IL36RN Gene Research Articles

IL36RN Mutations and Correlated Characteristics in Generalized Pustular Psoriasis Patients in Can Tho City, Vietnam: A Cross-Sectional Study

Plain Language SummaryThis study looks at the prevalence and impact of IL36RN gene mutations in patients with generalized pustular psoriasis (GPP) in Can Tho City, Vietnam. GPP is a severe and rare type of psoriasis that leads to widespread pustules and severe inflammation. Understanding the genetic basis of GPP, especially mutations in the IL36RN gene, is important for improving treatment options. The research involved 59 patients diagnosed with GPP using criteria from the European Rare and Severe Psoriasis Expert Network and the Japanese Dermatological Association. The study gathered information about the patients’ demographics, clinical features, and laboratory results, and genetic testing was carried out to find mutations in the IL36RN gene. The findings show a high prevalence of IL36RN mutations, with 44.1% of patients having the p.Arg10ArgfsX1 mutation. Other mutations found were p.Pro76Leu and p.Arg102Trp. Patients with IL36RN mutations were generally younger and developed GPP earlier. There were also significant associations between these mutations and certain clinical features, such as fever and geographic tongue, suggesting that these genetic changes play a strong role in these symptoms.

Targeted review of IL36RN mutations in patients with generalised pustular psoriasis.

Generalised 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. This 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. A 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 48.9years old, with most studies reporting a GPP age-of-onset between 20 and 40years 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.227C>T (p.Pro76Leu) (10 studies); and c.338C> 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%). Considering 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.

Mature IL-36γ Induces Stratum Corneum Exfoliation in Generalized Pustular Psoriasis by Suppressing Corneodesmosin

Loss-of-function sequence variations in the IL36RN gene encoding IL-36 receptor antagonist cause familial generalized pustular psoriasis, which begins shortly after birth and is difficult to treat, and its effects on the epidermis are unclear. This study investigated the involvement of IL-36 receptor agonists in the epidermal formation of generalized pustular psoriasis. We found that the IL-36 receptor agonists, especially mature IL-36γ, stimulated IL-8 and pro-IL-36γ production in the epidermis while downregulating the genes encoding epidermal cornified envelope-related proteins, for example, corneodesmosin. IL-36 receptor antagonist and monoclonal anti-IL-36γ antibodies counteracted the effect of mature IL-36γ on corneodesmosin in keratinocytes in a dose-dependent manner. In the epidermis of patients with generalized pustular psoriasis with IL36RN loss-of-function sequence variations, pro-IL-36γ was overproduced in the epidermis, and corneodesmosin protein expression was markedly decreased in the region of giant subcorneal pustules (Kogoj's spongiform pustules), with high neutrophil infiltration. IL-8 induced by mature IL-36γ stimulated the infiltration of several neutrophils in the epidermis. The newly produced pro-IL-36γ is cleaved to the mature form by neutrophil proteases. This newly produced mature IL-36γ was predicted to further suppress the gene expression of corneodesmosin, leading to significant stratum corneum exfoliation and formation of the pustules. Overall, our results elucidate the mechanism underlying the formation of Kogoj's spongiform pustules in generalized pustular psoriasis.

Cutaneous findings and treatments in deficiency of interleukin-36 receptor antagonist (DITRA): A review of the literature.

Deficiency of the interleukin-36 receptor antagonist (DITRA) is a rare autoinflammatory disorder caused by mutations in the IL36RN gene. This mutation leads to a lack of functional interleukin-36 receptor antagonists (IL-36Ra), which results in an overactive immune system and chronic inflammation. Despite its rarity, numerous case series and individual reports in the literature emphasize the importance of recognizing and managing DITRA. Early identification of the cutaneous signs of DITRA is crucial for accurate diagnosis and timely administration of appropriate treatment. This review article provides a comprehensive overview of the current understanding of the cutaneous, non-cutaneous and histopathological manifestations of DITRA, with a focus on reported treatments. The disease typically presents in early childhood, although the age of onset can vary. Patients with DITRA exhibit recurrent episodes of skin inflammation, often with a pustular or pustular psoriasis-like appearance. Additionally, non-cutaneous manifestations are common, with recurrent fevers and elevated acute-phase reactants being the most prevalent. The exact prevalence of DITRA is unknown. Some cases of loss-of-function mutations in the IL36RN gene, considered a hallmark for diagnosis, have been identified in patients with familial generalized pustular psoriasis (GPP). Biological therapies with inhibition of IL-12/23 and IL-17 are promising treatment options; paediatric patients with DITRA have shown complete response with mild relapses. New and emerging biologic therapeutics targeting the IL-36 pathway are also of interest in the management of this rare autoinflammatory disorder.

