Improvements in immune/melanocyte biomarkers with JAK3/TEC family kinase inhibitor ritlecitinib in vitiligo.

BACKGROUND: Vitiligo is an autoimmune depigmenting disorder with no effective and safe treatments. Its pathogenesis is not fully elucidated. OBJECTIVE: This substudy of a randomized, double-blind, placebo-controlled phase 2b trial (NCT03715829) evaluated effects of ritlecitinib, an oral JAK3/TEC family kinase inhibitor, on skin and blood biomarkers in participants with nonsegmental vitiligo (NSV). METHODS: Sixty-five adults with NSV participated in the substudy and received daily treatment for 24 weeks with placebo (n = 14) or ritlecitinib with or without a 4-week loading dose: 200 (loading dose)/50 mg (n = 13), 100/50 mg (n = 12), 50 mg (n = 11), 30 mg (n = 8), or 10 mg (n = 6). Skin (lesional and nonlesional) biopsy samples were obtained at baseline and at 4 and 24 weeks. Changes from baseline to weeks 4 and 24 in skin and blood molecular and cellular biomarkers were evaluated by RNA sequencing, quantitative real-time PCR, proteomic analysis, and flow cytometry. RESULTS: Ritlecitinib-treated groups showed downregulation of immune biomarkers and upregulation of melanocyte-related markers at weeks 4 and 24 compared to baseline and/or placebo. Significant reductions were seen in CD3+/CD8+ T-cell infiltrates, with significant increases in melanocyte markers (tyrosinase; Melan-A) in NSV lesions in the 50 mg ritlecitinib groups (both P < .05). There was significant, dose-dependent downregulation in T-cell activation, NK, cytotoxic, and regulatory markers in lesional skin (IL-2, IL2-RA, IL-15, CCR7, CD5, CRTAM, NCR1, XCL1, KIR3DL1, FASLG, KLRD; P < .05). TH1 and TH2 markers were also downregulated in lesional skin and blood in a dose-dependent manner (P < .05). Changes in immune biomarkers correlated with clinical response. CONCLUSIONS: Ritlecitinib significantly downregulated proinflammatory biomarkers and increased melanocyte products in skin and blood of participants with NSV, suggesting its potential in treatment. Ritlecitinib-mediated changes positively correlated with clinical response.

Pathogenesis of Alopecia Areata and Vitiligo: Commonalities and Differences.

Both alopecia areata (AA) and vitiligo are distinct, heterogenous, and complex disease entities, characterized by nonscarring scalp terminal hair loss and skin pigment loss, respectively. In AA, inflammatory cell infiltrates are in the deep reticular dermis close to the hair bulb (swarm of bees), whereas in vitiligo the inflammatory infiltrates are in the epidermis and papillary dermis. Immune privilege collapse has been extensively investigated in AA pathogenesis, including the suppression of immunomodulatory factors (e.g., transforming growth factor-ß (TGF-ß), programmed death-ligand 1 (PDL1), interleukin-10 (IL-10), α-melanocyte-stimulating hormone (α-MSH), and macrophage migration inhibitory factor (MIF)) and enhanced expression of the major histocompatibility complex (MHC) throughout hair follicles. However, immune privilege collapse in vitiligo remains less explored. Both AA and vitiligo are autoimmune diseases that share commonalities in pathogenesis, including the involvement of plasmacytoid dendritic cells (and interferon-α (IFN- α) signaling pathways) and cytotoxic CD8+ T lymphocytes (and activated IFN-γ signaling pathways). Blood chemokine C-X-C motif ligand 9 (CXCL9) and CXCL10 are elevated in both diseases. Common factors that contribute to AA and vitiligo include oxidative stress, autophagy, type 2 cytokines, and the Wnt/ß-catenin pathway (e.g., dickkopf 1 (DKK1)). Here, we summarize the commonalities and differences between AA and vitiligo, focusing on their pathogenesis.

[A case of immune-related gastroesophagitis with laryngopharyngitis caused by immune checkpoint inhibitors in nonsmall cell lung cancer].

