小宮根 真弓

IL-36γ is highly expressed in psoriatic skin lesions and promotes neutrophil infiltration through the induction of neutrophil chemotactic chemokines. While IL-36γ has been established to play an important role in the pathogenesis of psoriasis, its localization in the psoriatic epidermis has not been fully elucidated, and the difference in its expression patterns among other inflammatory skin diseases remains unclear. We investigated IL-36γ localization using immunohistochemistry in skin specimens from patients with psoriasis vulgaris (n = 36), generalized pustular psoriasis (n = 11), pyoderma gangrenosum (n = 6), palmoplantar pustulosis (n = 6), tumor necrosis factor inhibitor-induced paradoxical reaction (n = 3), pustular drug eruption (n = 5), atopic dermatitis (n = 11), tinea infection (n = 3), and mycosis fungoides (n = 9), as well as uninvolved skin adjacent to benign tumors (n = 4). Staining scores were assessed based on intensity and distribution, and nuclear positivity was compared among diseases. IL-36γ was strongly expressed in the upper epidermis of psoriasis vulgaris and generalized pustular psoriasis, with staining scores significantly higher than those in atopic dermatitis and adjacent normal skin. Expression in pyoderma gangrenosum, palmoplantar pustulosis, paradoxical reaction, and pustular drug eruption was comparable to psoriasis vulgaris. Nuclear staining of IL-36γ was frequent in psoriasis vulgaris (33/36, 92%) and generalized pustular psoriasis (11/11, 100%), but absent in pyoderma gangrenosum. The difference in nuclear positivity between psoriasis and pyoderma gangrenosum was statistically significant. These findings confirm that IL-36γ is highly expressed in psoriatic lesions but is not specific to psoriasis, as it is also upregulated in other inflammatory skin diseases. Nuclear staining was observed in psoriasis but not in pyoderma gangrenosum, suggesting a potential disease-specific localization pattern. The biological significance and mechanism of nuclear localization remain unclear, as the IL-36γ molecule lacks a nuclear localization signal. Our findings highlight that the localization of IL-36γ differs among inflammatory skin diseases, suggesting that it may reflect pathogenic differences and warrant further investigation.

Systemic therapies are required to control disease severity of patients with psoriasis vulgaris (PsO) and psoriatic arthritis (PsA) experiencing refractory skin lesions that persisted despite systemic therapies. Various oral medications and biologics are currently available in Japan. The aim of this study was to evaluate the treatment outcomes of refractory regions of PsO and PsA treated with systemic therapy. A total of 77 patients who received oral medications and biologics between 1 January 2010 and 31 March 2019 at the Jichi Medical University Hospital were enrolled. The PsO group included 39 men and 11 women, whereas the PsA group included 20 men and 7 women. Oral medications included etretinate (7 PsO patients and 3 PsA patients), cyclosporine (39 PsO patients and 20 PsA patients), apremilast (7 PsO patients), and methotrexate (5 PsA patients), including 4 patients treated with etretinate and cyclosporine combination (3 PsO patients and 1 PsA patient). The biologics included infliximab (5 PsO patients and 8 PsA patients), adalimumab (11 PsO patients and 11 PsA patients), ustekinumab (21 PsO patients and 6 PsA patients), guselkumab (5 PsO patients), secukinumab (2 PsO patients and 1 PsA patient), ixekizumab (5 PsO patients and 1 PsA patient), and brodalumab (1 PsO patient). The most common biologic-resistant regions were the lower extremities, followed by the upper extremities and back in patients with PsO, and the scalp, followed by the lower extremities and abdomen in patients with PsA. Despite the introduction of biologics, no significant differences were observed in the efficacy on the face, neck, palm, and buttocks in patients with PsO and the face, sole, and buttocks in patients with PsA compared to oral medications. These findings will provide useful information regarding biologic-resistant psoriatic regions in the Japanese patients.

