Chronic urticaria: unmet needs, emerging drugs, and new perspectives on personalised treatment.

Chronic urticaria is a common and debilitating mast cell-driven skin disease presenting with itchy wheals, angio-oedema, or both. Chronic urticaria is classified as spontaneous (without definite triggers) and inducible (with definite and subtype-specific triggers; eg, cold or pressure). Current management guidelines recommend step-up administration of second-generation H1-antihistamines to four-fold the approved dose, followed by omalizumab and ciclosporin. However, in many patients, chronic urticaria does not respond to this linear approach due to heterogeneous underlying mechanisms. A personalised endotype-based approach is emerging based on the identification of autoantibodies and other drivers of urticaria pathogenesis. Over the past decade, clinical trials have presented promising options for targeted treatment of chronic urticaria with the potential for disease modification, including Bruton's tyrosine kinase inhibitors, anti-cytokine therapies, and mast cell depletion. This Therapeutics article focuses on the evidence for these novel drugs and their role in addressing an unmet need for personalised management of patients with chronic urticaria.

Efficacy and safety of ligelizumab in adults and adolescents with chronic spontaneous urticaria: results of two phase 3 randomised controlled trials.

BACKGROUND: Many patients with chronic spontaneous urticaria (CSU) do not achieve complete control of their symptoms with current available treatments. In a dose-finding phase 2b study, ligelizumab improved urticaria symptoms in patients with H1-antihistamine (H1-AH) refractory CSU. Here, we report the efficacy and safety outcomes from two ligelizumab phase 3 studies. METHODS: PEARL-1 and PEARL-2 were identically designed randomised, double-blind, active-controlled and placebo-controlled parallel-group studies. Patients aged 12 years or older with moderate-to-severe H1-AH refractory CSU were recruited from 347 sites in 46 countries and randomly allocated in a 3:3:3:1 ratio via Interactive Response Technology to 72 mg ligelizumab, 120 mg ligelizumab, 300 mg omalizumab, or placebo, dosed every 4 weeks, for 52 weeks. Patients allocated to placebo received 120 mg ligelizumab from week 24. The primary endpoint was change-from-baseline (CFB) in weekly Urticaria Activity Score (UAS7) at week 12, and was analysed in all eligible adult patients according to the treatment assigned at random allocation. Safety was assessed throughout the study in all patients who received at least one dose of the study drug. The studies were registered with ClinicalTrials.gov, NCT03580369 (PEARL-1) and NCT03580356 (PEARL-2). Both trials are now complete. FINDINGS: Between Oct 17, 2018, and Oct 26, 2021, 2057 adult patients were randomly allocated across both studies (72 mg ligelizumab n=614; 120 mg ligelizumab n=616; 300 mg omalizumab n=618, and placebo n=209). A total of 1480 (72%) of 2057 were female, and 577 (28%) of 2057 were male. Mean UAS7 at baseline across study groups ranged from 29·37 to 31·10. At week 12, estimated treatment differences in mean CFB-UAS7 were as follows: for 72 mg ligelizumab versus placebo, -8·0 (95% CI -10·6 to -5·4; PEARL-1), -10·0 (-12·6 to -7·4; PEARL-2); 72 mg ligelizumab versus omalizumab 0·7 (-1·2 to 2·5; PEARL-1), 0·4 (-1·4 to 2·2; PEARL-2); 120 mg ligelizumab versus placebo -8·0 (-10·5 to -5·4; PEARL-1), -11·1 (-13·7 to -8·5; PEARL-2); 120 mg ligelizumab versus omalizumab 0·7 (-1·1 to 2·5; PEARL-1), -0·7 (-2·5 to 1·1; PEARL-2). Both doses of ligelizumab were superior to placebo (p<0·0001), but not to omalizumab, in both studies. No new safety signals were identified for ligelizumab or omalizumab. INTERPRETATION: In the phase 3 PEARL studies, ligelizumab demonstrated superior efficacy versus placebo but not versus omalizumab. The safety profile of ligelizumab was consistent with previous studies. FUNDING: Novartis Pharma.

Hospitalization and mortality in Asian autoimmune bullous dermatosis patients: A 17-year retrospective study.

