Evaluation of sweating responses in patients with collagen disease using the quantitative sudomotor axon reflex test (QSART): a study protocol for an investigator-initiated, prospective, observational clinical study.

INTRODUCTION: Sweat secretion is controlled by the sympathetic nervous system and is less active during winter than in the summer. Raynaud's phenomenon is affected by an excessive strain of the sympathetic nerves after exposure to a cold environment, thus reducing the quality of life of patients with collagen disease. Herein, we focus on the eccrine sweat glands that receive both adrenergic and cholinergic innervation. Our hypothesis is that excessive activation of sympathetic nerve in Raynaud's phenomenon can affect sweating, especially in winter. This study is designed to evaluate the neuroactive sweating responses in patients with collagen disease and to assess its association with skin findings in peripheral circulatory disorders. METHODS AND ANALYSIS: The study will be conducted at a single centre in Japan. Patients with systemic sclerosis, Sjogren's syndrome, systemic lupus erythematosus, mixed connective tissue disease, and dermatomyositis will be assessed using the quantitative sudomotor axon reflex test. The primary outcomes will be sweat volume and reaction time due to axon reflex and the Raynaud's condition score. The secondary outcomes will include patient background, skin symptoms (digital ulcers, pernio-like eruptions, subcutaneous calcifications, telangiectasia, nailfold capillary dilatation/bleeding and degree of skin sclerosis) and skin surface temperature. Evaluation will be done two times, during the summer and winter, allowing for the assessment of seasonal differences in sweating responses. ETHICS AND DISSEMINATION: Ethical approval of this study was certified by the clinical research review board of Nagasaki University Hospital (Reference number: CRB19-001). We will disseminate the findings of this study through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: jRCTs072190009; pre-results.

Multifaceted array-based keloidal gene expression profiling reveals specific MDFI upregulation in keloid lesions.

BACKGROUND: Keloid lesions are characterized by mesenchymal cell proliferation and excessive extracellular matrix deposition. Previous microarray analyses have been performed to investigate the mechanism of keloid development. However, the molecular pathology that contributes to keloid development remains obscure. AIM: To explore the underlying essential molecules of keloids using microarrays. METHODS: We performed microarray analyses of keloid and nonlesional skin tissues both in vivo and in vitro. Gene expression levels were compared between tissues and cells. Quantitative reverse transcription (qRT)-PCR and immunohistochemical staining were used to determine the expression levels of molecules of interest in keloid tissues. RESULTS: Several common molecules were upregulated in both keloid tissues and keloid-lesional fibroblasts. PTPRD and NTM were upregulated both in vivo and in vitro. The genes MDFI and ITGA4 were located at the centre of the gene coexpression network analysis using keloid tissues. qRT-PCR revealed significant expression levels of PTPRD and MDFI in keloid tissues. Immunopathological staining revealed that MDFI-positive cells, which have fibroblast characteristics, were located in the keloid-associated lymphoid tissue (KALT) portion of the keloid tissue. CONCLUSION: Our gene expression profiles of keloids could distinguish the difference between lesional tissue and cultured lesional fibroblasts, and MDFI was found to be commonly expressed in both tissues and cells. Thus, MDFI-positive cells, which were located in the KALT, may play an important role in keloid pathogenesis and thus might be useful for in vitro keloid studies.

Report from the fifth international consensus meeting to harmonize core outcome measures for atopic eczema/dermatitis clinical trials (HOME initiative).

This is the report from the fifth meeting of the Harmonising Outcome Measures for Eczema initiative (HOME V). The meeting was held on 12-14 June 2017 in Nantes, France, with 81 participants. The main aims of the meeting were (i) to achieve consensus over the definition of the core domain of long-term control and how to measure it and (ii) to prioritize future areas of research for the measurement of the core domain of quality of life (QoL) in children. Moderated whole-group and small-group consensus discussions were informed by presentations of qualitative studies, systematic reviews and validation studies. Small-group allocations were performed a priori to ensure that each group included different stakeholders from a variety of geographical regions. Anonymous whole-group voting was carried out using handheld electronic voting pads according to predefined consensus rules. It was agreed by consensus that the long-term control domain should include signs, symptoms, quality of life and a patient global instrument. The group agreed that itch intensity should be measured when assessing long-term control of eczema in addition to the frequency of itch captured by the symptoms domain. There was no recommendation of an instrument for the core outcome domain of quality of life in children, but existing instruments were assessed for face validity and feasibility, and future work that will facilitate the recommendation of an instrument was agreed upon.

