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Background: With the current trend in healthcare moving towards a more value-based approach, it is essential to understand what value encompasses. Objectives: To develop an actionable value-based outcome set (VOS) for daily practice. Methods: A mixed method approach was used consisting of four phases. Formerly, a systematic review was conducted, providing an overview of all patient-relevant outcomes defined in current literature. These 23 outcomes were then presented to a group of patients, using a modified nominal group technique (NGT), to establish whether these results represented all of their relevant outcomes. Subsequently, these outcomes were ranked according to importance by patients attending our academic specialized psoriasis clinic. A review of the literature was performed to assess which instruments were available and suitable to evaluate the outcomes in this VOS. Finally, a pilot feasibility test was performed amongst patients. Results: Of the 23 outcomes, two were omitted from the ranking exercise after the NGT. In the ranking exercise, 120 patients participated. The median age was 50.0 (IQR 25.0) years and 36.7% were female. Median PASI score was 2.4 (IQR 5.2), and treatments varied from topicals to biologicals. The outcomes scored as most important were symptom control, treatment efficacy, confidence in care and control of disease. The least important outcomes were comorbidity control, productivity and cost of care. A significant difference was shown between the ranking of the outcomes (p < 0.001). In total, 12 instruments were selected, which are reported by both patient and provider, to measure the outcomes in this VOS. Median completion time for the patient part was 30 min (IQR 2.8). Conclusions: This VOS is a first proposal to evaluate psoriasis care in a value-based manner. Measuring these outcomes can enable us to critically appraise and improve current care processes, within the reality of available resources, thereby increasing value for patients.

The efficacy and safety of tralokinumab, a fully human monoclonal antibody that specifically neutralizes interleukin-13, plus topical corticosteroids (TCS) as needed were evaluated over 32 weeks in the phase III ECZTRA 3 trial. Significantly more tralokinumab- versus placebo-treated patients achieved the primary endpoints of Investigator's Global Assessment (IGA) score of 0/1 and 75% improvement in Eczema Area and Severity Index (EASI-75) and all confirmatory endpoints at Week 16.This post hoc analysis investigated the impact of tralokinumab plus TCS on atopic dermatitis (AD) severity, symptoms, and health-related quality of life (QoL) over the entire 32-week treatment period of ECZTRA 3, including all patients initiated on tralokinumab irrespective of the response achieved at Week 16.Patients were randomized 2:1 to receive subcutaneous tralokinumab 300 mg or placebo every 2 weeks (q2w) with TCS as needed for an initial 16 weeks. At Week 16, patients who achieved the clinical response criteria (IGA 0/1 and/or EASI-75) with tralokinumab were re-randomized 1:1 to tralokinumab q2w or every 4 weeks (q4w), with TCS as needed, for another 16 weeks. Patients not achieving the clinical response criteria with tralokinumab received tralokinumab q2w plus TCS from Week 16. All patients randomized to tralokinumab in the initial treatment period were pooled for this analysis, irrespective of response at Week 16 or dosing regimen beyond Week 16.Continued tralokinumab (q2w, N = 164; q4w, N = 69) plus TCS treatment provided progressive improvements from Week 16 onwards in AD signs, with 70.2% (177/252) of patients achieving EASI-75 and 50.4% (127/252) achieving EASI-90 at Week 32. Improvements in patient-reported outcomes were observed within the first few weeks of tralokinumab q2w plus TCS treatment and were sustained throughout the 32-week period. At Week 32, patients initiated on tralokinumab q2w plus TCS achieved a relative improvement versus baseline of 70.8% (standard error (SE), 2.4) in eczema-related sleep interference numeric rating scale (NRS) and 66.8% (SE, 3.1) in Dermatology Life Quality Index (DLQI). Mean TCS use during Weeks 16-32 ranged from 9.2 to 13.6 g (SE, 1.2-2.0) q2w. Most patients (89.9% (222/247)) initiated on tralokinumab q2w plus TCS achieved a meaningful improvement in at least one of the three disease domains, including AD signs (EASI-50), symptoms (pruritus NRS improvement ≥ 3), and QoL (DLQI improvement ≥ 4) at Week 16. Of patients initiated on tralokinumab q2w plus TCS, 53.4% (132/247) achieved a clinically meaningful improvement in all three domains at Week 16 (vs. placebo, 28.5% (35/123); p 0.001).Continued tralokinumab treatment plus TCS as needed provides progressive and sustained improvements in AD signs, symptoms, and health-related QoL over 32 weeks.NCT03363854; study start date: 22 February 2018; primary completion date: 8 March 2019; study completion date: 26 September 2019.Atopic dermatitis (AD) is a chronic inflammatory disease that causes excessively dry and itchy skin that can negatively impact sleep and overall quality of life for patients. Topical corticosteroids (TCS) are the most common medication used for AD, but they are not able to control the most severe cases. Tralokinumab is a treatment injected under the skin that targets an immune messenger protein called interleukin 13, which plays a key role in driving the signs and symptoms of AD. The ECZTRA 3 clinical trial, funded by LEO Pharma, compared the use of TCS as needed with either tralokinumab or placebo in over 350 adult patients with moderate-to-severe AD over a 32-week period. After 16 weeks, more patients taking tralokinumab plus TCS had clear or almost clear skin compared with patients taking placebo plus TCS. Patients taking tralokinumab also used less TCS than patients taking placebo. In new analyses presented here, we found that the proportion of patients with clear or almost clear skin continued to increase with on-going treatment from Week 16 to Week 32. Tralokinumab plus TCS treatment also led to clinically meaningful improvements in outcomes important to patients, including itch, sleep, and quality of life. Improvements occurred early, within the first few weeks of therapy, and lasted through Week 32. Our assessment of multiple outcomes over time clearly demonstrates the positive impact of tralokinumab on different aspects of AD.

