Fears for tears? Targeted therapies for atopic dermatitis and ocular surface health

IF 8.4 2区 医学 Q1 DERMATOLOGY
Carolyn Jack, Aaron M. Drucker
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Reguiai et al.<span><sup>1</sup></span> have sought to describe this population with a 12-site French collaborative study and contribute new real-world information that may help to address ongoing gaps in knowledge at this ocular epithelial frontier.</p><p>The ocular surface is a dynamic mucosal system that provides lubrication to the eye as well as physical and immunological defence, see Figure 1a. Common criteria for AD include five features involving the eyes: conjunctivitis, keratoconus, cataracts and two signs of peri-orbital skin changes. Conjunctivitis is prevalent in nearly one third of AD patients, and there may be a causal effect from the skin to the eyes.<span><sup>2</sup></span> Shi et al.<span><sup>3</sup></span> recently provided an excellent overview of ocular surface disease (OSD), comprehensive of pathobiology and clinical outcomes in AD patients. More than half of adult AD patients eligible for systemic therapies may suffer from eye symptoms such as pruritus, and a majority can show signs of blepharitis and conjunctivitis, where the hidden palpebral conjunctiva is more commonly affected than that covering the orbit.<span><sup>4</sup></span> These findings may account for the higher rates of ocular adverse effects in pivotal Dupilumab studies for AD, versus asthma or nasal polyposis.<span><sup>3</sup></span></p><p>The Reguiai cohort included 83 patients (7.5% of 1109 Dupilumab-treated patients) who developed OSD leading to treatment switch; 71 patients were captured in follow-up, and 73% were assessed by ophthalmology (Figure 1b).<span><sup>1</sup></span> Most cases were mild–moderate forms of blepharo-conjunctivitis, the subtype of OSD most strongly associated with AD.<span><sup>1, 3</sup></span> Sixty-five % of patients were initially switched to a JAK inhibitor (JAKi) and 35% to the anti-IL-13 biologic Tralokinumab.<span><sup>1</sup></span> Although 30% of patients were subsequently switched again, 68% remained on a JAKi and 7% restarted Dupilumab.<span><sup>1</sup></span> At the end of the study, nearly one quarter of OSD patients had persistent disease, with slightly more still using topical therapies.<span><sup>1</sup></span> While the sample size of the cohort is small, leading to wide confidence intervals for the regression analyses, they did find significantly increased odds for complete resolution associated with switching to a JAKi.<span><sup>1</sup></span>.</p><p>Recent studies have helped initiate a mechanistic framework for understanding Dupilumab-associated OSD (DAOSD), which appears to involve increased Th1-type inflammatory pathways, remodelling mediators and stable goblet cell numbers yet lower mucin production.<span><sup>4, 5</sup></span> DAOSD may differ from allergic-type or AD-associated pathology characterized by increased and decreased goblet cells, respectively, although current data is quite limited.<span><sup>4</sup></span> As 44% of patients in the Reguiai cohort reported a history of conjunctivitis at baseline, and as patients with DAOSD who did not switch therapy are not included in this cohort, the factors contributing to a high prevalence of persistent OSD among all those who develop it remain unclear.<span><sup>1</sup></span></p><p>When considering atopic disease through the lens of systemic immune dysfunction, we can now coordinate the control of inflammation at most epithelial surfaces using systemic therapies. 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Watson Educational Grant, Innovaderm Research, McGill University Department of Medicine, McGill CPD MedUpdates, MITACS, Canadian Dermatology Foundation, Canadian Dermatology Association, and Eczema Society of Canada, as well as grants, involvement in clinical studies, and/or consultancy work for Sanofi, Eli Lilly, AbbVie, Novartis, Valeant, Bausch, Pfizer, Amgen, Celgene, Janssen, Boehringer Ingelheim, Asana, LEO, Dermavant, AntibioTx, Neokera, Kiniksa, Ralexar, Arcutis, BMS, Boston, Cara, Concert, Incyte, Sienna, Aristea, Target PharmaSolution, Lyceum Health, LaRoche-Posay, Johnson &amp; Johnson Inc., L'Oreal, Chronicle, Catalytic, Beiersdorf, Innomar, Apogee Therapeutics, Galderma, LEAD, and UCB. 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引用次数: 0

Abstract

Dupilumab is a monoclonal antibody that binds the IL-4 receptor alpha to block a key cytokine axis in atopy, with an excellent safety profile from infancy through old age. In a minority of patients with atopic dermatitis (AD), Dupilumab can be associated with worsening or new inflammation at the surface of the eye.1 For most patients, this adverse event is mild or readily managed; but for some, it can lead to Dupilumab discontinuation. Reguiai et al.1 have sought to describe this population with a 12-site French collaborative study and contribute new real-world information that may help to address ongoing gaps in knowledge at this ocular epithelial frontier.

