Trajectories of egg sensitization in childhood: Two birth cohorts in Asia and Europe.

BACKGROUND: Hen's egg exposure through impaired skin barrier is considered a major mechanism of sensitization to eggs. However, the impact of filaggrin (FLG) gene loss-of-function mutations on the natural history of egg sensitization lacks consensus among studies. OBJECTIVE: To evaluate the association between the natural course of egg sensitization and FLG mutations. METHODS: We used Japanese and the UK birth cohorts (CHIBA and MAAS) to identify the longitudinal patterns of egg sensitization until mid-school age and examined the relationship between the identified patterns and FLG mutations. Sensitization was assessed using egg white-specific IgE levels or skin prick tests (SPTs). Egg allergy was confirmed by parental reports and sensitization. Latent class growth analysis identified longitudinal patterns. RESULTS: Three similar patterns of egg sensitization (persistent, early-onset remitting, and no/low grade classes) were identified in both cohorts, with differing prevalence estimates. The proportion of children with egg allergy in the persistent class at 7 or 8 years of age was 23% (CHIBA) and 20% (MAAS). Consistently in both cohorts, FLG mutations were significantly associated only with the persistent class. Children with FLG mutations had an approximately four-fold increased risk of being in the persistent sensitization class (RRRs: 4.3, 95%C.I. (1.2-16.0), p = .03 in CHIBA; 4.3 (1.3-14.7), p = .02 in MAAS). CONCLUSION: FLG loss-of-function mutations are associated with persistent egg sensitization in both Japanese and European ethnicities, and the mutations might be a potential biomarker for identifying the risk of persistent egg sensitization/allergy in early infancy. Future studies should incorporate oral food challenges to confirm this relationship.

PD-L1 expression in keratinocyte and infiltration of CD4 + T lymphocyte can predict a severe type of erythema multiforme major induced by the anti-PD-1 antibody, pembrolizumab.

Skin toxicity is the most common adverse event of treatment with immune check point inhibitors. Among them, erythema multiforme is a rare occurrence with a frequency of 4%, with most of the cases developing grade 1/2 disease. We experienced high grade erythema multiforme major developing with pembrolizumab treatment for anal canal cancer with extensive skin metastases. Steroid ointment was ineffective, and the skin lesions with blisters expanded to > 45% of the body surface area. The patient was at risk for symptom aggravation, and a pulse therapy with methylprednisolone and increasing the dose of oral prednisolone (1 mg/kg) were started. The skin lesions improved in 1.8 months. Unless urgent and appropriate treatments such as high dose steroid administration were conducted, the skin toxicities could not be controlled. The presence of CD4+ T cells and PD-L1+ keratinocytes in the skin biopsy might be a predictive marker of erythema multiforme major resistant to standard steroid treatment. Supplementary Information: The online version contains supplementary material available at 10.1007/s13691-024-00676-4.

Treating epidermolytic ichthyosis and ichthyosis with confetti with epidermal autografts cultured from revertant skin.

BACKGROUND: No efficient treatment has yet been established for epidermolytic ichthyosis (EI), which is caused by pathogenic variants of KRT1 or KRT10. Patients with ichthyosis with confetti (IWC) have multiple normal-appearing spots, caused by the revertant somatic recombination of pathogenic variants that occurs at each spot independently. Additionally, some patients with EI have large areas of normal skin due to revertant postzygotic mosaicism. OBJECTIVES: To assess the feasibility of transplanting cultured epidermal autografts (CEAs) produced from revertant epidermal keratinocytes in patients with EI and IWC. METHODS: We performed a clinical trial of treatment with CEAs produced from each patient's own revertant epidermal keratinocytes as a proof-of-concept study. This was a single-arm, open, unmasked, uncontrolled, single-assignment, treatment-purpose study. The primary outcome was the percentage area that lacked recurrence of ichthyosis lesions 4 weeks after the final transplant. The secondary outcome was the percentage area lacking recurrence of ichthyosis lesions 24 weeks after the initial transplantation. The trial was registered with the Japan Registry of Clinical Trials (jRCTb041190097). RESULTS: We successfully produced CEAs from genetically confirmed revertant skin from two patients with mosaic EI and from one patient with IWC and confirmed by amplicon sequencing and droplet digital polymerase chain reaction analysis that the CEAs mainly consisted of revertant wild-type cells. Single-cell RNA sequencing analysis confirmed the normal proliferation and safety profiling of CEAs. CEAs were transplanted onto desquamated lesional sites in the patients. Four weeks post-transplantation, the percentage area lacking recurrence of ichthyosis lesions in the three patients was 40%, 100% and 100% respectively, although recurrence of ichthyosis lesions was seen at the site of CEA transplantation in all three patients at 24 weeks post-transplantation. CONCLUSIONS: CEAs from normal skin have the potential to be a safe and local treatment option for EI and IWC.

