Live zoster vaccine was well-tolerated by RA patients and no signs of hepes zoster events were observed within 42 days of vaccination.

Herpes zoster (HZ) has been reported to be one of the most common infections affecting older patients with a weakened immune system. As compared to the general population, the risk of developing HZ is 1.5-2 times higher in individuals who have rheumatoid arthritis (RA). The RA treatment drugs like biologic disease-modifying antirheumatic drugs (bDMARDs) and targeted synthetic DMARDs, such as Janus kinase inhibitors further augment the chances of developing HZ.  Researchers have failed to understand the mechanism related to the increase in the risk of developing HZ.

As per the recommendations of the American College of Rheumatology (ACR) and European League against Rheumatism (EULAR), live zoster vaccine (LZV) should be given to RA patients in order to prevent HZ, provided there are no contraindications. But, the effectiveness of LZV is weak and decreases as the age increases. A recent study found its efficacy to be 51.3% in immunocompetent patients above 60 years while in patients above 70 years, the effectiveness was found to be 37.6%.

Tofacitinib, an oral Janus kinase inhibitor, has been found to raise the risk of developing HZ in RA patients, and the chances are even higher in elderly patients on corticosteroid therapy and in many Asian populations. As per the findings of phase II, phase III, and long-term extension (LTE) studies, the incidence rate of HZ was found to be 4.4 per 100 patient-years on a global level and 9.2 per 100 patients’ years in Japan/Korea in RA patients who received tofacitinib 5 or 10 mg twice daily without prior LZV. However, the HZ events appeared in RA patients treated with tofacitinib were not found to be severe and were gone entirely after treatment with antiviral agents. Similar kind of results was also noted with another Janus kinase inhibitor, baricitinib. As RA patients are prone to develop HZ, it is essential to find out if vaccination could be useful in reducing the risk.

The ORAL Strategy, a 1-year, global phase IIIb/IV study was conducted to estimate the safety and effectiveness of tofacitinib monotherapy, tofacitinib with methotrexate (MTX), and adalimumab (ADA) with MTX. The included patients in the study could be given LZV on the choice of researcher prior to the initiation of the study treatment. The current study was the post-hoc analysis of the ORAL strategy.

Rationale behind research: As the risk of developing HZ is higher in patients with RA so it becomes important to explore the effectiveness of a vaccination in reducing the risk.

Objective: The present post-hoc analysis was conducted to examine the incidence of HZ events and also to find out the safety of LZV in RA patients.

Study Outcomes:

Baseline: Percentage of patients vaccinated along with the demographic and other characteristics of the treatment group and stratification as per vaccination status was reported

Outcomes:

• Potential opportunistic infection HZ events: These were defined as events that were disseminated or occurring in nonadjacent or more than 2 adjacent dermatomes.
• Serious HZ events: Those events that wee life-threatening or require parenteral antiviral medication or hospital admission or caused death, birth defect or serious disability.
• Adverse events including injection-site reactions or development of zoster like lesions

Outcomes:

Baseline: The proportion of the patients who received LZV was similar among the three treatment groups. No significant differences in demographic characteristics were noted between the different treatment groups.

Outcomes:

• HZ events: HZ was developed in 18 of the 1146 patients who received the study treatment. In 3 of the 216 patients and 15 of the 930 non-vaccinated patients, the occurrence of HZ events was noted. The patients who developed HZ events in tofacitinib monotherapy group had received corticosteroids at the baseline. One HZ was regarded as an opportunistic infection and none as serious infection in vaccinated patients. Zoster like lesions did not occur in any of the vaccinated patients within the 42 days of vaccination. Vaccination-site erythema was reported by only one patient who received tofacitinib monotherapy. Three HZ events were regarded as an opportunistic infection, and two were regarded as serious infection in non-vaccinated patients. 17 of the 18 were described as of moderate or mild severity by the investigator. One patient who reported varicella was considered as an HZ event. Two patients were reported to have wild type strains.

• HZ incidence: The incidence rates (IRs) of HZ in the ORAL strategy were found to be 1.1 for tofacitinib monotherapy group, 2.3 for the tofacitinib plus MTX group and 1.7 for ADA plus MTX group. The HZ IRs were found to 1.5, 3.0 and 0 for tofacitinib monotherapy, tofacitinib plus MTX and ADA plus MTX, respectively in vaccinated patients presented in the Figure below. 

In contrast, in nonvaccinated patients, these measures were found to be 1.0, 2.2 and 2.1, respectively. In vaccinated patients of more than 50 years of age, theses measures were 1.6, 3.1 and 0 while these were 0.9, 4.0 and 2.4 for the nonvaccinated patients. In 7 patients of age more than 50 years, no HZ events were noted due to protocol deviations. Six of the 930 patients of age more than 50years and were not vaccinated had HZ events (2 patients in the tofacitinib monotherapy group, 1 patient in tofacitinib plus MTX and 3 patients in ADA plus MTX).

The present post-hoc exploratory analysis of ORAL strategy estimated the LZV effect in RA patients who received the vaccine before study treatment. No significant difference was noted in the HZ IRs across different treatment group as well as between vaccinated and nonvaccinated patients. As ORAL strategy study was not planned to be conducted to compare vaccinated and non-vaccinate patients, LZV was received by even less than 20% of patients. Also, a significant proportion who had informed regarding previous HZ vaccination was considered to be nonvaccinated due to non-valid data regarding the date/year of the vaccination occurrence.

The study also represents limited efficacy of LZV in immunocompetent patients with up to 4.9 years of follow-up, whereas the ORAL strategy had 1 year of monitoring. Patients who developed HZ in tofacitinib monotherapy group were also taking corticosteroids before the initiation of the study. Similar results have been reported in the phase III studies in RA patients who were taking tofacitinib without previous LZV. HZ IRs were found to be significantly lower in patients who were receiving tofacitinib 5 mg without corticosteroids and conventional synthetic DMARDs (CsDMARDs) and were higher with tofacitinib 10 mg twice a day with corticosteroids and CsDMARDs.

In patients with age more than 50 years, stratified by vaccination status, the HZ IRs were found to be similar for the three treatment groups. HZ was not found to develop in 7 patients who were more than 50 years and received LZV while HZ was found to develop in patients who were less than 50 years but did not receive LZV. The results are indicative of decreased effectiveness of LZV with the increasing age.

Overall results depicted LZV to be well-tolerated in RA patients treated with tofacitinib or without tofacitinib. But, due to the significant limitations of this analysis, a definite conclusion cannot be made from the available data from the study. More comprehensives studies are required to describe and compare the effectiveness of LZV in RA patients and the general population.