Background/Purpose:

Biologic therapies that block tumor necrosis factor-alpha (TNF) increase the risk of tuberculosis (TB), and screening for latent tuberculosis infection (LTBI) before their initiation can prevent LTBI progression to active TB disease. Tofacitinib, a novel oral Janus kinase inhibitor investigated as a targeted immunomodulator and disease-modifying therapy for RA, partially and reversibly inhibits cytokine signaling thought to be important in TB immunity. It was shown recently that incidence rates for TB in patients (pts) treated with tofacitinib are consistent with those of TNF inhibitors in RA.¹

Methods:

Phase 2, 3, and long-term extension (LTE) clinical trial data from the tofacitinib RA program were reviewed. Before study entry, potential participants were screened for TB per protocol with Quantiferon-TB Gold^® or, if unavailable, a Mantoux PPD skin test (5 mm cutoff), and chest radiography performed within 3 months of screening. In Phase 3 trials, patients diagnosed with LTBI were allowed trial entry after completing 1 month of a planned 9-month isoniazid preventive therapy regimen. Active TB cases, reported by study investigators as of September 29, 2011, were identified and TB incidence rates (IRs; per 100 pt-years [95% CI]) calculated for patients exposed to tofacitinib, stratified by their region of enrollment. Regions were categorized according to background TB IR (per 100 person-years): low (≤0.01), medium (>0.01 to ≤0.05), and high (>0.05).²

Results:

Twelve pts with active TB were identified in 4791 (0.25%) total subjects enrolled. Median time between drug start and TB diagnosis for all TB cases was 38 weeks (range 22-137 weeks). Ten cases (83%) occurred in countries with high background TB IR; 11 cases (92%) occurred in pts with negative screening results at study entry (Mantoux PPD skin test or Quantiferon-TB Gold^®), and 4 cases (33%) were extrapulmonary or disseminated. Demographic characteristics and use of concomitant medications, including methotrexate and corticosteroids, were similar to those of the entire program population. Overall, the TB IR (95% CI) for tofacitinib-treated pts was 0.173 (0.098, 0.305), which varied according to regional background TB IR: low 0.037 (0.005, 0.261); medium 0.034 (0.005, 0.242); high 0.781 (0.420, 1.452). In Phase 3 studies, 209 tofacitinib-treated pts received concomitant isoniazid therapy for treatment of LTBI. None of these pts developed active TB and there was no apparent difference in the safety profile (eg elevated transaminases) in these pts.

Conclusion:

Within the large global tofacitinib development program for RA, TB was rare in regions of low and medium TB incidence and occurred most frequently in pts receiving higher doses of tofacitinib in endemic regions. As with biologic therapy, pts should be screened for TB before tofacitinib treatment using either Quantiferon-TB Gold^®or tuberculin skin test. Initial data indicate that pts diagnosed with LTBI can be successfully and safely treated with isoniazid while receiving tofacitinib.

References:

1. Cohen S et al. Arthritis Rheum 2011; 63 (Suppl 10): S153.
2. Global tuberculosis control: WHO report 2011; http://whqlibdoc.who.int/publications/2011/9789241564380_eng.pdf

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/tuberculosis-and-tofacitinib-therapy-in-patients-with-rheumatoid-arthritis/