Introduction There is a strong female preponderance reported in many connective tissue diseases and in almost all systemic sclerosis (SSc) case series. Methods We compared gender differences in SSc patients in a large single-center cohort, including demographic features, disease subtype, environmental exposures, disease-specific serum autoantibodies, organ system involvement (frequency and severity) and survival. Adjustment for cutaneous subset (diffuse cutaneous [dc] and limited cutaneous [lc]) was performed. Results We identified key characteristics which distinguished female from male SSc patients. Females were more frequently younger at disease onset with a longer disease duration at the time of their first visit. Females more often had lcSSc and, if an overlap syndrome was present, it was most often systemic lupus erythematosus. In contrast, males more frequently had dcSSc and overlap with myositis. Females more frequently had peripheral vascular involvement but in males it was more often severe. Males were more often cigarette smokers and more frequently had environmental exposures. Males more frequently had interstitial lung disease (ILD or pulmonary fibrosis) which was more severe. Females had a significantly increased frequency of anti-centromere antibody and males anti-topoisomerase I and anti-U3RNP antibody. Males had significantly reduced survival (73% at 5 years and 45% at 10 years after onset of SSc). The most frequent causes of death were ILD in males and pulmonary hypertension in females. Conclusions Gender differences may be important clues to understanding the natural history and pathogenesis of SSc.

IntroductionSystemic sclerosis (SSc) is more prevalent in women. Our goal is to determine the effects of 17β-estradiol (E2) on the development of fibrosis and to compare circulating levels of estrogens in SSc patients and healthy controls.MethodsUsing primary human dermal fibroblasts, we evaluated the effect of E2 on fibronectin (FN) expression with and without the estrogen receptor (ER) antagonist ICI 182,780, inhibitors of signaling, propyl-pyrazole-triol, an ERα specific ligand, and genistein, an ERβ selective ligand, to identify the signaling pathways mediating E2's effect. We confirmed the fibrotic effect of E2 in human skin using an ex vivo organ culture model. Lastly, we measured levels of E2 and estrone in serum samples from SSc patients with diffuse cutaneous involvement and healthy controls using mass spectrometry.ResultsE2 increased expression of FN in dermal fibroblasts. ICI 182,780, inositol-1,4,5-triphosphate inhibitor, and p38 mitogen-activated protein kinase inhibitor blocked the effects of E2 on FN. Propyl-pyrazole-triol, but not genistein, significantly increased FN expression. Ex vivo, E2 induced fibrosis of human skin. The effects of E2 were abrogated by ICI 182,780. Circulating levels of E2 and estrone were significantly increased in sera of patients with diffuse cutaneous SSc.ConclusionOur findings implicate estrogens in the fibrotic process and may explain the preponderance of SSc in women. ICI 182,780 or other ER signaling antagonists may be effective agents for the treatment of fibrosis.

Background Systemic sclerosis (SSc) is a female-predominant disease, characterized by excessive extracellular matrix deposition (ECM) with dermal and internal organ fibrosis. Considering the sex-based disparity in disease incidence, estradiol (E2), an estrogen form with pro-fibrotic effects, may play a role in SSc. We reported that post-menopausal women with diffuse cutaneous (dc)SSc have higher serum E2 levels compared to similar aged, healthy controls. Since males with SSc tend to have more severe disease, we examined serum E2 in dcSSc males in relation to disease characteristics and survival. Methods We measured serum E2 in 83 dcSSc men > 50 years old from the University of Pittsburgh Scleroderma Center and similar aged healthy controls. Using statistical modeling, we examined the associations between serum E2, internal organ involvement, autoantibody profiles, and survival. Results Male dcSSc patients had significantly higher serum E2 levels compared to healthy males and similar aged dcSSc post-menopausal women. Male dcSSc patients with high serum E2 had significantly more heart involvement, a trend for higher skin thickness progression rate, and worse survival. Using Cox regression modeling, increased serum E2 levels in anti-Scl-70 antibody-positive dcSSc males were associated with an increased risk of death. Conclusions dcSSc males > 50 years old have higher levels of serum E2 compared to healthy controls and dcSSc post-menopausal women. Elevated serum E2 levels in dcSSc males are associated with heart involvement, trend to progression of dermal fibrosis, and, if anti-Scl-70 antibody positive, worse survival. Our study expands on previous work implicating E2 in dermal fibrosis in SSc and associates E2 levels with internal organ involvement and survival. These data suggest a role for estrogen imbalance in dcSSc.

Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease diagnosed on the presence of a constellation of clinical and laboratory findings. At the pathogenetic level,

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