杜匹单抗可改善嗜酸性粒细胞食管炎 12 周治疗前的临床和组织学特征

IF 4.6 2区 医学 Q2 ALLERGY
Twan Sia, Amanda Miller, Leeon Bacchus, Jennie Young, Aditya P. Narayan, Rachel Solecki, Jerry Fu, Yuting Jiang, Raisa Khuda, Stanley Liu, Kathleen Love, Shibani Mallik, Amina Sara Matmatte, Paige McDonald, Tanvi Telukunta, Alyssa Roby, Saad Shami, Michelle Zheng, Madison Headen, John Leung
{"title":"杜匹单抗可改善嗜酸性粒细胞食管炎 12 周治疗前的临床和组织学特征","authors":"Twan Sia,&nbsp;Amanda Miller,&nbsp;Leeon Bacchus,&nbsp;Jennie Young,&nbsp;Aditya P. Narayan,&nbsp;Rachel Solecki,&nbsp;Jerry Fu,&nbsp;Yuting Jiang,&nbsp;Raisa Khuda,&nbsp;Stanley Liu,&nbsp;Kathleen Love,&nbsp;Shibani Mallik,&nbsp;Amina Sara Matmatte,&nbsp;Paige McDonald,&nbsp;Tanvi Telukunta,&nbsp;Alyssa Roby,&nbsp;Saad Shami,&nbsp;Michelle Zheng,&nbsp;Madison Headen,&nbsp;John Leung","doi":"10.1002/clt2.12333","DOIUrl":null,"url":null,"abstract":"<p>Dupilumab is a human monoclonal antibody against interleukin-4 receptor alpha subunit. Dupilumab is an approved treatment for inducing remission of eosinophilic esophagitis (EoE).<span><sup>1</sup></span> EoE histologic remission with dupilumab has only been demonstrated in patients after at least 12 weeks of treatment.<span><sup>2-6</sup></span> Current guidelines recommend waiting for histologic re-evaluation of EoE until after 20–24 weeks of dupilumab.<span><sup>1</sup></span> It is unknown if increasing dupilumab treatment length improves its efficacy. Because histologic re-evaluation of EoE requires invasive biopsies, and inducing remission of EoE is important to prevent progressive esophageal damage, research investigating the effects of dupilumab on EoE prior to 12 weeks of treatment is warranted.</p><p>We conducted a retrospective study at a single medical clinic. The electronic medical record was searched between 2017 and 2023 using International Classifications of Disease, 10th revision code K20.0 eosinophilic esophagitis. We excluded patients who had (1) never started dupilumab; (2) no histologic confirmation of EoE defined by ≥ 15 eos/hpf; or (3) no histologic re-evaluation of EoE while on dupilumab. Histologic evaluation of EoE assessed at least 2 biopsies each of the proximal, middle, and distal esophagus. Endpoints were peak eosinophil counts (eosinophils per high-power field; eos/hpf), EoE endoscopic reference scores (EREFS), and a composite symptom score in which each symptom (dysphagia, food impaction/choking, regurgitation/vomiting, heartburn/chest pain, and abdominal pain) was graded (0 = absent, 1 = mild, 2 = moderate, and 3 = severe) and summed. This study was deemed exempt from institutional review board approval by the WCG IRB.</p><p>From the electronic medical record, 658 patients with EoE were identified, of which 534 had never initiated dupilumab, 6 did not have histologic confirmation of EoE, and 39 did not have a repeat histologic evaluation after dupilumab initiation. Therefore, 79 patients were included in this study. The median age was 27.6 years (Q1 to Q3, 21.8–36.1), 48 patients (60.8%) were male, and 12 patients (15.2%) were pediatric (Table 1). Sixty patients (75.9%) had an atopic comorbidity, including allergic rhinitis (43 patients, 54.4%), asthma (27 patients, 34.2%), atopic dermatitis (13 patients, 16.5%), and food allergies (30 patients, 38.0%).</p><p>Patients were on dupilumab for median 22.7 weeks (Q1 to Q3, 16–26.7). Dosages included 300 mg every week (71 patients, 89.9%), 300 mg every other week with a loading dose of 600 mg for atopic dermatitis (7 patients, 8.9%), and 200 mg every other week with a loading dose of 400 mg for atopic dermatitis (1 patient, 1.3%).