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Item Metadata only Chronic urticaria: unmet needs, emerging drugs, and new perspectives on personalised treatment(2024-01-01) Zuberbier T.; Ensina L.F.; Giménez-Arnau A.; Grattan C.; Kocatürk E.; Kulthanan K.; Kolkhir P.; Maurer M.; Zuberbier T.; Mahidol UniversityChronic 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.Item Metadata only Urticaria(2022-12-01) Kolkhir P.; Giménez-Arnau A.M.; Kulthanan K.; Peter J.; Metz M.; Maurer M.; Mahidol UniversityUrticaria is an inflammatory skin disorder that affects up to 20% of the world population at some point during their life. It presents with wheals, angioedema or both due to activation and degranulation of skin mast cells and the release of histamine and other mediators. Most cases of urticaria are acute urticaria, which lasts ≤6 weeks and can be associated with infections or intake of drugs or foods. Chronic urticaria (CU) is either spontaneous or inducible, lasts >6 weeks and persists for >1 year in most patients. CU greatly affects patient quality of life, and is linked to psychiatric comorbidities and high healthcare costs. In contrast to chronic spontaneous urticaria (CSU), chronic inducible urticaria (CIndU) has definite and subtype-specific triggers that induce signs and symptoms. The pathogenesis of CSU consists of several interlinked events involving autoantibodies, complement and coagulation. The diagnosis of urticaria is clinical, but several tests can be performed to exclude differential diagnoses and identify underlying causes in CSU or triggers in CIndU. Current urticaria treatment aims at complete response, with a stepwise approach using second-generation H1 antihistamines, omalizumab and cyclosporine. Novel treatment approaches centre on targeting mediators, signalling pathways and receptors of mast cells and other immune cells. Further research should focus on defining disease endotypes and their biomarkers, identifying new treatment targets and developing improved therapies.Item Metadata only Blue Wheals and Blue Angioedema Induced by Blue Dyes: A Systematic Review(2023-01-01) Kulthanan K.; Tuchinda P.; Eimpunth S.; Chuthapisith S.; Rushatamukayanunt P.; Limphoka P.; Panjapakkul W.; Pochanapan O.; Maurer M.; Mahidol UniversityBackground: Blue wheals and blue angioedema, the adverse reactions to blue dye injections with or without anaphylaxis, are poorly defined. Objective: The objective is to review the characteristics (ie, sex and age at onset, interval between blue dye injection and symptom onset, clinical manifestations, duration of blue wheals or angioedema), natural courses, and treatments of blue dye adverse reactions. Methods: A review of the articles published through July 2021 was performed per the Preferred Reporting Items for Systematic Reviews and Meta-Analysis recommendations. Results: Across 523 patients (175 studies) with any adverse reactions to blue dye injections, wheals, angioedema, or both occurred in 193 patients (36.9%). Of these 193 patients, 68 patients (35.2%) developed blue wheals or angioedema, 118 (61.1%) had ordinary wheals or angioedema (nonbluish), and 7 had both (3.6%). We reviewed 169 patients with available data (99 with ordinary lesions and 70 with blue lesions). Patent blue violet had the highest rate of inducing blue wheals or angioedema (odds ratio 4.9). Almost half of the patients with blue wheals or angioedema developed systemic symptoms; and of those with systemic symptoms, all except 1 progressed to anaphylaxis. On-demand treatments with antihistamines, corticosteroids, and epinephrine were commonly used and effective. Conclusions: Using blue dyes can lead to blue wheals or angioedema and systemic reactions. In patients with a history of a severe allergic reaction to a blue dye, repeat administration of a blue dye should be used only after carefully weighing all the risks and benefits.Item Metadata only A Systematic Review of Aquagenic Urticaria—Subgroups and Treatment Options(2022-08-01) Rujitharanawong C.; Kulthanan K.; Tuchinda P.; Chularojanamontri L.; Metz M.; Maurer M.; Mahidol UniversityBackground: Aquagenic urticaria (AquaU) is a rare variant of chronic inducible urticaria