Ceramide deficiency in the stratum corneum (SC) is a key etiological factor in atopic dermatitis (AD). To clarify the direct role of SC ceramide depletion in impairing SC barrier and water-holding functions and in initiating AD-like skin symptoms and disease-specific molecular alterations, we generated Tg mice overexpressing a mutant form of acid ceramidase (aCDase) under the control of the involucrin promoter, resulting in targeted expression in the upper epidermis. By 3 weeks of age, Tg mice developed noninflammatory, scaly skin characterized by severely compromised barrier integrity and water-holding capacity, along with significantly elevated epidermal aCDase activity and markedly reduced ceramide levels in the SC. Compared to WT controls, Tg mice also exhibited increased epidermal innervation and reduced intraepidermal semaphorin 3a protein levels. Additionally, Tg skin showed substantial changes in the expression of AD-associated biomarkers involved in barrier impairment, pruritus, and Th2 polarization. These included increased levels of Il10, Il17a, S100a7, S100a8, and S100a9 and decreased levels of Cxcl10, Ifng, Il2, Il13, Il33, Sema3a, and Tlr9. Repeated topical application of mite antigens induced allergic responses in Tg mice, but not in WT mice. These responses were characterized by prominent eosinophil infiltration in the dermis and significantly elevated serum IgE levels. Allergen-challenged ear skin from Tg mice also demonstrated significantly increased expression of inflammatory mediators related to AD, including Ccl17, Ccl22, Ccl26, Ccl27, Il3, Il13, Il22, and Il33. These findings establish Tg mice as a pathophysiologically relevant model of AD, presenting key features such as xerotic, pruritic skin, impaired barrier and water-retention functions, and Th2-dominant allergic inflammation. This model provides important insights into ceramide-dependent mechanisms in AD pathogenesis and offers a useful platform for therapeutic development. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Generalized pustular psoriasis (GPP) is a heterogeneous, systemic neutrophilic inflammatory disease, characterized by chronic symptoms and recurrent flares, which can be potentially life-threatening. Spesolimab, an interleukin-36 receptor antagonist, has been approved to treat GPP flares in many countries including Japan. An expanded access program (EAP) in Japan provided early access to spesolimab for patients aged 18-75 years unable to participate in a clinical trial with no other treatment options. Patients received a single dose of 900 mg intravenous spesolimab for flare treatment, with an optional second dose after 1 week if symptoms persisted. Safety was monitored for 16 weeks post-treatment. Eleven patients (54.5% female; 51 years mean age; 26.7 kg/m2 mean body mass index) received 23 doses of intravenous spesolimab. Nine patients (81.8%) were diagnosed with GPP for > 5 years. Ten patients (90.9%) had ≥ 1 baseline medical condition. All patients used ≥ 1 concomitant medication prior to or during the spesolimab treatment period, most commonly immunosuppressants and non-steroidal anti-inflammatory agents. Seven patients (63.6%) experienced treatment-emergent adverse events, all of mild or moderate intensity, including skin and subcutaneous tissue disorders, general disorders and administration site conditions. No adverse event led to treatment discontinuation or death. A potential hypersensitivity event (face edema) resolved without intervention and was not considered treatment related. Spesolimab was well tolerated in a heterogeneous patient population with GPP, including those with comorbidities and concomitant medication use. The safety profile of spesolimab aligned with the EFFISAYIL 1 clinical trial results.

A chimeric protein of heparanase and Ig-Fc was designed as a novel tool to expand the detection of structurally heterogeneous heparan sulfate (HS) and related glycosaminoglycans. The whole mouse heparanase gene was combined with the gene segment encoding the mouse IgG1 hinge-Fc domain. A point mutation E335A was inserted to disable putative HS degradation activity. Chimeric proteins consisted of the latent form of the enzyme devoid of HS degradation activity. The chimeric proteins bound to heparin, N-desulfated heparin, and O-sulfated N-acetylheparosan. Their binding spectrum to glycosaminoglycans differed from that of anti-HS mAb 10E4. The chimeric proteins bound to Kato III and A549 cell lines. The binding was reduced by knocking down EXT1 gene expression. One of the chimeric proteins stained the epidermal cells in the hyperplastic spinous layer of inflamed atopic dermatitis skin and inflammatory cells in the dermis, which were not stained with mAb 10E4. The protein stained a polarized structure on the surface of monocytic U937 and THP1 cells. Similar polarized structures were observed with anti-syndecan-1 antibody staining. The chimeric protein and anti-syndecan-1 antibody precipitated similar sets of proteins that included syndecan-1 from the lysates of U937 cells. These novel chimeric proteins are useful to detect HS abundant in O-sulfation in histochemical, cytochemical, and biochemical studies.

We present an updated analysis of albinism in Japan, encompassing both oculocutaneous albinism (OCA) and ocular albinism (OA), based on 290 families, which expands our previous study by 100 additional families. The overall frequency distribution of major subtypes remained consistent with our previous findings: OCA4 remains the most prevalent subtype (67 patients, 23.1%), followed by OCA1 (57 patients, 19.7%), Hermansky-Pudlak syndrome (HPS) 1 (35 patients, 12.1%), and OCA2 (30 patients, 10.3%). Notably, our expanded analysis identified patients with rare subtypes, including OCA3, OCA6, HPS2, HPS3, HPS5, and HPS6, as well as OA, further demonstrating the genetic diversity of albinism in the Japanese population. Through comprehensive genetic screening of the additional 100 families, we identified 17 patients harboring previously unreported pathological variants across multiple albinism subtypes. These findings expand the variant spectrum of albinism in Japan, provide valuable insights for genetic counseling, and underscore the critical importance of comprehensive clinical evaluation and long-term multidisciplinary follow-up for patients with albinism, particularly those with HPS subtypes.

Melanoma treatment comprised a few treatment choices with insufficient efficacy before the emergence of molecularly targeted medication and immune checkpoint inhibitors, which dramatically improved patient outcomes. B-Rapidly Accelerated Fibrosarcoma (BRAF) and Mitogen-Activated Protein Kinase (MAPK) Kinase (MEK) inhibitors significantly improved survival in BRAF-mutant melanoma and immune checkpoint inhibitors, such as anti-programmed cell death 1 (PD-1) and Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) agents, established new standards of care. Challenges remain, however, including the existence of resistance mechanisms and the reduced efficacy of immune-based therapies in Asian populations, particularly for acral and mucosal subtypes. This review highlights historical and current therapeutic advancements, discusses regional considerations, and explores emerging strategies aiming at globally optimizing melanoma management.