</p><p>Of 79 patients, 12 patients (15.2%) were on dupilumab for 0–12 weeks. Patients on dupilumab for 0–12 weeks had a median composite symptom score of 5.5 (Q1 to Q3, 4–6), which significantly decreased to 0 (Q1 to Q3, 0–1; Wilcoxon matched-pairs signed rank test, <i>p</i> = 0.000488) on dupilumab. Median peak eosinophil counts in patients on dupilumab for 0–12 weeks significantly decreased from 44.5 eos/hpf (Q1 to Q3, 32.5–53.5) at baseline to 2 eos/hpf (Q1 to Q3, 0–15.5; Wilcoxon matched-pairs signed rank test, <i>p</i> = 0.000977) on dupilumab. Endoscopic reference scores were only available for 15 patients (19%) in our cohort. In patients on dupilumab for 0–12 weeks, EREFS did not significantly decrease from baseline (median, 2; Q1 to Q3, 1–4) versus on dupilumab (median, 0; Q1 to Q3, 0–1.5; Wilcoxon matched-pairs signed rank test, <i>p</i> = 0.25). However, change in EREFS was also insignificant in patients on dupilumab for 12–24 weeks (<i>p</i> = 0.13), and greater than 24 weeks (<i>p</i> = 0.25), suggesting insignificance may be due to low <i>n</i>. Therefore, dupilumab may induce histologic remission and clinical benefit in patients prior to 12 weeks of treatment.</p><p>There were no significant differences in changes in median composite symptom score (<i>p</i> = 0.1350), peak eosinophil count (<i>p</i> = 0.0746); and EREFS (<i>p</i> = 0.8771) between patients on dupilumab between 0 and 12, 12–24, and greater than 24 weeks (Table 1). In terms of histologic response, 9 patients (75%) were histologically responsive in the 0–12 weeks group, 28 patients (73.7%) were responsive in the 12–24 weeks group, and 26 patients (89.7%) were responsive in the longer than 24 weeks group. There was no significant difference in the proportion of histologic response between the 3 groups (Fisher's exact test, <i>p</i> = 0.2569).</p><p>Subanalysis in 7 patients with &gt;1 histologic evaluations on dupilumab is summarized in Figure 1. Three patients who were histologically unresponsive to dupilumab at early timepoints (Patient 4 between 0 and 12 weeks, Patient 3 and 5 between 12 and 24 weeks) were responsive after 24 weeks of treatment without addition of combination therapy. In contrast, Patient 1 was unresponsive at 0–12 weeks of dupilumab and remained unresponsive after over 24 weeks of dupilumab. Patient 2 and 6 had started combination therapy with omeprazole or mometasone, respectively. Therefore, their histologic remission may be due to combination therapy. Our subanalysis suggests that certain patients who are histologically unresponsive at early EGDs may or may not respond at later timepoints. Further research is needed to predict which patients benefit from repeat EGDs.</p><p>In conclusion, dupilumab induced histologic remission and clinical benefit before 12 weeks of treatment, and there were no significant differences in clinical, histologic, or endoscopic changes between patients on dupilumab for 0–12 weeks, 2–24 weeks, and greater than 24 weeks. It may be beneficial to identify treatment response earlier than previous guidelines indicate.<span><sup>1</sup></span> Further research should investigate the appropriate window of treatment before repeat EGDs are performed.</p><p><b>Twan Sia</b>: Conceptualization (equal); data curation (equal); formal analysis (equal); investigation (equal); methodology (equal); validation (equal); visualization (equal); writing—original draft (equal); writing—review and editing (equal). <b>Amanda Miller</b>: Data curation (equal); formal analysis (equal); validation (equal); visualization (equal); writing—original draft (equal); writing—review and editing (equal). <b>Leeon Bacchus</b>: Data curation (equal); formal analysis (equal); validation (equal); visualization (equal); writing—original draft (equal); writing—review and editing (equal). <b>Jennie Young</b>: Data curation (equal); validation (equal); visualization (equal); writing—review and editing (equal). <b>Aditya P. Narayan</b>: Data curation (equal); validation (equal); visualization (equal); writing—review and editing (equal). <b>Rachel Solecki</b>: Investigation (equal); validation (equal); writing—review and editing (equal). <b>Jerry Fu</b>: Investigation (equal); validation (equal); writing—review and editing (equal). <b>Yuting Jiang</b>: Investigation (equal); validation (equal); writing—review and editing (equal). <b>Raisa Khuda</b>: Investigation (equal); validation (equal); writing—review and editing (equal). <b>Stanley Liu</b>: Investigation (equal); validation (equal); writing—review and editing (equal). <b>Kathleen Love</b>: Investigation (equal); validation (equal); writing—review and editing (equal). <b>Shibani Mallik</b>: Investigation (equal); validation (equal); writing—review and editing (equal). <b>Amina Sara Matmatte</b>: Investigation (equal); validation (equal); writing—review and editing (equal). <b>Paige McDonald</b>: Investigation (equal); validation (equal); writing—review and editing (equal). <b>Tanvi Telukunta</b>: Investigation (equal); validation (equal); writing—review and editing (equal). <b>Alyssa Roby</b>: Investigation (equal); validation (equal); writing—review and editing (equal). <b>Saad Shami</b>: Investigation (equal); validation (equal); writing—review and editing (equal). <b>Michelle Zheng</b>: Investigation (equal); validation (equal); writing—review and editing (equal). <b>Madison Headen</b>: Investigation (equal); validation (equal); writing—review and editing (equal). <b>John Leung</b>: Conceptualization (equal); methodology (equal); project administration (equal); resources (equal); supervision (equal); writing—review and editing (equal).</p><p>John Leung: is a consultant for Devine; Millimet and Branch Professional Education; Sanofi; Huron Consulting Services LLC; Takeda; Ribon Therapeutics; Tegus; Slingshot; Guidepoint; Cowen; AstraZeneca; Regeneron; and AbbVie. None of the other authors have relevant conflicts of interests to disclose.</p><p>This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.</p>","PeriodicalId":10334,"journal":{"name":"Clinical and Translational Allergy","volume":null,"pages":null},"PeriodicalIF":4.6000,"publicationDate":"2024-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/clt2.12333","citationCount":"0","resultStr":"{\"title\":\"Dupilumab improves clinical and histologic features of eosinophilic esophagitis prior to 12 weeks of treatment\",\"authors\":\"Twan Sia,&nbsp;Amanda Miller,&nbsp;Leeon Bacchus,&nbsp;Jennie Young,&nbsp;Aditya P. Narayan,&nbsp;Rachel Solecki,&nbsp;Jerry Fu,&nbsp;Yuting Jiang,&nbsp;Raisa Khuda,&nbsp;Stanley Liu,&nbsp;Kathleen Love,&nbsp;Shibani Mallik,&nbsp;Amina Sara Matmatte,&nbsp;Paige McDonald,&nbsp;Tanvi Telukunta,&nbsp;Alyssa Roby,&nbsp;Saad Shami,&nbsp;Michelle Zheng,&nbsp;Madison Headen,&nbsp;John Leung\",\"doi\":\"10.1002/clt2.12333\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>Dupilumab is a human monoclonal antibody against interleukin-4 receptor alpha subunit. Dupilumab is an approved treatment for inducing remission of eosinophilic esophagitis (EoE).<span><sup>1</sup></span> EoE histologic remission with dupilumab has only been demonstrated in patients after at least 12 weeks of treatment.<span><sup>2-6</sup></span> Current guidelines recommend waiting for histologic re-evaluation of EoE until after 20–24 weeks of dupilumab.<span><sup>1</sup></span> It is unknown if increasing dupilumab treatment length improves its efficacy. Because histologic re-evaluation of EoE requires invasive biopsies, and inducing remission of EoE is important to prevent progressive esophageal damage, research investigating the effects of dupilumab on EoE prior to 12 weeks of treatment is warranted.</p><p>We conducted a retrospective study at a single medical clinic. The electronic medical record was searched between 2017 and 2023 using International Classifications of Disease, 10th revision code K20.0 eosinophilic esophagitis. We excluded patients who had (1) never started dupilumab; (2) no histologic confirmation of EoE defined by ≥ 15 eos/hpf; or (3) no histologic re-evaluation of EoE while on dupilumab. Histologic evaluation of EoE assessed at least 2 biopsies each of the proximal, middle, and distal esophagus. Endpoints were peak eosinophil counts (eosinophils per high-power field; eos/hpf), EoE endoscopic reference scores (EREFS), and a composite symptom score in which each symptom (dysphagia, food impaction/choking, regurgitation/vomiting, heartburn/chest pain, and abdominal pain) was graded (0 = absent, 1 = mild, 2 = moderate, and 3 = severe) and summed. This study was deemed exempt from institutional review board approval by the WCG IRB.