Background/Purpose: Patients (pts) with RA are at increased risk for herpes zoster (HZ) i.e. ‘shingles’. Tofacitinib, a novel oral Janus kinase inhibitor investigated as a targeted immunomodulator and disease-modifying therapy for RA, down-regulates cytokine-induced signalling that is potentially important to HZ immunity. It has been reported previously that HZ incidence rates (IRs) in the tofacitinib RA program are higher than those reported with biologic and non-biologic DMARDs,^1-4 however the reasons are unknown.

Methods: Adverse events of HZ were identified in the randomized controlled Phase 2, 3, and open-label long-term extension (LTE) tofacitinib RA studies (data cut March 29, 2011). HZ IRs (per 100 pt-years [pt-yrs] [95% CI]) were calculated and logistic regression was used to evaluate potential risk factors for HZ.

Results: In the tofacitinib RA program Phase 2, 3, and LTE studies (4789 pts with 5651 pt-yrs of tofacitinib treatment), 239 tofacitinib-treated pts experienced HZ. One case (0.4%) was multidermatomal, and none involved visceral dissemination or death. Twenty-five pts with HZ (10.5%) permanently discontinued tofacitinib and 16 (6.7%) were hospitalized or received intravenous antiviral drugs. In Phase 3 studies the number of HZ cases and IRs per 100 pt-yrs (95% CI) for each treatment were: tofacitinib 90 cases, IR 4.4 (3.5, 5.4); placebo 3 cases, IR 1.5 (0.5, 4.6); and adalimumab (included as active control in one study) 5 cases, IR 2.8 (1.2, 6.8). In LTE studies, 134 HZ cases were identified in tofacitinib recipients, with an IR of 4.5 (3.8, 5.3). Tofacitinib-associated HZ IRs varied widely across countries of enrollment and were significantly higher among Asians (7.6 [6.3, 9.2]) vs whites (3.3 [2.8, 4.0]), blacks (2.3 [0.7, 7.1]), and others (3.0 [1.8, 4.9]). For tofacitinib-treated pts, those aged ³65 years (odds ratio [OR] 1.26 [95% CI 0.91, 1.75]), females (OR 1.31 [95% CI 0.89, 1.92]), those using glucocorticoids (OR 1.24 [95% CI 0.95, 1.61]), and those with a longer disease duration (OR 1.02 for each extra year of RA [95% CI 1.00, 1.03]) were more likely to develop HZ. There was no association between HZ risk and background non-biologic DMARD use (i.e. tofacitinib monotherapy or in combination with DMARD), neutrophil or lymphocyte count, or baseline RA severity. In Phase 3 studies, patients treated with tofacitinib 5 mg BID were no more likely to develop HZ than those treated with 10 mg BID (OR 0.96 [95% CI 0.62, 1.51]).

Conclusion: In the tofacitinib RA program, rates of HZ observed among placebo, adalimumab, and tofacitinib-treated pts (particularly in pts of Asian race) were higher than those reported in the literature for patients with RA treated with biologic and non-biologic DMARDs (IRs 0.56-1.32 events per 100 pt-yrs).^2-4 HZ was more common among tofacitinib-treated pts compared with placebo-treated subjects, although confidence intervals were overlapping, with similar rates between tofacitinib 5 mg and 10 mg BID dose groups. Complicated HZ was rare in tofacitinib-treated pts.

References:

1. Cohen S et al. Arthritis and Rheumatism 2011; 63: S153.

2. McDonald JR et al. Clin Infect Dis 2009; 48: 1364-1371.

3. Strangfeld A et al. JAMA 2009; 301: 737-744.

4. Wolfe F et al. Rheumatology (Oxford) 2006; 45: 1370-1375.