Incidence of lymphoma in patients with rheumatoid arthritis: a systematic review of the literature.

To our knowledge, this review is the most broad and only systematic survey to date of the rheumatology, oncology, and epidemiology literature to determine the prevalence of lymphoma in patients with rheumatoid arthritis (RA). This survey is analyzed to determine whether the association between RA and increased lymphoma risk is a result of the risks conferred by medications used to treat RA or a result of the disease itself. PubMed was searched for articles from 1964 to May 2007 using the Medical Subject Heading terms "arthritis, rheumatoid, and lymphoma." Twenty-six studies met inclusion and exclusion criteria and are included for review. Most studies confirmed an approximate 2-fold increase in lymphoma incidence in patients with RA. Contrary to a widely held belief about medication toxicity in RA, most studies did not reveal a statistically significant increased risk of lymphoma with methotrexate or azathioprine. An increased lymphoma incidence with tumor necrosis factor-alpha inhibitors was suggested; however, follow-up in the studies considered was too short to definitively determine increased risk. Most studies differed in which medications they evaluated in determining their impact on lymphoma risk, making studies difficult to compare. Confounding by disease severity (patients with the most severe disease are treated with the strongest medications) in most studies makes the association between lymphoma risk and medications and/or disease severity difficult to assess. Recent work suggests that it is the disease itself, not its treatment, that is associated with increased risk of lymphoma in patients with RA.