T lymphocytes (T cells) are major players of the adaptive immune response. Naive T cells are primed in the presence of cytokines, leading to polarization into distinct T-cell subsets with specific functions. These subsets are classified based on their T-cell receptor profile, expression of transcription factors, surface cytokine and chemokine receptors, and their cytokine production, which together determine their specific function. This review provides an overview of the various T-cell subsets and their function in several inflammatory skin disorders ranging from allergic inflammation to skin tumors. Moreover, we highlight similarities of T-cell responses across different skin disorders, demonstrating the presence of similar and opposing functions for the different T-cell subsets. Finally, we discuss the effects of currently available and promising therapeutic approaches to harness T cells in inflammatory skin diseases for which efficacy next to unwanted side effects provide new insights into the pathophysiology of skin disorders.

The great milestones in medicine almost always have their precursors, which help the great event to break through. So it was with allergen-specific immunotherapy (AIT) and the great work of Noon and Freeman and their world-renowned publication in 1911. In this article, we want to outline AIT's long journey, from early attempts to achieve tolerance to allergens in the environment. Many very different methods were used; from homeopathy to the use of recombinant allergens. Initially, the allergen extracts were given only subcutaneously, but then also through other routes, such as nasal, rectal, intradermal, epicutaneous, in lymph nodes, or oral. It was the great merit of Bill Franklin, whom many of us still experienced as active participants in congresses, to point out that the effect of AIT must be documented not only by clinical observation but in a controlled form including placebo injections. AIT was thus transferred to evidence-based medicine, which we successfully apply today. We would like to express our gratitude to Bill Franklin himself and all others involved in the development of AIT with this summary of 111 years of immunotherapy.

Objective: We conducted a systematic review, on behalf of the EULAR Study Group on Microcirculation in Rheumatic Diseases (EULAR SG MC/RD), to investigate the value of nailfold videocapillaroscopy (NVC) in idiopathic inflammatory myopathies (IIM). Methods: Three electronic databases were systematically searched to find all relevant manuscripts reporting NVC outcomes in IIM patients. Articles were assessed based on study design, population, NVC methodology and description of NVC results. To allow comparison between the articles, all NVC results were interpreted according to standardised capillaroscopic terminology, as previously consented by the EULAR SG MC/RD and the Scleroderma Clinical Trials Consortium (SCTC) Group on Capillaroscopy. Results: Of the 653 identified records; five were retained after critical appraisal on title, abstract and manuscript level. A marked difference in NVC was observed between (juvenile) dermatomyositis [(j)DM] versus polymyo-sitis, healthy controls and systemic sclerosis patients. In addition, reduced capillary density and scleroderma pattern seem to be associated with active disease in (j)DM, while immunosuppressive treatment appears to reduce NVC abnormalities. Conclusion: This is the first systematic review investigating NVC in IIM, interpreting the results according to an international consented standardised manner, as proposed by the EULAR SG MC/RD and SCTC Group on Capillaroscopy. We can conclude that NVC presents a promising asset in the diagnosis of (j)DM. Moreover, NVC could be a biomarker for organ involvement and follow-up. Large multicentre prospective standardised studies are further needed to definitely describe associations with clinical and laboratory parameters in the different IIM subtypes.

Chronic spontaneous urticaria (CSU) imposes a significant burden on patients, families and healthcare systems. Management is difficult, due to disease heterogeneity and insufficient efficacy of classical drugs such as H1 R-antihistamines. Better understanding of the mechanisms has enabled a stratified approach to the management of CSU, supporting the use of targeted treatment with omalizumab. However, many practical issues including selection of responders, the definition of response, strategies to enhance the responder rate, the duration of treatment and its regimen (in the clinic or home-based) and its cost-effectiveness still require further clarification. The EAACI Guidelines on the use of omalizumab in CSU follow the GRADE approach in formulating recommendations for each outcome. In addition, future therapeutic approaches and perspectives as well as research priorities are discussed.

is missing (Short communication)

BACKGROUND Patients with severe atopic dermatitis (AD) not controlled with topical therapy have limited treatment options. Cyclosporine A (CSA) is a commonly used, broad immunosuppressant in AD, but treatment with CSA requires monitoring for potentially serious adverse effects. In a previous Phase 3 trial, tralokinumab plus topical corticosteroids (TCS) as needed provided early and sustained improvements in AD signs and symptoms. OBJECTIVES To evaluate the efficacy and safety of tralokinumab plus TCS in adult patients with severe AD, whose disease was not adequately controlled with or who had contraindications to oral CSA. METHODS In this 26-week, multicenter, parallel, randomized, double-blind, placebo-controlled, Phase 3 trial, European adults with severe AD were randomized 1:1 to subcutaneous tralokinumab 300 mg or placebo every 2 weeks plus TCS as needed. The primary endpoint was a 75% improvement in Eczema Area and Severity Index (EASI-75) at Week 16. RESULTS 277 patients were randomized. At Week 16, more patients treated with tralokinumab plus TCS vs placebo plus TCS achieved EASI-75 (64.2% vs 50.5%; difference [95% confidence interval] 14.1% [2.5-25.7]; P=0.018), which increased further up to Week 26. Improvements in AD severity were accompanied by early improvements in patient-reported outcomes, including Dermatology Life Quality Index, Patient-Oriented Eczema Measure, pruritus, and sleep interference. Tralokinumab plus TCS also showed a higher EASI-75 response at Week 16 among patients who had previously failed CSA therapy vs placebo plus TCS (57% vs 41%). The overall incidence of adverse events was similar between treatment arms. CONCLUSIONS Tralokinumab 300 mg plus TCS as needed was effective and well tolerated in patients with severe AD not adequately controlled with, or who had contraindications to, oral CSA.

