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Pustular psoriasis is a chronic inflammatory skin disease characterized by erythematous plaques with sterile pustules. It includes the distinct clinical entities generalized pustular psoriasis (GPP), acrodermatitis continua of Hallopeau (ACH) and palmoplantar pustular psoriasis (PPPP). Recently clarified pathomechanisms of pustular psoriasis indicate that hyperactivation of the skin innate immunity, including of the IL-1/IL-36 axis, plays an important role in the pathogenesis of pustular psoriasis. Autoinflammatory keratinization disease (AiKD) is the umbrella clinical entity for inflammatory keratinization disorders with genetic autoinflammatory pathomechanisms, and pustular psoriasis is a representative AiKD. To date, mutations/variants in five genes—IL36RN, CARD14, AP1S3, MPO and SERPINA3—have been reported to be genetic causative or predisposing factors for pustular psoriasis. The pathogenic mechanisms induced by the mutations/variants in these genes are all closely related to the excessive activation of skin innate immunity and autoinflammation. A number of biologics (e.g., tumor necrosis factor inhibitors, IL-17/IL-17 receptor inhibitors and IL-23 inhibitors) and granulocyte and monocyte adsorption apheresis are used to treat pustular psoriasis. Recently, based on novel information on the pathomechanisms of pustular psoriasis, which are mainly associated with autoinflammation, inhibitors of several pathogenic pathways, including of the IL-1, IL-36, IL-8 and granulocyte colony-stimulating factor signaling pathways, have been studied as emerging treatments.

Classifying inflammatory skin diseases is challenging, especially for the expanding group of disorders triggered by genetic factors resulting in hyperactivated innate immunity that result in overlapping patterns of dermal and epidermal inflammation with hyperkeratosis. For such conditions, the umbrella term “autoinflammatory keratinization diseases” (AIKD) has been proposed. AIKD encompasses diseases with mixed pathomechanisms of autoinflammation and autoimmunity, and includes IL-36 receptor antagonist (IL-36Ra)-related pustulosis, CARD14-mediated pustular psoriasis, pityriasis rubra pilaris (PRP) type V, and familial keratosis lichenoides chronica (KLC). Mechanistically, the entities include generalized pustular psoriasis (GPP) without psoriasis vulgaris, impetigo herpetiformis and acrodermatitis continua, which are IL-36Ra-related pustuloses caused by loss-of-function mutations in IL36RN; GPP with psoriasis vulgaris and palmoplantar pustular psoriasis which are CARD14-mediated pustular psoriasiform dermatoses with gain-of-function variants of CARD14; PRP type V which is caused by gain-of-function mutations in CARD14; and, familial KLC in which mutations in NLRP1, an inflammasome sensor protein predominantly expressed in skin, have been identified. It is likely that further inflammatory keratinization disorders will also fall within the concept of AIKD, as elucidation of novel pathogenic mechanisms of inflammatory keratinization diseases emerges. A better understanding of the pathophysiology of AIKD is likely to lead to innovative, targeted therapies that benefit patients., ファイル公開：2019-05-01

Background IL36RN mutation has been identified as one pathogenesis of generalized pustular psoriasis, but the existence of GPP patients without mutation makes this controversial. Objective Our study aimed at assessing the differences in clinical profiles of children with GPP, with and without IL36RN mutation. Methods An ambispective case series study involved review of the records of 66 childhood patients with pediatric-onset GPP and without previous psoriasis vulgaris. Results c.115 + 6T > C was the most common mutation in this Chinese population with GPP alone. The age at onset was nearly halved in the homozygotes/compound heterozygotes than in IL36RN-negative patients. Besides a more severe inflammatory progression, three minor signs could prioritize patients with GPP for IL36RN screening (confluent lakes of pus (P = 0.002), perianal erosion (P = 0.014), and flexural erosion (P = 0.007)). More patients with the pathogenic mutation converted to ACH than those without mutation (χ2 = 4.773, P = 0.029). Children with GPP with or without IL36RN mutation responded well to oral low-dose acitretin, but IL36RN-positive cases suffered a much higher half-year recurrence rate after withdrawl of acitretin treatment(χ2 = 10.370, P = 0.001). Conclusions Specific clinical features can remind dermatologists of the necessity of sequencing diagnosis. The mild pustular phenotype of those without mutation may imply the possible role of the epigenetic changes of IL36RN, or other IL36-blockers in the pathogenesis. Pediatric patients with GPP alone, both with and without IL36RN mutation responded well to low-dose acitretin.

