An inflammatory disease of the immune system, rheumatoid arthritis (RA) is associated with increased occurrence of lymphoma--or cancers of the lymphatic system, which plays an integral role in the body's ability to fight infection. While various studies have affirmed this link, none have been able to pinpoint the specific effects of disease activity on lymphoma risk, let alone distinguish them from the effects of disease treatment.
Are certain RA patients more vulnerable to developing lymphoma? Do certain RA therapies--from standard NSAIDs (nonsteroidal anti-inflammatory drugs) and DMARDs (disease-modifying antirheumatic drugs) to novel immunosuppressive agents like TNF (tumor necrosis factor) blockers--work to alleviate or aggravate lymphoma risk? On a quest for answers, researchers in Sweden conducted the largest investigation of the link between RA and lymphoma to date. Their findings, featured in the March 2006 issue of Arthritis & Rheumatism, indicate a substantially increased risk of lymphoma among patients with severe RA. Very high and prolonged inflammatory activity, not its treatment, is the major risk factor.
Drawing their sample from a national register of nearly 75,000 RA patients, the research team analyzed the medical records and case histories of 378 RA patients afflicted with malignant lymphoma between 1964 and 1995 and 378 individually matched, lymphoma-free controls. Using statistical analysis, the relative risks or odds ratios for lymphoma were assessed for three different levels of overall disease activity--low, medium, or high--based on disease duration and swollen and tender joint counts. Odds ratios for lymphoma were also compared to treatment in broad categories: any DMARD, any NSAID, aspirin, oral steroids, injected steroids, and cytotoxic drugs. No patient in the sample had received anti-TNF therapy. In addition, lymphoma specimens were reclassified and tested for Epstein-Barr virus (EBV).
Compared with low RA activity, medium RA activity was associated with an 8-fold increase in the risk for lymphoma. The odds ratio rose dramatically for high RA activity--to a 70-fold increase in lymphoma risk. The researchers also observed increased risks of lymphoma associated with pronounced, irreversible joint damage in the hands, feet, and knees documented in the last year before lymphoma diagnosis.
More than 70 percent of the RA patients in the sample, both cases and controls, had received DMARD treatment--including the popular drug methotrexate (MTX), which was recently linked to increased risk of EBV-positive lymphomas by researchers in France. In this study, however, MTX and other standard DMARDs were not associated with any increase in lymphoma risk, nor were NSAIDS, aspirin, or steroids. Interestingly, lymphoma risk was particularly low among patients who had received frequent corticosteroid injections in inflamed joints, indicating a possible lymphoma-protective role of potent anti-inflammatory drugs. Of all the medical treatments assessed, researchers observed increased lymphoma risk associated only with azathioprine (AZA), which is not regarded as a traditional DMARD for RA and rarely used in current treatment.
Given the many uncertainties surrounding the link between lymphoma and chronic inflammatory diseases, this study has substantial clinical implications. As its lead author, Dr. Lars Klareskog of Karolinska University Hospital in Stockholm, observes, since lymphoma risk is strongly associated with exceptionally severe and longstanding RA activity, aggressive treatment may reduce the risk by reducing cumulative inflammation. "From a drug safety perspective," he notes, "our results provide background data that should be considered essential for the evaluation of lymphoma risk following therapy with TNF blockers, for example, as well as other new drugs."