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背景：结节性痒疹（PN）是一种慢性、神经免疫介导的皮肤病，以剧烈瘙痒和结节性病变为特征，严重损害患者生活质量。传统疗法在提供症状缓解之外的局限性，促使研究人员开发针对该疾病异质性发病机制的新型方法。目标：本综述评估了当前的治疗算法以及未来可能根据PN的免疫和神经病理性内型（endotypes）定制的临床框架。方法：研究人员在PubMed/MEDLINE、Scopus和Google Scholar数据库中对截至2025年12月发表的英文同行评审文章、临床试验和指南进行了全面文献检索，重点关注结节性痒疹的靶向和传统疗法。结果：除了已获批的生物制剂如IL-4/IL-13通路抑制剂dupilumab和IL-31受体拮抗剂nemolizumab外，本综述还讨论了新兴选择，包括JAK抑制剂、肥大细胞靶向疗法和阿片类调节剂。当前证据表明，这些靶向药物通过作用于特定的分子驱动因素，在瘙痒和皮损消退方面均提供了显著改善。结论：PN的管理正在进入一个过渡阶段，新兴目标是从统一方法转向未来基于生物标志物和表型、疾病修饰和个性化的策略。更精确地定义这些内型对于优化潜在的治疗个体化和长期临床成功至关重要。论文主体部分总结如下：**1. 引言**结节性痒疹（PN）的管理本质上具有挑战性，需要多学科和个体化的治疗方法。治疗方案应包含多层面管理，包括全身和局部治疗，特别针对疾病的神经和免疫机制。治疗选择必须个体化，考虑患者年龄、合并症、疾病严重程度和潜在副作用。本综述旨在提供传统疗法、已获批生物制剂和新兴靶向治疗的全面临床概述，强调将神经免疫新见解转化为未来个性化PN管理策略的目标。**2. 方法**本叙述性综述通过对PubMed/MEDLINE、Scopus和Google Scholar数据库进行文献检索完成。检索包括截至2025年12月发表的文章，使用关键词组合如“prurigo nodularis”、“chronic prurigo”、“pathogenesis”、“endotypes”、“dupilumab”、“nemolizumab”、“JAK inhibitors”、“biologics”、“targeted therapy”、“IL-31”、“IL-4”、“IL-13”、“neuromodulators”和“treatment”。通过手动审查参考文献列表识别其他相关出版物。优先考虑随机对照试验、II期和III期临床试验、系统综述、荟萃分析、治疗指南和里程碑式研究。当缺乏更高级别证据时，纳入病例报告和小型病例系列，特别是针对新兴或研究性疗法。考虑以英文发表的文章。**3. 一般原则和传统疗法**治疗的首要步骤是全面的患者教育，重点关注避免瘙痒触发因素、维护皮肤屏障以及减少刺激和瘙痒。症状性控制瘙痒是治疗的基石；建议患者进行温和的皮肤护理，使用温和清洁剂，随后每日多次涂抹润肤剂以舒缓皮肤和缓解干燥。含炉甘石、薄荷醇或樟脑的冷却洗剂，以及含普莫卡因的局部麻醉制剂可用于缓解瘙痒。对于夜间瘙痒，睡前可首选镇静性第一代抗组胺药如羟嗪或苯海拉明。当慢性瘙痒伴有抑郁时，选择性5-羟色胺再摄取抑制剂或三环类抗抑郁药可作为合适选择。治疗的第三阶段旨在通过联合局部和全身疗法打破瘙痒-搔抓循环，促进结节愈合和皮损消退。**3.1. 局限性病变**对于局限性或有限的PN，局部和皮损内皮质类固醇构成一线治疗。冷冻疗法适用于少数病变的特定患者，但可能因疼痛、色素减退或色素沉着等副作用受限。除皮质类固醇外，其他局部替代药物在PN管理中发挥重要作用：0.025%浓度的局部辣椒素可降低P物质水平；局部Janus激酶（JAK）抑制剂，特别是1.5%芦可替尼乳膏，代表新兴治疗类别；局部钙调神经磷酸酶抑制剂如他克莫司和吡美莫司、维生素D类似物如卡泊三醇和他卡西醇，以及局部麻醉剂如1%普莫卡因洗剂或利多卡因喷雾可作为替代局部治疗选择。需注意，许多这些治疗的有效性尚未通过大规模随机对照试验验证。**3.2. 广泛性和难治性病变的管理****3.2.1. 光疗**光疗在广泛性PN管理中作为一线治疗手段，因其对免疫调节和神经机制的双重作用。窄谱UVB（NB-UVB）光疗被推荐用于广泛性疾病或对局部/皮损内皮质类固醇反应不佳的难治性病例。NB-UVB通过抗炎作用减轻瘙痒，并为有多重合并症的患者提供安全替代选择。治疗方案通常为每周2-3次，持续约10周，常联合局部皮质类固醇。若无NB-UVB，PUVA（补骨脂素+UVA）疗法仍为可行选择，尤其是浴-PUVA单用或联合准分子激光。联合紫外线与局部药物可增强疗效，例如改良Goeckerman方案（每日宽带UVB、煤焦油和局部皮质类固醇）在治疗抵抗患者中已证明成功。光疗期间可辅助使用抗组胺药、三环类抗抑郁药、加巴喷丁、普瑞巴林、润肤剂和局部皮质类固醇等控制瘙痒。**3.2.2. 传统全身疗法**对于广泛性疾病或对局部治疗和光疗无效或不适合的患者，传统免疫抑制剂和全身疗法是临床上有价值的替代方案。从监管角度看，这些药物是超说明书治疗方式，缺乏对PN的官方批准，但仍作为标准临床选择广泛使用。甲氨蝶呤通常是首选药物，而环孢素保留用于更严重或需要快速治疗反应的病例。甲氨蝶呤（每周口服或皮下7.5-20 mg）在小型观察性研究中显示对难治性PN有益，多数患者皮损数量和严重程度显著减轻，瘙痒消退并维持临床缓解。环孢素（口服2-5 mg/kg/天）可快速控制瘙痒，临床系列报道平均2-4周内显著反应，多数患者达到缓解，但需监测高血压和肌酐升高。其他免疫抑制剂如硫唑嘌呤和环磷酰胺可能有效，但硫唑嘌呤的瘙痒改善常短暂且副作用率高。全身性皮质类固醇仅用于急性发作的短期管理（通常<4周），因严重全身副作用不适合长期使用。全身治疗需针对免疫和神经病理性成分采取整体方法，要求仔细选择患者、定期临床监测和谨慎管理潜在并发症。**4. 新颖和新兴治疗方法****4.1. 靶向策略概述**近年来对PN发病机制的深入理解促进了针对免疫和神经通路的新型药物开发。这些当前和新兴的治疗方法旨在通过靶向瘙痒复杂病理生理学的不同阶段，提供更有效和选择性的管理。Th2介导的炎症、细胞因子释放和神经免疫相互作用构成了这些新治疗策略的基础。在PN中，靶向免疫通路的注射疗法已被证明能有效减轻瘙痒和促进皮损愈合，生物制剂因此在PN管理中占据重要地位。靶向IL-4和IL-13通路的dupilumab在临床试验中显著减轻瘙痒严重程度并改善结节性皮损，成为首个获批用于PN的生物制剂。**4.2. 靶向神经发病机制/神经调节疗法**针对神经机制的治疗是PN管理策略的重要组成部分，尤其适用于对传统抗炎方法反应不佳的病例。口服加巴喷丁类药物是最常用的药物。