Effects of Sex and Gender on Rheumatoid Arthritis Pathogenesis and Treatment - Rheumatology Advisor

Effects of Sex and Gender on Rheumatoid Arthritis Pathogenesis and Treatment

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  • Which Hormones Impact RA Risk?

    Which Hormones Impact RA Risk?

    Sex hormones have been shown to affect the immune system and serve as important modulators of autoimmune diseases. Compared with men, women experience significantly more natural and artificial sex hormone fluctuations throughout their lifetime, such as during the onset of puberty, menstruation, contraceptive use, and pregnancy. This has led investigators to closely examine the impact of sex hormones on the development of RA. The female-dominant hormones estrogen and prolactin and the male-dominant androgens have been shown to affect RA susceptibility.[2] Estrogen and prolactin are proinflammatory hormones and androgens are anti-inflammatory hormones. The overall increased exposure to proinflammatory hormones over a woman’s lifetime might explain the higher female to male ratio in RA, particularly among premenopausal women.[2] Additionally, men with RA have been shown to have lower testosterone levels than their non-RA counterparts, supporting the idea that androgens are protective. [2,4] Photo credit: SPL/Science Source

  • Hormonal status in women can significantly impact risk of developing RA. Women who start menstruating at an earlier age, have irregular periods because of excess hormone production, or breastfeed have been shown to be at higher risk of developing RA.[2,5] In breastfeeding mothers, the risk of developing RA increases fivefold after a first pregnancy, twofold after a second pregnancy, and then poses no increased risk in subsequent pregnancies.[2,6] Hormonal status can also impact RA symptoms. Disease remission is common in pregnancy, whereas exacerbation of symptoms often occurs in the postpartum period, particularly among women who breastfeed.[2,7] Numerous studies have shown that use of oral contraceptive pills might be protective against or delay the onset of RA, whereas use of hormone replacement therapy has not been shown to impact risk in either direction.[2]

    How Does Hormonal Status Impact Disease Risk and Symptoms?

    Hormonal status in women can significantly impact risk of developing RA. Women who start menstruating at an earlier age, have irregular periods because of excess hormone production, or breastfeed have been shown to be at higher risk of developing RA.[2,5] In breastfeeding mothers, the risk of developing RA increases fivefold after a first pregnancy, twofold after a second pregnancy, and then poses no increased risk in subsequent pregnancies.[2,6] Hormonal status can also impact RA symptoms. Disease remission is common in pregnancy, whereas exacerbation of symptoms often occurs in the postpartum period, particularly among women who breastfeed.[2,7] Numerous studies have shown that use of oral contraceptive pills might be protective against or delay the onset of RA, whereas use of hormone replacement therapy has not been shown to impact risk in either direction.[2]

  • Although genetic factors have been shown to affect the risk of developing RA, they often do not have the same effects in both sexes. In one study, the single nucleotide polymorphism (SNP) marker rs11761231on chromosome 7 did not affect men’s risk of developing RA, but it had a strong additive effect in women.[2,8] Similarly, genetic variants in Dectin-2, DC-SIGN, and MCP-1 were found to affect men and women differently.[9] Women with the Dectin-2rs4264222T or Dectin-2rs7134303G alleles had an increased risk of developing RA, whereas those with the MCP-1rs1024611G or MCP-1rs13900T alleles had a decreased risk compared with carriers of the wild-type genotype. Men did not show these same effects, but those with the DC-SIGNrs4804803G allele had a significantly decreased risk of developing RA.[9] These findings indicate that genetic polymorphisms within immune-related genes have different effects in men and women and warrant further investigation.[8,9]

    Do Genetic Factors Influence Risk for Developing RA in the Same Way in Both Sexes?

