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Abstract
Objectives This study aimed to determine the immunogenicity and the influence on disease activity of an adjuvanted recombinant varicella-zoster virus (VZV) subunit vaccine (RZV) in patients with rheumatoid arthritis (RA) treated with disease-modifying antirheumatic drugs (DMARDs).
Methods This prospective longitudinal study enrolled 53 patients with RA (aged ≥50 years) treated with DMARDs (conventional synthetic (cs)DMARDs 20, biological (b)DMARDs 23 and targeted synthetic (ts)DMARDs 10) and 10 control individuals. The participants received two intramuscular RZV 2 months apart. VZV-specific CD4+ T cell responses (cell-mediated immunity; CMI) and IgG antibody responses (humoral immunity; HI) were assessed at 0 and 3 months after the first RZV administration using flow cytometry and enzyme immunoassay, respectively. Disease activity (Disease Activity Score 28-C reactive protein and Clinical Disease Activity Index), flares and adverse events were monitored for 6 months after the first vaccination.
Results VZV-specific CMI and HI significantly increased in the three DMARDs-treated patients with RA after RZV administration compared with the corresponding prevaccination values (p<0.001–0.014), and the magnitudes and fold-increases of those responses were not significantly different among the three DMARDs-treated patients with RA. Furthermore, the vaccine response rates of CMI and HI were not significantly different between csDMARDs-treated patients and b-DMARDs or ts-DMARDs-treated patients. Meanwhile, no significant increases in disease activity indices or adverse events were observed in these patients during the 6-month follow-up period after the first vaccination. RZV-induced RA flares occurred in two patients (3.8%) but were mild and controllable.
Conclusion RZV is robustly immunogenic and has a clinically acceptable safety profile in elderly patients with RA receiving DMARDs.
- Vaccination
- Arthritis, Rheumatoid
- Antirheumatic Agents
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Patients with rheumatoid arthritis (RA), especially those treated with biological disease-modifying antirheumatic drugs (bDMARDs) and targeted synthetic (ts)DMARDs, are at an increased risk of developing herpes zoster; however, the immunogenicity and safety of the recombinant zoster vaccine (RZV) in patients with RA treated with DMARDs have not yet been elucidated.
WHAT THIS STUDY ADDS
RZV significantly increased varicella-zoster virus-specific cell-mediated immunity (CMI) and humoral immunity (HI) in conventional synthetic (cs)-DMARDs, b-DMARDs and ts-DMARDs-treated patients with RA.
The vaccine response rates of CMI and HI were not significantly different between csDMARDs-treated patients and b-DMARDs or ts-DMARDs-treated patients.
RZV administration did not significantly affect the disease activity nor induce flares in those patients.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
RZV is robustly immunogenic and has a clinically acceptable safety profile in elderly patients with RA receiving DMARDs.
Introduction
Herpes zoster (HZ) is caused by the reactivation of latent varicella-zoster virus (VZV) in people who have compromised VZV-specific cell-mediated immunity (CMI) with underlying diseases, increasing age and immunosuppressive therapies.1 The incidence of HZ is 2.3-fold higher in patients with rheumatoid arthritis (RA) compared with that in the general population, and RA disease severity is associated with the development of HZ.2 3 The use of methotrexate, a key drug of conventional synthetic (cs) disease-modifying antirheumatic drugs (DMARDs) (csDMARDs), however, was not significantly associated with the development of HZ in patients with RA.2 4 Treatment with biological DMARDs (bDMARDs) showed a significantly higher risk of developing HZ than csDMARDs.5 Moreover, the use of Janus kinase inhibitors, targeted synthetic DMARDs (tsDMARDs), in patients with RA is known to double the risk of developing HZ compared with bDMARDs.5 6 Based on these backgrounds, HZ vaccination has been recommended for patients with RA.7
Currently, two different vaccines are available for the prevention of HZ in healthy adults above the age of 50 years: a live-attenuated HZ vaccine (LZV) and an adjuvanted recombinant VZV glycoprotein E (gE) subunit (non-live) vaccine (recombinant HZ subunit vaccine, RZV).8 However, until recently, only LZV has been available for HZ prevention in patients with RA. Despite HZ being a vaccine-preventable disease, since a live-attenuated vaccine is generally contraindicated during the treatment with bDMARDs or tsDMARDs,7 patients with RA treated with these DMARDs did not benefit from standard prophylaxis of HZ. Therefore, only limited studies have assessed the safety and immunogenicity of LZV in patients with RA.9 10 Recently approved RZV is more effective than LZV in preventing HZ in healthy elderly populations, with long-term efficacy and safety.11–13 However, the immunogenicity and safety of RZV in patients with RA have not been determined yet. In other words, RZV might be less efficacious in patients with RA owing to the underlying immunosuppressed state and may potentially lead to the exacerbation of RA.