</p><p>From the electronic medical record, 658 patients with EoE were identified, of which 534 had never initiated dupilumab, 6 did not have histologic confirmation of EoE, and 39 did not have a repeat histologic evaluation after dupilumab initiation. Therefore, 79 patients were included in this study. The median age was 27.6 years (Q1 to Q3, 21.8–36.1), 48 patients (60.8%) were male, and 12 patients (15.2%) were pediatric (Table 1). Sixty patients (75.9%) had an atopic comorbidity, including allergic rhinitis (43 patients, 54.4%), asthma (27 patients, 34.2%), atopic dermatitis (13 patients, 16.5%), and food allergies (30 patients, 38.0%).</p><p>Patients were on dupilumab for median 22.7 weeks (Q1 to Q3, 16–26.7). Dosages included 300 mg every week (71 patients, 89.9%), 300 mg every other week with a loading dose of 600 mg for atopic dermatitis (7 patients, 8.9%), and 200 mg every other week with a loading dose of 400 mg for atopic dermatitis (1 patient, 1.3%).</p><p>Of 79 patients, 12 patients (15.2%) were on dupilumab for 0–12 weeks. Patients on dupilumab for 0–12 weeks had a median composite symptom score of 5.5 (Q1 to Q3, 4–6), which significantly decreased to 0 (Q1 to Q3, 0–1; Wilcoxon matched-pairs signed rank test, <i>p</i> = 0.000488) on dupilumab. Median peak eosinophil counts in patients on dupilumab for 0–12 weeks significantly decreased from 44.5 eos/hpf (Q1 to Q3, 32.5–53.5) at baseline to 2 eos/hpf (Q1 to Q3, 0–15.5; Wilcoxon matched-pairs signed rank test, <i>p</i> = 0.000977) on dupilumab. Endoscopic reference scores were only available for 15 patients (19%) in our cohort. In patients on dupilumab for 0–12 weeks, EREFS did not significantly decrease from baseline (median, 2; Q1 to Q3, 1–4) versus on dupilumab (median, 0; Q1 to Q3, 0–1.5; Wilcoxon matched-pairs signed rank test, <i>p</i> = 0.25). However, change in EREFS was also insignificant in patients on dupilumab for 12–24 weeks (<i>p</i> = 0.13), and greater than 24 weeks (<i>p</i> = 0.25), suggesting insignificance may be due to low <i>n</i>. Therefore, dupilumab may induce histologic remission and clinical benefit in patients prior to 12 weeks of treatment.</p><p>There were no significant differences in changes in median composite symptom score (<i>p</i> = 0.1350), peak eosinophil count (<i>p</i> = 0.0746); and EREFS (<i>p</i> = 0.8771) between patients on dupilumab between 0 and 12, 12–24, and greater than 24 weeks (Table 1). In terms of histologic response, 9 patients (75%) were histologically responsive in the 0–12 weeks group, 28 patients (73.7%) were responsive in the 12–24 weeks group, and 26 patients (89.7%) were responsive in the longer than 24 weeks group. There was no significant difference in the proportion of histologic response between the 3 groups (Fisher's exact test, <i>p</i> = 0.2569).</p><p>Subanalysis in 7 patients with &gt;1 histologic evaluations on dupilumab is summarized in Figure 1. Three patients who were histologically unresponsive to dupilumab at early timepoints (Patient 4 between 0 and 12 weeks, Patient 3 and 5 between 12 and 24 weeks) were responsive after 24 weeks of treatment without addition of combination therapy. In contrast, Patient 1 was unresponsive at 0–12 weeks of dupilumab and remained unresponsive after over 24 weeks of dupilumab. Patient 2 and 6 had started combination therapy with omeprazole or mometasone, respectively. Therefore, their histologic remission may be due to combination therapy. Our subanalysis suggests that certain patients who are histologically unresponsive at early EGDs may or may not respond at later timepoints. Further research is needed to predict which patients benefit from repeat EGDs.