For Ab purification, high-affinity chromatography is commonly used. This technique results in high-purity Abs, but it requires highly specific knowledge and equipment. Commercial kits for purification of IgE are not available. Therefore, we established a (to our knowledge) novel method for the purification of total IgE from human serum. Sera from 19 allergic and nonallergic patients were included. After depletion of polyclonal IgG, total serum IgE was captured using anti-human IgE Abs coupled to beads, eluted from the beads, and incubated with protein G–coupled beads to increase the final purity. Purity analysis and Ab detection were performed by Western blot. Total serum IgE and purified IgE concentrations were analyzed using ELISA. To determine their functionality, primary human mast cells were sensitized with purified IgE and activated with anti-IgE or a relevant allergen. CD63+ expression and histamine release were used as readout parameters. Concentrations of purified total IgE corresponded with the levels of total serum IgE. Minor fractions of IgE remained attached to the beads, confirming an effective elution of IgE Abs. Only minimal amounts of IgG were found in the purified IgE fractions, confirming a high purity of IgE. Mast cells sensitized with purified IgE and subsequent activation with anti-IgE Ab or a relevant allergen showed increased expression of CD63+ and increased histamine release. This (to our knowledge) novel method represents a highly effective and widely accessible approach for purification of human serum IgE, which can improve the use of IgE-based in vivo and in vitro models and contribute to allergy research.

As the international refugee crisis has reached new proportions,1 survivors of torture increasingly present to treating physicians with an array of acute or chronic skin lesions. Physicians should be aware of common presentations and likely differential diagnoses in order to avoid mislabeling or underrecognizing torture. Survivors of torture also frequently suffer from psychological sequelae, such as post- traumatic stress disorder, and appropriate referrals are essential in order to improve recovery trajectory. Skin sequelae are the most common physical findings of torture. Not all skin lesions seen in tortured survivors are due to perpetrator inflicted injuries, and many dermatological conditions can mimic lesions typical of torture, as can scars as a result of folk remedies or cultural practices specific to geographical regions. Medical documentation of torture includes injury and lesion description. While forensic dermatology and other forensic specialties use an injury description taxonomy, and the standard dermatologic taxonomy uses an anatomic description, they are complementary sciences for lesions inflicted by torture. This results in an opportunity for learning across disciplines in order to improve evidence documentation for survivors of torture. This article describes features of common skin lesions consistent with torture, including their clinical appearances, differential diagnoses, patterns of injury and appropriate clinical descriptions. This article is protected by copyright. All rights reserved.

Atopic dermatitis imposes a significant burden on patients, families and healthcare systems. Management is difficult, due to disease heterogeneity, co-morbidities, complexity in care pathways and differences between national or regional healthcare systems. Better understanding of the mechanisms has enabled a stratified approach to the management of atopic dermatitis, supporting the use of targeted treatments with biologicals. However, there are still many issues that require further clarification. These include the definition of response, strategies to enhance the responder rate, the duration of treatment and its regimen (in the clinic or home-based), its cost-effectiveness and long-term safety. The EAACI Guidelines on the use of dupilumab in atopic dermatitis follow the GRADE approach in formulating recommendations for each outcome and age group. In addition, future approaches and research priorities are discussed.

Atopic dermatitis (AD) is an itchy, non-contagious relapsing and chronic inflammatory skin disease that usually develops in early childhood. This pathology is associated with food allergy, allergic asthma, allergic rhinitis and anaphylaxis which may persist in adulthood. The underlying mechanisms of AD (endotypes) are just beginning to be discovered and show a complex interaction of various pathways including skin barrier function and immune deviation. Immune reactions to self-proteins (autoantigens) of the skin have been identified in patients with inflammatory skin diseases, such as chronic spontaneous urticaria, connective tissue disease, pemphigus vulgaris and bullous pemphigoid. IgE antibodies and T cells directed against epitopes of the skin were observed in adult patients with severe and chronic AD as well. This was associated with disease severity and suggests a progression from allergic inflammation to severe autoimmune processes against the skin. IgE-mediated autoimmunity and self-reactive T cells might accelerate the ongoing skin inflammation or might contribute to the relapsing course of the disease. However, to date, the exact mechanisms of IgE-mediated autoimmunity and self-reactive T cells in the pathophysiology of AD are still unclear. The aim of this review is to evaluate the development of (autoreactive) T cells and their response to (auto)antigens, as well as the role of the peripheral tolerance in autoimmunity in the pathophysiology of AD, including the unmet needs and gaps.