Expression of interleukin-36 receptor antagonist in a patient with generalized pustular psoriasis harboring the p.Pro82Leu variant in the IL36RN gene.

It has recently been revealed that mutation of the IL36RN gene contributes to the development of generalized pustular psoriasis (GPP). The IL36RN gene encodes interleukin (IL)-36 receptor antagonist (IL-36Ra), which has antagonistic roles against IL-36α, -36β, and -36γ. Previously, sanger sequencing performed in 62 Chinese GPP patients to identify IL36RN mutations revealed a new variant, c.245C>T (p.Pro82Leu), in a single heterozygous state in a patient with adult-onset GPP with psoriasis vulgaris. Since this p.Pro82Leu variant was not found in the psoriasis vulgaris or control groups in their study, they speculated that this variant might lead to exacerbated inflammatory responses. Meanwhile, Sorting Intolerant From Tolerant and PolyPhen-2, pathogenicity prediction tools, predict this variant as tolerated and benign. To date, its pathogenicity is unknown. We experienced a patient with GPP harboring the p.Pro82Leu variant, and investigated mRNA and protein expressions of IL-36Ra. Polymerase chain reaction conducted on hair follicle samples obtained from the scalp of the patient with GPP harboring the p.Pro82Leu using primers to detect mRNA of exons 2 and 5 in IL36RN demonstrated mRNA expression of IL36RN. Immunohistochemical staining revealed IL-36Ra expression in the keratinocytes of the patient with GPP harboring the p.Pro82Leu as in those of a GPP patient without the mutation (positive control). Furthermore, quantitative analysis of the immunofluorescent staining by ImageJ revealed that the expression level of IL-36Ra in the keratinocytes of the patient with GPP harboring p.Pro82Leu was higher than that in the healthy control and not lower than that in the GPP patients without the mutation. Our results indicate no aberrant splicing in this variant. In addition, according to the 1000 Genomes Project, this variant could be a founder mutation. Considering these factors together, this variant is unlikely to be associated with the development of GPP.

Identification of the BTN3A3 Gene as a Molecule Implicated in Generalized Pustular Psoriasis in a Chinese Population

The discovery of pathogenic variants provided biological insight into the role of host genetic factors in generalized pustular psoriasis (GPP). However, not all those affected by GPP carry variants in the reported genes. To comprehensively explore the molecular pathogenesis of GPP, whole-exome sequencing was performed, and two loci were identified with exome-wide significance through single variant association analysis: rs148755083 in the IL36RN gene (Pcombined= 1.19× 10-18, OR= 8.26) and HLA-C∗06:02 within the major histocompatibility complex region (Pcombined= 8.38× 10-12, OR= 2.98). Gene burden testing revealed that BTN3A3 correlated with GPP (Pcombined= 1.14× 10-10, OR= 5.59). Subtype analysis showed that IL36RN and BTN3A3 were both significantly associated with GPP alone and GPP with psoriasis vulgaris, whereas a correlation with HLA-C∗06:02 was only observed in GPP with psoriasis vulgaris. Functional analysis revealed that BTN3A3 regulated cell proliferation and inflammatory balance in GPP. In particular, loss of function of BTN3A3 activated NF-κB and promoted the production of inflammatory cytokines by inhibiting IL-36Ra expression to disturb the IL-1/IL-36 inflammatory axis and enhance the TNF-α-mediated pathway. Our findings identify BTN3A3 as, to our knowledge, a previously unreported pathogenic determinant, expanding our understanding of the genetic basis of GPP.

