Differential diagnosis of contact dermatitis: A practical-approach review by the EADV Task Force on contact dermatitis.

The diagnosis of eczema ('dermatitis') is mostly clinical and depends on the clinical history and exploratory objective findings (primary lesions, patterns). Contact dermatitis remains as an important condition in the group of eczematous disorders, with important socioeconomic and occupational relevance. Although irritant and allergic contact dermatitis have a different pathogenesis, both are characterized by a rather typical morphology, are triggered by external factors and tend to occur primarily in the area of contact with the exogenous agent. In addition, allergic and irritant dermatitis may also co-exist. The importance of diagnosing contact dermatitis, especially when allergic in nature, is both due to the possibility of avoiding the trigger, and due to its role in aggravating other skin conditions. Nevertheless, the heterogeneity of clinical presentations in daily practice may pose an important challenge for the suspicion and correct diagnosis of contact dermatitis. Furthermore, other conditions, with different pathogenesis and treatment, may clinically simulate contact dermatitis. The Task Force aims to conduct a review of the unifying clinical features of contact dermatitis and characterize its main clinical phenotypes, and its simulators, in order to contribute to an early suspicion or recognition of contact dermatitis and enable a correct differential diagnosis.

Non-Skin-Related Symptoms are Common in Chronic Spontaneous Urticaria and Linked to Active and Uncontrolled Disease: Results from CURE.

BACKGROUND: Chronic spontaneous urticaria (CSU) can present with non-skin-related symptoms (NSRS), including recurrent unexplained fever, joint/bone/muscle pain (JBMP), and malaise, which also occur in other conditions that manifest with wheals (e.g., urticarial vasculitis or autoinflammatory disorders) or without wheals (e.g., infection). OBJECTIVE: We sought to determine the rate of patients with CSU affected by fever, JBMP and malaise, their trigger factors, links with clinical and laboratory characteristics, and their impact on everyday life and treatment responses. METHODS: We analyzed baseline data from the Chronic Urticaria Registry (CURE) of 2,521 patients with CSU who were ≥16 years old. RESULTS: One-third of CSU patients (31.2%, 786/2,521) had ≥1 NSRS, including recurrent fever (5.3%), JBMP (19.1%), and/or malaise (18.6%). In a multivariable analysis, having ≥1 of these NSRS correlated with food and infection as trigger factors of urticaria (adjusted odds ratio [aOR]=1.7 and 1.5), wheals of ≥24 hours duration (aOR=2.5), sleep disturbance (aOR=2.4), anxiety (aOR=2.8), comorbid atopic dermatitis (aOR=2.1), gastrointestinal disease (aOR=1.8), elevated leukocytes (aOR=1.7) and erythrocyte sedimentation rate (aOR=1.5). In a bivariate analysis, these NSRS were additionally associated with higher disease activity (UAS7, median: 21 vs. 14, p=0.009), longer disease duration (years, median: 2 vs. 1, p=0.001), presence of angioedema (74.6% vs. 58.7%, p<0.001), worse quality of life (CU-Q2oL, median: 42 vs. 29, p<0.001) and more frequent poor control of CSU (78% vs. 69%, p<0.001). CONCLUSION: The presence of NSRS in a subpopulation of CSU patients points to a need for better control of the disease, exclusion of comorbid conditions and/or exclusion of urticarial vasculitis and urticarial autoinflammatory diseases.

Dupilumab in patients with chronic spontaneous urticaria (LIBERTY-CSU CUPID): Two randomized, double-blind, placebo-controlled, phase 3 trials.