Objective SSc and localized sclerosis (LoS) are considered clinically distinct entities. We describe herein the coexistence of SSc and LoS by both a systematic literature review and an observational cohort study of unselected SSc patients. Methods Original studies documenting the coexistence of SSc and LoS were identified in three electronic databases by means of a systematic literature search according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Additionally, the coexistence of SSc and LoS was studied in a prospective cohort of SSc patients visiting the Ghent University Scleroderma Unit for their yearly follow-up visit between January 2018 and January 2019. Results Five studies were finally included for quality appraisal and data extraction. The coexistence of SSc and LoS ranged between 2.4 and 7.4%. RP, scleroderma pattern on nailfold videocapillaroscopy (NVC) and the presence of SSc-specific antibodies were commonly observed in coexistent cases. Additionally, coexistence of SSc and LoS was found in 8/296 (2.7%) consecutive SSc patients of the Ghent University Scleroderma Unit. RP was present in 6/8 coexistent cases; a scleroderma pattern on NVC was observed in all coexistent cases, and SSc-specific antibodies (i.e. cenp-B) were found in 4/8 coexistent cases. Conclusion This is the first systematic literature review with additional cohort evaluation investigating the coexistence of SSc and LoS. A relatively high overlap of SSc and LoS was revealed, which is peculiar because both are rare diseases.

This systematic review evaluates the efficacy and safety of omalizumab for chronic spontaneous urticaria (CSU). PubMed, Embase, and Cochrane Library were searched for RCTs. Critical and important CSU-related outcomes were considered. The risk of bias and the certainty of the evidence were assessed using GRADE. Ten RCTs including 1620 subjects aged 12 to 75 years old treated with omalizumab for 16 to 40 weeks were evaluated. Omalizumab 150 mg does not result in clinically meaningful improvement (high certainty) of the urticaria activity score (UAS)7 (mean difference (MD) -5; 95%CI -7.75 to -2.25), and the itch severity score (ISS)7 (MD -2.15; 95% CI -3.2 to -1.1) does not increase (moderate certainty) quality of life (QoL) (Dermatology Life Quality Index (DLQI); MD -2.01; 95%CI -3.22 to -0.81) and decreases (moderate certainty) rescue medication use (MD -1.68; 95%CI -2.95 to -0.4). Omalizumab 300 mg results in clinically meaningful improvements (moderate certainty) of the UAS7 (MD -11.05; 95%CI -12.87 to -9.24), the ISS7 (MD -4.45; 95%CI -5.39 to -3.51), and QoL (high certainty) (DLQI; MD -4.03; 95% CI -5.56 to -2.5) and decreases (moderate certainty) rescue medication use (MD -2.04; 95%CI -3.19 to -0.88) and drug-related serious AEs (RR 0.77; 95%CI 0.20 to 2.91).

This systematic review evaluates the efficacy, safety and economic impact of dupilumab compared to standard of care for uncontrolled moderate-to-severe atopic dermatitis (AD). Pubmed, EMBASE and Cochrane Library were searched for RCTs and health economic evaluations. Critical and important AD-related outcomes were considered. The risk of bias and the certainty of the evidence were assessed using GRADE. Seven RCTs including 1845 subjects >12 years treated with dupilumab 16 to 52 weeks were evaluated. For adults, there is high certainty that dupilumab decreases SCORAD (MD -30,72; 95% CI -34,65% to -26,79%) and EASI-75 (RR 3.09; 95% CI 2.45 to 3.89), pruritus (RR 2.96; 95% CI 2.37 to 3.70), rescue medication (RR 3.46; 95% CI 2.79 to 4.30), sleep disturbance (MD -7.29; 95% CI -8.23 to -6.35) and anxiety/depression (MD -3.08; 95% CI -4.41 to -1.75) and improves quality of life (MD -4.80; 95% CI -5.55 to -4.06). The efficacy for adolescents is similar. Dupilumab-related adverse events (AEs) slightly increase (low certainty). The evidence for dupilumab-related serious AE is uncertain. The incremental cost-effectiveness ratio ranged from 28 500 pound (low certainty) to 124 541 US$ (moderate certainty). More data on long-term safety are needed both for children and for adults, together with more efficacy data in the paediatric population.Registration: PROSPERO (CRD42020153645).

This update on chronic urticaria (CU) focuses on the prevalence and pathogenesis of chronic spontaneous urticaria (CSU), the expanding spectrum of patient-reported outcome measures (PROMs) for assessing CU disease activity, impact, and control, as well as future treatment options for CU. This update is needed, as several recently reported findings have led to significant advances in these areas. Some of these key discoveries were first presented at past meetings of the Collegium Internationale Allergologicum (CIA). New evidence shows that the prevalence of CSU is geographically heterogeneous, high in all age groups, and increasing. Several recent reports have helped to better characterize two endotypes of CSU: type I autoimmune (or autoallergic) CSU, driven by IgE to autoallergens, and type IIb autoimmune CSU, which is due to mast cell (MC)-targeted autoantibodies. The aim of treatment in CU is complete disease control with absence of signs and symptoms as well as normalization of quality of life (QoL). This is best monitored by the use of an expanding set of PROMs, to which the Angioedema Control Test, the Cholinergic Urticaria Quality of Life Questionnaire, and the Cholinergic Urticaria Activity Score have recently been added. Current treatment approaches for CU under development include drugs that inhibit the effects of signals that drive MC activation and accumulation, drugs that inhibit intracellular pathways of MC activation and degranulation, and drugs that silence MCs by binding to inhibitory receptors. The understanding, knowledge, and management of CU are rapidly increasing. The aim of this review is to provide physicians who treat CU patients with an update on where we stand and where we will go. Many questions and unmet needs remain to be addressed, such as the development of routine diagnostic tests for type I and type IIb autoimmune CSU, the global dissemination and consistent use of PROMs to assess disease activity, impact, and control, and the development of more effective and well-tolerated long-term treatments for all forms of CU.

