Autoimmune diseases of all organ sites and systems affect approximately 8% of the population, around 78% of whom are women 1. The diseases are estimated as being the fourth leading cause of disability in women. There is a consistent female excess for the major connective tissue autoimmune diseases (Table 1); this excess varies between 2:1 and 9:1. Recent evidence has highlighted gender differences in disease activity as well as incidence, with women with rheumatoid arthritis (RA) having worse disease activity than men with RA 2; it is unclear, however, whether this relates to the measures of disease activity used rather than to the disease activity itself.

Interestingly, the peak female:male ratio for all three major autoimmune connective tissue disorders (RA, systemic lupus erythematosus (SLE) and scleroderma (Scl)) is generally observed in the late teens to the forties, coinciding with the greatest changes in hormone levels. RA affects around 0.8% of the UK adult population and is around three times more common in women than in men, with a peak age of onset in the fifth decade of life. In later years, the incidence-gender ratio reduces to around 2:1 in 55 to 64 year olds, shifting to a male excess in those over 75 years old 3. The gender ratio for Scl has been reported to vary between 1:1 and 14:1 4. The ratio varies between age groups with slightly higher ratios (3.4:1) in the childbearing years (aged 15 to 44 years) and lower ratios (2.4:1) in the postmenopausal years, with the female:male ratio averaging 3:1 5. SLE has an earlier disease onset than both RA and Scl, peaking in the childbearing years (late teens to early forties) with a female:male ratio of around 9:1 6.

Autoimmune diseases are known to vary by both ethnicity and geographical location. RA shows a wide variation in its incidence and prevalence worldwide. Southern European countries have a lower occurrence compared with north European and North American countries, and the disease also has a lower prevalence in developing countries 7. In all studies, the female RA rate is two to three times higher than that in males 8. SLE also varies geographically, with a higher prevalence in the USA compared with Scandinavian countries and the UK 9. Some studies have found a higher female:male ratio - about 14-fold higher in an English study compared with a fourfold difference in Sweden - but these differences are more likely to be due to the smaller number of cases in males, rather than to true geographical differences in gender ratios 10. There are also geographical variations in the occurrence of Scl. The prevalence is higher in the USA and Australia compared with Japan and Europe 4. There is some evidence of a north-south divide in Europe, with France and Greece having a higher number of cases than Iceland and England. There is a consistent female excess in all populations varying from 3:1 to 14:1 11.

African-Americans and African-Caribbeans both have an increased incidence of SLE compared with Caucasians, and race is associated with disease presentation 9. Whilst the incidence is higher in Africans than Caucasians, when comparing males and females the gender ratio remains about 9:1 10. Racial variations in the epidemiology of Scl show that the disease is higher and more severe in African American women and there is a younger age at onset 12.

While this epidemiological evidence can give us some insights into which populations are more susceptible to autoimmune diseases, it does not explain the excess of these diseases in women. We therefore must examine other hypotheses to explain the excess. The major focus of a number of studies has been a hormonal basis for the disease, due to the hormonal fluctuations to which women are exposed throughout life.

The higher incidence of autoimmune connective tissue disorders in women has led to much interest into whether or not there is a hormonal influence on disease risk. Females have enhanced immunoreactivity, compared with males, with higher immunoglobulin levels and enhanced antibody production to antigen stimulation 13. The immune response in women is more T-helper type 2 predominant compared with men, who have a T-helper type 1 response 1.

The sex hormones oestrogen, androgen and prolactin have all been proposed as having a role in susceptibility to autoimmune diseases. These hormones all modulate the immune response via androgen and oestrogen receptors. The role of sex hormones is not simple, however, and a complex interaction between the hormones may influence disease susceptibility. Oestrogen, progesterone and testosterone all have the same precursor: cholesterol. Further, their common intermediate metabolites (dehydroepiandrosterone and oestradiol) also interact with the immune system. The circulating levels of sex hormones in both genders represent the relative conversion of androgens and oestrogens 14. Levels of oestrogen and progesterone decline with increasing age, with an increased rate of decline in the perimenopausal and menopausal years, and with progesterone declining at a faster rate than oestrogen. Oestrogen and prolactin are both proinflammatory hormones 14 and the increased exposure in women may, in part, explain the high female:male ratio. How oestrogen exerts its action is discussed more fully in several review articles 1516.

There are some interesting observations, however, in relation to autoimmune diseases. Oestrogen may have a direct role in the pathogenesis of SLE: therefore, calcineurin (which enhances the inflammatory response) is induced by oestrogen in women with SLE, while in healthy women it is not 17. This response is thought to be gender specific, suggesting that the oestrogen receptor response is altered in female SLE patients 18. There is some evidence that the oestrogen receptor has a differential function in women with SLE whereby oestrogen enhances T-cell activation in women with SLE, resulting in amplified T-cell/B cell interactions, B-cell activation and autoantibody production 19. Hyperprolactinemia is observed in some autoimmune diseases - most notably in SLE 20. By contrast, androgens (such as testosterone) are anti-inflammatory hormones 14. Such data are consistent with studies showing that men with RA have significantly lower levels of testosterone 21.