加巴喷丁和普瑞巴林通过抑制钙信号转导减轻瘙痒。临床实践中，加巴喷丁应从低剂量起始（老年人起始100 mg夜间），缓慢滴定；年轻患者起始300 mg夜间，最大剂量约3600 mg/天（分三次）。普瑞巴林剂量范围为75-600 mg/天，需逐渐递增。加巴喷丁类药物对神经病理性成分突出的PN患者瘙痒减轻效果显著，但个体反应各异。最常见的剂量限制性副作用是镇静，尤其是高剂量时，需根据患者年龄、合并症和耐受性调整剂量。**4.2.1. 神经激肽-1受体（NK-1R）拮抗剂（阿瑞匹坦、塞洛匹坦）**NK-1R拮抗剂靶向P物质（SP）介导的信号级联。PN患者血清SP和NK-1R水平升高，以及真皮SP纤维密度增加，支持评估该通路的临床依据。阿瑞匹坦是一种口服NK-1R拮抗剂，在PN中超说明书使用（每日80 mg）。开放标签研究和小型病例系列报告阿瑞匹坦显著减轻瘙痒，但在随机II期试验中未能证明优于安慰剂。类似地，塞洛匹坦在II期试验中显著减轻瘙痒，但随后III期试验未达到主要终点，其用于PN的开发已终止。NK-1R拮抗剂可能对多数PN患者无效，但部分以神经功能障碍为主的亚组可能受益。此外，SP信号还可通过MRGPRX2等替代受体传递，可能解释NK-1R阻断的不足。因此，开发靶向MRGPRX2的新型拮抗剂是PN治疗的未来研究方向。**4.2.2. 沙利度胺和来那度胺**沙利度胺是一种超说明书使用的神经调节剂，用于对传统疗法抵抗的难治性PN。其疗效源于镇静、抗炎、免疫调节和抗血管生成特性。一项回顾性研究（n=42）显示口服沙利度胺100 mg/天约2年，50%病例获得中度至显著临床改善。然而，沙利度胺的使用因严重毒性（致畸性、血栓栓塞事件、中性粒细胞减少和剂量依赖性周围神经病变）而受限，神经毒性是长期使用中断的主要原因。来那度胺是其结构类似物，具有更强的抗炎效力，神经毒性和周围神经病变风险显著降低，但证据仅限于小型病例系列。两者均为顽固性患者的超说明书储备性全身治疗方式。**4.2.3. 靶向阿片受体的治疗****4.2.3.1. 阿片受体调节剂（纳布啡、布托啡诺、纳曲酮）**在PN发病机制中，瘙痒的中枢传递由脊髓阿片受体系统调节，致痒性μ-阿片受体（MOR）活性与止痒性κ-阿片受体（KOR）活性之间的失衡驱动慢性治疗抵抗性瘙痒。纳布啡是一种KOR激动剂和部分MOR拮抗剂。一项关键IIb/III期随机对照试验（n=371）显示，纳布啡在第10周时瘙痒严重程度显著降低（反应率25% vs 14%），但存在依赖风险。其他神经调节阿片类药物包括鼻内布托啡诺和口服纳曲酮。布托啡诺具有KOR激动剂和MOR拮抗剂特性，用于难治性病例中断瘙痒-搔抓循环，但缺乏对照试验支持。纳曲酮（口服50 mg/天）是纯MOR拮抗剂，在小型慢性瘙痒和PN患者队列中显示出部分止痒效果。**4.2.4. 抗抑郁药**在PN管理中，抗抑郁药作为止痒的辅助治疗选择，尤其适用于神经成分突出或靶向神经发病机制的情况。帕罗西汀、氟伏沙明、度洛西汀和阿米替林等药物可缓解轻中度瘙痒。抗抑郁药适合纳入个体化治疗方案，特别是对于神经发病机制占主导和潜在精神合并症的患者。使用抗抑郁药时需考虑副作用，如阿米替林和度洛西汀的镇静作用，三环类抗抑郁药因抗胆碱能副作用（口干、便秘、尿潴留）而受限，多塞平等药物有QT间期延长风险，需谨慎用于心脏病患者。**4.2.5. 大麻素**大麻素通过同时调节神经和免疫通路，具有独特的辅助治疗潜力，可显著减轻对一线疗法反应不佳的慢性瘙痒患者的症状。大麻素受体1（CB1）和2（CB2）在中枢神经系统和皮肤神经纤维中表达，参与抑制瘙痒信号传递。动物模型和有限临床数据表明大麻素激动剂具有强效止痒作用。一项开放标签临床研究显示，含选择性CB2激动剂N-棕榈酰乙醇胺的局部制剂在多数PN患者中显著减轻瘙痒。然而，当前证据仅限于小型患者队列，大麻素靶向制剂被归类为实验性、超说明书辅助选项，需大规模随机对照试验证实。**4.3. 当前和新兴靶向免疫通路的治疗**靶向免疫通路的新型药物通过抑制PN的炎症成分，在减轻瘙痒和促进皮损愈合中发挥关键作用。近年来，主要靶向机制包括白介素-31（IL-31）相关瘙痒信号、IL-4和IL-13介导的2型炎症，以及制瘤素Mβ（OSMβ）通路。针对这些通路的生物制剂和其他创新疗法在临床试验中显示出有希望的结果。**4.3.1. 生物治疗：已获批和新兴靶向药物****4.3.1.1. Dupilumab（IL-4Rα拮抗剂）**Dupilumab是一种人源化单克隆免疫球蛋白G4（IgG4）抗体，与白介素-4受体α（IL-4Rα）亚基结合，阻断IL-4和IL-13信号，抑制JAK-STAT通路介导的2型炎症反应。2022年9月，dupilumab成为首个获批用于成人PN的生物制剂（皮下注射），基于两项III期随机对照试验（LIBERTY-PN PRIME 1和PRIME 2，n=311）。第24周时，dupilumab组瘙痒反应（最严重瘙痒数字评分量表WI-NRS改善≥4分）达60%，安慰剂组为18%，45%-48%患者实现完全或近乎完全皮损清除。安全性良好，不良事件轻微，以结膜炎和疱疹感染最常见。Dupilumab无论患者特应性状态如何，均提供显著临床获益，尤其适用于对局部和传统全身治疗反应不佳的PN病例，特别是合并特应性皮炎（AD）者。**4.3.1.2. 靶向IL-31通路的生物治疗：Nemolizumab和Vixarelimab**Nemolizumab和vixarelimab是靶向IL-31通路的新一代生物制剂。Nemolizumab是针对IL-31受体的单克隆抗体，vixarelimab则同时抑制制瘤素M（OSM）和IL-31通路，抑制神经源性瘙痒和炎症。临床试验显示，IL-31抑制剂显著减轻瘙痒严重程度、改善睡眠质量和生活质量，是靶向、有效且耐受性良好的治疗选择，但需大规模研究评估其与其他全身治疗的比较疗效、长期安全性及预测治疗反应的生物标志物。**4.3.1.3. Nemolizumab（IL-31Rα靶向治疗）**Nemolizumab是一种人源化单克隆抗体，靶向白介素-31受体α（IL-31Rα），通过阻断IL-31介导的瘙痒信号抑制PN的神经成分。2024年8月，nemolizumab获批用于成人PN，推荐剂量为初始60 mg皮下负荷剂量，随后每4周30 mg维持剂量。关键III期试验（OLYMPIA 1和OLYMPIA 2，n=560）在第16周达到主要终点：nemolizumab组58.4%患者达到峰值瘙痒数字评分量表（PP-NRS）改善≥4分，安慰剂组16.7%；研究者整体评估（IGA）成功（0/1分）分别为26.3%和7.3%。止痒效果在48小时内开始，睡眠质量快速改善。