With the advent of immune checkpoint inhibitors (ICI), cancer treatment options have widened in recent years. However, ICI-specific adverse events (irAEs) have been reported. Lower gastrointestinal lesions, such as colitis and enteritis, account for most gastrointestinal irAEs, and reports of upper gastrointestinal lesions are rare. We report a rare case of gastroesophagitis associated with ICI. The patient was a 64-year-old male. He was diagnosed with lung adenocarcinoma stage IIIB (cT2aN3M0), and pembrolizumab (PEM) was started as a first-line treatment. Severe gastroesophagitis with laryngopharyngitis was confirmed 5 months after PEM administration. These improved after withdrawal of PEM and steroid administration. Reports of ICI-associated gastritis remain limited, especially with laryngopharyngitis;therefore, we consider this case as valuable, in which we confirmed the clinical features of ICI-associated gastroesophagitis and its therapeutic effects.

Efficacy and safety of oral ritlecitinib for the treatment of active nonsegmental vitiligo: A randomized phase 2b clinical trial.

BACKGROUND: Vitiligo is a chronic autoimmune disorder characterized by depigmented patches of the skin. OBJECTIVE: To evaluate the efficacy and safety of ritlecitinib, an oral JAK3 (Janus kinase)/TEC (tyrosine kinase expressed in hepatocelluar carcinoma) inhibitor, in patients with active nonsegmental vitiligo in a phase 2b trial (NCT03715829). METHODS: Patients were randomized to once-daily oral ritlecitinib ± 4-week loading dose (200/50 mg, 100/50 mg, 30 mg, or 10 mg) or placebo for 24 weeks (dose-ranging period). Patients subsequently received ritlecitinib 200/50 mg daily in a 24-week extension period. The primary efficacy endpoint was percent change from baseline in Facial-Vitiligo Area Scoring Index at week 24. RESULTS: A total of 364 patients were treated in the dose-ranging period. Significant differences from placebo in percent change from baseline in Facial-Vitiligo Area Scoring Index were observed for the ritlecitinib 50 mg groups with (-21.2 vs 2.1; P < .001) or without (-18.5 vs 2.1; P < .001) a loading dose and ritlecitinib 30 mg group (-14.6 vs 2.1; P = .01). Accelerated improvement was observed after treatment with ritlecitinib 200/50 mg in the extension period (n = 187). No dose-dependent trends in treatment-emergent or serious adverse events were observed across the 48-week treatment. LIMITATIONS: Patients with stable vitiligo only were excluded. CONCLUSIONS: Oral ritlecitinib was effective and well tolerated over 48 weeks in patients with active nonsegmental vitiligo.

Prevalence of Vitiligo among Children and Adolescents in the United States.

BACKGROUND: Vitiligo is an autoimmune disorder that causes patchy loss of skin pigmentation. Up to 2.16% of pediatric patients may have vitiligo. This study estimated vitiligo point prevalence in children and adolescents (ages: 4-11 and 12-17 years) in the United States (US). METHODS: An online, population-based survey of a nationally representative sample of individuals based on 2017 US Census Bureau estimates for age, race, Hispanic origin, income, and geographic region was conducted from December 2019 to March 2020. Parent/legal guardian proxies responded on behalf of their children or adolescents to vitiligo screening questions. Proxy-reported vitiligo status was adjudicated by expert dermatologists who reviewed photographs of vitiligo lesions uploaded by proxies using a teledermatology application. Estimated point prevalence (including diagnosed and undiagnosed vitiligo and its subtypes) was calculated for proxy-reported and clinician-adjudicated vitiligo. RESULTS: There were 9,118 eligible proxy responses (5,209 children, mean age 7.7 years; 3,909 adolescents, mean age 14.4 years). The proxy-reported vitiligo prevalence (95% confidence interval) for children and adolescents was 1.52% (1.11-1.93) and 2.16% (1.66-2.65), respectively. The clinician-adjudicated prevalence (sensitivity analysis bounds) was 0.84% (0.83-1.23) and 1.19% (1.18-1.74), respectively. Approximately 69% of children and 65% of adolescents had nonsegmental vitiligo (clinician adjudicated) and up to 50% may be undiagnosed. CONCLUSION: Based on the clinician-adjudicated prevalence estimates, there were more than 591,000 cases of vitiligo in children and adolescents in the US in 2020. More than two-thirds had nonsegmental vitiligo and nearly half may be undiagnosed. Future studies should confirm these findings.