Limited data exist on the factors associated with hospitalization and mortality in Asian inpatients with autoimmune bullous dermatoses (AIBDs). This study aimed to elucidate the risk factors affecting hospitalization and mortality rates in Asian patients with AIBDs. A retrospective analysis of patients with AIBDs treated at Siriraj Hospital during a 17-year period was performed using the International Classification of Diseases 10th revision codes. The characteristics of inpatients and outpatients were compared, and mortality rates and associated factors were identified. The study included 360 AIBD patients (180 inpatients, 180 outpatients). Inpatients were significantly younger than outpatients. The identified risk factors for hospitalization were malignancy (odds ratio [OR] 2.83, 95% confidence interval [CI] 1.13-8.04; p = 0.034), moderate to severe disease (OR 2.52, 95% CI 1.49-4.34; p < 0.001), systemic corticosteroid use ≥15 mg/day (OR 2.27, 95% CI 1.21-4.41; p = 0.013) and oral cyclophosphamide treatment (OR 9.88, 95% CI 3.82-33.7; p < 0.001). Kaplan-Meier analysis revealed mortality rates of 26%, 36% and 39% for inpatients with pemphigus at 1, 3 and 5 years, respectively. For inpatients with pemphigoid, the corresponding rates were 28%, 38% and 47%. Infections, particularly pneumonia, were the predominant cause of death in both conditions. This study confirmed that both Asian ethnicity and healthcare disparities may be correlated with adverse outcomes in patients with AIBDs. Pemphigus mortality rates were substantially greater in Asian patients than in Caucasian patients. Continuous monitoring of factors contributing to hospitalization and mortality is imperative to improve treatment outcomes.

Validity, reliability and responsiveness of digital visual analogue scales for chronic spontaneous urticaria monitoring: A CRUSE® mobile health study.

BACKGROUND: CRUSE® is an app that allows patients with chronic spontaneous urticaria (CSU) to monitor their daily disease activity through the use of visual analogue scales (VASs). We aimed to determine the concurrent validity, reliability, responsiveness and minimal important difference (MID) of CRUSE® VASs. METHODS: We evaluated the properties of three daily VASs: VAS for how much patients were affected by their CSU ('VAS urticaria'), VAS for the impact of urticaria on work/school productivity ('VAS productivity') and the VAS of EQ-5D. Concurrent validity was assessed by measuring the association between each VAS and the Urticaria Activity Score (UAS). Intra-rater reliability was determined based on the data of users providing multiple daily questionnaires within the same day. Test-retest reliability and responsiveness (ability to change), respectively, were tested in clinically stable and clinically unstable users. MIDs were determined using distribution-based methods. RESULTS: We included 5938 patients (67,380 days). Concurrent validity was high, with VAS urticaria being more strongly associated with the UAS score than the remaining VASs. Intra-rater reliability was also high, with intraclass correlation coefficients (ICC) being above 0.950 for all VASs. Moderate-high test-retest reliability and responsiveness were observed, with reliability ICC being highest for VAS EQ-5D and responsiveness being highest for VAS urticaria. The MID for VAS urticaria was 17 (out of 100) units, compared to 15 units for VAS productivity and 11 units for VAS EQ-5D. CONCLUSION: Daily VASs for CSU available in the CRUSE® app display high concurrent validity and intra-rater reliability and moderate-high test-retest reliability and responsiveness.

Revisiting serum storage protocols: assessing the impact of temperature variations on indirect immunofluorescence testing for pemphigus and bullous pemphigoid.

BACKGROUND: Indirect immunofluorescence (IIF) plays a crucial role in the diagnosis of pemphigus and bullous pemphigoid (BP) by detecting the presence of circulating autoantibodies in the serum of patients. The standard serum transportation method requires delivery to laboratories at 2-8 °C within a day and storage at -20 to -80 °C. However, this protocol poses logistical challenges. OBJECTIVES: We conducted a study to assess how temperature variations affect the effectiveness of IIF tests. METHODS: This case-control study analysed 203 serum specimens: 102 from patients with pemphigus and 101 from patients with BP. Specimens were stored at -80 °C (control), 24 °C, and 40 °C for seven days before analysis to investigate variations in IIF titres compared to the control conditions. RESULTS: In pemphigus serum, 95% at 24 °C and 76% at 40 °C showed no titre difference compared to controls. Similarly, 89% of BP serum at 24 °C and 82% at 40 °C matched the control titres. While 57 specimens across both groups experienced reduced titres, the decrease was primarily marginal (one-step reduction in 54 cases, two-step in 3), with no transition from positive to negative results. CONCLUSIONS: Storing serum at 24-40 °C for up to seven days before testing slightly influences IIF outcomes for pemphigus and BP. These findings could prompt a significant revision in the existing strict transport guidelines, ensuring efficient use of resources without sacrificing the accuracy of diagnostic tests.