where wheals occur after skin contact with water. Information on clinical manifestations and treatment outcomes is limited, which makes the management of AquaU challenging. Objective: To systematically review disease features and relevant triggers of AquaU and patients’ response to treatment. Methods: Related articles were searched by use of the terms “aquagenic urticaria” and “aquagenic angioedema” until June 2021 and reviewed according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis recommendations. Results: A total of 77 patients with AquaU were investigated in 59 studies including 47 case reports and 12 case series. AquaU predominantly presented in women (47 patients, 61%), and the mean age of onset of the disease was 19.6 ± 10.8 years (range: 0-54 years). Wheals commonly occurred in localized areas and regardless of the water temperature. Based on the reviewed evidence, AquaU can be classified as familial AquaU (FAquaU, 18.2%) and acquired AquaU (AAquaU, 81.8%). Although many treatments were used in both subtypes of AquaU, the use of second-generation H1 antihistamines (2ndAH1) was reported most often to achieve marked improvement in both subtypes. The use of topical therapies in AquaU, which most commonly use hydrophobic vehicles, is poorly documented and of controversial efficiency. Conclusions: AquaU is proposed to be classified into 2 subtypes, FAquaU and the more common AAquaU. Treatment with a 2ndAH1 is recommended as the first-line treatment for both types of AquaU. Further studies are required to fill knowledge gaps.Item Metadata only Food-Dependent Exercise-Induced Wheals/Angioedema, Anaphylaxis, or Both: A Systematic Review of Phenotypes(2023-01-01) Kulthanan K.; Ungprasert P.; Jirapongsananuruk O.; Rujitharanawong C.; Munprom K.; Trakanwittayarak S.; Pochanapan O.; Panjapakkul W.; Maurer M.; Mahidol UniversityBackground: Food-dependent exercise-induced allergic reactions can manifest with wheals, angioedema, and anaphylaxis, alone or in combination. Objective: To systematically review the clinical manifestation, culprit foods and exercise, augmenting factors, comorbidities, and treatment options of each phenotype. Methods: Using predefined search terms, we assessed and analyzed the relevant literature until June 2021. Preferred Reporting Items for Systematic Reviews and Meta-Analysis recommendations were applied to this systematic review. Results: A total of 231 studies with 722 patients were included. The most common phenotype was anaphylaxis with wheals, angioedema, or both, reported in 80% of patients. This was associated with a higher number of anaphylactic episodes, augmenting factors, and use of on-demand antihistamine compared with the least common phenotype, anaphylaxis without wheals or angioedema, reported in 4% of patients. Anaphylaxis with wheals/angioedema was also associated with distinct characteristics compared with stand-alone wheals, angioedema, or both, in 17% of patients. Patients with anaphylaxis were older at the time of disease onset, less often had a history of atopy, showed more positive results in response to food and exercise provocation tests, had a more restricted spectrum of culprit foods, and more often used on-demand epinephrine. Conclusions: The three phenotypes of allergic reactions to food and exercise differ in clinical characteristics, triggers, and response to treatment. Knowledge of these differences may help with patient education and counseling as well as disease management.Item Metadata only Food-Dependent Exercise-Induced Wheals, Angioedema, and Anaphylaxis: A Systematic Review(2022-09-01) Kulthanan K.; Ungprasert P.; Jirapongsananuruk O.; Rujitharanawong C.; Munprom K.; Trakanwittayarak S.; Pochanapan O.; Panjapakkul W.; Maurer M.; Mahidol UniversityBackground: Food-dependent exercise-induced wheals, angioedema, and anaphylaxis remain insufficiently characterized. Objective: We systematically reviewed the literature on clinical manifestations, laboratory investigations, culprit foods, triggering exercise, comorbidities, and treatment outcomes. Methods: Using predefined search terms and Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) recommendations, we searched 3 electronic