Identification of a neutrophil-specific PIK3R1 mutation facilitates targeted treatment in a patient with Sweet syndrome
Shreya Bhattacharya, … , Misha Rosenbach, Thomas H. Leung
Shreya Bhattacharya, … , Misha Rosenbach, Thomas H. Leung
Published November 10, 2022
Citation Information: J Clin Invest. 2023;133(1):e162137. https://doi.org/10.1172/JCI162137.
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Clinical Medicine Dermatology Inflammation

Identification of a neutrophil-specific PIK3R1 mutation facilitates targeted treatment in a patient with Sweet syndrome

Abstract

Background Acute 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.Methods A 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.Results We 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.Conclusion Dysregulated 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 Sources Berstein Foundation, NIH, Veterans Affairs (VA) Administration, Moseley Foundation, and H.T. Leung Foundation.

Authors

Shreya Bhattacharya, Sayon Basu, Emily Sheng, Christina Murphy, Jenny Wei, Anna E. Kersh, Caroline A. Nelson, Joshua S. Bryer, Hovik A. Ashchyan, Katherine Steele, Amy Forrestel, John T. Seykora, Robert G. Micheletti, William D. James, Misha Rosenbach, Thomas H. Leung

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Figure 1

The patient with refractory Sweet syndrome required multiple hospitalizations to control the disease.

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The patient with refractory Sweet syndrome required multiple hospitaliza...
(A) Clinical photographs of the patient’s skin lesions. Panels on the right are H&E-stained images of the patient’s skin biopsy, which demonstrate a diffuse dermal neutrophilic infiltration. Scale bar: 200 μM. Original magnification, ×20 (enlarged inset). (B and C) Time course of the patient’s peripheral neutrophilia (B) and liver enzyme fluctuations (C) during her multiple clinical flares. The patient’s 4 hospitalizations for disease flares are denoted by the green boxes. Alk phos, alkaline phosphatase; AST, aspartate aminotransferase.