Report from the fourth international consensus meeting to harmonize core outcome measures for atopic eczema/dermatitis clinical trials (HOME initiative).

This article is a report of the fourth meeting of the Harmonising Outcome Measures for Eczema (HOME) initiative held in Malmö, Sweden on 23-24 April 2015 (HOME IV). The aim of the meeting was to achieve consensus over the preferred outcome instruments for measuring patient-reported symptoms and quality of life for the HOME core outcome set for atopic eczema (AE). Following presentations, which included data from systematic reviews, consensus discussions were held in a mixture of whole group and small group discussions. Small groups were allocated a priori to ensure representation of different stakeholders and countries. Decisions were voted on using electronic keypads. For the patient-reported symptoms, the group agreed by vote that itch, sleep loss, dryness, redness/inflamed skin and irritated skin were all considered essential aspects of AE symptoms. Many instruments for capturing patient-reported symptoms were discussed [including the Patient-Oriented SCOring Atopic Dermatitis index, Patient-Oriented Eczema Measure (POEM), Self-Administered Eczema Area and Severity Index, Itch Severity Scale, Atopic Dermatitis Quickscore and the Nottingham Eczema Severity Score] and, by consensus, POEM was selected as the preferred instrument to measure patient-reported symptoms. Further work is needed to determine the reliability and measurement error of POEM. Further work is also required to establish the importance of pain/soreness and the importance of collecting information regarding the intensity of symptoms in addition to their frequency. Much of the discussion on quality of life concerned the Dermatology Life Quality Index and Quality of Life Index for Atopic Dermatitis; however, consensus on a preferred instrument for measuring this domain could not be reached. In summary, POEM is recommended as the HOME core outcome instrument for measuring AE symptoms.

Evolving understanding on the aetiology of thermally provoked itch.

BACKGROUND AND OBJECTIVES: Itch is one of the major symptoms in dermatology clinics, and severely impairs the quality of life. Itch is frequently produced by environmental stimuli, especially heat or warmth. Changes of temperature on the skin surface and noxious heat stimuli augment and develop itch, respectively. Thermally provoked itch is sometimes intractable with existing treatments. DATA BASES AND DATA TREATMENT: Recent researches, linking heat sensation and itch, were searched in MEDLINE literature database through PubMed. RESULTS: Recent studies of the transient receptor potential cation channel subfamily vanilloid type 1 (TRPV1), the calcitonin gene-related peptide (CGRP) and the vesicular glutamate transporter 2 (VGLUT2), which link noxious heat and itch, contribute to a much better understanding of the thermally evoked itch process. From a clinical perspective, a warm sensation is a major provocative factor for subjects with atopic dermatitis. The accumulation of artemin (also known as enovin or neublastin) in the dermis of lesional skin can possibly provide a pathological mechanism for warmth-provoked itch. CONCLUSIONS: This mini-review describes recent results of both basic and clinical research related to thermally provoked itch.

Increased frequency of skin-infiltrating FoxP3+ regulatory T cells as a diagnostic indicator of severe atopic dermatitis from cutaneous T cell lymphoma.

Differential diagnosis of cutaneous T cell lymphoma (CTCL) and severe atopic dermatitis (AD) is often difficult because of the similarity in their skin manifestations. However, such differentiation is extremely important because of the differences in remedy and prognosis. The aim of this study was to investigate new, helpful diagnostic aids for distinguishing CTCL from AD. The frequency of forkhead box protein 3(+) (FoxP3(+)) regulatory T cells (T(regs)) in cutaneous lesions was evaluated among the three populations. Serum-soluble interleukin-2 receptor (sIL-2R), immunoglobulin (Ig)E-radioimmunosorbent test, lactate dehydrogenase (LDH) and blood eosinophil count were measured in 11 CTCL patients (including three CTCL patients misdiagnosed previously with intractable AD), 10 adult AD patients and nine psoriasis patients. The frequency of T(regs) was increased significantly in cutaneous lesions of AD compared with those of CTCL. Serum IgE and LDH levels were also elevated significantly in AD compared with CTCL, whereas there were no significant differences in serum sIL-2R levels between CTCL and AD. In the three CTCL patients who were misdiagnosed with intractable AD, IgE and LDH levels were lower than in AD patients, whereas serum sIL-2R levels were as high as in AD patients and higher than in the other eight CTCL patients. The higher frequency of T(regs) in the cutaneous lesions of patients with AD than in those with CTCL and higher serum IgE and LDH levels in patients with AD than in those with CTCL might be helpful reference values for the differential diagnosis of these two diseases.