Primary malignant melanoma of the umbilicus is extremely rare; evidence guiding optimal resection and reconstruction is limited. A 47-year-old man with primary umbilical melanoma underwent full-thickness abdominal wall resection including the peritoneum. The abdominal wall defect was reconstructed using an autologous fascia lata graft. Histopathology confirmed malignant melanoma with a tumor thickness of 18 mm (pT4bN1aM0, Stage IIIC). At 6-month follow-up, no local recurrence or incisional hernia was observed, and at one year after surgery, no evidence of herniation or recurrence was noted. Autologous fascia lata offers a practical option for abdominal wall reconstruction after extensive oncologic resection of the umbilical region, achieving early freedom from recurrence and hernia in this case.

Interleukin-33 (IL-33) is an alarmin released upon epithelial tissue damage. It functions as a nuclear factor for regulating gene expression. We hypothesised that IL-33 is involved in the formation of decubitus ulcers through damaged epidermis. Therefore, this study aimed to clarify the mechanism of IL-33 action in decubitus ulcer formation. IL-33 knockout (KO), soluble stimulation-2 (ST2) transgenic, and wild-type (WT) mice were used to construct an ischemia-reperfusion (I/R) injury as a decubitus model. The ulcer area was significantly reduced in IL-33 KO mice compared to WT mice but was not reduced in ST2 transgenic mice. Anti-IL-33 receptor (transmembrane ST2) antibodies effectively prevented ulcer formation; however, an anti-IL-33 neutralising antibody was ineffective. The number of infiltrating macrophages was higher, while that of neutrophils and mast cells was lower in IL-33 KO mice than in WT mice. The number of M2 macrophages increased in IL-33 KO mice. Characterisation of gene expression levels revealed significantly reduced interleukin-1 beta (IL-1β) and increased C-C motif chemokine ligand 17 expression in IL-33 KO mice. Macrophages isolated from ulcers in WT or IL-33 KO mice stimulated with exogenous IL-33 produced comparable amounts of IL-1β. In conclusion, our study indicates that IL-33 is released in response to I/R injury in the skin, contributing to inflammatory macrophage and mast cell infiltration and stimulation, resulting in IL-1β production and the massive infiltration of effector cells, including neutrophils, which finally induces decubitus ulcer formation. These results suggest that suppressing IL-33 expression could be beneficial for treating early-phase decubitus ulcers.

The interleukin (IL)-1 superfamily upregulates immune responses and maintains homeostasis between the innate and adaptive immune systems. Within the IL-1 superfamily, IL-36 plays a pivotal role in both innate and adaptive immune responses. Of the four IL-36 isoforms, three have agonist activity (IL-36α, IL-36β, IL-36γ) and the fourth has antagonist activity (IL-36 receptor antagonist [IL-36Ra]). All IL-36 isoforms bind to the IL-36 receptor (IL-36R). Binding of IL-36α/β/γ to the IL-36R recruits the IL-1 receptor accessory protein (IL-1RAcP) and activates downstream signalling pathways mediated by nuclear transcription factor kappa B and mitogen-activated protein kinase signalling pathways. Antagonist binding of IL-36Ra to IL-36R inhibits recruitment of IL-1RAcP, blocking downstream signalling pathways. Changes in the balance within the IL-36 cytokine family can lead to uncontrolled inflammatory responses throughout the body. As such, IL-36 has been implicated in numerous inflammatory diseases, notably a type of pustular psoriasis called generalized pustular psoriasis (GPP), a chronic, rare, potentially life-threatening, multisystemic skin disease characterised by recurrent fever and extensive sterile pustules. In GPP, IL-36 is central to disease pathogenesis, and the prevention of IL-36-mediated signalling can improve clinical outcomes. In this review, we summarize the literature describing the biological functions of the IL-36 pathway. We also consider the evidence for uncontrolled activation of the IL-36 pathway in a wide range of skin (e.g., plaque psoriasis, pustular psoriasis, hidradenitis suppurativa, acne, Netherton syndrome, atopic dermatitis and pyoderma gangrenosum), lung (e.g., idiopathic pulmonary fibrosis), gut (e.g., intestinal fibrosis, inflammatory bowel disease and Hirschsprung's disease), kidney (e.g., renal tubulointerstitial lesions) and infectious diseases caused by a variety of pathogens (e.g., COVID-19; Mycobacterium tuberculosis, Pseudomonas aeruginosa, Streptococcus pneumoniae infections), as well as in cancer. We also consider how targeting the IL-36 signalling pathway could be used in treating inflammatory disease states.

