ReviewSexual disparities in the incidence and course 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.
References (94)
Sex hormone adjuvant therapy in rheumatoid arthritis
Rheum. Dis. Clin. North Am.
(2000)Progesterone and autoimmune disease
Autoimmun. Rev.
(2012)Hormonal modulation of B cell development and repertoire selection
Mol. Immunol.
(2005)- et al.
Sex affects immunity
J. Autoimmun.
(2012) - et al.
Prolactin and autoimmunity
Autoimmun. Rev.
(2012) Lupus erythematosus in the 1980s: a survey of 570 patients
Semin. Arthritis Rheum.
(1991)Increased X-inactivation skewing in SLE?
Immunol. Today
(1999)- et al.
The genetics and epigenetics of autoimmune diseases
J. Autoimmun.
(2009) Sex-specific differences in the relationship between genetic susceptibility, T cell DNA demethylation and lupus flare severity
J. Autoimmun.
(2012)Oral contraceptives and rheumatoid arthritis: results from a primary care-based incident case–control study
Semin. Arthritis Rheum.
(1997)
Pregnancy and rheumatoid arthritis
Rheum. Dis. Clin. North Am.
From T to B and back again: positive feedback in systemic autoimmune disease
Nat. Rev. Immunol.
Hormones, pregnancy, and autoimmune diseases
Ann. N. Y. Acad. Sci.
Sex hormones influence on the immune system: basic and clinical aspects in autoimmunity
Lupus
The unexplained female predominance of systemic lupus erythematosus: clues from genetic and cytokine studies
Clin. Rev. Allergy Immunol.
The role of sex hormones in systemic lupus erythematosus
Curr. Opin. Rheumatol.
Sex hormones and systemic lupus erythematosus
Lupus
Adrenal and gonadal steroid hormone deficiency in the pathogenesis of rheumatoid arthritis
J. Rheumatol. Suppl.
Hormonal regulation of B-cell function and systemic lupus erythematosus
Lupus
Th17 response and inflammatory autoimmune diseases
Int. J. Inflamm.
Clinical features of systemic lupus erythematosus: differences related to race and age of onset
Arthritis Rheum.
Review: male systemic lupus erythematosus: a review of sex disparities in this disease
Lupus
Environment versus genetics in autoimmunity: a geneticist's perspective
Lupus
Hair dye use and the risk of developing systemic lupus erythematosus
Arthritis Rheum.
Is lipstick associated with the development of systemic lupus erythematosus (SLE)?
Clin. Rheumatol.
Reproductive and menopausal factors and risk of systemic lupus erythematosus in women
Arthritis Rheum.
Combined oral contraceptive use and the risk of systemic lupus erythematosus
Arthritis Rheum.
Accelerated damage accrual among men with systemic lupus erythematosus: XLIV. Results from a multiethnic US cohort
Arthritis Rheum.
Gender and age differences in systemic lupus erythematosus. A study of 489 Greek patients with a review of the literature
Lupus
Systemic lupus erythematosus in men: a multivariate analysis of gender differences in clinical manifestations
J. Rheumatol.
Male systemic lupus erythematosus in a Latin-American inception cohort of 1214 patients
Lupus
Outcome in systemic lupus erythematosus: a prospective study of patients from a defined population
Medicine (Baltimore)
Prognosis in systemic lupus erythematosus. Negative impact of increasing age at onset, black race, and thrombocytopenia, as well as causes of death
Arthritis Rheum.
Systemic lupus erythematosus in men: a retrospective analysis in a Veterans Administration Healthcare System population
J. Clin. Rheumatol.
The clinical features and prognosis of male lupus in Taiwan
Lupus
The effect of combined estrogen and progesterone hormone replacement therapy on disease activity in systemic lupus erythematosus: a randomized trial
Ann. Intern. Med.
Safety of hormone replacement therapy (HRT) in systemic lupus erythematosus (SLE)
Lupus
Safety of hormonal replacement therapy in postmenopausal patients with systemic lupus erythematosus
Scand. J. Rheumatol.
Effect of hormone replacement therapy (HRT) on disease activity in postmenopausal patients with SLE. A two-year follow-up clinical trial [Abstract]
Arthritis Rheum.
Combined oral contraceptives in women with systemic lupus erythematosus
N. Engl. J. Med.
Dehydroepiandrosterone for systemic lupus erythematosus
Cochrane Database Syst. Rev.
Effects of prasterone on disease activity and symptoms in women with active systemic lupus erythematosus
Arthritis Rheum.
Bromocriptine in systemic lupus erythematosus: a double-blind, randomized, placebo-controlled study
Lupus
Prospective study of pregnancy in systemic lupus erythematosus. Results of a multidisciplinary approach
J. Rheumatol.
Systemic lupus erythematosus. VI. Analysis of the interrelationship with pregnancy
J. Rheumatol.
Frequency of lupus flare in pregnancy. The Hopkins Lupus Pregnancy Center experience
Arthritis Rheum.
Does lupus flare during pregnancy?
Lupus
Cited by (126)
Functional genomics in inborn errors of immunity
2024, Immunological ReviewsSex bias in immune response: it is time to include the sex variable in studies of autoimmune rheumatic diseases
2024, Rheumatology InternationalGender differences in retinal diseases: A review
2024, Clinical and Experimental Ophthalmology