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Introduction The neocortex is composed of 6 layers that are built during embryonic development through highly orchestrated processes of successive generation of cohorts of glutamatergic neurons in the proliferative zones [...], Reelin (RELN) is a secreted glycoprotein essential for cerebral cortex development. In humans, recessive RELN variants cause cortical and cerebellar malformations, while heterozygous variants were associated with epilepsy, autism, and mild cortical abnormalities. However, the functional effects of RELN variants remain unknown. We identified inherited and de novo RELN missense variants in heterozygous patients with neuronal migration disorders (NMDs) as diverse as pachygyria and polymicrogyria. We investigated in culture and in the developing mouse cerebral cortex how different variants impacted RELN function. Polymicrogyria-associated variants behaved as gain-of-function, showing an enhanced ability to induce neuronal aggregation, while those linked to pachygyria behaved as loss-of-function, leading to defective neuronal aggregation/migration. The pachygyria-associated de novo heterozygous RELN variants acted as dominant-negative by preventing WT RELN secretion in culture, animal models, and patients, thereby causing dominant NMDs. We demonstrated how mutant RELN proteins in vitro and in vivo predict cortical malformation phenotypes, providing valuable insights into the pathogenesis of such disorders.

Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease with a linear deposit of autoantibodies at the epidermal basement membrane zone. It was reported that diabetes patients who took a dipeptidyl peptidase‐4 inhibitor (DPP4i), an oral antidiabetic drug, had an increased incidence of BP. However, data on DPP4i‐related BP are limited. In our study, we measured serum levels of various cytokines using LEGENDplex and assessed correlations of these serum levels with clinical severity and laboratory data. Serum samples obtained from BP patients who visited our hospital from June 2016 to February 2023 were collected in this study. Patients' background, characteristics, and clinical data were retrospectively collected from their charts. Serum samples from 27 patients with DPP4i‐unrelated BP, 17 patients with DPP4i‐related BP, and 13 healthy controls were analyzed. Patients with DPP4i‐related BP had lower score of Bullous Pemphigoid Disease Area Index (BPDAI)‐erythema/urticaria, lower number of circulating eosinophils, and lower titer of anti‐BP180 antibody than patients with DPP4i‐unrelated BP. The serum interleukin (IL)‐6 level was significantly higher in patients with DPP4i‐related BP than in healthy controls (P = 0.0037). The serum IL‐10 level was significantly higher in patients with DPP4i‐related BP than in patients with DPP4i‐unrelated BP and in healthy controls (P = 0.0006, P = 0.0448), and was positively correlated with the BPDAI‐blister/erosions score (r = 0.757, P = 0.001), BPDAI‐erythema/urticaria score (r = 0.616, P = 0.013), and BPDAI‐total score (r = 0.833, P < 0.001) in patients with DPP4i‐related BP. In conclusion, patients with DPP4i‐related BP had increased serum levels of IL‐6 and IL‐10 compared with healthy controls and positive correlations between the serum IL‐10 level and BPDAI scores reflecting clinical severity, indicating that the serum IL‐10 level is a potential objective biomarker of disease severity in patients with DPP4i‐related BP. [ABSTRACT FROM AUTHOR]

Dupilumab, an anti‐interleukin (IL)‐4 receptor α‐antibody, was approved in 2018 for the treatment of moderate‐to‐severe atopic dermatitis (AD) in Japan. Although real‐world data have accumulated on the effectiveness and safety of dupilumab in patients with AD in the short term, real‐world data on its long‐term use are limited. In this study, we retrospectively investigated its effectiveness, safety and laboratory data in patients with AD who received dupilumab for 3 years. All adult patients with moderate‐to‐severe AD who were administered dupilumab between June 2018 and December 2020 and were treated with dupilumab for more than 3 years were included in this study. Sixty Japanese patients with AD (male, 48; female, 12) were included in this study. Their mean age was 36.6 ± 11.0 (standard deviation) years. The mean Eczema Area and Severity Index (EASI) was 29.9 ± 9.2. The clinical severity scales, including Investigator's Global Assessment (IGA), EASI and affected body surface area (BSA), and patient‐reported outcomes, such as Dermatology Quality Life Index (DLQI), Patient‐Oriented Eczema Measure (POEM) and visual analogue scale (VAS) of pruritus, significantly improved at 3 months, and at 1, 2 and 3 years after initiating dupilumab. The total EASI score significantly decreased by a mean of 66.8% at 3 months, 81.0% at 1 year, 85.3% at 2 years and 90.0% at 3 years after initiating dupilumab. The serum levels of thymus and activation‐regulated chemokine (TARC), immunoglobulin E (IgE) and lactate dehydrogenase (LDH) significantly decreased at 1, 2 and 3 years. A slight decrease in circulating neutrophils was observed in patients with AD treated with dupilumab over periods from 3 months to 3 years. The number of circulating eosinophils significantly decreased at 2 and 3 years after initiating dupilumab. The most common adverse event was ocular disorders observed in 23 patients (38.3%). Our study shows the sustained effectiveness and tolerable safety of 3‐year usage of dupilumab in Japanese patients with atopic dermatitis. Furthermore, dupilumab decreased neutrophil values at 3 months and later, and reduced the number of circulating eosinophils after long‐term use (≧ 2 years). [ABSTRACT FROM AUTHOR]

