Deficiency of interleukin-36 receptor antagonist

Deficiency of interleukin-36 receptor antagonist (DITRA) is a rare autosomal recessive autoinflammatory disease. It is is caused by biallelic loss-of-function genetic variants in IL36RN, which lead to deficiency of the interleukin-36 receptor antagonist, a negative regulator of the inflammatory system. Deficiency leads to childhood onset of pustular psoriasis with recurrent, systemic flares of disease including high fever, fatigue and joint pain. DITRA may arise in adulthood with atypical clinical features.

The hallmark feature of DITRA is generalised pustular psoriasis. This can be differentiated from other scaly rashes by:

• recurrent episodic flares of pustular and scaly lesions;
• presence on the trunk and/or limbs;
• presentation in localised patches;
• sterile pustular areas that may converge into pustular ‘lakes’;
• the presence of a Woronoff ring, a hypopigmented, non-erythematous region that may be seen surrounding psoriatic lesions; and
• resistance to standard topical and systemic psoriasis medication.

Other DITRA features include:

• recurrent high fevers;
• nail pitting;
• nail dystrophy; and
• secondary infections, particularly cutaneous infections.

Chronic features may occur in adulthood, particularly with untreated disease. These include:

• weight loss;
• fatigue;
• sclerosing cholangitis;
• renal dysfunction; and
• neutrophilic pneumonitis.

DITRA is caused by biallelic pathogenic genetic variants in IL36RN, located on chromosome 2q14.1. The gene encodes interleukin-36 receptor antagonist, a negative regulator of systemic cytokine release.

Pathogenic variants in IL36RN cause a loss of function of the protein with reduced production, or protein misfolding, which reduces anti-inflammatory activity and unregulated inflammation with increased production of the pro-inflammatory cytokines IL-36, IL-1, IL-6, IL-8 and TNF-α.

The most common pathogenic variant is c.115+6T>C, an Asian founder splice-site variant. Globally, missense, nonsense and splice-site variants have been reported.

Some compound heterozygous variants show variable severity or later-onset disease. Incomplete penetrance has also been described, even in biallelic disease. Despite the genetic mechanism of disease, flares may be triggered by environmental factors, such as upper respiratory infections, stress, and hormonal changes, such as those that occur during menstruation or pregnancy.

A diagnosis of DITRA may be made in patients presenting with suggestive clinical features, as listed above, alongside molecular confirmation of biallelic pathogenic variants in IL36RN.

Generalised pustular psoriasis activity should be classified according to the Generalised Pustular Psoriasis Physician Global Assessment (GPPGA) score.

Laboratory tests can help support the diagnosis. Results may include:

• elevated inflammatory markers (C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), ferritin) during episodic flares;
• raised white cell count (leukocytosis); and
• skin biopsy that may show spongiform pustules of Kogoj; these may be seen in inflammatory pustular psoriasis and are not pathognomonic of DITRA.

For information about testing, see ‘Child with a suspected autoinflammatory condition‘.

DITRA may be identified before any symptoms appear; for example, through the Generation Study. Confirmation of the diagnosis will require referral to autoinflammatory or specialist rheumatology services. Please refer to the local pathway for your region for this condition.

DITRA is inherited in an autosomal recessive pattern, and has been mostly been described with homozygous pathogenic variants – though individuals may also be compound heterozygous.

• If both parents are carriers of an autosomal recessive condition, with each pregnancy there is a:
  • 1-in-4 (25%) chance of a child inheriting both gene copies with the pathogenic variant and therefore being affected;
  • 1-in-2 (50%) chance of a child inheriting one copy of the gene with the pathogenic variant and one normal copy, and therefore being a healthy carrier themselves; and
  • 1-in-4 (25%) chance of a child inheriting both normal copies and being neither affected nor a carrier.

Rarely, incomplete penetrance has been described in some individuals. Heterozygous carriers are not affected.

If you are discussing genomics concepts with your patients, you may find it helpful to use the visual communication aids for genomics conversations.

DITRA is a rare, complex condition and is best managed by a multidisciplinary autoinflammatory and/or specialist dermatology service. Treatment is aimed at controlling inflammation and preventing life-threatening complications such as significant infections, pneumonitis or liver disease.

For adult patients with DITRA and established flares of pustular psoriasis, NICE guidance around treatment with the specific IL-36 receptor blocker spesolimab is available.

Other biologic agents, such as secukinumab (IL-17A blocker) and ustekinumab (IL-12/IL-23 blocker), are preferred in children with DITRA. Adalimumab (TNF-a blocker) and anti-IL-1 agents (anakinra, canakinumab) have more variable efficacy.

Limited psoriasis flares may be treated with topical or systemic corticosteroids, acitretin or ciclosporin.

DITRA may be identified before any symptoms appear; for example, through the Generation Study. Management of these individuals may differ from those presenting symptomatically.

For clinicians

• NICE guidance: Spesolimab for treating generalised pustular psoriasis flares
• OMIM: 614204 Psoriasis 14, pustular

References:

• Meertens B, Hoste L, Tavernier SJ and others. ‘The riddle of recurrent fever: A clinical approach to pediatric autoinflammatory diseases‘. Frontiers in Pediatrics 2024: volume 12. DOI: 10.3389/fped.2024.1448176
• Okorie CL, Nayudu K and Nambudiri VE. ‘Cutaneous findings and treatments in deficiency of interleukin-36 receptor antagonist (DITRA): A review of the literature‘. Experimental Dermatology 2024: volume 33, issue 1. DOI: 10.1111/exd.14934

For patients

• Autoinflammatory UK
• Royal Free London NHS Foundation Trust: Fever syndromes