ファイル公開：2019-05-01

Background: The Japanese Society for Psoriasis Research has conducted an annual survey of psoriasis patients in Japan from 1982 to 2001. Objective: To perform the epidemiological study about a survey of psoriasis patients conducted in Japan for twenty years. Methods: A sample of 28628 cases was collected from 148 dermatology centers throughout Japan. The reports from each center were analyzed. Results: Males (65.8%) were predominant over females (34.2%) in number. The vast majority of cases (86.0%) had plaque-form of psoriasis vulgaris, and 812 cases (2.8%) showed guttate psoriasis. Psoriatic erythroderma (0.8%), generalized pustular psoriasis (0.9%), and localized pustular psoriasis (0.5%) were rare. Three hundred of the patients (1.0%) manifested psoriatic arthritis. Local corticosteroids (67.8%) were the most used modalities, whereas local vitamin D 3 preparations (2.4%) were rarely used. For phototherapeutical treatments, topical (12.1%) and systemic (7.5%) PUVA were predominant over UVB therapy (0.5%). In systemic treatments, drugs from the herbal medicine was the first (14.2%), followed by etretinate (7.6%), nonsteroidal anti-inflammatory drugs (4.4%), oral corticosteroids (4.1%), methotrexate (2.8%), cyclosporine (1.6%), and anti-cancer drugs (1.4%). Conclusion: This survey was the first epidemiological study throughout Japan.

Tumor necrosis factor (TNF)-alpha is one of the proinflammatory cytokines and immunomodulators, and has an important pathogenetic role in psoriasis. The TNF-alpha gene (TNFA) is in the human leukocyte antigen (HLA) class III locus on chromosome 6, which might be related to the pathogenesis of psoriasis. It has been suggested that some polymorphisms of the TNFA gene promoter, especially G to A conversions at nt-238 and -308 (TNF-238A and -308A), may be associated with psoriasis in Caucasians. We investigated single nucleotide polymorphisms (SNPs) of the TNFA gene promoter in Japanese psoriasis patients, including 18 with psoriasis vulgaris (PsV), 11 with psoriatic arthritis (PsA), two with generalized pustular psoriasis (GPP), and six with GPP with arthritis. The DNA fragment of the TNFA gene from nt-400 to -69 was amplified by polymerase chain reaction (PCR) and the products were sequenced. Although TNF-238A and other polymorphisms were not found in PsV and psoriatic arthritis patients, one male patient with GPP and PsA had TNF-308A. This suggests that TNFA gene promoter polymorphism in the region examined is less associated with the pathogenesis of psoriasis in Japanese patients, however there might be the possibility that TNFA gene promoter polymorphism is associated with GPP. Further investigation will be required to prove this.

Background Generalized pustular psoriasis (GPP) is a rare type of psoriasis with potentially life-threatening implications. Mutations in IL36RN gene have been suggested to be causative or predisposing factors for GPP. Objective To evaluate the genetic heterogeneity of GPP, PV and GPP alone, GPP with PV. Methods We performed a sanger sequencing identify IL36RN mutations in 62 Chinese Han patients with sporadic GPP, including 17 GPP without psoriasis vulgaris (PV) (GPP alone) cases vs. 45 GPP with preceding, later or accompanied by PV (GPP with PV) cases; 16 patients with pediatric-onset GPP (PGPP) vs. 46 adult-onset GPP (AGPP). We included 96 healthy controls and 174 sporadic patients with PV. Resuts We found 2 new variants and 4 known IL36RN variants in 29 GPP patients, 18 individuals carried recessive (homozygous/compound heterozygous) alleles and 11 cases harbored a single heterozygous change. Twelve PV patients and six controls harbored a single heterozygous for three out of the six variants. Significant differences were observed between GPP and PV groups, GPP alone and GPP with PV groups when compared frequencies of IL36RN variants, but we did not found association between PGPP and AGPP groups. Conclusion Our study provided more evidence that GPP and PV are distinct subtypes of psoriasis caused by different pathogenesis, and GPP alone could be regarded as an especial entities of GPP which is different from GPP with PV on the etiology.

Generalized pustular psoriasis (GPP) is often present in patients with existing or prior psoriasis vulgaris (PV; "GPP with PV"). However, cases of GPP have been known to arise without a history of PV ("GPP alone"). There has long been debate over whether GPP alone and GPP with PV are distinct subtypes that are etiologically different from each other. We recently reported that the majority of GPP alone cases is caused by recessive mutations of IL36RN. In contrast, only a few exceptional cases of GPP with PV were found to have recessive IL36RN mutations. Very recently, we also reported that CARD14 p.Asp176His, a gain-of-function variant, is a predisposing factor for GPP with PV; in contrast, the variant is not associated with GPP alone in the Japanese population. These results suggest that GPP alone is genetically different from GPP with PV. IL36RN mutations are also found in some patients with severe acute generalized exanthematous pustulosis, palmar-plantar pustulosis, and acrodermatitis continua of hallopeau. CARD14 mutations and variants are causal or disease susceptibility factors of PV, GPP, or pityriasis rubra pilaris, depending on the mutation or variant position of CARD14. It is clinically important to analyze IL36RN mutations in patients with sterile pustulosis. For example, identifying recessive IL36RN mutations leads to early diagnosis of GPP, even at the first episode of pustulosis. In addition, individuals with IL36RN mutations are very susceptible to GPP or GPP-related generalized pustulosis induced by drugs (e.g., amoxicillin), infections, pregnancy, or menstruation.