The effect of Dunaliella tertiolecta supplementation on diet-induced obesity in UCP1-deficient mice.

We previously demonstrated that dietary supplementation with Dunaliella tertiolecta (DT) increases uncoupling protein 1 (UCP1) expression in brown adipose tissue (BAT) and improves diet-induced obesity (DIO) in C57BL/6 J mice at thermoneutrality (30 °C). Here, we investigated whether DT improves DIO in a thermoneutral UCP1-deficient (KO) animal. KO mice were fed a high-fat diet supplemented with DT for 12 weeks. Compared to control group without DT, body weight was significantly reduced in DT group with no difference in food intake. Dunaliella tertiolecta-supplemented mice exhibited lower adiposity and well-maintained multilocular morphology in BAT, in which a significant increase in gene expression of PR domain containing 16 was detected in DT group compared to control group. Moreover, increase in UCP2 level and/or decrease in ribosomal protein S6 phosphorylation were detected in adipose tissues of DT group relative to control group. These results suggest that DT supplementation improves DIO by stimulating UCP1-independent energy dissipation at thermoneutrality.

Role of Innate Immunity in Allergic Contact Dermatitis: An Update.

Our understanding of allergic contact dermatitis mechanisms has progressed over the past decade. Innate immune cells that are involved in the pathogenesis of allergic contact dermatitis include Langerhans cells, dermal dendritic cells, macrophages, mast cells, innate lymphoid cells (ILCs), neutrophils, eosinophils, and basophils. ILCs can be subcategorized as group 1 (natural killer cells; ILC1) in association with Th1, group 2 (ILC2) in association with Th2, and group 3 (lymphoid tissue-inducer cells; ILC3) in association with Th17. Pattern recognition receptors (PRRs) including toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) in innate immune cells recognize damage-associated molecular patterns (DAMPs) and cascade the signal to produce several cytokines and chemokines including tumor necrosis factor (TNF)-α, interferon (IFN)-α, IFN-γ, interleukin (IL)-1ß, IL-4, IL-6, IL-12, IL-13, IL-17, IL-18, and IL-23. Here we discuss the recent findings showing the roles of the innate immune system in allergic contact dermatitis during the sensitization and elicitation phases.

Determinants of quality of life in elderly rehabilitation users at a day care service center.

[Purpose] We investigated the relationship of quality of life (QOL) with cognitive function, physical function, and activity ability, and aimed to identify functions related to QOL improvement, among elderly people who use day-care rehabilitation. [Participants and Methods] The participants were 37 elderly rehabilitation users, whose QOL was assessed using the Health Organization QOL26 (WHOQOL26), which consists of a 26-item self-report questionnaire. Cognitive function was assessed using the Mini-Mental State Examination, while physical function was assessed with seated forward bending, knee extension, grip, 30-second chair stand test, timed up and go test, and gait speed. Activity ability was assessed using the Tokyo Metropolitan Institute of Gerontology Index of Competence (TMIG index). [Results] A positive correlation was found between five WHOQOL26 categories (psychological QOL, social QOL, environmental QOL, total QOL, and QOL average) and social role in the TMIG index. There was also a positive correlation between four WHOQOL26 categories (psychological QOL, social QOL, environmental QOL, and QOL average) and instrumental activity of daily living in the TMIG index. To identify factors influencing the QOL score, association with TMIG index was investigated. Social role in the TMIG index was a positive factor in psychological and social QOL. [Conclusion] Enhancing social role is important to improve QOL of elderly rehabilitation users.

Nostochopcerol, a new antibacterial monoacylglycerol from the edible cyanobacterium Nostochopsis lobatus.

A new antibacterial 3-monoacyl-sn-glycerol, nostochopcerol (1), was isolated from a cultured algal mass of the edible cyanobacterium Nostochopsis lobatus MAC0804NAN. The structure of compound 1 was established by the analysis of NMR and MS data while its chirality was established by comparison of optical rotation values with synthetically prepared authentics. Compound 1 inhibited the growth of Bacillus subtilis and Staphylococcus aureus at MIC of 50 µg/mL and 100 µg/mL, respectively.