BACKGROUND: Chronic spontaneous urticaria (CSU) is a chronic inflammatory disease characterized by recurrent pruritic wheals (hives) and/or angioedema. Patients with CSU could remain symptomatic despite standard-of-care H1 antihistamines (H1-AH) or anti-IgE (omalizumab) treatment. Dupilumab blocks IL-4/IL-13 signaling and is approved for multiple type 2/atopic indications. OBJECTIVE: We conducted two phase 3, randomized, placebo-controlled, double-blind trials comparing dupilumab with placebo in patients with symptomatic CSU despite H1-AH. METHODS: In LIBERTY-CSU CUPID Study A, patients were omalizumab-naive (n = 138, aged ≥6 years). In Study B, patients were omalizumab-intolerant/incomplete responders (n = 108, aged ≥12 years). The primary end point was either change from baseline over 7 days in the Urticaria Activity Score (UAS7) or Itch Severity Score (ISS7) at week 24, with the other as a key secondary end point, depending on regional regulatory requirements. Studies were pooled for safety assessment. RESULTS: In Study A, UAS7 and ISS7 improved with dupilumab versus placebo (difference -8.5 [95% CI, -13.2 to -3.9; P = .0003] and -4.2 [95% CI, -6.6 to -1.8; P = .0005]). In Study B, tested at α = 0.043 after interim analysis, UAS7 improved (difference -5.8 [95% CI, -11.4 to -0.3; P = .0390]), with a numerical trend in ISS7 (difference -2.9 [95% CI, -5.7 to -0.07; nominal P = .0449, not significant]). Pooled safety data were consistent between dupilumab and placebo and with the known dupilumab safety profile. CONCLUSIONS: Dupilumab reduced urticaria activity by reducing itch and hives severity in omalizumab-naive patients with CSU uncontrolled with H1-AH. Although the primary end point for Study B was not met, dupilumab effects were small in patients who were omalizumab-intolerant/incomplete responders.

Solar Urticaria: An Ambispective Study in a Long-term Follow-up Cohort with Emphasis on Therapeutic Predictors and Outcomes.

Solar urticaria is a rare photodermatosis with several unknown pathogenic, clinical and therapeutic aspects. This study analysed the clinical and therapeutic features of a long-term follow-up solar urticaria cohort, with a focus on omalizumab management and outcomes, and characterized omalizumab response with the use of the high-affinity immunoglobulin E (IgE) receptor (FcεRI) and the Urticaria Control Test. An observational, unicentric, ambispective study was conducted from 2007 to 2023. Solar urticaria was diagnosed in 41 patients with a median follow-up of 60 months. Thirteen patients were prescribed omalizumab, with a median treatment time of 48 months. A significant decrease in FcεRI baseline levels and subsequent median increase in Urticaria Control Test was evidenced after omalizumab prescription in all patients. Drug survival at 48 months was at 88.9%. Omalizumab stepping-down protocol led to sustained omalizumab discontinuation in only 1 patient. Median basal Urticaria Control Test was lower (p < 0.01) in patients who were prescribed omalizumab and in patients without remission. This study contributes to our knowledge of omalizumab outcomes in real-life clinical practice and highlights the pathogenic importance of IgE-mediated pathways in solar urticaria, where FcεRI emerges as a possible biomarker of omalizumab response.

CRUSE® -An innovative mobile application for patient monitoring and management in chronic spontaneous urticaria.

BACKGROUND: Chronic spontaneous urticaria (CSU) is unpredictable and can severely impair patients' quality of life. Patients with CSU need a convenient, user-friendly platform to complete patient-reported outcome measures (PROMs) on their mobile devices. CRUSE® , the Chronic Urticaria Self Evaluation app, aims to address this unmet need. METHODS: CRUSE® was developed by an international steering committee of urticaria specialists. Priorities for the app based on recent findings in CSU were defined to allow patients to track and record their symptoms and medication use over time and send photographs. The CRUSE® app collects patient data such as age, sex, disease onset, triggers, medication, and CSU characteristics that can be sent securely to physicians, providing real-time insights. Additionally, CRUSE® contains PROMs to assess disease activity and control, which are individualised to patient profiles and clinical manifestations. RESULTS: CRUSE® was launched in Germany in March 2022 and is now available for free in 17 countries. It is adapted to the local language and displays a country-specific list of available urticaria medications. English and Ukrainian versions are available worldwide. From July 2022 to June 2023, 25,710 observations were documented by 2540 users; 72.7% were females, with a mean age of 39.6 years. At baseline, 93.7% and 51.3% of users had wheals and angioedema, respectively. Second-generation antihistamines were used in 74.0% of days. CONCLUSIONS: The initial data from CRUSE® show the wide use and utility of effectively tracking patients' disease activity and control, paving the way for personalised CSU management.