Neglect and physical abuse of elderly are worrisome health problems, which are expected to grow even further, considering the aging of the population. By 2060, the number of people aged above 65 years is expected to double, whereas birth rates are low. This trend will cause a significant imbalance between different age groups and put more senior adults at risk for abuse. Risk factors, associated with abuse and neglect, are well established and can be categorized in sociodemographic-, victim-, or perpetrator-related risk factors. The effects of these risk factors depend mainly on the setting, which can be community-dwelling or institutionalized older adults. In community-based settings, 90% of perpetrators are family members. In each setting, suspicious physical injuries should be recognized and addressed promptly. This can be very challenging in elderly, among others, due to the age-related skin changes, which can mimic abuse; however, there are some cutaneous clues that should always raise suspicion of abuse, such as patterned shape or distribution, different healing stages of wounds, parallel injuries, signs of blunt trauma, and irregular patches of alopecia. General awareness is needed, and the advice of dermatologists, who are best trained to differentiate between those lesions, should be systematically sought, to reduce false-positive and false-negative interpretations.

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The vision of European Academy of Allergy and Clinical Immunology (EAACI) and the Union of European Medical Specialists Section and Board on allergology is to promote and to establish a full specialty of allergology in all European countries. In many European countries, a full specialty does not exist. In those countries, organ-based (sub)specialists or paediatricians and internists with an expertise in allergology may deliver allergy care. There are no generally accepted requirements for the training of subspecialists available. To fill the gap between the need and availability of experienced and accredited physicians who can deliver optimal care to the allergic patients, the EAACI Specialty Committee proposes the minimal requirements for training and certification of subspecialists in allergology. This paper describes the required theoretical knowledge, skills, competences and training facilities (staff and institution). The subspecialist as described in this paper should ideally show the necessary competence in providing good quality care to patients in an environment lacking those full specialists in allergology or tertiary care paediatric subspecialists in allergy.

Allergen-specific immunotherapy (AIT) is the only disease-modifying and curative treatment for allergic diseases. While in selected indications such as Hymenoptera venom allergy the curative success of AIT is impressingly high, in other disease manifestations it only reduces the symptoms to a certain extend in a fraction of patients. Key problems leading to a reduced efficacy of AIT seem to partly depend on local inflammatory processes that are not only causing side-effects, but additionally feed-back on the specific immune response. Thus, these inflammatory processes also influence the immunologic memory and impair the induction of immune tolerance (1). During the initial phase of AIT, a further increase of Th2 inflammation, including higher levels of allergen-specific IgE has been observed frequently and can be a reason for side-effects and even anaphylactic reactions during AIT. This article is protected by copyright. All rights reserved.

Background Janus kinase (JAK) inhibition may be a promising new treatment modality for inflammatory (skin) diseases. However, little is known about direct effects of kinase inhibitors on keratinocyte differentiation and function as well as skin barrier formation. Objective Our aim was to address the direct impact of kinase inhibition of the JAK1/3 pathways by tofacitinib on keratinocyte immune function and barrier formation in atopic dermatitis (AD) and psoriasis. Methods 3D skin equivalents of both diseases were developed and concurrently pretreated with tofacitinib. To induce AD, 3D skin equivalents were stimulated with recombinant human IL-4 and IL-13. Psoriasis-like conditions were induced by incubation with IL-17A, IL-22 and tumour necrosis factor α (TNFα). The activation of signal transducer and activator of transcription (STAT)1, STAT3 and STAT6 was assessed by Western blot analysis. Microarray analysis and quantitative real-time PCR were used for gene expression analysis. Results Tofacitinib pretreatment preserved epidermal morphology and reduced STAT3 and STAT6 phosphorylation of AD-like and STAT3 phosphorylation of psoriasis-like culture conditions in 3D skin models compared to sham-controls. Filaggrin expression was fully maintained in the AD-like models, but only partially in psoriasis-like conditions after pretreatment with tofacitinib. In addition, tofacitinib upregulated DSC1, FLG and KRT1. Using gene expression analysis, downregulation of POSTN and IL24 was observed in AD-like conditions, whereas downregulation of IL20 and IL1B was observed in psoriasis-like conditions. Conclusion JAK1/3 inhibition counteracted cytokine-induced AD- and psoriasis-like epidermal morphology and enhanced keratinocyte differentiation in 3D skin models. This effect was more pronounced in the AD-like models compared to the psoriasis-like 3D skin models.

