Background/Purpose: Systemic sclerosis (SSc) is a complex disease characterized by chronic inflammation, fibrosis, and vasculopathy. Genetic factors contribute to pathogenesis, but because it is a rare disease familial aggregation is uncommon and hard to detect. Cancer risk is increased in SSc patients, but it is not known whether this represents a shared genetic risk factor or a downstream effect of the disease. In this study we analyze 100 large families from Brazil for recurrence rates of SSc across three generations, along with risk of other autoimmune diseases and familial risk of cancer.

Methods: A total of 100 SSc consecutive patients were enrolled at the Rheumatology outpatient clinic at the State University of Campinas – UNICAMP, located in Southeastern Brazil. Patients who met the ACR/EULAR 2013 Criteria for SSc were included in this study. Personal interviews were conducted with each SSc patient to obtain data on a familial history of SSc, other autoimmune and rheumatic conditions, and neoplasia in the extended family. Large familial pedigrees inclusive of 3 degrees of relation to the SSc patient were drawn using the information obtained, and diagnoses of the relatives were analyzed within this framework.

Results: We observed a first-degree relative recurrence rate of 44.9 for SSc, which fell to 20.5 in second degree relatives, and 3.5 in third degree relatives. This recurrence rate pattern fits a polygenic inheritance model. We also observed a significantly increased rate of rheumatoid arthritis and SLE in first degree relatives (for RA, OR=4.5, p=3×10^-5; for SLE OR=7.05, p=0.04). Risk of these other autoimmune diseases was not significantly increased in second and third degree relatives. First degree relatives were reported to have breast cancer and stomach or esophagus cancer more frequently than second or third degree relatives (breast cancer OR=3.5, p=0.0056, stomach or esophagus OR=3.0, p=0.0077). A similar non-significant trend was observed in lung cancer in first degree relatives (OR=2.4, p=0.14 as compared to second and third degree relatives). Leukemia was reported more commonly in first and second degree relatives as compared to third degree relatives (OR=8.1, p=0.019).

Conclusion: We observed significant familial clustering of SSc, which fits a polygenic inheritance model. Rates of RA and SLE were significantly increased in first degree relatives, supporting the idea of shared genetic factors. Some cancers were reported more commonly in relatives that were more closely related to the SSc patient, as compared to more distant relatives. While these data are subject to the limitations inherent in family history studies, it could suggest a shared genetic cancer predisposition in SSc families. Studies in additional populations are needed to confirm this finding.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/familial-clustering-of-systemic-sclerosis-autoimmunity-and-cancer-history/