Long-term efficacy and safety of nonablative monopolar radiofrequency in the treatment of moderate to severe acne vulgaris.

BACKGROUND: Acne vulgaris (AV) is a prevalent skin condition known for its potential to cause scarring and psychological distress, often leading to diminished self-esteem. While topical and oral treatments are commonly prescribed, some patients experience treatment failure, adverse effects, or contraindications to conventional therapies. In response to these challenges, laser and energy-based device therapies have emerged as promising alternatives for individuals who fall into these categories, showing considerable potential in the treatment of AV. OBJECTIVE: This study aimed to evaluate the long-term efficacy and safety of a nonablative monopolar radiofrequency (NMRF) in treatment of moderate to severe AV. METHODS: Twenty-four patients with moderate to severe AV underwent a series of two NMRF treatment sessions, spaced 4 weeks apart. To evaluate treatment outcomes, live in-person lesion counts and measurements of pore size and volume, and sebum production were quantified using Antera® 3D imaging system, and Sebumeter®, respectively. Patients' self-assessment data regarding degree of improvement and facial oiliness were gathered. Dermatology life quality index (DLQI) questionnaire was utilized to assess the impact of AV on their quality of life. All objective and subjective evaluations were conducted at the baseline, 1 month after the first treatment, and during follow-up visits 1, 3, and 6 months after the last treatment sessions. Adverse effects were also recorded during each visit. RESULTS: Twenty out of the 24 subjects completed the study protocol. The mean inflammatory lesion counts significantly reduced by 42.86% and 45.71% from the baseline at 3 (p = 0.027) and 6 months (p = 0.032) after the second treatment. Sebum excretion likewise significantly decreased from baseline by 11.62% (p = 0.012), 13.37% (p < 0.001), and 21.51% (p = 0.004), 1 month after the first treatment, 1 and 6 months after the second treatment, respectively. The pore volume continued to decrease by 35% (p = 0.003) and 41.5% (p < 0.001) at 1 and 6 months following the final treatment, respectively. The DLQI significantly decreased from 10.00 (interquartile range [IQR]: 6.50-15.00) to 2.00 (IQR: 1.00-4.75), corresponding to 80% improvement of the index, 1 month after the last treatment and was sustained up to the last follow-up visit. Patients' self-assessments on degree of improvement and facial oiliness also significantly improved following NMRF treatments. The treatments were well-tolerated without significant adverse effects. CONCLUSION: NMRF appears to be an effective and safe treatment for inflammatory AV, with therapeutic outcomes persisting up to 6 months after two treatment sessions.

Baricitinib treatment rapidly improves the four signs of atopic dermatitis assessed by Eczema Area and Severity Index (EASI) clinical subscores.

BACKGROUND: Baricitinib treatment in adults with moderate-to-severe atopic dermatitis (AD) has demonstrated rapid improvements in itch as well as AD sign severity and affected body surface area as assessed by the Eczema Area and Severity Index (EASI) total score, whether administered as monotherapy or in combination with topical corticosteroids (TCS). As EASI clinical signs differ in time course and associated antecedents, the effects of baricitinib on each individual clinical sign are of interest. OBJECTIVES: In this post hoc analysis, we aimed to investigate the effects of baricitinib on individual EASI subscores, namely excoriation, oedema/papulation, erythema and lichenification, in both monotherapy and TCS combination therapy trials. METHODS: We analysed the percent change from baseline in individual EASI subscores from three phase-III, double-blind, 16-week trials of baricitinib in monotherapy (BREEZE-AD1/BREEZE-AD2) and TCS combination therapy (BREEZE-AD7) cohorts via mixed model repeated measures (MMRM). RESULTS: Baricitinib 4 mg showed rapid and sustained improvements in all four clinical signs in both cohorts. Significant effects emerged at week 1 for excoriation, oedema/papulation and erythema scores in monotherapy (p < 0.001) and TCS combination therapy (p < 0.001, p < 0.01, p < 0.001), plateaued at week 4, and remained significant versus placebo through week 16. The effect on lichenification scores also emerged early, at week 1 in monotherapy (p < 0.05) and week 2 in combination therapy (p < 0.001), with scores continuously improving without a clear plateau. Effect magnitude was highest in excoriation scores, exhibiting near-maximal reduction in week 1 of monotherapy and remaining highest across all timepoints in combination therapy. CONCLUSIONS: Rapid and sustained improvements were observed across clinical signs of inflammation and particularly on excoriation following baricitinib treatment. Our findings suggest that selective inhibition of janus kinases 1 and 2 leads to rapid and sustained control of skin inflammation, and that rapid reductions in itch translate into early disruption of the itch-scratch cycle.

