The OX40 Axis is Associated with Both Systemic and Local Involvement in Atopic Dermatitis.

Atopic dermatitis (AD) is a chronic, or chronically relapsing, inflammatory skin disease associated with asthma and allergic rhinitis, and is dominated by Th2 cells. The co-stimulatory T-cell receptor OX40 and its ligand, OX40L, play a central role in the pathogenesis of AD, as their interactions are crucial for the generation of TH2 memory cells. Using enzyme-linked immunoassay (ELISA) and flow cytometry on blood samples from patients with AD and healthy volunteers, this study shows that the serum level of soluble (s) OX40 is decreased in patients with AD, and the expression of OX40 by activated skin-homing CD4+ T cells is increased. This study further shows, using immunofluorescence on skin biopsies, that OX40+ and OX40L+ cells are co-located within the dermis, indicating local activity of OX40/OX40L. Serum levels of sOX40 were associated with atopic diseases and, together, these results support that the OX40 system is important for chronic inflammation in AD skin.

Emerging Treatment Options in Atopic Dermatitis: Systemic Therapies.

The pathogenesis of atopic dermatitis (AD) is multifactorial and intricate, and the clinical presentation of the condition varies greatly. Symptoms and severity depend on individual trigger factors and stage of the disease. The majority of AD patients are sufficiently treated with emollients in combination with existing topical or systemic therapies. Yet treatment failure with existing drugs and treatment options can be a significant clinical problem. New treatments are under development, and the majority of these new drugs focus on targeting a skewed immune response in AD. Novel therapeutic approaches, which target the pathways involved in the pathogenesis of AD, may provide a potentially more effective and less harmful approach to systemic therapy. These pharmaceutical agents are designed to narrowly modify or directly block a specific cellular signal or pro-inflammatory pathway. We review systemic drugs in the pipeline for AD. To make the review as current and pertinent as possible, we selected to focus on AD-related therapies available in the clinicaltrials.gov database with a first received date after January 1, 2014, up until May 31, 2017. We excluded therapies that could be categorized as either traditional Chinese medicine, herbal medicine, probiotics, histamine/leukotriene blockers, immuno-adsorption, or immunostimulants.

Emerging Treatment Options in Atopic Dermatitis: Topical Therapies.

Atopic dermatitis is a chronic inflammatory skin disorder affecting children and adults, with the majority presenting mild to moderate disease severity. The use of topical corticosteroids (TCSs) in combination with emollients has been the mainstay for treating mild to moderate atopic dermatitis since the 1950s, and as a supplement to systemic treatment in severe disease. However, while very effective, TCSs are often accompanied by poor adherence due to corticophobia (fear of using corticosteroids in patients or doctors), unwanted side effects, and in some cases insufficient clinical response. Topical calcineurin inhibitors (TCIs) are able to inhibit the activation of T-lymphocytes and thereby diminish inflammation. In some patients the use of TCIs has been limited due to a localized burning sensation on the first days of treatment, and also due to fear of other adverse effects. Consequently, there has been a need for the development of new topical products for atopic dermatitis. Novel topical therapies are in the pipeline and comprise both new doses and formulations of well-known pharmaceutical molecules and novel approaches targeting unique inflammatory pathways and mechanisms of disease, with a promise of higher efficacy and less harmful side effects. We review topical drugs in the pipeline for atopic dermatitis, and focus on those available in the clinicaltrials.gov database with a first received date from January 1, 2014 to May 31, 2017.

The "Alarmins" HMBG1 and IL-33 Downregulate Structural Skin Barrier Proteins and Impair Epidermal Growth.

The epidermal-derived "alarmins" high-mobility group box 1 (HMGB1) protein and interleukin-33 (IL-33) are upregulated in patients with atopic dermatitis. How-ever, their capacity as pro-inflammatory cytokines and their derived effects on skin barrier regulation are poorly elucidated. We investigated the impact of HMGB1 and IL-33 on gene transcription, protein expression and epidermal differentiation across 3 distinct keratinocyte in vitro models. Primary keratinocytes from healthy donors were used in submerged monolayer cultures, 3D human epidermis equivalents and 3D human skin equivalents. All keratinocyte models underwent 96-h stimulation with HMGB1 (100 µM) or IL-33 (100 ng/ml) using IL-4 (50 ng/ml) as positive control of regulation and vehicle as negative control. We found that HMGB1 and IL-33 downregulated transcription of several genes from members of the epidermal differentiation complex, including filaggrin. Furthermore, HMGB1 downregulated the expression of the encoded proteins in the upper epidermis. Finally, IL-33 and HMGB1 ultimately led to impaired epidermal growth and maturation. In conclusion, HMGB1 and IL-33 could play a significant role in the atopic dermatitis pathophysiology due to negative regulation of structural proteins, stratum corneum formation and epidermal growth.

