第一部分 红皮病型银屑病的血清蛋白组学特征及炎症表型

背景: 红皮病型银屑病（Erythrodermic psoriasis，EP）是银屑病的一种罕见且严重的临床变异型，伴有广泛的皮肤受累和全身炎症反应的激活，涉及免疫系统功能紊乱。先前的研究揭示了细胞因子的表达水平失调、粘附分子增加可能参与了EP的发病。然而，关于EP的血液分子表达谱特征和炎症表型尚不明确。

目的: 调查EP的血清蛋白组学分子特征，探究其炎症表型。

方法:

1.采用数据非依赖采集（Data-Independent Acquisition， DIA)的非标记蛋白质组学技术对20名EP患者和20名健康人对照（Healthy Controls，HCs）的血清进行非靶向蛋白组学分析，描绘EP血清整体蛋白组学特征。

2. 使用Olink高通量蛋白芯片对14名EP患者、14名寻常型银屑病患者和14名HCs的炎症、免疫反应和心血管疾病相关生物标志物进行靶向检测，探究EP炎症表型。

结果：DIA蛋白组学分析发现，与HCs相比，EP患者中鉴定得到197种差异表达蛋白（Differentially expressed proteins，DEPs），其中 123种蛋白表达上调，74种蛋白表达下调。功能注释及通路富集分析显示，DEPs主要富集在急性期炎症反应、补体系统激活、细胞粘附、凝血级联，以及代谢紊乱。Olink靶向蛋白组学分析显示，与HCs和寻常型银屑病患者相比，EP患者展现出更显著的循环蛋白表达水平失调、更强烈的免疫激活以及更高的银屑病典型炎症特征。辅助性T细胞（T helper cell，Th）17和Th1相关标志物在EP患者血清中明显表达上调，同时伴随着轻度的Th2相关炎症介质的偏移，表明EP中存在混合的系统性炎症特征。此外，和寻常型银屑病相比，心血管风险蛋白和动脉粥样硬化相关标志物在EP中显著增加。在EP患者中，疾病临床严重程度主要与促炎症介质呈显著正相关，包括整体性炎症介质、Th17反应和心血管疾病风险相关标志物。

结论：EP呈现出混合的系统性炎症表型，以Th17/Th1反应偏倚为主，具有轻微的Th2反应偏移。心血管疾病相关生物标志物在EP中显著失调。我们的发现突出了在EP中精准治疗的重要性，以及免疫靶向治疗的必要性。

第二部分 红皮病型银屑病与红皮病型特应性皮炎分子表型及标志物的比较分析

背景：银屑病和特应性皮炎（Atopic dermatitis, AD）是皮肤科常见的慢性炎症性疾病，其发病机制涉及不同的辅助性T细胞（T helper cell，Th）亚型和炎症极化。临床上，银屑病和AD在一定的诱发因素，如感染、药物、系统治疗突然中断、不当的治疗方式等刺激下，可以出现病情突然恶化，形成弥漫性的炎症性红斑和表皮剥脱，导致红皮病型银屑病（Erythrodermic psoriasis，EP）和红皮病型特应性皮炎（Erythrodermic atopic dermatitis，EAD）。由于临床表现、组织病理学和免疫学特征的重叠，临床上及时并早期鉴别诊断EP和EAD存在很大挑战。此外，对于EP和EAD的外周血的炎症表型和分子谱异同仍不清楚，缺乏两者之间的直接比较研究。

目的：

1.描述EP和EAD患者的血清的整体蛋白组学特征、分子表达谱及炎症表型；

2.比较分析EP和EAD患者血清中的炎症、免疫反应和心血管疾病相关蛋白组改变；

3.鉴定与EP和EAD患者疾病临床严重程度存在显著相关性的血清蛋白标志物；

4.基于机器学习算法筛选可用于辅助诊断EP和EAD的血清生物标志物。

方法：共纳入14名EAD患者、14名EP患者和14名健康正常人对照。采集血清样本，并使用Olink高通量平台分析269种与炎症、免疫应答和心血管疾病相关的生物标志物的表达水平。基于加权基因共表达网络分析（Weighted Gene Co-expression Network Analysis，WGCNA）鉴定与疾病表型相关的蛋白模块。3种机器学习算法（随机森林、支持向量机、LASSO回归）进一步筛选出鉴别诊断标志物。

结果：与健康人对照组相比，EAD和EP患者均表现出增强的免疫系统激活和心血管蛋白表达失调。EAD表现出更为显著的混合炎症特征，以Th1/Th2/Th22/IL-1为主要模式，以及增加的肿瘤细胞坏死因子（Tumor Necrosis Factor，TNF）超家族、Th17反应和凋亡相关标志物。相反，EP表现出Th1/Th17/TNF偏倚的炎症特征，并呈现轻度Th2标志物升高，同时伴随着表皮发育标志物的显著上调。EAD的疾病严重程度与凋亡、Th2反应标志物显著正相关，而EP的疾病严重程度与Th17反应标志物显著正相关。此外，WGCNA和机器学习算法证明了8个候选的生物标志物（IL-17A/IL-17C/PI3/CCL20/SH2D1A/SIRT2/DFFA/IL-13），且受试者工作曲线分析显示曲线下面积大于0.8，可以有效区分EP和EAD。

