Use of Immunosuppression and the Risk of Subsequent Overall or Cancer Mortality

OBJECTIVE: To determine the incidence of all-cause and cancer mortality in association with immunosuppression. DESIGN: Retrospective cohort study at ocular inflammatory disease (OID) subspecialty centers. We harvested exposure and covariate data retrospectively from clinic inception (earliest in 1979) through 2010 inclusive. Then we ascertained overall and cancer-specific mortalities by National Death Index linkage. We constructed separate Cox models to evaluate overall and cancer mortality for each class of immunosuppressant and for each individual immunosuppressant compared with person-time unexposed to any immunosuppression. PARTICIPANTS: Patients with non-infectious OID, excluding those with HIV infection or pre-existing cancer. INTERVENTIONS: Tumor necrosis factor (TNF) inhibitors (mostly infliximab, adalimumab, and etanercept); antimetabolites (methotrexate, mycophenolate mofetil, azathioprine); calcineurin inhibitors (cyclosporine); and alkylating agents (cyclophosphamide) were given when clinically indicated in this non-interventional cohort study. MAIN OUTCOMES AND MEASURES: Overall and cancer mortality. RESULTS: Over 187,151 person-years (median follow-up 10.0 years), during which 15,938 patients were at risk for mortality-we observed 1,970 deaths, 435 attributed to cancer. Both patients unexposed to immunosuppressants (Standardized Mortality Ratio (SMR)=0.95, 95% confidence interval (CI): 0.90-1.01) and those exposed to immunosuppressants but free of systemic inflammatory diseases (SID) (SMR=1.04, 95% CI: 0.95-1.14) had similar mortality risk to the US population. Comparing patients exposed to TNF inhibitors, antimetabolites, calcineurin inhibitors, and alkylating agents versus patients not exposed to any of these, we found that overall mortality (adjusted hazard ratio (aHR)=0.88, 0.89, 0.90, 1.11) and cancer mortality (aHR=1.25, 0.89, 0.89, 1.23) were not significantly increased. These results were stable in sensitivity analyses whether excluding or including patients with SID, across 0-, 3- or 5-year lags, and across quartiles of immunosuppressant dose and duration. CONCLUSIONS: Our results, in a cohort where the indication for treatment was proven unassociated with mortality risk, found that commonly used immunosuppressants-especially the antimetabolites methotrexate, mycophenolate mofetil and azathioprine; the TNF inhibitors adalimumab and infliximab, and cyclosporine-were not associated with increased overall and cancer mortality over a median cohort follow-up of 10.0 years. These results suggest safety of these agents with respect to overall and cancer mortality for patients treated with immunosuppression for a wide range of inflammatory diseases