安全性良好，最常见不良事件为头痛（6.6%）和AD发作（5.5%）。OLYMPIA DURABILITY维持试验（n=34）显示，继续治疗24周复发率显著低于停药（17% vs 75%）。长期安全性正在评估中。**4.3.1.4. Vixarelimab（KPL-716，抗OSMRβ单克隆抗体）/OSMRβ靶向治疗**Vixarelimab是一种针对制瘤素M受体β（OSMRβ）亚基的完全人源化单克隆抗体，靶向PN发病机制中的瘙痒和炎症。OSMRβ是IL-31和OSM信号通路的共同受体，阻断该通路可抑制瘙痒和炎症反应。目前为研究性药物，缺乏PN监管批准。一项IIa期随机双盲安慰剂对照试验（n=49）在第8周显示，vixarelimab使每周平均最严重瘙痒评分（WI-NRS）降低50.6%，安慰剂组为29.4%（p<0.05），同时改善睡眠障碍，耐受性良好。常见不良事件包括上呼吸道感染、鼻咽炎和荨麻疹。数据限于小样本，需更大规模研究明确其临床作用。**4.3.1.5. Barzolvolimab（CDX-0159）：新一代肥大细胞靶向治疗**Barzolvolimab是一种人源化单克隆抗体，靶向肥大细胞表面表达的受体酪氨酸激酶c-KIT，通过阻断KIT-干细胞因子（SCF）相互作用抑制肥大细胞活化和脱颗粒，减轻神经源性炎症和瘙痒。目前为研究性、超说明书生物制剂。一项Ib期开放标签剂量递增研究（n=24）在第12周显示，3.0 mg/kg静脉注射剂量组瘙痒评分降低57%，1.5 mg/kg组降低43%，安慰剂组降低25%，呈剂量依赖性止痒效果。血清类胰蛋白酶水平显著降低支持肥大细胞活性抑制。总体耐受性良好，无严重不良事件。鉴于肥大细胞在PN发病机制中的重要作用，barzolvolimab是肥大细胞靶向治疗中前景良好的药物。此外，靶向MRGPRX2和促肾上腺皮质激素释放因子（CRF）等替代通路的治疗被认为是PN管理的未来选择。**4.3.1.6. 白介素-5（IL-5）通路靶向治疗：Benralizumab**IL-5在嗜酸性粒细胞的分化、增殖、活化、粘附和存活中起核心作用，并促进肥大细胞和嗜碱性粒细胞向皮肤迁移。在PN发病机制中，嗜酸性粒细胞有助于维持神经免疫和炎症反应，尤其是在嗜酸性粒细胞内型中。Benralizumab是一种靶向IL-5受体α亚基（IL-5Rα）的单克隆抗体，通过抗体依赖性细胞介导的细胞毒性（ADCC）快速消耗循环和组织驻留嗜酸性粒细胞。目前获批用于严重嗜酸性粒细胞哮喘，在PN中为研究性、超说明书生物制剂，正处于II期临床试验中。可能为嗜酸性粒细胞炎症或嗜酸性粒细胞内型占主导的患者亚组提供潜在治疗选择。**4.3.1.7. Omalizumab――PN中的抗IgE方法**Omalizumab是一种抗IgE单克隆抗体，与游离免疫球蛋白E（IgE）结合，阻止其与高亲和力FcεRI受体相互作用，抑制肥大细胞、嗜碱性粒细胞和嗜酸性粒细胞上的IgE介导活化。在PN中，IgE介导的免疫反应、肥大细胞活化和嗜酸性粒细胞炎症可能起重要作用。Omalizumab通过结合游离IgE抑制这些细胞活化，减轻瘙痒和皮损，并通过降低神经生长因子（NGF）释放促进瘙痒-搔抓循环中断和皮损愈合。临床数据主要限于病例报告和小型病例系列，报告了结节性、丘疹性和斑块性PN亚型中瘙痒严重程度和皮损计数的显著降低。但缺乏随机对照试验数据，最佳患者选择标准尚未明确。新型抗IgE药物如ligelizumab正在研究中。**4.3.1.8. Tralokinumab和Lebrikizumab：PN中新兴的IL-13靶向治疗**Tralokinumab和lebrikizumab是靶向白介素-13（IL-13）的皮下注射单克隆抗体，目前为PN中的研究性、超说明书生物制剂。IL-13是2型炎症的关键细胞因子，与瘙痒发病机制和表皮屏障功能障碍密切相关。Tralokinumab直接结合IL-13，阻止其与IL-13Rα1和IL-13Rα2受体相互作用；Lebrikizumab通过阻止IL-13与IL-13Rα1和IL-4Rα形成功能性受体复合物来阻断IL-13信号。两者在AD中的II期临床试验显示快速显著减轻瘙痒，不良事件轻微（结膜炎和上呼吸道感染最常见）。针对PN的随机对照试验尚未完成，需进一步研究明确其疗效和安全性。**4.3.1.9. Rocatinlimab（OX40抑制剂）和PN中新型T细胞靶向方法**Rocatinlimab是一种完全人源单克隆IgG1抗体，靶向OX40（CD134），破坏OX40-OX40L通路，抑制T细胞增殖和存活，从而降低Th2、Th1、Th17和Th22反应，减少IL-4、IL-13和IL-22水平。在AD的IIb期试验中，rocatinlimab使EASI评分降低高达61%，显著控制瘙痒，并维持长期临床获益。目前，一项针对PN的III期试验（NCT06527404）正在进行中，评估皮下注射rocatinlimab的疗效和安全性，主要终点为第24周的瘙痒减轻和临床改善。**4.3.2. JAK抑制剂与PN**JAK抑制剂是小分子药物，靶向细胞因子信号通路，特别是JAK1和JAK2。与生物制剂相比，它们通过同时阻断多种细胞因子通路提供广谱效应。在PN中，口服和局部JAK抑制剂目前为超说明书使用。其最大优势是起效迅速，治疗数天内即可观察到瘙痒和皮肤疼痛显著减轻。主要安全警告包括增加病毒感染、主要不良心血管事件（MACE）和静脉血栓栓塞（VTE）风险，但这些风险高度受患者选择（如高龄、代谢合并症）和剂量策略影响。新型高选择性JAK1抑制剂如upadacitinib和abrocitinib在临床中显示出良好的安全性。需要仔细选择患者并密切监测，特别是老年、有显著合并症或高血栓栓塞风险的患者。**4.3.2.1. 局部芦可替尼（JAK1/JAK2抑制剂）**局部芦可替尼通过阻断JAK-STAT信号通路减轻炎症和瘙痒，抑制嗜酸性粒细胞活化和T调节（Treg）细胞抑制。已获批用于12岁以上轻中度AD。在TRuE-AD1和TRuE-AD2 III期试验中，首次涂抹后12小时即观察到瘙痒显著减轻，第8周约50%患者达到IGA 0-1反应，疗效持续至第52周。一项针对PN的III期随机双盲赋形剂对照试验（TRuE-PN）正在进行中，评估1.5%芦可替尼乳膏的安全性和有效性，预计纳入383例患者，第16周为初步评估时间点。常见不良事件包括头痛、上呼吸道感染和涂抹部位瘙痒或烧灼感。尽管全身吸收低，但处方信息包含与口服JAK抑制剂类似的MACE、血栓形成和恶性肿瘤警告。**4.3.2.2. Abrocitinib（选择性JAK1抑制剂）**Abrocitinib是一种选择性口服JAK1抑制剂，获批用于中重度AD。