Therefore, in this prospective longitudinal study, to determine the immunogenicity and safety of RZV in patients with RA treated with cs-DMARDs, b-DMARDs and ts-DMARDs, we examined the CMI and humoral immunity (HI) to VZV gE peptide and the vaccine response rate of those responses after RZV vaccination in patients with RA treated with the three DMARDs. We also evaluated the changes in disease activity and flares after vaccination in these patients.
Patients and methods
Study design and patients
This prospective longitudinal study enrolled 53 patients with RA treated with DMARDs (csDMARDs: n=20, bDMARDs: n=23, tsDMARDs: n=10) and 10 individuals (healthy subjects: n=5, Sjögren’s syndrome: n=3 and systemic sclerosis: n=2) with no history of immunosuppressive treatments within 6 months as controls. All participants were aged ≥50 years since the adjuvanted RZV was only approved for individuals aged ≥50 years in Japan when this study was conducted. All patients with RA met the 2010 American College of Rheumatology/European Alliance of Associations for Rheumatology criteria for RA diagnosis.14 Individuals who agreed to receive RZV were enrolled in this study between December 2021 and June 2022. Individuals who received a live-attenuated vaccine against varicella or HZ within 1 year and who had a history of HZ within 1 year were excluded.15 16
The participants received two intramuscular RZV (SHINGRIX, GlaxoSmithKline, UK) 2 months apart. Each RZV dose contained 50 µg of recombinant VZV gE antigen and liposome-based AS01B adjuvant system. Blood samples were collected at 0 (before the first vaccination) and 3 months after the first vaccination (ie, 4 weeks after the second vaccination) to assess the immunogenicity of RZV and were followed up for 6 months after the first administration of RZV for any adverse events, disease flare or the occurrence of HZ (online supplemental figure S1). All patients with RA received the same treatment for at least 3 months prior to the first vaccination. Baseline characteristics, such as medical history, chicken pox history, HZ history, RA disease activities, laboratory data and treatments, were also collected. Information on adverse events was collected using a questionnaire for the injection site reactions (pain, redness and swelling) and general symptoms (fatigue, fever, headache, gastrointestinal symptoms, myalgia, arthralgia and rash).
Supplemental material
CMI assessment of VZV gE-specific CD4+ T cells by flow cytometry
VZV gE-specific CD4+ T cells were assessed by measuring CD4+ T cells expressing CD40 ligand (CD40L) and at least one of the three activation cytokines (interferon-γ (IFNγ), interleukin-2 (IL-2) and tumour necrosis factor-α (TNF-α)) after in vitro stimulation with VZV gE peptides by flow cytometry.17 18 Briefly, peripheral blood mononuclear cells were stimulated with the VZV gE peptide pool (1 µg/mL/peptide) (LB01818, peptides & elephants) in a serum-free medium (X-VIVO 15, Lonza) for 18 hours at 37°C. After the first 2 hours of the culture, brefeldin A (1 µL/mL) (BD GolgiPlug) was added to the culture medium. The cells were then stained with a viability dye and surface markers (CD3 and CD4), fixed, permeabilised and stained with antibodies to CD40L, IFNγ, IL-2 and TNF-α. The frequencies of gE-specific CD4+ CD40L+ T cells expressing at least one of the three activation cytokines (hereafter termed CD4[2+] T cells) were measured by flow cytometry18 (gating strategy in online supplemental figure S2). Data were analysed using FlowJo software (BD Biosciences). To calculate the fold increase in the frequency of CD4[2+] T cells, the values of CD4[2+] T cell frequency at prevaccination <150 per 106 CD4+ T cells were treated as 150 per 106 CD4+ T cells to prevent overestimation of the fold-increase in the participants with low CD4[2+] T cell count at prevaccination.
Supplemental material
HI assessment
Serum anti-VZV IgG antibody concentrations were measured by ELISA using a Seiken anti-VZV IgG EIA kit (Denka Seiken) according to the manufacturer’s instructions. The minimum detectable anti-VZV IgG concentration was 100 mIU/mL.