Italian S3-Guideline on the treatment of Atopic Eczema - Part 1: Systemic therapy, adapted from EuroGuiDerm by the Italian Society of Dermatology and STD (SIDEMAST), the Italian Association of Hospital Dermatologists (ADOI) and the Italian Society of Allergological and Environmental Dermatology (SIDAPA).

SIDeMaST (Società Italiana di Dermatologia Medica, Chirurgica, Estetica e delle Malattie Sessualmente Trasmesse) contributed to the development of the present guideline on the systemic treatment of chronic plaque psoriasis. With the permission of EuroGuiDerm, SIDeMaST adapted the guideline to the Italian healthcare context to supply a reliable and affordable tool to Italian physicians who take care of patients affected by atopic dermatitis. The evidence- and consensus-based guideline on atopic eczema was developed in accordance with the EuroGuiDerm Guideline and Consensus Statement Development Manual. Four consensus conferences were held between December 2020 and July 2021. Twenty-nine experts (including clinicians and patient representatives) from 12 European countries participated. This first part of the guideline includes general information on its scope and purpose, the health questions covered, target users and a methods section. It also provides guidance on which patients should be treated with systemic therapies, as well as recommendations and detailed information on each systemic drug. The systemic treatment options discussed in the guideline comprise conventional immunosuppressive drugs (azathioprine, ciclosporin, glucocorticosteroids, methotrexate and mycophenolate mofetil), biologics (dupilumab, lebrikizumab, nemolizumab, omalizumab and tralokinumab) and janus kinase inhibitors (abrocitinib, baricitinib and upadacitinib). Part two of the guideline will address avoidance of provocation factors, dietary interventions, immunotherapy, complementary medicine, educational interventions, occupational and psychodermatological aspects, patient perspective and considerations for pediatric, adolescent, pregnant and breastfeeding patients.

Italian S3-Guideline on the treatment of Atopic Eczema - First Update, adapted from EuroGuiDerm by the Italian Society of Dermatology and STD (SIDEMAST), the Italian Association of Hospital Dermatologists (ADOI) and the Italian Society of Allergological and Occupational Dermatology (SIDAPA).

The evidence- and consensus-based guideline on atopic eczema, published in JEADV on 18 August 2022 (part 1) and 3 September 2022 (part 2) was developed in accordance with the EuroGuiDerm Guideline and Consensus Statement Development Manual. Four consensus conferences were held between December 2020 and July 2021. Twenty-nine experts (including clinicians and patient representatives) from 12 European countries participated. To reflect the most recent evidence on novel systemic medications, an update was published in October 2022. According to the purpose of the Italian Society of Dermatology and STD (SIDEMAST), the Italian Association of Hospital Dermatologists (ADOI) and the Italian Society of Allergological and Environmental Dermatology (SIDAPA) to adapt the EuroGuiDerm guideline on the treatment of atopic eczema into the Italian Healthcare setting, the original update has been supplemented by inserting notes, well highlighted by the original text, to emphasize the laws, rules, procedures and suggestions of the Italian Ministry of Health and regional Health authorities.

Italian S3-Guideline on the treatment of Atopic Eczema - Part 2: non-systemic treatments and treatment recommendations for special AE patient populations, adapted from EuroGuiDerm by the Italian Society of Dermatology and STD (SIDEMAST), the Italian Association of Hospital Dermatologists (ADOI) and the Italian Society of Allergological and Occupational Dermatology (SIDAPA).