We previously reported that a pathogenic abnormality in the barrier and water-holding functions of the stratum corneum (SC) in the skin of patients with atopic dermatitis (AD) is mainly attributable to significantly decreased levels of total ceramides in the SC. That decrease is mediated by the abnormal expression of a novel ceramide-reducing enzyme, sphingomyelin/glucosylceramide deacylase (SGDase), which is the β-subunit (ASAH1b) of acid ceramidase. In this study, we determined whether mice overexpressing ASAH1b in their epidermis develop AD-like skin symptoms. We generated transgenic (TG) mice overexpressing ASAH1b, regulated by the involucrin promoter, to localize its expression in the upper epidermis. After hair removal using a depilatory cream containing glycolic acid, the TG mice without any visible skin inflammation at 8 weeks of age had increased levels of ASAH1b and decreased levels of SC ceramide, with disrupted barrier functions measured by trans-epidermal water loss compared to the wild-type (WT) mice. Interestingly, enzymatic assays revealed that SGDase activity was not detectable in the skin of the TG mice compared to WT mice. Immunological staining revealed that there was an increased expression level of IL-33 in the epidermis and an accumulation of macrophages in the dermis of TG mice compared to WT mice, which are phenotypic characteristics of AD, that were exacerbated by tape-stripping of the skin. In the skin of the TG mice, the mRNA levels of IL-5, CCL11, IL-22, CXCL10, and IFNγ were significantly upregulated compared to the WT mice, and tape-stripping significantly increased the mRNA levels of IL-4, IL-33, CXCL1, CXCL12, TLR9, and CD163 compared to WT mice. These findings strongly indicate that the skin of the depilatory cream-treated TG mice exists in an atopic dry skin condition that is highly sensitive to various environmental stimuli. The sum of our results suggests that ASAH1b itself, even in the absence of its enzymatic activity, is a major etiologic factor for atopic dry skin symptoms via an unknown mechanism.

Plaque psoriasis (PsO) is a chronic immune-mediated inflammatory disease with skin lesions accompanied by an inflammation-related comorbidity risk. The development of various oral drugs and biologics for PsO has provided increasing systemic treatment options for patients with PsO, and the guidance regarding the use of biologics and PsO treatment schemes are widespread in Japan. However, no comprehensive guidelines regarding systemic drug use are available, and the current treatment patterns of systemic drugs for PsO in Japan remain unclear. We conducted a retrospective chart review to clarify the current treatment patterns of systemic drugs for PsO. We enrolled 114 patients who started systemic drugs for PsO between January 2017 and December 2020 at four institutes, with a mean follow-up of 37.2 months. The mean disease duration was 7.8 (standard deviation 9.5) years at the systemic drug initiation. Of all the patients, 78.1% started with oral drugs (phosphodiesterase [PDE] 4 inhibitors 56.1%. calcineurin inhibitors 14.0%. vitamin A derivatives 7.9%), whereas 21.9% started with biologics (interleukin [IL]-17 inhibitors 9.6%. tumor necrosis factor inhibitors 7.0%. IL-23 inhibitors 3.5%. IL-12/23 inhibitors 1.8%). Oral drugs had shorter drug persistence than biologics: the 12-month persistence of the oral drugs vitamin A derivative, calcineurin inhibitor, and PDE4 inhibitor, was 35.5%, 25.8%, and 60.1%, respectively, compared with that of the biologics IL-23 and IL-17 inhibitors, which was 85.6% and 84.7%, respectively. During the study period, the incidence of treatment changes was 59.1/100 patient-years. Lack of efficacy was the most common reason for treatment changes from monotherapy (34.1%). This retrospective medical chart review allowed us to understand the real-world, long-term treatment patterns of systemic drugs for PsO and the relationships between the reasons for treatment changes and subsequent treatment selection, indicating that there is still room for improvement in the appropriate use of systemic drugs for PsO in Japan.

Psoriasis is a chronic inflammatory skin disease in which growth activity is more prominent than inflammatory activity at the centre of lesional skin (CE skin). This growth activity is partly influenced by growth factors (GFs) that play an important role in cell growth and inflammation during the plaque development. In this study, we identified potential GFs in CE skin and predicted their regulatory functions and biological activity in mediating transcripts in the plaques. Samples of uninvolved skin (UN skin) and CE skin were biopsied from patients with psoriasis vulgaris for RNA-sequencing analysis in order to identify differentially expressed genes (DEGs). Our finding revealed that epidermal growth factor (EGF), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF) and hepatocyte growth factor (HGF) signalling were enriched by CE/UN skin-derived DEGs. Additionally, several EGFR ligands, namely EGF, heparin-binding EGF like growth factor (HB-EGF), amphiregulin (AREG) and transforming growth factor (TGF)-α, as well as TGF-β1, TGF-β2, vascular endothelial growth factor-A, FGFs, PDGF-B and HGF, were predicted to be GF regulators. The regulatory pattern and biological activity of these GF regulators on mediating the CE/UN skin-derived DEGs was demonstrated. This study provides a novel hypothesis regarding the overall regulatory function of GFs, which appear to modulate the expression of the transcripts involved in inflammation and growth in the CE skin. In addition, some GFs may exert anti-inflammatory effects. Further investigations on the mechanisms underlying this regulation may contribute to a deeper understanding of psoriasis and the identification of potential therapeutic targets for patients with psoriasis.

Pyoderma gangrenosum (PG) is a rare, neutrophilic skin disease. For the purpose of accurate diagnosis and proper treatment of PG, the Japanese clinical practice guidance for PG developed by the Japanese Dermatological Association was published in 2022. In this guidance, clinical aspects, pathogenesis, current therapies, and clinical questions on PG are described from the viewpoints of current knowledge and evidence-based medicine. Here, the English version of the Japanese clinical practice guidelines for PG is presented and is intended to be widely referred to in the clinical examination and treatment of PG.