BACKGROUND: Besides allergens, pollen release bioactive, low molecular weight compounds that modulate and stimulate allergic reactions. Clinical relevance of these substances hasn't been investigated to date. OBJECTIVE: To elucidate the effect of a non-allergenic, low molecular weight factors from aqueous birch pollen extracts (Bet-APE

Anaphylaxis is an emergency condition of which reliable epidemiological data are lacking. This study focusses on epidemiology and aetiology of anaphylactic reactions in an urban Belgian emergency department (ED).Patient data were collected from 04/2009 to 04/2013.During this period, emergency doctors completed a questionnaire for adult patients (15 years) with anaphylaxis presenting at the ED. Inclusion criteria were based on the Sampson criteria of anaphylaxis. Data were analysed using a Microsoft Excel database.Anaphylaxis accounted for 0.04% of all emergency visits in this 4-year period. In both women and men, dyspnoea and urticaria were noted most frequently. 51.7% of cases were possibly elicited by foods, 46.1% by drugs and 3.4% by hymenoptera stings. Women more often reported allergic diseases in their personal history. 55.7% of patients, who had a history of allergy, reported a suspected food-related allergy, 24.6% a drug-related allergy and 8.2% a hymenoptera venom-related allergy. In 76.5% of patients who reported a history of food allergy, food was the presumed elicitor of anaphylaxis. For patients with history of drug allergy, 88.2% had a presumed drug anaphylaxis at the time of presentation at the ED. 81% of cases presented with grade 4 or 5 anaphylaxis. With increasing age, the severity of anaphylaxis increased. Higher tryptase levels correlated with a higher grade of anaphylaxis.In this Belgian urban population, foods and drugs were by far the most common suspected elicitors of anaphylaxis. Personal history of allergic diseases was present in more than half of the cases.

Vitamin D seems to be associated with a protective effect in a vast range of diseases, including cardiovascular, autoimmune and oncologic conditions. Since ultraviolet (UV) B light is the most important prerequisite for the cutaneous synthesis of vitamin D, sunbeds are able to increase serum vitamin D levels, although only transiently in most cases. In this scenario, the artificial tanning industry relentlessly tries to promote the use of sunbeds as a 'safe' therapeutic measure to achieve an adequate serum vitamin D status. The World Health Organization classified UV-emitting tanning devices, as well as the whole UV spectrum, as group-1 carcinogens, as they significantly increase the risk of melanoma and non-melanoma skin cancer. In case of vitamin D deficiency or insufficiency, the current risk-benefit ratio is therefore in favour of vitamin D supplementation instead of sunbed use. Artificial tanning devices should never be considered as an option to achieve an appropriate vitamin D status. Their supposedly beneficial effects, vastly publicised by the artificial tanning industry, are not worth the carcinogenic risk associated with sunbed use.

A 63-year-old man presented in the emergency department with general malaise, asthenia, an erythematosquamous rash on face and forearms and severe hyponatremia. The rash appeared after working in his garden on a sunny afternoon without sunscreen protection (Figure 1A/B/C). Furosemide was stopped and once daily mometason furoate cream was prescribed. Hyponatremia was corrected by IV hypertonic fluids. Five days later, the rash spread to the upper legs, chest and back. Histopathology revealed damage of the basal layer with necrotic keratinocytes and dermal perivascular and adnexal infiltrates (Figure 2). This article is protected by copyright. All rights reserved.

Purpose: This study aimed to assess the safety, efficacy, and patient satisfaction of superficial radiation therapy in the treatment of Peyronie's disease (PD) in a retrospective analysis. Methods and materials: We performed a retrospective analysis of 83 patients who underwent radiation therapy between 1999 and 2008 with 8 fractions of 4 Gy over a period of 6 months. With a mean follow-up time of 52 months, patients responded to a comprehensive questionnaire that covered patient characteristics, disease duration before radiation therapy, course of disease, treatment response, side effects, and patient satisfaction. Results: After a mean follow-up time of 52 months, 78% of the treated patients reported that PD progression had stopped. Furthermore 47% of patients had a symptom regression. Only 7% of patients reported PD progression. The penile curvature was improved in 49% of patients, and plaque induration could be reduced in 42% of patients. Moreover, 71% of patients reported substantial pain relief, as measured by a visual analogue scale (1 = not satisfied; 10 = very satisfied). Treatment satisfaction was rated with a median of 8 in a visual analogue scale out of 10. Side effects included transient erythema in 38.6% of patients and 9.6% reported of transient or chronic dryness. No severe side effects were observed. Conclusions: Radiation therapy for PD in the disease's early stages proved to be a safe and well-tolerated method with good results in pain relief, especially in patients aged

This observational study assessed whether women descending from consanguineous unions have reduced ovarian reserve compared with daughters of non-consanguine couples. Two hundred and ninety-one women (= 9, compared with 63.9% of non-consanguineous patients. Consanguineous patients did not exhibit an age-dependent AFC-decline and displayed reduced AFC and AMH concentrations. The multivariate analysis revealed female consanguinity, as well as surgical history in non-consanguineous women, as strong positive predictors of low ovarian reserve. Parental consanguinity is strongly associated with reduced ovarian reserve. Future studies should evaluate a possible association between parental consanguinity and infertility. (C) 2015 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

Silica (SiO₂) nanoparticles (NPs) usage includes, but is not limited to, industrial and biomedical applications. Toxic effects of SiO₂ NPs have been explored either in vitro or in vivo, assessing different surface modifications to reduce their harmful effects. Here, murine bone marrow-derived dendritic (BMDC) and a mouse model of mild allergic inflammation were used to study inflammasome activation and lung inflammation. Our results showed that SiO₂ plain NPs induced NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome activation, increasing interleukin (IL)-1β release in vitro, and, to a lesser extent, in vivo. In addition, SiO₂ plain NPs triggered a pulmonary inflammatory milieu in both non-sensitized (NS) and sensitized (S) mice, by inducing the expression of key inflammatory cytokines and chemokines. Electron microscopy showed that SiO₂ NPs were mostly localized in alveolar macrophages, within vesicles and/or in phagolysosomes. Both the in vitro and the in vivo effects of SiO NPs were attenuated by coating NPs with phosphonate or amino groups, whereas PEGylation, although it mitigated inflammasome activation in vitro, was not a successful coating strategy in vivo. These findings highlight that multiple assays are required to determine the effect of surface modifications in limiting NPs inflammatory potential. Taken together, these data are obtained by comparing in vitro and in vivo effects of SiO₂ NPs suggest the use of amino and phosphonate coating of silica NPs for commercial purposes and targeted applications, as they significantly reduce their proinflammatory potential.