The ocular surface is a dynamic mucosal system that provides lubrication to the eye as well as physical and immunological defence, see Figure 1a. Common criteria for AD include five features involving the eyes: conjunctivitis, keratoconus, cataracts and two signs of peri-orbital skin changes. Conjunctivitis is prevalent in nearly one third of AD patients, and there may be a causal effect from the skin to the eyes.2 Shi et al.3 recently provided an excellent overview of ocular surface disease (OSD), comprehensive of pathobiology and clinical outcomes in AD patients. More than half of adult AD patients eligible for systemic therapies may suffer from eye symptoms such as pruritus, and a majority can show signs of blepharitis and conjunctivitis, where the hidden palpebral conjunctiva is more commonly affected than that covering the orbit.4 These findings may account for the higher rates of ocular adverse effects in pivotal Dupilumab studies for AD, versus asthma or nasal polyposis.3

The Reguiai cohort included 83 patients (7.5% of 1109 Dupilumab-treated patients) who developed OSD leading to treatment switch; 71 patients were captured in follow-up, and 73% were assessed by ophthalmology (Figure 1b).1 Most cases were mild–moderate forms of blepharo-conjunctivitis, the subtype of OSD most strongly associated with AD.1, 3 Sixty-five % of patients were initially switched to a JAK inhibitor (JAKi) and 35% to the anti-IL-13 biologic Tralokinumab.1 Although 30% of patients were subsequently switched again, 68% remained on a JAKi and 7% restarted Dupilumab.1 At the end of the study, nearly one quarter of OSD patients had persistent disease, with slightly more still using topical therapies.1 While the sample size of the cohort is small, leading to wide confidence intervals for the regression analyses, they did find significantly increased odds for complete resolution associated with switching to a JAKi.1.

Recent studies have helped initiate a mechanistic framework for understanding Dupilumab-associated OSD (DAOSD), which appears to involve increased Th1-type inflammatory pathways, remodelling mediators and stable goblet cell numbers yet lower mucin production.4, 5 DAOSD may differ from allergic-type or AD-associated pathology characterized by increased and decreased goblet cells, respectively, although current data is quite limited.4 As 44% of patients in the Reguiai cohort reported a history of conjunctivitis at baseline, and as patients with DAOSD who did not switch therapy are not included in this cohort, the factors contributing to a high prevalence of persistent OSD among all those who develop it remain unclear.1

When considering atopic disease through the lens of systemic immune dysfunction, we can now coordinate the control of inflammation at most epithelial surfaces using systemic therapies. There remains a gap in understanding refractory, paradoxical and organ-specific pathways of immune dysfunction, including ocular surface inflammation with Dupilumab, as well as with skin- or airway-specific responses to IL-13 and IL-5 blockade, respectively. While focused on adults, the results of this study are an important reminder to Dermatologists to consider ocular health in their AD patients, particularly those considering systemic therapy, and add increasing weight to the rationale that patient outcomes may be improved by considering this multi-epithelial disorder holistically.

C. Jack reports grants from the Montreal Dermatology Research Institute, Fonds de Recherche du Québec - Santé (FRQS), SkIN Canada, Programme d’aide à l’entrepreneuriat (PAEN), Mackenzie I. Watson Educational Grant, Innovaderm Research, McGill University Department of Medicine, McGill CPD MedUpdates, MITACS, Canadian Dermatology Foundation, Canadian Dermatology Association, and Eczema Society of Canada, as well as grants, involvement in clinical studies, and/or consultancy work for Sanofi, Eli Lilly, AbbVie, Novartis, Valeant, Bausch, Pfizer, Amgen, Celgene, Janssen, Boehringer Ingelheim, Asana, LEO, Dermavant, AntibioTx, Neokera, Kiniksa, Ralexar, Arcutis, BMS, Boston, Cara, Concert, Incyte, Sienna, Aristea, Target PharmaSolution, Lyceum Health, LaRoche-Posay, Johnson & Johnson Inc., L'Oreal, Chronicle, Catalytic, Beiersdorf, Innomar, Apogee Therapeutics, Galderma, LEAD, and UCB. Dr. Drucker has received compensation from the British Journal of Dermatology (reviewer and Section Editor), American Academy of Dermatology (guidelines writer), Canadian Dermatology Today (manuscript writer), and National Eczema Association (consultant) Canadian Agency for Drugs and Technologies in Health (consultant). Dr. Drucker has received research grants to his institution from the National Eczema Association, Eczema Society of Canada, Canadian Dermatology Foundation, Canadian Institutes for Health Research, US National Institutes of Health and Physicians Services Incorporated Foundation.

