Region-specific activation in the accumbens nucleus by itch with modified scratch efficacy in mice - a model-free multivariate analysis.

Itch is a protective/defensive function with divalent motivational drives. Itch itself elicits an unpleasant experience, which triggers the urge to scratch, relieving the itchiness. Still, it can also result in dissatisfaction when the scratch is too intense and painful or unsatisfactory due to insufficient scratch effect. Therefore, it is likely that the balance between the unpleasantness/pleasure and satisfaction/unsatisfaction associated with itch sensation and scratching behavior is determined by complex brain mechanisms. The physiological/pathological mechanisms underlying this balance remain largely elusive. To address this issue, we targeted the "reward center" of the brain, the nucleus accumbens (NAc), in which itch-responsive neurons have been found in rodents. We examined how neurons in the NAc are activated or suppressed during histamine-induced scratching behaviors in mice. The mice received an intradermal injection of histamine or saline at the neck, and the scratching number was analyzed by recording the movement of the bilateral hind limbs for about 45 min after injection. To experimentally manipulate the scratch efficacy in these histamine models, we compared histamine's behavioral and neuronal effects between mice with intact and clipped nails on the hind paws. As expected, the clipping of the hind limb nail increased the number of scratches after the histamine injection. In the brains of mice exhibiting scratching behaviors, we analyzed the expression of the c-fos gene (Fos) as a readout of an immediate activation of neurons during itch/scratch and dopamine receptors (Drd1 and Drd2) using multiplex single-molecule fluorescence in situ hybridization (RNAscope) in the NAc and surrounding structures. We performed a model-free analysis of gene expression in geometrically divided NAc subregions without assuming the conventional core-shell divisions. The results indicated that even within the NAc, multiple subregions responded differentially to various itch/scratch conditions. We also found different clusters with neurons showing similar or opposite changes in Fos expression and the correlation between scratch number and Fos expression in different itch/scratch conditions. These regional differences and clusters would provide a basis for the complex role of the NAc and surrounding structures in encoding the outcomes of scratching behavior and itchy sensations.

[RECOMMENDATION FOR ITCH ASSESSMENT FROM THE ATOPIC ITCH CONSENSUS MEETING (AICOM)].

BACKGROUND: Itch is the most troublesome symptom of atopic dermatitis, and it is important to assess it appropriately for optimal treatment. We discussed issues regarding itch and the most appropriate methods of assessment at the Atopic Itch Consensus Meeting (AICOM), attended by physicians and researchers with expertise in itch treatment and research. METHODS: The AICOM participants prepared a draft consensus statement that addressed the most appropriate itch assessment methods for age groups <2 years, 2-6 years, 7-14 years, and ≥15 years. Consensus was defined as agreement by ≥80% of the participants. RESULTS: Votes were cast by 20 participants (8 dermatologists, 7 pediatricians, and 5 researchers), and a consensus on the best current methods of itch assessment was reached with 95% agreement. For infants and preschool children, because subjective evaluation is difficult, a checklist for itch assessment was developed for caregivers. CONCLUSION: For itch assessment, we recommend subjective evaluation by the patient using a rating scale. For infants and preschoolers, evaluation should be done by the caregiver using a checklist, combined with objective evaluation (of skin lesions, for example) by a physician. We anticipate that more objective itch assessment indices will be established in the future.

[JAPANESE TRANSLATION AND LINGUISTIC VALIDATION OF THE RECAP OF ATOPIC ECZEMA (RECAP)].

BACKGROUND: The Recap of atopic eczema (RECAP), a new core outcome of the atopic dermatitis trial, was translated into Japanese and linguistically validated. METHODS: Translation into Japanese was accomplished according to the ISPOR (International Society for Pharmacoeconomics and Outcome Research) guidelines and the basic guidelines for scale translation. The translation process included two forward translations, reconciliation with native English speakers, third-party back translation, cognitive debriefing, review and harmonization by the original authors. Twenty-seven atopic dermatitis and pediatric specialists from 21 centers in Japan participated in the translation process. Cognitive debriefing was conducted through face-to-face interviews using a think-aloud method with the interview guide including questions about comprehensibility, relevance, comprehensiveness, recall period and suggested improvements, based on the COSMIN methodology. RESULTS: No linguistic or cultural problems were encountered in the translation into Japanese. Cognitive debriefings were conducted with 10 adult patients and 10 parents of pediatric patients. Some minor modifications were made following discussion and approval by the research team and the original authors. The Japanese version of RECAP was considered to be understandable, comprehensive and relevant for adult patients and families of pediatric patients. CONCLUSION: The Japanese version of the RECAP, which has been validated as linguistically equivalent to the original version, is now available. Further evaluation of the measurement properties is needed in the future.

