Hematologic Malignant Neoplasms After Drug Exposure in Rheumatoid Arthritis

BACKGROUND: Rheumatoid arthritis is a severe inflammatory polyarthritis that requires long-term treatment with disease-modifying antirheumatic drugs. There is increasing concern about the influence of rheumatoid arthritis therapy on the risk for hematologic malignant neoplasms. METHODS: We used a case-control design nested in a cohort of 23,810 patients with rheumatoid arthritis assembled from administrative databases covering the population of Quebec, Canada. The study was carried out from January 1, 1980, through December 31, 2003. Case patients having hematologic malignant neoplasms were ascertained from physician billing and hospitalization records; each case patient was matched for age and sex with 10 control subjects. Adjusting for clinical variables and concomitant medications, we used conditional logistic regression to analyze potential associations between disease-modifying antirheumatic drug exposures and risk for hematologic malignant neoplasms. We estimated rate ratios attributable to each disease-modifying antirheumatic drug exposure. RESULTS: During the study, hematologic malignant neoplasms developed in 619 patients, including lymphomas in 346 patients, leukemia in 178 patients, and multiple myelomas in 95 patients. The unadjusted rate ratios for hematologic malignant neoplasms after drug exposures were as follows: methotrexate, 1.18 (95% confidence interval CI, 0.99-1.40); azathioprine, 1.44 (95% CI, 1.01-2.03); and cyclophosphamide, 2.21 (95% CI, 1.52-3.20). Because biologic agents first appeared in the Régie d'Assurance Maladie du Quebec formulary in 2002, there were few exposures to these drugs. Adjusted estimates suggested that hematologic cancer risk was most elevated after exposure to cyclophosphamide (rate ratio, 1.84; 95% CI, 1.24-2.73). For lymphomas only, the adjusted rate ratio after cyclophosphamide exposure was 2.12 (95% CI, 1.33-3.54). CONCLUSIONS: In this large cohort of patients with rheumatoid arthritis, the greatest relative risk for hematologic malignant neoplasms was noted after use of cyclophosphamide. Assessments of risk related to newer and emerging therapies should carefully consider previous and concomitant medication exposures.