Objective: To investigate the relationship between the cumulative duration of exposure to immunosuppressive drugs and the risk of developing and/or dying from malignancy in patients with rheumatic diseases attending rheumatology practices throughout Europe.
Methods: Patients with rheumatic diseases who first started an immunosuppressive drug between 1979 and 1990 were studied. They were followed annually for up to 10 years through their rheumatologists. Information was collected on vital status, the development of malignancy, and starting and stopping dates of immunosuppressive drugs. Person-years of observation were attributed to one of 4 groups according to the cumulative duration of exposure to immunosuppressives. Age and sex adjusted incidence rate ratios (IRR) were calculated by comparing each of the higher 3 groups with the baseline exposure category.
Results: In total 1773 patients, from 15 countries, contributed 12,266 person-years of followup. The principal drugs used were azathioprine, methotrexate, cyclophosphamide, and chlorambucil. Patients in the highest cumulative exposure group had an IRR of 3.74 (95% CI 1.48-9.47) of developing a neoplasm of the immune system or skin or bladder cancer compared to those in the lowest category. A similar pattern was seen when the analysis was confined to patients who took only azathioprine. The risk estimates were unchanged after adjustment for disease duration since first treatment.
Conclusion: In addition to any increased risk of malignancy that may be conferred by individual rheumatic diseases, there is a further risk of specific types of malignancy that is related to the duration of exposure to immunosuppressive drugs.