Oncostatin M suppresses IL31RA expression in dorsal root ganglia and interleukin-31-induced itching.

Background: Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by intermittent itchy rash. Type 2 inflammatory cytokines such as interleukin (IL)-4, IL-13, and IL-31 are strongly implicated in AD pathogenesis. Stimulation of IL-31 cognate receptors on C-fiber nerve endings is believed to activate neurons in the dorsal root ganglion (DRG), causing itch. The IL-31 receptor is a heterodimer of OSMRß and IL31RA subunits, and OSMRß can also bind oncostatin M (OSM), a pro-inflammatory cytokine released by monocytes/macrophages, dendritic cells, and T lymphocytes. Further, OSM expression is enhanced in the skin lesions of AD and psoriasis vulgaris patients. Objective: The current study aimed to examine the contributions of OSM to AD pathogenesis and symptom expression. Methods: The expression levels of the OSM gene (OSM) and various cytokine receptor genes were measured in human patient skin samples, isolated human monocytes, mouse skin samples, and mouse DRG by RT-qPCR. Itching responses to various pruritogens were measured in mice by counting scratching episodes. Results: We confirmed overexpression of OSM in skin lesions of patients with AD and psoriasis vulgaris. Monocytes isolated from the blood of healthy subjects overexpressed OSM upon stimulation with IL-4 or GM-CSF. Systemic administration of OSM suppressed IL31RA expression in the mouse DRG and IL-31-stimulated scratching behavior. In contrast, systemic administration of OSM increased the expression of IL-4- and IL-13-related receptors in the DRG. Conclusion: These results suggest that OSM is an important cytokine in the regulation of skin monocytes, promoting the actions of IL-4 and IL-13 in the DRG and suppressing the action of IL-31. It is speculated that OSM released from monocytes in skin modulates the sensitivity of DRG neurons to type 2 inflammatory cytokines and thereby the severity of AD-associated skin itch.

Monitoring Sleep and Scratch Improves Quality of Life in Patients with Atopic Dermatitis.

Atopic dermatitis itch may cause sleep disturbance and impair quality of life. For patients finding topical therapy difficult to continue, it is important to control itch and reduce scratching. This study developed algorithms to measure nocturnal sleep and scratch, using an actigraph device worn on the back of the hand, and assessed smartphone application feedback to improve adherence with therapy. In the first trial, actigraph measurements in 5 participants who wore the device were highly correlated with measurements by a sleep-monitoring device beneath the mattress. Total actigraph-measured scratching duration for each hour of sleep was highly correlated with measurements by a person rating infrared video-recording of the sleepers. In the second trial, 40 patients with atopic dermatitis were randomly allocated into an intervention group that used the actigraph and smartphone application, and a control group that did not. Both groups were instructed to use the same moisturizer. Dermatology Life Quality Index scores decreased significantly from baseline and were lower than those in the control group at week 8. It is suggested that the device and associated smartphone application reinforced therapy adherence, moisturizer use, and contributed to improved quality of life in patients with atopic dermatitis.

Role of Eosinophil Relative Count and Neutrophil-to-Lymphocyte Ratio in the Assessment of Severity of Atopic Dermatitis.

The aim of this study is to elucidate the relationship between 2 different types of severity-indicating parameters (i.e. between subjective and objective severity-indicating parametersin patients with atopic dermatitis. The disease severity of 55 patients with atopic dermatitis was assessed using 7 subjective parameters indicating severity, including visual analogue scale for itch, Patient-Oriented Eczema Measure, 5-D itch scale, Dermatology Life Quality Index, Eczema Area and Severity Index, body surface area, and Investigator Global Assessment, and 8 objective parameters indicating severity, including eosinophil relative count, neutrophil-to-lymphocyte ratio, lactate dehydrogenase, and thymus and activation-regulated chemokine. Five subjective parameters reflecting itch correlated significantly with eosinophil relative count, but not with neutrophil-to-lymphocyte ratio. In contrast, 2 subjective parameters, mainly reflecting the degree of inflammation and area of affected regions, correlated significantly with neutrophil-to-lymphocyte ratio. The eosinophil relative count may correlate with the degree of itch, while the neutrophil-to-lymphocyte ratio may correlate with the degree of inflammation and the area of the affected region. The eosinophil relative count and neutrophil-to-lymphocyte ratio may thus be stand-alone parameters from each other in the assessment of the severity of atopic dermatitis.

