Risk of Tuberculosis Reactivation in Patients with Rheumatoid Arthritis, Ankylosing Spondylitis, and Psoriatic Arthritis Receiving Non-Anti-TNF-Targeted Biologics

Abstract

Tuberculosis (TB) still represents an important issue for public health in underdeveloped countries, but the use of antitumor necrosis factor agents (anti-TNF) for the treatment of inflammatory rheumatic disorders has reopened the problem also in countries with low TB incidence, due to the increased risk of TB reactivation in subjects with latent tuberculosis infection (LTBI). Over the last 5 years, several non-anti-TNF-targeted biologics have been licensed for the treatment of rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis. We reviewed the epidemiology of TB, the role of different cytokines and of the immune system cells involved in the immune response against TB infection, the methods to detect LTBI, and the risk of TB reactivation in patients exposed to non-anti-TNF-targeted biologics. Given the limited role exerted by the cytokines different from TNF, as expected, data from controlled trials, national registries of biologics, and postmarketing surveillance show that the risk of TB reactivation in patients receiving non-anti-TNF-targeted biologics is negligible, hence raising the question whether the screening procedures for LTBI would be necessary.

Figure 1

Schematic representation of the immune cells involved in Mycobacterium tuberculosis infection. Distinct types of T helper (Th) cells as Th1, Th2, Th17, and regulatory T cells (Treg) are present at the site of Mycobacterium tuberculosis (MTb) infection. These cells exert their functions mainly through soluble factors. In particular, Th1 cells producing IFN-γ play an essential role in MTb clearance enhancing the macrophage microbicidal mechanisms through the activation of the iNOS pathway and the induction of phagosomes acidification, maturation, and autophagy. Moreover, tumor necrosis factor- (TNF-) α, produced by antigen presenting cells (APCs) after MTb stimulation, acts synergically with IFN-γ thus contributing to MTb control. APCs produce also interleukin- (IL-) 12 and IL-1β that are essential for resistance to MTb. Moreover, IL-23 produced by APC induces the differentiation of Th17 cells producing IL-17, IL-17F, IL-6, and TNF-α. Th17 cells are associated with MTb protection; however, when Th17 cell responses became pathogenic rather than protective, Th1 cells are induced to stop these dangerous effects. Finally, the role of Th2, Treg, and B-cell subsets in human disease still remains controversial and needs further elucidations.