Dear Editors,

Recent studies have shed light on the significant connection of SARS-CoV-2 infection with a heightened risk of experiencing a wide range of newly emerging autoimmune conditions.¹ Among others, SARS-CoV-2 has been associated with exacerbation of acute pancreatitis² and new-onset diabetes, in line with viral infection of both endocrine and exocrine pancreatic cells.³ To what extent vaccines can either cause or trigger disease activity in rare autoimmune pancreatitis (AIP) remains unclear, albeit single observational reports on post-vaccination cases of acute pancreatitis revealed no evidence for a significant association.² Moreover, AIP patients represent a cohort at risk of a severe course of COVID-19 as they commonly use immunosuppressive medication along with frequent comorbidities. Here we report on infection- or vaccination-associated complications in an at least twice SARS-CoV-2 vaccinated AIP cohort and compare the results with a healthy control group.

In this cross-sectional study (Ethical Review Board Ulm University, number 259/22 and 118/21), 30 AIP patients (16 AIP type 1/IgG4-related disease (IgG4-RD), 14 type 2) were prospectively enrolled in a questionnaire-based (Supplementary Information S7) post-vaccination interview. Baseline characteristics are shown in Table 1 and Table S1. All patients received at least two vaccinations, while 90% (n = 27) and 43% (n = 13) received a third and fourth boost, respectively. Eighty percent (n = 24) received homologous mRNA vaccine immunization, whereas six patients (20%) had a heterologous regimen with at least one conventional SARS-CoV-2 vaccine. Vaccinations started in January 2021 and ended in October 2022 and thus covered a relevant SARS-CoV-2 variant spectrum.

Most patients (n = 20, 66.7%) reported no vaccine-related side effects, while only a few (n = 4, 13.3%) reported local symptoms defined as redness and/or swelling at the injection site. At the same time, six patients (20%) complained of systemic side effects such as cough, fever, headache, aching limbs, or insomnia after the first vaccination. Comparable symptoms were noted following the second (n = 30) and the third vaccination (n = 27), with 53.3% and 52% of individuals without adverse events. Meanwhile, 20% and 26% reported local symptoms, and 26.7% and 22% reported systemic symptoms. Next, we generated an age-matched cohort of 159 healthy volunteers (Table S2) from previously published data⁴ who willingly filled a questionnaire related to SARS-CoV-2 vaccine-related side effects. Interestingly, in this twice vaccinated cohort, systemic side effects occurred slightly more often than in the AIP patients, with 31.4% after the first vaccination and 44.7% after the second vaccination. Moreover, the incidence of local reactions was notably higher, 68.6% and 58.5% after the first and second vaccinations. Among the smaller group of AIP patients who received a fourth vaccination (n = 13), side effects were even rarer, 69.2% (n = 9) had no, 23.1% (n = 3) experienced local, and only one patient reported systemic symptoms. At the timepoints of first and second vaccination, 46.7% (14/30) had received immunosuppressive therapy for AIP (Table S3). This was even higher at the time of the third (64%, 16/25) and fourth (84.6%, 11/13) vaccinations. These findings suggest that vaccine-related side effects in AIP patients are comparable to those observed in healthy individuals (Figure 1a).

Only a small number of patients reported AIP-related symptoms (pain, weight loss, jaundice) prior to their vaccinations, three before the first and four before the second and third vaccination (Figure 1b). Notably, the number of patients experiencing these symptoms did not increase in the weeks following immunization, suggesting no exacerbation of the disease due to vaccination. Overall, none of the patients reported new onset of AIP related symptoms, but two AIP type 2 patients experienced a worsening of their pre-existing condition. One suffered from abdominal pain and the other one additionally from weight loss, each under medication with prednisolone. In the group of patients who received four vaccine shots, there was no documented deterioration of AIP-related symptoms (Figure 1b, Tables S4 and S5). Importantly, hospitalization was not required for any of these cases post-vaccination. In summary, these findings indicate that SARS-CoV-2 vaccines do not appear to influence either the number of patients affected by AIP-related symptoms or the severity of AIP.

Seventeen patients had confirmed SARS-CoV-2 infection within a median of 6 months of the last vaccination. None of the patients underwent repetitive infections. One of these patients suffered from a severe course with the need for hospitalization (due to pneumonia). Three patients received COVID-19 infection-related therapy. Symptoms were similar (e.g., upper respiratory tract symptoms, fever, see Table S6) to be usually reported in the general population,⁵ and lasted for a median of 8 days (range 2–15). In conclusion, vaccinated AIP patients are neither prone to infection nor have a severe disease course upon COVID-19.

With the next wave of SARS-CoV-2 infections on the horizon and the ongoing prevalence of this viral disease, our data demonstrate the safety of mRNA-based SARS-CoV-2 vaccines for the at-risk population of AIP patients. In our study involving 30 AIP type 1/IgG4-RD and AIP type 2 patients, we found that SARS-Cov-2 vaccination during the recent pandemic did not exacerbate the severity of AIP. Firstly, the specific symptoms following SARS-CoV-2 vaccination were not worsened in patients with AIP. In fact, the vaccines' effects in AIP patients closely resembled those in healthy individuals. Secondly, the vaccination against SARS-CoV-2 did not lead to an increased disease severity, as the majority of patients experienced no worsening of their condition after vaccination. Thirdly, the susceptibility to acquire a SARS-CoV-2 infection was similar between AIP patients and healthy individuals. Collectively, this study indicates that the administration of SARS-CoV-2 vaccines is a safe option for AIP patients.

