Epstein-Barr virus-associated lymphoproliferative disorder in a patient with rheumatoid arthritis on methotrexate and rofecoxib: idiosyncratic reaction or pharmacogenetics?

Rheumatoid arthritis (RA) is an autoimmune disease associated with altered immunoregulation and resulting in a deforming polyarthritis. Methotrexate (MTX) is a commonly used second line agent for RA, and there have been several recent reports of Epstein-Barr virus (EBV)-associated polyclonal B cell lymphoproliferative disorder in MTX-treated RA patients. The patient in this report had long standing RA treated with MTX and had recently begun taking a cyclooxygenase-2 (COX-2) inhibitor. She developed a febrile illness associated with severe pancytopenia and leukocytoclastic vasculitic rash followed by diffuse adenopathy, with serologic and pathologic evidence of EBV infection. Previous studies have demonstrated the interaction of MTX and a variety of non-steroidal, anti-inflammatory drugs (NSAIDs) with various clinical manifestations including acute renal failure, pancytopenia, vomiting, diarrhea, elevated liver transaminases, jaundice, mucosal ulcerations, and pyrexia. However, we have not identified previous reports suggesting interaction between MTX and COX-2 inhibitors. We hypothesize that decreased renal elimination of MTX induced by the COX-2 inhibitor resulted in enhanced hematopoietic toxicity and immunosuppression causing the EBV-associated lymphoproliferative disease.