An anti-OX40 antibody to treat moderate-to-severe atopic dermatitis: a multicentre, double-blind, placebo-controlled phase 2b study.

BACKGROUND: OX40 is crucial for T-cell differentiation and memory induction. The anti-OX40 antibody, rocatinlimab inhibits the OX40 pathway. We evaluated the efficacy and safety of rocatinlimab in adults with moderate-to-severe atopic dermatitis. METHODS: This multicentre, double-blind, placebo-controlled phase 2b study was done at 65 secondary and tertiary sites in the USA, Canada, Japan, and Germany. Eligible patients were adults (aged 18 years or older) with confirmed atopic dermatitis (American Academy of Dermatology Consensus Criteria or local diagnostic criteria) with moderate-to-severe disease activity, as defined by an Eczema Area and Severity Index (EASI) score of 16 or more, validated Investigator's Global Assessment for Atopic Dermatitis score of 3 (moderate) or 4 (severe), and affected body surface area 10% or higher at both screening and baseline, with documented history (within 1 year) of inadequate response to topical medications or if topical treatments were medically inadvisable. Patients were randomly assigned (1:1:1:1:1) to receive subcutaneous rocatinlimab every 4 weeks (150 mg or 600 mg) or every 2 weeks (300 mg or 600 mg) or subcutaneous placebo up to week 18, with an 18-week active-treatment extension and 20-week follow-up. Percentage change from baseline in EASI score was assessed as the primary endpoint at week 16 and during the active extension and follow-up in all randomly assigned patients exposed to study drug with a post-baseline EASI score at week 16 or earlier according to the group they were randomly assigned to. Safety was assessed in all randomly assigned patients exposed to study drug; patients were analysed according to the group they were randomly assigned to. The study is registered with ClinicalTrials.gov, NCT03703102. FINDINGS: Between Oct 22, 2018, and Oct 21, 2019, 274 patients (114 [42%] women, 160 [58%] men; mean age 38·0 years [SD 14·5]) were randomly assigned to one of the rocatinlimab groups (217 [79%] patients) or to the placebo group (57 [21%] patients). Compared with placebo (-15·0 [95% CI -28·6 to -1·4]), significant least-squares mean percent reductions in EASI score at week 16 were observed in all rocatinlimab groups (rocatinlimab 150 mg every 4 weeks -48·3 [-62·2 to -34·0], p=0·0003; rocatinlimab 600 mg every 4 weeks -49·7 [-64·3 to -35·2], p=0·0002; rocatinlimab 300 mg every 2 weeks -61·1 [-75·2 to -47·0], p<0·0001; and rocatinlimab 600 mg every 2 weeks -57·4 [-71·3 to -43·4], p<0·0001). The most common adverse events during the double-blind period in patients receiving rocatinlimab (adverse events ≥5% of patients in the total rocatinlimab group and more common than the placebo group) were pyrexia (36 [17%] patients), nasopharyngitis (30 [14%] patients), chills (24 [11%] patients), headache (19 [9%] patients), aphthous ulcer (15 [7%] patients), and nausea (13 [6%] patients). There were no deaths. INTERPRETATION: Patients treated with rocatinlimab had progressive improvements in atopic dermatitis, which was maintained in most patients after treatment discontinuation. Treatment was well tolerated. FUNDING: Kyowa Kirin.

A ubiquitin-like protein encoded by the "noncoding" RNA TINCR promotes keratinocyte proliferation and wound healing.

Although long noncoding RNAs (lncRNAs) are transcripts that do not encode proteins by definition, some lncRNAs actually contain small open reading frames that are translated. TINCR (terminal differentiation-induced ncRNA) has been recognized as a lncRNA that contributes to keratinocyte differentiation. However, we here show that TINCR encodes a ubiquitin-like protein that is well conserved among species and whose expression was confirmed by the generation of mice harboring a FLAG epitope tag sequence in the endogenous open reading frame as well as by targeted proteomics. Forced expression of this protein promoted cell cycle progression in normal human epidermal keratinocytes, and mice lacking this protein manifested a delay in skin wound healing associated with attenuated cell cycle progression in keratinocytes. We termed this protein TINCR-encoded ubiquitin-like protein (TUBL), and our results reveal a role for TINCR in the regulation of keratinocyte proliferation and skin regeneration that is dependent on TUBL.

