Supplementary Material for: Treatment Experiences with Intravenous Immunoglobulins, Ixekizumab, Dupilumab, and Anakinra in Netherton Syndrome: A Case Series

<b><i>Background:</i></b> Netherton syndrome (NS) is a rare potential life-threatening disorder that causes severe defects to the skin barrier. No effective treatment options are available for patients with NS and current therapy is mostly supportive. The effects of intravenous immunoglobulins (IVIGs), ixekizumab, and dupilumab have scarcely been reported. Additionally, the role of anakinra in patients with NS has never been investigated. <b><i>Objectives:</i></b> The objective was to report our experiences of treatment with IVIG, ixekizumab, dupi­lumab, and anakinra in patients with NS. <b><i>Methods:</i></b> A retrospective case series, including 5 patients with NS, was performed in a tertiary referral hospital between 2016 and 2021. Patients were treated with IVIG, ixekizumab, dupilumab, and/or anakinra. Long-term experiences with treatment regimens and adverse events requiring medical attention were reported. <b><i>Results:</i></b> IVIG, ixekizumab, dupilumab, and anakinra were well tolerated with no severe adverse events. The 2 patients that received IVIG showed clinical response for 6 months and 2.5 years. Ixekizumab was effective in 1 of our patients for 3.5 years, while in another patient ixekizumab lost its effect after 1.5 years. Dupilumab treatment did not result in persistent improvement of NS-related skin symptoms in 1 patient. Anakinra showed physician-assessed clinical response during the first months of treatment in 4 patients with NS. During anakinra treatment, no changes in blood levels of IL-1β, IL-6, and TNF-α levels were measured at routine blood examinations. <b><i>Conclusions:</i></b> This case series suggests that the use of IVIG, ixekizumab, dupilumab, and anakinra in NS is safe and moderately effective on the short term. On the long term, a decline in effect was observed. Our experiences may help clinicians and researchers to provide adequate care and develop treatment for these severely affected patients. More international research, especially on the long term, is needed to determine if and which patients benefit most from the emerging therapies for NS.

**背景**：内瑟顿综合征（Netherton syndrome, NS）是一种罕见的潜在致死性皮肤疾病，可导致皮肤屏障出现严重损伤。目前NS患者尚无有效的治疗方案，现有治疗手段多以支持性治疗为主。静脉注射免疫球蛋白（intravenous immunoglobulins, IVIGs）、依奇珠单抗（ixekizumab）与度普利尤单抗（dupilumab）用于NS的治疗效果鲜有报道，而阿那白滞素（anakinra）在NS患者中的治疗价值尚未有相关研究探索。
**目的**：本研究旨在报告我们应用IVIG、依奇珠单抗、度普利尤单抗及阿那白滞素治疗NS患者的临床经验。
**方法**：本研究为回顾性病例系列研究，于2016年至2021年间在一家三级转诊医院开展，共纳入5例NS患者。所有患者均接受IVIG、依奇珠单抗、度普利尤单抗和/或阿那白滞素治疗。本研究报告了长期治疗方案的应用经验以及需临床干预的不良事件情况。
**结果**：IVIG、依奇珠单抗、度普利尤单抗及阿那白滞素均具有良好的耐受性，未出现严重不良事件。2例接受IVIG治疗的患者分别获得了6个月和2.5年的临床应答。依奇珠单抗在1例患者中展现出长达3.5年的治疗效果，而在另1例患者中，该药物在治疗1.5年后疗效减退。1例接受度普利尤单抗治疗的患者未出现NS相关皮肤症状的持续性改善。4例NS患者在阿那白滞素治疗的最初数月内，经医师评估获得了临床应答。在阿那白滞素治疗期间，常规血液检查未检测到IL-1β、IL-6及TNF-α的血清水平变化。
**结论**：本病例系列研究表明，在NS治疗中应用IVIG、依奇珠单抗、度普利尤单抗及阿那白滞素具有安全性，且在短期内具备中等疗效。长期使用时，观察到疗效出现下降趋势。本研究的临床经验可为临床医师与科研人员为这类重症患者提供恰当诊疗及开发治疗方案提供参考。未来需开展更多国际研究，尤其是长期随访研究，以明确NS新兴疗法的适用人群及获益最优的患者群体。