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Role of Interleukin 36 in Generalised Pustular Psoriasis and Beyond.

ABSTRACT: Generalised pustular psoriasis (GPP), a severe neutrophilic skin disease characterised by the sudden and widespread eruption of superficial sterile pustules, remains a challenging disease with limited treatment options. The recent discovery of genetic mutations associated with GPP and advances in understanding of the molecular mechanisms of autoinflammation have resulted in identification of key cytokines that drive the development and progression of GPP. Accumulating evidence demonstrates that interleukin (IL)-36 acts as a central node cytokine by orchestrating the hyperactivation of key pro-inflammatory cytokines and stimulating immune cells, including neutrophilic accumulations, a unique feature of GPP skin lesions. These findings are paving the way for the discovery and development of novel targeted GPP therapeutics that block the IL-36 pathway and neutralise the pathogenic immunologic mechanisms and pro-inflammatory cytokines. This article provides an overview of the current evidence that supports the role of IL-36 as a central node cytokine in GPP pathogenesis.

SUBMITTER: Sugiura K

PROVIDER: S-EPMC8850521 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Role of Interleukin 36 in Generalised Pustular Psoriasis and Beyond.

Sugiura Kazumitsu K

Dermatology and therapy 20220121 2

Generalised pustular psoriasis (GPP), a severe neutrophilic skin disease characterised by the sudden and widespread eruption of superficial sterile pustules, remains a challenging disease with limited treatment options. The recent discovery of genetic mutations associated with GPP and advances in understanding of the molecular mechanisms of autoinflammation have resulted in identification of key cytokines that drive the development and progression of GPP. Accumulating evidence demonstrates that ...[more]

PMID: 35060076

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Project description:BackgroundGeneralised pustular psoriasis (GPP) is a rare and chronic skin disease historically treated with therapies that were originally intended to treat plaque psoriasis (PsO). However, GPP and plaque PsO have distinct pathogeneses and clinical courses.ObjectivesThis study aimed to further characterise the unique genetic background of GPP by summarising evidence on the frequency and type of IL36RN gene mutation, a gene that normally suppresses proinflammatory responses, in patients with GPP compared to patients with GPP and plaque PsO, and patients with plaque PsO only.Methods and resultsA targeted literature review was conducted to identify studies reporting IL36RN mutations and/or HLA-Cw6 allele frequency in patients with GPP. Meta-analyses showed a significantly higher rate of IL36RN mutations in the GPP-only population compared to the GPP + plaque PsO population (OR 3.51; 95% CI 2.29, 5.38). Monoallelic mutations of IL36RN were found in up to 33.3%, and biallelic mutations in up to 73.2% of patients with GPP (GPP-only and GPP + plaque PsO), in contrast with mono- and biallelic frequencies of only 0%-11.9% and 0%, respectively, in patients with plaque PsO only. Mean age-of-onset ranged from 5.9 to 48.9 years old, with most studies reporting a GPP age-of-onset between 20 and 40 years old. Twenty-one mutations were identified in the biallelic state and three in monoallelic. The most reported mutations were c.115 + 6T > C (p. Arg10ArgfsX1) (18 studies); c.227 C > T (p.Pro76Leu) (10 studies); and c.338 C > T (p.Ser113Leu) (8 studies). Mutations varied depending on geography and ethnicity, with the most frequently reported mutation predominantly reported in East Asian studies and international studies that included Asian patients. Rates of HLA-Cw6, the risk allele most strongly associated with plaque PsO, were 0%-28.6% for patients with GPP, similar to rates in the general population (10.5%-20%).ConclusionConsidering the differences between GPP and plaque PsO in aetiology and disease symptoms, effective, GPP-specific treatment options are needed, and recent research suggests that blockade of IL-36 signalling may be an effective target for treatment of GPP.

Project description:BackgroundGeneralized pustular psoriasis (GPP) is a systemic inflammatory disease with poor outcomes, and several studies have suggested that the mutation of the interleukin 36 receptor antagonist gene (IL36RN) is related to GPP, where the polymorphism c.115+6T>C is reported to be the most common mutation of IL36RN. This study was performed to clarify and comprehensively evaluate the relationship between IL36RN gene polymorphism and the susceptibility of GPP subtypes.MethodsTo conduct a thorough literature review, studies were obtained using databases such as Pubmed, EMBASE, Cochrane, China National Knowledge Infrastructure, and the Wanfang database. Only studies published up to December 2019 were included. The quality of the research studies was estimated using the Newcastle-Ottawa scale. The total odds ratios (ORs) and corresponding 95% confidence intervals (95% CIs) were pooled and analysed using STATA 14. The publication bias was evaluated through the Egger test, performed using the aforementioned software. Five common gene models were built and analysed to assess the association between the polymorphism c.115+6T>C and subtypes of GPP.ResultsA total of 10 studies were selected, including 683 cases of GPP patients. Meta-analyses showed that there was a significant statistical correlation of IL36RN mutation between GPP with or without psoriasis vulgaris (OR = 3.82, 95%CI 2.63-5.56) and between adult GPP and paediatric GPP (OR = 0.42, 95%CI 0.23-0.77). No obvious discrepancy between European patients (OR = 4.03, 95%CI 2.23-7.26) and Asian patients was found. The gene models showed clear associations between the polymorphism c.115+6T>C and GPP through the dominant model (CC+ TC vs TT, OR 2.74, 95%CI 2.06-3.64), recessive model (CC vs CT + TT, OR 4.33, 95%CI 2.84-6.60), homozygote model (CC vs TT, OR 4.37, 95%CI 2.88-6.62), heterozygote model (CT vs TT, OR 2.26, 95%CI 1.32-3.85) and allelic model (C vs T, OR 3.35, 95%CI 2.63-4.27).ConclusionThe IL36RN mutation is strongly related to GPP without psoriasis vulgaris and the early onset of GPP. Furthermore, the single-nucleotide polymorphism c.115+6T>C of the IL36RN gene plays a significant role in GPP vulnerability, especially in homozygous mutation. GPP could be a different inflammatory disease, independent of psoriasis.

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Role of Interleukin 36 in Generalised Pustular Psoriasis and Beyond.

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Role of Interleukin 36 in Generalised Pustular Psoriasis and Beyond.

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