TB Infections in RA Linked to Tofacitinib Treatment

Patients with rheumatoid arthritis are known to be at increased risk for opportunistic infections, in part, because of therapies. Now, a new study assesses the prevalence of opportunistic infections in rheumatoid arthritis patients who have been prescribed tofacitinib, finding tuberculosis to be the most common. Writing in the Sept. 25 issue of Annals of the Rheumatic Diseases, the researchers recommend screening for tuberculosis infections prior to starting tofacitinib and treating tofacitinib infections with isoniazid during tofacitinib therapy. The study is based on data from phase I, II and long-term extension clinical trial data from a tofacitinib rheumatoid arthritis (RA) program. It included 5,671 patients from six phase II, six phase III and two open-label long-term extension studies. Researchers identified 60 opportunistic infections among the 5,671 patients, but all within patients treated with tofacitinib from phase III and LTE studies. No infections were identified in phase II studies. The highlights: 

• Median time between drug start and diagnosis was 64 weeks (range 15–161 weeks)
• Tuberculosis (crude IR 0.21, 95% CI of (0.14 to 0.30)) was the most common opportunistic infection (n=26)
• Twenty-one cases (81%) occurred in countries with high background tuberculosis incidence rates , and the rate varied with regional background tuberculosis incidence rates: low 0.02 (0.003 to 0.15), medium 0.08 (0.03 to 0.21) and high 0.75 (0.49 to 1.15).
• In Phase III studies, 263 patients diagnosed with latent tuberculosis infection were treated with isoniazid and tofacitinib concurrently; none developed TB
• For opportunistic infections (OI) other than tuberculosis, 34 events were reported (crude IR 0.25 (95% CI 0.18 to 0.36))

 “Tofacitinib is a small molecule oral Janus kinase ( JAK) inhibitor approved for the treatment of adult patients with rheumatoid arthritis. Tofacitinib preferentially inhibits JAK3 and JAK1, modulating the immune response via downregulation of several cytokines (eg, interleukins (ILs) 2, 4, 7, 9, 15 and 21) that are integral to lymphocyte development and function. Given its mechanism of action, the risk of TB and other OIs could potentially be elevated in tofacitinib-treated patients, and accordingly, we undertook a retrospective evaluation of all OIs reported within the tofacitinib RA clinical development program,” wrote researchers who were led by Kevin L Winthrop, MD, of Oregon Health and Science University. The risk of infections in rheumatoid arthritis patients is heightened by the use of prednisone and some biological disease-modifying antirheumatic drugs (DMARDs). For anti-TNF therapies, the increased risk of infections has been linked to pathogens that rely on granuloma-inducing pathogens. Infections occurred rarely and less frequently in patients treated with 5 mg of tofacitinib twice daily, as compared to 10 mg twice daily. Although tuberculosis was the most common opportunistic infection, it was rare in regions where tuberculosis was not prevalent.  The following infections were also identified, but far less frequently:  non-tuberculous mycobacterium (NTM) infections, all fungal infections (with the exception of oral or vaginal candidiasis and chromomycosis), listeria and viral infections typically associated with immunosuppression, including multidermatomal or disseminated herpes zoster, disseminated herpes virus, cytomegalovirus (CMV), BK virus and progressive multifocal leukoencephalopathy (PML). “A biological mechanism for how tofacitinib could increase the risk of TB or other intracellular infections is not yet clear. It could theoretically inhibit the development and/or maintenance of pathogen-specific memory T cells by inhibiting the intracellular signaling of IL-12, interferon (IFN)-y and other relevant cytokines.  An increased risk for serious TB disease has been documented with mutations affecting IL-12, IFN-y and STAT1 pathways,” the authors wrote. 

References:

Winthrop KL, Park SH, et al. "Tuberculosis and other opportunistic infections in tofacitinib-treated patients with rheumatoid arthritis,"Annals of the Rheumatic Diseases. Published Sept. 25, 2015. (http://dx.doi.org/10.1136/annrheumdis-2015-207319)