Deficiency of IL-36 receptor antagonist, an autoinflammatory disorder


Interleukin-36 receptor antagonist deficiency ( DITRA ) is a hereditary auto-inflammatory disease characterized by repeated flares of generalized pustular psoriasis ( GPP ). The flares include sudden diffuse pustular erythematous rash associated with high fever, general malaise, systemic inflammation and sometimes geographic tongue and nail dystrophy.
Organ inflammation such as cholangitis can occur during the disease course.

In most patients, symptoms develop during childhood though the age of onset can vary considerably. Neonatal onset has also been reported. Failure to thrive may occur.

Elevated C-reactive protein serum levels and marked leukocytosis are constant during disease attacks. Differential diagnosis includes other causes of GPP, mainly DIRA, in cases where symptoms appear during the first weeks of life.

There is no established treatment. Topical and oral steroids, Vitamin D3, Acitretin and anti-TNF-alpha therapy, are effective. Our group has recently successfully treated an infant with DITRA not responding to topical and oral steroids or to Acitretin ( Soriatane ) with Anakinra ( Kineret ).

IL-36 receptor antagonist ( IL-36RA ) is a natural antagonist of IL-36 alpha, IL-36 beta and IL-36 gamma, three cytokines belonging to the IL-1 family.
Mutations result in decreased IL-36RA antagonistic effects due to a reduction of both IL-36RA protein stability and affinity for its receptor, the consequence of which is uncontrolled inflammation.
The high resulting expression of IL-36R and of the three agonists in epithelial tissues like skin likely causes GPP, the main clinical feature in all DITRA patients.

In a study, Setta-Kafetzi et al have identified IL36RN variant alleles in palmarplantar pustulosis and acrodermatitis continua of hallopeau, two forms of GPP genetically distinct from psoriasis vulgaris. ( Xagena )

Touitou I et al, Orphanet Journal of Rare Diseases 2013, 8:162

XagenaMedicine_2013



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