Determination of vaccine response rate in CMI and HI
In reference to a previous study,18 CMI responders were defined as those with a ≥2 fold increase in the frequency of gE-specific CD4[2+] T cells compared with the prevaccination values. HI responders were defined as those with a ≥4 fold increase in the anti-VZV IgG antibody concentration compared with the prevaccination concentration.18
Evaluations of disease activity and RA flares after RZV vaccination
We assessed the disease activities (Disease Activity Score 28 (DAS28)-C reactive protein (CRP) and Clinical Disease Activity Index (CDAI))19 of patients with RA before and 3 and 6 months after the first RZV administration. We also evaluated a vaccination-related flare of RA, which was defined as occurring within 8 weeks of RZV administration, along with either (1) escalation of RA treatment, (2) new glucocorticoid administration or (3) diagnosis of flare by the physician in charge. All potential RA flares were confirmed by reviewing the medical records and interviewing the physicians in charge.
Statistical analysis
Statistical analyses were performed using GraphPad Prism (V.9.4.0) and SPSS software (V.28). Continuous variables were expressed as means and SD or medians and IQR and were compared using the Mann-Whitney U test or Kruskal-Wallis test. Wilcoxon’s signed-rank test was used to compare two paired samples. Categorical variables were described as numbers and percentages and were compared using the χ2 test or Fisher’s exact test. A multigroup comparison was performed using the Kruskal-Wallis test or Friedman test with Dunn’s correction. P values <0.05 were considered significant.
Results
Baseline characteristics of participants
The baseline characteristics of 53 patients with RA treated with DMARDs and 10 controls are shown in table 1. The number of patients with RA treated with csDMARDs, bDMARDs or tsDMARDs was 20, 23 and 10, respectively. The mean age of the participants was 70 years. Ages were not significantly different between patients with RA and controls. The mean disease duration in patients with RA was 11 years. Regarding the disease activity of patients with RA, DAS28-CRP score and CDAI score at enrolment were 1.4 and 2.1, respectively. Thirty-two per cent of patients with RA had a history of HZ more than 1 year before the first RZV vaccination. There were no significant differences in the frequency of history of HZ among the three RA groups with different types of DMARDs.
Baseline characteristics of patients with RA stratified by treatments
VZV gE-specific CD4 T cells and anti-VZV IgG levels significantly increase after RZV vaccination in patients with RA treated with DMARDs
To determine the immunogenicity of RZV in patients with RA treated with cs-DMARDs, b-DMARDs and ts-DMARDs, we first assessed CMI to VZV gE by examining the frequency of activated gE-specific CD4[2+] T cells by flow cytometry before and 3 months after the first RZV vaccination (ie, 4 weeks after the second vaccination) (figure 1A,B). We found that gE-specific CD4[2+] T cells were significantly increased in controls and patients with RA treated with cs-DMARDs, b-DMARDs and ts-DMARDs compared with the corresponding prevaccination values (p<0.001–0.014) (figure 1A). The frequencies of gE-specific CD4[2+] T cells after vaccination were 1369 (811–2239) per 106 CD4+ T cells (median (IQR)) in controls and 1771 (568–2605), 1120 (275–2599) and 1023 (225–5217) per 106 CD4+ T cells in cs-DMARDs, b-DMARDs and ts-DMARDs-treated patients with RA, respectively (figure 1B). The fold-increases in the frequency of gE-specific CD4[2+] T cells were 6.7 (2.9–9.7) fold in controls and 4.6 (1.0–12.8), 4.5 (1.5–8.7) and 2.9 (1.1–20.1) fold in cs-DMARDs, b-DMARDs and ts-DMARDs-treated patients with RA, respectively (figure 1C). The magnitudes and fold-increases of the CMI responses were not statistically significantly different between controls and either of the three DMARDs-treated patients with RA or between csDMARDs-treated patients and b-DMARDs or ts-DMARDs-treated patients.
