Individuals with rheumatoid arthritis (RA) are at an increased risk for lymphoma compared to the general population, with the risk increasing in proportion to cumulative exposure to systemic inflammation. Whether RA therapies, such as biologic and non-biologic DMARDs, contribute to this risk is controversial. Here, Wolfe et al (Arthritis Rheum 2007; 56: 1433) explore lymphoma risk in a large cohort of DMARD treated RA patients.
Subjects were participants in the National Data Bank for Rheumatic Diseases (NDB) in which patients with RA are followed longitudinally with semiannual patient-derived questionnaires, including RA medications and incident comorbidities (such as new lymphoma diagnosis). Reports of incident lymphomas were confirmed with medical records. Incidence rates for lymphoma in RA subjects were compared to the U.S. Surveillance, Epidemiology, and End-Results (SEER) database and within RA subjects according to treatment allocation, with conditional logistic regression used to account for entry time into the study.
19,562 RA subjects with a total of 89,710 person-years of observation were analyzed. The majority of subjects were female (77%) with an average age at enrollment of 59 ± 13.2 years and an average RA duration at enrollment of 14.1 ± 12.1 years. More that half (55.3%) of subjects received a biologic DMARD during follow-up and 68% received methotrexate. Of the biologics represented, infliximab was the most frequent (40.3%) followed by etanercept (19.2%) and adalimumab (7.6%). Prednisone was used in 45.7% of subjects at enrollment.
Among the RA cohort there were 95 incident lymphoma cases corresponding to an incidence rate of 106 per 100,000. Compared to the SEER registry, the expected number of incident cases was 52.2, resulting in a standardized incidence ratio (SIR) of 1.8 (95% CI 1.5 – 2.2). Treatment with TNF inhibitors as a class, or analyzed by specific agent, were not associated with an increased risk of lymphoma either with or without the consideration of concomitant medications or the timing of the TNF inhibitor within the treatment course.
While RA was associated with an increased risk of incident lymphoma, TNF inhibitor therapy was not a significant contributor to the increased risk observed.
These findings contrast with a recent report of post hoc analyses from clinical trials of infliximab and etanercept than identified an increased and early risk of malignancy (including solid tumors, hematologic malignancies, and non-melanoma skin cancers) in RA patients compared to placebo. The data presented here have the advantage of involving a larger cohort with longer follow-up and a more representative sample of subjects cared for in clinical practice. While the techniques used to account for non-random treatment assignment are an advantage of this study compared to other observational studies, they cannot completely control for the effect of confounding by indication. However, as biologic DMARD treated patients often have more disease activity and systemic inflammation than those not treated in clinical practice, they are also those most at risk for comorbidities related to disease activity and inflammation, such as lymphoma. The findings here are reassuring that biologics do not appear to contribute to this risk, either by themselves or combined with other DMARDs. However, continued vigilance is required, particularly as a substantial number of biologic treated patients are entering into their second decade of use.