Recently, we had a patient with acute febrile neutrophilic dermatosis (Sweet syndrome), a potentially fatal multiorgan inflammatory disease. While corticosteroids and steroid sparing agents remain mainstays of treatment, she was refractory to these treatments and posed a clinical challenge. Using whole genome sequencing and transcriptomic profiling, we identified a PIK3R1 gain-of-function mutation that is specifically found in neutrophils. This mutation specifically increased neutrophil migration towards IL-1β. Targeted treatment with an IL-1 receptor antagonist in the refractory patient resulted in a dramatic therapeutic response and enabled tapering of corticosteroids. 

 

Dysregulated PI3K-AKT signaling is the first signaling pathway linked to Sweet syndrome. Our data counters the current dogma that Sweet Syndrome is simply a “reactive” process to an unknown antigen. Integration of molecular data across multiple levels identified a distinct subtype within a heterogenous disease that resulted in a successful clinical intervention enabling disease control. This rational and personalized therapy is, to our knowledge, the first example of identifying a targeted treatment for Sweet syndrome. It showed how the use of modern molecular and genetic techniques may create a personalized treatment approach in a challenging patient. We are using this approach for mechanistic interrogation of diseased skin to other skin diseases.