结论：我们的研究全面描述了EAD和EP患者的循环蛋白分子表达谱失调，深入分析了它们的炎症分子表型的相似性和复杂性。确定的血清生物标志物有助于区分EP和EAD，可用于辅助诊断和指导个体化治疗。

第三部分 依奇珠单抗治疗红皮病型银屑病的疗效、药物留存率及安全性分析

背景：红皮病型银屑病（Erythrodermic psoriasis, EP）是一种严重且罕见的银屑病亚型。EP患者常伴有全身症状和严重的合并症，增加了死亡风险，因此对其进行及时有效的治疗十分重要。目前对EP的最佳治疗策略尚未形成统一标准，缺乏高质量的临床研究数据。依奇珠单抗作为一种针对IL-17A的人源化单克隆抗体，已有多项研究证实了其在EP治疗中的有效性和安全性。然而，关于依奇珠单抗在中国汉族人群EP患者中的疗效和安全性的研究数据仍然有限。

目的：评估52周依奇珠单抗治疗中国汉族人群中EP患者的有效性、安全性和药物留存率。

方法：本研究为单中心、回顾性、非干预性的观察性研究。连续纳入2022年1月至2024年4月在北京协和医院皮肤科门诊接受依奇珠单抗治疗的EP患者44例。随访时间点包括基线和治疗后第2、4、12、24、36、52周。PASI评分相对于基线的改善百分比(ΔPASI50、ΔPASI75、ΔPASI90、ΔPASI100)被作为主要终点进行临床疗效评估。记录随访期间不良事件的发生情况。采用Kaplan-Meier生存曲线分析评估药物留存率。

结果：依奇珠单抗的起效迅速，治疗第2周时56.82%的患者达到PASI50，13.64%的患者达到PASI75。第4周时，85%的患者达到PASI50，55%达到PASI75，10%达到PASI90。第12周时，15.15%的患者达到PASI100，60.61%达到PASI90，90.91%达到PASI75。连续治疗24周后，100%的患者达到PASI75，92.59%达到PASI90，29.63%达到PASI100。基于长期疗效分析，持续治疗36周后，超过1 / 3的患者达到皮损完全清除，92.31%达到PASI90。虽然52周时仅有50%的患者（22例）完成了连续随访，但仍有90.91%的患者达到PASI90，31.82%达到PASI100，证明了依奇珠单抗治疗EP的长期的稳定疗效。接受依奇珠单抗连续治疗52周的患者的累积药物生存率为70.5%。随访期间未观察到严重的安全性事件，最常报告的不良事件包括：注射部位反应（n=7，15.9%）、湿疹样皮炎（n=7，15.9%）和鼻咽炎（n=4，9.1%），并且在整个治疗期间依奇珠单抗的总体耐受性良好。截至第52周，没有死亡病例或严重感染的报告。

结论：依奇珠单抗在中国汉族EP人群的真实临床实践中显示出较高的有效性和可耐受的安全性，接受治疗的患者有较高的药物留存率。

Part I: Serum proteomic features and inflammatory phenotypes of erythrodermic psoriasis

Background: Erythrodermic psoriasis (EP), a rare and severe clinical variant of psoriasis with extensive severe cutaneous and systemic inflammation, involves immune dysfunction. Previous studies have revealed that dysregulation of cytokines and increased adhesion molecules may be involved in the pathogenesis of EP. However, the systemic inflammatory signature and molecular profile in EP are poorly understood.

Objectives: To investigate the serum proteome of EP, and to characterize its molecular phenotype using an integrative proteomic approach.

Methods:

1. Data-independent acquisition (DIA)-mass spectrometry was conducted to profile serum proteins in 20 EP patients and 20 healthy controls (HCs).

2. Olink targeted arrays were performed to assess inflammation, immune response, and cardiovascular disease-related biomarkers in 14 EP patients, 14 psoriasis vulgaris (PsV) patients, and 14 HCs.

Results: DIA-proteomics analysis identified 197 differentially expressed proteins (DEPs; 123 upregulated and 74 downregulated) in EP patients compared to HCs. Functional profiling revealed that DEPs were focused on acute inflammatory responses, complement activation, cell adhesion, coagulation cascade, and metabolic disturbance. Olink array showed that EP patients exhibited greater circulating proteins dysregulation, more robust immune activation, and higher psoriatic inflammation tone, compared with HCs and PsV patients. Th17 and Th1 response-related markers were significantly elevated in EP, with a slight bias toward Th2-related mediators, indicating an overlapping inflammatory profile in EP. Cardiovascular risk proteins and atherosclerosis-related markers were substantially increased in EP. Clinical severity was mainly correlated with proinflammatory mediators, including general inflammation, Th17 response-related, and cardiovascular risk markers.