The first Japanese family of CDH3-related hypotrichosis with juvenile macular dystrophy.

BACKGROUND: Hypotrichosis with juvenile macular dystrophy (HJMD) is a rare autosomal recessive inherited disorder caused by biallelic variants in the CDH3 gene encoding P-cadherin. Here, we report two Japanese sibling patients with HJMD. METHODS: Whole-exome sequencing (WES) was performed to identify disease-causing variants. In addition, ophthalmic and dermatological examinations were performed to classify the phenotype of each patient. RESULTS: The WES analysis revealed novel compound heterozygous CDH3 variants [c.123_129dupAGGCGCG (p.Glu44fsX26) and c.2280+1G>T] in both patients; the unaffected, nonconsanguineous parents each exhibited one of the variants. Both patients showed the same clinical findings. Ophthalmologically, they exhibited progressive loss of visual acuity and chorioretinal macular atrophy, as examined with fundoscopy, fundus autofluorescence imaging, and optical coherence tomography. Full-field electroretinography, assessing generalized retinal function, revealed nearly normal amplitudes of both rod- and cone-mediated responses. Multifocal electroretinography, reflecting macular function, showed extremely decreased responses in the central area, corresponding to the chorioretinal atrophy. Dermatological examination revealed diffuse thinning of the scalp hair, which was sparse and fragile. CONCLUSION: This is the first report of Japanese patients with HJMD and novel compound heterozygous truncating variants in CDH3. Our findings can expand the knowledge and understanding of CDH3-related HJMD, which could be helpful to ophthalmologists and dermatologists.

Direct evidence that the brain reward system is involved in the control of scratching behaviors induced by acute and chronic itch.

In the present study, we demonstrated that there is a direct relationship between scratching behaviors induced by itch and functional changes in the brain reward system. Using a conditional place preference test, the rewarding effect was clearly evoked by scratching under both acute and chronic itch stimuli. The induction of ΔFosB, a member of the Fos family of transcription factors, was observed in dopamine transporter (DAT)-positive dopamine neurons in the ventral tegmental area (VTA) of mice suffering from a chronic itch sensation. Based on a cellular analysis of scratching-activated neurons, these neurons highly expressed tyrosine hydroxylase (TH) and DAT genes in the VTA. Furthermore, in an in vivo microdialysis study, the levels of extracellular dopamine in the nucleus accumbens (NAcc) were significantly increased by transient scratching behaviors. To specifically suppress the mesolimbic dopaminergic pathway using pharmacogenetics, we used the TH-cre/hM4Di mice. Pharmacogenetic suppression of mesolimbic dopaminergic neurons significantly decreased scratching behaviors. Under the itch condition with scratching behaviors restricted by an Elizabethan collar, the induction of ΔFosB was found mostly in corticotropin-releasing hormone (CRH)-containing neurons of the hypothalamic paraventricular nucleus (PVN). These findings suggest that repetitive abnormal scratching behaviors under acute and chronic itch stimuli may activate mesolimbic dopamine neurons along with pleasant emotions, while the restriction of such scratching behaviors may initially induce the activation of PVN-CRH neurons associated with stress.

Cyclosporine Improves Sleep Quality in Patients with Atopic Dermatitis.

INTRODUCTION: Atopic dermatitis (AD) is a chronic, relapsing, inflammatory skin disease characterized by eczema and pruritus, and frequently impairs sleep quality. Although cyclosporine improves symptoms of AD, objective evaluation of sleep in patients with AD treated with cyclosporine has not been reported. This study was conducted to elucidate the effects of cyclosporine on sleep quality for patients with AD. METHODS: Twelve patients with moderate-to-severe AD were recruited. Nocturnal sleep quality was evaluated for 7 days using a sleep analyzer, which patients wore at the waist before and after cyclosporine was administered at 2.0-4.0 mg/kg per day. Seven parameters of sleep quality were measured before and after cyclosporine administration for a period of 7 days for each patient. RESULTS: The administration of cyclosporine significantly improved total sleep time in four cases, sleep latency in two cases, wake after sleep onset in six cases, number of awakenings in two cases, sleep efficiency in seven cases, number of awakenings for more than 8 min in three cases, and number of position changes recorded every 2 min in three cases. The mean values of sleep latency significantly decreased after cyclosporine administration (P = 0.023). The mean value of sleep efficiency significantly increased after the administration (P = 0.002). CONCLUSION: Cyclosporine improves sleep quality in patients with moderate-to-severe AD.