Nocturnal Scratching and Quality of Sleep in Children with Atopic Dermatitis.

Itching due to atopic dermatitis causes sleep disorders in children, but its pathology is unknown. The aim of this study is to investigate nocturnal scratching as an indirect index of itching during sleep and its relationship with depth of sleep in children with atopic dermatitis. Nocturnal scratching was measured in a total of 20 children with atopic dermatitis, using a smartwatch installed with the application Itch Tracker. Depth of sleep was analysed using polysomnography. The severity of atopic dermatitis was scored using Eczema Area and Severity Index (EASI) and Patient-Oriented Eczema Measure (POEM). The number and time of nocturnal scratching measured by Itch Tracker had a significantly positive correlation with EASI scores, whereas POEM scores were not correlated with EASI scores. Mean sleep efficiency was 90.0% and scratching episodes (n = 67) started mainly during the awake stage or light sleep stages. In the scratching episodes that started during sleep stages (n = 34), the sleep stage changed to a lighter one or to the awake stage in 35.5% of episodes. Itch Tracker is applicable to measure nocturnal scratching in children. Nocturnal scratching can deteriorate quality of sleep by changing the sleep stage to a lighter one or to the awake stage.

The HOME Core outcome set for clinical trials of atopic dermatitis.

Core outcome sets are critically important outcomes that should be measured in clinical trials. Their absence in atopic dermatitis is a form of research waste and impedes combining evidence to inform patient care. Here, we articulate the rationale for core outcome sets in atopic dermatitis and review the work of the international Harmonising Outcome Measures for Eczema group from its inception in Munich, 2010. We describe core domain determination (what should be measured), to instrument selection (how domains should be measured), culminating in the complete core outcome measurement set in Tokyo, 2019. Using a "road map," Harmonising Outcome Measures for Eczema includes diverse research methods including Delphi and nominal group techniques informed by systematic reviews of properties of candidate instruments. The 4 domains and recommended instruments for including in all clinical trials of atopic dermatitis are patient symptoms, measured by Patient-Oriented Eczema Measure and peak Numerical Rating Scale 11 for itch intensity over 24 hours, clinical signs measured using the Eczema Area and Severity Index, quality of life measured by the Dermatology Life Quality Index series for adults, children, and infants, and long-term control measured by either Recap of atopic eczema or Atopic Dermatitis Control Tool.

Bioactive substances in the stratum corneum of the epidermis found as indicators of skin damage due to sun exposure.

BACKGROUND/PURPOSE: Although an inflammatory response upon acute injury caused by ultraviolet radiation (UV) can be observed immediately, the influence of long-term, repetitive low-dose UV exposure on the skin cannot be precisely perceived, making early detection of chronic damage difficult. This study investigated bioactive substances in the stratum corneum as a potential early and sensitive indicator of the influence of sun exposure on the skin using receiver operating characteristic (ROC) analysis. METHODS: Receiver operating characteristic analysis was performed to assess the responsiveness of cytokines [interleukin (IL)-1α, IL-1 receptor antagonist (IL-1ra), IL-10, tumor necrosis factor (TNF)-α], BCL2-associated protein X (Bax), Toll-like receptor (TLR)3, and TLR4 in the stratum corneum of healthy people exposed (dorsum of the hand) and unexposed (inner arm) to UV. Sunscreen was applied to patients with photodermatosis for 4 weeks to evaluate changes in IL-1ra/IL-1α, TNF-α, Bax, and TLR3 levels after sunscreen application, as these molecules exhibited high responsiveness to sun exposure according to ROC analysis. In addition, IL-1ra, IL-1α, and IL-10 levels were quantified by enzyme-linked immunosorbent assay, and TNF-α, Bax, TLR3, and TLR4 levels were semi-quantitatively assessed by immunocytochemistry. RESULTS: Receiver operating characteristic analysis identified IL-1ra/IL-1α, TNF-α, Bax, and TLR3 in the stratum corneum as highly responsive to sun exposure. Moreover, in participants, including patients with photodermatosis, IL-1ra/IL-1α, TNF-α, and Bax levels decreased significantly after sunscreen application. CONCLUSION: The results revealed that IL-1ra/IL-1α, TNF-α, and Bax in the stratum corneum represent sensitive indicators of the influence of sun exposure on the skin.