通过选择性抑制JAK1，抑制多种致痒和致炎细胞因子（尤其是IL-4、IL-13和IL-31）的信号传导。在一项II期开放标签非随机试验（n=12）中，abrocitinib 200 mg/天单药治疗12周，在PN和不明原因慢性瘙痒（CPUO）患者中显著改善瘙痒严重程度和生活质量。PN组报告了临床显著且高比例的瘙痒评分降低。治疗耐受性良好，无严重不良事件。需更广泛的对照临床试验阐明其疗效和安全性。**4.3.2.3. Upadacitinib（选择性JAK1抑制剂）**Upadacitinib是一种选择性口服JAK1抑制剂，通过抑制JAK-STAT信号通路减轻瘙痒传递和皮肤炎症，目前已获批用于中重度AD，并正在研究用于难治性PN。一项24周真实世界回顾性队列研究（n=10）显示，每日口服upadacitinib 15 mg可快速显著减轻瘙痒严重程度、疾病活动性和改善皮肤病变，生活质量显著提高。治疗耐受性良好，无严重不良事件。这些有限但有希望的数据表明upadacitinib可能是难治性PN的快速起效的口服靶向治疗选择，但需更大规模对照试验确定长期安全性和疗效。**4.3.2.4. Povorcitinib（选择性口服JAK1抑制剂）**Povorcitinib是一种选择性口服JAK1抑制剂，目前正在研究用于PN。一项II期随机双盲安慰剂对照试验（n=126）的40周结果显示，povorcitinib治疗使瘙痒严重程度（NRS≥4）和皮肤病变（IGA-TS）显著改善，治疗反应在整个延长期内维持。药物耐受性良好，长期随访未发现新安全信号。目前正在进行的III期STOP-PN1研究正在评估不同剂量方案在约140例PN患者中的疗效和安全性。**4.3.2.5. Tofacitinib和Baricitinib（JAK抑制剂）**关于tofacitinib（JAK1/3抑制剂）和baricitinib（JAK1/2抑制剂）的病例报告和小型病例系列表明，这些药物可能为难治性PN提供潜在治疗益处。目前证据仅限于小型队列（n≤3），缺乏大规模试验。Tofacitinib治疗导致瘙痒严重程度和疾病活动性显著降低，报道起效迅速（平均约11天），大部分患者维持持续缓解。推测tofacitinib通过抑制STAT6/STAT3介导的Th2/Th17炎症发挥强效止痒和抗炎作用。需对照大规模临床试验充分阐明其疗效和安全性。**4.4. 补充剂：N-乙酰半胱氨酸（NAC）在PN中的应用**NAC是一种硫醇化合物，具有抗氧化、抗炎和神经递质调节特性。它可能通过调节谷氨酸能系统、减少氧化应激和抑制细胞增殖来影响瘙痒和神经炎症。通过抑制成纤维细胞和角质形成细胞增殖，有助于恢复表皮屏障功能。NAC在皮肤搔抓障碍、拔毛癖等精神相关皮肤病以及表皮屏障功能障碍疾病中已显示获益。关于NAC在PN中的临床证据有限，小型病例系列报告口服NAC 1200 mg/天可部分改善亚急性PN患者的临床症状。现有数据表明NAC可能作为PN的支持性和潜在治疗选择，但需更大规模对照研究确定其确切疗效。**5. 结论**PN是一种慢性、神经免疫介导的皮肤病，严重损害生活质量。其发病机制具有多因素结构，涉及Th1、Th2、Th17和Th22免疫失调、神经元敏感性增加和神经肽改变。尽管这种异质性发病机制在概念上支持基于临床表型和生物标志物谱定义不同内型的潜力，但将这种分层转化为日常实践仍是精准皮肤病学的新兴目标。目前，临床决策主要依赖疾病严重程度、临床范围和个体全身合并症。近期临床框架已确立明确治疗路径：获批的靶向IL-4/IL-13和IL-31轴的生物制剂在特应性和非特应性人群中均提供持久疗效；同时，JAK抑制剂对难治性疾病提供高效、多细胞因子抑制和超快速起效，但需严格患者选择和专科监测。阿片受体调节剂和NK1受体拮抗剂等替代选择在广泛人群水平上缺乏疗效，但在管理以神经功能障碍为主的特定患者亚组中具有有限的辅助作用。这些进展强调统一方法在现代PN护理中不足，凸显向定制化治疗框架的明确临床转变。未来对内型的更精细验证有望优化免疫调节和神经调节治疗的序贯、轮换和长期维持方案。

Initiated Phase 3 OCEAN-1 trial for patients with idiopathic pulmonary fibrosis-related chronic cough in the second quarter; Phase 3 OCEAN-2 trial expected to initiate in the third quarter of 2026 Initiated Phase 2b LAKE trial for patients with refractory chronic cough in the second quarter; sample size re-estimation expected in the fourth quarter of 2026 Management to host a conference call and webcast today at 4:30 p.m. ET  NEW HAVEN, Conn., Aug. 06, 2026 (GLOBE NEWSWIRE) -- Trevi Therapeutics, Inc. (Nasdaq: TRVI), a clinical-stage biopharmaceutical company developing the investigational therapy Haduvio™ (oral nalbuphine ER) for the treatment of chronic cough in patients with idiopathic pulmonary fibrosis (IPF), non-IPF interstitial lung disease (non-IPF ILD), and refractory chronic cough (RCC), today announced financial results for the quarter ended June 30, 2026, and provided business updates. ezstandalone.cmd.push(function () { ezstandalone.showAds(131); }); “We are on track with our clinical trial plans as we initiated our first Phase 3 trial of Haduvio in patients with IPF-related chronic cough