IL-36RN Mutations and Pediatric Pustular Psoriasis: A New Era of Precision Medicine

Abstract

Pediatric pustular psoriasis (PPP) is a very rare and inflammatory cutaneous disorder, with the presence of sterile pustules over erythematous skin. Recent reports of genetic findings have identified the IL-36RN gene coding for the interleukin-36 receptor antagonist (IL-36Ra) as a causative factor for the pathogenesis of PPP. IL-36RN mutations disturb IL-36 cytokine signal regulation, leading to hyper-inflammation and dysregulation of the immune system. Elucidation of the molecular pathways through which IL-36RN affects PPP progression is important for the design of targeted therapies. This review discusses the genetic and immunological profile of IL-36RN in PPP, its role in disease severity, and possible treatment options, such as biologics and gene therapy strategies.

Introduction

Pustular psoriasis (PP) is a rare but severely incapacitating subtype of psoriasis, especially when it occurs in children. In contrast to plaque psoriasis, which is primarily T-cell mediated, PPP is closely linked to innate immune dysregulation. New evidence indicates that mutations in the IL-36RN gene are key to this disease. IL-36RN produces IL-36Ra, an essential negative regulator of IL-36 cytokine function. When IL-36RN is mutated, uncontrolled activation of IL-36 cytokines leads to exaggerated inflammatory reactions, which eventually play a role in the development of PPP. This article summarizes the pathophysiological significance of IL-36RN mutations, their effect on the progression of PPP, and developments in therapeutic approaches against this pathway.

Genetic Basis of IL-36RN in Pediatric Pustular Psoriasis

IL-36RN mutations have also been found in a large percentage of patients with generalized pustular psoriasis (GPP), a severe form of pustular psoriasis. In children, IL-36RN mutations have been determined to cause an autosomal recessive pattern of inheritance, where patients carry defective alleles from each parent. The impairment of function in IL-36Ra will cause dysregulation of the balance in IL-36 cytokine signaling and lead to hyperinflammatory reactions.

Research utilizing whole-exome sequencing has uncovered several pathogenic mutations in IL-36RN, such as nonsense and missense mutations, which hamper the protein's capacity to block IL-36 receptor activation. Such mutations lead to the persistent activation of keratinocytes, neutrophils, and other immune cells, magnifying the inflammatory cascade that defines PPP.

Pathophysiology: IL-36 Signaling and Inflammation

IL-36 cytokines, including IL-36α, IL-36β, and IL-36γ, belong to the IL-1 family and are potent mediators of skin inflammation. In healthy individuals, IL-36Ra binds to the IL-36 receptor (IL-36R) and prevents the activation of downstream proinflammatory pathways. However, in patients with IL-36RN mutations, this regulatory mechanism is impaired, leading to:

• Increased production of proinflammatory cytokines, such as TNF-α, IL-8, and IL-1β

• Hyperactivation of neutrophils and monocytes, contributing to pustule formation

• Dysregulated keratinocyte proliferation and differentiation, resulting in epidermal hyperplasia and pustular eruptions

The unchecked IL-36-driven inflammation seen in PPP often results in systemic symptoms, including fever, leukocytosis, and elevated C-reactive protein (CRP) levels. The severity of these systemic manifestations correlates with the extent of IL-36RN dysfunction.

Clinical Presentation and Diagnosis

Pediatric pustular psoriasis presents with the abrupt onset of widespread pustules on an erythematous background. The disease may be accompanied by fever, malaise, and joint pain. Common diagnostic criteria include:

• The presence of sterile pustules on the skin

• Histological findings of spongiform pustules and epidermal hyperplasia

• Genetic testing for IL-36RN mutations, particularly in early-onset and familial cases

Misdiagnosis is common, as PPP shares features with infectious pustular dermatoses and autoinflammatory syndromes. Therefore, genetic screening for IL-36RN mutations is recommended in refractory cases.

Current Treatment Strategies

Given the central role of IL-36RN mutations in PPP, treatment strategies focus on dampening IL-36-driven inflammation. Conventional therapies include:

• Topical Therapies: Corticosteroids and calcineurin inhibitors are used to manage localized skin inflammation.

• Systemic Therapies: Retinoids, cyclosporine, and methotrexate are commonly employed for severe cases but have variable efficacy.

• Biologic Therapies: TNF inhibitors (etanercept, infliximab), IL-17 inhibitors (secukinumab), and IL-23 inhibitors (ustekinumab) have shown promise in managing PPP. However, direct inhibition of IL-36 signaling is an emerging therapeutic approach.

Targeted Therapies and Future Directions

Recent advancements in targeted therapies have paved the way for IL-36-specific inhibitors:

• Spesolimab: A monoclonal antibody that directly blocks IL-36R signaling. Early clinical trials have demonstrated significant improvements in pustular psoriasis patients with IL-36RN mutations.

• Biologic Agents Targeting IL-1 Pathway: Since IL-1 cytokines play a complementary role in PPP pathogenesis, IL-1 inhibitors (e.g., anakinra, canakinumab) have been explored as potential adjunct therapies.

• Gene Therapy: Future strategies may involve CRISPR-based correction of IL-36RN mutations to restore normal IL-36Ra function.

Conclusion

IL-36RN mutations are a primary force behind pediatric pustular psoriasis, leading to unchecked inflammation and disease severity. New insight into IL-36 signaling has created targeted therapies that hold the promise of better disease control. Spesolimab and other IL-36 inhibitors hold great promise as a future direction in PPP therapy, with future studies focused on optimizing therapeutic strategy and the investigation of possible gene-based therapies. Subsequent research should address individualized treatment plans to maximize patient outcomes in pediatric PPP.