Epidermolytic ichthyosis is a rare skin condition that causes redness, blistering and thickening of the skin. There is currently no effective treatment for the disease, which is caused by mutations in the genes KRT1 or KRT10. People with a type of the disease called 'ichthyosis with confetti' have many normal-appearing spots that are caused by the natural repair of the gene mutations. Some people with epidermolytic ichthyosis have large areas of healthy skin as a result of genetic mutations having been corrected. In this study, we successfully produced skin grafts from the healthy skin of two patients with epidermolytic ichthyosis and one with 'ichthyosis with confetti'. We confirmed that the skin grafts mainly consisted of repaired skin cells. A technique called 'single-cell RNA sequencing' confirmed the skin cells in the skin grafts behaved like healthy skin cells and that the grafts were safe. Overall, our study findings suggest that skin grafts taken from skin consisting of genetically normal keratinocytes that have undergone self-repair have potential to be a safe treatment option for patients with severe epidermolytic ichthyosis and 'ichthyosis with confetti'.

Optimizing random skin biopsies: a review of techniques and indications for intravascular large B-cell lymphoma.

Intravascular large B-cell lymphoma (IVLBCL), a rare subtype of malignant lymphoma, is diagnosed by observation of intravascular proliferation of tumor cells in samples taken from affected organs. However, diagnosis of IVLBCL is usually difficult due to the lack of mass formation. IVLBCL may be fatal when the diagnosis is delayed, so an accurate early diagnosis is the key to successful treatment. Random skin biopsy (RSB), in which specimens are sampled from normal-appearing skin, has been reported as useful. However, the specific method of RSB remains controversial, with individual institutions using either the punch method or the incisional method. Research has shown that the incisional method has higher sensitivity than the punch method. We discuss whether this difference might owe to the collection of punch specimens from an insufficient depth and whether the punch method might result in false negatives. For RSB, we recommend taking specimens not only from normal-appearing skin, but also from any lesional skin, because lesions may reflect micro IVLBCL lesions. To ensure accurate diagnosis, both dermatologists and hematologists should know the proper method of RSB. This review summarizes the appropriate biopsy method and sites for RSB.

A genome-wide association study identified PTPN2 as a population-specific susceptibility gene locus for primary biliary cholangitis.

BACKGROUND AND AIMS: Previous genome-wide association studies (GWAS) have indicated the involvement of shared (population-nonspecific) and nonshared (population-specific) susceptibility genes in the pathogenesis of primary biliary cholangitis (PBC) among European and East-Asian populations. Although a meta-analysis of these distinct populations has recently identified more than 20 novel PBC susceptibility loci, analyses of population-specific genetic architecture are still needed for a more comprehensive search for genetic factors in PBC. APPROACH AND RESULTS: Protein tyrosine phosphatase nonreceptor type 2 ( PTPN2) was identified as a novel PBC susceptibility gene locus through GWAS and subsequent genome-wide meta-analysis involving 2181 cases and 2699 controls from the Japanese population (GWAS-lead variant: rs8098858, p = 2.6 × 10 -8 ). In silico and in vitro functional analyses indicated that the risk allele of rs2292758, which is a primary functional variant, decreases PTPN2 expression by disrupting Sp1 binding to the PTPN2 promoter in T follicular helper cells and plasmacytoid dendritic cells. Infiltration of PTPN2-positive T-cells and plasmacytoid dendritic cells was confirmed in the portal area of the PBC liver by immunohistochemistry. Furthermore, transcriptomic analysis of PBC-liver samples indicated the presence of a compromised negative feedback loop in vivo between PTPN2 and IFNG in patients carrying the risk allele of rs2292758. CONCLUSIONS: PTPN2 , a novel susceptibility gene for PBC in the Japanese population, may be involved in the pathogenesis of PBC through an insufficient negative feedback loop caused by the risk allele of rs2292758 in IFN-γ signaling. This suggests that PTPN2 could be a potential molecular target for PBC treatment.