Subcorneal pustular dermatosis, a rare, benign skin disease, is a type of neutrophilic dermatosis. The authors reported three cases of subcorneal pustular dermatosis. In case 1, a 9-year-old girl developed a skin rash with blisters following a mycoplasma infection and had a flare-up due to a common cold. She was successfully treated with a topical corticosteroid. In case 2, a 70-year-old woman who had been treated for rheumatoid arthritis with adalimumab, salazosulfapyridine, and leflunomide developed 3- to 5-mm pustules on her trunk and thighs 4 days after flu vaccination. The rash disappeared with drug withdrawal and treatment with diaminodiphenyl sulfone. In case 3, an 81-year-old man, who was diagnosed with pyoderma gangrenosum at 61 years old, developed multiple small flaccid pustules on his trunk and extremities due to an infection in the arteriovenous shunt area on the forearm. The pustule disappeared with intravenous antibiotic therapy; however, the pustules subsequently flared up along with ulcers typical of pyoderma gangrenosum. He was given oral prednisolone therapy, which was effective for the small pustules and some ulcers. Immunohistochemical examination of the three cases revealed neutrophilic infiltration in the subcorneal layer of the epidermis. The pustules contained neutrophils as well as some CD68+ and a few CD1a+ cells. The epidermis and dermis were more predominantly infiltrated by CD4+ cells than by CD8+ cells. Positive stainings for interleukin 8, interleukin 36γ, and phospho-extracellular signal-regulated kinases 1 and 2 were observed in the upper layers of the epidermis below the pustules. Although the pathogenesis of subcorneal pustular dermatosis has not been clarified, the current results suggest that a variety of inflammatory cells, including those responsible for both innate and acquired immunity, are involved in the accumulation of neutrophils in subcorneal pustular dermatosis.

Psoriasis is an immune-mediated chronic inflammatory disease that predominantly affects the skin and joints. Systemic therapies are required for patients with moderate-to-severe psoriasis, and biologics can provide significant symptomatic improvement. Computed tomography (CT) analysis is recommended before and after biologic therapy to exclude the possibility of comorbid infections and malignancies; incidental findings are often detected in asymptomatic patients. In this study, we analyzed the common incidental findings on CT in 227 patients with psoriasis on biologic therapy and 219 living-kidney transplant donors at our hospital. Incidental findings on CT were observed in 176 (77.5%) patients with psoriasis. The most common were fatty liver (82 patients, 36.1%), urolithiasis (54 patients, 23.8%), pulmonary lesions (47 patients, 20.7%), gallstones or postoperative gallstones (38 patients, 16.7%), liver cysts (36 patients, 15.9%), renal cysts (33 patients, 14.5%), and colonic diverticulum (22 patients, 9.7%), which were observed in 38 (17.4%), eight (3.7%), 68 (31.1%), 12 (5.5%), 58 (26.5%), 88 (40.2%), and 10 (4.6%) donors, respectively. The prevalence of fatty liver, urolithiasis, gallstones, and postoperative gallstones was significantly higher in patients with psoriasis. Multivariate logistic regression showed that psoriasis was a risk factor for fatty liver disease, urolithiasis, and gallstones. Currently, incidental findings on CT in patients with psoriasis have not been well studied. The results of this survey will lead to increased awareness of the incidental findings on CT as a complication of psoriasis.

INTRODUCTION: This study aimed to retrospectively examine the drug survival of tumor necrosis factor (TNF)-alpha inhibitors and switched subsequent biologic agents after discontinuation of TNF inhibitors. METHODS: This real-world setting study was conducted at a single academic center. We included patients who were treated with adalimumab (n = 111), certolizumab pegol (n = 12), and infliximab (n = 74) at Jichi Medical University Hospital from 1 January 2010 to 31 July 2021. RESULTS: No significant differences were noted in drug survival between the three TNF inhibitors. The 10-year drug survival rate for adalimumab and infliximab was 14% and 18%, respectively. Of the patients who discontinued TNF inhibitors for any reason (n = 137), 105 chose biologics as their subsequent treatment. The subsequent biologics included 31 cases of TNF inhibitors (adalimumab in 20, certolizumab pegol in 1, and infliximab in 10), 19 of interleukin-12/23 inhibitor (ustekinumab), 42 of interleukin-17 inhibitors (secukinumab in 19, brodalumab in 9, and ixekizumab in 14) and 13 of interleukin-23 inhibitors (guselkumab in 11, risankizumab in 1, and tildrakizumab in 1). Cox proportional hazards analysis for the subsequent drugs in cases of discontinuation due to inadequate efficacy revealed that female sex was a predictor of drug discontinuation (hazard ratio 2.58, 95% confidence interval 1.17-5.70) and that taking interleukin-17 inhibitors rather than TNF inhibitors was a predictor of drug persistence (hazard ratio 0.37, 95% confidence interval 0.15-0.93). CONCLUSIONS: Interleukin-17 inhibitors may be a favorable option for patients who need to switch from TNF inhibitors due to inadequate efficacy. However, this study is limited by the small number of cases and its retrospective design.

