Background/Purpose: Severe gastrointestinal (GI) disease is associated with considerable morbidity and high mortality in systemic sclerosis (SSc). There are no known preventative treatments. We wished to test the hypothesis that exposure to immunosuppression (for skin, lung, joint or muscle condition) in early disease could modify the risk of severe GI disease in SSc.

Methods: Subjects with < 3 years of disease duration (since the onset of the first non-RaynaudÕs disease manifestation) and without severe GI disease at baseline study visit were identified from the Canadian Scleroderma Research Group registry. Severe GI disease was defined using a previously published definition (Steen and Medsger, A and R 2000) as follows: malabsorption, hyperalimentation, pseudo-obstruction, or either antibiotics for bacterial overgrowth or esophageal stricture requiring dilatation with >10% associated weight loss. A retrospective cohort study was performed with immunosuppression to methotrexate, azathioprine, mycophenolate and/or cyclophosphamide as the exposure of interest and severe GI disease as the outcome. Descriptive statistics were used to compare the baseline characteristics of the subjects, according to exposure status. The risk of severe GI disease in exposed versus unexposed subjects was estimated using a Cox proportional hazard model, with exposure to immunosuppression modeled as a time-dependent variable and including inverse probability of treatment weights (IPTW) to account for confounding. The model was adjusted for potential demographic and disease-related confounders.

Results: This study included 285 subjects, 84% female, mean age 53 years old, mean disease duration at baseline 1.6 years, proportion limited/diffuse cutaneous SSc 54%/46%. During a mean follow-up time of 3.8 years, 152 (53%) subjects were exposed to immunosuppression and 133 (47%) were not. In univariate analyses, subjects exposed to immunosuppression were more likely to have diffuse disease (62.5% vs 26.3%, p<0.001), interstitial lung disease (37.8% vs 18.9%, p<0.001), inflammatory myositis (14.6% vs. 1%, p<0.001) and worse skin scores (16.5 ± 11.2 vs 8.4±9.5, p<0.001) at baseline study visit. In a multivariate Cox proportional hazard analysis modeling immunosuppression as a time-dependent variable and incorporating IPTW, exposure to immunosuppression did not modify the risk of developing severe GI disease: hazard ratio 0.71, 95% confidence interval 0.32, 1.58 (Table). 

Conclusion: Contrary to our hypothesis, exposure to immunosuppression did not prevent severe GI disease. Further research is required to identify effective prevention and treatment interventions for severe GI disease in SSc.