Potentially compromised systemic and local lactate metabolic balance in glaucoma, which could increase retinal glucose and glutamate concentrations.

To investigate the association between lactate metabolism and glaucoma, we conducted a multi-institutional cross-sectional clinical study and a retinal metabolomic analysis of mice with elevated intraocular pressure (IOP) induced by intracameral microbead injection. We compared lactate concentrations in serum and aqueous humor in age-matched 64 patients each with primary open-angle glaucoma (POAG) and cataract. Neither serum nor aqueous humor lactate concentrations differed between the two groups. Multiple regression analysis revealed that only body mass index showed a significant positive correlation with serum and aqueous humor lactate concentration in POAG patients (rs = 0.376, P = 0.002, and rs = 0.333, P = 0.007, respectively), but not in cataract patients. L-Lactic acid was one of the most abundantly detected metabolites in mouse retinas with gas chromatography and mass spectrometry, but there were no significant differences among control, 2-week, and 4-week IOP elevation groups. After 4 weeks of elevated IOP, D-glucose and L-glutamic acid ranked as the top two for a change in raised concentration, roughly sevenfold and threefold, respectively (ANOVA, P = 0.004; Tukey-Kramer, P < 0.05). Glaucoma may disrupt the systemic and intraocular lactate metabolic homeostasis, with a compensatory rise in glucose and glutamate in the retina.

Real-world retention rates and effectiveness of secukinumab in psoriasis: Results from a multicenter cohort study (RAILWAY).

Psoriasis is a chronic, immune-mediated inflammatory skin disease with a high negative impact on patient's quality of life. Secukinumab, the first interleukin 17A inhibitor, has been used for the systemic treatment of psoriasis, but its long-term, real-world retention rates in Japan have not been fully investigated. In this multicenter, noninterventional, retrospective chart review study, the retention rate of secukinumab and its effectiveness among patients with psoriasis in Japan was evaluated up to 5 years. Data of patients who received secukinumab after December 26, 2014, were collected from medical charts obtained from seven sites, all certified for biologics use by the Japanese Dermatological Association. Patient characteristics, secukinumab retention, factors affecting secukinumab retention, reason for drug discontinuation, and effectiveness data were collected. The primary end point was secukinumab retention rate at week 52. A total of 123 patients were included in the analysis. Of these, 27 patients discontinued secukinumab by week 52, yielding a 78.0% (95% confidence interval, 69.6-84.4) retention rate at week 52. For patients whose Psoriasis Area and Severity Index (PASI) score was available, mean ± standard deviation PASI at baseline and at week 52 were 9.21 ± 7.37 and 1.4 ± 2.6, respectively. During the entire study period, "insufficient response" was the most common reason for discontinuation, and "history of biologics use" was a factor significantly associated with secukinumab discontinuation (hazard ratio, 1.72; p = 0.018). This study demonstrates the real-world retention rate and effectiveness of secukinumab in patients with psoriasis in Japan for up to 5 years and provides clinical insights into psoriasis treatment strategies.

Eosinophil-derived galectin-10 upregulates matrix metalloproteinase expression in bullous pemphigoid blisters.

BACKGROUND: Bullous pemphigoid (BP) is an autoimmune bullous disease in which abundant eosinophils accumulate in the blisters. Galectin-10 abounds in the cytoplasm of eosinophils and is released as a result of eosinophil extracellular trap cell death (EETosis). OBJECTIVE: To identify EETosis and the pathological roles of galectin-10 in BP. METHODS: EETosis and galectin-10 in BP blisters were confirmed by immunofluorescence and transmission electron microscopy. The concentrations of galectin-10 in serum and blister fluid from BP patients were studied by ELISA. The matrix metalloproteinase (MMP) expression in BP blisters was immunohistochemically compared to that in healthy controls. As an in vitro assay, normal human epidermal keratinocytes (NHEKs) and normal human dermal fibroblasts (NHDFs) were stimulated with galectin-10, followed by MMP expression measurement by real-time PCR and ELISA. The signaling pathways activated by galectin-10 were studied using Western blotting and confirmed by inhibition assays. RESULTS: Galectin-10-containing eosinophil infiltration and the extracellular deposition of major basic protein were observed in BP blisters. The ultrastructural characteristics of tissue eosinophils indicated piecemeal degranulation and EETosis. In the BP patients, the concentration of galectin-10 was higher in the blister fluid than in the serum. Several types of MMPs were upregulated in BP blisters. Galectin-10 upregulated the production of MMPs through the pathways of p38 MAPK, ERK and JNK in NHEKs and NHDFs. CONCLUSION: In the BP blisters, the eosinophils underwent EETosis and released galectin-10. Galectin-10 might contribute to BP blister formation through the production of MMPs by keratinocytes and fibroblasts.

