Elsevier

Joint Bone Spine

Volume 81, Issue 3, May 2014, Pages 215-221
Joint Bone Spine

Original article
Risk of herpes/herpes zoster during anti-tumor necrosis factor therapy in patients with rheumatoid arthritis. Systematic review and meta-analysis

https://doi.org/10.1016/j.jbspin.2013.07.009Get rights and content

Abstract

Background

TNF blockers have demonstrated efficacy in inflammatory rheumatic diseases (IRDs). The drugs are associated with a moderate but definite risk of bacterial infection, but risk of viral infection is not clearly known.

Objective

To assess the risk of herpes zoster (HZ) reactivation in patients with rheumatoid arthritis (RA) receiving TNF blockers as compared with DMARDs.

Methods

A systematic search of literature up to March 2013 was performed, in MEDLINE, EMBASE, the Cochrane library and abstracts from the ACR and EULAR congresses from 2008 to 2011. Studies were included if they reported the incidence of HZ, respectively, in patients receiving anti-TNF and conventional DMARDs.

Results

The literature search identified 3446 articles and 88 congress abstracts; a manual search retrieved seven articles. Finally, 26 articles and nine abstracts were included; six articles and one abstract were of meta-analyses estimating the relative risk of HZ in patients with RA with a total follow-up of 163,077 patient-years. From the meta-analyses of data for seven registries, the pooled risk ratio for HZ with TNF blockers was 1.61 [95%CI 1.16–2.23] (P = 0.004). Proportions of severe HZ ranged from 4.9% to 20.9% with TNF-blockers and from 2.0% to 5.5% with conventional DMARDs, in the different registries.

Conclusions

This meta-analysis revealed a significantly increased risk of HZ, up to 61%, in patients with IRD receiving TNF blockers. These data raise the issue of systematic prophylactic treatment with known history of HZ or vaccination without this history.

Introduction

The spectrum of therapeutic strategies for chronic IRD, mainly RA and spondyloarthritis, is increasing. In particular, a better understanding of the pathogenesis of these diseases has led to new-targeted treatments. The most widely used, TNF blockers, are highly efficient in patients with IRD that cannot be controlled with conventional DMARDs. However, the drugs have side effects, in particular increased risk of infection. The overall rate of severe infections with TNF blockers is estimated at about five PY upon 100, mainly related to bacterial agents [1], [2].

The risk of infection with TNF blockers has received much interest, with many studies or meta-analyses conducted on the topic. Initially, opportunistic infection, including granulomatosis infection, such as tuberculosis, was reported in patients receiving TNF blockers [3]. However, we lack data on risk of viral infection, especially that due to herpes species, in patients with IRD receiving anti-TNF drugs. Although herpes infection is frequent and often trivialized, there are severe forms such as HZ multidermatomal forms or those requiring hospitalization or intravenous treatment in patients receiving biologics [4]. Known risk factors for HZ are especially older age and immunosuppressive therapy [5], [6]. In fact, herpes virus infections, especially with HZ, exhibit reactivation of latent VZV infection and can cause substantial mortality among elderly and immunodeficient patients. The risk of HZ clearly increases in a very non-liner manner with increasing age, with a dramatically higher susceptibility to this reactivation in elderly people. The most common complications are bacterial secondary infection and post-herpetic neuralgia.

We aimed to assess the safety of TNF blockers in terms of HZ in patients with RA by a meta-analysis of data from observational registries or RCTs. The primary objective was the analysis of an association of RA treated with TNF blockers as compared with conventional DMARDs and risk of HZ.

Section snippets

Data retrieval

We systematically searched the literature for articles reporting herpes virus infection in patients with IRD receiving TNF blockers that were published in English or French up to March 2013 in MEDLINE via PubMED, EMBASE, Cochrane library databases, and American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) abstracts (from 2008 to 2011). Search keywords were (immunosuppressive agents [Mesh] OR antirheumatic agents [Mesh] OR infliximab [substance name] OR adalimumab

Literature search

The literature search identified 3446 articles and 88 congress abstracts, from which 28 were considered relevant for the present study. The manual search of registries retrieved seven additional articles. Finally, 26 articles and nine abstracts were included in the study (Fig. 1). Reasons for exclusion were especially treatment different from TNF-blockers, disease of interest different from IRD, no quantitative data about HZ incidence or case reports. Among included publications, six articles

Discussion

To our knowledge, this is the first study to estimate, by pooled RR, the relative risk of HZ for patients with RA receiving TNF blockers in comparison with conventional DMARDs.

Several points were highlighted by our meta-analysis and systematic review of literature.

With data from seven registries, the pooled risk of HZ with TNF blockers was estimated significantly increased, up to 61%.

The annualized incidence of HZ is about three cases per 1000 PY in large general population-based studies and

Disclosure of interest

The authors declare that they have no conflicts of interest concerning this article.

Acknowledgments

Abbott France pharmaceutical company provided logistic support by organizing a meta-analysis methods workshop but played no further role in the project.

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