Pyogenic Arthritis, Pyoderma Gangrenosum, and Acne (PAPA) Syndrome

Abstract

Pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome is a rare autosomal dominant autoinflammatory syndrome characterized by early onset of recurrent episodes of severe inflammation of skin and joints. PAPA is caused by different mutations in the proline-serine-threonine phosphatase-interacting protein (PSTPIP1) gene located on chromosome 15. Mutations in PSTPIP1 are incompletely penetrant and variably expressed in the PAPA syndrome. The pathogenesis of PAPA is complex, as the PSTPIP1/CD2BP1 protein acts as a scaffold protein participating in the organization of the actin cytoskeleton and modulates T cell activation and IL-1β release. Indeed, PSTPIP1 interacts with many intracellular proteins involved in the immune response among which pyrin and WASP. PSTPIP1 mutations increase the strength of the interaction between PSTPIP1 and pyrin leading to the activation of the inflammasome and the consequent release of IL-1β. A conserved PSTPIP1-WASP interaction is essential to ensure a correct podosome formation and extracellular matrix degradation. PSTPIP mutations, affecting this interaction, lead to aberrant chemotaxis and extracellular matrix degradation. Because of its clinical heterogeneity and the complex pathogenesis, treatment of this condition is not yet well defined. In addition to steroids, IL-1- and TNF-targeted therapies represent, until now, the most successful treatment solution.