Different patterns in the corneal endothelial cell loss after pars plana and pars limbal insertion of the Baerveldt glaucoma implant.

PURPOSE: To assess corneal endothelial cell (CE) loss after pars plana (PP) and pars limbal (PL) insertion of a Baerveldt glaucoma implant (BGI). DESIGN: Retrospective multicenter interventional comparative study. METHODS: We studied central CE loss for 5 years after BGI surgery in 192 eyes. RESULTS: The prevalence of bullous keratopathy (BK) was greater in the PL cohort than in the PP cohort (P = .003). The CE loss after simultaneous PP vitrectomy and tube insertion into the vitreous cavity was 11.9% in the first year, which was greater than that of 2.9% in eyes where the tube was inserted simply into the vitreous cavity after a prior vitrectomy (P = .046). The annual percentage CE loss after the first year decreased unidirectionally in both of those groups and was 1.3% and 1.0% in the fifth year, respectively (P < .001). For limbal insertion, the CE loss in the simple PL cohort was biphasic, decreasing from 10.5% in the first year to 7.0% in the fifth year. Simultaneous cataract and BGI surgery enhanced the CE loss slightly in the first year in the PP and PL cohorts to 13.0% and 14.0%, respectively. However, these increases were not significant (P = .816 and .358, respectively). Low preoperative CE density (P < .001) and insertion site (P = .020) were significant risk factors for the development of BK. CONCLUSIONS: CE loss in the PL and PP cohorts was biphasic and unidirectional, respectively. The difference in annual CE loss became evident over time. PP tube implantation may be advantageous when the preoperative CE density is low.

Cytokine and chemokine multiplex analysis-based exploration for potential treatment and prognostic prediction in large-vessel vasculitis: A preliminary observational study.

Large-vessel vasculitis (LVV) is subclassified into two phenotypes; Takayasu arteritis and giant cell arteritis. Although the pathogenesis of LVV is not fully established, IL-6-IL-17 axis and IL-12-IFN-γ axis play critical roles in the disease development. We aimed to clarify the association between the disease state and cytokine/chemokine levels, to assess disease course as prognosis and to predict regulators in patients with LVV using the blood profiles of multiple cytokines/chemokines. This retrospective analysis comprised 35 LVV patients whose blood were collected, and multiplex cytokine/chemokine analysis with 28 analytes was performed. The differences of cytokines/chemokines corresponding disease status, upstream regulator analysis, pathway analysis and cluster analysis were conducted using the cytokines/chemokines profile. Relapse-free survival rate was calculated with Kaplan-Meier analysis in the classified clusters. In the robust analysis, IL-4, CCL2/MCP-1, TNFSF13/APRIL, TNFSF13B/BAFF, CHI3L1 and VEGF-A levels were significantly changed after treatment. Untreated LVV patients demonstrated activation of NFκB-related molecules and these patients are potentially treated with JAK/STAT inhibitors, anti-TNF-α inhibitors and IL-6 inhibitors. Cluster analysis in active LVV patients revealed two clusters including one with high blood levels of IL-1ß, IL-6, IL-17, IL-23 and CCL20/MIP-3. A subgroup of the LVV patients showed activated IL-17 signature with high relapse frequency, and JAK/TyK2 inhibitors and IFN-γ inhibitors were detected as potentially upstream inhibitors. Blood cytokine/chemokine profiles would be useful for prediction of relapse and potentially contributes to establish therapeutic strategy as precision medicine in LVV patients.

Darier disease successfully treated with a topical agent containing vitamin A (retinyl palmitate), vitamin E, and urea.