CRUSE - What the first 100 days have taught us.

Introduction: Health apps play an increasing role in everyday healthcare, especially for chronic diseases. The Chronic Urticaria Self Evaluation (CRUSE) is a new mobile health app for chronic spontaneous urticaria (CSU) patients, which replaces disease tracking via paper and pen, thus making disease monitoring more convenient, increasing tracking compliance, and improving data quality and access. Methods: CRUSE enables patients to complete patient-reported outcome measures on their smartphone and send the results, along with current medication and pictures, to their treating physician via email. CRUSE captures the urticaria (UAS) and angioedema activity (AAS) scores and the urticaria and angioedema control tests (UCT and AECT). In this work, a descriptive analysis of CRUSE users and reported days was performed. The global network of Urticaria Centers of Reference and Excellence (UCARE) provides the app and its data. Results: CRUSE is now available in Germany, Switzerland, Austria, the UK, Italy, Spain, France, and Turkey. Of 620 newly registered users (from July 1st until November 18th of 2022), 72 % were female, and the mean age was 36.6 years (17 - 78 years). The average daily UAS and AAS value (mean ± standard deviation) were 2.1 ± 1.9 and 7.2 ± 3.3, respectively. Most CRUSE patients had poorly controlled disease, with mean UCT values of 7.0 ± 4.4 and mean AECT values of 8.1 ± 4.5. Conclusion: The first days of patients with CSU using CRUSE confirm the high need for an app that helps to monitor disease activity, impact, and control. The first results indicate low levels of disease control in most CRUSE users, with low UCT and AECT values. Future analyses will assess follow-up documentation data and evaluate the effects of treatment changes on CSU activity, impact, and control.

A concept for integrated care pathways for atopic dermatitis-A GA2 LEN ADCARE initiative.

INTRODUCTION: The integrated care pathways for atopic dermatitis (AD-ICPs) aim to bridge the gap between existing AD treatment evidence-based guidelines and expert opinion based on daily practice by offering a structured multidisciplinary plan for patient management of AD. ICPs have the potential to enhance guideline recommendations by combining interventions and aspects from different guidelines, integrating quality assurance, and describing co-ordination of care. Most importantly, patients can enter the ICPs at any level depending on AD severity, resources available in their country, and economic factors such as differences in insurance reimbursement systems. METHODS: The GA2 LEN ADCARE network and partners as well as all stakeholders, abbreviated as the AD-ICPs working group, were involved in the discussion and preparation of the AD ICPs during a series of subgroup workshops and meetings in years 2020 and 2021, after which the document was circulated within all GAL2 EN ADCARE centres. RESULTS: The AD-ICPs outline the diagnostic procedures, possible co-morbidities, different available treatment options including differential approaches for the pediatric population, and the role of the pharmacists and other stakeholders, as well as remaining unmet needs in the management of AD. CONCLUSION: The AD-ICPs provide a multidisciplinary plan for improved diagnosis, treatment, and patient feedback in AD management, as well as addressing critical unmet needs, including improved access to care, training specialists, implementation of educational programs, assessment on the impact of climate change, and fostering a personalised treatment approach. By focusing on these key areas, the initiative aims to pave the way for a brighter future in the management of AD.

Autoimmune Diseases and Low Baseline IgE in Chronic Spontaneous Urticaria: A Clinical and Therapeutic Prospective Analysis in Real-Life Clinical Practice.

