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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,
Autoinflammatory Pustular Neutrophilic Diseases
Section snippets
Key points
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).1, 2, 3, 4, 5, 6 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
Deficiency of the IL-36 receptor antagonist, a monogenic form of pustular psoriasis
Although most patients with pustular psoriasis lack a family history of similar disease, several familial cases have been reported, leading to a potential insight into common pathways of pustular skin disease.8, 9, 10, 11, 12, 13, 14, 15 In 2011, Marrakchi and colleagues13 identified inactivating mutations in the IL-36 receptor antagonist (IL-36RN) gene in 9 Tunisian families with an autosomal-recessive form of generalized pustular psoriasis (GPP). This disease, known as deficiency of the IL-36
CARD14-mediated pustular psoriasis
De novo mutations in caspase recruitment domain family member 14 (CARD14) have also been described in a monogenic form of childhood GPP called CARD14-mediated pustular psoriasis (CAMPS).9, 10 CARD14 mutations have also been previously implicated in plaque-type psoriasis and pityriasis rubra pilaris (PRP).9, 10, 17 CARD14 activates NFκB. Activating missense mutations in CARD14 upregulate NFκB, subsequently increasing the transcription of psoriasis-associated chemokines and cytokines, including
Pyogenic arthritis, pyoderma gangrenosum, and acne syndrome
The syndrome of pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) was coined by Lindor and colleagues in 1997,19 although it was first described in 1975 in a patient with “streaking leukocyte factor.”20 This rare autosomal-dominant autoinflammatory syndrome is caused by mutations in the gene encoding CD2-binding protein 1, also known as proline-serine-threonine-phosphatase-interacting protein 1 (PSTPIP1). Mutations in PSTPIP1 lead to hyperphosphorylation of the protein and subsequent
SAPHO syndrome
Since the 1960s, associations between pustular dermatologic manifestations and osteoarticular manifestations have been reported under various designations, including pustulotic arthro-osteitis, sternocostoclavicular hyperostosis, acne-associated spondyloarthropathy, acquired hyperostosis syndrome, and CRMO. In 1987, Chamot and colleagues37 proposed a unifying syndrome known as SAPHO syndrome. The prevalence of this rare syndrome is estimated to be fewer than 4 in 10,000, with a female
Overview
Genetic advances in monogenic pustular diseases such as DIRA and DITRA have implicated IL-1 family proteins in the development of pustular disease and have led to the successful use of targeted IL-1–blocking agents for these conditions. These insights may provide clues to the pathogenesis of other pustular dermatoses that are believed to have a polygenic cause, such as pustular psoriasis and its variants, and to the potential application of similar targeted therapies for these recalcitrant skin
Summary
Pustular psoriasis and its variants share several overlapping cutaneous, systemic, and osteoarticular features. The classification of these diseases will continue to evolve over the coming years as underlying biological pathways are elucidated, allowing differentiation based on shared mechanisms of disease rather than clinical similarities alone. Recent genetic insights into several rare monogenic forms of pustular disease have already revealed new autoinflammatory pathways and highlight the
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Disclosures: None.