“We already know that the risk of bacterial infections is higher in patients treated with biologic agents—especially at the beginning of the therapy. Less is known about the risk of viral infections. Therefore the results of this investigation highlight an new aspect of the safety profile of anti-TNF agents,” said Dr. Strangfeld, who is at the German Rheumatism Research Centre, Berlin, Germany. The study is the German biologics register RABBIT prospective cohort, conducted between May 2001 and December 2006.
Vaccination of adults over age 60 with live attenuated varicella zoster vaccine (Zostavax®, Merck) has been shown to reduce the incidence of herpes zoster. Dr. Strangfeld would like to see studies analyzing the risk for RA patients that had been vaccinated in comparison to those who were not vaccinated.
This study suggests that RA patients at highest risk for a reactivation of latent VZV are those who are older, have high disease severity, are on high doses of glucocorticoids, or who have already had an outbreak of herpes zoster. The subgroup of patients who had previous unsuccessful treatment with anti-TNF agents were at higher risk than those who continued successful anti-TNF treatment (HR 2.4).
Richard J. Whitley, MD, who coauthored an accompanying editorial in JAMA, told MSKreport.com that, even though the increased shingles risk did not rise to the predefined benchmark for clinical significance (HR 2.0), he is convinced that there is an increased risk for reactivation of latent organisms, including zoster as well as tuberculosis.
“My colleague and co-author John Gnann, MD, and I are monitoring our patients very very carefully. We may be in a numbers game,” Dr. Whitley said.
Dr. Strangfeld told Musculoskeletal Report that the researchers were surprised to find that the monoclonal antibody drugs adalimumab and infliximab were associated with herpes zoster, but the fusion protein etancercept was not.
Dr. Whitley was similarly surprised. “I am clueless about this one,” he said. “I have talked at length to my rheumatology colleagues to try and find a mechanism that would allow us to answer this question.”
Robert S. Wallis, MD, who has studied a number of infectious diseases associated with tumor necrosis factor antagonists, commented, “These findings are also consistent with case reports in hepatitis B infection, in which reactivation has mainly been associated with anti-TNF antibodies rather than etanercept. I believe that these findings will be one additional factor influencing clinical choices regarding arthritis therapies.” Dr. Wallis is Senior Medical Director and leader of the anti-infectives clinical group at Pfizer, which markets Neurontin® (gabapentin) and Lyrica® (pregabalin) for postherpetic neuralgia.
But does anti-TNF-α treatment prevent post-herpetic neuralgia?
In their editorial, Drs. Whitley and Gnann note that only 2 patients in this study (2.4%) experienced postherpetic neuralgia, compared with rates of 20%-30% for adults with herpes zoster. “This is exceedingly important. Postherpetic neuralgia is the bane of existence of a zoster patient,” Dr. Whitley said. He told MSKreport.com that he had initially questioned these data when reviewing the article for JAMA, but that if the data are correct, they raise very important questions about how TNF inhibitors may influence the development, perception, or relief of neuropathic pain.
Dr. Wallis agreed that the relative lack of postherpetic neuralgia is important. “The paper did not indicate whether physicians elected to continue anti-TNF therapy after the zoster diagnosis was established, but I suspect that in most instances they did. It would be of interest whether a decision to discontinue anti-TNF therapy was associated with worse long-term outcomes. TNF blockade, like corticosteroids, might reduce the frequency of post-herpetic neuralgia, whereas recovery of TNF-dependent inflammation might result in greater tissue and nerve damage. The authors may be able to address this question,” he suggested.
TNF inhibitors and shingles: Translating research into practice
“Rheumatologists should alert their patients to signs and symptoms of zoster and instruct them to seek medical care immediately,” Dr. Whitley advised. He agrees with Dr. Strangfeld on the need for a trial to determine whether vaccination before beginning TNF inhibitors would decrease herpes zoster risk.
Dr. Wallis suspects that few clinicians will elect to delay anti-TNF therapy to administer the vaccine “given the uncertainties of its safety and effectiveness in TNF blocker recipients, the availability of effective antiviral therapy, and the relatively good outcomes that are described.”
Dr. Whitley was similarly cautious. “Please remember that there is no evidence based medicine to support this vaccine strategy,” he said. “However,” he added, “when it is me, I will get immunized.”
References
1. Strangfeld A, Listing J, Herzer P, et al. Risk of herpes zoster in patients with rheumatoid arthritis treated with anti-TNF-α agents. JAMA 2009;301:737-744.
2. Whitley RJ, Gnann JW. Herpes zoster in the age of focused immunosuppressive therapy (editorial). JAMA 2009;301:774-775.