Electrical stimulation of the lower eyelid orbicularis oculi muscle improves periocular dark circles.

BACKGROUND: We developed and tested the safety and efficacy of a cosmetic device to improve dark circles using electrical muscle stimulation of the orbicularis oculi muscle. METHODS: Overall, 18 participants (36 eyes) were studied. The following five items were evaluated before and after the intervention:(1) the Clinical Dark Circle Score using clinical findings and photographs, (2) transcutaneous oxygen partial pressure (TcPO2) on the lower eyelid, (3) thermography, (4) two-dimensional laser blood flowmetry, and (5) spectrophotometry. RESULTS: The mean score at baseline was 2.0 ± 0.90 (mean ± standard deviation), and that at the end of the study was 1.2 ± 1.0 (Wilcoxon signed-rank sum test, p < 0.0001), indicating a significant reduction. The spectrophotometer showed a significant decrease in a* and L* values before and after use (Wilcoxon signed-rank sum test, p < 0.0001). There was also a weak negative correlation between the change in score and the change in blood flow and TcPO2 measured using a laser perfusion device (Spearman's rank correlation coefficient, r = -0.32 and -0.39, respectively). Stratified analysis of the baseline score showed a strong negative correlation between the change in score and the change in spectrophotometric a* in the subjects/group with mild periocular dark circles (Spearman's rank correlation coefficient, r = -0.46). Contrastingly, no correlation was observed for any of the measurements in the subjects/group with severe periocular dark circles. After 1 month, no device-related ophthalmic adverse events were observed in any of the participants. CONCLUSION: Electrical muscle stimulation could improve periocular dark circles, especially in the subjects/group with mild periocular dark circles, and was safe.

Analyses of tertiary lymphoid structures observed in cases of Merkel cell carcinoma showing spontaneous regression.

Merkel cell carcinoma (MCC) is a high-grade skin cancer, but spontaneous regression is observed at a markedly higher frequency than in other carcinomas. Although spontaneous regression is a phenomenon that greatly impacts treatment planning, we still cannot predict it. We previously reported on the prognostic impact of the presence or absence of tertiary lymphoid structures (TLS) and of Merkel cell polyomavirus (MCPyV) infection. To learn more about the spontaneous regression of MCC, detailed analyses were performed focusing on spontaneous regression cases. We collected 71 Japanese patients with MCC including 6 cases of spontaneous regression. Samples were analysed by immunostaining, spatial single-cell analysis using PhenoCycler, and RNA sequencing using the next-generation sequencer (NGS). All 6 cases of spontaneous regression were positive for MCPyV. TLS was positive in all 5 cases analysed. Spatial single-cell analyses revealed that PD-L1-positive tumour cells were in close proximity to CD20-positive B cell and CD3-, 4-positive T cells. Gene set enrichment analysis between MCPyV-positive and TLS-positive samples and other samples showed significantly high enrichment of "B-cell-mediated immunity" gene sets in the MCPyV-positive and TLS-positive groups. In conclusion, TLS may play an important role in the spontaneous regression of MCC.

Deucravacitinib in moderate-to-severe plaque psoriasis: Pooled safety and tolerability over 52 weeks from two phase 3 trials (POETYK PSO-1 and PSO-2).

BACKGROUND: Two phase 3 trials, POETYK PSO-1 and PSO-2, previously established the efficacy and overall safety of deucravacitinib, an oral, selective, allosteric tyrosine kinase 2 (TYK2) inhibitor, in plaque psoriasis. OBJECTIVES: To further assess the safety of deucravacitinib over 52 weeks in the pooled population from these two trials. METHODS: Pooled safety data were evaluated from PSO-1 and PSO-2 in which patients with moderate-to-severe plaque psoriasis were randomized 1:2:1 to receive oral placebo, deucravacitinib or apremilast. RESULTS: A total of 1683 patients were included in the pooled analysis. Adverse event (AE) incidence rates were similar in each treatment group, serious AEs were low and balanced across groups, and discontinuation rates were lower with deucravacitinib versus placebo or apremilast. No new safety signals emerged with longer deucravacitinib treatment. Exposure-adjusted incidence rates of AEs of interest with placebo, deucravacitinib and apremilast, respectively, were as follows: serious infections (0.8/100 person-years [PY], 1.7/100 PY, and 1.8/100 PY), major adverse cardiovascular events (1.2/100 PY, 0.3/100 PY, and 0.9/100 PY), venous thromboembolic events (0, 0.2/100 PY, and 0), malignancies (0, 1.0/100 PY and 0.9/100 PY), herpes zoster (0.4/100 PY, 0.8/100 PY, and 0), acne (0.4/100 PY, 2.9/100 PY, and 0) and folliculitis (0, 2.8/100 PY, and 0.9/100 PY). No clinically meaningful changes from baseline in mean levels, or shifts from baseline to CTCAE grade ≥3 abnormalities, were reported in laboratory parameters with deucravacitinib. CONCLUSIONS: Deucravacitinib was well-tolerated with acceptable safety over 52 weeks in patients with psoriasis.

