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

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.

Neopterin serum level does not reflect the disease activity in rheumatoid arthritis: A systematic review and meta‐analysis

“…Also, the evaluation of neopterin concentration has clinical value in individuals with HIV infection 36 . In the context of autoimmune disorders, RA shows a high concentration of neopterin accompanied by disease progression; however, this association has not been confirmed among existing data 18 . The results of this meta‐analysis indicated that the concentration of neopterin was increased significantly in RA patients.…”

“…36 In the context of autoimmune disorders, RA shows a high concentration of neopterin accompanied by disease progression; however, this association has not been confirmed among existing data. 18 The results of this meta-analysis indicated that the concentration of neopterin was increased significantly in RA patients. The pooled analyses revealed a similar rising concentration of neopterin in RA patients with three categories of high, intermediate, and low disease activity scores, which indicates that the neopterin level is not affected by RA progression.…”

“…Ultimately, of 98 articles screened, 15 studies met the eligibility criteria. [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31] The characteristics of the included studies are described in Table 1, and the study selection process is given in Figure 1.…”

“…Twenty‐three studies have been selected for full‐text analysis; after securitization of them, eight studies were excluded due to the lack of sufficient data or similar results that were also reported in other publications. Ultimately, of 98 articles screened, 15 studies met the eligibility criteria 17–31 . The characteristics of the included studies are described in Table 1, and the study selection process is given in Figure 1.…”

Preventive therapy for tuberculosis in rheumatological patients undergoing therapy with biological drugs

“…The clinical significance of IGRA conversion and reversion remains uncertain and somewhat confusing for clinicians who may alert toward the possible active TB onset [104], thus inducing to perform additional investigations. In this regard reliable predictors of active TB onset are still lacking [105].…”