BACKGROUND: Autoimmunity contributes to the pathogenesis of chronic spontaneous urticaria (CSU). The subtyping of CSU has revealed an autoimmune form of CSU. Despite autoimmune diseases having been associated with CSU, there are few prospective studies that have evaluated the characteristics and biomarkers of patients with CSU and autoimmune disease in a real-life practice setting. OBJECTIVE: To evaluate the presence of specific biomarkers for the presence of autoimmune disease in CSU and to analyze the clinical and therapeutic features of patients with CSU and autoimmune disease. METHODS: The clinical, laboratory, and therapeutic features of patients with CSU at a tertiary-level center were prospectively collected. Data obtained were compared in function of the presence/absence of autoimmune disease and typified according to IgE levels. RESULTS: Patients with CSU who had associated autoimmune disease corresponded to middle-aged women with a common pattern of blood test findings: both low baseline IgE and high-affinity receptor of IgE expression, basopenia, eosinopenia, higher baseline erythrocyte sedimentation rate and D-dimer, increased presence of antinuclear antibodies, IgG against thyroid peroxidase, and positive autologous serum skin test result. Total baseline IgE less than or equal to 43.8 IU/mL was both the optimal cutoff to predict autoimmune disease in the CSU cohort and a significant risk factor for the presence of autoimmune disease in the regression analysis. CONCLUSIONS: In real-life clinical practice, characteristics of patients with CSU and autoimmune disease share common features with type IIb autoimmune CSU. Total baseline IgE less than or equal to 43.8 IU/mL has been detected as a possible biomarker of autoimmune disease in patients with CSU.

Patients With Chronic Spontaneous Urticaria Who Have Wheals, Angioedema, or Both, Differ Demographically, Clinically, and in Response to Treatment-Results From CURE.

BACKGROUND: Patients with chronic spontaneous urticaria (CSU) have spontaneous wheals (W), angioedema (AE), or both, for longer than 6 weeks. Clinical differences between patients with standalone W, standalone AE, and W and AE (W+AE) remain incompletely understood. OBJECTIVE: To compare W, AE, and W+AE CSU patients regarding demographics, disease characteristics, comorbidities, disease burden, and treatment response. METHODS: Baseline data from 3,698 CSU patients in the ongoing, prospective, international, multicenter, observational Chronic Urticaria REgistry (CURE) were analyzed (data cut: September 2022). RESULTS: Across all CSU patients, 59%, 36%, and 5% had W+AE, W, and AE, respectively. The W+AE patients, compared with W and AE patients, showed the lowest male-to-female ratio (0.33), higher rates of concomitant psychiatric disease (17% vs 11% vs 6%, respectively), autoimmune disease (13% vs 7% vs 9%, respectively), and nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity (9% vs 5% vs 2%, respectively) and the highest disease impact. The W patients, compared with W+AE and AE patients, showed the lowest rates of concomitant hypertension (15% vs 21% vs 40%, respectively) and obesity (11% vs 16% vs 17%, respectively), the highest rate of concomitant inducible urticaria (24% vs 22% vs 6%, respectively), and shorter W duration. The AE patients, compared with W+AE and W patients, were older at disease onset, showed longer AE duration, and the best response to increased doses of H1-antihistamines (58% vs 24% vs 31%, respectively) and omalizumab (92% vs 67% vs 60%, respectively). CONCLUSIONS: Our findings provide a better understanding of CSU phenotypes and may guide patient care and research efforts that aim to link them to pathogenic drivers.

Current perspectives and future directions in the management of chronic spontaneous urticaria and their link to disease pathogenesis and biomarkers.

Chronic spontaneous urticaria (CSU) is a relatively common, persistent, debilitating inflammatory skin disorder, having a global point prevalence ~0.5-1%. This disorder considerably worsens the patient's quality of life, and also poses a burden for the society. It is primarily an IgE mediated mast cell disorder, histamine being the principal mediator. So, the current treatment recommendations are aimed at antagonizing the effect of histamine, block mast cell activation by reducing IgE, or immunomodulate the inflammatory response. However, almost one in five CSU patients remain uncontrolled with the current safe treatments comprising antihistamines and add-on anti-IgE omalizumab. Thus, newer and more targeted therapeutic strategies are needed to overcome this unmet need, based on the various interlinked ligands and receptors involved in disease pathogenesis. Considerable progress has been made in understanding the pathogenesis of CSU, beyond the IgE-FceR1-mast cell axis, which has enabled the development of newer and more targeted promising therapeutic strategies. Several biomarkers are also being evaluated which would better define the disease characteristics and foretell treatment outcome even before its initiation. This would enable specific and targeted precision therapy based on disease characteristics, with better effectiveness-safety ratio. The present article discusses the current understanding about CSU, and recent up-to-date perspectives pertaining to disease pathogenesis, emerging treatments, and their link to biomarkers. These authors hope that the article would be helpful for all specialists and CSU treating physicians, in providing optimum care to their patients, based on latest evidence and concepts.

