The Safety and Immunogenicity of Live Zoster Vaccination in Patients With Rheumatoid Arthritis Before Starting Tofacitinib: A Randomized Phase II Trial

Abstract

Objective: Patients with rheumatoid arthritis (RA) are at increased risk of herpes zoster, and vaccination is recommended for patients ages 50 years and older, prior to starting treatment with biologic agents or tofacitinib. Tofacitinib is an oral JAK inhibitor for the treatment of RA. We evaluated its effect on the immune response and safety of live zoster vaccine (LZV).

Methods: 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 2-3 weeks postvaccination. We measured humoral responses (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 2 weeks, 6 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 (number of spot-forming cells/10⁶ peripheral blood mononuclear cells) at 6 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 3 patients in the tofacitinib group (5.5%) and 0 patients (0.0%) in the placebo group. One patient, who lacked preexisting VZV immunity, developed cutaneous vaccine dissemination 2 days after starting tofacitinib (16 days postvaccination). This resolved after tofacitinib was discontinued and the patient received antiviral treatment.

Conclusion: Patients who began treatment with tofacitinib 2-3 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 1 patient who lacked preexisting VZV immunity.

Trial registration: ClinicalTrials.gov NCT02147587.

Figure 1

Analyses of varicella zoster virus (VZV)–specific IgG levels. Live zoster vaccine was given on day −14; a blood sample from each subject was obtained at that time to evaluate the baseline immune response to VZV immediately before vaccination. A, Mean absolute VZV‐specific IgG levels (glycoprotein enzyme‐linked immunosorbent assay [gpELISA] titer) in the tofacitinib group and the placebo group at baseline (day −14, before vaccination) and 2, 6, and 12 weeks postvaccination. B, Proportion of patients with a ≥1.5‐fold change in VZV‐specific IgG levels (gpELISA titer) in the tofacitinib group and the placebo group at 2, 6, and 12 weeks postvaccination. ∗ = The 80% confidence intervals (80% CIs) were calculated using the Clopper‐Pearson exact method. GMT = geometric mean titer; BID = twice daily.

Figure 2

Analyses of VZV‐specific T cell responses, measured by enumeration of interferon‐γ spot‐forming cells (SFCs) using enzyme‐linked immunospot (ELISpot) assay. Live zoster vaccine was given on day −14; a blood sample from each subject was obtained at that time to evaluate the baseline immune response to VZV immediately before vaccination. A, Mean absolute values of VZV‐specific reactive T cells, as determined by ELISpot assay, in the tofacitinib group and the placebo group at baseline (day −14, before vaccination) and 2, 6, and 12 weeks postvaccination. B, Proportion of patients with a ≥1.5‐fold change in the VZV‐specific T cell response, as determined by ELISpot assay, in the tofacitinib group and the placebo group at 2, 6, and 12 weeks postvaccination. ∗ = The 80% confidence intervals (80% CIs) were calculated using the Clopper‐Pearson exact method. GMC = geometric mean count (see Figure 1 for other definitions).