BACKGROUND: ImmunoCAP ISAC 112, is a commercially available molecular allergy IgE multiplex test. Data on the comparison of this rather novel test with extract-based as well as molecular ImmunoCAP singleplex IgE tests is missing. OBJECTIVE: To perform a comparison between the ISAC multiplex IgE assay and the ImmunoCAP singleplex test results. METHODS: Serum samples of 101 adults with grass pollen allergy were analysed for sIgE to 112 allergenic molecules represented on the ISAC test as well as to common atopy-related extract-based allergy tests with the ImmunoCAP System (house dust mite [d1], cat [e1], dog [e5], cow's milk [f2], hen's egg [f1], hazelnut [f17], celery [f85], Alternaria alternate [m6], as well as pollen from birch [t3], hazel [t4], mugwort [w6], and ragweed [w1]). Subsequently statistical analysis was performed with the Spearman rank correlation test and the Clopper-Pearson method in order to compare the ISAC multiplex results with the sIgE singleplex results. RESULTS: The positive percent agreements (PPA) and negative percent agreement (NPA) of corresponding allergens between the ISAC sIgE test and the extract-based singleplex ImmunoCAP results at cutoff 0.1 kUA/l varied between 60-100 % for PPA and 78-97 % for NPA. CONCLUSION: When taking into account corresponding allergens molecular testing with the ISAC multiplex test correlates well with ImmunoCAP singleplex results.

Background B cells play a central role in IgE-mediated allergies. In damaged airway epithelium, they are exposed directly to aeroallergens. We aimed to assess whether direct exposure of B cells to pollen constituents affects allergic sensitization. Methods B cells from murine splenocytes and from blood samples of healthy donors were incubated for 8 days under Th2-like conditions with aqueous ragweed pollen extracts (Amb-APE) or its constituents. Secreted total IgM, IgG, and IgE was quantified by ELISA. Additionally, birch, grass, or pine-pollen extracts were tested. The number of viable cells was evaluated by ATP measurements. B-cell proliferation was measured by CFSE staining. IgE class switch was analyzed by quantitation of class switch transcripts. In an OVA/Alum i.p.-sensitization mouse model, Amb-APE was intranasally instilled for 11 consecutive days. Results Upon Th2 priming of murine B cells, ragweed pollen extract caused a dose-dependent increase in IgE production, while IgG and IgM were not affected. The low-molecular-weight fraction and phytoprostane E1 (PPE1) increased IgE production, while Amb a 1 did not. PPE1 enhanced IgE also in human memory B cells. Under Th1 conditions, Amb-APE did not influence immunoglobulin secretion. The IgE elevation was not ragweed specific. It correlated with proliferation of viable B cells, but not with IgE class switch. In vivo, Amb-APE increased total IgE and showed adjuvant activity in allergic airway inflammation. Conclusions Aqueous pollen extracts, the protein-free fraction of Amb-APE, and the pollen-contained substance PPE1 specifically enhance IgE production in Th2-primed B cells. Thus, pollen-derived nonallergenic substances might be responsible for B-cell-dependent aggravation of IgE-mediated allergies.

Hundred years ago, Leonhard Noon and John Freeman published their pioneering works on allergen-specific immunotherapy (ASIT) using grass pollen extracts. To honor their contribution to the development of ASIT as the only causal treatment of IgE-mediated allergies, we review the history of ASIT that started with the anecdotal descriptions of ASIT performed by the ancient king Mithridates (132-63 B.C.) and Jenner's development of a cowpox vaccine. Following Noon's and Freeman's first controlled human trials, ASIT was performed by a large number of modalities and with a myriad of pharmacologic preparations. These developments range from early aqueous pollen extracts and whole bee extracts to chemically modified allergens (allergoids) and various recombinant allergens. In addition to allergen-specific immunotherapy, non-specific immune response modifiers have been used in the past or are in the developmental stage. Also, currently many innovative experimental approaches of ASIT are studied in animal models and human in vitro systems and will hopefully further broaden the range of allergies that can be treated by ASIT, with enhanced efficacy and further reduced side-effects.

Background Ragweed (Ambrosia artemisiifolia) is a strong elicitor of allergic airway inflammation with worldwide increasing prevalence. Various components of ragweed pollen are thought to play a role in the development of allergic responses. The aim of this study was to identify critical factors for allergenicity of ragweed pollen in a physiological model of allergic airway inflammation. Methods Aqueous ragweed pollen extract, the low molecular weight fraction or the major allergen Amb a 1 was instilled intranasally on 1–11 consecutive days, and allergic airway inflammation was evaluated by bronchoalveolar lavage, lung histology, serology, gene expression in lung tissue, and measurement of lung function. Pollen-derived adenosine was removed from the extract enzymatically to analyze its role in ragweed-induced allergy. Migration of human neutrophils and eosinophils toward supernatants of ragweed-stimulated bronchial epithelial cells was analyzed. Results Instillation of ragweed pollen extract, but not of the major allergen or the low molecular weight fraction, induced specific IgG1, pulmonary infiltration with inflammatory cells, a Th2-associated cytokine signature in pulmonary tissue, and impaired lung function. Adenosine aggravated ragweed-induced allergic lung inflammation. In vitro, human neutrophils and eosinophils migrated toward supernatants of bronchial epithelial cells stimulated with ragweed extract only if adenosine was present. Conclusions Pollen-derived adenosine is a critical factor in ragweed-pollen-induced allergic airway inflammation. Future studies aim at therapeutic strategies to control these allergen-independent pathways.