Recent updates in urticaria.

Urticaria is a skin-condition characterized by sudden-onset pruritic wheals with/without angioedema. Urticaria can be acute or chronic. Chronic urticaria may be spontaneous or inducible, based on absence/presence of specific triggers. Chronic spontaneous urticaria is most frequent (∼80%). Urticaria is primarily a mast-cell mediated histaminergic-disorder. Recently, other inflammatory cells and pro-inflammatory cytokines have been implicated. Deeper understanding has unmasked two endotypes - IgE-mediated type I autoimmunity/autoallergy and IgG-mediated type IIb autoimmunity. Current treatment recommendation involving second-generation H1-antihistamines, omalizumab and cyclosporine is effective in 60-80% patients. So, newer treatment options are being explored based on emerging targets. Despite being non-lethal, urticaria considerably impairs patient's quality-of-life and may be associated with extra-cutaneous comorbidities. Several "patient reported outcome measures" have been proposed to evaluate disease-activity, impact and control, for effective treatment modulation till complete disease control. This review discusses the current understanding about urticaria and its future directions, to facilitate optimum evidenced-based care.

Remibrutinib inhibits hives effector cells stimulated by serum from chronic urticaria patients independently of FcεR1 expression level and omalizumab clinical response.

BACKGROUND: Despite advances in the treatment of chronic urticaria, in a significant percentage of the patients symptoms are not fully controlled with conventional approaches. New strategies under development include blocking intracellular mediators of mast cell and basophil activation. OBJECTIVE: We aim to investigate the effects of the Bruton's tyrosine kinase (BTK) inhibitor remibrutinib on human blood basophils and CD34+ -derived mast cells activation induced by serum obtained from chronic urticaria patients. METHODS: Twenty-two patients with chronic spontaneous urticaria (mean age 52 years, 27% women) and 22 patients with chronic inducible urticaria (46 years, 27% women) were included in the study together with a sex-matched control group. Patients were classified as responders or non-responders to anti-IgE therapy on the basis of their clinical data, FcεR1a expression on blood basophils and total IgE levels. Changes on CD63 expression-as an activation marker-, were used to evaluate in vitro the response of basophils and mast cells to serum exposure and the inhibitory effects of remibrutinib. RESULTS: Remibrutinib inhibits degranulation induced by IgE cross-linking in mast cells and basophils and also the activation triggered by factors present in the sera of spontaneous and inducible chronic urticaria patients. Patient's serum induces a greater degranulation of effector cells than controls. Activation of mast cells and basophils by patient sera and remibrutinib effects were not related to omalizumab responsiveness. CONCLUSION: Remibrutinib inhibits activation of human basophils and mast cells induced in vitro by exposure to the serum of chronic urticaria patients independently of their response to omalizumab.

Occupational contact allergy: The European perspective-Analysis of patch test data from ESSCA between 2011 and 2020.

