Palmoplantar pustulosis (PPP) is an inflammatory skin disease characterized by chronic and relapsing eruptions of multiple sterile pustules on the palms and soles, which subsequently crust and desquamate. In addition to pustules, vesicles and pustulo-vesicles are often observed simultaneously. It is more prevalent among Japanese individuals, and the number of affected patients in Japan is estimated to be approximately 140,000 based on national health insurance claims data in Japan. Sterile osteitis occurs in 10%-30% of patients with PPP or a history of PPP, a condition referred to as pustulotic arthro-osteitis. Because it has become evident that focal infections act as triggering factors in approximately 80% of both conditions, their therapeutic algorithms differ fundamentally from those for psoriasis. The aim of the Treatment Guidance for Palmoplantar Pustulosis 2022 was to clarify the clinical manifestations and histopathological findings supporting the diagnosis of PPP, and to explain treatment algorithms and recommendation grades based on differences in triggering factors and pathophysiology between PPP and psoriasis. Although the level of evidence is limited due to the ethical and practical difficulties in conducting rigorous double-blinde clinical trials to evaluate the efficacy of focal infection treatment, the treatment recommendations were determined through expert consensus based on extensive clinical experience accumulated in Japan, together with relevant basic research findings.

Nail psoriasis can have a substantial negative impact on both the physical and emotional well-being of patients, and is a risk factor for psoriatic arthritis. Achieving complete clearance of nails in addition to skin is therefore an important treatment goal. We aimed to evaluate concurrent complete skin and nail clearance in patients with moderate-to-severe plaque psoriasis treated with bimekizumab or active comparators. Data were analyzed from the BE SURE and BE VIVID phase III trials, their open-label extension BE BRIGHT, and the BE RADIANT phase IIIb trial and its open-label extension. Included patients had baseline modified Nail Psoriasis Severity Index (mNAPSI) >0 and entered their respective open-label extension. Proportions of patients achieving complete skin (PASI 100; 100 An investigation of how well bimekizumab works in completely clearing skin and nail psoriasis together. What is psoriasis? Psoriasis is a long-lasting disease that can cause red, scaly patches on the skin, and it can cause symptoms in other parts of the body because it affects more than just one area. These patches can flake, itch, and hurt. The nails are also affected in up to six out of ten people living with psoriasis, causing discomfort and impacting quality of life, even though nails are small. Nail psoriasis takes longer to treat than skin psoriasis. It is associated with the development of psoriatic arthritis, which causes joint pain, swelling, and stiffness, and can cause permanent changes to the joints. Many people with psoriasis therefore want treatments that can clear both skin and nail symptoms. What did we do? In this global study, we looked at how well bimekizumab, a psoriasis medication, works to clear both skin and nail psoriasis at the same time. We analyzed how many patients treated with bimekizumab had achieved completely clear skin and nails after up to 1 year compared with other medications (adalimumab, ustekinumab, and secukinumab). We also looked over the long term in patients receiving bimekizumab throughout or those switching from other medications to bimekizumab. What did we find? More patients treated with bimekizumab achieved completely clear skin and nails compared with other medications. Similar numbers of bimekizumab-treated patients maintained completely clear skin and nails through up to 4 years, including those switching from other medications. These results suggest bimekizumab helps improve different areas of psoriasis that affect patients.

Aberrant immune responses to viral pathogens contribute to pathogenesis, but our understanding of pathological immune responses caused by viruses within the human virome, especially at a population scale, remains limited. We analyzed whole-genome sequencing datasets of 6,321 Japanese individuals, including patients with autoimmune diseases (psoriasis vulgaris, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), pulmonary alveolar proteinosis (PAP) or multiple sclerosis) and coronavirus disease 2019 (COVID-19), or healthy controls. We systematically quantified two constituents of the blood DNA virome, endogenous HHV-6 (eHHV-6) and anellovirus. Participants with eHHV-6B had higher risks of SLE and PAP; the former was validated in All of Us. eHHV-6B-positivity and high SLE disease activity index scores had strong correlations. Genome-wide association study and long-read sequencing mapped the integration of the HHV-6B genome to a locus on chromosome 22q. Epitope mapping and single-cell RNA sequencing revealed distinctive immune induction by eHHV-6B in patients with SLE. In addition, high anellovirus load correlated strongly with SLE, RA and COVID-19 status. Our analyses unveil relationships between the human virome and autoimmune and infectious diseases. Analysis of the blood DNA virome in patients with COVID-19 and autoimmune disease associates endogenous HHV-6 (eHHV-6) and high anellovirus load with increased disease risk, most notably for systemic lupus erythematosus. eHHV-6 carriers show a distinct immune response.