亲爱的编辑们，

最近的研究揭示了 SARS-CoV-2 感染与罹患多种新出现的自身免疫性疾病的风险增加之间的显着联系。^{1其中，SARS-CoV-2 与急性胰腺炎2}和新发糖尿病的恶化有关，与内分泌和外分泌胰腺细胞的病毒感染一致。 ³疫苗在多大程度上会导致或触发罕见自身免疫性胰腺炎 (AIP) 的疾病活动尚不清楚，尽管对疫苗接种后急性胰腺炎病例的单一观察报告显示没有证据表明存在显着关联。²此外，AIP 患者是面临严重 COVID-19 病程风险的人群，因为他们通常使用免疫抑制药物并伴有频繁的合并症。在这里，我们报告了至少两次接种 SARS-CoV-2 疫苗的 AIP 队列中与感染或疫苗接种相关的并发症，并将结果与​​健康对照组进行比较。

在这项横断面研究中（乌尔姆大学伦理审查委员会，编号 259/22 和 118/21），30 名 AIP 患者（16 名 AIP 1 型/IgG4 相关疾病 (IgG4-RD)，14 名 2 型）前瞻性入组基于问卷（补充信息 S7）的疫苗接种后访谈。基线特征如表 1 和表 S1 所示。所有患者都至少接种了两次疫苗，其中 90% ( n  = 27) 和 43% ( n  = 13) 分别接受了第三次和第四次加强疫苗接种。 80% ( n  = 24) 接受了同源 mRNA 疫苗免疫，而 6 名患者 (20%) 接受了至少一种常规 SARS-CoV-2 疫苗的异源治疗方案。疫苗接种于 2021 年 1 月开始，于 2022 年 10 月结束，因此涵盖了相关的 SARS-CoV-2 变异谱。

大多数患者（n  = 20，66.7%）报告没有与疫苗相关的副作用，而只有少数（n  = 4，13.3%）报告有注射部位发红和/或肿胀的局部症状。与此同时，6名患者（20%）在第一次接种疫苗后抱怨出现咳嗽、发烧、头痛、四肢酸痛或失眠等全身副作用。第二次（ n  = 30）和第三次疫苗接种（n = 27）后出现了类似的症状 ，分别有 53.3% 和 52% 的人没有出现不良事件。与此同时，20%和26%的人报告了局部症状，26.7%和22%的人报告了全身症状。接下来，我们根据之前发布的数据⁴生成了由 159 名健康志愿者组成的年龄匹配队列（表 S2），这些志愿者自愿填写了与 SARS-CoV-2 疫苗相关副作用相关的调查问卷。有趣的是，在这两次接种疫苗的队列中，全身性副作用的发生率略高于 AIP 患者，第一次接种疫苗后为 31.4%，第二次接种疫苗后为 44.7%。而且，第一次和第二次接种后局部反应的发生率明显较高，分别为68.6%和58.5%。在接受第四次疫苗接种的一小部分 AIP 患者中 ( n  = 13)，副作用更加罕见，69.2% ( n  = 9) 没有出现副作用，23.1% ( n  = 3) 出现局部副作用，只有 1 名患者报告出现全身副作用症状。在第一次和第二次疫苗接种时，46.7% (14/30) 接受了 AIP 免疫抑制治疗（表 S3）。在第三次（64%，16/25）和第四次（84.6%，11/13）疫苗接种时这一比例甚至更高。这些发现表明，AIP 患者中与疫苗相关的副作用与健康个体中观察到的副作用相当（图 1a）。

只有少数患者在接种疫苗前报告了 AIP 相关症状（疼痛、体重减轻、黄疸），其中 3 例在第一次疫苗接种前报告，4 例在第二次和第三次疫苗接种前报告（图 1b）。值得注意的是，在免疫接种后几周内，出现这些症状的患者数量没有增加，表明疫苗接种不会导致疾病恶化。总体而言，没有患者报告新出现 AIP 相关症状，但两名 AIP 2 型患者的原有病情恶化。一名患者出现腹痛，另一名患者体重减轻，两人均接受泼尼松龙治疗。在接受四次疫苗注射的患者组中，没有记录到 AIP 相关症状恶化（图 1b，表 S4 和 S5）。重要的是，这些病例在接种疫苗后都不需要住院治疗。总之，这些发现表明 SARS-CoV-2 疫苗似乎不会影响受 AIP 相关症状影响的患者数量或 AIP 的严重程度。

17 名患者在最后一次疫苗接种后平均 6 个月内确诊感染 SARS-CoV-2。没有患者出现重复感染。其中一名患者病情严重，需要住院治疗（因肺炎）。三名患者接受了 COVID-19 感染相关治疗。症状与普通人群中通常报告的症状相似（例如上呼吸道症状、发烧，参见表 S6）⁵，持续时间中位数为 8 天（范围 2-15）。总之，接种疫苗的 AIP 患者既不容易感染 COVID-19，也不会出现严重的病程。

随着下一波 SARS-CoV-2 感染即将到来以及这种病毒性疾病的持续流行，我们的数据证明了基于 mRNA 的 SARS-CoV-2 疫苗对 AIP 患者高危人群的安全性。在我们涉及 30 名 AIP 1 型/IgG4-RD 和 AIP 2 型患者的研究中，我们发现最近大流行期间接种 SARS-Cov-2 疫苗并没有加剧 AIP 的严重程度。首先，AIP 患者接种 SARS-CoV-2 疫苗后的具体症状并未恶化。事实上，疫苗对 AIP 患者的效果与健康人的效果非常相似。其次，针对 SARS-CoV-2 的疫苗接种并没有导致疾病严重程度增加，因为大多数患者在接种疫苗后病情没有恶化。第三，AIP 患者和健康个体感染 SARS-CoV-2 的易感性相似。总的来说，这项研究表明，接种 SARS-CoV-2 疫苗对于 AIP 患者来说是一种安全的选择。