SIDeMaST (Società Italiana di Dermatologia Medica, Chirurgica, Estetica e delle Malattie Sessualmente Trasmesse) contributed to the development of the present guideline on the systemic treatment of chronic plaque psoriasis. With the permission of EuroGuiDerm, SIDeMaST adapted the guideline to the Italian healthcare context to supply a reliable and affordable tool to Italian physicians who take care of patients affected by atopic dermatitis. The evidence- and consensus-based guideline on atopic eczema was developed in accordance with the EuroGuiDerm Guideline and Consensus Statement Development Manual. Four consensus conferences were held between December 2020 and July 2021. Twenty-nine experts (including clinicians and patient representatives) from 12 European countries participated. This second part of the guideline includes recommendations and detailed information on basic therapy with emollients and moisturizers, topical anti-inflammatory treatment, antimicrobial and antipruritic treatment and UV phototherapy. Furthermore, this part of the guideline covers techniques for avoiding provocation factors, as well as dietary interventions, immunotherapy, complementary medicine and educational interventions for patients with atopic eczema and deals with occupational and psychodermatological aspects of the disease. It also contains guidance on treatment for pediatric and adolescent patients and pregnant or breastfeeding women, as well as considerations for patients who want to have a child. A chapter on the patient perspective is also provided. The first part of the guideline, published separately, contains recommendations and guidance on systemic treatment with conventional immunosuppressive drugs, biologics and janus kinase (JAK) inhibitors, as well as information on the scope and purpose of the guideline, and a section on guideline methodology.

Attention-Deficit/Hyperactivity Disorder in Atopic Dermatitis: An Appraisal of the Current Literature.

Atopic dermatitis (AD) is a chronic inflammatory skin disease with hallmark characteristics in terms of pruritus, psychological stress, and sleep disturbance, all possibly associated with an increased risk of attention-deficit/hyperactivity disorder (ADHD). Epidemiological data indicate that AD and ADHD exhibit a parallel rise in global prevalence, and several cross-sectional studies have indicated co-occurrence of the 2 conditions. Furthermore, recent cohort studies have reported a temporal association between AD and later development of ADHD. However, underlying pathophysiological mechanisms of this association are insufficiently explored. The aim of the present review was to provide any clinician encountering AD an update on the most recent studies examining the possible AD-ADHD association. In turn, this could aid counseling of patients and parents. This review may encourage healthcare providers to refer AD patients and families to psychiatric specialists when ADHD is suspected.

Measuring serum concentrations of interleukin-33 in atopic dermatitis is associated with potential false positive results.

BACKGROUND: In the search for valid biomarkers in inflammatory diseases, cytokine serum concentrations are often measured by enzyme-linked immunosorbent assay and correlated to disease activity. Interleukin-33 is a relatively newly described cytokine, which holds a promising potential as a biomarker for different diseases including atopic dermatitis. However, interfering human anti-animal IgG antibodies and heterophilic antibodies might give rise to false positive or negative results that often go unnoticed. FINDINGS: We performed a three-step validation of commercially available and widely used human interleukin-33 enzyme-linked immunosorbent assay kit with serum samples from eight atopic dermatitis patients and five healthy controls. Through addition of unspecific animal IgG (rabbit, mouse, goat and bovine) and unspecific human IgG to the assay diluent, we disclosed false positive values in 12 out of 13 samples. CONCLUSION: This study show that the present human interleukin-33 enzyme-linked immunosorbent assay kit might give rise to a high prevalence of false positive values if not validated. This inaccuracy is easily eliminated with a simple set of validation steps.

Injuries during football tournaments in 45,000 children and adolescents.

Four percent of the world's population, or 265 million people, play football, and many players are injured every year. The present study investigated more than 1800 injuries in over 45,000 youth players participating in three consecutive international football tournaments in Denmark in 2012-2014. The aim was to investigate the injury types and locations in children and adolescent football players and the differences between genders and age groups (11-15 and 16-19 years of age). An overall injury rate of 15.3 per 1000 player hours was found. The most common injury location was lower extremities (66.7%), and the most common injury type was contusion (24.4%). Girls had a relative risk of injury of 1.5 compared with boys, p < .001, and they had a higher proportion of injuries to knee and lower leg, 23.8%, than boys, 19.0%, p < .01. Boys had a higher proportion of fracture, 6.8%, as opposed to 3.3% among girls, p < .001. In conclusion, we found the youngest girls to have a higher incidence of almost all injury categories than any other group. In general, the incidence of injury decreased with age. The study provides a detailed insight into the injuries that may be expected at a large youth football tournament. These findings are of great value for organizations and healthcare professionals planning similar events and for planning injury prevention strategies, which would be of special interest in the youngest female players in general.