    Although genetic factors have been shown to affect the risk of developing RA, they often do not have the same effects in both sexes. In one study, the single nucleotide polymorphism (SNP) marker rs11761231on chromosome 7 did not affect men’s risk of developing RA, but it had a strong additive effect in women.[2,8] Similarly, genetic variants in Dectin-2, DC-SIGN, and MCP-1 were found to affect men and women differently.[9] Women with the Dectin-2rs4264222T or Dectin-2rs7134303G alleles had an increased risk of developing RA, whereas those with the MCP-1rs1024611G or MCP-1rs13900T alleles had a decreased risk compared with carriers of the wild-type genotype. Men did not show these same effects, but those with the DC-SIGNrs4804803G allele had a significantly decreased risk of developing RA.[9] These findings indicate that genetic polymorphisms within immune-related genes have different effects in men and women and warrant further investigation.[8,9]

  • Two lifestyle-related factors that have been reported to affect RA risk and disease activity include smoking and being overweight. Cigarette smoking has been reported to increase the risk of developing RA in both sexes,[2] but results have been varied. In one study, men with a smoking history had an increased risk of rheumatoid factor (RF)-positive RA, whereas women showed no significant association between current or past smoking and RF-positive or RF-negative disease.[10] In another study, white women who lacked genetic risk factors for RA became at increased risk if they had been exposed to tobacco smoke.[11] Furthermore, women with a ≥20 pack-year history of smoking have been reported to have more severe RA, including more nodules and reduced grip strength.[12] The impact of body mass index (BMI) on RA disease activity was assessed in the QUEST-RA study.[13] In the study, women’s disease activity scores increased with increasing BMI, whereas the reverse trend was observed among men. Debora Cartagena/CDC Phil

    Do Lifestyle Factors Affect RA Risk and Disease Activity Differently in Men and Women?

    Two lifestyle-related factors that have been reported to affect RA risk and disease activity include smoking and being overweight. Cigarette smoking has been reported to increase the risk of developing RA in both sexes,[2] but results have been varied. In one study, men with a smoking history had an increased risk of rheumatoid factor (RF)-positive RA, whereas women showed no significant association between current or past smoking and RF-positive or RF-negative disease.[10] In another study, white women who lacked genetic risk factors for RA became at increased risk if they had been exposed to tobacco smoke.[11] Furthermore, women with a ≥20 pack-year history of smoking have been reported to have more severe RA, including more nodules and reduced grip strength.[12] The impact of body mass index (BMI) on RA disease activity was assessed in the QUEST-RA study.[13] In the study, women’s disease activity scores increased with increasing BMI, whereas the reverse trend was observed among men. Debora Cartagena/CDC Phil

  • The increased use of cosmetics and hair dyes by women has been suggested to increase exposure to chemicals that could potentiate the development of autoimmune diseases.[2] In one study, women who wore lipstick ≥3 days per week were found to be at significantly increased risk of systemic lupus erythematosus,[2,14] but no such association has been reported for RA. In another study, investigators assessed the impact of skin care product use on RA and found no increase in risk with normal use in either sex, but the authors could not rule out the potential for increased risk in persons with certain genotypes or exposures to other risk factors.[15] The investigators focused on products containing mineral oil, an agent they previously showed to increase the risk of RF-positive and anticitrulline peptide antibody-positive RA in men who were occupationally exposed.[16]

    How Can Sex and Gender Influence Environmental Factors and Impact RA Risk?

    The increased use of cosmetics and hair dyes by women has been suggested to increase exposure to chemicals that could potentiate the development of autoimmune diseases.[2] In one study, women who wore lipstick ≥3 days per week were found to be at significantly increased risk of systemic lupus erythematosus,[2,14] but no such association has been reported for RA. In another study, investigators assessed the impact of skin care product use on RA and found no increase in risk with normal use in either sex, but the authors could not rule out the potential for increased risk in persons with certain genotypes or exposures to other risk factors.[15] The investigators focused on products containing mineral oil, an agent they previously showed to increase the risk of RF-positive and anticitrulline peptide antibody-positive RA in men who were occupationally exposed.[16]

  • The gut microbiome has been shown to affect immunity and influence the development of autoimmune disorders, including RA.[17,18] More recent evidence suggests the gut microbiome might also interact with sex hormones to modulate disease progression.[18] This process has not been well studies and remains poorly understood, but is likely to differ between autoimmune diseases and be confounded by the complex interaction between host genotype, sex steroids, and overall composition of the gut microbes, with some microbes being protective and others increasing the risk of developing RA and other autoimmune diseases.[18] Nevertheless, the association between the gut microbiome and autoimmunity indicates that altering gut microbial composition might be an effective novel target for treating RA and other autoimmune diseases.[18] However, when developing such strategies, sex differences should be accounted for.[18] CDC/Dr. Sam Formal, Walter Reed Army Institution of Research

    Has the Gut Microbiome Shown To Be Associated With RA Differentially in Men and Women?

