Anti-TNF-alpha monoclonal antibodies associated with increased risk of herpes zoster

In a study published in the Journal of the American Medical Association, investigators demonstrated an association between treatment with the anti-tumor necrosis factor (TNF)-alpha monoclonal antibodies (mAbs) adalimumab and infliximab and risk of herpes zoster events in patients with rheumatoid arthritis (RA). The TNF-alpha inhibitor etanercept was not associated with a significantly increased risk of herpes zoster.

For this study, investigators analyzed data from a German biologics register (RABBIT) that was initiated in 2001. From May 2001 to December 2006, patients with RA who were beginning treatment with infliximab, etanercept, adalimumab, or anakinra or who were changing their disease-modifying antirheumatic drug (DMARD) treatment after failure of ≥1 DMARD therapy were invited to participate in the register. All herpes zoster-related events reported before November 1, 2007, were included in this analysis.

A total of 5,040 patients were included in this analysis; 86 cases of herpes zoster were reported among 82 of these patients. Of the herpes zoster cases, 18 were serious. The crude incidence rate of herpes zoster events per 1,000 patient-years was 8.9 (95% CI, 5.6–13.3) for etanercept-treated patients, 11.1 (95% CI, 7.9–15.1) for infliximab- or adalimumab-treated patients, and 5.6 (95% CI, 3.6–8.3) for patients treated with conventional DMARDs (P=.01 for anti-TNF-alpha treatment vs control). Multivariate Cox regression analysis demonstrated that anti-TNF-alpha treatment as a class was not associated with a significantly increased risk of herpes zoster events (HR=1.63; 95% CI, 0.97–2.74; P=.07). Treatment with etanercept was not associated with an increased risk of herpes zoster (HR=1.36; 95% CI, 0.73–2.55; P=.33), whereas treatment with infliximab or adalimumab was associated with an increased risk (HR=1.82; 95% CI, 1.05–3.15; P=.03).

The authors pointed out that "it is possible that the observed effect of the different drugs on risk of herpes zoster is the consequence of their different molecular mechanisms of action." They suggested that patients treated with anti-TNF-alpha mAbs should be carefully monitored for signs and symptoms of herpes zoster.

In a related editorial, Richard J. Whitley, MD, and John W. Gnann Jr, MD, stated that this study "provides the best evidence to date for a positive association with reactivation of latent varicellazoster virus," adding, "TNF-alpha inhibitors have revolutionized the management of a number of difficult diseases, especially inflammatory arthritis, but clinicians must continue to remain aware of the potential for serious infectious complications, which now include herpes zoster."

SOURCES

Strangfeld A, Listing J, Herzer P, et al. Risk of herpes zoster in patients with rheumatoid arthritis treated with anti-TNF-alpha agents. JAMA. 2009;301:737–744.

Whitley RJ, Gnann JW Jr. Herpes zoster in the age of focused immunosuppressive therapy [editorial]. JAMA. 2009;301:774–775.