Abstract Image

害怕流泪?特应性皮炎和眼表健康的靶向疗法。
杜比鲁单抗是一种单克隆抗体,能与 IL-4 受体α结合,从而阻断特应性皮炎的关键细胞因子轴,而且从婴儿到老年都具有极佳的安全性。在少数特应性皮炎(AD)患者中,杜比鲁单抗可能会导致眼部表面炎症恶化或出现新的炎症。1 对于大多数患者来说,这种不良反应是轻微的或容易控制的;但对于某些患者来说,这种不良反应可能会导致杜比鲁单抗停药。Reguiai等人1试图通过一项12个研究地点的法国合作研究来描述这一人群,并提供新的真实世界信息,这些信息可能有助于解决眼上皮这一前沿领域的知识缺口。眼表是一个动态粘膜系统,为眼睛提供润滑以及物理和免疫防御,见图1a。注意力缺失症的常见标准包括涉及眼部的五个特征:结膜炎、角膜炎、白内障和两个眶周皮肤变化的迹象。结膜炎在近三分之一的 AD 患者中普遍存在,可能存在从皮肤到眼睛的因果效应。2 Shi 等人3 最近对眼表疾病(OSD)进行了出色的概述,全面介绍了 AD 患者的病理生物学和临床结果。符合全身治疗条件的成年 AD 患者中,半数以上会出现瘙痒等眼部症状,大多数患者会出现睑缘炎和结膜炎的症状,其中隐蔽的睑结膜比覆盖眼眶的结膜更常受到影响4。Reguiai 队列中有 83 名患者(占 1109 名杜匹单抗治疗患者的 7.5%)出现了导致治疗转换的 OSD;71 名患者接受了随访,73% 接受了眼科评估(图 1b)、3 65% 的患者最初改用 JAK 抑制剂 (JAKi),35% 改用抗 IL-13 生物制剂 Tralokinumab。1 虽然 30% 的患者后来再次改用 JAKi,但 68% 的患者仍在使用 JAKi,7% 的患者重新开始使用 Dupilumab。最近的研究有助于建立一个机理框架来理解杜匹鲁单抗相关的 OSD(DAOSD),这似乎涉及 Th1 型炎症通路增加、重塑介质和小管细胞数量稳定但粘蛋白分泌减少、5 DAOSD 可能不同于过敏型或 AD 相关病理,其特点分别是上皮细胞增加和减少,但目前的数据非常有限。4 由于 Reguiai 队列中有 44% 的患者在基线时报告有结膜炎病史,而且未更换疗法的 DAOSD 患者未包括在该队列中,导致所有 OSD 患者中持续 OSD 患病率高的因素仍不清楚。从全身免疫功能失调的角度来考虑特应性疾病,我们现在可以协调使用全身疗法来控制大多数上皮表面的炎症。在了解免疫功能障碍的难治性、矛盾性和器官特异性途径方面仍然存在差距,包括使用杜比鲁单抗治疗眼表炎症,以及皮肤或气道对 IL-13 和 IL-5 阻断剂的特异性反应。C. Jack报告了蒙特利尔皮肤病研究所、Fonds de Recherche du Québec - Santé (FRQS)、SkIN Canada、Programme d'aide à l'entrepreneuriat (PAEN)、Mackenzie I. Watson Educational Grant、Innovation.Watson Educational Grant、Innovaderm Research、麦吉尔大学医学系、麦吉尔 CPD MedUpdates、MITACS、加拿大皮肤病基金会、加拿大皮肤病协会和加拿大湿疹协会,以及赛诺菲的资助、临床研究和/或顾问工作、Eli Lilly、AbbVie、Novartis、Valeant、Bausch、Pfizer、Amgen、Celgene、Janssen、Boehringer Ingelheim、Asana、LEO、Dermavant、AntibioTx、Neokera、Kiniksa、Ralexar、Arcutis、BMS、Boston、Cara、Concert、Incyte、Sienna、Aristea、Target PharmaSolution、Lyceum Health、LaRoche-Posay、Johnson &amp;Johnson Inc.,欧莱雅、Chronicle、Catalytic、拜尔斯道夫、Innomar、Apogee Therapeutics、Galderma、LEAD 和 UCB。博士
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
10.70
自引率
8.70%
发文量
874
审稿时长
3-6 weeks
期刊介绍: The Journal of the European Academy of Dermatology and Venereology (JEADV) is a publication that focuses on dermatology and venereology. It covers various topics within these fields, including both clinical and basic science subjects. The journal publishes articles in different formats, such as editorials, review articles, practice articles, original papers, short reports, letters to the editor, features, and announcements from the European Academy of Dermatology and Venereology (EADV). The journal covers a wide range of keywords, including allergy, cancer, clinical medicine, cytokines, dermatology, drug reactions, hair disease, laser therapy, nail disease, oncology, skin cancer, skin disease, therapeutics, tumors, virus infections, and venereology. The JEADV is indexed and abstracted by various databases and resources, including Abstracts on Hygiene & Communicable Diseases, Academic Search, AgBiotech News & Information, Botanical Pesticides, CAB Abstracts®, Embase, Global Health, InfoTrac, Ingenta Select, MEDLINE/PubMed, Science Citation Index Expanded, and others.
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