Psoriasis is a chronic inflammatory skin disease that significantly impacts patients' quality of life (QoL). While the Psoriasis Area and Severity Index (PASI) has traditionally been used to assess disease severity and treatment response, achieving substantial improvement in QoL has become an increasingly important therapeutic goal. Recent advances in biologic therapies have enabled higher rates of PASI 90 and PASI 100 responses; however, PASI 75 is no longer considered sufficient for optimal patient outcomes. Calculating PASI improvement rates in daily practice remains challenging, shifting focus toward absolute PASI values as a practical indicator of disease control. In this study, we analyzed 235 psoriasis patients treated with biologics at Nagoya City University Hospital, evaluating 3526 data points collected over a maximum of 288 weeks. We found that PASI positively correlated with DLQI (r = 0.5696, p < 0.001), and that an absolute PASI score of ≤2.2 was associated with DLQI remission (AUC = 0.8140). Notably, 82.6% of patients achieving PASI 100 also achieved DLQI 0/1 status. However, 1.0% of patients with a PASI score of 0 still reported a DLQI ≥10, suggesting that factors beyond skin lesions, such as stigma or residual damage, may contribute to impaired QoL. These findings underscore the importance of evaluating absolute PASI values to guide treatment decisions and achieve DLQI remission. Additionally, the psychosocial burden of psoriasis must be addressed to ensure comprehensive care and sustained improvements in QoL.

Psoriasis vulgaris (PsV) is an immune-mediated inflammatory skin disorder with complex genetic architecture. Most genome-wide association studies (GWASs) of PsV have been limited to analyzing common single-nucleotide variants in Europeans, lacking diversity in the variant spectrum and ancestral background. To investigate the contribution of rare variants (RVs) and structural variants (SVs), we perform a whole-genome sequencing study involving 1,415 PsV cases and 3,968 controls in Japanese. A GWAS signal at IFNLR1 is fine-mapped to a 3.3-kb deletion SV disrupting an epithelium-specific putative enhancer, which is validated by PacBio long-read sequencing. Gene-based RV analyses identify two susceptibility genes: IFIH1 (p = 9.8 × 10-6) and CERCAM (p = 4.1 × 10-7). Notably, IL36RN, a causative gene for generalized pustular psoriasis, a rare and lethal multi-systemic inflammatory disorder, is associated with common PsV (p = 1.2 × 10-4). Finally, Cercam knockout (Cercam-/-) in an imiquimod-induced psoriasis mouse model aggravates dermatitis with elevated T cell retention in the subepidermis. Our study elucidates the overlooked genetic basis of PsV.

Here we report the largest Asian genome-wide association study (GWAS) for systemic sclerosis performed to date, based on data from Japanese subjects and comprising of 1428 cases and 112,599 controls. The lead SNP is in the FCGR/FCRL region, which shows a penetrating association in the Asian population, while a complete linkage disequilibrium SNP, rs10917688, is found in a cis-regulatory element for IRF8. IRF8 is also a significant locus in European GWAS for systemic sclerosis, but rs10917688 only shows an association in the presence of the risk allele of IRF8 in the Japanese population. Further analysis shows that rs10917688 is marked with H3K4me1 in primary B cells. A meta-analysis with a European GWAS detects 30 additional significant loci. Polygenic risk scores constructed with the effect sizes of the meta-analysis suggest the potential portability of genetic associations beyond populations. Prioritizing the top 5% of SNPs of IRF8 binding sites in B cells improves the fitting of the polygenic risk scores, underscoring the roles of B cells and IRF8 in the development of systemic sclerosis. The results also suggest that systemic sclerosis shares a common genetic architecture across populations.