</p><p>In conclusion, dupilumab induced histologic remission and clinical benefit before 12 weeks of treatment, and there were no significant differences in clinical, histologic, or endoscopic changes between patients on dupilumab for 0–12 weeks, 2–24 weeks, and greater than 24 weeks. It may be beneficial to identify treatment response earlier than previous guidelines indicate.<span><sup>1</sup></span> Further research should investigate the appropriate window of treatment before repeat EGDs are performed.</p><p><b>Twan Sia</b>: Conceptualization (equal); data curation (equal); formal analysis (equal); investigation (equal); methodology (equal); validation (equal); visualization (equal); writing—original draft (equal); writing—review and editing (equal). <b>Amanda Miller</b>: Data curation (equal); formal analysis (equal); validation (equal); visualization (equal); writing—original draft (equal); writing—review and editing (equal). <b>Leeon Bacchus</b>: Data curation (equal); formal analysis (equal); validation (equal); visualization (equal); writing—original draft (equal); writing—review and editing (equal). <b>Jennie Young</b>: Data curation (equal); validation (equal); visualization (equal); writing—review and editing (equal). <b>Aditya P. Narayan</b>: Data curation (equal); validation (equal); visualization (equal); writing—review and editing (equal). <b>Rachel Solecki</b>: Investigation (equal); validation (equal); writing—review and editing (equal). <b>Jerry Fu</b>: Investigation (equal); validation (equal); writing—review and editing (equal). <b>Yuting Jiang</b>: Investigation (equal); validation (equal); writing—review and editing (equal). <b>Raisa Khuda</b>: Investigation (equal); validation (equal); writing—review and editing (equal). <b>Stanley Liu</b>: Investigation (equal); validation (equal); writing—review and editing (equal). <b>Kathleen Love</b>: Investigation (equal); validation (equal); writing—review and editing (equal). <b>Shibani Mallik</b>: Investigation (equal); validation (equal); writing—review and editing (equal). <b>Amina Sara Matmatte</b>: Investigation (equal); validation (equal); writing—review and editing (equal). <b>Paige McDonald</b>: Investigation (equal); validation (equal); writing—review and editing (equal). <b>Tanvi Telukunta</b>: Investigation (equal); validation (equal); writing—review and editing (equal). <b>Alyssa Roby</b>: Investigation (equal); validation (equal); writing—review and editing (equal). <b>Saad Shami</b>: Investigation (equal); validation (equal); writing—review and editing (equal). <b>Michelle Zheng</b>: Investigation (equal); validation (equal); writing—review and editing (equal). <b>Madison Headen</b>: Investigation (equal); validation (equal); writing—review and editing (equal). <b>John Leung</b>: Conceptualization (equal); methodology (equal); project administration (equal); resources (equal); supervision (equal); writing—review and editing (equal).</p><p>John Leung: is a consultant for Devine; Millimet and Branch Professional Education; Sanofi; Huron Consulting Services LLC; Takeda; Ribon Therapeutics; Tegus; Slingshot; Guidepoint; Cowen; AstraZeneca; Regeneron; and AbbVie. None of the other authors have relevant conflicts of interests to disclose.</p><p>This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.</p>\",\"PeriodicalId\":10334,\"journal\":{\"name\":\"Clinical and Translational Allergy\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":4.6000,\"publicationDate\":\"2024-01-17\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1002/clt2.12333\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Clinical and Translational Allergy\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1002/clt2.12333\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"ALLERGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Clinical and Translational Allergy","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/clt2.12333","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"ALLERGY","Score":null,"Total":0}
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摘要