    The gut microbiome has been shown to affect immunity and influence the development of autoimmune disorders, including RA.[17,18] More recent evidence suggests the gut microbiome might also interact with sex hormones to modulate disease progression.[18] This process has not been well studies and remains poorly understood, but is likely to differ between autoimmune diseases and be confounded by the complex interaction between host genotype, sex steroids, and overall composition of the gut microbes, with some microbes being protective and others increasing the risk of developing RA and other autoimmune diseases.[18] Nevertheless, the association between the gut microbiome and autoimmunity indicates that altering gut microbial composition might be an effective novel target for treating RA and other autoimmune diseases.[18] However, when developing such strategies, sex differences should be accounted for.[18] CDC/Dr. Sam Formal, Walter Reed Army Institution of Research

  • Compared with men, women have been reported to have a lower response rate to many RA therapies, including disease-modifying antirheumatic drugs (DMARDs) and tumor necrosis factor (TNF) blockers.[19-21] In one large study, male sex was associated with sustained remission in early RA, but this did not carry over to established RA.[20] In another study, differences in remission were not observed between the sexes until 12 months, when men vs women receiving rituximab achieved remission more frequently (18% vs 12%; P =.045).[19] Additionally, men with anti-TNF failure were more likely than their female counterparts to achieve remission with rituximab at 6, 12, and 18 months.[19] In a study of the anti-TNF-α therapies etanercept (ETA) and infliximab (INF), women were significantly less likely than men to achieve remission following therapy with both drugs.[21] The odds ratio (OR) was similar between agents, with an OR of 0.61 and 0.60 for ETA and INF, respectively.

    How Does Gender Affect Response to RA Treatment?

    Compared with men, women have been reported to have a lower response rate to many RA therapies, including disease-modifying antirheumatic drugs (DMARDs) and tumor necrosis factor (TNF) blockers.[19-21] In one large study, male sex was associated with sustained remission in early RA, but this did not carry over to established RA.[20] In another study, differences in remission were not observed between the sexes until 12 months, when men vs women receiving rituximab achieved remission more frequently (18% vs 12%; P =.045).[19] Additionally, men with anti-TNF failure were more likely than their female counterparts to achieve remission with rituximab at 6, 12, and 18 months.[19] In a study of the anti-TNF-α therapies etanercept (ETA) and infliximab (INF), women were significantly less likely than men to achieve remission following therapy with both drugs.[21] The odds ratio (OR) was similar between agents, with an OR of 0.61 and 0.60 for ETA and INF, respectively.

  • What Might Account for the Gender Disparity Found in Response to RA treatment?

    What Might Account for the Gender Disparity Found in Response to RA treatment?

    In many studies, women often have more severe disease at baseline, including worse measures of disease activity and increased prevalence of chronic pain, disability, and depression, each of which has independently been shown to reduce response to treatment and affect outcomes.[1,22] There is also some indication that women with RA are undertreated. One study found that women scored significantly higher than men on subjective disease activity measures, even when objective measures showed similar disease activity, suggesting subjective disease measures might not be given enough weight in treatment decision-making, potentially leading women to be undertreated.[22] Véronique Burger/Science Source

Autoimmune diseases have been shown to disproportionately affect women. In patients with rheumatoid arthritis (RA), the female to male ratio is 3:1, with women making up more than 75% of all cases of RA. [1,2] This ratio decreases to 2:1 after the fifth decade of life, becoming  male predominant among those in the seventh decade of life.[2] Numerous factors have been implicated in the overrepresentation of women in RA and other autoimmune diseases, including hormonal, genetic, lifestyle, and environmental factors.[2]

Although women are significantly more likely than men to develop RA, which has been reported to be the fourth leading cause of disability in women, it has been unclear whether they also have worse outcomes.[3] To answer this question, more recent studies have examined the impact of sex chromosomes on RA disease course, response to treatment, and overall prognosis. Although the findings in each of these areas have varied somewhat, they indicate sex is an important consideration when caring for the RA patient.

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