Elevated Neopterin Levels Are Associated with Increased Tuberculosis Risk in Rheumatoid Arthritis Patients with QuantiFERON Conversion during Biologic Therapy.

Der-Yuan Chen,Yea-Wen Yeh,Chia-Wei Hsieh,Yi-Ming Chen,Joung-Liang Lan,Ju-Pi Li,Tsai-Ling Liao,Hsin-Hua Chen,Miguel Santin

doi:10.1371/journal.pone.0166301

Abstract

QuantiFERON-TB-Gold (QFT-G) conversion is frequently observed in rheumatoid arthritis (RA) patients receiving biologic therapy. However, there have not been any known biomarkers available for detecting tuberculosis (TB) in QFT-G converters. We aimed to evaluate clinical utility of cytokines/chemokines for detecting TB in patients with QFT-G conversion. Among a total of 227 RA patients who underwent QFT-G assay, 187 QFT-G-negative patients received biologic therapy without isoniazid prophylaxis. QFT-G assay was repeated at week 52 of biologic therapy or at the time of TB diagnosis. Levels of cytokines/chemokines were determined by magnetic bead array or ELISA in QFT-G converters and 12 non-RA patients with TB (non-RA TB). QFT-G conversion was found in 54 (28.9%) of 187 baseline QFT-G-negative patients, of which 7 (13.0%) developed active TB during the one-year follow-up period. Among the examined cytokines/chemokines, non-stimulated and TB-antigen-stimulated neopterin levels were significantly higher in RA patients who developed TB (RA-TB) (median, 24.5pg/ml and 23053pg/ml, respectively) and non-RA TB patients (12.2pg/ml and 9633pg/ml, respectively) compared with QFT-G converters without TB (3.0pg/ml and 2720pg/ml, respectively, both p<0.001). Rising levels of neopterin relative to baseline (non-stimulated levels, 4.4pg/ml vs. 24.5pg/ml; TB-antigen-stimulated levels, 1801pg/ml vs. 23053pg/ml) were observed in QFT-G converters who developed TB. A high proportion (85.7%) of QFT-G converters with high plasma neopterin levels developed TB during the one-year follow-up period. In conclusion, RA patients with QFT-G conversion during the period of biologic therapy should be carefully monitored for elevation of neopterin levels, which is associated with TB risk in QFT-G converters, particularly in TB-endemic areas.

Highlights

Tuberculosis (TB) remains a major global public health issue
Accumulating evidence indicates that QuantiFERON-TB Gold (QFT-G) assays, which detect interferon (IFN)-γ secreted by T-cells stimulated with M. tuberculosis (Mtb)-specific antigens, offer higher specificity than tuberculin skin test (TST) in detecting latent TB infection (LTBI) or active TB within a Bacillus Calmette-Guerin (BCG)-vaccinated population [8,9]
QFT-G assays have been used to detect active TB, the pooled sensitivity and specificity were at merely 80% and 79% respectively [32]

Summary

Introduction

Tuberculosis (TB) remains a major global public health issue. An estimated 9.0 million people developed TB and 1.5 million died from the disease in 2013 [1]. An increased TB prevalence has been reported in rheumatoid arthritis (RA) patients [3], and its risk increased further in those receiving biologic therapy [4,5,6]. Accumulating evidence indicates that QuantiFERON-TB Gold (QFT-G) assays, which detect interferon (IFN)-γ secreted by T-cells stimulated with M. tuberculosis (Mtb)-specific antigens, offer higher specificity than tuberculin skin test (TST) in detecting LTBI or active TB within a BCG-vaccinated population [8,9]. QFT-G assays are preferred when testing for LTBI in BCG-vaccinated subjects [10,11], and replacing TST with QFT-G assays for LTBI detection allowed 16.4% of RA patients to avoid unnecessary prophylactic therapy [12]. Neither QFT-G assay nor TST allows for discrimination between LTBI and active TB [13]

Objectives

Methods

Results

Conclusion