HLA analysis of immune checkpoint inhibitor-induced and idiopathic isolated ACTH deficiency.

PURPOSE: Isolated adrenocorticotropic hormone deficiency is a rare disease; however, since immune check point inhibitors (ICIs) have become widely used, many more cases have been reported. In this study, we compared the human leukocyte antigen (HLA) signatures between ICI-induced isolated adrenocorticotropic hormone deficiency (IAD) and idiopathic IAD (IIAD). DESIGN AND METHODS: Clinical features and HLA frequencies were compared among 13 patients with ICI-induced IAD, 8 patients with IIAD, and healthy controls. HLA frequencies of healthy controls were adopted from a HLA database of Japanese population. RESULTS: Age and body mass index were higher, while the rate of weight loss was lower, in patients with ICI-induced IAD than in those with IIAD. No HLA alleles had a significantly higher frequency in patients with ICI-induced IAD than in healthy controls, whereas the frequencies of HLA-DRB1*09:01, HLA-DQA1*03:02, and DQB1*03:03 were significantly higher in patients with IIAD than in healthy controls. CONCLUSIONS: ICI-induced IAD and IIAD were different in terms of HLA frequencies. There were no specific HLAs related to ICI-induced IAD, whereas several HLAs in strong linkage disequilibrium were associated with IIAD. This might suggest that the two diseases have different pathological mechanisms. HLAs unique to IIAD may be helpful in predicting its pathophysiology.

Use of the Tokyo Cognitive Assessment for mild cognitive impairment to characterize elderly people that use day care services in Japan.

[Purpose] This study compared the motor skills and cognitive functions of elderly participants who required support with those who did not require support. We aimed to evaluate the characteristics of impairment in sub-items of cognitive function in patients who needed support to predict future clinical issues. [Participants and Methods] We surveyed 31 participants requiring support under the day care service insurance system for which they attended day care service centers in Japan (rehabilitation users) and 10 healthy participants who attended a university for lifelong learning (healthy elders). Data on personal attributes of the participants were collected, and the Cardio-Ankle Vascular Index and motor and cognitive functions were assessed. [Results] Although the participants undergoing rehabilitation were, on average, 6 years older than the healthy elders, we found no significant differences between the two groups in closed-eye, one-legged standing, grip strength, or quadriceps muscle strength. In terms of the Tokyo Cognitive Assessment for mild cognitive impairment, we found no significant differences between those undergoing rehabilitation and healthy elders in clock drawing performance, serial 7 task performance, or orientation; however, there were significant differences in erase character, copy of triangular pyramid, composition, read of digits, go/no-go, word recall, story reproduction, ToCA total score. [Conclusion] We believe that it is imperative for day care service centers to conduct programs that maintain cognitive function in addition to programs for improvement of physical function.

The effects of intensive oral care before surgery for gastric cancer patients.

OBJECTIVES: Oral function management has been recognized as important strategy for preventing postoperative complications. In this historical cohort study, we focused on the patients who planed gastrectomy, and investigated the appropriate duration and frequency of preoperative oral care to prevent complications after surgery. METHODS: Patients who planed surgery for gastric cancer between 2012 and 2018 were enrolled. We defined intensive oral care (IOC) as initial intervention at least three weeks before surgery and follow-up intervention within a week before surgery. As the primary outcome, the incidence of postoperative infectious complications was compared between the IOC and non-intensive oral care groups. RESULTS: A total of 576 patients were enrolled, including 66 with IOC. The incidence of infectious complications was 2/66 (3.0%) in the IOC group and 64/510 (12.5%) in the non-intensive oral care group. After adjusting for confounding factors, patients with IOC exposure had a lower chance of developing postoperative infectious complications (odds ratio; 0.217, 0.051-0.927). CONCLUSIONS: Intensive oral care can help prevent postoperative infectious complications after gastrectomy. These findings suggest that appropriate preoperative oral care includes at least two interventions: three weeks or more before and within one week before surgery.

Clinical impact of periodontal disease on postoperative complications in gastrointestinal cancer patients.

