Background

Immunosuppressive treatments inhibit vaccine-induced immunity against SARS-CoV-2. We evaluated whether a 2-week interruption of methotrexate treatment immediately after the COVID-19 vaccine booster improved antibody responses against the S1 receptor-binding domain (S1-RBD) of the SARS-CoV-2 spike protein compared with uninterrupted treatment in patients with immune-mediated inflammatory diseases.

Methods

We did an open-label, prospective, two-arm, parallel-group, multicentre, randomised, controlled, superiority trial in 26 hospitals in the UK. We recruited adults from rheumatology and dermatology clinics who had been diagnosed with an immune-mediated inflammatory disease (eg, rheumatoid arthritis, psoriasis with or without arthritis, axial spondyloarthritis, atopic dermatitis, polymyalgia rheumatica, and systemic lupus erythematosus) and who were taking low-dose weekly methotrexate (≤25 mg per week) for at least 3 months. Participants also had to have received two primary vaccine doses from the UK COVID-19 vaccination programme. We randomly assigned the participants (1:1), using a centralised validated computer randomisation program, to suspend methotrexate treatment for 2 weeks immediately after their COVID-19 booster (suspend methotrexate group) or to continue treatment as usual (continue methotrexate group). Participants, investigators, clinical research staff, and data analysts were unmasked, while researchers doing the laboratory analyses were masked to group assignment. The primary outcome was S1-RBD antibody titres 4 weeks after receiving the COVID-19 booster vaccine dose, assessed in the intention-to-treat population. This trial is registered with ISRCT, ISRCTN11442263; following the pre-planned interim analysis, recruitment was stopped early.

Findings

Between Sept 30, 2021 and March 3, 2022, we recruited 340 participants, of whom 254 were included in the interim analysis and had been randomly assigned to one of the two groups: 127 in the continue methotrexate group and 127 in the suspend methotrexate group. Their mean age was 59·1 years, 155 (61%) were female, 130 (51%) had rheumatoid arthritis, and 86 (34%) had psoriasis with or without arthritis. After 4 weeks, the geometric mean S1-RBD antibody titre was 22 750 U/mL (95% CI 19 314–26 796) in the suspend methotrexate group and 10 798 U/mL (8970–12 997) in the continue methotrexate group, with a geometric mean ratio (GMR) of 2·19 (95% CI 1·57–3·04; p<0·0001; mixed-effects model). The increased antibody response in the suspend methotrexate group was consistent across methotrexate dose, administration route, type of immune-mediated inflammatory disease, age, primary vaccination platform, and history of SARS-CoV-2 infection. There were no intervention-related serious adverse events.

Interpretation

A 2-week interruption of methotrexate treatment for people with immune-mediated inflammatory diseases resulted in enhanced boosting of antibody responses after COVID-19 vaccination. This intervention is simple, low-cost, and easy to implement, and could potentially translate to increased vaccine efficacy and duration of protection for susceptible groups.

Funding

National Institute for Health and Care Research.

中文翻译：

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甲氨蝶呤治疗中断 2 周与继续治疗对患有炎症的成人 COVID-19 加强疫苗免疫力的影响（VROOM 研究）：一项随机、开放标签、优效性试验

 背景

免疫抑制治疗会抑制疫苗诱导的针对 SARS-CoV-2 的免疫力。我们评估了在接受 COVID-19 疫苗加强接种后立即中断甲氨蝶呤治疗 2 周是否可以改善针对 SARS-CoV-2 刺突蛋白 S1 受体结合域 (S1-RBD) 的抗体反应，与不间断治疗相比，免疫介导的炎症性疾病。

 方法

我们在英国 26 家医院进行了一项开放标签、前瞻性、双臂、平行组、多中心、随机、对照、优效性试验。我们从风湿病学和皮肤病学诊所招募了被诊断患有免疫介导的炎症性疾病（例如类风湿性关节炎、伴或不伴关节炎的银屑病、中轴型脊柱关节炎、特应性皮炎、风湿性多肌痛和系统性红斑狼疮）且正在服用低剂量药物的成年人。 -每周服用甲氨蝶呤（每周≤25毫克），持续至少3个月。参与者还必须从英国 COVID-19 疫苗接种计划中接种两剂初级疫苗。我们使用集中验证的计算机随机化程序，对参与者进行随机分配 (1:1)，在其接受 COVID-19 加强免疫后立即暂停甲氨蝶呤治疗 2 周（暂停甲氨蝶呤组）或照常继续治疗（继续甲氨蝶呤组）。参与者、研究人员、临床研究人员和数据分析师都被揭露，而进行实验室分析的研究人员则被隐藏到分组分配中。主要结局是在意向治疗人群中评估接受 COVID-19 加强疫苗剂量 4 周后的 S1-RBD 抗体滴度。该试验已在 ISRCT 注册，ISRCTN11442263；经过预先计划的中期分析后，招募工作提前停止。

 发现

2021年9月30日至2022年3月3日期间，我们招募了340名参与者，其中254名被纳入中期分析，并被随机分配到两组之一：继续甲氨蝶呤组127名，暂停甲氨蝶呤组127名。他们的平均年龄为 59·1 岁，其中 155 人 (61%) 为女性，130 人 (51%) 患有类风湿性关节炎，86 人 (34%) 患有伴有或不伴有关节炎的银屑病。 4周后，暂停甲氨蝶呤组的几何平均S1-RBD抗体滴度为22 750 U/mL (95% CI 19 314–26 796)，继续甲氨蝶呤组为10 798 U/mL (8970–12 997) ，几何平均比 (GMR) 为 2·19（95% CI 1·57–3·04；p<0·0001；混合效应模型）。暂停甲氨蝶呤组中抗体反应的增加在甲氨蝶呤剂量、给药途径、免疫介导的炎症疾病类型、年龄、主要疫苗接种平台和 SARS-CoV-2 感染史方面是一致的。没有发生与干预相关的严重不良事件。

 解释

对免疫介导的炎症性疾病患者进行为期 2 周的甲氨蝶呤治疗中断，可导致接种 COVID-19 疫苗后抗体反应增强。这种干预措施简单、成本低且易于实施，并有可能提高疫苗功效和对易感人群的保护持续时间。

 资金

国家健康与护理研究所。