403 A novel IL36RN mutation in squamous cell carcinoma developed in pustular psoriasis

Squamous cell carcinoma is known to have various precursors and precancerous lesions. Although it is thought to be based on chronic intractable inflammation such as burn scars, intractable ulcers, lupus vulgaris and discoid lupus erythematosus, there are many unclear points about the mechanism leading to carcinogenesis. Psoriasis, a representative chronic intractable inflammatory skin disease, has enhanced epidermal turnover and is considered to be a state close to cancer, but there are not many cases in which squamous cell carcinoma actually develops. Pyoderma gangrenosum is one of the precancerous conditions, whereas pustular psoriasis, also characterized by neutrophil infiltration, is considered to be more rarely secondary to squamous cell carcinoma. We once reported a 61-year-old woman with pustular psoriasis lesions with squamous cell carcinoma (Kaminaka et al, 2010 in Japanese). Collecting the cases with skin malignant tumors secondary to psoriasis reported in Japan from 1990 to 2010, it was found that there are 3 other cases of pustular psoriasis with secondary squamous cell carcinoma. Since the association between generalized pustular psoriasis and the IL36RN gene mutation has been revealed, DNA was extracted from the skin biopsy and/or surgical specimens of these four cases that had already died, and the IL36RN gene mutations were searched. As a result, in all 4 cases, the T123M mutation already reported in generalized pustular psoriasis and the unreported novel mutation were found in homozygous, heterozygous, and mosaic. Although a structural analysis suggests any functional significance, in vitro analysis has not revealed any alteration on the function of IL-36 receptor antagonist by the novel mutation. Although the analysis of healthy, psoriasis and cancerous tissues has not been performed separately, the state of mutation differs depending on the section, suggesting that the presence of the novel mutation identified this time may be involved in canceration.

32339 Expression of interleukin 36 receptor antagonist in a patient with generalized pustular psoriasis harboring the p.Pro82Leu variant in the IL36RN gene

Background: Mutation of the IL36RN gene contributes to the development of generalized pustular psoriasis (GPP). The IL36RN gene encodes interleukin (IL)-36 receptor antagonist (IL-36Ra), which has antagonistic roles against IL-36. Li et al. performed sanger sequencing to identify IL36RN mutations in 62 Chinese GPP patients, and reported a new variant, c.245C>T (p.Pro82Leu) in a patient with GPP. Since this p.Pro82Leu variant was not found in the psoriasis vulgaris and control groups in their study, they speculated that this variant might lead to exacerbated inflammatory responses.

Pustular psoriasis of pregnancy: Clinical and genetic characteristics in a series of eight patients and review of the literature.

Pustular psoriasis of pregnancy (PPP) can lead to life-threatening complications. The objective of this study is to report clinical and genetic spectrum, prognostic factors and management options. A retrospective study was designed including eight PPP patients. Clinical data were collected, and performed genetic and statistical analysis to identify factors associated with fetal complications, resistance to treatment and post-partum flare extension. A systematic review of the literature was also carried out. Eight Tunisian patients, with a mean age of 23 ± 3.3 years, were included. They presented 14 flares (F) during pregnancies and one flare after delivery. Additional GPP flares outside pregnancy periods were noted in 2/8 of patients. The mean duration of PPP flares was 16.66 ± 7.8 weeks. The first flare occurred at a gestational age of 26 ± 5 weeks. Only 2/8 studied patients presented a homozygous mutation c.80 T > C (p.L27P) in IL36RN gene. Used treatments were topical steroids (n=12F), systemic steroids (n=5F), ciclosporin (n=1F), UVB (n=1F) and acitretin (in post-partum n=6F). Complications were oligoamnios (n=2), intra-uterine growth retardation (n=1), fetal death in utero (n=1), prematurity (n=3), low weight at birth (n=2). A significant association was found between (i) occurrence of fetal complications and early gestational age at the onset (p=0.036), (ii) resistance to topical steroids and body surface affected area (p=0.008), (iii) presence of mutation c.80 T > C in PPP flares and low serum levels of calcium (p=0.01). Our systematic review of the literature identified 39 patients with 41 flares of PPP. Only 7/39 patients presented a causative mutation in IL36RN and CARD14 genes. PPP is characterized by a phenotypic heterogeneity and can be associated to IL36RN mutations. Its early onset can be associated with fetal complications. Systemic steroids and cyclosporine remain the most used therapies.