BACKGROUND: The effectiveness of perioperative oral management in gastrointestinal surgery remains unclear. To elucidate the clinical significance of oral care, we investigated the relationship between the oral environment and postoperative infectious complications (POICs) in patients undergoing gastrointestinal surgery. METHODS: This was a single-institute and historical cohort study of 341 patients. The participants were isolated from consecutive patients undergoing planned radical resection for gastrointestinal carcinoma from January 2016 to June 2017. Dentists assessed the oral environment for periodontal disease, hygiene status, dry mouth, fur on tongue, and tooth stumps. All patients received scaling and tooth brushing instructions. A stepwise logistic regression analysis was conducted to identify risk factors for POICs among the different oral statuses. RESULTS: The surgical procedures performed were gastrectomy in 123 (36.1%), colorectal resection in 185 (54.2%), and pancreatoduodenectomy or others in 38 (11.1%). POICs occurred in 48 patients (14.1%), including deep organ space infection in 20, surgical site infection in 11, anastomotic leakage in 5, urinary tract infection in 4, pneumonia in 2, and others in 6. After adjusting for confounding factors, periodontal disease was isolated as an independent risk factor for POICs (odds ratio 2.091, p = 0.037, 95% confidence interval 1.045-4.183). Other variables of oral environment such as hygiene status, dry mouth, fur on tongue, and tooth stumps did not have a significant impact on POICs. CONCLUSIONS: Periodontal disease is a risk factor for infectious complications after gastrointestinal surgery.

Therapeutic Efficacy of Twin-Block and Fixed Oral Appliances in Patients with Obstructive Sleep Apnea Syndrome.

PURPOSE: To compare the efficacy of twin-block (i.e., allows mouth opening) and fixed (i.e., maintains mouth closure) mandibular advancement splints (MASs) for the treatment of obstructive sleep apnea-hypopnea syndrome (OSA). MATERIALS AND METHODS: From 2011 to 2013, 23 patients with OSA in the twin-block group, and from 2013 to 2015, 29 patients in the fixed MAS group were included. All patients underwent polysomnography before and after 3 months of treatment. The two sets of polysomnographic and cephalometric variables were compared. RESULTS: A significant difference (p < 0.001) was observed in the apnea-hypopnea index before and after MAS treatment in both groups (twin-block group: 20.6 ± 11.5 vs. 14.7 ± 9.4; fixed group: 21.4 ± 15.2 vs. 11.2 ± 9.7). In the twin-block group, 5 patients (21.7%) were complete responders, 9 (39.1%) were fair responders, and 9 (39.1%) were nonresponders; the corresponding figures for the fixed group were 14 (48.3%), 9 (31.0%), and 6 (20.7%) patients. A significant between-group difference was observed in the distribution of responders (p = 0.046). The fixed group showed a significant improvement in the snoring index (p = 0.003), arousal index (p = 0.036), and desaturation rate (p = 0.012). Finally, the change in incisal overjet was larger in the fixed group than in the twin-block group (p < 0.001). CONCLUSIONS: These results suggest that fixed oral appliances are superior in treating OSA, based on their ability to prevent mouth opening and reduce incisal overjet.

Epidemiology of hyperhidrosis in 2 population-based health care databases.

BACKGROUND: Population-based and clinical case reports of hyperhidrosis (HH) provide prevalence estimates that vary widely across reported studies because of differences in case ascertainment. OBJECTIVE: In this study, we specify diagnostic, symptom, and prescription codes for HH to estimate incidence and prevalence for the United Kingdom and the United States. METHODS: Data from UK and US health care databases were analyzed to ascertain HH cases and estimate incidence and prevalence from health care records during calendar years 2011 through 2013. RESULTS: On the basis of 2013 data for the United States and United Kingdom, between 1.0% and 1.6% of these populations have health care records indicating diagnosis or treatment of HH. Women accounted for approximately 60% of incident and prevalent cases in both databases. LIMITATIONS: Because the case ascertainment methods rely on available data for those seeking health care, we may have underestimated the number of HH cases in both countries. CONCLUSIONS: The findings represent a plausible estimate for incidence and prevalence of HH among persons seeking medical care for excessive sweating. Improved practices for identifying HH in clinical settings may increase the sensitivity and specificity of future studies and improve characterization and quantification of the population burden of this significant disease.