and a Phase 2b trial in patients with RCC during the second quarter. We expect to initiate our second Phase 3 trial in IPF-related chronic cough during the third quarter and meet with the FDA regarding our planned non-IPF ILD-related chronic cough trial,” said Jennifer Good, President and CEO of Trevi Therapeutics. “With an experienced team dedicated to advancing our trials across all three of our chronic cough indications, and a strong balance sheet following our April financing, we are well positioned to execute on our plans. We recognize the significant unmet need these patients have and are working diligently to enroll our trials. Following the recent changes in the competitive landscape, and with no FDA-approved therapies currently available, Haduvio has the potential to become a first-in-class therapy that makes a meaningful difference in patients' lives.” Recent Business Highlights IPF-Related Chronic Cough The Company initiated the Phase 3 OCEAN-1 trial , the first of two parallel conducted Phase 3 trials in patients with IPF-related chronic cough, in the second quarter of 2026. Topline data from the 52-week fixed dosing OCEAN-1 trial is expected in the first half of 2028. The Company plans to initiate the 12-week fixed dosing OCEAN-2 trial, in the third quarter of 2026, with topline results expected in the second half of 2027. Non-IPF ILD-Related Chronic Cough The Company recently submitted a meeting request to the FDA to discuss the proposed development plan for non-IPF ILD-related chronic cough and to align on the overall regulatory strategy and requirements to support registration. Refractory Chronic Cough The Company initiated the Phase 2b LAKE trial in patients with RCC in the second quarter of 2026. The protocol includes a sample size re-estimation (SSRE) analysis once 50% of the participants complete treatment which is expected to occur in the fourth quarter of 2026. The Company will report the outcome of the SSRE once available and expects to report topline results from the trial in the second half of 2027. Second Quarter 2026 Financial Highlights  Cash, cash equivalents and marketable securities: The Company ended the second quarter of 2026 with $318.9 million. In April 2026, the Company completed an underwritten common stock offering , resulting in net proceeds of approximately $162.3 million, after deducting underwriting discounts, commissions and offering expenses. The Company expects its current cash, cash equivalents and marketable securities to extend its cash runway into 2030 and fund the development of Haduvio for the treatment of patients with IPF-related chronic cough, through potential FDA approval. The Company also expects these cash resources will enable the Company to fund the clinical development program through Phase 3 for the treatment of patients with