Targeted inhibition of EPAS1-driven IL-31 production by a small-molecule compound.

BACKGROUND: IL-31 is a major pruritogen associated with atopic dermatitis (AD). Although a specific antibody for IL-31 receptor has been shown to alleviate pruritus in patients with AD, therapeutic approaches to inhibition of IL-31 production remain unexploited. IL-31 production by TH cells critically depends on the transcription factor EPAS1, which mediates IL31 promoter activation in collaboration with SP1. OBJECTIVE: We aimed at developing small-molecule inhibitors that selectively block IL-31 production by TH cells. METHODS: We generated the reporter cell line that inducibly expressed EPAS1 in the presence of doxycycline to mediate Il31 promoter activation, and we screened 9600 chemical compounds. The selected compounds were further examined by using TH cells from a spontaneous mouse model of AD and TH cells from patients with AD. RESULTS: We have identified 4-(2-(4-isopropylbenzylidene)hydrazineyl)benzoic acid (IPHBA) as an inhibitor of IL31 induction. Although IPHBA did not affect nonspecific T-cell proliferation, IPHBA inhibited antigen-induced IL-31 production by TH cells from both an AD mouse model and patients with AD without affecting other cytokine production and hypoxic responses. In line with this, itch responses induced by adoptive transfer of IL-31-producing TH cells were attenuated when mice were orally treated with IPHBA. Mechanistically, IPHBA inhibited the association between EPAS1 and SP1, resulting in defective recruitment of both transcription factors to the specific sites of the IL31 promoter. We also determined the structure-activity relationship of IPHBA by synthesizing and analyzing 201 analogous compounds. CONCLUSION: IPHBA could be a potential drug leading to inhibition of EPAS1-driven IL-31 production.

Role of ERK Pathway in the Pathogenesis of Atopic Dermatitis and Its Potential as a Therapeutic Target.

Atopic dermatitis (AD) is an eczematous skin disorder characterized by type 2 inflammation, barrier disruption, and intense itch. In addition to type 2 cytokines, many other cytokines, such as interferon gamma (IFN-γ), interleukin 17 (IL-17), and interleukin 22 (IL-22), play roles in the pathogenesis of AD. It has been reported that the extracellular signal-regulated kinase (ERK) is downstream of such cytokines. However, the involvement of the ERK pathway in the pathogenesis of AD has not yet been investigated. We examined the expression of p-ERK in mouse and human AD skin. We also investigated the effects of the topical application of an ERK inhibitor on the dermatitis score, transepidermal water loss (TEWL), histological change, and expression of filaggrin, using an AD-like NC/Nga murine model. The effects of an ERK inhibitor on filaggrin expression in normal human epidermal keratinocytes (NHEKs) and on chemokine production from bone marrow-derived dendritic cells (BMDCs) were also evaluated. p-ERK was highly expressed in mouse and human AD skin. Topical application of an ERK inhibitor alleviated the clinical symptoms, histological changes, TEWL, and decrease in expression of filaggrin in the AD-like NC/Nga murine model. The ERK inhibitor also restored the IL-4 induced reduction in the expression of filaggrin in NHEK, and inhibited chemokine production from BMDC induced by IL-4. These results indicate that the ERK pathway is involved in the pathogenesis of AD, and suggest that the ERK pathway has potential as a therapeutic target for AD in the future.