This is the English version of Japanese guidance for the use of oral Janus kinase (JAK) inhibitors (JAK1 and tyrosine kinase 2 [TYK2] inhibitors) in the treatments of psoriasis. Several cytokines, such as interleukin (IL)-6, IL-7, IL-12, IL-21, IL-22, IL-23, interferon (IFN)-α, and IFN-γ, are involved in the pathogenesis of psoriasis (including psoriatic arthritis). As oral JAK inhibitors hinder the JAK-signal transducers and activators of transcription signal transduction routes involved in the signal transduction of these cytokines, they may be effective for the treatment of psoriasis. JAK has four types: JAK1, JAK2, JAK3, and TYK2. Regarding the use of oral JAK inhibitors for the treatment of psoriasis in Japan, indications of the JAK1 inhibitor upadacitinib were extended also to psoriatic arthritis in 2021, and the use of the TYK2 inhibitor deucravacitinib for plaque-type psoriasis, pustular psoriasis, and erythrodermic psoriasis became covered by health insurance in 2022. This guidance was developed for board-certified dermatologists who specialize in the treatment of psoriasis and to promote the proper use of oral JAK inhibitors. In the package inserts and guides for appropriate use, upadacitinib and deucravacitinib are classified as a "JAK inhibitor" and a "TYK2 inhibitor", respectively, and it is possible that there may be differences in safety between the two drugs. The safety of these drugs will be evaluated for the future by the postmarketing surveillance for molecularly targeted drugs for psoriasis of the Japanese Dermatological Association.

This real-world study at a single academic center retrospectively examined the drug survival of apremilast for patients with psoriasis. Retrospective information was extracted from the medical records of patients with psoriasis treated with apremilast at the Department of Dermatology, Jichi Medical University Hospital, between March 1, 2017, and June 31, 2021. In total, 281 patients were included in this study. Of these patients, 22% had psoriatic arthritis and 57% had a history of prior systemic treatment, including biologics, before the initiation of apremilast. The 1-, 2-, 3-, and 4-year drug survival rates were 54%, 41%, 32%, and 30%, respectively. Cox regression analysis revealed that sex, duration of plaque psoriasis (<10 years vs ≥10 years), presence of psoriatic arthritis, involvement of scalp lesions, involvement of palmoplantar lesion, involvement of nail lesions, having cardiometabolic comorbidities, and a history of prior systemic treatment did not have any significant impact on drug survival. The most common reason for apremilast discontinuation was inadequate efficacy (27%), followed by adverse events (12%). Approximately 49% of the patients experienced one or more adverse events. Diarrhea was the most common adverse event (24%), followed by nausea (19%) and headache (11%).

Narrow band-ultraviolet B (NB-UVB) is an effective treatment for psoriasis. We aim to generate a potential mechanism of NB-UVB through comparing the transcriptomic profile before and after NB-UVB treatment between the peripheral edge of lesional skin (PE skin) and the center of lesional skin (CE skin) on the basis of molecular mechanisms of these two areas display different downstream functions. More than one-fourth of the NB-UVB-altered genes were found to be plaque-specific. Some of them were psoriasis signature genes that were downregulated by NB-UVB in, both, PE and CE skin (core alteration), such as IL36G, DEFB4A/B, S100A15, KRT16, and KRT6A. After NB-UVB treatment, the activity score of upstream cytokines, such as interferons, interleukin (IL)-6, IL-17, and IL-22 in pathogenesis decreased. In addition, NB-UVB could restore normal keratinization by upregulating LORICRIN and KRT2, particularly in the CE skin. Finally, we illustrated that NB-UVB is capable of suppressing molecules from the initiation to maintenance phase of plaque formation, thereby normalizing psoriatic plaques. This finding supports the usefulness of NB-UVB treatment in clinical practice and may help in the development of new treatment approaches in which NB-UVB treatment is included for patients with psoriasis or other inflammatory skin diseases.

Long-term psoriasis (PsO) management remains challenging. With growing variation in treatment efficacy, cost, and modes of administration, patient preferences for different treatment characteristics are not well understood. A discrete choice experiment (DCE), informed by qualitative patient interviews, was conducted to assess patient preferences for different attributes of PsO treatments; 222 adult patients with moderate-to-severe PsO receiving systemic therapy participated in the DCE web survey. Better long-term efficacy and lower cost were preferred (preference weights p < 0.05). Long-term efficacy had the highest relative importance (RI) and mode of administration was as important as the outcome attributes (efficacy and safety). Patients also preferred oral to injectable administration. In subgroup analyses by disease severity, residence, psoriatic arthritis as a comorbidity, and gender, the trends for each subgroup were the same as the overall population although the extent of RI for administration mode varied. Mode of administration was more important for patients with moderate versus severe disease, or rural versus urban residence. This DCE utilized attributes related to both oral and injectable treatment as well as a broad study population of systemic treatment users. Preferences were further stratified by patient characteristics to explore trends in different subgroups. Understanding the RI of treatment attributes and the attribute trade-offs acceptable to patients helps inform moderate-to-severe PsO systemic treatments decisions.