Deucravacitinib, an oral, selective, allosteric tyrosine kinase 2 inhibitor, in Japanese patients with moderate to severe plaque, erythrodermic, or generalized pustular psoriasis: Efficacy and safety results from an open-label, phase 3 trial.

Deucravacitinib, an oral, selective, allosteric tyrosine kinase 2 inhibitor, is approved in Japan for adult patients with plaque (PP), generalized pustular (GPP), and erythrodermic (EP) psoriasis who have had an inadequate response to conventional systemic therapies. This approval is based on results from the global phase 3 POETYK PSO-1 and PSO-2 trials in which deucravacitinib was associated with significantly improved efficacy outcomes compared with placebo in adults with moderate to severe plaque psoriasis, and results described here from POETYK PSO-4, an open-label, single-arm, phase 3 trial (NCT03924427), which evaluated the efficacy and safety of deucravacitinib 6 mg once daily in adult Japanese patients with PP, GPP, or EP. The coprimary endpoints were the proportion of patients achieving a ≥75% reduction from baseline in the Psoriasis Area and Severity Index (PASI 75) and a static Physician's Global Assessment score of 0 (clear) or 1 (almost clear) (sPGA 0/1) with at least a two-point improvement from baseline at week 16. Nonresponder imputation was used for missing data. Efficacy responses, adverse events (AEs), and serious AEs (SAEs) were recorded for up to 52 weeks. Seventy-four patients were treated (PP, n = 63; GPP, n = 3; EP, n = 8). At week 16, 76.2%, 66.7%, and 37.5% of patients with PP, GPP, and EP, respectively, had achieved PASI 75, and 82.5%, 0.0%, and 50.0% had achieved sPGA 0/1. Responses were overall maintained through week 52. AEs occurred in 74.6% of patients with PP, 100% of patients with GPP, and 87.5% of patients with EP. The most common AEs were nasopharyngitis and acne. Rates of SAEs and discontinuations were low. There were no deaths. Deucravacitinib was effective and well tolerated in Japanese patients with moderate to severe PP and in a limited number of patients with GPP or EP.

GWAS for systemic sclerosis identifies six novel susceptibility loci including one in the Fcγ receptor region.

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.

Treatment patterns and drug survival for generalized pustular psoriasis: A patient journey study using a Japanese claims database.

Generalized pustular psoriasis (GPP) is a potentially life-threatening skin disease. Although several medications are approved for treating GPP in Japan, there are limited data on real-world treatment patterns or drug survival (the number of prescribed days of treatment). This retrospective cohort study describes drug survival and treatment patterns of patients with newly diagnosed GPP (International Classification of Diseases, 10th Revision code L40.1), and ≥1 year of follow-up, using de-identified claims data (Medical Data Vision Co., Ltd.) from January 2016 to August 2021. Most (97.0%) of the 434 Japanese patients received first-line therapy of etretinate (26.4%), topical medications (14.7%), or cyclosporin (14.3%); 80.0% and 60.1% of patients received a second and third line of therapy (LOT), respectively. Use of etretinate (12.6%) and cyclosporin (5.9%) decreased in second-line therapies, whereas use of biologics (interleukin [IL]-17, 14.3%; IL-23 inhibitors, 7.6%) and topical medications (22.1%) increased or remained consistent. Approximately 50% of biologics were prescribed in combination with systemic medications or systemic corticosteroids. Median (range) time to next therapy (TTNT) was 2.8 (0.03-48.07) months for first-line therapy and 3.3 (0.03-52.97) months for all other LOTs. TTNT was longer for combination therapies (up to 16.5 months) compared with monotherapies (up to 7.5 months). Biologics exhibited longer drug survival with fewer treatment episodes compared with non-biologic systemic medications. Among frequently used therapies, the median (95% confidence interval) drug survival was 8.8 (5.8-11.8) months for etretinate, 4.3 (2.2-6.9) months for systemic corticosteroids, and 19.6 (16.1-26.7) months for secukinumab. Treatment patterns varied considerably, highlighting the need for treatment algorithms and effective, well-tolerated medications to support patients to help them remain on long-term therapy.

Cigarette smoking is an independent risk factor for developing vitiligo on the hands.

