Pyoderma gangrenosum and its syndromic forms: evidence for a link with autoinflammation

Abstract

Pyoderma gangrenosum is a rare inflammatory neutrophilic dermatosis manifesting as painful ulcers with violaceous, undermined borders on the lower extremities. It may occur in the context of classic syndromes like PAPA (pyogenic arthritis, pyoderma gangrenosum and acne) and SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis), as well as in a recently described entity named PASH (pyoderma gangrenosum, acne and suppurative hidradenitis). Pyoderma gangrenosum has recently been included within the spectrum of autoinflammatory diseases, which are characterized by recurrent episodes of sterile inflammation, without circulating autoantibodies and autoreactive T cells. In PAPA syndrome, different mutations involving the PSTPIP1 gene, via an increased binding affinity to pyrin, induce the assembly of inflammasomes. These are molecular platforms involved in the activation of caspase 1, a protease that cleaves inactive prointerleukin (pro-IL)-1β to its active isoform IL-1β. The overproduction of IL-1β triggers the release of a number of proinflammatory cytokines and chemokines, which are responsible for the recruitment and activation of neutrophils, leading to neutrophil-mediated inflammation. In SAPHO syndrome, the activation of the PSTPIP2 inflammasome has been suggested to play a role in inducing the dysfunction of the innate immune system. Patients with PASH have recently been reported to present alterations of genes involved in well-known autoinflammatory diseases, such as PSTPIP1, MEFV, NOD2 and NLRP3. Pyoderma gangrenosum and its syndromic forms can be regarded as a single clinicopathological spectrum in the context of autoinflammation.

Pyoderma gangrenosum, acne, and hidradenitis suppurativa (PASH) syndrome with recurrent vasculitis

“…The overproduction of IL-1ß leads to uncontrolled release of pro-inflammatory cytokines, particularly IL-17, which direct recruitment and activation of neutrophils. 3,4 This corresponds to neutrophil-mediated inflammation of the skin clinically as PG, HS, and acne. Our patient had a steroid resistant vasculitis that developed while other PASH symptoms were also active.…”

“…Several treatments for PASH syndrome exist with varying degrees of efficacy, [2][3][4] but no treatment has been accepted as the standard therapy. Prolonged antibiotic therapy, topical tacrolimus ointment, and surgical ablation of abscesses and sinus tracts related to HS lesions have all been described.…”

Acne-Associated Syndromes

“…SAPHO syndrome is a rare disease so usually misdiagnosed because this syndrome have similar clinical features with infectious discitis, seronegative SpA, and psoriatic arthritis (PsA), and skin and bone lesions may appear at diferent times [34].…”

“…PPP is the most common skin involvement, including pustular psoriasis, representing 50-75% of all dermatologic manifestations, psoriasis vulgaris may also be seen among the dermatologic manifestations of SAPHO. One fourth of patients have acne conglobata and fulminans with men clearly predominating [34]. Hidradenitis suppurativa may also be seen.…”

Old but Gold: The Importance of Medical History in Diagnosing Neutrophilic Dermatoses Characterized by Pathergy. A Case of Pyoderma Gangrenosum

“…One helpful clinical feature for diagnosing active PG may be the presence of "pathergy" or the occurrence of lesions at sites of trauma, in up to 30% of the patients [2][3][4]. PG may be idiopathic, but it is associated with an underlying disease in 50% of patients [5].…”