Immunogenicity of recombinant zoster vaccine in Rheumatoid arthritis patients

风湿性关节炎（RA）是最常见的炎症性关节炎，患病率约为0.6% 在一般人群中，是退伍军人群体中常见的慢性自身免疫性疾病。RA患者 传染病的死亡率和发病率更高。这种增加的负担部分与 RA本身的免疫紊乱，其中一些可归因于免疫抑制治疗， 用于治疗RA。 带状疱疹（HZ）再激活是治疗的RA患者最常见的机会性感染， 是普通人的两倍HZ已经有20-30%的终身风险， 人口直到最近批准的重组带状疱疹疫苗（RZV，品牌名Shingrix）， 只有减毒活疫苗Zostavax它很少用于治疗类风湿关节炎患者， 免疫抑制的个体禁忌，因为它是活病毒疫苗。RZV是亚单位疫苗 没有这个限制。此外，RZV已被发现在一般成人人群中高度 有效（>90%），即使在80岁以上的人。这带来了一个重大的潜在机会， 保护RA患者，即使在免疫抑制治疗。 对HZ的免疫保护与对原发性水痘带状疱疹（VZV）感染的免疫保护有很大不同 （水痘），其主要是抗体介导的。一个创新的HZ灵长类动物模型的工作表明， 细胞介导的免疫（CMI），特别是CD 4 + T细胞，是保护的关键。所有的疫苗 先前在RA患者中研究的是通过抗体介导的机制引起保护的那些 而不是CMI。缓解疾病的抗风湿药物（DMARD）对疫苗免疫原性或 疗效，特别是集中在CMI的RZV诱发是未知的。因此，拟议的研究 创新之处在于，他们提出确定RA和DMARD治疗对 RZV本研究中提出的RA患者对RZV的反应分析具有直接的临床相关性， 平移势这可能会影响要使用的DMARD的选择，因为有许多选择， 治疗RA。它可以提供支持使用药物窗口的临床试验的数据，其中使用 接种疫苗后暂时停止DMARD，以改善应答。 他们假设RZV在RA患者中的免疫原性较 非RA对照组，服用抗代谢合成DMARD的RA患者 免疫原性高于生物DMARD如TNFi。 他们将对100名RA患者进行实验室盲法观察研究， 其中大多数正在服用DMARD，以及100名年龄匹配的非风湿病受试者来确定 这些人群之间RZV的免疫原性差异。 具体目标：目标1。确定合成和生物的影响程度和差异 DMARD疗法对RA患者中RZV免疫原性的影响 目的2确定疫苗特异性应答降低和增强的机制途径 RZV使用系统生物学方法，并确定与 这些反应发生在DMARDS的RA患者身上。 目标3。比较RA患者与年龄匹配的非RA患者接种RZV疫苗的不良事件特征， 风湿性疾病患者。

Rheumatoid arthritis (RA) is the most common inflammatory arthritis with a prevalence of around 0.6% in the general population and is a common chronic autoimmune disease in the veteran population. RA patients suffer greater mortality and morbidity from infectious diseases. This increased burden is in part related to the immune derangements of RA itself, and some of it is attributable to the immunosuppressive therapies that are used to treat RA. Herpes Zoster (HZ) reactivation is the most common opportunistic infection of treated RA patients and is about double that of the general population. HZ already has a lifetime risk of 20-30% in the general population. Until the recent approval of a recombinant zoster vaccine (RZV, brand name Shingrix) there was only the live attenuated vaccine, Zostavax. It was infrequently used in RA patients on treatment due to its contraindication in immunosuppressed individuals as it is a live virus vaccine. RZV being a subunit vaccine does not have this limitation. In addition, RZV has been found in the general adult population to be highly efficacious (>90%) even in persons over age 80. This has resulted in a significant potential opportunity to protect RA patients even on immunosuppressive therapy. Immune protection from HZ is much different than immunity to primary varicella zoster (VZV) infection (chickenpox) which is primarily antibody-mediated. Work from an innovative primate model of HZ suggests that cell-mediated immunity (CMI), specifically by CD4+ T cells, is a key for protection. All of the vaccines previously studied in RA patients have been ones that elicit protection through antibody-mediated mechanisms and not CMI. The effect of disease-modifying antirheumatic drugs (DMARDs) on vaccine immunogenicity or efficacy, in particular focused on RZV elicitation of CMI is not known. The proposed study is therefore innovative, in that they propose to determine the effect of RA and DMARD treatment on the immunogenicity of RZV. Analysis of response to RZV in RA patients proposed in this study has direct clinical relevance and translational potential. It may influence the choices of DMARDs to be utilized as there are many options for treating RA. It could provide data that supports a clinical trial using drug windowing where the treatment with DMARD is withheld transiently after vaccination to improve the response. They hypothesize that RZV will have a reduced immunogenicity in RA patients compared to non-RA controls and that RA patients on anti-metabolite synthetic DMARDs will have reduced immunogenicity more than those on biologic DMARDs such as TNFi. They will perform a laboratory blinded observational study of 100 RA patients, the overwhelming majority of whom are on DMARDs, and 100 age-matched non-rheumatology subjects to determine the difference in immunogenicity of RZV between these populations. Specific Aims: Aim 1. To determine the magnitude and differential effects of synthetic and biologic DMARD therapies on the immunogenicity of RZV in RA patients. Aim 2 To determine the mechanistic pathways of both reduced and robust vaccine specific responses to RZV using systems biology approaches and to determine the signatures that is associated with these responses in RA patients on DMARDS. Aim 3. To compare adverse event profile of RZV vaccination in RA patients to age-matched non- rheumatic disease individuals.