The principal pathology of psoriasis is impaired skin barrier function, epidermal thickening, and granular layer loss. Exposure to extrinsic factors such as tobacco smoke and air pollutants is associated with the development of psoriasis. Aryl hydrocarbon receptors (AHRs) are activated by extrinsic factors associated with the development of psoriasis and act as transcriptional regulators. Expression of aldo–keto reductase (AKR) 1C3 in the epidermal spinous layer regulates epidermal keratinocyte differentiation via the AHR signaling pathway. We investigated whether single nucleotide polymorphisms (SNPs) in AKR1C3 are associated with the pathogenesis of psoriasis. The proportions of rs12529 G/C, C/C variants, and rs12387 A/A, A/G variants were twofold higher in Japanese psoriasis patients (n = 231) compared with a Japanese healthy cohort. The SNPs were significantly more common than the majority variants in female patients with disease onset ≤ 22 years of age. Patients with rs12529 G > C and rs12387 A > G SNPs exhibited significantly lower AKR1C3 expression and higher expression of late differentiation markers. In conclusion, AKR1C3 downregulation caused by rs12529 G > C and rs12387 A > G SNPs in the epidermis induces abnormal early differentiation of keratinocytes and skin barrier dysfunction, which may contribute to the genetic pathogenesis of psoriasis in young females.

To the Editor, Although excess sun exposure has deleterious effects, some exposure to UV radiation can be beneficial, and UV-based therapies are safe and effective treatments for many dermatologic conditions [[1]Yones S.S. Palmer R.A. Garibaldinos T.T. Hawk J.L. Randomized double-blind trial of the treatment of chronic plaque psoriasis: efficacy of psoralen-UV-A therapy vs narrowband UV-B therapy.Arch. Dermatol. 2006; 142: 836-842Crossref PubMed Scopus (114) Google Scholar]. Psoriasis is a cutaneous and systemic chronic inflammatory disease closely associated with multiple comorbidities, including cardiovascular disease, diabetes, and metabolic syndrome. Boehncke et al. [[2]Boehncke W.H. Boehncke S. Tobin A.M. Kirby B. The 'psoriatic march': a concept of how severe psoriasis may drive cardiovascular comorbidity.Exp. Dermatol. 2011; 20: 303-307Crossref PubMed Scopus (415) Google Scholar] conceptualized the "psoriatic march", describing a causal link between psoriasis, obesity, and metabolic syndrome. Skin and joint inflammation in psoriatic patients contributes to systemic inflammation via peripheral blood circulation, which is further promoted by obesity-associated adipokines and leads to insulin resistance, the main pathophysiology underlying metabolic syndrome [[2]Boehncke W.H. Boehncke S. Tobin A.M. Kirby B. The 'psoriatic march': a concept of how severe psoriasis may drive cardiovascular comorbidity.Exp. Dermatol. 2011; 20: 303-307Crossref PubMed Scopus (415) Google Scholar]. These inflammatory cascades trigger endothelial cell dysfunction, potentially leading to atherosclerosis, myocardial infarction, and stroke. Psoriasis is an independent risk factor for cardiovascular disease and mortality, compared with mild psoriasis, severe psoriasis is associated with an increased risk of cardiovascular mortality [[3]Armstrong E.J. Harskamp C.T. Armstrong A.W. Psoriasis and major adverse cardiovascular events: a systematic review and meta-analysis of observational studies.J. Am. Heart Assoc. 