Recent studies indicate that hepatic diseases are associated with psoriasis. Non‐invasive tests, including the Fibrosis‐4 (FIB‐4) index, which can confidently rule out the presence of advanced fibrosis, are currently receiving attention. However, data on the FIB‐4 index in psoriasis patients and the effects of biologics on the FIB‐4 index are limited. We investigated the relationships between the FIB‐4 index and demographic or clinical characteristics as well as the effects of biologics on the FIB‐4 index in psoriasis patients. Psoriasis patients aged 36–64 years, whose treatment was initiated with interleukin (IL)‐17 inhibitors or IL‐23 inhibitors for psoriasis from May 2015 to December 2022, were consecutively included. Data were collected retrospectively from the patients' charts. A total of 171 psoriasis patients were included in this study. Thirty‐four, 43, 21, 32, and 41 psoriasis patients were treated with secukinumab, ixekizumab, brodalumab, guselkumab, or risankizumab, respectively. In biologics‐naïve patients, a significant but weak positive correlation was observed between the FIB‐4 index and age (r = 0.3246, p = 0.0018). There was no significant correlation between the FIB‐4 index and other demographic or clinical characteristics. Regarding the effects of biologics on the FIB‐4 index, no significant change was observed in psoriasis patients treated with any biologics. However, in psoriasis patients with a baseline FIB‐4 index of >1.3, patients treated with guselkumab and those treated with either IL‐23 inhibitor showed significantly decreased FIB‐4 index scores 6 months after initiating the biologics (p = 0.0323, p = 0.0212). In contrast, no change was observed in FIB‐4 index scores in patients treated with IL‐17 inhibitors. In conclusion, our study revealed that the FIB‐4 index was correlated with age in psoriasis patients. Furthermore, IL‐23 inhibitors (but not IL‐17 inhibitors) decreased the FIB‐4 index score at 6 months in psoriasis patients with elevated FIB‐4 index scores at baseline. Further studies are needed to clarify whether IL‐23 inhibitors improve liver fibrosis physiologically and functionally. [ABSTRACT FROM AUTHOR]

Psossibility and appropriate timing of discontinuation of dupilumab for atopic dermatitis (AD) remain unclear. We explored the possibility of patients, who could maintain remission with topical therapy alone after withdrawing dupilumab in the real world. Furthermore, we identified their characteristics. All adult AD patients who initiated dupilumab from June 2018 to July 2022 and were treated with dupilumab for more than 3 months at our hospital were included in this study. The observation period was from June 2018 to July 2023. In 138 patients, 58 (42.0%) discontinued dupilumab at least once. Among them, 18 (13.0%) discontinued dupilumab but reinitiated dupilumab later due to exacerbation. Only seven patients (5.1%) could maintain remission with topical therapy alone after discontinuation of dupilumab, with characteristics of lower POEM, VAS of pruritus, serum levels of TARC and LDH, and neutrophil counts at baseline, and those of longer duration of dupilumab until its discontinuation (24.0 ± 13.3 vs. 12.8 ± 7.3 months) and lower EASI and affected BSA at the discontinuation of dupilumab. In 118 patients treated with dupilumab for at least 1 year, 38 patients (32.2%) discontinued at least once. Only four patients (3.4%) could maintain remission with topical therapy alone after discontinuation of dupilumab, with characteristics of lower POEM at baseline and lower EASI at the discontinuation of dupilumab. In conclusion, maintaining remission after withdrawing dupilumab is challenging. Discontinuation of dupilumab may be considered in patients with low baseline POEM, after more than 2 years of dupilumab treatment, with a substantial decrease in EASI. [ABSTRACT FROM AUTHOR]

Dupilumab was approved for treating adult patients with atopic dermatitis (AD) refractory to topical therapy in Japan in April 2018, and self‐injection of dupilumab has been available since May 2019. Subcutaneous self‐injection of medication has benefits for patients and the healthcare system. However, anxiety about self‐injection, lack of confidence, and the complicated procedure could prevent initiating self‐injection. In this study, we assessed the experience of AD patients treated with dupilumab before and after introducing self‐injection, utilizing the Self‐Injection Assessment Questionnaire (SIAQ). Adult AD patients who received dupilumab by self‐injection and had been treated for more than 3 months after initiating self‐injection in our hospital from March 1, 2020, to June 19, 2021, were included in this study. Patients rated their perceptions about self‐injections using the SIAQ before the first self‐injection and 3 months after initiating self‐injection. Data were collected retrospectively from their charts. Data on 36 patients were analyzed. The mean age was 34.1 ± 11.5 years. Twenty patients used a prefilled auto‐injector, and the others used a prefilled syringe. Scores on self‐confidence and satisfaction with self‐injection significantly improved after introducing self‐injection. Feelings about injections improved in patients over 40 years and in those who felt anxious about self‐injection. A strong correlation in scores between satisfaction with self‐injection and the ease of use was observed. The results were not affected by clinical severity, gender, or device. Our results could encourage patients who dither to introduce self‐injection of dupilumab due to anxiety and/or lack of self‐confidence about self‐injection to initiate self‐injection. [ABSTRACT FROM AUTHOR]