Risk of Herpes Zoster in Patients with Rheumatoid Arthritis Treated with Anti TNF-alpha Agents

clonal anti-TNF-alpha antibodies may be associated with increased risk of herpes zoster, but this requires further study.Context: The risk of bacterial infection is increased in patients treated with drugs that inhibit tumor necrosis factor a (TNF-alpha). Little is known about the reactivation of latent viral infections during treatment with TNF-a inhibitors. Objective: To investigate whether TNF-a inhibitors together as a class, or separately as either monoclonal anti-TNF-alpha antibodies (adalimumab, infliximab) or a fusion protein (etanercept), are related to higher rates of herpes zoster in patients with rheumatoid arthritis. Design, Setting and Patients: Patients were enrolled in the German biologics register RABBIT, a prospective cohort, between May 2001 and December 2006 at the initiation of treatment with infliximab, etanercept, adalimumab, or anakinra, or when they changed conventional disease-modifying antirheumatic drug ( DMARD). Treatment, clinical status, and adverse events were assessed by rheumatologists at fixed points during follow-up. Main Outcome Measures: Hazard ratio (HR) of herpes zoster episodes following anti-TNF-alpha treatment. Study aims were to detect a clinically significant difference (HR,2.0) between TNF-a inhibitors as a class compared with DMARDs and to detect an HR of at least 2.5 for each of 2 types of TNF-a inhibitors, the monoclonal antibodies or the fusion protein, compared with conventional DMARDs. Results: Among 5040 patients receiving TNF-alpha inhibitors or conventional DMARDs, 86 episodes of herpes zoster occurred in 82 patients. Thirty-nine occurrences could be attributed to treatment with anti-TNF-alpha antibodies, 23 to etanercept, and 24 to conventional DMARDs. The crude incidence rate per 1000 patient-years was 11.1 (95% confidence interval [CI], 7.9-15.1) for the monoclonal antibodies, 8.9 ( 95% CI, 5.6 -13.3) for etanercept, and 5.6 ( 95% CI, 3.6-8.3) for conventional DMARDs. Adjusted for age, rheumatoid arthritis severity, and glucocorticoid use, a significantly increased risk was observed for treatment with the monoclonal antibodies (HR, 1.82 [ 95% CI, 1.05-3.15]), although this risk was lower than the threshold for clinical significance. No significant associations were found for etanercept use (HR, 1.36 [95% CI, 0.732.55]) or for anti-TNF-alpha treatment (HR, 1.63 [95% CI, 0.97- 2.74]) as a class. Conclusion: Treatment with mono-