Mechanisms of Inflammation in the Neutrophilic Dermatoses

Abstract

Neutrophilic dermatoses are a heterogenous group of conditions characterized by accumulation of neutrophils in the skin and, rarely, the internal organs [1, 2]. The cutaneous manifestations of neutrophilic dermatoses are polymorphic, including pustules, bullae, abscesses, papules, nodules, plaques and ulcers, and almost any organ system can be involved, giving rise to the term ‘neutrophilic disease’ [2]. The definition of neutrophilic dermatoses is similar to that of autoinflammatory diseases, which encompass a wide spectrum of conditions that are hallmarked by recurrent episodes of inflammation in the affected organs, in the absence of infection, allergy and high titer of circulating autoantibodies or autoreactive T cells [3]. The prototype of neutrophilic dermatoses is pyoderma gangrenosum, which typically manifests as a skin ulcer with undermined erythematous-violaceous borders, but it may also present with pustular, bullous and vegetating plaque-type lesions [1, 4]. Pyoderma gangrenosum may be isolated or associated with systemic conditions (i.e. inflammatory bowel diseases, rheumatological disorders and lymphoproliferation as well as other blood disorders), or occur in the context of autoinflammatory syndromes such as PAPA (pyogenic arthritis, PG and acne) [5], PASH (PG, acne and suppurative hidradenitis [also known as hidradenitis suppurativa; HS) [4, 6, 7] or other more recently described syndromes such as PAPASH (pyogenic arthritis, acne, PG and suppurative hidradenitis) [8]. The classic monogenic autoinflammatory syndromes such as PAPA are due to mutations of single genes regulating the innate immunity [5, 9]; however, there is increasing evidence that mutations in different genes involved in autoinflammation are associated with other neutrophilic dermatoses [7, 8, 10]. Here we review the pathophysiology of neutrophilic dermatoses focusing on the expression of cytokines and other effector molecules involved in autoinflammation as well as on their genetic profile, in order to support the inclusion of pyoderma gangrenosum and the other neutrophilic dermatoses in the spectrum of autoinflammatory diseases. This inclusion may provide the rationale for treatment aimed at blocking the cytokines crucially involved in autoinflammation.