Exploration of biomarkers to predict clinical improvement of atopic dermatitis in patients treated with dupilumab: A study protocol.

BACKGROUND: Atopic dermatitis (AD) is a common eczematous skin disorder that profoundly reduces the quality of life due to intractable pruritus. Excellent therapeutic success of the anti-interleukin 4 receptor-α antibody dupilumab in clinical trials and a real-world clinical context indicates the crucial roles of interleukin (IL)-4 and IL-13 in the pathogenesis of AD. Along with the clinical improvement in skin scores and pruritus, dupilumab significantly and progressively reduces and normalizes the upregulated expression of T helper type 2 signatures such as Chemokine (C-C motif) ligand (CCL)17, CCL18, CCL22, and CCL26 in the lesional skin of AD. However, no blood/serum biomarkers are known to predict good or poor outcome in patients with AD treated with dupilumab. METHODS: Patients are at least 18 years of age and have moderate-to-severe AD with Eczema Area and Severity Index (EASI) ≥16, Investigator's Global Assessment ≥3, and body surface area ≥10%. We are going to enroll more than 130 subjects from 18 medical facilities. Clinical objective findings will be evaluated by EASI. Subjective symptoms will be assessed by Patient-Oriented Eczema Measure, Numerical Rating Scale for Pruritus (Pruritus-NRS), Skin Comfort-NRS, and Treatment Satisfaction-NRS. We will measure 18 blood/serum biomarkers including % eosinophils in blood cell count, lactate dehydrogenase, total IgE, soluble interleukin 2 receptor, CCL17, CCL18, CCL22, CCL26, CCL27, IL-13, IL-22, IL-24, IL-25, IL-31, IL-33, thymic stromal lymphopoietin, periostin, and squamous cell carcinoma antigen-2. The clinical evaluation and biomarker sampling will be performed at 0, 2, 4, 8, and 16 weeks of dupilumab treatment. We will also perform proteomic analysis (of roughly 300 proteins) of the patients' sera obtained at 0 and 2 weeks of treatment. The primary endpoint is the association between "baseline levels of 18 biomarkers" and "% change from baseline of EASI at 16 weeks of dupilumab treatment." DISCUSSION: This is the first clinical trial to explore the biomarkers, including potential proteomic markers, most strongly associated with improvement in EASI in patients with moderate-to-severe AD treated with dupilumab for 16 weeks (B-PAD study). A limitation is that we will only enroll Japanese patients.

Addiction and the itch-scratch cycle. What do they have in common?

Itch is a multidimensional experience involving various brain regions associated with sensory perception and emotion, as well as an urge to scratch employing the motor system. Scratch temporarily relieves itch sensation in healthy subjects. However, in patients with chronic itch, rather than inhibit, scratch may aggravate itch. Patients with chronic itch, such as those with atopic dermatitis, experience severe itch and a strong desire to scratch. This urge to scratch is the driving force underlying the formation of the itch-scratch-cycle, an addictive and vicious cycle in chronic itch patients. This vicious itch-scratch behaviour and various types of addiction (henceforth, including recreational drug use) were shown to share common sensory mechanisms. Abnormalities have been observed in central neural circuits, including the reward, motivation/drive, control and learning/memory circuits, as well as other brain systems. Reward systems, including the ventral tegmental area (VTA), nucleus accumbens (NAc) and striatum, are important for brain processing of both addiction and itch. In addition to reward, addicted individuals can experience severe disruptions in motor control, cognitive awareness, executive function, learning/memory and even emotional functions. Findings showing that addiction and itch share a common neurobiological foundation could have important mechanistic and therapeutic implications. Here we propose that similar neuroadaptations exist in addiction and chronic itch patients.

Chronic intestinal pseudo-obstruction with pneumatosis cystoides intestinalis in a patient with systemic sclerosis: A case report.