Inhibition of mite-induced dermatitis, pruritus, and nerve sprouting in mice by the endothelin receptor antagonist bosentan.

BACKGROUND: Endothelin-1 (EDN1) can evoke histamine-independent pruritus in mammals and is upregulated in the lesional epidermis of atopic dermatitis (AD). EDN1 increases the production of interleukin 25 (IL-25) from keratinocytes to accelerate T helper type 2 immune deviation. Plasma EDN1 levels are positively correlated with the clinical severity and itch intensity of AD. Therefore, we hypothesized that the inhibition of EDN1 might be useful for treating atopic inflammation and itch and investigated the effects of the topical application of the EDN1 receptor antagonist bosentan on the skin inflammation and itch in a murine AD model. METHODS: We analyzed the mite-induced AD-like NC/Nga murine model, which was topically applied with bosentan or ethanol control every day for 3 weeks. We also subjected in vitro primary sensory neuron culture systems to nerve elongation and branching assays after EDN1 stimulation. RESULTS: Topical application of bosentan significantly attenuated the development of mite-induced AD-like skin inflammation, dermatitis scores, ear thickness, scratching bouts, and serum level of thymus and activation-regulated chemokine in NC/Nga mice. Bosentan application also significantly reduced the gene expression of Il13, Il17, and Ifng in the treated lesions. Histologically, the number of infiltrated dermal cells, the epidermal EDN1 expression, and the number of intraepidermal nerve fibers were significantly inhibited upon bosentan application. While EDN1 significantly elongated the neurites of dorsal root ganglion cells in a dose- and time-dependent manner, bosentan treatment attenuated this. CONCLUSIONS: EDN1 plays a significant role in mite-induced inflammation and itch. Topical bosentan is a potential protective candidate for AD.

BRAF Heterogeneity in Melanoma.

OPINION STATEMENT: In the era of molecular targeted therapy, the accurate detection of BRAF mutation in melanoma has become increasingly important. With the advances of molecular analyses and immunohistochemistry, the presence of BRAF mutational heterogeneity in melanoma has been widely recognized. Although most patients with melanoma have a homogeneous BRAF mutation status because the BRAF mutation occurs at an early stage of melanoma development and acts as a driver gene mutation, BRAF mutational heterogeneity does exist, among different tumor sites of a single patient (intertumor heterogeneity) and/or even within a single tumor (intratumor heterogeneity). To summarize the published reports, about 10% of melanoma patients may show intertumorally discordant BRAF status and about 15% of BRAF-mutated melanomas may have intratumor BRAF heterogeneity, although the reported results vary strikingly among the studies and methods used. Considering the BRAF heterogeneity of melanoma, a single biopsy from a single tumor may not be sufficient to uncover the entire BRAF status of a patient. Multiple samples from different sites may be preferable to assess the indication of BRAF/MEK inhibitors, as recommended by the current clinical guidelines. The impact of BRAF heterogeneity on patient survival or the response to treatment with BRAF/MEK inhibitors is an interesting issue, but requires further investigation.

Aryl Hydrocarbon Receptor and Dioxin-Related Health Hazards-Lessons from Yusho.

