The severity of disease, not its treatments, is a risk factor for the development of malignant lymphomas in rheumatoid arthritis (RA) patients, according to a new study which sought to clarify the connection between lymphoma and RA.

This study, which appears in the March issue of Arthritis & Rheumatism,¹ was designed to identify which patients are at highest risk for the development of malignant lymphoma and to determine whether antirheumatic treatments may potentiate risk or have a protective role.

In RA patients with high overall disease activity, there was a 70-fold increase in lymphoma risk, whereas patients with medium RA activity had an 8-fold increase in the risk for lymphoma, compared to their counterparts with low overall RA disease activity, according to researchers at the Akademiska Hospital in Uppsala, Sweden. In addition, they report that there was also an observed increased risk of lymphoma associated with pronounced, irreversible joint damage in the hands, feet, and knees in the last year before lymphoma diagnosis.

More than 70% of the RA patients in the sample, including both cases and lymphoma-free controls, had received treatment with disease-modifying antirheumatic drugs (DMARDs) including methotrexate (MTX), sulfasalazine, antimalarials, and intramuscular gold. In this study, however, MTX and other standard DMARDs were not associated with any increase in lymphoma risk, nor were non-steroidal anti-inflammatory drugs (NSAIDs), aspirin, or steroids.

The Swedish team analyzed the medical records and case histories of 378 RA patients diagnosed with malignant lymphoma between 1964 and 1995 and 378 individually matched, lymphoma-free controls. The study patients were drawn from a national registry of nearly 75,000 RA patients. Odds ratios for lymphoma were compared to treatment in broad categories: any DMARD, any NSAID, aspirin, oral steroids, injected steroids, and cytotoxic drugs. In addition, lymphoma specimens were reclassified and tested for Epstein-Barr virus (EBV).     

In addition, the study showed that lymphoma risk was particularly low among RA patients who had received frequent corticosteroid injections, which is suggestive of a potential lymphoma-protective role of potent anti-inflammatory drugs. No patient in the sample had received anti-tumor necrosis factor-alpha (TNF-α) therapy. 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.

The researchers, led by Eva Baecklund, MD, a rheumatologist at Akademiska Hospital, conclude that "the implications of the present results are substantial. The association between lymphoma risk and very high and/or very long-standing disease activity indicates that most patients with RA will never have any clinically relevant increased lymphoma risk." Therefore, the authors write, "RA patients who do have highly increased risks can readily be identified based on their accrued inflammatory burden" and that their "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."

Traditional DMARDs exonerated in lymphoma risk among RA patients

"This is the ongoing excellent work by Baeckund [and colleagues] on patients in Sweden with RA that has shown repeatedly that it is the disease, and not its treatment, that is linked to development of lymphoma, especially diffuse large B cell lymphomas," says Vibeke Strand, MD, biopharmaceutical consultant and adjunct clinical professor in the division of immunology at Stanford University School of Medicine in Palo Alto, California, and a member of the CIAOMed Editorial Board. The new study "answers important questions [including that fact that] most lymphomas were not EBV-positive and few, very few spontaneously regressed," she points out.

The new findings also exonerate the traditional DMARDs studied "with the exception of AZA, although the longer-term exposure data do not support AZA as being related," Dr Strand tells CIAOMed. "Rheumatologists need to treat the patients as aggressively as possible. I think the jury is coming in that the disease is more risky than the treatment."

What about biologics and lymphoma?

Postmarketing surveillance and safety data from clinical trials of TNF-α antagonists have led to concern that their use is associated with an increased risk of lymphoma. However, CIAOMed recently reported on new retrospective data showing that RA patients treated with these biologics are not at elevated risk for lymphoma when compared to their counterparts not on anti-TNF-α threrapy.² The study of several large Swedish cohorts confirms the historical finding that RA patients are at an increased risk of lymphoma in comparison to the general population, and the authors cite other evidence suggesting that this risk increases with disease activity.

References

1. Baecklund E, Iliadou A, Askling J, et al. Association of chronic inflammation, not its treatment with increased lymphoma risk in rheumatoid arthritis. Arthritis Rheum. 2006;54:692-701.
2. Askling J, Fored CM, Baecklund E, et al. Hematopoietic malignancies in rheumatoid arthritis: Lymphoma risk and characteristics after exposure to tumor necrosis factor antagonists. Ann Rheum Dis. 2005;64:1414-1420.