CMI responses to VZV gE in patients with RA treated with DMARDs and controls before and after RZV administration. The frequencies of VZV gE-specific CD4[2+] T cells were examined by flow cytometry in 53 DMARDs-treated patients with RA (csDMARDs: 20, bDMARDs: 23 and tsDMARDs: 10) and 10 controls before and 3 months after the first RZV administration. Changes in the frequencies of VZV gE-specific CD4[2+] T cells between 0 and 3 months in each participant (A) are shown. The magnitudes (B) and fold-increases (C) in the frequencies of VZV gE-specific CD4[2+] T cells in each treatment group (median (IQR)) are also shown. P values were assessed by Wilcoxon’s signed-rank test or Kruskal-Wallis test. A p<0.05 was considered significant. bDMARDs, biological disease-modifying antirheumatic drugs; CMI, cell-mediated immunity; csDMARDs, conventional synthetic DMARDs; RA, rheumatoid arthritis; RZV, recombinant herpes zoster subunit vaccine; tsDMARDs, targeted synthetic DMARDs; VZV, varicella-zoster virus.
We also assessed HI to VZV gE by measuring the levels of anti-VZV IgG by enzyme immunoassay (figure 2). At prevaccination, all participants had anti-VZV IgG levels above the minimum detection concentration (≥100 mIU/mL). The anti-VZV IgG levels 3 months after the first vaccination were significantly higher than those before vaccination in controls and patients with RA treated with DMARDs (p<0.001–0.002) (figure 2A). There were no statistically significant differences in anti-VZV IgG levels after the vaccination between controls and either of the three DMARDs-treated patients with RA (controls: 7950 (4656–10575), csDMARDs: 7075 (2800–13313), bDMARDs: 4100 (1310–6400) and tsDMARDs: 3688 (745–12888) mIU/mL) (figure 2B). The fold-increases in anti-VZV IgG levels were 5.8 (4.0–15.8) fold (median (IQR)) in controls and 7.3 (5.3–13.6), 5.6 (2.8–8.1) and 4.1 (1.6–7.8) fold in patients with RA treated with cs-DMARDs, b-DMARDs and ts-DMARDs, respectively (figure 2C), which were not significantly different between controls and either of the three DMARDs-treated patients with RA.
HI responses to VZV in patients with RA treated with DMARDs and controls before and after RZV administration. Anti-VZV IgG levels were measured by enzyme immunoassay in 53 DMARDs-treated patients with RA (csDMARDs: 20, bDMARDs: 23 and tsDMARDs: 10) and 10 controls before and 3 months after the first RZV administration. Changes in anti-VZV IgG levels between 0 and 3 months in each participant (A) are shown. The magnitudes (B) and fold-increases (C) in anti-VZV IgG levels in each treatment group (median (IQR)) are also shown. P values were assessed by Wilcoxon’s signed-rank test or Kruskal-Wallis test. A p<0.05 was considered significant. bDMARDs, biological disease-modifying antirheumatic drugs; csDMARDs, conventional synthetic DMARDs; HI, humoral immunity; RA, rheumatoid arthritis; RZV, recombinant herpes zoster subunit vaccine; tsDMARDs, targeted synthetic DMARDs; VZV, varicella-zoster virus.
In addition, although the baseline frequencies of gE-specific CD4[2+] T cells were not significantly different between patients with RA with and without a history of HZ (gE-specific CD4[2+] T cells: HZ(−) 26 (0–339) vs HZ(+) 68 (0–285) per 10⁶ CD4+ T cells, p=0.943), those frequencies after vaccination were significantly higher in patients with RA with a history of HZ than in those without it (gE-specific CD4[2+] T cells: HZ(−) 1022 (142–2081) vs HZ(+) 2530 (873–3281) per 106 CD4+ T cells, p=0.026). Baseline anti-VZV IgG levels were higher in patients with RA with a history of HZ than in those without it (HZ(−) 508 (308–1060) vs HZ(+) 1070 (645–1630) mIU/mL, p=0.017) but were no longer significant after RZV vaccination (HZ(-) 4750 (1319–11663) vs HZ(+) 4625 (2185–8550) mIU/mL, p=0.802).