Darier disease (DD), also called keratosis follicularis, is an autosomal dominant hereditary keratinization disorder that manifests as keratotic papules with plaques in seborrheic areas. There are no validated curative treatments for DD, with the majority of cases treated symptomatically. We report the efficacy of a topical over-the-counter agent which contains retinyl palmitate, vitamin E, and urea for a patient with DD. A 13-year-old girl had brown papules on her scalp, neck, shoulders, and axillae since entering elementary school. A skin biopsy revealed hyperkeratosis, suprabasal acantholysis, and dyskeratosis manifested as corps ronds and grains in the epidermis. Sanger sequencing found the previously reported heterozygous mutation c.1484C>T in ATP2A2. The application of an over-the-counter topical agent containing retinyl palmitate 2750 µg/g (5000 IU/g), tocopheryl acetate 20 mg/g, urea 200 mg/g, and monoammonium glycyrrhizinate 5 mg/g twice daily for 2 months improved the papules without serious adverse events. Oral or topical aromatic vitamin A analogs (retinoids) are often used to treat DD. However, several adverse events are associated with retinoid treatment, and many patients only undergo their intermittent use or discontinue the treatments. Retinyl palmitate is more stable and has a lower irritative profile than other retinoic acids. When applied topically, however, retinyl palmitate cannot penetrate the skin as well as retinol can. Some reports have noted that vitamin E increases the biological availability of vitamin A and that urea helps mechanical percutaneous drug delivery. Our case suggests that retinyl palmitate has a sufficient therapeutic effect when combined with vitamin E and urea. In conclusion, we propose that topical agents containing retinyl palmitate, vitamin E, and urea might have a satisfactory effect on the skin lesions of DD patients, without the serious risks of adverse events.

Branch Retinal Vein Occlusion after Messenger RNA-Based COVID-19 Vaccine.

Two days after the second dose of the messenger RNA-based COVID-19 vaccine (BNT162b2), a healthy 38-year-old man developed branch retinal vein occlusion (BRVO) in his left eye (OS). His previous medical history was unremarkable and he was a nonsmoker. His blood pressure was 117/78 mm Hg. Blood examination did not suggest thrombophilia. His best-corrected visual acuity (BCVA) was 0.9 OS with myopic correction. A fundus examination showed a retinal hemorrhage and cotton wool spots in the superotemporal region of the posterior pole OS. Optical coherence tomography macular scans showed subfoveal fluid accumulation and retinal thickening in the superior macular region OS. Two intravitreal injections of aflibercept were administered 2 months apart. By 7 months after the initial visit, the BCVA was 1.2 OS and the retinal hemorrhage and macular edema have resolved. BRVO can be seen after BNT162b2 vaccinations. Because the third doses of the vaccine are beginning to be administered more widely, ocular complications including RVO can develop and require attention.

Noninferiority of Microhook to Trabectome: Trabectome versus Ab Interno Microhook Trabeculotomy Comparative Study (Tram Trac Study).

PURPOSE: To elucidate the noninferiority of ab interno microhook trabeculotomy (µTLO) using a recently developed reusable stainless spatula-type microhook device to incise the trabecular meshwork to Trabectome (Neomeix, Inc) surgery in terms of the 1-year postoperative outcomes of Japanese patients with glaucoma by means of propensity score analyses. DESIGN: Multicenter, retrospective cohort study. PARTICIPANTS: We enrolled 553 and 392 patients who underwent Trabectome surgery and µTLO, respectively, between January 2014 and March 2020 at 10 facilities. METHODS: Logistic regression analysis was conducted to calculate the propensity score, which indicates the likelihood of treatment assignment (Trabectome or µTLO). We set the following factors as outcome-related covariates: age, sex, facility, glaucoma disease types, preoperative intraocular pressure (IOP), glaucoma drug score, mean deviation of Humphrey visual field test results, antithrombotic drug use, the presence or absence of combined cataract surgery, and incision range of the trabecular meshwork (1 or 2 quadrants). We analyzed 4 different methods (matching, inverse probability of treatment weighting [IPTW], stratification, and regression adjustment) using the propensity score. We set 15% as the noninferiority margin based on previous Trabectome meta-analysis results. MAIN OUTCOME MEASURES: The primary outcome was surgical success at 1 year after surgery. We defined surgical success as satisfying all 3 criteria: (1) IOP within 5 to 21 mmHg, (2) IOP reduction of 20% or more from preoperative IOP, and (3) no additional glaucoma surgery. RESULTS: The 95% confidence interval of risk difference of surgical failure in µTLO in reference to Trabectome surgery was -12.1% to +9.5% in matching, -12.7% to +11.1% in IPTW, -12.2 to +7.0 in stratification, and -9.7% to +8.1% in regression adjustment, all of which fell within the predetermined noninferiority margin of 15%. CONCLUSIONS: Surgical success of µTLO at 1 year after was not inferior to that of Trabectome surgery.