Background/Purpose: Systemic sclerosis (SSc) is a multisystem autoimmune disease characterized by inflammation, autoantibody production, and increased production of extracellular matrix (ECM), resulting in fibrosis. We demonstrated that estradiol (E2) promotes the development of a fibrotic phenotype, and serum levels of E2 were significantly elevated in female patients with diffuse cutaneous SSc (dcSSc) (postmenopausal, no hormone replacement therapy [HRT]) when compared to controls. Prompted by these findings, we compared gender differences in disease type, disease specific clinical manifestations, disease severity, and analysis of serum E2 levels in patients with SSc. 

Methods: Using the University of Pittsburgh Scleroderma Databank and Serumbank, we identified a total of 2,503 patients (1985-2011) with a clinical diagnosis of SSc. Differences between male and female patients were examined, including disease type, disease specific clinical manifestations including organ system involvement and autoantibody profile, and disease severity using the modified Medsger Disease Severity Scale. Serum levels of E2 in male dcSSc patients (N = 89) were measured using ELISA. We utilized t-test, Chi-square test of proportions, and Fisher’s exact where appropriate.  

Results: There were 1,994 female and 509 male patients with SSc. Most patients were Caucasian (89% in males, 91% in females, p = 0.37). Men with SSc were significantly more likely to have dcSSc than women (p < 0.0001). Males had significantly higher incidence of pulmonary fibrosis (PF) (p < 0.0001), cardiac involvement (p < 0.0001), mean maximum modified Rodnan skin score (p < 0.001), and presence of tendon friction rubs (p = 0.0002). Males also had a significantly higher prevalence of anti-Scl-70 autoantibody as compared to females (p < 0.0001), whereas females had a significantly higher prevalence of anti-centromere antibody (p < 0.0001) with a trend of higher prevalence of anti-U1RNP (p = 0.068) and anti-PM-Scl (p = 0.055). Males also had more severe vascular (p = 0.012), joint (p = 0.013), skin (p = 0.046), pulmonary (p < 0.0001), and cardiac involvement (p = 0.011) in addition to PF (p = 0.0001). For patients with dcSSc, there were 317 males and 939 females. Males had significantly higher incidence of PF (p = 0.0001) and GI involvement (p = 0.0488). There were no significant differences in regards to peripheral vascular, muscle, pulmonary arterial hypertension, or renal involvement. The mean Health Assessment Questionnaire score was significantly higher in females vs. males (p < 0.001). Serum E2 levels were elevated in patients with dcSSc compared with controls. E2 levels were also significantly higher in male dcSSc patients as compared to female dcSSc patients (p = 0.035). 

Conclusion: SSc is more severe in male than female patients, especially regarding skin, pulmonary, cardiac, and GI involvement. This can be explained, in part, by increased circulating levels of E2, a pro-fibrotic hormone. Blocking the actions of E2 represents a viable therapeutic approach, especially with the wide availability of estrogen receptor antagonists and aromatase inhibitors.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/gender-differences-in-systemic-sclerosis-relationship-to-disease-specific-clinical-manifestations-and-estradiol-levels/