CMI and HI response rates in patients with RA treated with DMARDs
We next evaluated CMI and HI response rates in controls and patients with RA treated with DMARDs (figure 3). The CMI and HI responders were defined as ≥2 fold and ≥4 fold increases in the CMI and HI responses, respectively, compared with the prevaccination values.18
CMI and HI response rates in patients with RA treated with DMARDs and controls. The vaccine response rates of CMI and HI were assessed in 53 DMARDs-treated patients with RA and 10 controls. The definitions of CMI and HI responders are described in the Methods section. Response rates of CMI (A) and HI (B) were compared among patients with RA stratified by their treatment (csDMARDs: 20, bDMARDs: 23 and tsDMARDs: 10) or between all DMARDs-treated patients with RA (n=53) and controls (n=10). P values were assessed by χ2 test or Fisher’s exact test. A p<0.05 was considered significant. bDMARDs, biological disease-modifying antirheumatic drugs; CMI, cell-mediated immunity; csDMARDs, conventional synthetic DMARDs; HI, humoral immunity; RA, rheumatoid arthritis; RZV, recombinant herpes zoster subunit vaccine; tsDMARDs, targeted synthetic DMARDs; VZV, varicella-zoster virus.
The CMI response rates for the frequencies of gE-specific CD4[2+] T cells were 90.0% in controls and 70.0%, 69.6% and 50.0% in patients with RA treated with cs-DMARDs, b-DMARDs and ts-DMARDs, respectively (figure 3A). The CMI response rate in the controls was compatible with previous data on RZV administration in immunocompetent individuals.18 However, the differences in the CMI response rates were not statistically significant between controls and either of the three DMARDs-treated patients with RA, or between csDMARDs-treated patients and b-DMARDs or ts-DMARDs-treated patients (figure 3A).
The HI response rates were 80.0% in controls and 80.0%, 60.9% and 50.0% in patients with RA treated with cs-DMARDs, b- and ts-DMARDs, respectively (figure 3B). The differences in the HI response rates were not statistically significant between controls and either of the three DMARDs-treated patients with RA, or between csDMARDs-treated patients and b-DMARDs or ts-DMARDs-treated patients (figure 3B).
Disease activity and flares after RZV vaccination in patients with RA
We then evaluated the influence of RZV vaccination on disease activity and RA flares in patients with RA treated with DMARDs. Most of the three DMARDs-treated patients with RA were in disease remission before RZV vaccination (DAS28-CRP<2.3 and CDAI≤2.8) (table 1). During the 6-month follow-up period after the first administration of RZV, no significant increases in disease activity indices were observed in these patients with RA (table 2).
Disease activities before and after RZV administration
RA flares within 8 weeks after RZV administration were observed in two patients (3.8%), one at 5 weeks after the first vaccination in a 60-year-old male patient treated with methotrexate 6 mg/week and bucillamine 200 mg/day, and the other 2 weeks after the second vaccination in a 78-year-old male patient treated with tofacitinib 5 mg/every other day. Both flare cases were confirmed by detecting active synovitis by musculoskeletal ultrasound of their symptomatic joints but were well controlled by increasing the dose of ongoing methotrexate or tofacitinib.
RZV-related other adverse events
We then assessed RZV-related adverse events and safety profiles in all participants. In patients with RA, local reactions at the injection site were observed in 43.4% of the patients after the first vaccination (local pain: 39.6%, swelling: 13.2%, redness: 5.7%) and 54.7% after the second vaccination (local pain: 49.1%, swelling: 20.8%, redness: 17.0%). General reactions were observed in 18.9% of the patients after the first vaccination (fever: 9.4%, fatigue: 13.2%, other general reactions: <10.0%) and 39.6% after the second vaccination (fever: 22.6%, fatigue: 26.4%, other general reactions: <10.0%). Except for reduced swelling and redness at the injection site in the patients, there were no significant differences in the frequencies between patients with RA and the controls. No serious adverse events (emergency room visits or hospitalisations) related to RZV administration were observed. Further details of adverse events related to vaccination are provided in online supplemental table S1. Finally, no HZ occurrence was observed during the observation period of 6 months.
Supplemental material
Discussion
In this prospective longitudinal study, since DMARDs-treated patients with RA are at an increased risk for HZ,5 6 20 we evaluated the immunogenicity and the influence on disease activity of RZV in patients with RA treated with cs-DMARDs, b-DMARDs and ts-DMARDs. We show for the first time that RZV administration significantly increases VZV-specific CD4+ T cell and IgG antibody responses in the DMARDs-treated patients with RA (figures 1 and 2). On the other hand, we also show that RZV administration does not significantly affect the disease activity in these patients (table 2). Since it has been shown that the efficacy of RZV vaccination for the prevention of HZ development is overall parallel to the immunogenicity of RZV in the CMI response in immunocompetent individuals aged ≥50 years,12 13 18 these results suggest that RZV vaccination would be useful for preventing HZ development and is safe in patients with RA treated with cs-DMARDs, b-DMARDs and ts-DMARDs.
