The COVID-19 pandemic has posed a unique challenge in the management of rheumatic diseases. Immunosuppressed patients are at an increased risk of developing severe COVID-19 and may not derive full protection from the vaccine (1-5). Thus, it is paramount that clinicians develop strategies to protect rheumatic disease patients from infection with SARS–CoV-2 and its variants.

In this letter, we describe the clinical response in a 74-year-old man with seropositive, erosive rheumatoid arthritis (RA) that was initially diagnosed in 1974. The patient is currently receiving 200 mg of hydroxychloroquine daily, 25 mg of etanercept weekly, and 20 mg of leflunomide daily. With this RA treatment regimen, low levels of disease activity have been maintained over the last 5 years.

The patient received 2 doses of the messenger RNA (mRNA) vaccine mRNA-1273 (Moderna) without interruption of his RA treatment, with the first dose administered January 18, 2021 and the second dose administered February 11, 2021. In mid-April, a semiquantitative analysis revealed a spike protein receptor-binding domain (RBD) antibody level of 53.9 units/ml (normal reference range 0–2,500), and the results of a SARS–CoV-2 anti-spike (S1/RBD) IgG test were negative. An assay designed to detect blocking of the interaction between the SARS–CoV-2 spike protein RBD and the human angiotensin-converting enzyme 2 (ACE-2) receptor demonstrated <10% blocking activity (6). The results of an interferon-γ–release assay detecting SARS–CoV-2–specific T cells were also negative (7). The patient and his care team presumed that his suboptimal response to the vaccine was due to the immunosuppressive medications he was taking at the time of vaccination.

Based on his test results, the patient obtained an additional vaccine dose on his own accord. On June 6, 2021, he received 1 dose of the viral vector SARS–CoV-2 vaccine Ad26.COV2.S (Johnson & Johnson). No side effects developed. In late June, a repeat semiquantitative analysis revealed a spike protein RBD antibody level of 2,455.0 units/ml, and the results of an S1/RBD IgG test were positive. The ACE-2 blocking assay demonstrated 90–100% blocking activity (Figure 1). The results of the interferon-γ release assay remained negative, suggesting that T cell–mediated immunity was not achieved. A blunted T cell response to the SARS–CoV-2 vaccine has been demonstrated in patients receiving medications such as methotrexate or tacrolimus, but, to our knowledge, it has not been evaluated in patients treated with leflunomide (8, 9).

In summary, we describe an immunosuppressed patient who experienced an ineffective immune response after 2 doses of an mRNA SARS–CoV-2 vaccine. The patient subsequently achieved a robust antibody response after a booster vaccination with the Johnson & Johnson SARS–CoV-2 vaccine, all while continuing treatment with RA medications. Current guidance put forth by the American College of Rheumatology (ACR) does not recommend obtaining antibody testing after vaccination, in part due to a lack of clinically meaningful cutoff values for available antibody tests (10). The US Food and Drug Administration revised the emergency use authorization on August 12, 2021 for the 2 available mRNA SARS–CoV-2 vaccines to permit a third dose for certain immunocompromised patients, and the ACR does support booster vaccination (11). Our report demonstrates the possibility of achieving humoral immunity against SARS–CoV-2 after initial failure through the use of a cross-platform booster vaccination strategy. Prior research has demonstrated that heterologous vaccination strategies may induce a more robust immune response in healthy adults (12-14). We believe future research is needed to establish relevant antibody reference values to identify patients without adequate protection against COVID-19 infection, and to understand the role of cross-platform booster vaccination when primary mRNA vaccination and/or booster vaccination fails to induce a sufficient immune response.

COVID-19 大流行给风湿性疾病的管理带来了独特的挑战。免疫抑制患者患重症 COVID-19 的风险增加，并且可能无法从疫苗中获得充分保护 ( 1-5 )。因此，临床医生制定保护风湿病患者免受 SARS-CoV-2 及其变种感染的策略至关重要。

在这封信中，我们描述了一名 74 岁男性患者的临床反应，该患者于 1974 年首次诊断出患有血清反应阳性、糜烂性类风湿性关节炎 (RA)。该患者目前每天接受 200 毫克羟氯喹治疗，每周接受 25 毫克依那西普治疗，每天 20 毫克来氟米特。通过这种 RA 治疗方案，过去 5 年中疾病活动度一直保持在较低水平。

该患者在未中断 RA 治疗的情况下接受了 2 剂信使 RNA (mRNA) 疫苗 mRNA-1273 (Moderna)，第一剂于 2021 年 1 月 18 日接种，第二剂于 2021 年 2 月 11 日接种。半定量分析显示，刺突蛋白受体结合域 (RBD) 抗体水平为 53.9 单位/ml（正常参考范围 0-2,500），并且 SARS-CoV-2 抗刺突 (S1/RBD) IgG 测试结果均为阴性。一项旨在检测 SARS-CoV-2 刺突蛋白 RBD 与人血管紧张素转换酶 2 (ACE-2) 受体之间相互作用阻断的检测显示出 <10% 阻断活性 ( 6 )。检测 SARS-CoV-2 特异性 T 细胞的干扰素-γ 释放测定结果也呈阴性 ( 7 )。患者和他的护理团队推测他对疫苗的反应不佳是由于他在接种疫苗时服用了免疫抑制药物。

根据检测结果，患者自愿额外注射了一剂疫苗。 2021 年 6 月 6 日，他接受了 1 剂病毒载体 SARS-CoV-2 疫苗 Ad26.COV2.S（强生公司）。没有出现副作用。 6月下旬，重复半定量分析显示刺突蛋白RBD抗体水平为2,455.0单位/ml，S1/RBD IgG检测结果呈阳性。 ACE-2 阻断测定显示出 90-100% 的阻断活性（图 1）。干扰素-γ释放测定的结果仍为阴性，表明未实现 T 细胞介导的免疫。在接受甲氨蝶呤或他克莫司等药物治疗的患者中，已证实 T 细胞对 SARS-CoV-2 疫苗的反应减弱，但据我们所知，尚未在接受来氟米特治疗的患者中进行评估 ( 8, 9 )。

总之，我们描述了一名免疫抑制患者在注射 2 剂 mRNA SARS-CoV-2 疫苗后出现无效免疫反应的情况。在使用强生 SARS-CoV-2 疫苗加强接种后，该患者随后获得了强劲的抗体反应，同时继续接受 RA 药物治疗。美国风湿病学会 (ACR) 目前提出的指南不建议在接种疫苗后进行抗体检测，部分原因是现有抗体检测缺乏有临床意义的临界值 ( 10 )。美国食品和药物管理局于 2021 年 8 月 12 日修订了 2 种可用 mRNA SARS-CoV-2 疫苗的紧急使用授权，允许某些免疫功能低下患者接种第三剂，并且 ACR 确实支持加强疫苗接种 ( 11 )。我们的报告表明，在最初失败后，通过使用跨平台加强疫苗接种策略，有可能实现针对 SARS-CoV-2 的体液免疫。先前的研究表明，异源疫苗接种策略可能会在健康成年人中诱导更强大的免疫反应（ 12-14 ）。我们认为，未来的研究需要建立相关的抗体参考值，以识别对 COVID-19 感染没有足够保护的患者，并了解当初次 mRNA 疫苗接种和/或加强疫苗接种未能诱导足够的免疫时，跨平台加强疫苗接种的作用回复。