Autoinflammatory Pustular Neutrophilic Diseases

This article provides a new categorization of inflammatory pustular dermatoses in the context of recent genetic and biological insights. Monogenic diseases with pustular phenotypes are discussed, including deficiency of interleukin 1 receptor antagonist, deficiency of the interleukin 36 receptor antagonist, CARD14-associated pustular psoriasis, and pyogenic arthritis, pyoderma gangrenosum, and acne. How these new genetic advancements may inform how previously described pustular diseases are viewed, including pustular psoriasis and its clinical variants, with a focus on historical classification by clinical phenotype, is also discussed.

Key points

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Deficiency of the interleukin 1 (IL-1) receptor antagonist (DIRA) is an autosomal-recessive autoinflammatory disease characterized by perinatal-onset pustular dermatosis resembling pustular psoriasis, multifocal aseptic osteomyelitis, and periostitis. It can be effectively treated with IL-1 receptor antagonists.
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Pyogenic arthritis, pyoderma gangrenosum, and acne compose PAPA syndrome, an autosomal-dominant autoinflammatory syndrome caused by mutations in the PSTPIP1 gene.
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Synovitis, acne, pustulosis, hyperostosis, and osteitis compose the autoinflammatory syndrome known as SAPHO. Chronic recurrent multifocal osteomyelitis is likely a subtype of SAPHO that predominantly affects children.
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Pustular psoriasis constitutes a spectrum of inflammatory pustular dermatoses ranging from localized acrodermatitis continua of Hallopeau and palmoplantar pustulosis to generalized disorders including von Zumbusch pustular psoriasis and impetigo herpetiformis.
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The clinical similarities between defined autoinflammatory diseases with neutrophilic pustules and pustular psoriasis provides potential new mechanisms of treatment with biological agents targeting autoinflammatory pathways.

Deficiency of the interleukin 1 receptor antagonist

In 2009, Goldbach-Mansky and colleagues described an autosomal-recessive autoinflammatory disorder known as deficiency of the interleukin 1 (IL-1) receptor antagonist (DIRA) ( Fig. 1 ). DIRA is caused by homozygous loss of function mutations in IL1RN , the gene encoding the IL-1 receptor antagonist. Mutations lead to unopposed IL-1 signaling and resultant uncontrolled life-threatening systemic inflammation. Heterozygous carriers of loss of function mutations in IL1RN seem to be asymptomatic. Fewer than 20 cases from the United States, Canada, the Netherlands, Brazil, and Puerto Rico have been described. First-generation mutations in these distinct geographic populations are believed to be founder mutations. The allele frequencies of the founder mutations in Newfoundland and Puerto Rico are estimated at 0.2% and 1.3%, respectively.