BACKGROUND: Vitiligo presents with varying clinical features based on the type and location. Treatment tends to be more effective on the face, neck, trunk, and mid-extremities, while the lips and distal extremities may be more resistant. Vitiligo in frequently exposed areas such as the face, arms, legs, and hands is typically associated with a lower Dermatology Life Quality Index. OBJECTIVES: We aimed to identify the characteristics and potential causes of vitiligo in challenging-to-treat regions, with particular focus on the hands. METHODS: We analyzed the clinical data of 337 patients with generalized vitiligo who visited our hospital between 2016 and 2022. For this study, we focused on patients with non-segmental vitiligo (NSV) specifically on their hands. Of the 337 patients, 248 had NSV and 89 had segmental vitiligo; 119 (47%) of those with NSV had vitiligo on their hands. Logistic regression models were applied to identify factors the factors linked to hand vitiligo, such as age, sex, duration of the condition, and smoking and alcohol history. RESULTS AND CONCLUSIONS: We developed a model to predict the risk of hand vitiligo using several factors. Among the factors analyzed, only smoking history was significantly associated with an increased risk (odds ratio: 3.13). In addition, we used clinical photography to evaluate color-graded frequency heat maps comprising 528 pixels. Vitiligo in nonsmokers widely distributed over the hand, predominantly the fingertips and joints, whereas vitiligo in smokers tended to be distributed mostly at the fingertips.

Awareness of sun exposure risks and photoprotection for preventing pigmentary disorders in Asian populations: Survey results from three Asian countries and expert panel recommendations.

BACKGROUND: In this article, we review and discuss the photoprotection behavior of Asians based on the literature, along with a subanalysis of an original online survey, and make recommendations to optimize photoprotection for Asian populations to prevent photoaging and pigmentary disorders. METHODS: An international panel of eight dermatologists from Asia (China, Korea, Japan, Singapore, Indonesia, and Vietnam) met to discuss sunscreen photoprotection for Asian patients. Additionally, a subanalysis of an online survey by 3000 respondents from three Asian countries (China, Indonesia, and Japan) investigated general public awareness and attitudes to sun exposure. RESULTS: A pre-meeting survey of the eight experts from Asia showed key concerns of Asian patients consulting dermatologists are pigmentary disorders, especially actinic/senile lentigo, post-inflammatory hyperpigmentation, melasma, vitiligo, and Hori's nevus. The survey subanalysis of participants from China, Indonesia, and Japan with predominantly Fitzpatrick skin types (FST) II to IV revealed that they are particularly concerned about sun exposure causing photoaging and pigmentary disorders. Most of the respondents indicated they have limited knowledge on sunlight radiation and appropriate sunscreen protection factors. Only 22%, 13%, and 3% for China, Indonesia, and Japan, respectively, systematically use multiple protective measures (using sunscreen, avoiding midday sun, staying in the shade, wearing a hat, protective clothing, and sunglasses) when exposed to the sun. CONCLUSIONS: Further education is needed for Asian populations on the importance of comprehensive daily photoprotection, including broad-spectrum sunscreen, with high UVA and visible light protection, to reduce and prevent photoaging and pigmentary disorders.

Treatment patterns of systemic drug use in Japanese patients with plaque psoriasis: A retrospective chart review.

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.

Pediatric psoriasis: Understanding pathological conditions and advances in treatment.

Psoriasis is a long-lasting skin disease that primarily affects the skin, nails, and joints and is characterized by inflammation. Genetic factors contribute to its development and environmental triggers can worsen symptoms. Pathologically, psoriasis is characterized by uncontrolled keratinocyte proliferation and abnormal differentiation, and histological features include acanthosis with inflammatory cell infiltration and neovascularization. Psoriasis often starts in childhood, with about one-third of cases beginning during this time. Its prevalence steadily increases from the ages of 1 to 18 years in a linear fashion. Young people with psoriasis often require treatment throughout their childhood and adolescence, and into adulthood. However, prolonged treatment may increase the risk of complications and adverse events, so it is important to adopt an effective treatment approach that minimizes this risk. In addition, psoriasis is often associated with various comorbidities that may place a great burden on the physical and mental health of the children beyond those due to psoriasis itself. To ensure good long-term health outcomes, individuals with psoriasis should undergo regular screening. Treatment should be provided not only for skin lesions, but also for any comorbidities; however, currently there is not enough evidence on the treatment of pediatric psoriasis and no globally agreed-on guidelines exist for treating psoriasis in children. This article describes the etiology, clinical symptoms, and disease burden of pediatric psoriasis, the pathological conditions and diagnosis of plaque psoriasis, psoriatic arthritis, and generalized pustular psoriasis, and the available treatments for these conditions in Japan.

Deucravacitinib, a selective, allosteric tyrosine kinase 2 inhibitor, in scalp psoriasis: A subset analysis of two phase 3 randomized trials in plaque psoriasis.