Clinical and Psychological Implications of Genital Vitiligo in a Thai Population.

BACKGROUND: The understanding of genital vitiligo among Thai individuals is limited. OBJECTIVES: This study evaluated the clinical presentation, quality of life, and sexual health consequences of genital vitiligo. METHODS: This cross-sectional, questionnaire-based study involving vitiligo patients aged 18 years or older with past or present genital involvement was conducted at Siriraj Hospital. It also measured aspects of sexual health and quality of life. RESULTS: The mean age of the 41 participants was 48.2 years, and 24 (58.5%) were males. All participants presented with genital vitiligo. In males, the penile shaft (45.8%), scrotum (45.8%), and glans (33.3%) were predominantly affected. In females, the mons pubis (64.7%), labia majora (23.5%), and labia minora (23.5%) were frequently involved. Both sexes reported afflictions in the pubic area (41.5%), inguinal region (36.6%), buttocks (34.1%), and oral mucosa (34.1%). Itching was the principal symptom in 26.8% of the patients. The median Dermatology Life Quality Index scores were significantly different (females 6, males 3.5). Compared with their male counterparts, females exhibited lower self-esteem (41.2% vs 29.2%), greater apprehension about marriage (11.8% vs 8.3%), and embarrassment about sexual activities (23.5% vs 16.7%). Remarkably, 65.9% of patients had not discussed their genital vitiligo with their doctors, and 51.2% of physicians had not inquired about or examined for genital involvement. CONCLUSIONS: Genital vitiligo adversely impacts quality of life and self-esteem, particularly among female patients. The lack of discourse between patients and physicians highlights a need for increased awareness and proactive clinical investigations to enhance patient care and satisfaction.

A Review of the Challenges and Nuances in Treating Rosacea in Asian Skin Types Using Cleansers and Moisturizers as Adjuncts.

BACKGROUND: Rosacea is primarily an inflammatory disease of facial skin associated with impaired skin barrier function. While it is commonly thought of as a Caucasian person's disease, it is likely underdiagnosed in people of color, including Asians, leading to missed and delayed diagnoses and increased morbidity. The purpose of this review is to highlight literature on rosacea in Asian people and the role of non-prescription skincare in managing rosacea. METHODS: Four dermatologists (the panel) completed pre-meeting surveys and participated in a web meeting to discuss the role of skin care in treating rosacea in the Asia Pacific (APAC) region. The survey results were summarized, then presented during the virtual meeting. These survey results and relevant papers identified through a literature review were then discussed. This review shows the fruit of these discussions, as well as the advisors' expert opinions and experiences. RESULTS: The panel crafted 5 consensus statements regarding the role of skin care in the treatment of rosacea in the APAC region. The most common forms of rosacea seen by the advisors are mostly erythematous and papulopustular. Among the panel, doxycycline is the most popular treatment for papulopustular rosacea. The panel prioritize gentleness when choosing skincare products for patients with rosacea. CONCLUSIONS: In Asian patients with rosacea, adjunctive skincare is an important part of treatment, maintenance, and prescription treatment. Given the highly sensitive skin of certain Asian patients with rosacea, avoiding potentially irritating substances is crucial. J Drugs Dermatol. 2023;22(1):45-53. doi:10.36849/JDD.7021.

Unveiling the role of neutrophils in chronic spontaneous urticaria: Beyond mast cells.