RATIONALE: Chronic intestinal pseudo-obstruction (CIPO) and pneumatosis cystoides intestinalis (PCI) are rare abdominal diseases and the pathological mechanisms have not been fully elucidated. Systemic sclerosis (SSc), which is characterized by the progressive sclerotic changes of skin and internal organs, is a refractory collagen disease and is frequently associated with digestive disorders including CIPO. PATIENT CONCERNS: A 68-year-old woman who has been well managed for SSc over the long term, who presented with abdominal fullness for the first time. DIAGNOSES: Abdominal X-ray and computed tomography (CT) images showed PCI with pneumoperitoneum findings. Based on the diagnosis of CIPO, we evaluated the intestinal peristalsis of the patient by using cine magnetic resonance imaging (MRI). INTERVENTIONS: Oral medications of 15 g/d of Daikenchuto, 750 mg/d of Metronidazole and Sodium Picosulfate were started for improving the bowel peristaltic movement and decreasing intestinal gas production. OUTCOMES: A great improvement of CIPO and PCI by multidrug therapy without any surgical treatments for such an unusual case. LESSONS: This case indicates that SSc can be accompanied with not only CIPO but also PCI as digestive disorders and that cine MRI, which is a definitely beneficial imaging modality, can intelligibly visualize the peristalsis of the intestines and lead to successful medical control by noninvasive treatment.

Relationship between the Degrees of Itch and Serum Lipocalin-2 Levels in Patients with Psoriasis.

BACKGROUND: Lipocalin-2 (LCN2), a protein secreted mainly by activated neutrophils, has been associated with neurodegeneration, obesity, and inflammatory responses. Serum LCN2 concentration has been reported elevated in patients with psoriasis, but lower in patients with atopic dermatitis (AD). Spinal astrocyte-derived LCN2 was found to be involved in enhancement of itch in a mouse model of AD. However, the relationship between LCN2 and itch in patients with psoriasis has not been determined. Objective. This study examined the correlation between serum LCN2 levels and the degrees of itch in patients with psoriasis. METHODS: Serum LCN2 concentrations were measured by enzyme-linked immunosorbent assays (ELISA) in patients with psoriasis and AD and in healthy controls. The degree of itch was assessed using a visual analog scale (VAS), and disease severity was determined by measuring psoriasis area and severity index (PASI) and scoring atopic dermatitis (SCORAD). Correlations among serum LCN2 level, VAS, PASI, and SCORAD were analyzed statistically. We further examined the serum LCN levels in psoriasis patients before and after biological treatment. RESULTS: Serum LCN2 concentrations were significantly higher in patients with psoriasis and AD than those in healthy controls. In patients with psoriasis, serum LCN2 concentrations were significantly correlated with VAS, but not with PASI. In contrast, serum LCN2 concentrations did not correlate with VAS or SCORAD in patients with AD. Serum LCN2 levels in psoriasis patients significantly decreased after the biological treatment along with improvement of VAS. CONCLUSION: Serum LCN2 concentration is associated with the degree of itch in patients with psoriasis, suggesting that serum LCN2 may be a useful clinical marker for itch in psoriasis.

Expression of T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain on CD4+ T cells in patients with atopic dermatitis.

The T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) is a co-inhibitory receptor mainly expressed on T cells. Although TIGIT plays an important role in various autoimmune diseases, its role in atopic dermatitis (AD) remains unclear. In this study, we examined the expression levels of TIGIT and their association with clinical features in patients with AD. TIGIT expression on CD4+ T cells, central memory T cells, effector memory T cells and regulatory T cells was determined by flow cytometry. CD4+ T cells exhibited enhanced TIGIT expression in patients with AD compared with healthy individuals. In particular, effector memory T cells and regulatory T cells, but not central memory T cells, exhibited higher TIGIT expression in patients with AD than in healthy individuals. The frequency of TIGIT+ cells among CD4+ T cells was significantly increased in patients with mild AD compared with healthy individuals, while decreased in patients with severe AD. Consistently, the frequency of TIGIT+ cells among CD4+ T cells was negatively correlated with both serum thymus and activation-regulated chemokine levels and immunoglobulin E levels in patients with AD. Furthermore, TIGIT expression on CD4+ T cells inhibited cell proliferation in patients with AD. These results suggest that TIGIT expression on CD4+ T cells in patients with AD may be increased to suppress chronic cutaneous inflammation. Moreover, TIGIT expression may be impaired in a subset of patients with AD, leading to a deterioration of skin inflammation. Our study may provide new insight into a TIGIT pathway-based therapeutic approach for AD.