2013; 2e000062Crossref Scopus (334) Google Scholar] Therefore, tight control of psoriatic skin lesions, e.g., PASI90 or PASI100, might reduce future comorbidities. Here we focused on the systemic effects of bathwater delivery of PUVA (bath-PUVA) therapy and comprehensively analyzed serum proteins to clarify changes in mainly inflammatory- and cardiovascular system-associated protein levels before and after therapy. The study included 20 patients with psoriasis for whom bath-PUVA therapy was first initiated between 2007 and 2011. These patients comprised the same cohort reported previously [[4]Kanayama Y. Torii K. Ikumi K. Morita A. Bath psoralen plus UVA therapy suppresses keratinocyte-derived chemokines in pathogenetically relevant cells.JID Innov. 2021; 1100027Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar] All experiments with human samples complied with the ethical principles of the Declaration of Helsinki and were approved by the Institutional Review Board of Nagoya City University (approval numbers 312, 325-4, and 325-5). Levels of 92 inflammatory- and cardiovascular system-associated proteins (Olink Target 96 Cardiovascular II, Olink Proteomics, Uppsala, Sweden) were assessed by high-throughput proteomic assays of serum. Of the 20 patients, serum samples from 19 met the assay performance quality requirements (the data from Case 12 was excluded) (Supplementary Table S1). Supplementary Table S2 shows the baseline characteristics of these 19 patients (14 men, 5 women; age 27–75 [mean: 52.4] years; disease duration 0.160–30 [median: 9.0] years). Approximately 90 % of patients achieved PASI75, 50 % achieved PASI90, and 5 % achieved PASI100 (Supplementary Table S3). First, to investigate whether the severity of psoriatic skin influences the blood marker levels, we correlated serum proteins with the PASI before bath-PUVA therapy. Nine proteins positively correlated with pre-treatment PASI scores (r > 0.4; Fig. 1). The correlation between CCL17 and pre-treatment PASI was described previously [[4]Kanayama Y. Torii K. Ikumi K. Morita A. Bath psoralen plus UVA therapy suppresses keratinocyte-derived chemokines in pathogenetically relevant cells.JID Innov. 2021; 1100027Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar]. Eight of these proteins could serve as new biomarkers, as we found no previous reports of these proteins in blood samples of psoriasis patients; 6 of these proteins (not MARCO and CA5A) were previously reported to be associated with atherosclerosis and cardiovascular disease (supplementary Table S4). THBS2 correlated highly with the pre-treatment PASI. In a multiple linear regression analysis, the levels of THBS-2 were independently and significantly associated with a history of atrial fibrillation, homeostatic model assessment for insulin resistance, high-sensitivity C-reactive protein, and N-terminal prohormone brain natriuretic peptide in a general population [[5]Morikawa N. Adachi H. Enomoto M. Fukami A. Kumagai E. Nakamura S. et al.Thrombospondin-2 as a potential risk factor in a general population.Int. Heart J. 2019; 60: 310-317Crossref PubMed Scopus (12) Google Scholar] THBS2 was also recently reported to be a biomarker for nonalcoholic steatohepatitis (NASH) [[6]Kozumi K. Kodama T. Murai H. Sakane S. Govaere O. Cockell S. et al.Transcriptomics identify thrombospondin-2 as a biomarker for NASH and advanced liver fibrosis.Hepatology. 2021; 74: 2452-2466Crossref PubMed Scopus (56) Google Scholar]. Serum THBS-2 levels are significantly higher in patients with NASH than in those with nonalcoholic fatty liver (NAFL), and increase in parallel to the fibrosis stage [[6]Kozumi K. Kodama T. Murai H. Sakane S. Govaere O. Cockell S. et al.Transcriptomics identify thrombospondin-2 as a biomarker for NASH and advanced liver fibrosis.Hepatology. 