non-IPF ILD-related chronic cough, and the ongoing Phase 2b LAKE trial for the treatment of patients with RCC. The planned spending of these resources does not include any commercial expenses related to the commercial launch of Haduvio or a Phase 3 clinical trial in RCC. Research and development (R&D) expenses: R&D expenses for the second quarter of 2026 increased to $15.2 million from $9.4 million in the same period in 2025, primarily due to increased clinical development expenses for the Phase 3 OCEAN-1 trial, the Phase 2b LAKE trial, the Phase 3 OCEAN-2 trial and the Phase 1 NDA supportive studies, as well as increases in stock-based compensation and personnel related expenses. These increases were partially offset by decreased costs for the Phase 2b CORAL trial of Haduvio for patients with IPF-related chronic cough. General and administrative (G&A) expenses: G&A expenses for the second quarter of 2026 increased to $5.4 million from $4.3 million in the same period in 2025, primarily due to an increase in stock-based compensation and personnel related expenses, partially offset by decreased outside services and professional fees. Other Income, net: Other Income, net for the second quarter of 2026 increased to $2.7 million from $1.4 million in the same period in 2025, primarily due to an increase in interest income from higher invested cash equivalent and marketable securities balances. Net loss: For the second quarter of 2026, the Company reported a net loss of $17.8 million, compared to a net loss of $12.3 million in the same period in 2025. Conference Call and Webcast The Company plans to hold a conference call and webcast to discuss the Company’s financial results and business highlights. To register for the live conference call and webcast, please visit the ‘Investors & News’ section of the Company’s website or access directly at  ir.trevitherapeutics.com/news-events/events . Please note for phone participants: Once registered, you will receive an email with unique call-in details. An archived replay of the webcast will also be available for 30 days on the Company's website following the event. Upcoming Meetings The Company plans to participate in the following events:    August 10-12: Stifel’s 2026 Biotech Summer Summit September 9-11: 2026 Cantor Global Healthcare Conference September 14-16: H.C. Wainwright 28th Annual Global Investment Conference September 14-16: Morgan Stanley 24th Annual Global Healthcare Conference About Trevi Therapeutics, Inc. Trevi Therapeutics, Inc. is a clinical-stage biopharmaceutical company developing the investigational therapy Haduvio™ (oral nalbuphine extended-release) for the treatment of chronic cough in patients with idiopathic pulmonary fibrosis (IPF), non-IPF interstitial lung disease (non-IPF ILD), and refractory chronic cough (RCC). In clinical