DataSheet_1_Outcomes of Systemic Treatment in Children and Adults With Netherton Syndrome: A Systematic Review.pdf

BackgroundComèl-Netherton syndrome (NS) is a rare disease caused by pathogenic variants in the SPINK5 gene, leading to severe skin barrier impairment and proinflammatory upregulation. Given the severity of the disease, treatment of NS is challenging. Current treatment regimens are mainly topical and supportive. Although novel systemic treatment options for NS have been suggested in recent literature, little is known about their outcomes.
Objectiveto provide an overview of systemic treatment options and their outcomes in adults and children with NS.
MethodsEmbase, MEDLINE, Web of Science, Cochrane Central Register of Controlled Trials, and Google Scholar were searched up to July 22, 2021. Empirical studies published in English language mentioning systemic treatment in NS were enrolled. Studies that did not define a treatment period or report at least one outcome were excluded. Methodological quality was evaluated by the Joanna Briggs Institute critical appraisal checklist for case reports or case series. Overall quality of evidence of the primary outcome, skin, was assessed by the GRADE approach.
Results36 case series and case reports were included. The effects of 15 systemic therapies were described in 48 patients, of which 27 were children. Therapies included retinoids, prednisolone, cyclosporine, immunoglobulins, and biologicals. In retinoids both worsening (4/15 cases) and improvement (6/15 cases) of the skin was observed. Use of prednisolone and cyclosporine was only reported in one patient. Immunoglobulins (13/15 cases) and biologicals (18/21 cases) showed improvement of the skin. Certainty of evidence was rated as very low.
ConclusionNS is a rare disease, which is reflected in the scarce literature on systemic treatment outcomes in children and adults with NS. Studies showed large heterogeneity in outcome measures. Adverse events were scarcely reported. Long-term outcomes were reported in a minority of cases. Nonetheless, a general beneficial effect of systemic treatment was found. Immunoglobulins and biologicals showed the most promising results and should be further explored. Future research should focus on determining a core outcome set and measurement instruments for NS to improve quality of research.
Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?RecordID=217933, PROSPERO (ID: 217933).

背景 科梅尔-内瑟顿综合征（Comèl-Netherton syndrome）是由SPINK5基因（SPINK5 gene）致病性变异引发的罕见疾病，可导致严重的皮肤屏障功能受损与促炎通路上调。鉴于该疾病的危重程度，其治疗极具挑战性。当前的治疗方案以局部治疗与支持治疗为主。尽管近年已有文献提出针对该病的新型系统性治疗方案，但学界对其临床疗效仍知之甚少。

目的 全面概述成人与儿童科梅尔-内瑟顿综合征患者的系统性治疗方案及其临床疗效。

方法 检索截至2021年7月22日的Embase、MEDLINE、Web of Science、Cochrane对照试验中心注册库（Cochrane Central Register of Controlled Trials）及谷歌学术（Google Scholar）。纳入以英文发表的、提及科梅尔-内瑟顿综合征系统性治疗的实证研究。排除未明确治疗周期或未报告至少一项疗效结局的研究。采用乔安娜·布里格斯研究所（Joanna Briggs Institute）病例报告/病例系列临界评价量表评估方法学质量，通过GRADE分级法（GRADE approach）对主要结局指标（皮肤相关）的整体证据质量进行评价。

结果 共纳入36项病例系列研究与病例报告。涉及48例患者（其中27例为儿童），共描述了15种系统性治疗方案的疗效，包括维A酸类（retinoids）、泼尼松龙（prednisolone）、环孢素（cyclosporine）、免疫球蛋白（immunoglobulins）及生物制剂（biologicals）。在维A酸类药物治疗中，既观察到皮肤症状恶化（4/15例），也观察到症状改善（6/15例）。泼尼松龙与环孢素的使用仅各有1例患者被报告。免疫球蛋白（13/15例）与生物制剂（18/21例）可改善皮肤症状。证据确定性被评为极低。

结论 科梅尔-内瑟顿综合征作为罕见病，其成人与儿童患者系统性治疗疗效的相关文献较为匮乏。现有研究的疗效评价指标异质性较强，不良事件报告极少，仅少数病例报告了长期随访结局。尽管如此，研究仍发现系统性治疗总体上具有有益效果，其中免疫球蛋白与生物制剂的疗效最为可观，值得进一步探索。未来研究应聚焦于确立科梅尔-内瑟顿综合征的核心结局指标集与标准化测评工具，以提升研究质量。

系统评价注册 https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=217933，PROSPERO（编号：217933）。