2021; 74: 2452-2466Crossref PubMed Scopus (56) Google Scholar]. THBS2 might be a significant predictor of the severity of heart disease and liver fibrosis as complications of psoriasis. Next, we detected differentially expressed proteins before and after bath-PUVA therapy. Compared with before treatment levels, median after treatment levels of 88 of the 92 proteins were decreased. We identified 38 proteins with significantly decreased levels (adjusted p-value < 0.05); Fig. 2a; supplementary Table S5). Serum CCL17 and SPON2 levels correlated with pre-treatment PASI, and decreased after treatment. Serum CCL17 is independently associated with coronary artery disease. Furthermore, serum CCL17 levels positively associate with the type and severity of coronary artery disease [[7]Ye Y. Yang X. Zhao X. Chen L. Xie H. Zeng Y. et al.Serum chemokine CCL17/thymus activation and regulated chemokine is correlated with coronary artery diseases.Atherosclerosis. 2015; 238: 365-369Abstract Full Text Full Text PDF PubMed Google Scholar]. In psoriasis or atherosclerosis, detailed mechanisms of SPON2 are not yet clear. We also performed functional enrichment analysis in the webtool Metascape for gene sets coding these 38 proteins [[8]Zhou Y. Zhou B. Pache L. Chang M. Khodabakhshi A.H. Tanaseichuk O. et al.Metascape provides a biologist-oriented resource for the analysis of systems-level datasets.Nat. Commun. 2019; 101523Google Scholar]. The “cytokine-cytokine receptor interaction”, “inflammatory response”, and “lipid and atherosclerosis” processes were among the top 10 processes (Fig. 2b; supplementary Table S6). Of the 38 proteins, CD40LG, CXCL1, IL-6, IL-18, SOD2, NEMO, and TNFRSF10A are involved in "lipid and atherosclerosis" processes (supplementary Table S7). CXCL1, IL-6, and IL-18 are chemo/cytokines involved in disease progression in both psoriasis and atherosclerosis. A meta-analyses showed that a 1-standard deviation higher baseline level for each IL-6, IL-18, and TNF-α associated with a 10–25 % higher risk of non-fatal myocardial infarction or death due to CHD in initially healthy people [[9]Kaptoge S. Seshasai S.R. Gao P. Freitag D.F. Butterworth A.S. Borglykke A. et al.Inflammatory cytokines and risk of coronary heart disease: new prospective study and updated meta-analysis.Eur. Heart J. 2014; 35: 578-589Crossref PubMed Scopus (451) Google Scholar] IL-6 and IL-18 are secreted by keratinocytes and immune cells in psoriasis. UVA irradiation may suppress the secretion of these proteins in psoriasis, thereby reducing the progression of plaque formation by vascular endothelial cells, vascular smooth muscle cells, and immune cells. Serum protein levels associated with the cardiovascular risk in psoriasis patients decreased by ustekinumab [[10]Koschitzky M. Navrazhina K. Garshick M.S. Gonzalez J. Han J. Garcet S. et al.Ustekinumab reduces serum protein levels associated with cardiovascular risk in psoriasis vulgaris.Exp. Dermatol. 2022; https://doi.org/10.1111/exd.14582Crossref PubMed Scopus (4) Google Scholar] Following treatment of psoriasis skin lesions with ustekinumab for 12 weeks, 43 of 273 proteins were downregulated in an Olink Target 96 Cardiovascular II, Cardiovascular III, and inflammation panel (Olink Proteomics, Uppsala, Sweden). Compared with our results, 4 proteins (CCL17, IL-6, BMP-6, ADM) were common, suggesting that decreasing the serum levels of these proteins might contribute to improving psoriasis, whereas differences in the sets of reduced markers between bath-PUVA therapy and ustekinumab might be due to their different mechanisms. In conclusion, bath-PUVA therapy might have systemic effects beyond the skin to improve systemic inflammation and cardiovascular risk associated with psoriasis. This work was funded by a Grant-in-Aid for Scientific Research B 20H03703 (AM) from the Japan Society for the Promotion of Science. and AMED under Grant Number JP22km0405217.