trials, Haduvio showed a statistically-significant reduction in cough frequency, consistent across baseline cough frequencies, and showed improvements in patient-reported outcomes, in both patients with IPF-related chronic cough and in patients with RCC. Haduvio is believed to act on the cough reflex arc both centrally and peripherally as a kappa agonist and a mu antagonist (KAMA), targeting opioid receptors that play a key role in controlling chronic cough. Nalbuphine is not currently scheduled by the U.S. Drug Enforcement Agency. Chronic cough in patients with IPF and non-IPF ILD is a condition with high unmet need and no FDA-approved therapies. There are ~140,000 U.S. patients with IPF, and two-thirds of these patients are faced with uncontrolled chronic cough. Additionally, there are ~228,000 U.S. patients with non-IPF ILD, with 50-60% having uncontrolled chronic cough. The impact of chronic cough is significant, with patients coughing up to 1,500 times per day. This consistent cough, and any associated damage, may lead to a higher risk of morbidity and mortality, including worsening disease, a higher risk of progression, increased respiratory hospitalizations, and a decline in patients' quality of life. RCC is a condition with high unmet need and no FDA-approved therapies. RCC is defined as a persistent cough lasting >8 weeks despite treatment for an underlying condition (i.e., asthma, gastroesophageal reflux disease, non-asthmatic eosinophilic bronchitis, upper airway cough syndrome, or post-nasal drip) and includes unexplained chronic cough. There are ~2-3 million U.S. patients with RCC, and it is believed to be associated with cough reflex hypersensitivity involving both the central and peripheral nervous systems. RCC is highly debilitating and may impact patients physically, psychologically, and socially. Trevi intends to propose Haduvio as the trade name for oral nalbuphine ER. Its safety and efficacy have not been evaluated by any regulatory authority. For more information, visit  and follow Trevi on  X  (formerly Twitter) and  LinkedIn .   Forward-Looking Statements Statements contained in this press release regarding matters that are not historical facts are “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. Such statements are subject to risks and uncertainties and actual results may differ materially from those expressed or implied by such forward-looking statements. Such statements include, but are not limited to, Trevi’s estimated cash runway, statements regarding Trevi’s business plans and objectives, including future plans or expectations for Haduvio and plans and timing with respect to clinical trials and clinical data, as well as regulatory submissions, statements regarding FDA guidance and approval, and expectations regarding Trevi’s uses and sufficiency of capital, and