Mast cells and eosinophils are considered pivotal contributors to the pathogenesis of chronic spontaneous urticaria (CSU). However, emerging evidence suggests that neutrophils also play a central role. Cutaneous mast cells and macrophages orchestrate the recruitment of neutrophils through the regulation and activation of diverse processes, including heightened local vascular permeability and chemokine release. Studies have demonstrated increased activation and elevated levels of neutrophil-related cytokines in CSU patients. Moreover, neutrophils have been proposed as antigen-presenting cells during the late-phase reaction of immunoglobulin E-mediated allergy and have been associated with the expression of calcitonin gene-related protein and vascular endothelial growth factor in CSU. Histopathological analysis of lesional skin in CSU patients revealed significantly higher eosinophil and neutrophil counts than unaffected skin. However, the extent of neutrophil infiltration in the skin does not appear to correlate with the number of neutrophils in peripheral blood. The utility of the neutrophil-lymphocyte ratio as a marker for disease activity or remission in CSU remains inconclusive. Neutrophil-targeted therapy may confer benefits for CSU patients who exhibit resistance to antihistamines. Omalizumab has demonstrated its ability to reduce neutrophil counts, the neutrophil-lymphocyte ratio, and the neutrophil-monocyte ratio in peripheral blood. While dapsone and colchicine are recommended as alternative treatment options for CSU, their evidential support from published studies remains limited. Inhibitors targeting interleukin-1 and neutrophil-related cytokines have been proposed as potential therapeutic interventions for patients exhibiting neutrophil predominance. Further research is warranted to gain deeper insights into the involvement of neutrophils in CSU and to explore potential therapeutic interventions.

Prevalence of concomitant angioedema in chronic spontaneous urticaria: A systematic review and meta-analysis.

BACKGROUND: Angioedema (AE) is a condition associated with considerable morbidity and mortality that can significantly affect quality of life. AE often occurs in patients with CSU although the true prevalence remains unknown. Therefore, we conducted this systematic review and meta-analysis to summarize the available data. OBJECTIVE: This study is conducted with the aim of retrieving data from all published studies and create the pooled prevalence of AE in CSU patients. METHODS: Narrative reviews of AE and CSU, a systematic review, and a meta-analysis were conducted. The Ovid Medline and Embase databases were systematically searched per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations. Studies were eligible if they were in English and measured the prevalence of AE in CSU in adults or children. Two reviewers independently extracted data and appraised each study's quality. Estimated prevalence and 95% confidence interval (CI) values were pooled using random-effects meta-analysis. RESULTS: Seventeen studies from 16 countries were included. The pooled prevalence of AE in patients with CSU was 36.5% (95%CI, 30.9-42.5%; I2 = 96%). The pooled estimated prevalence of AE in patients with CSU was 44.0% (95%CI, 34.1-54.5%) in Europe, 44.5% (95%CI, 28.5-61.8%), America, and 29.4% (95%CI, 24.7-34.7%) in Asia. CONCLUSIONS: Our systematic review and meta?analysis showed that AE affects over one-third of CSU patients, although the prevalence from individual study varied considerably, ranging from 5 to 67 percent. Subgroup-analysis found that AE is more prevalent in Europe and America than in Asia.

A double-blinded, randomized, split-side, vehicle-controlled study of the efficacy of cleanser containing Acanthus ebracteatus Vahl., Suregada multiflora, and Acacia concinna in patients with atopic dermatitis: A pilot study.

BACKGROUND: Barrier repair therapy is the key management approach for both eczematous and non-lesional skin of atopic dermatitis. The use of appropriate cleansers to enhance skin hydration is an adjunctive treatment that increases topical drug penetration. Anti-inflammatory properties of various medicinal plants in tropical Asia have been reported. OBJECTIVE: Investigate the efficacy of herbal cleanser containing a combination of herbal extracts from Acanthus ebracteatus Vahl., Suregada multiflora, and Acacia concinna on seemingly intact skin in patients with atopic dermatitis by measuring improvements in the skin barrier function. METHODS: This 2-week pilot study was a split-side, randomized, double-blinded, vehicle-controlled trial. All patients (n = 30) were asked to use both a cleanser with an active formulation containing the herbal extracts and a vehicle- controlled cleanser on each side of mid-volar forearm. Biophysical assessments including transepidermal water loss (TEWL), skin hydration, skin pH, and skin roughness were performed at baseline and upon study completion. RESULTS: Compared to baseline, the median percentage change in TEWL at the end of the study was significantly greater for the active side 10.4 (-19, 20.7) g/m2h than the control side -13.2 (-28.7, 9.1) g/m2h; p = 0.01. The median percentage change of skin hydration, skin pH, and skin roughness of the active side compared to the control side had no a statistical significance. CONCLUSIONS: This cleanser is beneficial when used as adjunctive therapy. Further studies should evaluate its anti- sinflammatory properties in the remedy or active phase of atopic dermatitis or other inflammatory skin diseases.

The validity and reliability of a Thai version of the Angioedema Control Test: Which recall period is preferable?