杜比鲁单抗是一种针对白细胞介素-4 受体α亚基的人类单克隆抗体。目前的指南建议在使用杜利单抗 20-24 周后再进行 EoE 组织学再评估1。由于对EoE进行组织学再评估需要进行侵入性活检,而诱导EoE缓解对于预防进行性食管损伤非常重要,因此有必要在治疗12周之前研究杜必鲁单抗对EoE的影响。我们在一家医疗诊所开展了一项回顾性研究。我们使用国际疾病分类第 10 次修订版代码 K20.0 嗜酸性粒细胞食管炎检索了 2017 年至 2023 年期间的电子病历。我们排除了以下患者:(1)从未开始使用杜度单抗;(2)未从组织学角度确认嗜酸性食管炎(定义为≥15 eos/hpf);或(3)在使用杜度单抗期间未从组织学角度重新评估嗜酸性食管炎。EoE的组织学评估对食管近端、中部和远端至少各进行2次活检。终点是嗜酸性粒细胞计数峰值(每高倍视野嗜酸性粒细胞数;eos/hpf)、EoE内镜参考评分(EREFS)和综合症状评分,其中每种症状(吞咽困难、食物嵌塞/呛咳、反胃/呕吐、胃灼热/胸痛和腹痛)均被分级(0 = 无、1 = 轻度、2 = 中度和 3 = 重度)并求和。从电子病历中确定了 658 例咽喉炎患者,其中 534 例从未使用过杜比鲁单抗,6 例未进行咽喉炎组织学确诊,39 例在使用杜比鲁单抗后未进行重复组织学评估。因此,本研究纳入了 79 名患者。中位年龄为 27.6 岁(Q1-Q3,21.8-36.1),48 名患者(60.8%)为男性,12 名患者(15.2%)为儿童(表 1)。60名患者(75.9%)患有特应性合并症,包括过敏性鼻炎(43名患者,54.4%)、哮喘(27名患者,34.2%)、特应性皮炎(13名患者,16.5%)和食物过敏(30名患者,38.0%)。用药剂量包括每周 300 毫克(71 名患者,89.9%)、每两周 300 毫克,特应性皮炎患者的负荷剂量为 600 毫克(7 名患者,8.9%),以及每两周 200 毫克,特应性皮炎患者的负荷剂量为 400 毫克(1 名患者,1.3%)。服用杜匹鲁单抗 0-12 周的患者的综合症状评分中位数为 5.5(第一季度至第三季度,4-6 分),服用杜匹鲁单抗后显著降至 0(第一季度至第三季度,0-1 分;Wilcoxon 匹配配对符号秩检验,p = 0.000488)。服用杜比卢单抗 0-12 周的患者嗜酸性粒细胞计数峰值中位数从基线时的 44.5 eos/hpf(第一季度至第三季度,32.5-53.5)显著降至 2 eos/hpf(第一季度至第三季度,0-15.5;Wilcoxon 匹配配对符号等级检验,p = 0.000977)。在我们的队列中,只有 15 名患者(19%)获得了内镜参考评分。在使用杜必鲁单抗 0-12 周的患者中,EREFS 从基线(中位数,2;第一季度至第三季度,1-4)与使用杜必鲁单抗(中位数,0;第一季度至第三季度,0-1.5;Wilcoxon 匹配配对符号秩检验,p = 0.25)相比没有显著下降。然而,EREFS的变化在使用杜比鲁单抗12-24周(p = 0.13)和24周以上(p = 0.25)的患者中也不显著,这表明不显著可能是由于n较低所致。在0至12周、12至24周和超过24周之间,接受杜比鲁单抗治疗的患者在中位综合症状评分(p = 0.1350)、嗜酸性粒细胞计数峰值(p = 0.0746)和EREFS(p = 0.8771)方面的变化无明显差异(表1)。在组织学反应方面,0-12周组有9名患者(75%)出现组织学反应,12-24周组有28名患者(73.7%)出现反应,24周以上组有26名患者(89.7%)出现反应。图 1 总结了对 7 名使用杜匹单抗进行&gt;1 组织学评估的患者进行的子分析。三名在早期时间点对杜匹单抗无组织学反应的患者(患者 4 在 0 到 12 周之间,患者 3 和 5 在 12 到 24 周之间)在治疗 24 周后出现了反应,且无需添加联合疗法。与此相反,患者 1 在使用杜利单抗 0-12 周时无反应,在使用杜利单抗超过 24 周后仍无反应。患者 2 和 6 已分别开始接受奥美拉唑或莫米松的联合治疗。 因此,他们的组织学缓解可能是由于联合治疗所致。我们的子分析表明,某些在早期胃肠道造影检查中组织学无反应的患者可能在之后的时间点有反应,也可能没有反应。总之,在治疗 12 周之前,杜比单抗可诱导组织学缓解和临床获益,在接受杜比单抗治疗 0-12 周、2-24 周和超过 24 周的患者之间,临床、组织学或内镜变化没有显著差异。进一步的研究应探讨在进行重复胃肠镜检查之前的适当治疗窗口期:Twan Sia:概念化(等同);数据整理(等同);正式分析(等同);调查(等同);方法学(等同);验证(等同);可视化(等同);写作-原稿(等同);写作-审阅和编辑(等同)。阿曼达-米勒数据整理(等同);正式分析(等同);验证(等同);可视化(等同);撰写原稿(等同);撰写-审阅和编辑(等同)。利昂-巴克斯数据整理(等同);形式分析(等同);验证(等同);可视化(等同);撰写原稿(等同);撰写-审阅和编辑(等同)。詹妮-杨数据整理(相同);验证(相同);可视化(相同);写作-审阅和编辑(相同)。Aditya P. Narayan:数据整理(相同);验证(相同);可视化(相同);撰写-审查和编辑(相同)。Rachel Solecki:调查(等同);验证(等同);撰写-审阅和编辑(等同)。Jerry Fu:调查(等效);验证(等效);撰写-审阅和编辑(等效)。蒋玉婷:调查(等效);验证(等效);撰写-审阅和编辑(等效)。雷萨-胡达调查(等效);验证(等效);撰写-审阅和编辑(等效)。Stanley Liu:调查(相同);验证(相同);撰写-审阅和编辑(相同)。Kathleen Love:调查(相同);验证(相同);撰写-审阅和编辑(相同)。Shibani Mallik:调查(相同);验证(相同);撰写-审查和编辑(相同)。Amina Sara Matmatte:调查(相同);验证(相同);撰写-审阅和编辑(相同)。Paige McDonald:调查(相同);验证(相同);撰写-审阅和编辑(相同)。Tanvi Telukunta:调查(相同);验证(相同);写作-审阅和编辑(相同)。Alyssa Roby:调查(相同);验证(相同);撰写-审阅和编辑(相同)。Saad Shami:调查(相同);验证(相同);撰写-审阅和编辑(相同)。Michelle Zheng:调查(相同);验证(相同);撰写-审阅和编辑(相同)。麦迪逊-海登调查(相同);验证(相同);撰写-审阅和编辑(相同)。John Leung:是 Devine、Millimet and Branch Professional Education、Sanofi、Huron Consulting Services LLC、Takeda、Ribon Therapeutics、Tegus、Slingshot、Guidepoint、Cowen、AstraZeneca、Regeneron 和 AbbVie 的顾问。本研究未从公共、商业或非营利部门的任何资助机构获得具体资助。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Dupilumab improves clinical and histologic features of eosinophilic esophagitis prior to 12 weeks of treatment

Dupilumab improves clinical and histologic features of eosinophilic esophagitis prior to 12 weeks of treatment

Dupilumab is a human monoclonal antibody against interleukin-4 receptor alpha subunit. Dupilumab is an approved treatment for inducing remission of eosinophilic esophagitis (EoE).1 EoE histologic remission with dupilumab has only been demonstrated in patients after at least 12 weeks of treatment.2-6 Current guidelines recommend waiting for histologic re-evaluation of EoE until after 20–24 weeks of dupilumab.1 It is unknown if increasing dupilumab treatment length improves its efficacy. Because histologic re-evaluation of EoE requires invasive biopsies, and inducing remission of EoE is important to prevent progressive esophageal damage, research investigating the effects of dupilumab on EoE prior to 12 weeks of treatment is warranted.