Bexarotene is an effective oral drug for the treatment of cutaneous T-cell lymphoma, but careful management is required due to its various side effects. In particular, hypertriglyceridemia often requires a reduction or even suspension of bexarotene therapy. The risk factors of bexarotene-associated severe hypertriglyceridemia are not clear. Here, we conducted a post hoc analysis of the data from our previous clinical trial, which confirmed the efficacy and safety of combined bexarotene and phototherapy, to evaluate the effect of body mass index on bexarotene-associated hypertriglyceridemia. Twenty-five subjects were divided into two subgroups: normal and underweight (body mass index [BMI] <25 kg/m(2) group) and overweight and obese (BMI = 25 kg/m(2) group) patients. The overall incidence of hypertriglyceridemia was 81.3% (13/16) in the BMI <25 kg/m(2) group and 88.9% (8/9) in the BMI = 25 kg/m(2) group. The incidence of grade = 3 hypertriglyceridemia (= 500 mg/dL) was 7.7% (1/13) in the BMI <25 kg/m(2) group and 7/8 (87.5%) in the BMI =25 kg/m(2) group (P < 0.001). Consequently, dose reduction in the BMI =25 kg/m(2) group was larger than that in the BMI <25 kg/m(2) group. The bexarotene-induced change in the serum triglyceride concentration was significantly increased in cutaneous T-cell lymphoma patients with a higher body mass index (? = 0.508, P = 0.009). The area under the curve was 0.886 (95% confidence interval 0.748-1.000, P = 0.002). With a body mass index cut-off of 24.85 kg/m(2), the sensitivity and specificity for identifying grade = 3 hypertriglyceridemia were 0.875 and 0.882, respectively. The present findings suggest that BMI =25 kg/m(2) is a risk factor for bexarotene-associated severe hypertriglyceridemia, therefore overweight and obese patients treated with bexarotene should receive lipid-lowering drugs prophylactically. Further studies for optimizing the initial bexarotene dose in such patients are required.

82 歳,男性。約 3 カ 月前からの物忘れを主訴に近医内科より当院脳神経内科を紹介され受診した。頭部 MRI にて特徴的な所見を認めたため神経核内封入体病(neuronal intranuclear inclusion disease)を疑われ,診断のための皮膚生検を目的として当科へ紹介となった。腹部から脂肪織を含めて皮膚生検を施行した。病理組織学的に,汗腺細胞や血管内皮細胞の核の一部にごく小さな空胞状変化を認め,核内にユビキチン陽性の小型球状物を少数認めたものの典型像とは言えず確定診断には至らなかった。再度腹部から皮膚生検を行い,電子顕微鏡にて観察すると線維芽細胞,毛細血管内皮細胞において核内封入体を認め,神経核内封入体病と診断した。神経核内封入体病は皮膚生検により確定診断が得られる疾患であるため,今後も皮膚科への皮膚生検の依頼を受ける機会が見込まれる。診断には汗腺細胞や脂肪細胞を多く含む組織から生検を行うことが重要であり,生検部位は安全面・整容面を考慮し,腹部からの皮膚生検を提案する。またヘマトキシリン・エオジン(HE)染色のみでなくユビキチンなどの免疫組織化学染色を行うこと,さらに電子顕微鏡検査を行い核内封入体を正確に捉えることで,より診断に結びつきやすくなると考える。

An immunohistochemical study of human vitiligo case was performed. The excimer laser irradiation may induce the differentiation of melanoblasts and melanocytes from bulge stem cell. Pigment regeneration in vitiligo is often observed perifollicular following ultraviolet (UV) therapy, suggesting that a reservoir of melanocytes is present in the hair follicles move to the epidermis and differentiate into melanocytes.1 While the 308-nm excimer laser is effective for vitiligo, the mechanisms underlying pigment regeneration are not yet clear. To investigate the relationship between pigment regeneration and pigment stem cells in vitiligo, we obtained biopsy specimens from a patient treated with the XTRAC Velocity 7™ (Strata Science). Immunohistochemical examination was performed with anti-cytokeratin 15 (anti-CK15 mouse monoclonal antibody, Clone: LKH15; Gene Tex Inc.) and anti-microphthalmia transcription factor (anti-MITF mouse monoclonal antibody, clone: D5; Neomarkers). CK15 is a marker of stem cells in the hair follicle bulge lesion,2 and MITF is a melanocyte lineage marker expressed in melanoblasts and melanocytes.3 This study aimed to determine the association between excimer laser irradiation and MITF-positive cells in the bulge region indicated as CK15-positive cells. CK15- and MITF-positive cells in the bulge lesion were considered melanoblasts. Biopsy specimens were obtained from the lower thigh of a male patient in his 70s, from a normal non-irradiated area, a pigment regeneration area with a follicular pattern, and a non-pigment regeneration area in vitiligo after 20 sessions of treatment. In samples from the normal non-irradiated area, bulge lesion in the follicle were indicated as CK15-positive cell (Figure 1A). MITF-positive cells were observed in the epidermis and hair follicles (Figure 1B). MITF-positive cells observed in the bulge lesions indicated CK15-positive