PAPA and related syndromes

Pyoderma gangrenosum (PG) is a prototypical neutrophilic dermatosis that usually manifests itself in the form of cutaneous ulcers with undermined erythematous-violaceous borders. It may be isolated or associated with systemic conditions (i.e. inflammatory bowel diseases, rheumatological disorders and lymphoproliferation), or occur in the context of autoinflammatory syndromes such as PAPA (pyogenic arthritis, PG and acne), PASH (PG, acne and suppurative hidradenitis) or other more recently described syndromes such as PAPASH (pyogenic arthritis, acne, PG and suppurative hidradenitis). Autoinflammatory diseases (AIDs) are characterised by apparently unprovoked episodes of systemic inflammation in the absence of the typical features of autoimmunity, such as autoantibodies or antigen-specific T lymphocytes. All of the autoinflammatory syndromes described here have the shared characteristic of skin involvement, hallmarked by an accumulation of neutrophils. Inflammatory conditions characterised by infiltrates mainly consisting of mature neutrophils without infection are defined as neutrophilic dermatoses. Originally, the main forms of neutrophilic dermatoses included prototypical conditions such as PG, Sweet’s syndrome, subcorneal pustular dermatosis, and erythema elevatum diutinum, but this list was subsequently extended to other diseases, including syndromic entities. From a pathophysiological point of view, these neutrophilic dermatoses present high levels of the same pro-inflammatory cytokines, chemokines and tissue damage effector molecules as those found in AIDs. Taken together, these aspects suggest that autoinflammatory syndromes and neutrophilic dermatoses have the common pathological mechanisms of an overactivated innate immune system leading to the increased production of the IL-1 family and “sterile” neutrophil-rich cutaneous inflammation. The autoinflammatory syndromes characterised by neutrophilic dermatoses therefore represent a model of integration between two conditions that can probably be considered “innate immune disorders”