Shingles, also known as herpes zoster (HZ), is a common and sometimes debilitating disease that disproportionately affects elderly individuals and those who are immunocompromised. Patients with rheumatoid arthritis (RA) have a 1.5–2-fold higher risk of developing HZ compared with healthy adults. Treatment with some disease-modifying anti-rheumatic drugs (DMARDs) has been shown to increase this risk. Tofacitinib has been shown to increase the risk of developing HZ, particularly when it is given in combination with methotrexate or prednisone.
Thus, vaccination is recommended for patients ages 50 years and older, prior to starting treatment with biologic agents or tofacitinib. Two studies in this issue of Arthritis & Rheumatology tackle the topic of live zoster vaccination in patients with rheumatoid arthritis before starting and concomitant with tofacitinib.
Study 1
The first, “The Safety and Immunogenicity of Live Zoster Vaccination in Patients with Rheumatoid Arthritis Before Starting Tofacitinib,” evaluated the effect of tofacitinib, an oral JAK inhibitor used for the treatment of RA, on the immune response to and safety of live zoster vaccine (LZV).1
In this phase II, 14-week, placebo-controlled trial, patients ages 50 years and older who had active RA and were receiving background methotrexate were given LZV and randomized to receive tofacitinib 5 mg twice daily or placebo two to three weeks postvaccination. The researchers measured humoral responses (the varicella zoster virus [VZV]–specific IgG level as determined by glycoprotein enzyme-linked immunosorbent assay) and cell-mediated responses (VZV-specific T cell enumeration, as determined by enzyme-linked immunospot assay) at baseline and two weeks, six weeks and 14 weeks postvaccination. End points included the geometric mean fold rise (GMFR) in VZV-specific IgG levels (primary end point) and T cells (spot-forming cells/106 peripheral blood mononuclear cells) at six weeks postvaccination.
Results: One hundred twelve patients were randomized to receive tofacitinib (n=55) or placebo (n=57). Six weeks postvaccination, the GMFR in VZV-specific IgG levels was 2.11 in the tofacitinib group and 1.74 in the placebo group, and the VZV-specific T cell GMFR was similar in the tofacitinib group and the placebo group (1.50 and 1.29, respectively). Serious adverse events occurred in three patients in the tofacitinib group (5.5%) and 0 patients (0.0%) in the placebo group. One patient who lacked preexisting VZV immunity developed a disseminated rash on day 16 postvaccination (two days after starting tofacitinib). This resolved after tofacitinib was discontinued and the patient received antiviral treatment.
Study 2
The second study, “Herpes Zoster and Tofacitinib: Clinical Outcomes and the Risk of Concomitant Therapy,” evaluated whether concomitant treatment with conventional synthetic DMARDs (csDMARDs) or glucocorticoids (GCs) contributes to the increased risk of HZ in RA patients treated with tofacitinib.2
HZ cases were identified from the databases of two phase I, nine phase II, six phase III and two long-term extension studies of tofacitinib in RA patients. Crude incidence rates (IRs) of all HZ events (serious and nonserious) per 100 patient-years (with 95% confidence intervals) were calculated for unique patients. Within phase III studies, the researchers described HZ rates according to concomitant csDMARD treatment and baseline corticosteroid use. A multivariable Cox regression model was used to evaluate HZ risk factors across studies.
Across all studies (6,192 patients; 16,839 patient-years), HZ was reported in 636 tofacitinib-treated patients (IR 4.0, 95% CI 3.7–4.4). In most cases (93%), HZ was classified as nonserious, and the majority of patients (94%) had involvement of only one dermatome. HZ IRs varied across regions, from 2.4 (95% CI 2.0–2.9) in Eastern Europe to 8.0 (95% CI 6.6–9.6) in Japan and 8.4 (95% CI 6.4–10.9) in Korea. Within phase III studies, HZ IRs varied according to tofacitinib dose, background csDMARD treatment, and baseline use of GCs. The IRs were numerically lowest for monotherapy with tofacitinib 5 mg twice daily without GCs (IR 0.56 [95% CI 0.07–2.01]) and highest for tofacitinib 10 mg twice daily with csDMARDs and GCs (IR 5.44 [95% CI 3.72–7.68]). Age, GC use, tofacitinib dose, and enrollment within Asia were independent risk factors for HZ.
Conclusions
In the first study, patients who began treatment with tofacitinib two to three weeks after receiving LZV had VZV-specific humoral and cell-mediated immune responses to LZV similar to those in placebo-treated patients. Vaccination appeared to be safe in all of the patients except one patient who lacked preexisting VZV immunity.
From a safety standpoint, the single event of disseminated HZ in a patient without prior immunity suggests that patients should be screened for prior immunity (i.e., by eliciting a history of chickenpox or testing with commercially available VZV serologic tests) before administration of this vaccine, or that the time periods between vaccination and initiation of tofacitinib treatment should be longer (e.g., four weeks).
The researchers in the second study found that the risk of HZ is likely to be greater in patients receiving tofacitinib in combination with GCs compared with those receiving monotherapy without GCs. Given that similar efficacy has been observed with tofacitinib in phase III clinical studies regardless of whether it is administered as monotherapy or in combination with csDMARDs and/or GCs, the use of tofacitinib monotherapy without GCs could represent a risk-reduction strategy for physicians and patients with regard to HZ and provide an effective treatment strategy for reduction of the signs and symptoms of RA, provided the patient’s RA remains controlled.
Excerpted and adapted from:
- Winthrop KL, Ann Wouters A, Choy E, et al. The safety and immunogenicity of live zoster vaccination in patients with rheumatoid arthritis before starting tofacitinib: A randomized phase II trial. Arthritis Rheumatol. 2017 Oct;69(10):1969–1977.
- Winthrop KL, Curtis JR, Lindsey S, et al. Herpes zoster and tofacitinib: Clinical outcomes and the risk of concomitant therapy. Arthritis Rheumatol. 2017 Oct;69(10):1960–1968.
