Biphasic emergence of active tuberculosis in rheumatoid arthritis patients receiving TNFα inhibitors: the utility of IFNγ assay

Objectives The risk of active tuberculosis increases in rheumatoid arthritis (RA) patients receiving antitumour necrosis factor alpha (TNF alpha) therapy. Longitudinal data concerning serial interferon gamma (IFN gamma) assays for detecting tuberculosis have been limited. This study investigated the time course of the development of active tuberculosis, and evaluated the utility of serial QuantiFERON-TB Gold (QFT-G) assays for detecting its emergence in RA patients undergoing long-term anti-TNF alpha therapy. Methods 242 RA patients who received anti-TNF alpha therapy and serial QFT-G assays were prospectively evaluated. QFT-G was performed by measuring IFN gamma levels in whole blood treated with tuberculosis-specific antigens. Results Among 242 RA patients, 75 (31.0%) had a positive tuberculin skin test (TST) and 45 (18.6%) had positive QFT-G results, with another nine (3.7%) showing indeterminate QFT-G assay. Isoniazid prophylaxis was given to 37 patients with TST+/QFT-G+ results and 24 TST+/QFT-G- patients with TST induration diameter >= 10 mm. Four patients (three with baseline QFT-G+ results) developed tuberculosis within the first 3 months of anti-TNF alpha therapy, whereas five patients with baseline TST-/QFT-G- results developed active tuberculosis after 20-24 months' anti-TNF alpha therapy. Progressively rising levels of released IFN gamma (2.17+/-0.98 vs 5.93+/-2.92 IU/ml in early secretory antigenic target-6-stimulated well; 1.12+/-0.84 vs 2.96+/-1.02 IU/ml in culture filtrate protein-10-stimulated well) were observed in those who developed tuberculosis early in anti-TNF alpha therapy. QFT-G conversion was found in baseline QFT-G-negative patients who developed tuberculosis late in treatment. Conclusion The emergence of active tuberculosis follows a biphasic pattern. Persistently high levels of released IFN gamma or QFT-G conversion strongly indicate the development of active tuberculosis in patients undergoing long-term anti-TNF alpha therapy.