A case of generalized acanthosis nigricans with positive lupus erythematosus-related autoantibodies and antimicrosomal antibody: autoimmune acanthosis nigricans?

Acanthosis nigricans (AN) is a hyperpigmented keratotic skin lesion known to be associated with malignant disease and endocrinopathy. We report a very rare case of generalized AN with Sjögren's syndrome- and systemic lupus erythematosus-like features but without type B insulin resistance. Neither internal malignancy nor other endocrinological disorders, including glucose intolerance, were detected during a 10-year clinical course with benign diffuse papillomatosis extending from the mucosa of the larynx to the esophagogastric junction. The case was complicated with chronic thyroiditis and interstitial pneumonia, which were not treated with any medication. AN skin lesions and mucosal papillomatosis regressed with oral cyclosporine A, accompanied by the lowering of autoantibody titers. This is the first report of generalized AN involving an area from the mucosa of the larynx to the esophagogastric junction accompanied by autoimmune manifestations which responded to systemic immunosuppressive therapy.

Diminished regulatory T cells in cutaneous lesions of thymoma-associated multi-organ autoimmunity: a newly described paraneoplastic autoimmune disorder with fatal clinical course.

Thymoma-associated multi-organ autoimmunity is a rare, autoimmune disease that causes colitis, liver dysfunction and cutaneous graft-versus-host (GVH)-like skin damage. This paraneoplastic autoimmune disorder may be due to inadequate T cell selection in the tumour environment of the thymus. Although sporadic case reports have revealed its clinical features, little is known about its pathological mechanism. By comparing the skin-infiltrating T cell subsets with those of GVH disease (GVHD) and other inflammatory skin diseases, we sought to elucidate the pathological mechanism of thymoma-associated multi-organ autoimmunity. Histopathological and immunohistochemical analysis of skin biopsies was performed for three patients with thymoma-associated multi-organ autoimmunity. Histopathological findings of thymoma-associated multi-organ autoimmunity were indistinguishable from those of patients with acute GVHD, although the aetiologies of these diseases are completely different. The frequency of regulatory T cells (T(regs)) is reduced in cutaneous lesions and CD8+ cytotoxic T lymphocytes that massively infiltrate into the epidermis of patients with thymoma-associated multi-organ autoimmunity. Additionally, the ratio of T helper type 17 (Th17) cells to CD4+ cells in patients with thymoma-associated multi-organ autoimmunity and acute GVHD was higher than that in healthy controls, but similar to that in psoriasis vulgaris patients. Similarity of the skin-infiltrating T cell subsets with those of acute GVHD suggested that skin damage in patients with thymoma-associated multi-organ autoimmunity might be induced by self-reactive cytotoxic T lymphocytes under the diminished suppressive capacity of T(regs).

Effects of a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor and low-density lipoprotein on proliferation and migration of keratinocytes.

BACKGROUND: Keratinocytes can obtain cholesterol either by de novo synthesis or by extraction, primarily from low-density lipoprotein (LDL). LDL is internalized following binding to the LDL receptor (LDLR). Because LDLR is expressed at a higher level in the cells of the basal layer of the epidermis, it might be assumed that LDLR upregulation is associated with keratinocyte proliferation. However, the effect of LDLR stimulation on keratinocyte function remains unclear. OBJECTIVES: To investigate the effects and mechanism of action of pitavastatin and effects of LDL on proliferation and migration of keratinocytes. METHODS: Pitavastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, was used to induce upregulation of LDLR. LDLR expression was evaluated by immunofluorescence staining, fluorescence-activated cell sorting, immunohistochemical staining and real-time polymerase chain reaction (PCR). HaCaT cells and normal human keratinocytes (NHKs) were used for evaluation of migration. 5-Bromo-2'-deoxyuridine incorporation was used to evaluate keratinocyte proliferation and differentiation. C57BL6 mice were used for in vivo evaluation of the effect of topical pitavastatin or lovastatin. RESULTS: Pitavastatin was most effective in LDLR induction at a concentration of 1 micromol L(-1) in NHKs. Real-time PCR showed that pitavastatin significantly increased LDLR and liver X receptor (LXR) beta mRNA expression in these cells. Similar results were obtained in vivo. However, pitavastatin had no effect on the migration of NHKs. After the addition of LDL and/or mevalonate concomitantly with pitavastatin to NHK cultures, or topical application of pitavastatin on mouse skin, keratinocyte proliferation was significantly increased. CONCLUSIONS: Pitavastatin significantly upregulates LDLR in both NHKs and C57BL6 mouse skin, resulting in increased keratinocyte proliferation. LXRbeta may be involved in the pitavastatin-induced keratinocyte proliferation.