other statements containing the words “believes,” “anticipates,” “plans,” “expects,” “may,” and similar expressions. Risks that contribute to the uncertain nature of the forward-looking statements include: uncertainties inherent in estimating Trevi’s cash runway, future expenses and other financial results, including Trevi’s ability to fund future operations, including clinical trials; uncertainties regarding the success, cost and timing of Trevi’s product candidate development activities and clinical trials, including with respect to the timing of the initiation of and generation of data from clinical trials; the risk that positive data from a clinical trial may not necessarily be predictive of the results of later clinical trials in the same or a different indication; uncertainties regarding Trevi’s ability to execute on its strategy; uncertainties with respect to regulatory authorities' views as to the data from Trevi’s clinical trials and next steps in the development path for Haduvio in the United States and foreign countries; as well as other risks and uncertainties set forth in the annual report on Form 10-K for the year ended December 31, 2025 filed with the Securities and Exchange Commission and in subsequent filings with the Securities and Exchange Commission. All forward-looking statements contained in this press release speak only as of the date on which they were made. Trevi undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made. Trevi Therapeutics, Inc. Selected Balance Sheet Data (unaudited) (amounts in thousands) June 30, 2026 December 31, 2025 Cash and cash equivalents $ 54,302 $ 18,914 Marketable securities 264,568 169,346 Working capital 316,969 181,907 Total assets 330,518 193,439 Stockholders' equity 321,506 183,244 Trevi Therapeutics, Inc. Selected Statement of Operations Data (unaudited) (amounts in thousands, except per share amounts) Three Months Ended June 30, Six Months Ended June 30, 2026 2025 2026 2025 Operating expenses: Research and development $ 15,152 $ 9,389 $ 25,093 $ 17,200 General and administrative 5,357 4,333 10,328 7,992 Total operating expenses 20,509 13,722 35,421 25,192 Loss from operations (20,509 ) (13,722 ) (35,421 ) (25,192 ) Other income, net 2,693 1,400 4,393 2,519 Loss before income taxes (17,816 ) (12,322 ) (31,028 ) (22,673 ) Income tax benefit (19 ) (21 ) (39 ) (32 ) Net loss $ (17,797 ) $ (12,301 ) $ (30,989 ) $ (22,641 ) Basic and diluted net loss per common share outstanding $ (0.11 ) $ (0.09 ) $ (0.21 ) $ (0.18 ) Weighted average common shares used in net loss per share attributable to common stockholders, basic and diluted 156,602,158 130,350,391 151,127,942 124,015,763 Investor Contact Jonathan Carlson Trevi Therapeutics, Inc. (203) 654 3286 IR@trevitx.com Media Contact Rosalia Scampoli 914-815-1465 rscampoli@marketcompr.com