Poisoning by high concentrations of dioxin and its related compounds manifests variable toxic symptoms such as general malaise, chloracne, hyperpigmentation, sputum and cough, paresthesia or numbness of the extremities, hypertriglyceridemia, perinatal abnormalities, and elevated risks of cancer-related mortality. Such health hazards are observed in patients with Yusho (oil disease in Japanese) who had consumed rice bran oil highly contaminated with 2,3,4,7,8-pentachlorodibenzofuran, polychlorinated biphenyls, and polychlorinated quaterphenyls in 1968. The blood concentrations of these congeners in patients with Yusho remain extremely elevated 50 years after onset. Dioxins exert their toxicity via aryl hydrocarbon receptor (AHR) through the generation of reactive oxygen species (ROS). In this review article, we discuss the pathogenic implication of AHR in dioxin-induced health hazards. We also mention the potential therapeutic use of herbal drugs targeting AHR and ROS in patients with Yusho.

NECTIN4: A Novel Therapeutic Target for Melanoma.

Malignant melanoma is the most common lethal skin cancer and causes death in a short time when metastasized. Although BRAF inhibitors (BRAFi) have greatly improved the prognosis of BRAF-mutated melanoma, drug resistance is a major concern even when they are combined with MEK inhibitors. Alternative treatments for BRAFi-resistant melanoma are highly anticipated. Nectin cell adhesion molecule 4 (NECTIN4) is highly expressed and associated with progression in tumors. We aimed to investigate the role of NECTIN4 in melanoma and its potency as a therapeutic target using 126 melanoma samples and BRAFi-resistant cells. Immunohistochemically, most of the clinical samples expressed NECTIN4, at least in part. NECTIN4 was highly expressed in BRAF-mutated melanoma and its high expression was associated with disease-free survival. In BRAFi-resistant melanoma cells, NECTIN4 and the PI3K/Akt pathway were upregulated, along with the acquisition of BRAFi resistance. Monomethyl auristatin E, a cytotoxic part of NECTIN4-targeted antibody-drug conjugate, was effective for BRAF-mutated or BRAFi-resistant melanoma cells. NECTIN4 inhibition increased the sensitivity of BRAFi-resistant cells to BRAFi and induced apoptosis. In conclusion, we revealed the expression and roles of NECTIN4 in melanoma. Targeted therapies against NECTIN4 can be a novel treatment strategy for melanoma, even after the acquisition of BRAFi resistance.

Anti-Interleukin-31 Receptor A Antibody for Atopic Dermatitis.

BACKGROUND: Interleukin-31 may play a role in the pathobiologic mechanism of atopic dermatitis and pruritus. We wanted to assess the efficacy and safety of nemolizumab (CIM331), a humanized antibody against interleukin-31 receptor A, in the treatment of atopic dermatitis. METHODS: In this phase 2, randomized, double-blind, placebo-controlled, 12-week trial, we assigned adults with moderate-to-severe atopic dermatitis that was inadequately controlled by topical treatments to receive subcutaneous nemolizumab (at a dose of 0.1 mg, 0.5 mg, or 2.0 mg per kilogram of body weight) or placebo every 4 weeks or an exploratory dose of 2.0 mg of nemolizumab per kilogram every 8 weeks. The primary end point was the percentage improvement from baseline in the score on the pruritus visual-analogue scale (on which a negative change indicates improvement) at week 12. Secondary end points included changes in the score on the Eczema Area and Severity Index (EASI, on which a negative change indicates improvement), and body-surface area of atopic dermatitis. RESULTS: Of 264 patients who underwent randomization, 216 (82%) completed the study. At week 12, among the patients who received nemolizumab every 4 weeks, changes on the pruritus visual-analogue scale were -43.7% in the 0.1-mg group, -59.8% in the 0.5-mg group, and -63.1% in the 2.0-mg group, versus -20.9% in the placebo group (P<0.01 for all comparisons). Changes on the EASI were -23.0%, -42.3%, and -40.9%, respectively, in the nemolizumab groups, versus -26.6% in the placebo group. Respective changes in body-surface area affected by atopic dermatitis were -7.5%, -20.0%, and -19.4% with nemolizumab, versus -15.7% with placebo. Among the patients receiving nemolizumab every 4 weeks, treatment discontinuations occurred in 9 of 53 patients (17%) in the 0.1-mg group, in 9 of 54 (17%) in the 0.5-mg group, and in 7 of 52 (13%) in the 2.0-mg group, versus in 9 of 53 (17%) in the placebo group. CONCLUSIONS: In this phase 2 trial, nemolizumab at all monthly doses significantly improved pruritus in patients with moderate-to-severe atopic dermatitis, which showed the efficacy of targeting interleukin-31 receptor A. The limited size and length of the trial preclude conclusions regarding adverse events. (Funded by Chugai Pharmaceutical; XCIMA ClinicalTrials.gov number, NCT01986933 .).

