The interleukin (IL)-36 cytokines include 3 agonists, IL-36α, IL-36β, and IL-36γ that bind to a common receptor composed of IL-36R and IL-1RAcP to stimulate inflammatory responses. IL-36Ra is a natural antagonist that binds to IL-36R, but does not recruit the co-receptor IL-1RAcP and does not stimulate any intracellular responses. The IL-36 cytokines are expressed predominantly by epithelial cells and act on a number of cells including immune cells, epithelial cells, and fibroblasts. Processing of the N-terminus is required for full agonist or antagonist activity for all IL-36 members. The role of IL-36 has been extensively demonstrated in the skin where it can act on keratinocytes and immune cells to induce a robust inflammatory response that has been implicated in psoriatic disorders. Emerging data also suggest a role for this cytokine family in pulmonary and intestinal physiology and pathology.

Regulation and function of interleukin-36 cytokines.

Background: Rare variants in the genes IL36RN, CARD14 and AP1S3 have been identified to cause or contribute to pustular skin diseases, primarily generalized pustular psoriasis (GPP). Objective: To better understand the disease relevance of these genes, we screened our cohorts of patients with pustular skin diseases [primarily GPP and palmoplantar pustular psoriasis (PPP)] for coding changes in these three genes. Carriers of single heterozygous IL36RN mutations were screened for a second mutation in IL36RN. Methods: Coding exons of IL36RN, CARD14 and AP1S3 were sequenced in 67 patients - 61 with GPP, two with acute generalized exanthematous pustulosis and four with acrodermatitis continua of Hallopeau. We screened IL36RN and AP1S3 for intragenic copy-number variants and 258 patients with PPP for coding changes in AP1S3. Eleven heterozygous IL36RN mutations carriers were analysed for a second noncoding IL36RN mutation. Genotype-phenotype correlations in carriers/noncarriers of IL36RN mutations were assessed within the GPP cohort. Results: The majority of patients (GPP, 64%) did not carry rare variants in any of the three genes. Biallelic and monoallelic IL36RN mutations were identified in 15 and five patients with GPP, respectively. Noncoding rare IL36RN variants were not identified in heterozygous carriers. The only significant genotype-phenotype correlation observed for IL36RN mutation carriers was early age at disease onset. Additional rare CARD14 or AP1S3 variants were identified in 15% of IL36RN mutation carriers. Conclusion: sThe identification of IL36RN mutation carriers harbouring additional rare variants in CARD14 or AP1S3 indicates a more complex mode of inheritance of pustular psoriasis. Our results suggest that, in heterozygous IL36RN mutation carriers, there are additional disease-causing genetic factors outside IL36RN. What's already known about this topic? The genes IL36RN, CARD14 and AP1S3 have been implicated in pustular skin disease with IL36RN having a major role. Most studies have analysed variants in different genes separately. Significant subsets of patients with a pustular skin disease carry a single heterozygous mutation in IL36RN, leaving unanswered whether and how the variant is disease-contributing. What does this study add? Intragenic copy-number variants or noncoding mutations in carriers of single IL36RN mutations were not found. In total, 15% of patients with generalized pustular psoriasis (GPP) with IL36RN mutations carried variants in CARD14 or AP1S3, providing evidence for a complex inheritance. Lack of causal /disease-contributing variants in 64% of GPP patients suggests a role for other, not yet identified genes. Genotype-phenotype correlation did not reveal significant correlations aside from the presence of IL36RN mutations with age at onset. What is the translational message? This study of three genes provides evidence that the inheritance of GPP is more complex than previously understood. The role of known genes in GPP is rather limited, as almost two-thirds of patients do not carry a variant in any of these genes. In palmoplantar pustular psoriasis, the percentage of noncarriers is even lower. Further genetic studies will reveal the diseases' pathogenesis and provide a basis to use/develop more specific treatments. Linked Comment:Capon. Br J Dermatol 2018;178:589-590 Respond to this article

https://onlinelibrary.wiley.com/doi/pdf/10.1111/bjd.15867

The genetic basis for most patients with pustular skin disease remains elusive

Autoinflammatory diseases are conditions in which pathogenic inflammation arises primarily through antigen-independent hyperactivation of immune pathways. First recognized just over 2 decades ago, the autoinflammatory disease spectrum has expanded rapidly to include more than 40 distinct monogenic conditions. Related mechanisms contribute to common conditions such as gout and cardiovascular disease. Here, we review the basic concepts underlying the "autoinflammatory revolution" in the understanding of immune-mediated disease and introduce major categories of monogenic autoinflammatory disorders recognized to date, including inflammasomopathies and other IL-1-related conditions, interferonopathies, and disorders of nuclear factor kappa B and/or aberrant TNF activity. We highlight phenotypic presentation as a reflection of pathogenesis and outline a practical approach to the evaluation of patients with suspected autoinflammation.

Monogenic autoinflammatory disorders: Conceptual overview, phenotype, and clinical approach

Background Palmoplantar pustular psoriasis (PPP) is a debilitating disease of the palms and/or soles that is resistant to treatment. Secukinumab, an anti–interleukin 17A monoclonal antibody, is highly efficacious in the treatment of moderate-to-severe psoriasis. Objective The primary objective was to determine the rate of achievement of a 75% improvement from baseline in Palmoplantar Psoriasis Area and Severity Index (PPPASI75) with secukinumab at week 16 versus with placebo (at a 2.5% significance level). Methods 2PRECISE was a phase 3b multicenter, randomized, double-blind, placebo-controlled, parallel-group study comparing treatment with 300 mg of secukinumab (n = 79), 150 mg of secukinumab (n = 80), and placebo (n = 78) in subjects with moderate-to-severe PPP over a period of 52 weeks. Results The primary end point was not met. At week 16, 26.6% of subjects treated with 300 mg of secukinumab achieved PPPASI75 versus 14.1% of those who received placebo (P = .0411) (odds ratio, 2.62; 95% confidence interval, 1.04-6.60). At week 52, 41.8% of subjects treated with 300 mg of secukinumab had achieved ppPASI75. More Dermatology Life Quality Index responses of 0 or 1 were achieved with 300 mg of secukinumab (13.0%) than with placebo (4.3%) at week 16. At week 52, 43.1% of subjects receiving 300 mg of secukinumab had a Dermatology Life Quality Index response of 0 or 1. No unexpected adverse events were observed. Limitations Small sample size and characteristics of the PPP disease course. Conclusion Patients with PPP who were treated with secukinumab, 300 mg, showed benefit in terms of PPPASI75 responses over 52 weeks and improved quality of life.

Secukinumab for moderate to severe palmoplantar pustular psoriasis: Results of the 2PRECISE study

Interleukin (IL)-36 is a member of the IL-1 superfamily and includes three agonists (IL-36α, IL-36β, and IL-36γ) and an antagonist (IL-36Ra). IL-36 agonists bind to heterodimeric receptor complexes. Then, the heterotrimer complexes signal via intracellular functional domains, binding to downstream signaling proteins and inducing inflammatory responses. In this review, we summarized the current knowledge about the biological role of IL-36 and its correlation with systemic inflammatory diseases. The information collected will help to increase the understanding of the potential of IL-36 and may give clues for developing novel therapeutic strategies.

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Bakar Bouajar

Papers

IL36RN Mutations Affect Protein Expression and Function: A Basis for Genotype-Phenotype Correlation in Pustular Diseases