This is the English version of Japanese guidance for use of biologics for psoriasis (the 2022 version). As the first biologics for psoriasis in Japan, infliximab and adalimumab, anti-tumor necrosis factor-α antibodies, became available in the field of dermatology in 2010, followed by ustekinumab, an anti-interleukin (IL)-12/IL-23p40 antibody, which was launched in Japan in 2011. Moreover, after 2015, three IL-17 inhibitors, the IL-17A antibody preparations secukinumab and ixekizumab, and an anti-IL-17 receptor antibody preparation brodalumab were marketed. Furthermore, after 2018, the anti-IL23p19 antibody preparations guselkumab and risankizumab, the TNF inhibitor certolizumab pegol, the IL-23 inhibitor tildrakizumab, and the anti-IL-17A/F antibody bimekizumab were marketed. It is important for physicians to select appropriate biologic therapy for each psoriatic patient after due consideration of disease factors, treatment factors, and patient background factors, sharing such information with patients. The followings can be listed as points to be considered for the selection of biologics: drug effects (e.g., strength of effectiveness, time to onset of effectiveness, effectiveness against arthritis, primary failure, secondary failure), safety (e.g., infections, administration-related reactions, and relationships with other comorbidities), convenience for patients (e.g., hospital visit intervals, self-injection, maintenance therapy at clinics, feasibility of drug discontinuation/re-administration), and payment (medical costs) borne by patients. This guidance has been prepared with the aim of allowing dermatologists experienced in the treatment of psoriasis to use biologics appropriately according to the circumstances of individual patients after consideration of the above-mentioned factors.

Abstract SLC29A3, also known as ENT3, is a lysosomal transmembrane protein that transports nucleosides from the lysosomes to the cytoplasm¹. Loss-of-function mutations inSLC29A3cause lysosomal nucleoside storage and histiocytosis: phagocyte accumulation in multiple organs^2,3. However, little is known about the mechanism through which lysosomal nucleoside storage drives histiocytosis. Herein, histiocytosis inSlc29a3^−/−mice was demonstrated to depend on TLR7, which senses a combination of nucleosides and oligoribonucleotides^4,5. TLR7 responded to lysosomal nucleoside storage and enhanced proliferation of Ly6C^hiCX3CR1^lowimmature monocytes and their maturation into Ly6C^lowphagocytes inSlc29a3^−/−mice. Because accumulated nucleosides primarily originated from cell corpse phagocytosis, TLR7 in immature monocytes recognized nucleoside storage as lysosomal stress and increased phagocyte numbers. This non-inflammatory compensatory response is referred to as the TLR7 stress response where Syk, GSK3β, β-catenin, and mTORC1 serve as downstream signalling molecules. In SLC29A3 disorders, histiocytosis accompanies inflammation^6,7. Nucleoside storage failed to induce pro-inflammatory cytokine production inSlc29a3^−/−mice, but enhanced ssRNA-dependent pro-inflammatory cytokine production in Ly6C^hiclassical monocytes and peripheral macrophages, not proliferating immature monocytes. Patient-derived monocytes harbouring G208RSLC29A3mutation showed higher survival and proliferation in the presence of M-CSF and produced larger amounts of IL-6 upon ssRNA stimulation than did those derived from healthy subjects. A TLR8 antagonist inhibited the survival/proliferation of patient-derived macrophages. These results demonstrated that TLR7/8 responses to lysosomal nucleoside stress drive SLC29A3 disorders.

COVID-19 is a recently emerged viral infection worldwide. SARS-CoV-2, the causative virus, is believed to have emerged from bat coronaviruses, probably through host conversion. The bat coronavirus which has the highest gene homology to SARS-CoV-2 specifically infects deep forest bats in China whose habitat extends through the Middle East to Southern Europe. Host conversion might have occurred due to the deforestation by humans exposing wild bats to the environment they had never encountered before. SARS-CoV-2 infects cells through two mechanisms: through its receptor ACE2 with the help of enzyme TMPRSS and through membrane fusion with the help of elastases in the inflammatory condition. Obesity, hypertension, diabetes mellitus, and pulmonary diseases cause poor prognosis of COVID-19. Aging is another factor promoting poor prognosis. These diseases and aging cause low-level and persistent inflammation in humans, which can promote poor prognosis of COVID-19. Psoriasis and atopic dermatitis are the major inflammatory skin diseases. These inflammatory skin conditions, however, do not seem to cause poor prognosis for COVID-19 based on the epidemiological data accumulated so far. These mechanisms need to be elucidated.