The CCL20 and CCR6 axis in psoriasis.

Psoriasis is a TNF-α/IL-23/IL-17A-mediated inflammatory skin disease that causes a significant socioeconomic burden in afflicted patients. IL-17A-producing immune cells, including Th17 cells, are crucial effector cells in the development of psoriasis. IL-17A stimulates epidermal keratinocytes to produce CCL20, which eventually recruits CCR6 + Th17 cells into the lesional skin. Thus, the CCL20/CCR6 axis works as a driving force that prepares an IL-17A-rich cutaneous milieu. In this review, we summarize the current research topics on the CCL20/CCR6 axis and the therapeutic intervention of this axis for psoriasis.

Measuring atopic eczema symptoms in clinical practice: The first consensus statement from the Harmonising Outcome Measures for Eczema in clinical practice initiative.

BACKGROUND: Measuring patient-centered outcomes in clinical practice is valuable for monitoring patients and advancing real-world research. A new initiative from the Harmonising Outcome Measures for Eczema (HOME) group aims to recommend what might be recorded for atopic eczema patients in routine clinical care. OBJECTIVES: Prioritize outcome domains to measure atopic eczema in clinical practice and select valid and practical outcome measurement instruments for the highest-priority domain. METHODS: An online survey of HOME members identified and ranked 21 possible health domains. Suitable instruments were then selected for the top-prioritized domain at the HOME VI meeting, using established consensus processes informed by systematic reviews of instrument quality. RESULTS: Patient-reported symptoms was the top-prioritized domain. In accordance with psychometric properties and feasibility, there was consensus that the recommended instruments to measure atopic eczema symptoms in clinical practice are the POEM, the PO-SCORAD index, or both. The numeric rating scale for itch received support pending definition and validation in atopic eczema. CONCLUSION: Following the first step of the HOME Clinical Practice initiative, we endorse using the POEM, the PO-SCORAD index, or both for measuring atopic eczema symptoms in clinical practice. Additional high-priority domains for clinical practice will be assessed at subsequent HOME meetings.

Insight into innate immune response in "Yusho": The impact of natural killer cell and regulatory T cell on inflammatory prone diathesis of Yusho patients.

BACKGROUND: In 1968 in western Japan, polychlorinated biphenyl-contaminated "Kanemi rice oil" was used in cooking, causing food poisoning in many people. More than 50 years have passed since the Yusho incident, and although inflammatory disorders such as suppuration have been observed in Yusho patients, the etiology of this inflammation susceptibility remains obscure. OBJECTIVES: To investigate the mechanisms of susceptibility to inflammation in Yusho patients, peripheral immune cell fractions and concentrations of inflammatory cytokines were evaluated in blood samples collected from both Yusho patients and age-matched healthy subjects undergoing medical examination in Nagasaki. METHODS: To exclude diagnostic uncertainty, serum levels of polychlorinated biphenyl (PCB), polychlorinated quarterphenyl (PCQ), and polychlorinated dibenzofuran (PCDF) were measured. Immune cell (e.g. natural killer and regulatory T cell) populations were analyzed by flow cytometry. Serum cytokines involved in immune cell activation were measured by ELISA. RESULTS: The relative proportion of natural killer cells was higher in Yusho patients than in healthy subjects, while the proportion of regulatory T cells did not differ between groups. Serum concentrations of IL-36 and IFN-γ were significantly lower in Yusho patients than in healthy subjects. Conversely, serum cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), which is a cytokine related to activated NK cells, was higher in Yusho patients than in healthy subjects and was positively correlated with PCDF blood levels. CONCLUSION: Increased numbers of NK cells in Yusho patients suggests that the innate immune response has been activated in Yusho patients. The seemingly paradoxical results for CTLA-4 and IFN-γ may reflect counterbalancing mechanisms preventing excessive NK cell activation. This dysregulation of innate immunity might contribute to the inflammation observed in Yusho patients.

