The neutrophilic dermatitides: a contemporary reassessment of pathophysiological mechanisms, clinical phenotypes and therapeutic stratification

Abstract

The neutrophilic dermatitides constitute a heterogeneous spectrum of inflammatory cutaneous disorders unified by a dominant histopathological motif of sterile neutrophilic infiltrates within the dermis, in the absence of primary infection or vasculitis. This extensive review synthesizes contemporary insights into their complex pathophysiology, which is increasingly understood as a dysregulated interplay between the innate immune system, specifically involving the interleukin-1 (IL-1) family cytokines, NLRP3 inflammasome activation, and neutrophil extracellular traps (NETs), and a permissive genetic background often influenced by somatic mutations in clonal hematopoiesis-related genes. We provide a critical analysis of the expanding clinical and histological continuum, encompassing classic entities such as Sweet’s syndrome, pyoderma gangrenosum, Behçet’s disease, and the autoinflammatory syndromes, while addressing overlapping and atypical presentations that pose significant diagnostic challenges. Furthermore, we systematically evaluate the evolving therapeutic landscape, moving beyond traditional immunosuppressants toward targeted biologic agents and small molecules that inhibit specific pro-inflammatory pathways. By integrating the latest molecular discoveries with clinical pragmatism, this review aims to refine diagnostic criteria, elucidate pathogenic connections to underlying systemic disease—particularly myeloid dyscrasias and gastrointestinal inflammation—and propose a rationale for personalized, mechanism-driven treatment algorithms. This reassessment underscores the paradigm of these conditions as cutaneous reflexes of systemic autoinflammation.