cells were melanoblasts (Figure 1C). Similarly in samples from the pigment-regenerated area, pigment stem cells were indicated by CK15-positive cell (Figure 1D) and MITF-positive cells were observed in the epidermis and hair follicles (Figure 1E). MITF- and CK15-positive cells were considered melanoblasts observed in bulge lesion (Figure 1F). In contrast, although a few CK15-positive cells were observed in hair follicles (Figure 1G), MITF-positive cells were not observed in the bulge region and the epidermis in the non-pigment-regenerated area (Figure 1H). This result suggested that excimer laser irradiation may induce the differentiation of melanoblasts and melanocytes from bulge stem cells. The differentiation of melanocyte stem cells into melanoblasts in hair follicles is followed by the induction of epidermal melanocyte differentiation by repetitive UVB irradiation. Melanocyte stem cell differentiation is triggered by Wnt7a through β-catenin activation.4 Excimer laser stimulates melanogenesis by acting on the Wnt/β-catenin signaling pathway in B16 cells.5 The rate of UVB irradiation (mW/cm2) plays a more important role than the dose of irradiation (mJ/cm2) in determining light absorption by DNA and intracytoplasmic photoreceptors, as well as subsequent differentiation of immature pigment cells,6 confirming the effect of excimer laser on vitiligo. In conclusion, our study helps to elucidate the mechanism by which pigment stem cells in the bulge region differentiate into melanocytes and migrate to the epidermis in vitiligo following excimer laser irradiation. To the best of our knowledge, immunohistochemical examination of these factors in human cases of vitiligo has not yet been reported. Approval of the research protocol: This clinical study was approved by the Ethics Committee of Kansai Medical University Kori Hospital. Informed Consent: Informed consent was obtained from all patients. Registry and the Registration No.: This study was registered at the University Hospital Medical Information Network (UMIN ID: UMIN00032165). Animal Studies: N/A. The authors declare no conflict of interest. Dr. Akimichi Morita is a member of the Journal of Cutaneous Immunology and Allergy Editorial Board. The management of the peer-review process, and all editorial decision making, for this article, was undertaken by Editor-in-Chief.

Cutaneous T-cell lymphoma (CTCL) is a chronic condition with low malignancy. The combined use of therapeutic agents and photo(chemo)therapy is widely applied for the treatment of CTCL. The efficacy and safety of bexarotene and photo(chemo)therapy combination therapy were previously confirmed in Japanese patients with CTCL. The efficacy and safety of the bexarotene and photo(chemo)therapy combination therapy was compared with bexarotene monotherapy in Japanese patients with CTCL. This was a randomized, open-label, two-parallel-group, active-control specified clinical study in Japanese patients diagnosed with CTCL carried out over 8 weeks with a study extension conducted at two institutions. This study was registered in Japan Registry of Clinical Trials (jRCTs041180094). In the combination therapy group, 22 subjects received oral bexarotene (300 mg/m2 body surface area) once daily, followed by bath-psoralen and ultraviolet (UV) A or narrowband UVB. In the monotherapy group, 24 subjects received oral bexarotene (300 mg/m2) once daily. The efficacy analysis using the modified Severity-Weighted Assessment Tool, which included 39 patients, showed a response rate of 81.0% (17/21) in the combination therapy group and 83.3% (15/18) in the monotherapy group. No statistically significant difference was detected between groups. In the combination therapy group, four subjects showed a complete clinical response or complete response, and subjects with a partial response exhibited a high rate of skin lesion resolution, significantly better than in the monotherapy group. In the safety analysis, which included 46 treated subjects (22 in the combination therapy group and 24 in the monotherapy group), no adverse events or adverse drug reactions were reported in either group. Both bexarotene and photo(chemo)therapy combination therapy and bexarotene monotherapy were therapeutically effective in Japanese patients with CTCL and well tolerated. Combination therapy led to a higher skin lesion resolution rate and greater therapeutic effects