Elsevier

Clinical Immunology

Volume 149, Issue 2, November 2013, Pages 211-218
Clinical Immunology

Review
Sexual disparities in the incidence and course of SLE and RA

https://doi.org/10.1016/j.clim.2013.03.003Get rights and content

Highlights

  • Discusses the pathogenesis of SLE and RA.

  • Reviews hypotheses about the different incidence and morbidity of SLE and RA.

  • Incorporates both epidemiologic and basic science data to explain hypotheses.

Abstract

Systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) disproportionately affect females compared to males, with female to male prevalence ratios of 7–9:1 for SLE and 2–3:1 for RA. Interestingly, epidemiologic studies indicate that men that develop SLE may have more morbidity than women, but the same is not true for RA. Given the sex and age bias of SLE and RA, sex hormones may influence the pathogenesis of these diseases. However, the ways in which, and to what degree, sex hormones affect disease incidence and severity remain unclear and is the topic of ongoing research. Recent findings have implicated interactions between sex hormones, the immune system, genetic factors, and epigenetic modifications in influencing SLE and RA disease activity. This article reviews current hypotheses regarding the potential impact of sex hormones and genetics on disease pathogenesis, incidence, and severity of SLE and RA.

Introduction

Systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are chronic autoimmune diseases of incompletely understood etiologies, both of which disproportionately affect females compared to males. Female to male prevalence ratios are 7–9:1 for SLE and 2–3:1 for RA. Interestingly, however, epidemiologic studies indicate that men that develop SLE may have more morbidity than women, but the same is not true for RA. The peak age of incidence is younger in SLE (15–40 years) than in RA (45–55 years). Given the sex and age bias of SLE and RA, sex hormones may be involved in the pathogenesis of these related diseases. However, the ways in which, and to what degree, sex hormones affect disease incidence and severity remain unclear and is the topic of ongoing research. Recent findings have implicated interactions between sex hormones, the immune system, genetic factors — including the presence of a second X chromosome in women — and epigenetic modifications in influencing SLE and RA incidence and disease activity. This article will review current hypotheses regarding the potential impact of sex hormones and genetics on disease pathogenesis, incidence, and severity of SLE and RA.

Although both SLE and RA are immune-mediated disorders, they have been thought to originate from disparate arms of the immune response. In the case of SLE, the humoral immune response, resulting from CD4 + T helper 2 (Th2) activity that leads to B cell activation and antibody production, is abnormally increased and dysregulated [1]. In RA, by contrast, CD4 + T helper 1 (Th1) activity is dysregulated, leading to an increase in the cell-mediated immune response particularly among synovial macrophages [2], [3]. Deviating from this traditional line of thought, recent studies have suggested that SLE and RA may share similar underlying immunologic mechanisms, such as dysregulated B and T cell interactions, overproduction of inflammatory cytokines, and involvement of CD4 + T helper 17 (Th17) cells [4], [5], [6].

Section snippets

Effects of sex hormones on immunologic abnormalities in SLE and RA

Sex hormones, including estrogen, progesterone, androgen and prolactin, have numerous well-studied effects upon immune function, as summarized in Table 1. Alterations in hormone levels or hormone-mediated activities could thus potentially affect disease susceptibility or activity [4], [5], [7], [8], [9], [10]. For example, estrogen receptors are present on a variety of immune system cells, including B and T cells [9]. Estrogen has been found to stimulate the Th2/humoral immune response,

Incidence of SLE among females compared with males

The commonly-cited female to male ratio of 9:1 characterizes incident cases of SLE during the childbearing years (Table 2). Prior to puberty this ratio has been shown to be lower, on the order of 2–6:1, and after menopause, it is on the order of 3–8:1 [15], [16]. This pattern suggests that some factor associated with female reproduction may underlie the uptick in incidence among women during the reproductive years. Mohan has suggested that the skewed female prevalence of SLE may result from a

Incidence of RA among females compared with males

RA affects females twice as often as males and has a peak incidence at age 45–55, which coincides with the peri-menopausal years and suggests a possible association between estrogen deficiency and disease onset [61], [62] (Table 3). Data concerning estrogen exposure and RA risk are varied, however. One case–control study found that current oral contraceptive use may protect against RA development, but no effect was apparent for prior oral contraceptive use [63]. Among women followed since the

Conclusions

Sex differences in SLE and RA incidence and severity result from a complex interaction of hormonal, genetic, and epigenetic factors. Both diseases affect women more frequently than men, yet striking differences in the peak age of incidence and the degree of sex-based disparity are seen. Men seem to have a more severe course of SLE compared to women, whereas men may be less severely affected than women with RA. The study of how epigenetic modifications are involved in the pathogenesis and

Conflict of interest statement

Sara Tedeschi, MD has nothing to disclose.

Bonnie Bermas, MD is a consultant for UCB Pharmaceuticals < $5000/year.

Karen Costenbader, MD, MPH has nothing to disclose.

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