BACKGROUND: Occupational skin diseases have led the occupational disease statistics in Europe for many years. Especially occupational allergic contact dermatitis is associated with a poor prognosis and low healing rates leading to an enormous burden for the affected individual and for society. OBJECTIVES: To present the sensitization frequencies to the most relevant allergens of the European baseline series in patients with occupational contact dermatitis (OCD) and to compare sensitization profiles of different occupations. METHODS: The data of 16 022 patients considered having OCD after patch testing within the European Surveillance System on Contact Allergies (ESSCA) network between January 2011 and December 2020 were evaluated. Patients (n = 46 652) in whom an occupational causation was refuted served as comparison group. RESULTS: The highest percentages of OCD were found among patients working in agriculture, fishery and related workers, metal industry, chemical industry, followed by building and construction industry, health care, food and service industry. Sensitizations to rubber chemicals (thiurams, carbamates, benzothiazoles) and epoxy resins were associated with at least a doubled risk of OCD. After a decline from 2014 onwards, the risks to acquire an occupation-related sensitization to methyl(chloro)isothiazolinone (MCI/MI) and especially to methylisothiazolinone (MI) seem to increase again. Sensitization rates to formaldehyde were stable, and to methyldibromo glutaronitrile (MDBGN) slightly decreasing over time. CONCLUSIONS: Among allergens in the European Baseline Series, occupational relevance is most frequently attributed to rubber accelerators, epoxy resins and preservatives.

Which outcomes should be measured in hand eczema trials? Results from patient interviews and an expert survey.

BACKGROUND: Hand eczema (HE) is a common skin disease characterized by itch, pain and visible skin changes such as fissures, erythema and vesicles. It is not yet clear which outcome domains are most important for patients. The Hand Eczema Core Outcome Set (HECOS) initiative is developing a consented set of core domains and suitable measurement instruments for the future application in all HE trials. This includes an online Delphi survey about core domains, which requires a 'Long List' of all domains that might be important to measure. OBJECTIVES: To compile a 'Long List' of candidate outcome domains for therapeutic HE trials with suggestions from patients and experts. METHODS: First, 60 patients with chronic HE were interviewed at seven study sites in Croatia, Denmark, Germany, the Netherlands and Spain. Patients were asked about domains that were important from their perspectives. Second, 185 HE experts were invited by email to complete an online survey. With an open question, they were asked to suggest up to six domains. RESULTS: Suggestions were provided by 58 patients and 82 experts. Most patients and experts suggested to measure the domains 'signs', 'symptoms' and 'HE-related quality of life'. Specifically, >25% of patients said that less itch, pain or fissures indicated a successful treatment. Among experts, >25% suggested 'itch' and 'ability to work' as core sub-domains. Further outcomes from the domains 'HE control over time', 'patient-reported treatment experience' and 'skin barrier function' were mentioned. CONCLUSION: 'Itch' was rated high among patients with HE and professional HE experts. While patients emphasized fissures as important, experts underlined the ability to work. This investigation allowed us to define a 'Long List' of 7 candidate outcome domains with 58 sub-domains. From this list, a panel of stakeholders will select core domains during an online Delphi survey.

Chronic spontaneous urticaria: Focus on pathophysiology to unlock treatment advances.

Chronic spontaneous urticaria (CSU) is a debilitating skin disease characterized by intensely itchy wheals, angioedema, or both. Symptoms recur spontaneously, on a near-daily basis, over >6 weeks; many patients experience flare-ups over several years and, consequently, reduced quality of life. Differences between the inflammatory profiles of the skin of CSU patients (wheals and nonlesional sites) and healthy controls indicate that key drivers such as mast cells, eosinophils, and basophils interact, release vasoactive mediators, and prime the skin, leaving patients predisposed to symptoms. Many cytokines and chemokines involved in these inflammatory networks and their corresponding intracellular signaling cascades have been identified. These insights informed the development of therapies such as omalizumab, dupilumab, and Bruton's tyrosine kinase (BTK) inhibitors, marking a renewed focus on pathogenesis in CSU clinical research. Despite progress, current therapies provide symptomatic control but do not appear to redress the inflammatory balance in the skin permanently. A deeper understanding of CSU pathogenesis will permit a more targeted approach to developing novel treatments with curative intent. Here, we review what is known about the pathogenesis of CSU and consider how this can be used to identify rational targets to improve patient care further.

The European baseline series and recommended additions: 2023.

The European baseline series was last updated in 2019. This article discusses the reasoning behind a further iteration of the series for 2023.