Anti-PSTPIP1 monoclonal antibody, clone 2E6

Background Hidradenitis suppurativa (HS) has recently been described as a component of two autoinflammatory syndromes: PASH (pyoderma gangrenosum, acne, and HS) and PAPASH (pyoderma gangrenosum, acne, pyogenic arthritis, and HS). These associations together with others such as inflammatory bowel diseases suggest that defects in autoinflammatory pathways may play a role in the pathogenesis of HS. Objectives To describe clinical and genetic characteristics of two unrelated patients with HS and familial Mediterranean fever (FMF). Methods Case study. Results Besides FMF and HS, the first patient had acne conglobata, and the second patient had pyoderma gangrenosum and ankylosing spondyloarthropathy. Both patients had M694V/V726A MEFV gene mutations. Conclusion PASH and PAPASH have recently been associated with genetic alterations of gene encoding proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1), which interacts with the product of MEFV gene in the autoinflammatory pathway. This intriguing molecular interaction may explain shared phenotypic characteristics seen in genetic defects. Association of one more autoinflammatory disorders with HS adds another brick to the wall.

Objective To describe the genotypes, phenotypes, immunophenotypes, and treatments of PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, and acne), a rare autoinflammatory disease, in 5 patients. Methods Clinical information was gathered from medical records and through interviews with 5 patients from 4 kindreds. PSTPIP1 (CD2BP1) exon 10 and exon 11 sequencing was performed in each patient. Neutrophil granule content and cytokine levels were determined in plasma and stimulated peripheral blood mononuclear cells (PBMCs) from patients and controls. Results We identified 2 previously described PAPA syndromeassociated PSTPIP1 mutations, A230T and E250Q, and a novel change, E250K. Disease penetrance was incomplete, with variable expressivity. The cutaneous manifestations included pathergy, cystic acne, and pyoderma gangrenosum. Interleukin-1 beta (IL-1 beta) and circulating neutrophil granule enzyme levels were markedly elevated in patients compared to those in controls. PBMC stimulation studies demonstrated impaired production of IL-10 and enhanced production of granulocytemacrophage colony-stimulating factor. Good resolution of pyoderma gangrenosum was achieved in 3 patients with tumor necrosis factor a (TNFa) blockade treatment. Conclusion This analysis of 5 patients demonstrates that mutations in PSTPIP1 are incompletely penetrant and variably expressed in the PAPA syndrome. Neutrophil granule proteins are markedly elevated ex vivo and in the plasma, and elevated levels might be compatible with a diagnosis of PAPA syndrome. TNFa blockade appears to be effective in treating the cutaneous manifestations of PAPA syndrome.