Herpes Zoster and Tofacitinib Therapy in Patients With Rheumatoid Arthritis

The reactivation of varicella zoster virus (VZV), also known as herpes zoster (HZ) or shingles, is of substantial public health importance, as up to one-third of adults in the US will develop HZ within their lifetime (1–4). Nearly 100% of individuals in the US age 40 years or older have been exposed to this virus, and its reactivation is related to diminished VZV-specific cell-mediated immunity associated with increasing age and immunosuppressive conditions. Among patients who develop HZ, postherpetic neuralgia occurs in ∼15%, causing long-term disability. More rarely, disseminated forms of HZ occur, potentially leading to encephalitis and death. In the US, the annual incidence rates (IRs) of HZ vary between 0.4 and 1.1 per 100 patient-years in patients ages 50–80 years, with the highest rates seen in women (1). In patients with rheumatoid arthritis (RA), the risk of HZ is elevated 2–3-fold (5,6). Although certain disease-modifying therapies, such as anti–tumor necrosis factor α (anti-TNFα) therapies, have been linked to further increases in risk, studies evaluating this have produced conflicting results. To date, only prednisone has been consistently shown to increase the risk of shingles by an additional 1.5–2-fold (7). Furthermore, although disseminated HZ is much more common in immunosuppressed populations, it is unclear whether RA and/or its disease-modifying therapies increase the risk (7,8). Tofacitinib is an oral JAK inhibitor for the treatment of RA. Tofacitinib preferentially inhibits JAK-3 and/or JAK-1, modulating the immune response via down-regulation of several cytokines (e.g., interleukins 2, 4, 7, 9, 15, and 21) that are integral to lymphocyte development and function (9). Given its mechanism of action and the increased baseline risk of HZ among patients with RA, an increased risk of HZ is a theoretical concern. Accordingly, we undertook a retrospective evaluation of HZ cases as reported within the Tofacitinib RA Development Program, with the objectives of describing the outcomes of and identifying risk factors for HZ among tofacitinib-treated patients, as well as evaluating the relative incidence of HZ in tofacitinib-treated patients as compared with those receiving placebo.