compared with monotherapy. jRCTs041180094. This study evaluated the efficacy and safety of bexarotene monotherapy compared with bexarotene and photo(chemo)therapy combination therapy in Japanese patients with cutaneous T-cell lymphoma (CTCL). The study was a randomized, open-label, two-parallel-group, active-control specified clinical study in patients diagnosed with CTCL performed over an 8-week period with a study extension conducted in two institutions. In the combination therapy group, bexarotene (300 mg/m2 body surface area) was administered orally once daily to 22 subjects, followed by treatment with bath-psoralen and ultraviolet A (bath-PUVA) or narrowband UVB. In the bexarotene monotherapy group, bexarotene (300 mg/m2) was administered orally once daily to 24 subjects. Efficacy was assessed using the modified Severity-Weighted Assessment Tool. Among the 39 subjects analyzed for treatment efficacy, the response rate of the combination therapy group was 81.0% (17/21) and that of the monotherapy group was 83.3% (15/18). Differences between the two treatment groups were not statistically significant. Of the 21 subjects in the combination therapy group, 4 had a complete clinical response or complete response, and those with a partial response showed a higher skin lesion resolution rate than in the monotherapy group. The safety analysis revealed no reports of adverse events or adverse drug reactions among the 46 treated subjects (combination therapy group = 22; monotherapy group = 24). Thus, both bexarotene and photo(chemo)therapy combination therapy and bexarotene monotherapy were therapeutically effective and well tolerated in Japanese patients with CTCL. Patients receiving the combined therapy, however, showed a higher rate of skin lesion resolution.

Photochemotherapy with psoralen and ultraviolet A (PUVA) is widely used for refractory skin diseases. Bathwater delivery of 8‐methoxypsoralen (8‐MOPS) with subsequent UVA irradiation (bath‐PUVA) or oral administration of 8‐MOPS with UVA is used to treat mycosis fungoides. We retrospectively analyzed 62 patients with mycosis fungoides (8 stage IA, 30 stage IB, 5 stage IIB, 18 stage IIIA, and 1 stage IVA2) treated with bath‐PUVA at the Dermatology Clinic of Nagoya City University Hospital from November 2004 to December 2013. A complete response was achieved in 37 (59.7%) patients, a partial response was achieved in 16 (25.8%), and stable disease was achieved in 6 (9.7%). Progressive disease was observed in 3 (4.8%) patients. Almost all patients in stage IA/IB achieved a complete response. Of the 5 stage IIB patients, 2 achieved a partial response, 1 achieved stable disease, and 2 had progressive disease. The serum concentrations of soluble interleukin‐2 receptor and lactate dehydrogenase decreased significantly following treatment with bath‐PUVA ( p < 0.001). We examined the risk factors of patients whose stage progressed despite PUVA treatment. A multivariate Cox regression analysis of risk factors associated with stage progression yielded a hazard ratio of 28.5 for stage IIb. Treatment with bath‐PUVA is highly effective in the early stages of mycosis fungoides, and partially effective in advanced stages.

Heterozygous mutations in JAK1 which result in JAK-STAT hyperactivity have been implicated in an autosomal dominant disorder that features multi-organ immune dysregulation. This study identifies another previously unreported heterozygous missense JAK1 mutation, H596D, in an individual with a unique autoinflammatory keratinization disease associated with early-onset liver dysfunction and autism. Using CRISPR-Cas9 gene targeting, we generated mice with an identical Jak1 knock-in missense mutation (Jak1H595D/+;I596I/+;Y597Y/+ mice) that recapitulated key aspects of the human phenotype. RNA sequencing of samples isolated from the Jak1H595D/+;I596I/+;Y597Y/+ mice revealed the upregulation of genes associated with the hyperactivation of tyrosine kinases and NF-κB signaling. Interestingly, there was a strong correlation between genes downregulated in Jak1H595D/+;I596I/+;Y597Y/+ mice and those downregulated in the brain of model mice with 22q11.2 deletion syndrome that showed cognitive and behavioral deficits, such as autism spectrum disorders. Our findings expand the phenotypic spectrum of JAK1-associated disease and underscore how JAK1 dysfunction contributes to this autoinflammatory disorder.