Dermatology Department, Perelman School of Medicine, University of Pennsylvania; Philadelphia, Pennsylvania, USA.
Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, Pennsylvania, USA.
J Clin Invest. 2023 Jan 3;133(1):e162137. doi: 10.1172/JCI162137.
BackgroundAcute febrile neutrophilic dermatosis (Sweet syndrome) is a potentially fatal multiorgan inflammatory disease characterized by fever, leukocytosis, and a rash with a neutrophilic infiltrate. The disease pathophysiology remains elusive, and current dogma suggests that Sweet syndrome is a process of reactivity to an unknown antigen. Corticosteroids and steroid-sparing agents remain frontline therapies, but refractory cases pose a clinical challenge.MethodsA 51-year-old woman with multiorgan Sweet syndrome developed serious corticosteroid-related side effects and was refractory to steroid-sparing agents. Blood counts, liver enzymes, and skin histopathology supported the diagnosis. Whole-genome sequencing, transcriptomic profiling, and cellular assays of the patient's skin and neutrophils were performed.ResultsWe identified elevated IL-1 signaling in lesional Sweet syndrome skin caused by a PIK3R1 gain-of-function mutation specifically found in neutrophils. This mutation increased neutrophil migration toward IL-1β and neutrophil respiratory burst. Targeted treatment of the patient with an IL-1 receptor 1 antagonist resulted in a dramatic therapeutic response and enabled a tapering off of corticosteroids.ConclusionDysregulated PI3K/AKT signaling is the first signaling pathway linked to Sweet syndrome and suggests that this syndrome may be caused by acquired mutations that modulate neutrophil function. Moreover, integration of molecular data across multiple levels identified a distinct subtype within a heterogeneous disease that resulted in a rational and successful clinical intervention. Future patients will benefit from efforts to identify potential mutations. The ability to directly interrogate the diseased skin allows this method to be generalizable to other inflammatory diseases and demonstrates a potential personalized medicine approach for patients with clinically challenging disease.Funding SourcesBerstein Foundation, NIH, Veterans Affairs (VA) Administration, Moseley Foundation, and H.T. Leung Foundation.
急性发热性嗜中性皮病（Sweet 综合征）是一种潜在致命的多器官炎症性疾病，其特征为发热、白细胞增多和伴有中性粒细胞浸润的皮疹。该疾病的病理生理学仍不清楚，目前的主流观点认为 Sweet 综合征是对未知抗原的反应过程。皮质类固醇和类固醇类药物仍然是一线治疗方法，但难治性病例构成了临床挑战。
一名 51 岁女性患有多器官 Sweet 综合征，出现严重的皮质类固醇相关副作用且对类固醇类药物不耐受。血液计数、肝酶和皮肤组织病理学检查支持诊断。对患者的皮肤和中性粒细胞进行了全基因组测序、转录组分析和细胞检测。
我们发现，在病变的 Sweet 综合征皮肤中，IL-1 信号转导升高，这是一种特定存在于中性粒细胞中的 PIK3R1 功能获得性突变引起的。这种突变增加了中性粒细胞向 IL-1β 的迁移和中性粒细胞呼吸爆发。使用一种 IL-1 受体 1 拮抗剂靶向治疗患者，产生了显著的治疗反应，并使皮质类固醇得以减量。
失调的 PI3K/AKT 信号转导是与 Sweet 综合征相关的第一个信号通路，并表明该综合征可能是由调节中性粒细胞功能的获得性突变引起的。此外，整合多个层面的分子数据，在异质性疾病中确定了一个独特的亚型，从而产生了合理且成功的临床干预。未来的患者将受益于识别潜在突变的努力。直接检测患病皮肤的能力使这种方法可推广到其他炎症性疾病，并为患有具有挑战性的临床疾病的患者展示了一种潜在的个性化医疗方法。
Bernstein 基金会、NIH、VA 管理局、Moseley 基金会和 H.T. Leung 基金会。