BACKGROUND: The Angioedema Control Test (AECT) is a questionnaire that monitors disease control in patients with angioedema, with a recall period of 4 weeks (AECT-4wk) or 3 months (AECT-3mo). OBJECTIVE: This study investigated the psychometric properties of a Thai version of the AECT. METHODS: Of 54 patients, 46, 5, 2, and 1 had recurrent angioedema with chronic spontaneous urticaria, hereditary angioedema, idiopathic histaminergic angioedema, and acquired angioedema due to C1 esterase inhibitor deficiency, respectively. The AECT, Angioedema Activity Score (AAS), Dermatology Life Quality Index (DLQI), Angioedema Quality of Life Questionnaire (AE-QoL), and anchors for disease control (numeric rating scale [NRS] and patient global assessment-Likert scale [PatGA-LS]) were used. The patients rated the efficacy of their treatment. RESULTS: Fifty-four and 47 patients completed the AECT-4wk and AECT-3mo, respectively. Both AECT versions showed significant correlations with disease activity (AAS, r = 0.6-0.8), disease control (NRS and PatGA-LS, r = 0.7-0.9), and quality of life impairment (DLQI and AE-QoL, r = 0.6-0.8). Higher correlations were found for the AECT-4wk than for the AECT-3mo. Excellent internal consistency (alpha = 0.98 and 0.97, respectively) and intraclass correlation (0.96 and 0.94, respectively) were found. A cutoff ≥ 10 was confirmed to identify patients with well-controlled disease for both AECT versions (AUCs = 0.89 and 0.97). CONCLUSIONS: The Thai version of the AECT is a valid and reliable tool for clinical practice. Due to the shorter recall period, the AECT-4wk may be more accurate than, and preferable to, the AECT-3mo. A cutoff ≥ 10 should be used to identify patients with well-controlled disease.

Systematic comparisons of various markers for mast cell activation in RBL-2H3 cells.

Mast cell activation plays a key role in various allergic diseases and anaphylaxis. Several methods/techniques can be used for detection of mast cell activation. However, there was no previous systematic evaluation to compare the efficacy of each method/technique. The present study thus systematically compared various markers for mast cell activation induced by IgE cross-linking. The widely used RBL-2H3 mast cells were sensitized with anti-DNP (dinitrophenyl) IgE overnight and activated with DNP-BSA (bovine serum albumin) for up to 4 h. The untreated cells and those with anti-DNP IgE sensitization but without DNP-BSA activation served as the controls. Intracellular calcium level gradually increased to ~2-fold at 1 h, reached its peak (~5-fold) at 2 h, and returned to the basal level at 3-h post-activation. The increases in cellular tryptase level (by Western blotting) (~0.3- to 0.4-fold) and average cell size (~2.5-fold) and decrease of nucleus/cytoplasm ratio (~0.4- to 0.5-fold) were marginal at all time-points. By contrast, ß-hexosaminidase release and CD63 expression (by both flow cytometry and immunofluorescence detection/localization), secreted tryptase level (by Western blotting), and tryptase expression (by immunofluorescence detection/localization) stably and obviously increased (~10-fold as compared with the untreated control and sensitized-only cells or detectable only after activation). Based on these data, the stably obvious increases (by ≥ 10-fold) in ß-hexosaminidase release, CD63 expression (by both flow cytometry and immunofluorescence staining), secreted tryptase level (by Western blotting), and tryptase expression (by immunofluorescence staining) are recommended as the markers of choice for the in vitro study of mast cell activation using RBL-2H3 cells.

Differential cytokine profiles produced by anti-epileptic drug re-exposure of peripheral blood mononuclear cells derived from severe anti-epileptic drug patients and non-allergic controls.

Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug reactions with eosinophilia and systemic symptoms (DRESS) are the most common severe cutaneous adverse drug reactions (SCARs). Anti-epileptic drugs are one of the most common drugs causing SCARs. Cytokine profiles of SCARs during culprit drug exposure have never been characterized. This study aimed to identify cytokine patterns between SCARs and non-SCARs in epilepsy patients and the patterns of DRESS and SJS/TEN. Epilepsy patients that showed allergic responses to anti-epileptic drugs that manifested as SJS/TEN or DRESS were recruited. Epilepsy patients with no drug allergy symptoms and healthy people were also recruited as control groups. Peripheral blood mononuclear cells (PBMCs) were isolated and co-cultured with assigned anti-epileptic drugs according to the lymphocyte transformation test (LTT). LTT and measurement of cytokine levels in supernatants were performed on day six of cell cultivation. This study identified different cytokine expression patterns between SCAR and non-SCAR in epilepsy patients. Significant levels of IL-10, IL-12, IL-17, and GM-CSF were detected in non-SCAR epilepsy. However, the levels of IL-2, IL-5, IL-13, and IFN-gamma were significantly higher in supernatants of PBMCs of DRESS cultivated with AEDs relative to those of SJS/TEN. These cytokine levels were positively correlated with the cell proliferation index. Production of IL-5 and IL-13 was a unique characteristic of DRESS PBMCs. This study was the first to demonstrate distinct differences in cytokine levels between SCAR and non-SCAR PBMCs in epilepsy, which could help explain the immune-pathomechanism of drug hypersensitivity in SCARs. Different patterns of cytokine production and cell proliferation between DRESS and SJS/TEN in AED hypersensitivity were also demonstrated. Production of IL-5 and IL-13 might be a promising marker to define drug hypersensitivity in DRESS.

The international EAACI/GA²LEN/EuroGuiDerm/APAAACI guideline for the definition, classification, diagnosis, and management of urticaria.

This update and revision of the international guideline for urticaria was developed following the methods recommended by Cochrane and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group. It is a joint initiative of the Dermatology Section of the European Academy of Allergology and Clinical Immunology (EAACI), the Global Allergy and Asthma European Network (GA²LEN) and its Urticaria and Angioedema Centers of Reference and Excellence (UCAREs and ACAREs), the European Dermatology Forum (EDF; EuroGuiDerm), and the Asia Pacific Association of Allergy, Asthma and Clinical Immunology with the participation of 64 delegates of 50 national and international societies and from 31 countries. The consensus conference was held on 3 December 2020. This guideline was acknowledged and accepted by the European Union of Medical Specialists (UEMS). Urticaria is a frequent, mast cell-driven disease that presents with wheals, angioedema, or both. The lifetime prevalence for acute urticaria is approximately 20%. Chronic spontaneous or inducible urticaria is disabling, impairs quality of life, and affects performance at work and school. This updated version of the international guideline for urticaria covers the definition and classification of urticaria and outlines expert-guided and evidence-based diagnostic and therapeutic approaches for the different subtypes of urticaria.

Risk factors for systemic reactions in typical cold urticaria: Results from the COLD-CE study.

BACKGROUND: Cold urticaria (ColdU), that is, the occurrence of wheals or angioedema in response to cold exposure, is classified into typical and atypical forms. The diagnosis of typical ColdU relies on whealing in response to local cold stimulation testing (CST). It can also manifest with cold-induced anaphylaxis (ColdA). We aimed to determine risk factors for ColdA in typical ColdU. METHODS: An international, cross-sectional study COLD-CE was carried out at 32 urticaria centers of reference and excellence (UCAREs). Detailed history was taken and CST with an ice cube and/or TempTest® performed. ColdA was defined as an acute cold-induced involvement of the skin and/or visible mucosal tissue and at least one of: cardiovascular manifestations, difficulty breathing, or gastrointestinal symptoms. RESULTS: Of 551 ColdU patients, 75% (n = 412) had a positive CST and ColdA occurred in 37% (n = 151) of the latter. Cold-induced generalized wheals, angioedema, acral swelling, oropharyngeal/laryngeal symptoms, and itch of earlobes were identified as signs/symptoms of severe disease. ColdA was most commonly provoked by complete cold water immersion and ColdA caused by cold air was more common in countries with a warmer climate. Ten percent (n = 40) of typical ColdU patients had a concomitant chronic spontaneous urticaria (CSU). They had a lower frequency of ColdA than those without CSU (4% vs. 39%, p = .003). We identified the following risk factors for cardiovascular manifestations: previous systemic reaction to a Hymenoptera sting, angioedema, oropharyngeal/laryngeal symptoms, and itchy earlobes. CONCLUSION: ColdA is common in typical ColdU. High-risk patients require education about their condition and how to use an adrenaline autoinjector.

A web-based survey on the behavior of moisturizer used in adults with and without atopic dermatitis in Thailand.

