Herpes zoster (HZ) incidence is higher in patients with rheumatoid arthritis (RA) compared with the general population,[@R1] and it may be further increased with disease-modifying antirheumatic drugs (DMARDs).[@R2] Tofacitinib is an oral Janus kinase inhibitor for the treatment of RA.  Real-world data indicate that HZ incidence is approximately twofold higher with tofacitinib versus biologic DMARDs (bDMARDs).[@R3]

Current American College of Rheumatology guidelines conditionally recommend that patients with RA aged ≥50 years receive HZ vaccine prior to tofacitinib or bDMARDs.[@R4] We previously evaluated the immunogenicity of a live attenuated zoster vaccine (LZV), administered 2--3 weeks prior to tofacitinib or placebo with background conventional synthetic DMARDs.  Both groups had similar varicella zoster virus (VZV)-specific immune responses, and overall immune responses were comparable with those of healthy volunteers in previous studies.[@R5] We have now followed this patient cohort in an open-label, long-term extension (LTE) study of tofacitinib. 

Patients enrolled in the index study (A3921237; NCT02147587)[@R5] could join ORAL Sequel (LTE study; A3921024; NCT00413699) 14 weeks post-vaccination, where they received open-label tofacitinib 5 or 10 mg two times per day ([online supplementary figure S1](#SP1){ref-type="supplementary-material"}); background RA therapy was also allowed.  Patients were followed for 27 months.  Post-vaccination, adverse events (AEs), including discontinuations due to AEs, were recorded during the study within 28 days of the last dose.  Incidence rates (IRs; patients with events/100 patient-years (PY)) and 95% CIs for HZ post-vaccination were calculated based on time to first event (patients not reporting an event were censored at last treatment dose).  Short-term VZV-specific immunity was evaluated at baseline and week 6 post-vaccination during the index study.10.1136/annrheumdis-2019-216566.supp1Supplementary data

Vaccine-related AEs in the index study included mild injection-site pain, swelling, redness, itching and myalgia.  Disseminated vaccine-strain varicella was also reported in a patient with no previous exposure to VZV.[@R5] After rollover into ORAL Sequel, 100 patients received an average tofacitinib dose of 5 mg (n=46) or 10 mg (n=54) two times per day.  Mean (range) tofacitinib exposure was 489 (46--811) days and overall exposure was 139 PY. 

LZV did not provide adequate protection to all patients.  Five HZ cases (\#1--5) occurred in the LTE study 218, 280, 748, 741 and 544 days post-vaccination, respectively (IR=3.60(1.17, 8.39); [table 1](#T1){ref-type="table"}).  Cases \#1--4 were monodermatomal and case \#5 involved five dermatomes.  All HZ events were mild/moderate in severity and resolved with antiviral treatment. 

###### 

Patient profiles of HZ cases

  ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
                                                  Case \#1                  Case \#2                    Case \#3                                   Case \#4                     Case \#5
  ----------------------------------------------- ------------------------- --------------------------- ------------------------------------------ ---------------------------- ----------------------------
  Age, years                                      65                        60                          77                                         74                           74

  Sex                                             Female                    Male                        Female                                     Male                         Male

  Race                                            White                     White                       White                                      White                        White

  Study drug\                                     Tofacitinib\              Tofacitinib\                Placebo                                    Placebo                      Placebo
  (A3921237)                                      5 mg two times per day    5 mg two times per day                                                                              

  Study drug\                                     Tofacitinib\              Tofacitinib\                Tofacitinib\                               Tofacitinib\                 Tofacitinib\
  (ORAL Sequel)                                   10 mg two times per day   5 mg two times per day      5 mg two times per day                     10 mg two times per day      10 mg two times per day

  Background RA drugs                             MTX 15 mg/week\           MTX 20 mg/week              None                                       None                         MTX 20 mg/week
                                                  Prednisone 5 mg/day                                                                                                           

  Type of HZ                                      Monodermatomal            Monodermatomal              Monodermatomal                             Monodermatomal               5 dermatomes

  Severity of HZ\*                                Moderate                  Mild                        Moderate                                   Mild                         Mild

  Duration of HZ, days                            49                        14                          14                                         16                           10

  Action to study drug                            No action taken           Stopped temporarily         No action taken                            No action taken              Stopped temporarily

  Outcome of HZ                                   Resolved with acyclovir   Resolved with famciclovir   Resolved with acyclovir and azithromycin   Resolved with valacyclovir   Resolved with valacyclovir

  Occurrence of HZ                                                                                                                                                               

   Time after LZV vaccination, days               218                       280                         748                                        741                          544

   Time after initiation of tofacitinib, days     202                       267                         702                                        699                          466

  VZV humoral immunity (IgG titre), U/mL†                                                                                                                                        

   Baseline                                       224.3                     36.9                        96.6                                       237.3                        208.3

   Week 6                                         444.0                     70.9                        186.9                                      231.5                        222.5

   Change from baseline (fold rise at week 6)     1.98                      1.92                        1.93                                       0.98                         1.07

  VZV cell-mediated immunity, SFCs/10^6^ PBMCs‡                                                                                                                                  

   Baseline                                       25                        41                          25                                         25                           25

   Week 6                                         25                        76                          51                                         25                           25

   Change from baseline (fold rise at week 6)     1.00                      1.85                        2.04                                       1.00                         1.00
  ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

\*Determined by the investigator. 