Clinical characteristics of Japanese pustular psoriasis: A multicenter observational study.

Generalized pustular psoriasis (GPP) is a rare and severe subtype of psoriasis. Because of its rarity, GPP studies with a large sample size have been scarce. We studied the characteristics of GPP and pustular psoriasis using data from the West Japan Psoriasis Registry that had been registered until the end of December 2020. The dataset included 104 patients with pustular psoriasis and 1290 patients with other subtypes of psoriasis. Multivariate analysis revealed a significantly greater number of female patients, a significantly lower mean body mass index, and a significantly lower ratio of habitual drinkers in pustular psoriasis, compared to other subtypes of psoriasis. Of the 104 patients, 102 had GPP, including 88 von Zumbusch, 10 juvenile-onset, and four annular pustular psoriasis. Although the male:female ratio of GPP with psoriasis vulgaris (GPP+PsV) (47/20) was similar to that of psoriasis in Japan, the GPP without PsV (GPP-PsV) group highlighted a female predominance (13/22). The mean age at GPP onset was 45.3years, and the mean interval from PsV onset to GPP onset was 12.5years. Four of nine patients with GPP had an IL36RN gene mutation. Infection, medicine, and pregnancy were the precipitating factors for GPP. A family history of psoriasis was present in eight (7.8%) patients with GPP. Twenty-four patients with GPP had psoriatic arthritis. Biologics were used in 76.5% of patients with GPP, followed by etretinate (37.3%), cyclosporine (24.5%), methotrexate (13.7%), apremilast (8.8%), and granulocyte and monocyte adsorption apheresis (6.9%). Etretinate was used in 17 (51.5%) of 33 patients with GPP with less than 10-year history. Thus, etretinate remains a good treatment option for GPP even in the era of biologics. Hypertension was the most commonly identified comorbidity, followed by diabetes. We believe that the characteristics revealed in this study can further contribute to effective GPP management.

Hydroxychloroquine-induced acute generalized exanthematous pustulosis: a series of seven patients and review of the literature.

Hydroxychloroquine (HCQ)-induced acute generalized exanthematous pustulosis (AGEP) is poorly described in the literature. The aim of our study was to characterize the clinical, laboratory, allergological, and genetic features of HCQ-induced AGEP. We conducted a retrospective study of patients with HCQ-induced AGEP diagnosed between 2011 and 2019. We performed molecular analysis to identify variations in the IL36RN gene. We also reviewed similar cases reported between 1991 and March 2020. Seven female patients were included. The mean age was 47years old, and the average time from HCQ start to onset of symptoms was 40days. All patients received topical steroids with a full resolution of the rash within an average of 39days after HCQ withdrawal. Patch tests were performed for three patients with positive results in one case. Genetic analyses were performed for three patients, and no mutation in the IL36RN gene was identified. The latent period and the duration for resolution of HCQ-induced AGEP may be longer than with other drugs due to the metabolic characteristics of HCQ. Mutations in the IL36RN gene were not identified in our patients.

Excellent response to secukinumab in an infant with severe generalized pustular psoriasis.