It was previously reported that peripheral blood mononuclear cells (PBMC) from the patients with psoriasis vulgaris (PV) showed a reduced proliferative response in vitro to the stimulation of a lyophilized preparation of penicillin-treated low virulence Su-strain of Streptococcus pyogenes group 3, OK-432. In this study, at first it was examined whether OK-432 acts as a superantigen. By analyzing the usage of Vbeta T-cell receptor (TCR) of proliferating T cells stimulated with OK-432, it was found that OK-432 stimulated preferentially Vbeta2 TCR-bearing T cells. Next, to find differences in in vitro responses of PBMC among various types of sterile pustular dermatoses such as pustulosis palmaris et plantaris (PPP), acrodermatitis continua of Hallopeau (AC), and generalized pustular psoriasis (GPP), the proliferative responses of PBMC obtained from these patients under the stimulation of OK-432 were compared. When the PBMC was stimulated with interleukin (IL)-2, no significant difference was found in their proliferative responses among those obtained from the patients with these sterile pustular dermatoses, PV or healthy controls. However, like those from PV patients, PBMC from AC and GPP patients showed significantly smaller responses to OK-432 than those from the healthy controls. In contrast, the proliferative responses of PBMC from the patients with PPP to OK-432 was comparable to those from healthy controls. These results, in addition to its unique clinical and histopathological characteristics, suggest that PPP has a different pathogenetic background from that underlying PV, AC, or GPP.

Sjgren syndrome (SjS) is an auto-immune disease and immunological mechanisms have recently been suggested in the pathogenesis of psoriasis; however, co-existence of these diseases is relatively rare. To determine whether or not there exist the nature of common underlying abnormalities, five patients with psoriasis and SjS were studied. Two patients had psoriasis vulgaris (PV), two had psoriasis arthropathica (PA), and the other had generalized pustular psoriasis (GPP). Lymphocyte response against staphylococcal enterotoxin B was examined by 3H-thymidine incorporation. In one patient with GPP, T-cell receptor (TCR) V beta repertoire of infiltrating T-cells into the lesional skin was examined by reverse transcriptase-polymerase chain reaction (RT-PCR). Stimulation index (S.I.) level of patients with psoriasis and SjS did not show any significant increases compared with patients with psoriasis or SjS alone; however, one patient with PV and SjS, who showed several serological immune imbalances, demonstrated a significant increase of S.I. level. Analysis of TCR V beta repertoire of the lesion of GPP showed strong expression of V beta 14 and 16 with mild expression of V 13-2 and 19, which may suggest that TCR V beta repertoire became oligoclonal in case of complication of these two disorders. In conclusion, our data did not suggest any common immunological responses to staphylococcal enterotoxin in induction of both psoriasis and SjS.

Hereditary autoinflammatory syndromes are monogenic disorders with an inborn error of innate immunity, and include periodic fever syndromes such as familial Mediterranean fever (FMF), tumor necrosis factor receptor-associated periodic syndrome and cryopyrin-associated periodic syndromes (CAPS), pyogenic diseases such as pyogenic arthritis, pyoderma gangrenosum and acne syndrome (PAPAS), and granulomatous diseases such as Blau syndrome. By identifying the genetic abnormalities and subsequent analyses of the molecular mechanisms underlying these disorders, several critical in vivo pathways for inflammatory processes have been discovered. In this review, three categories of autoinflammatory disorders are discussed: inflammasomopathies, receptor antagonist deficiencies and proteasome disability syndromes. Inflammasomopathies are diseases with dysregulated NLRP3 inflammasome activation, and include CAPS with NLRP3, FMF with MEFV, and PAPAS with PSTPIP1 mutations. Analyses of these diseases have clarified some critical pathways regulating NLRP3 inflammasome signaling. Receptor antagonist deficiencies include the newly defined deficiency for interleukin-1 receptor antagonist resulting in sterile multifocal osteomyelitis with periostosis and pustulosis, and deficiency for interleukin-36 receptor antagonist resulting in generalized pustular psoriasis. The identification of these genetic abnormalities has revealed a critical role for receptor antagonists of IL-1 family cytokines in regulating neutrophil activation/recruitment. Finally, proteasome disability syndromes with PSMB8 mutations include Nakajo-Nishimura syndrome and related disorders distributed globally. Analyses of these diseases have unexpectedly shown a critical role of the ubiquitin-proteasome system in the regulation or homeostasis of inflammation/metabolism. Since there still remain a number of predicted but undefined hereditary autoinflammatory syndromes, further clinical and genetic approaches are required to discover novel in vivo critical inflammatory pathways.