We conducted a retrospective study at a single medical clinic. The electronic medical record was searched between 2017 and 2023 using International Classifications of Disease, 10th revision code K20.0 eosinophilic esophagitis. We excluded patients who had (1) never started dupilumab; (2) no histologic confirmation of EoE defined by ≥ 15 eos/hpf; or (3) no histologic re-evaluation of EoE while on dupilumab. Histologic evaluation of EoE assessed at least 2 biopsies each of the proximal, middle, and distal esophagus. Endpoints were peak eosinophil counts (eosinophils per high-power field; eos/hpf), EoE endoscopic reference scores (EREFS), and a composite symptom score in which each symptom (dysphagia, food impaction/choking, regurgitation/vomiting, heartburn/chest pain, and abdominal pain) was graded (0 = absent, 1 = mild, 2 = moderate, and 3 = severe) and summed. This study was deemed exempt from institutional review board approval by the WCG IRB.

From the electronic medical record, 658 patients with EoE were identified, of which 534 had never initiated dupilumab, 6 did not have histologic confirmation of EoE, and 39 did not have a repeat histologic evaluation after dupilumab initiation. Therefore, 79 patients were included in this study. The median age was 27.6 years (Q1 to Q3, 21.8–36.1), 48 patients (60.8%) were male, and 12 patients (15.2%) were pediatric (Table 1). Sixty patients (75.9%) had an atopic comorbidity, including allergic rhinitis (43 patients, 54.4%), asthma (27 patients, 34.2%), atopic dermatitis (13 patients, 16.5%), and food allergies (30 patients, 38.0%).

Patients were on dupilumab for median 22.7 weeks (Q1 to Q3, 16–26.7). Dosages included 300 mg every week (71 patients, 89.9%), 300 mg every other week with a loading dose of 600 mg for atopic dermatitis (7 patients, 8.9%), and 200 mg every other week with a loading dose of 400 mg for atopic dermatitis (1 patient, 1.3%).

Of 79 patients, 12 patients (15.2%) were on dupilumab for 0–12 weeks. Patients on dupilumab for 0–12 weeks had a median composite symptom score of 5.5 (Q1 to Q3, 4–6), which significantly decreased to 0 (Q1 to Q3, 0–1; Wilcoxon matched-pairs signed rank test, p = 0.000488) on dupilumab. Median peak eosinophil counts in patients on dupilumab for 0–12 weeks significantly decreased from 44.5 eos/hpf (Q1 to Q3, 32.5–53.5) at baseline to 2 eos/hpf (Q1 to Q3, 0–15.5; Wilcoxon matched-pairs signed rank test, p = 0.000977) on dupilumab. Endoscopic reference scores were only available for 15 patients (19%) in our cohort. In patients on dupilumab for 0–12 weeks, EREFS did not significantly decrease from baseline (median, 2; Q1 to Q3, 1–4) versus on dupilumab (median, 0; Q1 to Q3, 0–1.5; Wilcoxon matched-pairs signed rank test, p = 0.25). However, change in EREFS was also insignificant in patients on dupilumab for 12–24 weeks (p = 0.13), and greater than 24 weeks (p = 0.25), suggesting insignificance may be due to low n. Therefore, dupilumab may induce histologic remission and clinical benefit in patients prior to 12 weeks of treatment.

There were no significant differences in changes in median composite symptom score (p = 0.1350), peak eosinophil count (p = 0.0746); and EREFS (p = 0.8771) between patients on dupilumab between 0 and 12, 12–24, and greater than 24 weeks (Table 1). In terms of histologic response, 9 patients (75%) were histologically responsive in the 0–12 weeks group, 28 patients (73.7%) were responsive in the 12–24 weeks group, and 26 patients (89.7%) were responsive in the longer than 24 weeks group. There was no significant difference in the proportion of histologic response between the 3 groups (Fisher's exact test, p = 0.2569).

