Herpes Zoster and Tofacitinib Therapy in Patients With Rheumatoid Arthritis

Abstract

ObjectivePatients with rheumatoid arthritis (RA) are at increased risk for herpes zoster (HZ) (i.e., shingles). The aim of this study was to determine whether treatment with tofacitinib increases the risk of HZ in patients with RA.MethodsHZ cases were identified as those reported by trial investigators from the databases of the phase II, phase III, and long-term extension (LTE) clinical trials in the Tofacitinib RA Development Program. Crude incidence rates (IRs) of HZ per 100 patient-years (with 95% confidence intervals [95% CIs]) were calculated by exposure group. Logistic regression analyses were performed to evaluate potential risk factors for HZ (e.g., age, prednisone use).ResultsAmong 4,789 participants, 239 were identified as having tofacitinib-associated HZ during the phase II, phase III, and LTE trials, of whom 208 (87%) were female and whose median age was 57 years (range 21–75 years). One HZ case (0.4%) was multidermatomal; none of the cases involved visceral dissemination or death. Twenty-four patients with HZ (10%) permanently discontinued treatment with tofacitinib, and 16 (7%) were either hospitalized or received intravenous antiviral drugs. The crude HZ IR across the development program was 4.4 per 100 patient-years (95% CI 3.8–4.9), but the IR was substantially higher within Asia (7.7 per 100 patient-years, 95% CI 6.4–9.3). Older age was associated with HZ (odds ratio 1.9, 95% CI 1.5–2.6), and IRs for HZ were similar between patients receiving 5 mg tofacitinib twice daily (4.4 per 100 patient-years, 95% CI 3.2–6.0) and those receiving 10 mg twice daily (4.2 per 100 patient-years, 95% CI 3.1–5.8). In the phase III trials among placebo recipients, the incidence of HZ was 1.5 per 100 patient-years (95% CI 0.5–4.6).ConclusionIn the Tofacitinib RA Development Program, increased rates of HZ were observed in patients treated with tofacitinib compared with those receiving placebo, particularly among patients within Asia. Complicated HZ among tofacitinib-treated patients was rare.

Safety and Efficacy of Baricitinib Through 128 Weeks in an Open-label, Longterm Extension Study in Patients with Rheumatoid Arthritis

“…Event types such as malignancies or opportunistic infections did not emerge with prolonged treatment. Herpes zoster infections were reported without evidence of a dose effect during the OLE period at incidence rates (2.3/100 patient-yrs) similar to those described in association with biologic DMARD in RA 7,8 . Laboratory abnormalities leading to discontinuation were uncommon.…”

Safety and Efficacy of Tofacitinib, an Oral Janus Kinase Inhibitor, for the Treatment of Rheumatoid Arthritis in Open-label, Longterm Extension Studies

“…ACR20, ACR50, and ACR70 response rates were sustained over time between Months 1 and 48 ( Figures 2A-C). At Month 1, ACR20, ACR50, and ACR70 response rates for patients were 72.5% (n = 2923/4032), 48.0% (n = 1937/4032), and 27.4% (n = 1104/4032), respectively; corresponding rates at Month 48 were 74.4% (n = 96/129), 49.6% (n = 64/129), and 34.1% (n = 44/129).…”

“…It is noteworthy that the rates of herpes zoster in the phase III cohorts of patients receiving placebo and adalimumab in the tofacitinib program were also higher than those in the literature overall 47,48 . Recently reported risk factor analyses have shown that Asian patients exposed to tofacitinib had a higher IR of herpes zoster infection 49 . The rate of herpes zoster infection did not appear to increase after longterm treatment and followup 48 .…”

“…The safety reported here relates only to findings in the LTE phase of the tofacitinib development program, with the exception of GI perforations, where an integrated analysis is presented (the majority of cases occurred in LTE studies). A detailed discussion of safety events of special interest is, however, warranted and will be addressed in dedicated safety reports in preparation, which will integrate safety findings from LTE, phase II, and phase III studies, to provide an integrated summary from across the development program 37,38,48,49,52,53 .…”

Impact of irradiation and immunosuppressive agents on immune system homeostasis in rhesus macaques

“…In that study, renal transplant recipients received CsA or tacrolimus as well as azathioprine (AZA) or mycophenolate mofetil (MMF); liver transplant recipients received similar treatment to renal transplant patients, with the addition of solumedrol and prednisone; finally, heart and lung transplant patients received ATG, AZA or MMF, CsA or tacrolimus and prednisone. Recently, a greater rate of herpes zoster was also observed in patients treated with an oral JAK inhibitor (tofacitnib) for the treatment of rheumatoid arthritis [44]. Therefore, in this study we monitored SVV reactivation in latently infected RM undergoing immunosuppression using clinically relevant therapies.…”