Studies on hormone levels are difficult as treatment for the disease or the disease itself can often affect hormone levels and reports on pre-disease hormone levels are not always available. Pre-disease hormone levels may give an insight into why some people develop RA and others do not, and this was examined in a nested case-control study 22. There were no differences, however, in pre-disease testosterone and dehydroepiandrosterone sulphate levels between cases and controls in either men or women 22. A cross-sectional study found that both free and serum testosterone levels were lower in males with RA compared with healthy controls, which supports the hypothesis that male sex hormones may protect against the development of RA 23. Although testosterone levels were reduced, one study found that this was not related to disease activity in RA 21. Multivariate analysis showed that men with both low serum cortisol and low testosterone levels were at an increased risk of developing RA 2425.

Men with RA have variations in a number of sex hormones 26. Dehydroepiandrosterone sulphate and oestrone concentrations have been found to be lower in male RA patients compared with healthy controls 26, while oestradiol was higher and correlated with inflammation levels. A recent review and meta-analysis of the role of the sex hormones (dehydroepiandrosterone/dehydroepiandrosterone sulphate, progesterone, testosterone, oestradiol and prolactin) in SLE showed that female SLE patients have an altered sex hormone milieu, with increased prolactin and oestradiol levels and reduced androgen levels, and suggested that SLE development in women is more closely related to gonadal sex steroid alterations 27.

X chromosome inactivation is an epigenetic system whereby one of the X chromosomes in females gets switched off to ensure that only one copy of X chromosome genes is available in early embryonic cells. This random switching off happens early in development and can either switch off the maternal or the paternal X chromosome. Women are thus functional mosaics for X-linked genes, although several genes can escape this inactivation in physiologic conditions 54.

In some cases this activation can be skewed, with either the maternal or the paternal X chromosome being more frequently active. This skewed X chromosome inactivation has been implicated in Scl development 55. In a recent study, the X chromosome inactivation patterns of female Scl patients and the parental origin of the inactive X chromosome were investigated 56. The authors found that skewed X chromosome inactivation was observed in over 40% of patients compared with 8% of controls (OR = 9.3, 95% CI = 4.3 to 20.6). Extremely skewed X chromosome inactivation was present in around 30% of patients compared with 2% of controls (OR = 16.9, 95% CI = 4.8 to 70.4). It is unlikely that such skewing can by itself explain the increased susceptibility in women but this may be a co-factor in the pathogenetic trail.

X chromosome monosomy - where one X chromosome is absent - is another hypothesis that may explain the increased excess of Scl in females. The rate of monosomy X, in peripheral white blood cells, was found to be significantly increased in a study of women with Scl or autoimmune thyroid disease when compared with healthy age-matched women (6.2 ± 0.3% and 4.3 ± 0.3%, respectively, vs. 2.9 ± 0.2% in healthy women; P < 0.0001 in both comparisons) 57. This may suggest a common role in autoimmune diseases. A recent study in women with SLE, however, found no increase in X monosomy rates when compared with healthy women 58.

Klinefelter's syndrome (47,XXY) - a genetic chromosomal abnormality associated with the presence of one additional X chromosome in men due to abnormal division - has in isolated reports been reported to co-exist with SLE. A recent study has investigated this syndrome in a large population of patients with SLE 59. The authors found that the frequency of Klinefelter's syndrome, which was often subclinical, was 14-fold higher in male SLE patients than in an unselected population. This increased susceptibility could be explained by an X chromosome gene-dose effect.

One of the major differences between the genders is in occupational exposures to potential toxins. For many occupations, however, males are traditionally exposed to more harmful products - so far more male cases would be expected from these risk factors alone. Although occupational exposure to silica is a known risk factor for autoimmune diseases, even in women 70, exposure to silica (for example, coal mining) is much more common in males.

There are some suggestions that chemicals to which women are exposed from the use of cosmetics and hair dyes could help to explain why women get more autoimmune disease. Lupus can be induced by ingestion of drugs containing aromatic amines or hydrazine. The use of hair dye products have been postulated as a possible risk factor for SLE as they contain aromatic amines, but a large cohort study (the Nurses' Health Study) found no increased risk 71.

An interesting association has been found with lipstick use and SLE 72. Researchers found that using lipstick for 3 days/week was significantly associated with SLE and this may be worth considering in future studies on environmental risk factors. The authors suggest that chemicals present in lipsticks may be absorbed across the buccal mucosa and have a biological effect on disease development.

Nearly 30 years ago there were several case reports indicating a connection between silicone implants and Scl 73. This has been the subject of some debate as many reports have found no increased risk, including a large case-control study on the risk of SLE with silicone implants 74. A recent review of a number of case-control studies, cohort studies and critical reviews summarized that there is no connection between connective tissue diseases, including RA, SLE and Scl, and silicone implants 75. Even if there was a risk for women who have implants, given the prevalence of autoimmune diseases and the proportion of women with implants, it is unlikely that this risk factor is substantial enough to make a difference to disease incidence.

Cigarette smoking is a risk factor for RA in both genders, although there do appear to be some interesting gender effects. Cohort studies of postmenopausal women have shown that smoking (both duration and intensity) is linked with an increased risk of RA 76. A case-control study in Finland showed that there is a statistical interaction between smoking and gender 77. Amongst women there are significant interactions between smoking and age. It may be that gender is a biological effect modifier in the association between smoking and RA. There is also a gene-environment interaction between smoking and the risk of RA, which has been observed in a cohort of women with both the shared epitope and a polymorphism in glutathione S-transferase M1 78. The disease phenotype for RA is different between genders, with males having a later disease onset, being more likely to show seropositivity for rheumatoid factor and having higher levels of anti-citrullinated peptide antibodies 79. These results cannot just be attributed to differences in tobacco exposure or to the presence of the shared epitope of other HLA genetic variation.