Subanalysis in 7 patients with >1 histologic evaluations on dupilumab is summarized in Figure 1. Three patients who were histologically unresponsive to dupilumab at early timepoints (Patient 4 between 0 and 12 weeks, Patient 3 and 5 between 12 and 24 weeks) were responsive after 24 weeks of treatment without addition of combination therapy. In contrast, Patient 1 was unresponsive at 0–12 weeks of dupilumab and remained unresponsive after over 24 weeks of dupilumab. Patient 2 and 6 had started combination therapy with omeprazole or mometasone, respectively. Therefore, their histologic remission may be due to combination therapy. Our subanalysis suggests that certain patients who are histologically unresponsive at early EGDs may or may not respond at later timepoints. Further research is needed to predict which patients benefit from repeat EGDs.

In conclusion, dupilumab induced histologic remission and clinical benefit before 12 weeks of treatment, and there were no significant differences in clinical, histologic, or endoscopic changes between patients on dupilumab for 0–12 weeks, 2–24 weeks, and greater than 24 weeks. It may be beneficial to identify treatment response earlier than previous guidelines indicate.1 Further research should investigate the appropriate window of treatment before repeat EGDs are performed.

Twan Sia: Conceptualization (equal); data curation (equal); formal analysis (equal); investigation (equal); methodology (equal); validation (equal); visualization (equal); writing—original draft (equal); writing—review and editing (equal). Amanda Miller: Data curation (equal); formal analysis (equal); validation (equal); visualization (equal); writing—original draft (equal); writing—review and editing (equal). Leeon Bacchus: Data curation (equal); formal analysis (equal); validation (equal); visualization (equal); writing—original draft (equal); writing—review and editing (equal). Jennie Young: Data curation (equal); validation (equal); visualization (equal); writing—review and editing (equal). Aditya P. Narayan: Data curation (equal); validation (equal); visualization (equal); writing—review and editing (equal). Rachel Solecki: Investigation (equal); validation (equal); writing—review and editing (equal). Jerry Fu: Investigation (equal); validation (equal); writing—review and editing (equal). Yuting Jiang: Investigation (equal); validation (equal); writing—review and editing (equal). Raisa Khuda: Investigation (equal); validation (equal); writing—review and editing (equal). Stanley Liu: Investigation (equal); validation (equal); writing—review and editing (equal). Kathleen Love: Investigation (equal); validation (equal); writing—review and editing (equal). Shibani Mallik: Investigation (equal); validation (equal); writing—review and editing (equal). Amina Sara Matmatte: Investigation (equal); validation (equal); writing—review and editing (equal). Paige McDonald: Investigation (equal); validation (equal); writing—review and editing (equal). Tanvi Telukunta: Investigation (equal); validation (equal); writing—review and editing (equal). Alyssa Roby: Investigation (equal); validation (equal); writing—review and editing (equal). Saad Shami: Investigation (equal); validation (equal); writing—review and editing (equal). Michelle Zheng: Investigation (equal); validation (equal); writing—review and editing (equal). Madison Headen: Investigation (equal); validation (equal); writing—review and editing (equal). John Leung: Conceptualization (equal); methodology (equal); project administration (equal); resources (equal); supervision (equal); writing—review and editing (equal).

John Leung: is a consultant for Devine; Millimet and Branch Professional Education; Sanofi; Huron Consulting Services LLC; Takeda; Ribon Therapeutics; Tegus; Slingshot; Guidepoint; Cowen; AstraZeneca; Regeneron; and AbbVie. None of the other authors have relevant conflicts of interests to disclose.

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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来源期刊
Clinical and Translational Allergy
Clinical and Translational Allergy Immunology and Microbiology-Immunology
CiteScore
7.50
自引率
4.50%
发文量
117
审稿时长
12 weeks
期刊介绍: Clinical and Translational Allergy, one of several journals in the portfolio of the European Academy of Allergy and Clinical Immunology, provides a platform for the dissemination of allergy research and reviews, as well as EAACI position papers, task force reports and guidelines, amongst an international scientific audience. Clinical and Translational Allergy accepts clinical and translational research in the following areas and other related topics: asthma, rhinitis, rhinosinusitis, drug hypersensitivity, allergic conjunctivitis, allergic skin diseases, atopic eczema, urticaria, angioedema, venom hypersensitivity, anaphylaxis, food allergy, immunotherapy, immune modulators and biologics, animal models of allergic disease, immune mechanisms, or any other topic related to allergic disease.
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