Deficiency of IL-36 receptor antagonist L44.4

Interleukin-36 receptor antagonist deficiency syndrome (DITRA) is a rare autoinflammatory disorder caused by mutations in the IL36RN gene. This mutation leads to a deficiency of functional interleukin-36 receptor antagonists (IL-36Ra), resulting in an overactive immune system and chronic inflammation.

The exact prevalence of DITRA is unknown.

IL-36a is an antagonist of 3 pro-inflammatory interleukins of the interleukin-1 family (IL-36alpha, IL-36beta, IL-36gamma). Its dysfunction leads to a predominance of pro-inflammatory cytokines.

Such mutations are also found in about 80% of sporadic cases of pustular psoriasis without additional manifestations of psoriasis vulgaris. In contrast, IL-36RN gene mutations are only found in 10% of PPG with psoriasis vulgaris.

Patients with DITRA experience recurrent episodes of skin inflammation, often with a pustular or psoriasis-like appearance. In addition, non-cutaneous manifestations are common, with recurrent fever and increased acute phase reactants being the most frequent.

In some cases, loss-of-function mutations in the IL36RN gene have been identified in patients with familial generalized pustular psoriasis (GPP) and are considered a hallmark for diagnosis. DITRA appears to be associated with reduced wound healing (Saito K et al. 2020)

Despite its rarity, numerous case series and anecdotal reports in the literature emphasize the importance of recognizing and treating DITRA. Early recognition of the cutaneous signs of DITRA is crucial for accurate diagnosis and timely initiation of appropriate treatment.

Therapies with biologics targeting the inhibition of IL-12/23 and IL-17 are promising treatment options; pediatric patients with DITRA have shown a complete response with mild relapses.

Mutations in the IL-36RN gene can also be detected in exfoliatio areata linguae.

1. Bal E et al. (2019) Mutation in IL36RN impairs the processing and regulatory function of the interleukin-36-receptor antagonist and is associated with DITRA syndrome. Exp Dermatol 28:1114-1117.
2. Cowen EW et al. (2012) DIRA, DITRA, and new insights into pathways of skin inflammation: what's in a name? Arch Dermatol 148:381-384.
3. Marrakchi S et al. (2011) Interleukin-36-receptor antagonist deficiency and generalized pustular psoriasis. N Eng J Med 365:620-628.
4. Okorie CL et al. (2023) Cutaneous findings and treatments in deficiency of interleukin-36 receptor antagonist (DITRA): A review of the literature. Exp Dermatol doi: 10.1111/exd.14934.

5. Saito K et al. (2020) IL-36 receptor antagonist deficiency resulted in delayed wound healing due to excessive recruitment of immune cells. Sci Rep 10:14772.

6. Zelickson BD et al. (1991) Generalized pustular psoriasis in childhood. Report of thirteen cases. J Am Acad Dermatol 24:186-194.