Generalized pustular psoriasis (GPP) represents the rarest form of psoriasis, which may be potentially fatal. In the last decade, (likely) pathogenic variants in the IL36RN, CARD14 and AP1S3 genes have been associated with monogenic GPP forms. Despite these advances, the genetic basis of most patients with GPP remains unidentified. Treatment of GPP patients is often difficult, with no consensus about the best available options to date. We report herein an infant with severe GPP in whom the disease started at the age of 2months. Genetic investigations identified a heterozygous pathogenic variant in the IL36RN gene associated with a heterozygous variant of uncertain significance in the CARD14 gene. After previous treatment failures with acitretin, cyclosporin and anakinra, treatment with the interleukin-17 antagonist secukinumab resulted in a dramatic and prompt positive response that persisted at 12-month follow up. According to our experience, we believe secukinumab can be an effective and safe treatment for pediatric patients with GPP even before 1year of age.

Intensive granulocyte and monocyte adsorption apheresis for generalized pustular psoriasis.

Granulocyte and monocyte adsorption apheresis (GMA) is usually performed weekly (consisting of five sessions) for refractory skin diseases, such as generalized pustular psoriasis (GPP). The time to remission of inflammatory bowel diseases has been reported to be significantly shorter in intensive GMA (twice a week) than in regular GMA (once a week). Despite several reports of GPP cases treated with intensive GMA, the efficacy of intensive GMA has not been verified in GPP. Herein, we present two GPP patients with a mutation in the IL36RN gene, who initially received regular GMA, and intensive GMA upon recurrence. There were no adverse effects during regular and intensive GMA for both patients. Because concomitant medication was only prednisolone (20mg/day) during regular and intensive GMA, intensive GMA showed superiority to regular GMA in patient 1. Although concomitant medications were different between regular and intensive GMA in patient 2, these drugs had been used before the start of each GMA therapy. We cannot neglect the effects of concomitant drugs, but we observed a shorter time to remission in intensive GMA than that in regular GMA in both patients. More case studies will be necessary for evaluating the clinical efficacy of intensive GMA.

Lack of association between mutation in IL36RN and palmoplantar pustular psoriasis in Chinese patients

BackgroundPalmoplantar pustulosis is considered to be a localized pustular psoriasis confined to the palms and soles. Mutation of the IL36RN gene, encoding interleukin-36 receptor antagonist (IL-36Ra), is associated with generalized pustular psoriasis, but IL36RN mutations in Chinese palmoplantar pustulosis patients have not previously been investigated. ObjectiveThe aim of this study was to evaluate the mutation of IL36RN in Chinese patients with palmoplantar pustulosis. MethodsFifty-one Han Chinese patients with palmoplantar pustulosis were recruited. All exons and exon-intron boundary sequences of IL36RN were amplified in polymerase chain reactions, and Sanger sequencing of the amplicons was performed. ResultsAmong the 51 palmoplantar pustulosis patients, four different single-base substitutions were identified in nine patients. The mutations were c.140A>G/p.Asn47Ser in five patients, c.258G>A/p.Met86IIe in two patients, and c.115+6T>C and c.169G>A/p.Val57IIe in one patient each. All mutations were heterozygous. Comparison with the human genome database and reported literature suggested that these variants may not be pathogenic mutations causing palmoplantar pustulosis. Furthermore, there was no difference in disease severity, onset age, or disease duration between patients with these heterozygous IL36RN variants and those without (p>0.1). Study limitationLack of the further evaluation of IL36Ra protein in palmoplantar pustulosis lesions. ConclusionsThe four variants of IL36RN identified did not appear to be associated with the specific phenotypes of palmoplantar pustulosis.

Pustulosis palmoplantar: características epidemiológicas, clínicas y genéticas de una serie de 41 casos