†Assessed by gpELISA (PPD Vaccines and Biologics); mean VZV IgG titres in patients receiving tofacitinib and placebo, respectively, in the index study were 201 and 182 U/mL at baseline and 403 and 323 U/mL at week 6 (fold rise at week 6 was 2.11 with tofacitinib and 1.74 with placebo).[@R5]

‡Assessed by IFNγ ELISPOT (Pfizer Inc Vaccine Research Unit, Pearl River, New York, USA); limit of detection was 25 SFCs/10^6^ PBMCs; values in the table shown as 25 SFCs/10^6^ PBMCs may be below this threshold; mean VZV cell-mediated immunity in patients receiving tofacitinib and placebo, respectively, in the index study was 48 SFCs/10^6^ PBMCs and 43 SFCs/10^6^ PBMCs at baseline, and 70 SFCs/10^6^ PBMCs and 56 SFCs/10^6^ PBMCs at week 6 (fold rise at week 6 was 1.50 with tofacitinib and 1.29 with placebo).[@R5]

ELISPOT, enzyme-linked immunosorbent spot; gpELISA, glycoprotein-based enzyme-linked immunosorbent assay; HZ, herpes zoster; IFNγ, interferon gamma; IgG, immunoglobulin G; LZV, live zoster vaccine; MTX, methotrexate; PBMCs, peripheral blood mononuclear cells; RA, rheumatoid arthritis; SFCs, spot-forming cells; VZV, varicella zoster virus. 

VZV humoral immunity (immunoglobulin G (IgG) titre) and VZV cell-mediated immunity (interferon-γ enzyme-linked immunosorbent spot (ELISPOT)) in patients receiving tofacitinib or placebo in the index study[@R5] are shown in [table 1](#T1){ref-type="table"}.  In terms of immunity after LZV in this analysis, cases \#1, \#4 and \#5 had undetectable VZV cell-mediated immunity, at baseline and week 6; cases \#2 (patient received tofacitinib 5 mg two times per day in index and LTE studies) and \#3 (patient received placebo and tofacitinib 5 mg two times per day in index and LTE studies, respectively) responded adequately to vaccination by both IgG and ELISPOT measures but had lower than average VZV IgG levels at baseline (case \#2: 36.9 U/mL vs average of 201 U/mL; case \#3: 96.6 U/mL vs average of 182 U/mL) and week 6 (case \#2: 70.9 U/mL vs average of 403 U/mL; case \#3: 186.9 U/mL vs average of 323 U/mL; [table 1](#T1){ref-type="table"}). 

HZ incidence was similar to that in patients receiving tofacitinib in phase 1/2/3/LTE studies up to 9.5 years (IR=3.6 (3.4, 3.9); n=782/7061\]),[@R6] although the present analysis was limited due to the small number of patients, and 95% CIs were wide.  Cell-mediated responses in cases \#2 and \#3 may have been short-lived; however, serial longitudinal data are required to confirm this. 

These results suggest that LZV may not provide adequate long-term protection, as previously demonstrated in healthy individuals aged ≥60 years 3 years post-vaccination, in which HZ risk was reduced by 51%.[@R2] While it is possible that LZV booster vaccinations may improve vaccine efficacy, to date there is a lack of data on the use and timing of booster vaccinations, and no recommendations on the use of LZV booster vaccinations currently exist.  This highlights the importance of evaluating the newly approved subunit non-live vaccine (Shingrix) in patients with RA receiving tofacitinib. 

The authors would like to acknowledge Lisa McNeil for managing the ELISPOT assay and for her contributions to the interpretation of the ELISPOT and ELISA results.  Medical writing support, under the guidance of the authors, was provided by Anthony G McCluskey, PhD, CMC Connect, McCann Health Medical Communications and was funded by Pfizer Inc, New York, New York, USA in accordance with Good Publication Practice (GPP3) guidelines (Ann Intern Med 2015;163:461--464). 

**Handling editor:** Josef S Smolen

**Presented at:** These data were presented at the American College of Rheumatology Annual Scientific Meeting in 2017 (Winthrop KL et al.  Ann Rheum Dis 2017;76\[Suppl 2\]) and are used here with permission from John Wiley & Sons, Inc.

**Contributors:** All authors were involved in the analysis and interpretation of data, critically revising the text for important intellectual content.  All authors agree to be accountable for all aspects of the work and read and approved the final version to be published. 

**Funding:** This study was sponsored by Pfizer Inc.

**Competing interests:** KLW has acted as a consultant for AbbVie, Bristol-Myers Squibb, Eli Lilly, Galapagos, Gilead, Pfizer Inc and UCB; and he has received grant/research support from Bristol-Myers Squibb.  EHC has received grant/research support from BioCancer, Pfizer Inc, Roche and UCB; has acted as a consultant for Amgen, Biogen, Chugai Pharma, Eli Lilly, Janssen, Novartis, Pfizer Inc, Regeneron, Roche, R-Pharm and Sanofi; and has participated in speakers' bureaus for Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharma, Eli Lilly, Hospira, MSD, Novartis, Pfizer Inc, Regeneron, Roche, Sanofi-Aventis and UCB.  WFCR has received grant/research support from Pfizer Inc and has acted as a consultant for Pfizer Inc and Roche.  AW, CC, PB, LW, KS, EN and HV are employees and shareholders of Pfizer Inc.

**Patient and public involvement:** Patients and/or the public were not involved in the design, conduct, reporting or dissemination plans of this research. 

**Patient consent for publication:** Not required. 

**Provenance and peer review:** Not commissioned; externally peer reviewed.