Conclusions: The mixed systemic inflammation phenotype in EP is dominated by Th17/Th1 skewing, a mild Th2 bias, and cardiovascular disease-related biomarker dysregulation. Our findings highlight the importance of precise therapeutics and the essentiality for immune-targeting in EP.

Part II: Comparative proteomics analysis reveals distinct molecular phenotype and biomarkers in patients with erythrodermic atopic dermatitis and erythrodermic psoriasis

Background: Psoriasis and atopic dermatitis (AD) are prevalent chronic inflammatory diseases that have distinct underlying mechanisms involving different helper T-cell (Th) subtypes and inflammation polarization.  Both diseases can occur acute exacerbations and result in erythrodermic psoriasis (EP) and erythrodermic atopic dermatitis (EAD), respectively.  Despite their clinical and histological similarities, the underlying molecular mechanisms and systemic biomarkers of these diseases are substantially unclear.

Objectives: We sought to investigate the differential serum proteome of EP and EAD patients and identify biomarkers for these two subtypes of erythroderma.

Methods: We recruited 14 EAD patients, 14 EP patients and 14 healthy controls. Serum samples were analyzed using the Olink high-throughput platform to assess the levels of 269 inflammation-/immune response-/cardiovascular-related biomarkers.  Weighted Gene Co-expression Network Analysis (WGCNA) was used to identify key protein modules. Machine learning models (random forest, support vector machine, and LASSO regression) were applied to further refine diagnostic markers.

Results: Both EAD and EP patients exhibited enhanced immune activation and dysregulated cardiovascular profiles compared to healthy controls. EAD demonstrated a more pronounced inflammation tone, characterized by Th1/Th2/Th22/IL-1-dominant patterns, as well as increased TNF superfamily, Th17, and apoptosis markers. Conversely, EP displayed inflammation with Th1/Th17/TNF-skewing and mild Th2 upregulation, along with notable increases in epidermal-development markers. Disease severity in EAD was strongly correlated with apoptosis and Th2-related markers, while correlated with Th17-related markers in EP. Furthermore, a panel of eight markers (IL-17A/IL-17C/PI3/CCL20/SH2D1A/SIRT2/DFFA/IL-13) was identified that effectively discriminated between EP and EAD, with an Area Under the Curve greater than 0.8.

Conclusions: Our study comprehensively characterizes the circulating molecular profiles in EAD and EP patients, providing insights into the similarities and complexities of inflammation phenotypes. The identified biomarkers have the potential to differentiate between EP and EAD, which could aid in the diagnosis and guiding tailored therapeutics.

Part III: Real-world data on the efficacy, drug survival and safety of ixekizumab in patients with erythrodermic psoriasis

Background: Erythrodermic psoriasis (EP) is a rare and debilitating psoriasis subtype, which is challenging to manage.Ixekizumab, a humanized monoclonal antibody targeting IL-17A, has shown effectiveness in treating EP. Nevertheless, long-term real-life data regarding its effectiveness and safety in the Chinese Han population are currently limited.

Objectives: To evaluate the effectiveness, safety and drug survival of ixekizumab in EP patients from the Chinese Han population in a real-life setting up to 52 weeks.  

Methods: This is a non-interventional retrospective monocentric study. A total of 44 patients with EP who underwent ixekizumab treatment were recruited consecutively at Peking Union Medical College Hospital from January 2022 to January 2024. The visit points included baseline and week 2, 4, 12, 24, 36, and 52 after treatment. The percentage improvement in PASI scores from baseline (ΔPASI50, ΔPASI75, ΔPASI90, ΔPASI100) were evaluated as the primary endpoints. Adverse events (AEs) reported were documented.  Kaplan-Meier survival curve was employed to analyze drug survival .

Results:  Ixekizumab demonstrated rapid onset of action, with 56.82% of patients achieving PASI50 and 13.64% achieving PASI75 at week 2. At week 4, 85% of patients achieved PASI50, 55% achieved PASI75, and 10% achieved PASI90. At week 12, 15.15% of patients achieved PASI100, 60.61% achieved PASI90, and 90.91% achieved PASI75. After continuous treatment for 24 weeks, all patients achieved PASI75, 92.59% achieved PASI90, and 29.63% achieved PASI100. After 36 weeks of continuous treatment, over one-third of patients achieved complete clearance of lesions, and 92.31% achieved PASI90. Although only 50% of patients (22 cases) completed follow-up at week 52, 90.91% still achieved PASI90 and 31.82% achieved PASI100. The cumulative drug survival of patients receiving continuous treatment with Ixekizumab for 52 weeks was 70.5%. No unexpected safety findings were observed, and the most commonly reported AEs included injection site reactions (n=7, 15.9%), eczematous dermatitis (n=7, 15.9%), and nasopharyngitis (n=4, 9.1%). There were no reported deaths or serious infections up to week 52.

Conclusions: Ixekizumab showed high effectiveness and reassuring safety profiles in real-life practice among the Chinese Han EP population up to 52 weeks, with high drug survival of treated patients.