Previous studies have shown that the risk of HZ increases 1.6-fold in bDMARDs-treated patients with RA5 and over 3-fold in tsDMARDs-treated patients with RA5 20 compared with those treated with csDMARDs, respectively. However, we found that the magnitudes of the VZV-specific CMI and HI responses after RZV administration were not significantly different between csDMARDs-treated patients with RA and the b-DMARDs or ts-DMARDs-treated patients (figures 1 and 2). Our results thus indicate that RZV is immunogenic, even in b-DMARDs or ts-DMARDs-treated patients with RA.
We also evaluated the vaccine response rate of RZV in patients with RA for the first time according to the definition of CMI and HI responders.18 We found that the CMI response rates were not significantly different among the three DMARDs-treated patients with RA (figure 3A). The CMI response rate in the controls was compatible with previous clinical trial data on RZV in immunocompetent individuals.18 The HI response rates were not significantly different among the three DMARDs-treated patients with RA, either (figure 3B). These findings also suggest that RZV vaccination would effectively prevent HZ development in DMARDs-treated patients with RA.
However, because the CMI response rate was as low as 50% in tsDMARDs-treated patients with RA (figure 3) and the number of those patients was relatively small in this study, which may have reduced the statistical power of the results, further large-scale confirmatory studies are needed to confirm the results of the CMI response rates in tsDMARDs-treated patients observed in this exploratory study.
CMI to VZV has been shown to play a crucial role in suppressing the reactivation of latent VZV and preventing HZ development, whereas the antibody response to VZV does not, in immunocompetent or immunosuppressed subjects.21 22 A decline in VZV-specific CMI has been shown to correlate with an increase in the incidence and severity of HZ, whereas VZV-specific antibody titre did not.23 It has also been demonstrated that the clinical efficacy of the zoster vaccine results from its capacity to increase VZV-specific CMI in adults.21 22 Furthermore, a recent study suggests that the generation of gE-specific Th1 cells is important for the immunogenicity of RZV.24 Because the development of HZ induces sufficient CMI responses to VZV to prevent HZ recurrence,16 we also analysed the magnitude of CMI to VZV gE stratified by the presence or absence of a history of HZ. We found that the magnitude of CMI after RZV vaccination was significantly higher in patients with RA with a history of HZ than in those without it, while the baseline CMI was not significantly different between those with and without a history of HZ. In contrast, similar to a previous report,25 we showed that prevaccination anti-VZV IgG levels were significantly higher in patients with RA with a history of HZ than in those without it but were no longer significantly different after RZV vaccination.
We also showed that the disease activity of DMARDs-treated patients with RA was not significantly affected by RZV vaccination (table 2). Although there is a concern that adjuvants could potentially lead to the exacerbation of underlying autoimmune diseases,26 possible RZV-induced RA flares were observed in two patients (3.8%) but were mild and controllable by increasing the dose of ongoing DMARDs. RZV consists of recombinant VZV gE antigen and the AS01B adjuvant system27 and strongly induces gE-specific CD4+ T cell activation and the development of a memory phenotype.18 27 The AS01B adjuvant enhances CMI to VZV gE five times higher than the administration of gE alone in adults aged ≥50 years.28 A recent retrospective study showed that mild flares were observed after receiving RZV in 21 (24%) of 88 patients with RA treated with methotrexate (49%), bDMARDs (45%) and tsDMARDs (16%).29 Although the disease activity data were not presented in that study, the differences in the incidence of RA flares between their study and ours might be due to the difference in baseline disease activities before RZV vaccination. Stevens et al also retrospectively investigated the disease flares and side effects of RZV in 239 patients with RA and found that five percent of the patients experienced a mild flare,30 which is consistent with our results, and the side effects were also mild.
No serious adverse events were observed on RZV administration in DMARD-treated patients with RA or controls in this study (online supplemental table S1). The most frequent adverse events were pain and swelling at the local injection site and fatigue and fever as general reactions; however, the overall percentage was low compared with that observed in the ZOE-70 trial.13 Since the ZOE-70 trial was performed in immunocompetent individuals, the lower incidence of adverse events in our DMARDs-treated patients with RA may be due to concomitant immunosuppressive treatment with DMARDs.
