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

Pyoderma gangrenosum is a rare inflammatory neutrophilic dermatosis manifesting as painful ulcers with violaceous, undermined borders on 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) syndromes 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 (proline-serine-threonine phosphatase-interacting protein 1) 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 which cleaves inactive pro-interleukin (IL)-1 beta to its active isoform IL-1 beta. The overproduction of IL-1 beta triggers the release of a number of proinflammatory cytokines and chemokines which are responsible for the recruitment and activation of neutrophils, leading to a 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. PASH patients have recently been reported to present alterations of genes involved in well known autoinflammatory diseases, such as PSTPIP1, MEFV (mediterranean fever), NOD2 (nucleotide-binding oligomerization domain-containing protein 2) and NLRP3 (NOD-like receptor family, pyrin domain containing 3). Pyoderma gangrenosum and its syndromic forms can be regarded as a single clinicopathological spectrum in the context of autoinflammation. This article is protected by copyright. All rights reserved.