Treatment of Rheumatoid Arthritis and Risk of Serious Infection

Abstract & Commentary

By Stan Deresinski, MD, FACP, Clinical Professor of Medicine, Stanford, Associate Chief of Infectious Diseases, Santa Clara Valley Medical Center, is Editor for Infectious Disease Alert.

Synopsis: Anti-TNF antibody therapy of rheumatoid arthritis is associated with significantly increased risks of malignancies and of serious infections.

Source: Bongartz T, et al. Anti-TNF Antibody Therapy in Rheumatoid Arthritis and the Risk of Serious Infections and Malignancies: Systematic Review and Meta-Analysis of Rare Harmful Effects in Randomized Controlled Trials. JAMA. 2006;295:2275-2285. Erratum in: JAMA. 2006;295:2482.

While the use of anti-tnf agents for the treatment of diseases such as rheumatoid arthritis (RA) is known to be associated with an increased risk of serious infections and malignancies, the degree of risk has remained undefined. Bongartz and colleagues evaluated 9 randomized, placebo-controlled trials in which one of the 2 US FDA licensed anti-TNF antibodies (infliximab and adalimumab) was administered for at least 12 weeks. The trials involved 3493 patients who received active therapy and 1512 who received placebo.

Anti-TNF therapy was associated with a pooled odds ration for the development of malignancy of 3.3 (95%; CI, 1.2-9.1), and were significantly more common in patients given higher doses of ant-TNF antibody. The number needed to harm (analogous to the number needed to treat, but dealing with adverse outcomes) was 154 for one additional malignancy within a treatment period of 6-12 months. The pooled odds ratio (anti-TNF relative to placebo) for serious infection, defined as one that required antimicrobial therapy and/or hospitalization, was 2.0 (95%; CI, 1.3-3.1). The number needed to harm was 59 within 3 to 12 months of treatment. Only 12 of 126 serious infections were identified as being granulomatous, including 10 cases of tuberculosis and one each of histoplasmosis and coccidioidomycosis.

Commentary

Expression of the risk in terms of patient-years of exposure may have provided a more insightful and reliable result. These results, nonetheless, provide a more quantitative assessment of the risk of these two complications in patients with RA receiving one of 2 anti-TNF antibody therapies. Comparable information regarding the use of anti-TNF treatment of other diseases, such as Crohn's disease, would be welcome. While the development of granulomatous infections has been recognized in patients receiving these therapeutics, these accounted for only 9.5% of the cases of serious infection in this study. Thus, while the overall risk of such infections appears to be low, the relative risk remains poorly quantified.

Examination of a large database has identified a similar risk of serious infections in RA patients treated with anti-TNF therapy. Adjusted relative risks of serious infections in patients with RA in the German biologics register were 2.2 (95% CI, 0.9-5.4) for patients receiving etanercept and 2.1 (95% CI, 0.8-5.5) for patients receiving infliximab, when compared with controls.1

In contrast to these findings, assessment of another database has failed to identify a risk of pneumonia severe enough to require hospitalization in RA patients receiving anti-TNF therapy. Evaluation of almost 17,000 RA patients in the National Databank for Rheumatic Diseases who were evaluated semiannually for 3.5 years found no significant risk of hospitalization for pneumonia among infliximab or adalimumab recipients.2 Methotrexate therapy was also not associated with increased risk of hospitalization for pneumonia, but prednisone use was, with a hazard ration of 1.7 (95% CI, 1.5-2.0). This risk of prednisone therapy was dose-related and, surprisingly, was present even in patients receiving < 5 mg prednisone daily (HR 1.7; 95% CI, 1.5-2.0). Leflunomide was also associated with increased risk.

References

  1. Listing J, et al. Infections in Patients with Rheumatoid Arthritis Treated with Biologic Agents. Arthritis Rheum. 2005;52:3403-3412.
  2. Wolfe F, et al. Treatment for Rheumatoid Arthritis and the Risk of Hospitalization for Pneumonia: Associations with Prednisone, Disease-Modifying Antirheumatic Drugs, and Anti-Tumor Necrosis Factor Therapy. Arthritis Rheum. 2006;54:628-634.