Image: CC/Martin Steinhoff. Arthritis of the interphalangeal joints.
Primer: In certain rheumatoid arthritis (RA) patients, treatment with typical disease-modifying anti-rheumatic drugs (DMARDs), including methotrexate, may can prove to be ineffective or intolerable. Biologic response modifiers (BRMs), including TNF inhibitors, provide an important second-line therapeutic option.
However, as BRMs act primarily on the body’s immune system, concerns have arisen regarding their role in the development and progression of malignancies. While data from the Adverse Event Reporting System have suggests an increased risk of lymphomas in children and adolescents treated with TNF inhibitors, the published observational studies and meta-analyses have not arrived at a definitive conclusion.
The authors sought to conduct a systematic review and meta-analysis of the published literature to answer two important questions:
1. Do BRMs increase the risk of malignancy in patients who are being treated only for RA?
2. What are the malignancy risks associated with each of the nine BRMs currently approved for the treatment of RA?
This [meta-analysis]: Six databases were search for publications that met the following inclusion criteria: 1. Compared the safety of BRMs with placebo and/or DMARDs, 2. Included only patients with RA, and 3. Reported a minimum of 24-weeks follow up.
A total of 29,423 patients were studied. Of the patients treated with BRM monotherapy, 0.64% (CI: 0.42%-0.95%) developed malignancies, compared to 0.77% in those treated with BRM/DMARD combination therapy (CI 0.65%-0.92%) and 0.66% in controls (CI: 0.52%-0.84%). Further, none of the nine BRMs were associated increased cancer risk with the exception of the TNF inhibitor/methotrexate combination therapy (Peto Odds Ratio = 2.1, CI: 1.1-3.9), which was positively associated with malignancy at 52 weeks follow up (but not at 104 or 156 weeks nor with TNF inhibitor monotherapy). Moreover, one BRM (anakinra, in combination therapy with methotrexate) was associated with decreased risk of cancer (Peto Odds Ratio = 0.11, CI: 0.03-0.45).
In sum: This is the largest systematic review and meta-analysis of randomized controlled trials examining the risk of malignancy in patients receiving BRM for the treatment of their RA. Overall, the authors of the study concluded that there was no statistically significant increased risk of any type of cancer in those with RA treated with BRMs versus DMARDS or controls. This is in contrast to a meta-analysis published in 2006, which found increased malignancy risk in RA patients treated with TNF inhibitors, as well as several observational studies that have linked BRM use with heightened cancer risk. The authors also note the need for further systematic reviews to establish malignancy risks for a longer term.
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