Supplementary Material for: Swallowed topical tacrolimus induces clinical and histological remission in a subset of patients with severe lymphocytic esophagitis

Introduction: Lymphocytic esophagitis (LyE) represents a chronic inflammatory disease of the esophagus with low response rates to topical steroids. Thus, novel treatment options such as swallowed topical tacrolimus, particularly for refractory cases, are urgently needed. Methods: We retrospectively analyzed patients with LyE enrolled in the Swiss EoE database that received treatment with a swallowed tacrolimus syrup (1mg bid). We compared clinical (VAS 0-10), endoscopic (visual analogue score VAS, Endoscopic Reference Score EREFS) and histological (peak lymphocyte count) disease activity before vs after treatment. Results: Out of 17 LyE patients, we identified a total of 7 patients undergoing tacrolimus treatment (4 males, median age 71.3y, IQR, 61.3-76.5, median diagnostic delay of 51.0 months, IQR 24.5-62.0). Six patients had been previously treated with PPI, five with topical and/or systemic steroids. All patients were treated with topical tacrolimus corresponding to 1mg bid (for a median of 13 weeks, IQR 11-15). All Patients had clinically, and histologically active disease at baseline. Topical tacrolimus treatment resulted in histological remission (<30 lymphocytes/hpf) in 3/7 patients (42.9%), while 4/7 patients achieved symptomatic remission (VAS for dysphagia ≤2, 57.1%). Overall, clinical (VAS 5 vs 2, p=0.0625) and endoscopic activity (VAS 5 vs 2, p=0.0625, and EREFS 3 vs 2, p=0.125) decreased. Measurement of tacrolimus trough levels in 4/7 patients (range 2.1-3.9ug/L) revealed some degree of systemic absorption. Mild adverse events to the tacrolimus treatment were seen in two patients (esophageal candidiasis, hyposensitivity around lips). No impact on kidney function was observed during the treatment period. Conclusion: Topical tacrolimus appears to be a potential treatment option for severe LyE, particularly after failure of PPI and/or topical steroids. Further studies are needed, in particular regarding the optimal galenic formulation to avoid systemic absorption.引言：淋巴细胞性食管炎（Lymphocytic esophagitis, LyE）是一种食管慢性炎症性疾病，局部类固醇治疗应答率较低，因此亟需开发新型治疗方案，例如经口吞服的局部用他克莫司制剂，尤其适用于难治性病例。 研究方法：本研究回顾性分析了瑞士嗜酸性粒细胞性食管炎（Eosinophilic Esophagitis, EoE）数据库中纳入的接受经口吞服他克莫司糖浆（1mg，每日两次）治疗的淋巴细胞性食管炎患者。对比了治疗前后的临床（视觉模拟评分（Visual Analogue Score, VAS）0~10）、内镜（视觉模拟评分VAS、内镜参考评分（Endoscopic Reference Score, EREFS））及组织学（淋巴细胞峰值计数）疾病活动度。 研究结果：本研究共纳入17例淋巴细胞性食管炎患者，其中7例接受了他克莫司治疗（4例男性，中位年龄71.3岁，四分位间距61.3~76.5岁；中位诊断延迟51.0个月，四分位间距24.5~62.0个月）。6例患者既往接受过质子泵抑制剂（Proton Pump Inhibitor, PPI）治疗，5例接受过局部或全身类固醇治疗。所有患者均接受1mg每日两次的局部他克莫司治疗，中位治疗时长13周，四分位间距11~15周。所有患者基线时均存在临床及组织学活动性疾病。局部他克莫司治疗后，3/7例患者（42.9%）达到组织学缓解（淋巴细胞计数<30个/高倍视野（high power field, hpf）），4/7例患者（57.1%）达到症状缓解（吞咽困难VAS评分≤2）。整体而言，临床活动度（VAS评分从5降至2，p=0.0625）、内镜活动度（VAS评分从5降至2，p=0.0625；EREFS评分从3降至2，p=0.125）均有所下降。对7例患者中的4例进行他克莫司谷浓度检测（范围2.1~3.9μg/L），结果显示存在一定程度的全身吸收。2例患者出现与他克莫司治疗相关的轻度不良反应（食管念珠菌病、口唇周围感觉减退）。治疗期间未观察到肾功能受到影响。 研究结论：局部他克莫司有望成为重度淋巴细胞性食管炎的潜在治疗方案，尤其适用于质子泵抑制剂和/或局部类固醇治疗失败的患者。未来仍需开展进一步研究，尤其是优化药剂学配方以避免全身吸收。