Supplementary Material for: Developing a core outcome set for Netherton syndrome: An international multi-stakeholder e-Delphi consensus study

Introduction: Netherton syndrome (NS; OMIM#256500) is a rare and severe disorder of epidermal maturation and keratinization caused by pathogenic variants in the serine protease inhibitor Kazal type 5 (SPINK5), leading to severe skin barrier impairment. Although effective treatment is crucial for NS patients, there is a lack of knowledge on what the best treatment options are for these patients. Large heterogeneity in reported outcomes and measurement instruments hinders accurate comparison of treatment results across studies and the development of a treatment guideline. Therefore, we aimed to develop a core outcome set (COS) for NS that can be used in clinical care and research. Methods: This study was performed in accordance with the recommendations of the Core Outcome Measures in Effectiveness Trials (COMET) initiative. After identification of outcomes through a literature search and classification based on the International Classification of Functioning and taxonomies published by the COMET initiative, discussion groups were organized at the 2nd International Netherton Congress 2022 to finalize the provisional outcome list. Through a 2-round e-Delphi, 41 stakeholders (patients and family members, professionals, and representatives of industry) from 14 countries rated the importance of the outcomes using a 9-point Likert scale. An online consensus meeting attended by 14 stakeholders finalized the COS. Results: The core outcome set for NS comprised 21 outcomes in 10 domains. These included four ‘skin’ outcomes, two ‘sensation’ outcomes, two ‘side-effects of treatment’ outcomes, one ‘vitality’ outcome, one ‘emotional functioning’ outcome, two ‘physical development’ outcomes, two ‘nutrition’ outcomes, two ‘infections’ outcomes, two ‘allergies’ outcomes, and three ‘assessment results’ outcomes. Conclusion: In this study, consensus was reached on 21 outcomes to be included in the COS for NS. The selection of outcomes in the COS underlines that NS not only affects the skin, but is a disease requiring a broad multidisciplinary approach in clinical care and research. International implementation of this COS will lead to more uniform reporting, thereby enabling comparison of study results, which may facilitate future treatment guideline development. The next step is to further conceptually define the outcomes and reach consensus on how the measure these.

引言：Netherton综合征（Netherton syndrome, NS; OMIM#256500）是一种罕见且严重的表皮成熟与角质化障碍性疾病，由丝氨酸蛋白酶抑制剂Kazal型5（serine protease inhibitor Kazal type 5, SPINK5）的致病变异引发，会导致严重的皮肤屏障功能受损。虽然有效的治疗对NS患者至关重要，但目前学界对这类患者的最佳治疗方案仍缺乏认知。已报道的结局指标与测量工具存在较大异质性，阻碍了不同研究间治疗效果的精准对比，也妨碍了治疗指南的制定。因此，本研究旨在开发一套可用于临床诊疗与研究的NS核心结局集（core outcome set, COS）。

方法：本研究遵循《疗效试验核心结局指标》（Core Outcome Measures in Effectiveness Trials, COMET）倡议的推荐方案开展。首先通过文献检索确定结局指标，并依据《国际功能分类》与COMET倡议发布的分类体系进行分类；随后于2022年第二届国际Netherton综合征大会组织研讨小组，敲定临时结局清单。通过两轮电子德尔菲（e-Delphi）调查，来自14个国家的41名利益相关方（包括患者与家属、专业人员及行业代表）采用9分李克特（Likert）量表对结局指标的重要性进行评分。最终由14名利益相关方参与的线上共识会议确定了这套核心结局集。

结果：NS的核心结局集包含10个维度下的21项结局指标，具体包括4项“皮肤”相关结局、2项“感觉”相关结局、2项“治疗不良反应”相关结局、1项“活力”相关结局、1项“情绪功能”相关结局、2项“体格发育”相关结局、2项“营养状况”相关结局、2项“感染”相关结局、2项“过敏”相关结局，以及3项“评估结果”相关结局。

结论：本研究就纳入NS核心结局集的21项结局指标达成了共识。该核心结局集的指标选择凸显了NS并非仅累及皮肤的疾病，而是一类需要在临床诊疗与研究中采用多学科综合干预手段的疾病。这套核心结局集的国际推广将实现结局报告的标准化，从而支持不同研究结果的对比分析，有望为未来治疗指南的制定提供助力。下一步工作将是进一步明确各项结局指标的概念内涵，并就其测量方法达成共识。