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

PLoS One. 2016 Nov 18;11(11):e0166301. doi: 10.1371/journal.pone.0166301. eCollection 2016.

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.

MeSH terms

  • Adult
  • Aged
  • Antirheumatic Agents / therapeutic use
  • Arthritis, Rheumatoid / blood*
  • Arthritis, Rheumatoid / complications*
  • Arthritis, Rheumatoid / drug therapy
  • Biomarkers
  • Comorbidity
  • Cytokines / blood
  • Disease Progression
  • Female
  • Humans
  • Interferon-gamma Release Tests*
  • Latent Tuberculosis / complications
  • Latent Tuberculosis / diagnosis
  • Male
  • Middle Aged
  • Neopterin / blood*
  • Prognosis
  • Risk
  • Tuberculosis / complications*
  • Tuberculosis / diagnosis*

Substances

  • Antirheumatic Agents
  • Biomarkers
  • Cytokines
  • Neopterin

Grants and 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-993804C), and by the China Medical University Hospital, Taiwan (DMR-C1030224007, J-LL).