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Nov 18, 2016 - Chia-Wei Hsieh1,2, Yea-Wen Yeh1, Joung-Liang Lan5,6*. 1 Division of Allergy, ... Chen H-H, Hsieh C-W, et al. (2016) ...... Liao Tsai-Ling, Lin Ching-Heng, Shen Gwan-Han, Chang Chia-Li, Lin Chin-Fu, Chen Der-Yuan. Risk.
RESEARCH ARTICLE

Elevated Neopterin Levels Are Associated with Increased Tuberculosis Risk in Rheumatoid Arthritis Patients with QuantiFERON Conversion during Biologic Therapy Der-Yuan Chen1,2,3,4, Ju-Pi Li5,6☯, Yi-Ming Chen1,2☯, Tsai-Ling Liao3☯, Hsin-Hua Chen1,3, Chia-Wei Hsieh1,2, Yea-Wen Yeh1, Joung-Liang Lan5,6*

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OPEN ACCESS Citation: Chen D-Y, Li J-P, Chen Y-M, Liao T-L, Chen H-H, Hsieh C-W, et al. (2016) Elevated Neopterin Levels Are Associated with Increased Tuberculosis Risk in Rheumatoid Arthritis Patients with QuantiFERON Conversion during Biologic Therapy. PLoS ONE 11(11): e0166301. doi:10.1371/journal.pone.0166301 Editor: Miguel Santin, Hospital Universitari de Bellvitge, SPAIN Received: April 13, 2016 Accepted: October 26, 2016 Published: November 18, 2016 Copyright: © 2016 Chen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All data cannot be made due to ethical restrictions. Data are available upon request from the Ethics Committee of Taichung Veterans General Hospital (e-mail address: [email protected] Tel.: +886423592525 ext. 4006) for researchers who meet the criteria for access to confidential data. Funding: This study was supported by a grant (NSC-100-2321-B-075A-001) from the National Science Council, Taiwan, a grant from Taichung Veterans General Hospital, Taiwan (TCVGH-

1 Division of Allergy, Immunology and Rheumatology, Department of Medical Education and Research, Taichung Veterans General Hospital, Taichung, Taiwan, 2 Faculty of Medicine, National Yang Ming University, Taipei, Taiwan, 3 Institute of Biomedical Science and Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, Taiwan, 4 Institute of Biochemistry, Microbiology and Immunology, Chung Shan Medical University, Taichung, Taiwan, 5 Division of Immunology and Rheumatology, Department of Medicine, China Medical University Hospital, Taichung, Taiwan, 6 College of Medicine, China Medical University, Taichung, Taiwan ☯ These authors contributed equally to this work. * [email protected]

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 nonRA 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