Finally, our findings should be carefully applied to general patients with RA still in active disease states because the participants in this study were relatively old patients with RA with low disease activity. Regarding the old ages of patients with RA in this study (mean age 69.5 years), our findings of the immunogenicity and safety of RZV administration in patients with RA are in agreement with the results in the ZOE-70 study for elderly healthy participants.13 As to the disease activity of patients with RA, as flares occurred in two patients (3.8%) even with low disease activity (DAS28-CRP 1.2 and 1.3, respectively), RZV should be carefully administered for patients with RA in active disease states. In addition, the relatively low dose of methotrexate used in this study may be attributed to factors such as older age and lower disease activity in the study participants.
In conclusion, we have shown that CMI and HI to VZV gE significantly increase in cs-DMARDs, b-DMARDs and ts-DMARDs-treated patients with RA on RZV administration and that the CMI response rates are not significantly different between csDMARDs-treated patients and b-DMARDs or ts-DMARDs-treated patients. We have also shown that disease activity does not significantly increase in the DMARDs-treated patients with RA after vaccination and that RZV-induced RA flares are mild and controllable. Taken together, RZV is robustly immunogenic and has a clinically acceptable safety profile in elderly patients with RA receiving cs-DMARDs, b-DMARDs or ts-DMARDs. However, since the CMI response rate was found to be 50% in tsDMARDs-treated patients with RA, further large-scale studies of the immunogenicity of RZV would be needed in those patients.
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
Ethics statements
Patient consent for publication
Ethics approval
This study involves human participants and this study was approved by the Research Ethics Committee of Chiba University Graduate School of Medicine (reference number: M10042). Participants gave informed consent to participate in the study before taking part.
Acknowledgments
We thank all the staff at Chiba University Hospital, Chiba Aoba Municipal Hospital, and Seikeikai Chiba Medical Center for taking care of the patients who were enrolled in this study.
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
Presented at The work on which this article is based was previously presented at EULAR 2023 Annual European Congress of Rheumatology, Milano, Italy, 31 May 2023–3 June 2023. Kojima S, Iwamoto T, Kobayashi Y, et al. POS0572 Immunogenicity and safety of adjuvanted recombinant zoster vaccine in patients with rheumatoid arthritis treated with disease-modifying anti-rheumatic drugs. Annals of the Rheumatic Diseases 2023;82:554-555.
Contributors SK and TIwamoto contributed equally to this study. TIwamoto has full access to all the data in the study and responsible for the overall content as the guarantor. Study conception and design: SK, TIwamoto, AI, KI and HN. Data acquisition: SK, TIwamoto, YK, MK, TIda, YT, KM, JS, SF, KI and FT. Statistical analysis and data interpretation: SK, TIwamoto and KI. Manuscript preparation: SK, TIwamoto, SF, KI and HN. All authors were involved in drafting the article and all authors approved the final version to be published.
Funding This work was supported in part by grants from Chiba University Synergy Institute for Futuristic Mucosal Vaccine Research and Development (cSIMVa), Agency for Medical Research and Development (AMED)-SCARDA (223fa627003h0002).
Competing interests TIwamoto has received honoraria for lectures from AstraZeneca and GlaxoSmithKline, all unrelated to the current manuscript. SF has received consulting fees from Asahi Kasei Pharma and has received honoraria for lectures from Asahi Kasei Pharma, Eisai, Daiichi Sankyo, Chugai Pharmaceutical and Kissei Pharma, all unrelated to the current manuscript. KI has received research grants from Mitsubishi-Tanabe Pharma and has received honoraria for lectures from Abbvie, Eli Lilly Japan, and AstraZeneca, all unrelated to the current manuscript. HN has received research grants from Chugai Pharmaceutical, Abbvie, Takeda Pharmaceutical, Astellas Pharma, Eli Lilly Japan, Asahi Kasei Pharma, Pfizer Japan, UCB Japan, Eizai, Mitsubishi Tanabe Pharma, and Bristol Myers Squibb and has received honoraria for lectures from Chugai Pharmaceutical, Abbvie, Takeda Pharmaceutical, Astellas Pharma, Eli Lilly Japan, Asahi Kasei Pharma, Janssen Pharmaceutical, Mitsubishi Tanabe Pharma, Eisai, Bristol Myers Squibb, and Nippon Kayaku, all unrelated to the current manuscript. The other authors have no competing interests to declare.
Provenance and peer review Not commissioned; externally peer reviewed.
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