BACKGROUND: Moisturizers play an important role in restoring the skin barrier. They should be used to treat and prevent eczema, especially in atopic dermatitis (AD). OBJECTIVE: To evaluate the factors that influence selection of moisturizers in adult patients with AD and without it. Usage behavior between the two groups was also determined. METHODS: A cross-sectional web-based survey was performed. RESULTS: A total of 1,195 participants with mean age of 46.5 ± 14.5 were enrolled. Fifty participants (4.2%) met the William's criteria for AD diagnosis. Most participants reported using moisturizer every day or two times per day. A non-sticky moisturizer, followed by pleasant odor were considered important properties. For choosing a moisturizer, personal satisfaction was the most common answer given by participants. The most common locations that participants applied moisturizer were the extremities (85.1%) and face (84.9%). Physicians' suggestion was also a significant factor that led to moisturizer use by AD patients but it was not significant in the non-AD group (29.2% vs 14.7%, p = 0.007, OR 2.4). A pH of 5.5 and the anti-inflammatory property were important factors in choosing a moisturizer in the AD group. Both AD and non-AD participants preferred liquid soap over bar soap in daily life. CONCLUSIONS: Our results showed that most participants have basic knowledge of how to use a moisturizer. Physicians' suggestion influenced the selection of moisturizer in AD patients. Thus, physicians should continue to educate in order to achieve good clinical outcomes.

The validity and reliability of the Thai-version of 5-D itch scale.

BACKGROUND: Pruritus is commonly associated with skin disorders. The 5-D itch scale was developed as a specific questionnaire for pruritus. OBJECTIVE: This study aimed to evaluate the validity, reliability, and sensitivity to change of the Thai 5-D itch scale in Thai patients. METHODS: The Thai Dermatology Life Quality Index (DLQI), patient's global assessment of disease severity (PatGA-VAS), Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL), and seven-day urticaria activity score (UAS7) were evaluated as correlation with Thai 5-D itch scale. Seventy-five stable patients (42 chronic urticaria patients and 33 eczema patients), who had no change in disease severity after 4-weeks were assessed for test-retest reliability. RESULTS: Of 130 pruritus patients who were treated at Department of Dermatology, Siriraj Hospital, 65 patients were diagnosed with chronic urticaria. The others were diagnosed with eczema. The validity of Thai 5-D itch scale correlated strongly with Thai DLQI total score (r = 0.76, p < 0.0001) and PatGA-VAS (r = 0.79, p < 0.0001). The strong reliability of Thai 5-D itch scale was demonstrated as intraclass correlation coefficient of 0.90. The changes in Thai 5-D itch scale was correlated with the changes in PatGA-VAS and UAS7 which indicated that the Thai 5-D itch scale had good sensitivity to change (r = 0.66) and (r = 0.67), respectively. CONCLUSIONS: The Thai 5-D itch scale is a questionnaire with good validity, reliability and sensitivity to change to evaluate pruritus in Thai patients. This will support the use of 5-D itch scale in practice, in other languages.

Disease activity of patients with chronic urticaria receiving COVID-19 vaccines.

BACKGROUND: Cutaneous adverse events after receiving a COVID-19 vaccine were identified. The disease activity of urticaria after a COVID-19 vaccine has never been explored in chronic urticaria patients. OBJECTIVE: To evaluate disease activity of chronic urticaria after receiving a COVID-19 vaccine. METHODS: A prospective cross-sectional study was conducted in chronic urticaria patients aged 18 or above who visited Siriraj Hospital between July and September 2021, and received the first and second dose of COVID-19 vaccine. The status prior to vaccination, including disease activity, disease control and disease severity was assessed by a urticaria activity score over seven days, urticaria control test, and modified medication score. The disease activity after vaccination was recorded. RESULTS: A total of 130 patients with a mean age of 45.9 ± 14.7 were enrolled in this study. Adenoviral and inactivated vaccines were administered to 85 (65.4%) and 45 patients (34.6%), respectively. Exacerbation was reported in 20 cases (15.4%) after the first dose and 17 cases (13.1%) after the second dose. Nine patients (45%) reported exacerbation after both the first and second dose. The majority of patients only had wheal, while three patients reported wheal with angioedema. No anaphylaxis was reported. Factor predicting exacerbation was concurrent thyroid disease (aRR 2.78, p < 0.01). CONCLUSIONS: Approximately 15% of chronic urticaria patients reported exacerbation after receiving a COVID-19 vaccination. No serious events were observed. Chronic urticaria patients should be vaccinated against COVID-19 after a discussion of the risk of disease flare-up.