Emedastine difumarate inhibits histamine-induced collagen synthesis in dermal fibroblasts.

BACKGROUND: Mast cell-derived histamine is known to act on dermal fibroblasts and contribute to formation of an intractable chronic allergic dermatitis. Although this fibrotic event may also occur in other organs such as the nasal mucosa, no direct evidence has been reported as to whether responsiveness to histamine by fibroblasts derived from different organs is of the same intensity. Furthermore, while type 1 histamine receptor (H1R) blockers have been shown to be effective for alleviation of the symptoms of allergic diseases, their ability to affect histamine-induced tissue remodeling has not yet been clarified. OBJECTIVE: Our aim was to study the effect of H1R-blockers on histamine-induced tissue remodeling. METHODS: A macroarray assay was used for a comprehensive analysis of histamine-induced gene expression by normal human fibroblasts. Fibroblasts derived from skin or nasal mucosa were cultured in the presence of various concentrations of histamine, and the synthesis of type 1 collagen was measured by means of semi-quantitative reverse-transcriptase polymerase chain reaction and enzyme-linked immunosorbent assay. To determine the effect of H1R blockers, diphenhydramine hydrochloride and emedastine difumarate were investigated in this assay. RESULTS: Histamine induced expression of various kinds of fibrogenic molecules in fibroblasts. Increased type 1 collagen expression was observed in fibroblasts treated with high-dose (0.1 mM to 1 microM) and low-dose (1 pM) histamine. This histamine-induced type 1 collagen synthesis was effectively diminished by emedastine difumarate. While organ specificity seems to be involved, emedastine difumarate is considered to be an effective drug for reversal of such histamine-induced remodeling in the skin. CONCLUSIONS: We found that the expression of fibroblast-derived genes is differentially regulated by different concentrations of histamine and that the robustness of the inhibitory action of H1R blockers is different for skin-derived and nasal mucosa-derived fibroblasts. We believe that our findings may contribute to a better understanding of the mechanisms of histamine-induced tissue remodeling and provide information useful for the management of refractory allergic dermatitis.

Oral steroid improves bullous pemphigoid-like clinical manifestations in non-Herlitz junctional epidermolysis bullosa with COL17A1 mutation.

Non-Herlitz junctional epidermolysis bullosa (JEB-nH), a nonlethal variant of junctional epidermolysis bullosa (JEB), is an autosomal recessive disorder characterized by separation of the dermal-epidermal junction. JEB-nH is caused by mutations in several genes and lack of the COL17A1 gene product may lead to skin fragility. A 41-year-old Japanese man with JEB-nH, featuring mutations in the gene encoding type XVII collagen, presented with great blisters over his entire body accompanied by severe itching and eosinophilia usually observed in bullous pemphigoid (BP). To our knowledge, our patient is the first with JEB-nH to be treated successfully with an oral steroid to control his skin affliction, symptoms and eosinophilia. This suggests that in the case of JEB-nH with eosinophilia caused by some secondary immune activation, oral steroids may constitute an alternate therapy to improve aggravated skin conditions and severe itching, both of which tend to show resistance to usual dermatological treatments.

Chemoembolization of head and neck cancer with carboplatine microcapsules.

Fourteen patients with malignant tumor in the head and neck region were treated with infusion of carboplatine microcapsules (CBDCA-mc) via percutaneous super-selective catheterization. A microcatheter was advanced into a feeding artery using a coaxial catheter system. Eleven patients had over 30% reduction of the tumor size on CT within 1 month after embolization. Twelve patients had an increased amount of low attenuation tissue in the tumor on CT after embolization, suggesting increased necrosis in the tumor. No definite hematologic toxicity was found. A majority of patients complained of moderate pain in the embolized region immediately after embolization, easily relieved by i.v. analgesics. Chemoembolization using CBDCA-mc may be an effective therapeutic modality in advanced cases of head and neck cancer.