IntroductionPalmoplantar pustulosis (PPP) is characterised by the presence of sterile association with other diseases differ among published studies. IL36RN gene mutation has recently been identified in patients with mainly generalised pustular forms, but also in some patients with PPP. The objective of this study is to describe clinical and epidemiological characteristics, the incidence of inflammatory diseases in PPP, and to study the frequency of IL36RN gene mutations. MethodsAn observational, retrospective, longitudinal study is presented, which includes all patients attended in our centre between 2009 and 2017 with a PPP diagnosis if only they were controlled by photography. Results41 patients were included (90% women; average age of 55, 8). 94% were smokers or ex-smokers, 24% had a history of plaque psoriasis, 39% ungueal psoriasis and 27% a positive familiar background. On analysing IMIDs (immune mediated inflammatory disorders) incidence in PPP patients, 7% had inflammatory bowel disease, 10% psoriatic arthritis, and 22% other types of arthritis. No IL36RN gene mutations were found in any of the 11 patients in whom a genetic study was performed. ConclusionsPatients with PPP are mostly women who smoke, in the fifth decade of life, with an incidence of IMIDs higher than expected, as well as with a high prevalence of personal and family history of psoriasis.

Polymorphisms in IL36G gene are associated with plaque psoriasis

BackgroundPlaque psoriasis is a non-contagious skin disease in which characteristic red and flaky lesions result from a dysregulation involving both innate and adaptive immune mechanisms. Several cytokines have been implicated in these processes and lately interleukin (IL)-36 family members have become more recognised among them. Thus far, genetic studies have only investigated IL36RN gene of this family in relation to pustular psoriasis. Since IL36G has previously demonstrated markedly increased levels in plaque psoriasis patients and is linked to IL-23/IL-17 axis critical in psoriasis pathology, it was chosen to be the focus of current report.MethodsEleven SNPs from IL36G region were genotyped in 728 plaque psoriasis patients and 320 healthy control individuals. Allele and haplotype frequencies between patients and controls were assessed by respective association tests. For more specific analyses, the patients were assigned into subgroups according to sex, age of disease onset, occurrence of psoriasis among relatives, seasonal aggravation, arthritis symptoms, body surface area (BSA) scores, and Psoriasis Area and Severity Index (PASI) scores.ResultsThe most significant results were obtained with SNPs rs28947206, rs28947207 and rs28947211 that were associated in entire plaque psoriasis analysis (multiple testing adjusted p value (padj) = 0.0054, padj = 0.0017 and padj = 0.0001) and also several subgroups. The first two of those SNPs were included in the same haplotype block with rs28947205 and rs12328178, and two of the respective haplotypes, CAGC and TGTT, provided similarly significant associations (padj = 0.0462 and padj = 0.0047).ConclusionsThe associated SNPs of this study or those in linkage disequilibrium with them could potentially affect the functionality of IL-36γ cytokine, which in turn may impact plaque psoriasis pathology. For instance, these variants could influence IL-36γ expression or 3D structure, thereby altering its ability to induce chemokine production in keratinocytes and various immune cells. The precise mechanisms of these actions are currently unknown and out of the scope of this study. To conclude, the present genetic association results confirm the proposed role of IL-36γ in plaque psoriasis development, with corresponding causal effects to be determined in forthcoming research.

Genetic polymorphism of IL36RN in Han patients with generalized pustular psoriasis in Sichuan region of China: A case-control study.

The aim of this study was to detect IL36RN variant types and frequency in Han patients with generalized pustular psoriasis (GPP) in Sichuan region of China, reveal the difference of variant frequency between GPP alone and GPP + PV (psoriasis vulgaris), and preliminarily clarify the pathogenesis of GPP in this region.Genomic DNA was extracted and subjected to polymerase chain reaction (PCR) for the amplification of the entire encoding and splice sites of the IL36RN gene followed by bidirectional sequencing. Differences in frequencies of IL36RN variants between groups were analyzed by SPSS Statistics 17.0 software. Meanwhile, the IL36RN variant frequency between GPP alone and GPP + PV was compared.The total IL36RN variant frequency was 60.47% in Han GPP patients from Sichuan region of China. Three variant types (c.115 + 6T > C, c.140A > G, c.227C > T) were identified, among which c.115 + 6T > C exhibited the highest frequency (55.81%). All the 3 variants’ frequency of GPP alone group had statistical significance when compared with PV patients and normal controls (P < .05). The IL36RN variant frequency of GPP alone group was statistically higher than that of GPP + PV group (79.17% vs 36.84%, P < .05).IL36RN may be the major disease-causing gene in GPP patients in Han population in Sichuan region of China. c.115 + 6T > C is a possible hot-spot mutation within the IL36RN gene. In contrast to GPP + PV, IL36RN mutations possibly play a more important role in the development of GPP alone.