Increased IL-25 levels in the peritoneal fluid of patients with endometriosis.

Previous studies have indicated a higher prevalence of allergic disease among women with endometriosis. It is already well established that type 1 allergies develop in a Th2 cytokine environment. Recent studies have shown, however, that IL-25 induces a Th2 development of naive T lymphocytes and is central in the Th2 response. The aim of this case-control study was to investigate the presence of IL-25 in the peritoneal fluid of women suffering from endometriosis. PF was obtained both from women undergoing laparoscopic surgery due to endometriosis (25 cases) and from women wanting sterilisation (19 controls). IL-25 levels were then investigated by ELISA. Women with endometriosis showed significantly higher levels of IL-25 in their PF (p=0.019) compared to controls. IL-25 levels did not correlate with the stage of endometriosis. Both Th2-cells and mast cells express IL-25, which could favor the development of allergies by perpetuating a hypersensitivity reaction. Further, IL-25 may also hold a role as a diagnostic tool.

Large eccrine angiomatous hamartoma: a novel clinical presentation of disease.

BACKGROUND: Eccrine angiomatous hamartoma is a rare benign cutaneous malformation with a diverse clinical appearance, therefore likely to be misdiagnosed and underreported. MAIN OBSERVATIONS: A 44-year-old man presented with a congenital erythematous hyperhidrotic plaque on the left upper back measuring 18 x 25 cm. No pain or tenderness nor hypertrichosis were observed. Histopathology was consistent with the mucinous variant of eccrine angiomatous hamartoma. Intralesional injection of botulinum toxin type A greatly reduced localized sweating, improving patient quality of life. CONCLUSIONS: This article describes a novel clinical presentation of eccrine angiomatous hamartoma: large, erythematous, and slightly indurated plaque localized on the upper back. It emphasizes the role of histopathology in the diagnostic process and botulinum toxin as a viable treatment option.

Allergic contact dermatitis induced by textile necklace.

Allergic contact dermatitis to textile dyes is considered to be a rare phenomenon. A recent review reported a prevalence of contact allergy to disperse dyes between 0.4 and 6.7%. The relevance of positive patch testing was not reported in all studies. Textile dye allergy is easily overlooked and is furthermore challenging to investigate as textile dyes are not labelled on clothing. In this report, we present a case of allergic contact dermatitis to a textile necklace. The patch test showed strong reactions to the necklace and the azo dyes Disperse Orange 1 and Disperse Yellow 3. Despite the European legislation and the reduced use of disperse dyes in Third World countries, disperse azo dyes still induce new cases of allergic contact dermatitis.

Lymphocyte apoptosis is resistant to erythropoietin in porcine endotoxemia.

Sepsis-induced lymphocyte apoptosis plays an important role in the development of immune suppression in septic patients. Erythropoietin (EPO) is a multifunctional cytokine with antiapoptotic properties. We hypothesized that EPO could mitigate mononuclear cell (MNC) apoptosis and modify the dynamic changes of MNCs during endotoxemia. Twenty-six pigs were randomized into three groups: (i) lipopolysaccharides (LPS), (ii) EPO (epoetin-α, 5000 IU/kg) administered 60 min prior to LPS, and (iii) sham. At 120 min of endotoxemia, the animals were fluid resuscitated and the LPS infusion was reduced. MNCs were isolated at 0, 60, 240, and 540 min of endotoxemia, and apoptosis was assessed by flow cytometry. Apoptosis in splenic biopsies was quantified by immunohistochemistry. Endotoxemia increased the number of apoptotic MNCs in the blood (p ≤ 0.01) and the spleen (p = 0.03), and EPO did not modify this increase. The number of T-helper and cytotoxic T cells declined during endotoxemia. The dynamic changes of the MNC subsets were not modified by treatment with EPO. In conclusion, EPO did not modify the LPS-induced changes of MNC subsets or mitigate the levels of apoptosis of MNCs in the blood or in the spleen. This study does not support that EPO confers protection against lymphocyte apoptosis.