compared women with uncomplicated pregnancies to those who had very low or extremely low birthweight babies. It found that women with these complicated pregnancies had a higher risk for RA -- particularly the rheumatoid-factor (RF)-positive form.⁵  Why? The researchers speculate the association may reflect risk factors common to pregnancy complications and RF-positive RA.⁵

Studies show that women using oral contraceptives at RA onset tend to have milder disease. But a number of randomized controlled trials to assess post-menopausal hormone therapy on the severity and progression of RA have met with mixed results.⁶

A study from Sweden presented at ACR 2013 found a strikingly decreased rates of anti–cyclic citrullinated peptide antibody (ACPA)-positive RA among current users of hormones ages 50 to 70, but not of ACPA-negative RA.⁶

“ACPA-positive RA compared to ACPA-negative is a more serious disease, so our study showed that postmenopausal hormones might prevent a disease that is more severe,” study co-author Cecilia Orellana, PhD, a researcher at the Karolinska Institute in Stockholm, said in an interview.

Indeed, age age-adjusted death rates for ACPA–positive RA may be as much as two times greater in older women, according to a study of post-menopausal women in the Women’s Health Initiative.⁷   The increased risk couldn’t be explained by age alone.⁶

However, taking hormones may also compound the increased risk for cardiovascular (CV) disease among women with RA. “We don’t know exactly the contribution of hormones to CV risk in RA,” observed Joan M. Bathon MD, director of the Division of Rheumatology at Columbia University in New York.

The X factor

In 2012, genes specific to the X chromosome were linked to RA for the first time. The 14 genes were identified by researchers at the Arthritis Research UK epidemiology unit at the University of Manchester, using DNA samples from more than 27,000 patients with RA and healthy controls in six countries, around 70% of whom were women.²

“This is the first association of the X-chromosome locus with rheumatoid arthritis and is of relevance given the female predominance of both diseases (9:1 and 3:1 ratios of females to males in systemic lupus erythematosus and rheumatoid arthritis, respectively)," the research team wrote in Nature Genetics.² "Interestingly, this locus has been shown to occasionally escape X inactivation in female cells.”

In a press release from the university, lead author Jane Worthington PhD, professor of chronic disease genetics, said the discovery may help explain why women are three times more likely than men to develop RA.⁸

In an animal study that looked directly at the chromosomes themselves, rather than at their gene products, something about the X was suspect. The experiments in mice involved switching X and Y chromosomes between males and females. Ram Raj Singh, MD, professor of Medicine and Pathology at the UCLA School of Medicine, reported the results at the 2013 ACR session on sex and autoimmunity.⁴

Whatever their gender at birth, “mice with two X chromosomes have higher levels of autoantibodies than mice with an XY combination,” Singh explained. In the sex chromosome-altered mice, having an XX duo produced greater disease severity and organ damage than the XY combination in experimental models of lupus and autoimmunity.⁴

Environmental Effects

Environmental factors such as medications, pesticides, and even cosmetics may also play a role in women's RA risk. A literature review from Yale University has cited possible sex-specific environmental effects in case-control studies of occupational exposure to hair dyes and nail polish (among salon employees) as well as of lipstick use in the general population.³

The review cited previous studies showing an increased risk of RA among  beauticians and others exposed to hairdressing chemicals. However, a Study from Sweden found no evidence to incriminate cosmetics such as body lotions and ointments.⁹

The Yale review also cited infectious agents such as Epstein Barr virus that may have greater effects among women.³

Being Female

In accounting for the increased RA risk among women, “hormones are the easy way out,” Gershwin told the 2013 ACR annual meeting, but went on to say why their role is not so "easy" to understand.

"They all influence that immune system...at different times and different ways and at different ages.”⁴

"There will never be a simple answer,” he added. “The lessons here are that there’s an awful lot of room for study.”⁴
 

References:

1.  Fagan TF, Faustman DL. Sex differences in autoimmunity. Advances in Molecular and Cell Biology (2004) 34:295–306

2.  Eyre S, Bowes J, Diogo D, et al., High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis. Nature Genetics (2012) 44:1336–1340. doi:10.1038/ng.2462.

3.  Tiniakou E, Costenbader KH, Kriegel MA. Sex-specific environmental Influences on the development of autoimmune diseases. Clinical Immunology (2013) 149:182–191 [E-pub 28 February 2013].

4.   Gershwin ME, Singh RR, Gilkeson GS, “Sex and Autoimmunity: Hormones and Beyond.” American College of Rheumatology (ACR) 2013 Annual Meeting, San Diego, CA. ACR Session, Sunday October 27, 2013.

5.  Ma KK, Nelson JL, Guthrie KA et al. Adverse pregnancy outcomes and risk of subsequent rheumatoid arthritis. Arthritis & Rheumatism. (2013) Accepted article, Dec 23, 2013. DOI: 10.1002/art.38247

6.   Saevarsdottir S, Klareskog L, Alfredsson, L, et al., Postmenopausal Hormone Therapy and The Risk Of Rheumatoid Arthritis: Results From The Swedish EIRA Study. ACR Abstract: #117. Sunday, October 27, 2013.

7.   Kuller LH, Mackey RH, Chang Y, et al. Determinants of Mortality Among Postmenopausal Women in the Women’s Health Initiative Who Report Rheumatoid Arthritis.Arthritis & Rheumatology (2014) 66:497–507. DOI 10.1002/art.38268.

8.   Arthritis UK Press Release, Arthritis study reveals why gender bias is all in the genes, Published on 15 November 2012. http://www.arthritisresearchuk.org/news/press-releases/2012/november/arthritis-study-reveals-why-gender-bias-is-all-in-the-genes.aspx  Retrieved 3/19/2014.

9.  Sverdrup BM, Källberg H, Klareskog L, et al., Usage of skin care products and risk of rheumatoid arthritis: results from the Swedish EIRA study. Arthritis Research & Therapy (2012) 14:R41 doi:10.1186/ar3749.