Mortality in Yusho patients exposed to polychlorinated biphenyls and polychlorinated dibenzofurans: a 50-year retrospective cohort study.

BACKGROUND: In 1968, the Yusho incident resulted in accidental exposure to polychlorinated biphenyls (PCBs), polychlorinated dibenzofurans (PCDFs), and related compounds in Japan. This study updated the risk of mortality in Yusho patients. METHODS: We obtained updated cohort data for all Yusho patients for the period 1968-2017. We calculated standardized mortality ratios (SMRs) for all-cause and cause-specific mortality over a 50-year follow-up period compared with the general population in Japan. RESULTS: A total of 1664 Yusho patients with 63,566 person-years of follow up were included in the analysis. Among males, excess mortality was observed for all cancers (SMR: 1.22, 95% confidence interval [CI]: 1.02 to 1.45) and lung cancer (SMR: 1.59, 95% CI: 1.12 to 2.19). Among females, increased mortality was observed for liver cancer (SMR: 2.05, 95% CI: 1.02 to 3.67). No significant increase was seen in non-cancer-related mortality compared with the general population. CONCLUSIONS: Carcinogenic risk in humans after exposure to PCBs and PCDFs remains higher among Yusho patients. Our findings suggest the importance of care engagement and optimum management to deal with the burden of Yusho disease.

Patient-Oriented Eczema Measure score: A Useful Tool for Web-Based Surveys in Patients with Atopic Dermatitis.

The Patient-Oriented Eczema Measure (POEM, 0-28 points) is a self-assessed, repeatable measurement tool for measuring atopic dermatitis (AD) severity. How-ever, whether POEM score is influenced by allergic comorbidities and whether POEM's severity banding is applicable in web-based surveys for AD remain unclear. A web-based questionnaire survey was conducted in 329 patients with AD. POEM, self-reported severity of AD, and comorbidity of allergic diseases including asthma, pollen rhinitis, allergic conjunctivitis, and food allergy were assessed. POEM scores were not affected by a history of comorbid allergic diseases. The severity banding for POEM scores on the web-based survey was as follows: clear/almost clear = 0, mild = 1-8, moderate = 9-21, and severe/very severe = 22-28, which was comparable to previous banding. These results suggest that POEM is useful for determining AD severity, even in web-based surveys. Patients with POEM scores above 9 points may be grouped into moderate, severe, and very severe AD.

A case of overlapping adult-onset linear scleroderma and Parry-Romberg syndrome presenting with widespread ipsilateral neurogenic involvement.

Linear scleroderma is a variant of localized scleroderma. We report a 43-year-old woman who had developed left arm weakness and linear scleroderma on her back during pregnancy at 25 years of age, followed by left hemifacial atrophy and left leg weakness. She had multiple linear scleroderma lesions on her trunk and left limbs, left eyelid ptosis, impairment of vertical movement and abduction of the left eye, left hemifacial atrophy, and weakness and atrophy of the sternocleidomastoid, trapezius, and proximal limb muscles on the left side. On serology, antibodies to U1-ribonucleoprotein and Jo-1 were positive; anti-scleroderma-70 antibody was negative. Skin biopsy demonstrated increased hypertrophic collagen fibers without inflammatory infiltrates. Needle electromyography of left limb muscles revealed mild neurogenic patterns; left quadriceps muscle biopsy showed chronic neurogenic changes. Brain magnetic resonance imaging revealed mild left hemispheric atrophy. This is a rare case of linear scleroderma and Parry-Romberg syndrome presenting with widespread ipsilateral neurogenic manifestations.