BACKGROUND: Scalp involvement in plaque psoriasis is challenging to treat. OBJECTIVE: To evaluate the efficacy and safety of deucravacitinib (DEUC) in scalp psoriasis. METHODS: POETYK PSO-1 and PSO-2 were global phase 3, 52-week, double-blinded trials in adults with moderate to severe psoriasis. Patients were randomized 1:2:1 to oral placebo, DEUC 6 mg once daily, or apremilast 30 mg twice daily. This pooled secondary analysis evaluated scalp-specific Physician Global Assessment score of 0 or 1 (0/1), ≥90% improvement from baseline in Psoriasis Scalp Severity Index, and change from baseline in Psoriasis Scalp Severity Index. Adverse events were evaluated through week 16. RESULTS: Overall, 1084 patients with moderate to severe scalp psoriasis at baseline were included. At week 16, response rates were greater with DEUC versus placebo or apremilast for scalp-specific Physician Global Assessment 0/1 (64.0% vs 17.3% vs 37.7%; P < .0001), ≥90% improvement from baseline in Psoriasis Scalp Severity Index (50.6% vs 10.5% vs 26.1%; P < .0001), and change from baseline in Psoriasis Scalp Severity Index. Responses were maintained through 52 weeks with continuous DEUC. Safety was consistent with the entire study population. LIMITATIONS: Lack of data in milder scalp psoriasis. CONCLUSION: DEUC was significantly more efficacious than placebo or apremilast in improving moderate to severe scalp psoriasis and was well tolerated.

Eosinophil may be a predictor of immune-related adverse events induced by different immune checkpoint inhibitor types: A retrospective multidisciplinary study.

BACKGROUND: Immune checkpoint inhibitors (ICIs) can cause severe immune-related adverse events (irAEs). However, biomarkers for irAEs common to different types of ICIs and cancers have not been reported. This study examined whether eosinophils can be used as a predictor of irAEs. METHODS: Six hundred fourteen patients with cancer (esophageal, gastric, head and neck, lung, melanoma, renal cell, urothelial, and other cancer) received anti-PD-1, anti-PD-L1, or anti-CTLA-4 plus anti-PD-1 therapy. The patients were divided into two groups depending on whether they experienced irAEs (irAE group) or not (non-irAE group). Eosinophils were examined before the two-course treatment. RESULTS: Patients in the irAE group who received anti-PD-1 or anti-CTLA-4 plus anti-PD-1 therapy had higher eosinophils before the two-course treatment than those in the non-irAE group (p < 0.05). The eosinophils in the anti-PD-L1 therapy group tended to increase in the irAE group. Furthermore, eosinophils in gastric, head and neck, lung, melanoma, renal, and urothelial cancers were significantly higher in the irAE group than in the non-irAE group (p < 0.05). The optimal cutoff value for eosinophils against irAEs was 3.0% (area under the curve = 0.668). In multivariate analyses, eosinophils of ≥3.0% were an independent factor for irAEs (odds ratio: 2.57, 95% CI: 1.79-3.67). CONCLUSION: An increased eosinophil before the two-course treatment may be a predictor of irAEs in various cancers treated with different ICIs.

Effectiveness Treatment of a BRAF-ZKSCAN5 Fusion Gene Melanoma Case with Dabrafenib/Trametinib.

The most important driver gene in malignant melanoma is the BRAF mutation, and molecularly targeted therapies targeting mutations, mainly V600E and V600k, are used in clinical practice. In this report, we treated a patient with malignant melanoma expressing a rare BRAF-ZKSCAN5 fusion gene with dabrafenib/trametinib. The patient was a 71-year-old female. She was diagnosed with malignant melanoma (pT4aN3M0, STAGE IIIC) of the abdomen with axillary lymph node metastasis. She underwent extended resection and axillary lymph node dissection and was treated with adjuvant therapy, but lung and mediastinal lymph node metastases developed. The patient was treated with immune checkpoint inhibitors for metastatic lesions and achieved complete remission, but relapsed and metastatic lesions appeared in the cervical lymph nodes. Next-generation sequencing revealed the BRAF-ZKSCAN5 fusion gene, and treatment with dabrafenib/trametinib was initiated. After 1 month of treatment, tumor growth stopped and the length of the tumor shrank by 22.2%, but she developed grade 3 adverse events of nausea, fatigue, and diarrhea and had difficulty exercising, forcing her to discontinue treatment after 6 weeks. The tumor continued to shrink during drug administration. This case report may provide insight into treatment options for cases in which the BRAF fusion gene was observed, which is expected to be detected in large numbers by next-generation sequencing in the future.