Increased transepidermal water loss (TEWL) and decreased skin capacitance are characteristic features of the disturbed epidermal barrier in atopic eczema (AE). The "acid mantle", which is a slightly acidic film on the surface of the skin has led to the development of acidic emollients for skin care. In this context, the effect of citric acid-coated textiles on atopic skin has not been examined to date. A textile carrier composed of cellulose fibres was coated with a citric acid surface layer by esterification, ensuring a constant pH of 5.5-6.5. Twenty patients with AE or atopic diathesis were enrolled in the study. In a double-blind, half-side experiment, patients had to wear these textiles for 12 h a day for 14 days. On day 0 (baseline), 7 and 14, tolerability (erythema, pruritus, eczema, wearing comfort) and efficacy on skin barrier were assessed by TEWL skin hydration (corneometry/ capacitance), pH and clinical scoring of eczema (SCO-RAD). Citric acid-coated textiles were well tolerated and improved eczema and objective parameters of skin physiology, including barrier function and a reduced skin surface pH, with potential lower pathogenic microbial colonisation.

The utility of allogeneic hematopoietic stem cell transplantation is limited by graft-versus-host disease (GVHD), a significant cause of morbidity and mortality. Patients with GVHD exhibit cutaneous manifestations with histological features of interface dermatitis followed by scleroderma-like changes. JAK inhibitors represent a class of immunomodulatory drugs that inhibit signaling by multiple cytokines. Herein we report the effects of tofacitinib in a murine model of GVHD. Oral administration of tofacitinib prevented GVHD-like disease manifested by weight loss and mucocutaneous lesions. More importantly, tofacitinib was also effective in reversing established disease. Tofacitinib diminished the expansion and activation of murine CD8 T cells in this model, and had similar effects on IL-2-stimulated human CD8 T cells. Tofacitinib also inhibited the expression of IFN-γ-inducible chemoattractants by keratinocytes, and IFN-γ-inducible cell death of keratinocytes. Tofacitinib may be an effective drug for treatment against CD8 T-cell–mediated mucocutaneous diseases in patients with GVHD.

Viviana Marzaioli,1 Juan Antonio Aguilar-Pimente,1,2 Ingrid Weichenmeier,1 Georg Luxenhofer,3 Martin Wiemann,4 Robert Landsiedel,5 Wendel Wohlleben,5 Stefanie Eiden,6 Martin Mempel,7 Heidrun Behrendt,1 Carsten Schmidt-Weber,1 Jan Gutermuth,1,8 Francesca Alessandrini1 1Center of Allergy and Environment (ZAUM), Technische Universität and Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Munich, Germany; 2Department of Dermatology and Allergy Biederstein, Technische Universität München (TUM) and German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany, 3Institute of Developmental Genetics, Helmholtz Zentrum München, Neuherberg, Germany; 4IBE R&D gGmbH, Münster, Germany; 5BASF, Ludwigshafen, Germany; 6Bayer Technology Services, Leverkusen, Germany; 7Department of Dermatology, Venereology and Allergology, Universitätsmedizin Göttingen (UMG), Göttingen, Germany; 8Department of Dermatology, Vrije Universiteit Brussel, Brussels, Belgium Background: Silica (SiO2) nanoparticles (NPs) are widely used in diverse industrial and biomedical applications. Their applicability depends on surface modifications, which can limit potential health problems. Objective: To assess the potential impact of SiO2 NP exposure and NPs chemical modifications in allergic airway inflammation. Methods: Mice were sensitized by five repetitive intraperitoneal injections of ovalbumin/aluminum hydroxide (1 µg) over 42 days, then intratracheally instilled with plain or modified SiO2 NPs (50 µg/mouse), and subsequently aerosol challenged for 20 minutes with ovalbumin. One or 5 days later, allergic inflammation was evaluated by cell differentiation of bronchoalveolar lavage fluid, lung function and gene expression and histopathology, as well as electron and confocal microscopy of pulmonary tissue. Results: Plain SiO2 NPs induced proinflammatory and immunomodulatory effects in vivo, highlighted by enhanced infiltration of inflammatory cells in the bronchoalveolar lavage fluid, induction of a pulmonary T helper type 2 (Th2) cytokine pattern, differentiation of type 2 macrophages, and by morphological changes in the lung of sensitized mice. These effects were dramatically attenuated using surface-functionalized NPs with amino and phosphate groups, but not with polyethylene glycol. The role of macrophages in taking up SiO2 NPs was confirmed by flow cytometry, confocal microscopy, and gene expression analysis. Conclusion: Our data suggest that amino and phosphate surface modifications, but not polyethylene glycol (PEG), mitigate the proinflammatory and immunomodulatory effect of SiO2 NPs in allergic airway inflammation, paving the way for new strategies in the production of nanomaterials with lower health impact for humans. Keywords: immunomodulation, allergic inflammation, health impact