Elsevier

Joint Bone Spine

Volume 78, Issue 3, May 2011, Pages 279-284
Joint Bone Spine

Original article
Incidence of tuberculosis in patients with rheumatoid arthritis. A systematic literature review

https://doi.org/10.1016/j.jbspin.2010.12.004Get rights and content

Abstract

Objectives

To determine the incidence and risk of tuberculosis in rheumatoid arthritis (RA) patients exposed or unexposed to TNFα antagonists, the impact of recommendations about managing latent tuberculosis, the time to diagnosis of active tuberculosis, and the proportion of extrapulmonary forms.

Methods

Systematic review of articles retrieved using Medline. From each article, we abstracted the incidence and risk of tuberculosis in RA patients exposed or unexposed to TNFα antagonists, the duration of TNFα antagonist exposure at the diagnosis of tuberculosis, and the distribution of the tuberculosis foci.

Results

We selected 14 articles. The risk of tuberculosis was increased 2- to 10-fold in RA patients unexposed to TNFα antagonists and 2- to 4-fold in those exposed to TNFα antagonists, compared to the general population. The incidence of tuberculosis in TNFα antagonist-treated patients varied across studies (9.3 to 449/100,000) according to the country, observation period, and TNFα antagonist used. The risk was greater with monoclonal antibodies than with the soluble receptor. Official recommendations have decreased the risk of tuberculosis in TNFα antagonist-treated patients. Over half the cases of active tuberculosis were diagnosed during the first treatment year. Among TNFα antagonist-treated patients with tuberculosis, 60% had extrapulmonary lesions. Disseminated tuberculosis was more common with monoclonal antibodies.

Conclusions

The risk of tuberculosis is increased during TNFα antagonist therapy, and the increase is larger with the monoclonal antibodies than with the soluble receptor. Tuberculosis during TNFα antagonist therapy is a rare event that occurs early after treatment initiation. Extrapulmonary involvement is common and potentially severe. Therefore, clinicians should direct careful attention to the risk of tuberculosis associated with TNFα antagonist therapy.

Introduction

TNFα antagonist therapy has radically changed the management of patients with rheumatoid arthritis (RA). TNFα antagonists not only alleviate the symptoms of RA, but also prevent the development of joint damage and deformities. TNFα is a pivotal factor in the inflammatory, anti-tumor, and anti-infectious immune responses. During tuberculosis, TNFα plays a crucial role in the development of the granulomas that limit lesion extension [1].

Early cohort studies showed an excess risk of tuberculosis in TNFα antagonist-treated RA patients. This finding rapidly prompted the development of recommendations about the screening and treatment of latent tuberculosis and the management of active tuberculosis during TNFα antagonist therapy. In France, the first set of recommendations was issued in 2002 by the Agency for Healthcare Product Safety (AFSSAPS) [2]. Active surveillance registries established in several countries provided additional information on the risk of tuberculosis associated with TNFα antagonists. In contrast, few epidemiological data are available on the risk of tuberculosis in RA patients before the introduction of TNFα antagonists.

The objectives of this systematic literature review were to evaluate the incidence and risk of tuberculosis in RA patients with or without exposure to TNFα antagonists, the time to the diagnosis of tuberculosis with each type of TNFα antagonist, and the proportion of extrapulmonary cases.

Section snippets

Methods

We conducted a systematic literature review by searching the Medline database using the terms tuberculosis (MeSH) and arthritis, rheumatoid (MeSH). Limits were “humans” and “French” or “English” language. We selected retrospective and prospective studies published after January 2003 in which patients met American College of Rheumatology (ACR) criteria for RA and tuberculosis cases were documented by bacteriological studies. Only studies done in Western countries or Japan were considered.

We used

Results of the literature search

Of the 709 publications retrieved by the literature search, 14 were selected. Fig. 1 shows the flow chart of article selection. Publications excluded based on the titles and abstracts were case-reports, therapeutic guidelines, and studies whose main objective was not relevant to tuberculosis.

Incidence of tuberculosis in the general population

Fig. 2 shows WHO data on the incidence of tuberculosis in the general population in various countries.

Incidence and relative risk of tuberculosis in patients with rheumatoid arthritis

Before the introduction of TNFα antagonists, few epidemiological data were obtained about the incidence

Discussion

Few data on the epidemiology of tuberculosis among RA patients were obtained before the advent of TNFα antagonists. Several studies showed a 2-fold to 10-fold increase in the risk of tuberculosis among RA patients naive to TNFα antagonists, compared to the general population [6], [7], [12]. In patients on TNFα antagonist therapy, the risk was increased 2-fold to 4-fold [12], [16].

The increase in the risk of tuberculosis seems greater with the monoclonal antibodies to TNFα than with the soluble

Conflicts of interest statement

T. Schaeverbeke contributed to clinical trials sponsored by Wyeth, Abbott, Schering, MSD, and Pfizer; occasionally produced expert reports for Abbott and Wyeth; occasionally actes as a consultant for Wyeth, Abbott, Schering, MSD, and Pfizer; and participated in conferences sponsored by Wyeth, Pfizer, MSD, Abbott, and Schering.

C. Richez contributed to clinical trials sponsored by Wyeth, Abbott, Schering, MSD, and Pfizer; and occasionally produced expert reports for Wyeth-Pfizer.

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