464 Analysis of IL36RN and CARD14 gene mutation in Japanese patients with generalized pustular psoriasis and palmoplanter pustulosis

464 Analysis of IL36RN and CARD14 gene mutation in Japanese patients with generalized pustular psoriasis and palmoplanter pustulosis

Association of IL36RN mutations with clinical features, therapeutic response to acitretin, and frequency of recurrence in patients with generalized pustular psoriasis.

Previous studies have revealed that IL36RN mutations play a pivotal role in the pathogenesis of generalized pustular psoriasis (GPP), however, the clinical relevance is unclear. To investigate the correlation between IL36RN mutations and clinical features, recurrence frequency, and therapeutic response to acitretin in GPP patients with long-term follow-up. This retrospective cohort study, lasting 2-4 years, included 61 GPP and 48 psoriasis vulgaris (PV) patients. Sequence analysis of all five exons of the IL36RN gene revealed two genetic variants (c.115+6 T>C and c.227C>T). The cohort was divided into three subgroups according to the c.115+6 T>C mutation (present in 52.5% of the patients): homozygous mutation group (HOMG), heterozygous mutation group (HEMG), and non-mutation group (NMG). Initially, 21/25 HOMG patients were diagnosed with GPP with provocative factors, but 13 developed erythrodermic psoriasis after the pustular phase. Patients in the HEMG (5/7) and NMG (23/29) maintained PV diagnosis before and after the pustular phase. Most patients exhibited a marked response to acitretin, but patients who were prescribed a maintenance dosage (10-30mg/d) had mild recurrence (0-2 times/year) during follow-up. IL36RN mutations were strongly linked with early onset and hyponychial pustules, but not with therapeutic efficacy of acitretin or recurrence frequency. Early onset and hyponychial pustules may be specific to IL36RN mutation, however this alone is an insufficient biomarker for acitretin therapy. Other provocative factors play important roles in disease onset, clinical manifestations, and disease outcome. Low-dose maintenance therapy with acitretin might help reduce the recurrence of GPP.

Mutations in IL36RN are associated with geographic tongue

Geographic tongue (GT) is a benign inflammatory disorder of unknown etiology. Epidemiology and histopathology in previous studies found that generalized pustular psoriasis (GPP) is a factor associated with GT, but the molecular mechanism remains obscure. To investigate the mechanism of GT, with and without GPP, three cohorts were recruited to conduct genotyping of IL36RN, which is the causative gene of GPP. In a family spanning three generations and diagnosed with only GT (“GT alone”), GT was caused by the c.115+6T>C/p.Arg10ArgfsX1 mutation in the IL36RN gene. An autosomal dominant inheritance pattern with incomplete penetrance was observed. In the cohort consisting of sporadic cases of “GT alone” (n = 48), significant associations between GT and three IL36RN variants (c.115+6T>C/p.Arg10ArgfsX1, c.169G>A/p.Val57Ile and c.29G>A/p.Arg10Gln) were shown. In the GPP patient cohort (n = 56) and GPP family member cohort (n = 67), a significant association between the c.115+6T>C mutation and the simultaneous presence of GPP and GT was observed when compared to the presence of GPP without GT (P < 0.05). Biopsies revealed similarities among GT patients with different genotypes (AA, Aa and aa), with the neutrophils prominently infiltrating the epidermis. Western-blot analysis showed that the expression ratio of IL-36Ra/IL-36γ in lesioned tongues with individuals harboring different genotypes (AA, Aa and aa, n = 3, respectively) decreased significantly compared to controls (n = 3). We describe the mechanism of GT for the first time: some cases of GT are caused by IL36RN mutations, while those lacking mutations are associated with an imbalance in expression between IL-36Ra and IL-36γ proteins in tongue tissue.