Terazulene Isomers: Polarity Change of OFETs through Molecular Orbital Distribution Contrast.

Intermolecular orbital coupling is fundamentally important to organic semiconductor performance. Recently, we reported that 2,6':2',6″-terazulene (TAz1) exhibited excellent performance as an n-type organic field-effect transistor (OFET) via molecular orbital distribution control. To validate and develop this concept, here we present three other terazulene regioisomers, which have three azulene molecules connected at the 2- or 6-position along the long axis of the azulene, thus constructing a linear expanded π-conjugation system: 2,2':6',2″-terazulene (TAz2), 2,2':6',6″-terazulene (TAz3), and 6,2':6',6″-terazulene (TAz4). TAz2 and TAz3 exhibit ambipolar characteristics; TAz4 exhibits clear n-type transistor behavior as an OFET. The lowest unoccupied molecular orbitals (LUMOs) of all terazulenes are fully delocalized over the entire molecule. In contrast, the highest occupied molecular orbitals (HOMOs) of TAz2 and TAz3 are delocalized over the 2,2'-biazulene units; the HOMOs of TAz4 are localized at one end of the azulene unit. These findings confirm that terazulene isomers which are simple hydrocarbon compounds are versatile materials with a tunable-polarity FET characteristic that depends on the direction of the azulene unit and the related contrast of the molecular orbital distribution in the terazulene backbone.

Evaluation of the charge transfer efficiency of organic thin-film photovoltaic devices fabricated using a photoprecursor approach.

Recently, a unique 'photoprecursor approach' was reported as a new option to fabricate a p-i-n triple-layer organic photovoltaic device (OPV) through solution processes. By fabricating the p-i-n architecture using two kinds of photoprecursors and a [6,6]-phenyl C71 butyric acid methyl ester (PC71BM) as the donor and the acceptor, the p-i-n OPVs afforded a higher photovoltaic efficiency than the corresponding p-n devices and i-devices, while the photovoltaic efficiency of p-i-n OPVs depended on the photoprecursors. In this work, the charge transfer efficiency of the i-devices composed of the photoprecursors and PC71BM was investigated using high-sensitivity fluorescence microspectroscopy combined with a time-correlated single photon counting technique to elucidate the photovoltaic efficiency depending on the photoprecursors and the effects of the p-i-n architecture. The spatially resolved fluorescence images and fluorescence lifetime measurements clearly indicated that the compatibility of the photoprecursors with PC71BM influences the charge transfer and the photovoltaic efficiencies. Although the charge transfer efficiency of the i-device was quite high, the photovoltaic efficiency of the i-device was much lower than that of the p-i-n device. These results imply that the carrier generation and carrier transportation efficiencies can be increased by fabricating the p-i-n architecture.

Effects of vasodilatation and pressor response on neurovascular coupling during dynamic exercise.

PURPOSE: Visual stimulation increases the blood flow in the posterior cerebral artery (PCA), which supplies blood to the visual cortex by neurovascular coupling (NVC). Relative contributions of vasodilatation and pressor response on NVC during dynamic exercise are still unknown. METHODS: We measured the blood flow velocity in the PCA (PCAv) by transcranial Doppler ultrasound flowmetry during rest and exercise in 14 healthy males while they performed 12-min submaximal leg-cycle exercises at mild-, moderate-, and high-intensity, which corresponded to heart rates of 120, 140, and 160 bpm, respectively. NVC was estimated as the relative change in PCAv from 20 s eye-closing to the peak response during 40 s looking at a reversed checkerboard. Conductance index was calculated for evaluating vasodilatation as pressure divided by blood flow. RESULTS: In response to visual stimulation, a magnitude of vasodilatation was significantly decreased under the moderate-intensity, while pressor response was significantly suppressed under the high-intensity exercises, compared with the control condition. Conversely, peak response to visual stimulation in PCAv was not affected by exercise intensity though relative and absolute responses were significantly lower in the moderate- and high-intensity exercises than the control. CONCLUSION: It is suggested that the contributions of pressor response and vasodilatation were modified by exercise intensity, partly playing a role for stabilizing the peak response of PCAv with visual stimulation during dynamic exercise.