Upregulation of IL-36 cytokines in folliculitis and eosinophilic pustular folliculitis.

BACKGROUND: Members of the interleukin (IL)-36 family, IL-36α, IL-36ß and IL-36γ, are potent chemoattractive cytokines for neutrophils and eosinophils. IL-36 receptor antagonist (IL-36Ra) inhibits IL-36α, IL-36ß and IL-36γ activity. However, the immunohistological expression of IL-36α, IL-36ß, IL-36γ and IL-36Ra has never been addressed in normal follicles, folliculitis or eosinophilic pustular folliculitis (EPF). METHODS: We performed immunohistochemical staining for IL-36α, IL-36ß, IL-36γ and IL-36Ra using 10 cases of EPF, nine of non-specific folliculitis, 10 normal skin samples and 10 samples of normal follicles adjacent to a sebaceous naevus as a control. Two dermatologists, who were blind to the patient records, evaluated all of the slides. RESULTS: The immunoreactive IL-36α was hardly detected in the follicular epithelium and epidermis in the normal skin, folliculitis or EPF. The expression of IL-36ß, IL-36γ and IL-36Ra was augmented in both folliculitis and EPF compared with that in normal follicles. Negative correlations were detected between IL-36ß and IL-36Ra and between IL-36γ and IL-36Ra in normal follicles; however, these were absent in folliculitis. In contrast to normal follicles and folliculitis, a significant positive correlation between IL-36ß/γ and IL-36Ra was shown in EPF. CONCLUSIONS: The overexpression of IL-36ß, IL-36γ and IL-36Ra is an integral part of the inflammatory response of folliculitis and EPF. The coordinated expression of IL-36γ and IL-36Ra may be related to the pathomechanism of EPF.

Serum canine thymus and activation-regulated chemokine (TARC/CCL17) concentrations correlate with disease severity and therapeutic responses in dogs with atopic dermatitis.

BACKGROUND: Thymus and activation-regulated chemokine (TARC/CCL17) has been implicated in the pathogenesis of canine atopic dermatitis (cAD). Serum TARC concentrations are a reliable biomarker for human atopic dermatitis; however, their potential as a biomarker for cAD has not been investigated. HYPOTHESIS/OBJECTIVES: To investigate whether serum TARC concentrations correlate with disease severity and therapeutic responses for cAD. ANIMALS: Thirty-nine dogs with cAD and 42 healthy dogs were recruited. METHODS AND MATERIALS: Serum TARC concentrations in dogs with cAD and healthy dogs were measured by sandwich ELISA with anti-canine TARC antibodies. The clinical severity of cAD was scored using the validated Canine Atopic Dermatitis Extent and Severity Index, 4th iteration (CADESI-04). Serum TARC concentrations were compared between dogs with cAD and healthy controls, and their relationship with CADESI-04 was examined. Serum TARC concentrations also were measured in 20 dogs with cAD treated with prednisolone or oclacitinib for four weeks. RESULTS: Serum TARC concentrations were significantly higher in dogs with cAD than in healthy dogs (P < 0.001). In dogs with cAD, serum TARC concentrations correlated with CADESI-04 scores (ρ = 0.457, P < 0.01). Furthermore, serum TARC concentrations significantly decreased in treated dogs with the attenuation of clinical signs (P < 0.001). Changes in serum TARC concentrations before and after treatment correlated with those in CADESI-04 scores (ρ = 0.746, P < 0.001). CONCLUSIONS AND CLINICAL RELEVANCE: Serum TARC concentrations have potential as a clinical and research tool for the objective evaluation of disease severity and therapeutic responses for cAD.