Background/Purpose: Tofacitinib
is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis
(RA). Clinical guidelines recommend using live zoster vaccine (LZV) to prevent
shingles in RA, but this vaccine has not been previously studied in RA patients
(pts) and the effect of tofacitinib on humoral or cell-mediated live vaccine
responses is unknown.

Methods:
To evaluate the effect of tofacitinib upon the immune response and safety of LZV,
we recruited pts aged ≥50 years with active RA (≥4 tender/painful joints and ≥4 swollen joints) despite
methotrexate (MTX) therapy (≥4
months of treatment with 15–25 mg/week [wk] before screening) (study NCT02147587).
Pts with prior history of zoster vaccination were excluded, as were those
receiving any vaccine in the 6 wks prior to randomization. After screening,
eligible pts were given LZV and then randomized to either tofacitinib 5 mg
BID or placebo (PBO) to start 2–3
wks post-vaccination with continuation of background MTX. We measured both
humoral (varicella-zoster virus [VZV]-specific IgG via gpELISA) and
cell-mediated responses (VZV-specific T cell enumeration via ELISPOT) prior to
vaccination (baseline, day of vaccination), and then at 2, 6, and 14 wks
post-vaccination. The primary endpoint was an assessment of the geometric mean
fold rise (GMFR) in VZV-specific IgG titer at 6 wks post-vaccination. Secondary
endpoints included the proportion of patients achieving a ≥1.5 fold rise
in VZV-specific IgG titer 6 wks post-vaccination. Exploratory endpoints
included the GMFR in VZV-specific T cells (spot-forming cells/10⁶ peripheral blood mononuclear cells [PBMCs])
by ELISPOT between baseline and 6 wks post-vaccination. Pts were followed for
12 wks after randomization for safety.

Results: 112
pts were randomized into PBO (n=57) and tofacitinib arms (n=55). Most PBO (93%)
and tofacitinib (98%) pts were evaluable for immune response endpoints. Pts were
similar with regard to sex, age, baseline disease activity, and baseline VZV
immune measures (i.e. IgG, ELISPOT). The GMFR in VZV-specific IgG titer
at 6 wks was 2.11 for tofacitinib pts and 1.74 for PBO pts. The GMFRs both in
tofacitinib and PBO pts were comparable with the GMFRs in healthy people
≥50 years as indicated in the LZV labels. The proportion of patients
developing a 1.5 fold post-vaccination rise in IgG titer at 6 wks trended
higher for tofacitinib (57.4%) versus PBO (43.4%). For cell-mediated immune responses,
the VZV-specific T cell GMFR at 6 wks increased similarly for tofacitinib pts (1.50)
and PBO pts (1.29). SAEs occurred in 0 (0%) and 3
(5.5%) of PBO and tofacitinib arms respectively. One pt in the study developed
cutaneous dissemination with vaccine-strain VZV (Oka strain virus) that
occurred 2 days after starting tofacitinib (16 days post-vaccination).
Subsequently, this pt was found to lack pre-existing immunity to VZV,
consistent with vaccine-induced disease. This event resolved after tofacitinib
discontinuation and antiviral therapy.

Conclusion:
Pts starting tofacitinib had similar VZV-specific humoral and cell-mediated immune
responses to LZV as compared to PBO-treated pts. Vaccination appeared safe in
all pts but one who lacked pre-existing VZV immunity.