BACKGROUND: Peripheral edge (PE) of plaques contains inflammatory molecules and has potential to initiate plaque formation, while the center (CE) of plaques has regression trends. OBJECTIVE: To elucidate the chronological molecular events by comparing the gene profiles in PE skin to those in CE skin. METHODS: Biopsied PE, CE, and uninvolved (UN) skin samples were analyzed by next-generation sequencing. Three groups of differentially expressed genes (DEGs) were analyzed, PE/UN-, CE/UN-, and PE/CE-skin-derived DEGs. RESULTS: PE skin contained inflammation-priming molecules, such as S100A7 and S100A15, and inflammatory drivers, such as interleukin (IL)-36α. IL-6 signaling was more active in PE than in CE skin. IL-8, S100A7, S100A8, S100A9, and human β-defensin-2 were all regulated with the similar pattern in both areas. However, PE skin created a more active inflammatory network and downstream functions, including chemotaxis and angiogenesis, were more prominent than in CE skin. Conversely, CE skin, where epidermal growth factor and hepatocyte growth factor increased their activity, was found to be more stable. CONCLUSION: This is the first RNA-seq-based report to determine the chronological molecular events in plaque formation. In the early phase, inflammation might be initiated through molecules, such as IL-36α, S100A7, and S100A15, as observed in PE skin. The inflammation state in PE skin progresses to the more stable state found in CE skin. In CE skin, the growth factor activities are increased, which might lead to attenuation of initial inflammation and initiation of the regression phase. These molecular events may accelerate research towards developing novel therapies for psoriasis.

Melanoma and nonmelanoma skin cancers (NMSCs) are recognized as among the most common neoplasms, mostly in white people, with an increasing incidence rate. Among the NMSCs, squamous cell carcinoma (SCC) is the most prevalent malignancy known to affect people with a fair complexion who are exposed to extreme ultraviolet radiation (UVR), have a hereditary predisposition, or are immunosuppressed. There are several extrinsic and intrinsic determinants that contribute to the pathophysiology of the SCC. The therapeutic modalities depend on the SCC stages, from actinic keratosis to late-stage multiple metastases. Standard treatments include surgical excision, radiotherapy, and chemotherapy. As SCC represents a favorable tumor microenvironment with high tumor mutational burden, infiltration of immune cells, and expression of immune checkpoints, the SCC tumors are highly responsive to immunotherapies. Until now, there are three checkpoint inhibitors, cemiplimab, pembrolizumab, and nivolumab, that are approved for the treatment of advanced, recurrent, or metastatic SCC patients in the United States. Immunotherapy possesses significant therapeutic benefits for patients with metastatic or locally advanced tumors not eligible for surgery or radiotherapy to avoid the potential toxicity caused by the chemotherapies. Despite the high tolerability and efficiency, the existence of some challenges has been revealed such as, resistance to immunotherapy, less availability of the biomarkers, and difficulty in appropriate patient selection. This review aims to accumulate evidence regarding the genetic alterations related to SCC, the factors that contribute to the potential benefits of immunotherapy, and the challenges to follow this treatment regime.

BACKGROUND: Psoriasis is a common inflammatory skin disease resulting from dysregulation of the IL-23/TH17 immune axis. The prevalence and severity of psoriasis is higher in men than in women, although the underlying reasons for this are unclear. OBJECTIVE: We studied whether estradiol, a female hormone, plays protective roles in imiquimod-induced psoriatic inflammation in mice by regulating neutrophil and macrophage functions. METHODS: Wild-type mice and conditional knockout mice were ovariectomized, supplemented with placebo or estradiol pellets, and an imiquimod-containing cream applied. RESULTS: Mice without endogenous ovarian hormones exhibited exacerbated psoriatic inflammation including increased production of IL-17A and IL-1β, which was reversed by exogenously added estradiol. The suppressive effect of estradiol on the production of IL-1β and IL-17A was abolished in mice lacking estrogen receptors in neutrophils and macrophages (Esr1f/fEsr2f/fLysM-Cre+ mice). IL-1β, which is required for production of IL-17A in the psoriasis model, was mainly produced by neutrophils and inflammatory macrophages. Estradiol suppressed IL-1β production from neutrophils and macrophages in mice both in vivo and in vitro and from human neutrophils in vitro. CONCLUSION: Our results suggest a novel mechanism for sex-dependent differences in psoriasis clinical phenotypes that may shed new light on the pathology of psoriasis.

Elucidating transcriptome in the peripheral edge of the lesional (PE) skin could provide a better understanding of the molecules or signalings that intensify inflammation in the PE skin. Full-thickness biopsies of PE skin and uninvolved (UN) skin were obtained from psoriasis patients for RNA-seq. Several potential differentially expressed genes (DEGs) in the PE skin compared to those in the UN skin were identified. These DEGs enhanced functions such as angiogenesis, growth of epithelial tissue, chemotaxis and homing of cells, growth of connective tissues, and degranulation of myeloid cells beneath the PE skin. Moreover, the canonical pathways of IL-17A, IL-6, and IL-22 signaling were enriched by the DEGs. Finally, we proposed that inflammation in the PE skin might be driven by the IL-36/TLR9 axis or IL-6/Th17 axis and potentiated by IL-36α, IL-36γ, IL-17C, IL-8, S100A7, S100A8, S100A9, S100A15, SERPINB4, and hBD-2. Along with IL-36α, IL-17C, and IκBζ, ROCK2 could be an equally important factor in the pathogenesis of psoriasis, which may involve self-sustaining circuits between innate and adaptive immune responses via regulation of IL-36α and IL-36γ expression. Our finding provides new insight into signaling pathways in PE skin, which could lead to the discovery of new psoriasis targets.