databases to identify relevant literature published before July 2021. Results: Of 722 patients (median age 25 years; 55.4% male) from 231 studies (43 cohort studies, 15 cases series, and 173 case reports), 79.6% and 3.7% had anaphylaxis with and without wheals and/or angioedema, respectively. The remaining 16.6% had wheals and/or angioedema without anaphylaxis. The duration from eating to exercising and from exercising to symptom onset ranged from 5 minutes to 6 hours (median 1 hour) and from 5 minutes to 5 hours (median 30 minutes), respectively, and virtually all patients exercised within 4 hours after eating and developed symptoms within 1 hour after exercising. Wheat was the most common culprit food. Running was the most common trigger exercise. Most patients were atopic, and 1 in 3 had a history of urticaria. Aspirin and wheat-based products were the most frequent augmenting factors. On-demand antihistamines, corticosteroids, and epinephrine were commonly used and reported to be effective. Patients who stopped eating culprit foods before exercise no longer developed food-dependent exercise-induced allergic reactions. Conclusions: Food-dependent exercise-induced allergic reactions are heterogeneous in their clinical manifestations, triggers, and response to treatment. Patients benefit from avoidance of culprit foods before exercise, which highlights the need for allergological diagnostic workup and guidance.Item Metadata only Evidence for histamine release in chronic inducible urticaria – A systematic review(2022-07-28) Kulthanan K.; Church M.K.; Grekowitz E.M.; Hawro T.; Kiefer L.A.; Munprom K.; Nanchaipruek Y.; Rujitharanawong C.; Terhorst-Molawi D.; Maurer M.; Mahidol UniversityBackground: Chronic inducible urticaria (CIndU) constitutes a group of nine different CIndUs in which pruritic wheals and/or angioedema occur after exposure to specific and definite triggers. Histamine released from activated and degranulating skin mast cells is held to play a key role in the pathogenesis of CIndU, but evidence to support this has, as of yet, not been reviewed systematically or in detail. We aim to characterize the role and relevance of histamine in CIndU. Methods: We systematically searched 3 electronic databases (PubMed, Scopus, and Embase) for studies that reported increased serum or skin histamine concentration (direct evidence) or in vitro or ex vivo histamine release (indirect evidence) following trigger exposure. Results: An initial total of 3,882 articles was narrowed down to 107 relevant studies of which 52 were in cold urticaria, 19 in cholinergic urticaria, 14 in heat urticaria, 10 in contact urticaria, 7 each in solar urticaria and vibratory angioedema, 4 each in symptomatic dermographism and aquagenic urticaria, and 3 in delayed pressure urticaria. The results of our review support that histamine has a key pathogenic role in the pathogenesis of all CIndUs, but it is not the sole mediator as evidenced by the often poor relationship between the level of histamine and severity of symptoms and the variable clinical efficacy of H1-antihistamines. Conclusions: Histamine released from skin mast cells is a key driver of the development of signs and symptoms and a promising therapeutic target in CIndU.Item Metadata only Patients With Chronic Spontaneous Urticaria Who Have Wheals, Angioedema, or Both, Differ Demographically, Clinically, and in Response to Treatment—Results From CURE(2023-01-01) Buttgereit T.; Vera C.; Aulenbacher F.; Church M.K.; Hawro T.; Asero R.; Bauer A.; Bizjak M.; Bouillet L.; Dissemond J.; Fomina D.; Giménez-Arnau A.M.; Grattan C.; Gregoriou S.; Kulthanan K.; Kasperska-Zajac A.; Kocatürk E.; Makris M.; Kolkhir P.; Weller K.; Magerl M.; Maurer M.; Mahidol UniversityBackground: 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.Item Metadata only Non–Skin Related Symptoms Are Common in Chronic Spontaneous Urticaria and Linked to Active and Uncontrolled Disease: Results From the Chronic Urticaria Registry(2024-01-01) Pyatilova P.; Hackler Y.; Aulenbacher F.; Asero R.; Bauer A.; Bizjak M.; Day C.; Dissemond J.; Du-Thanh A.; Fomina D.; Giménez-Arnau A.M.; Grattan C.; Gregoriou S.; Hawro T.; Kasperska-Zajac A.; Khoshkhui M.; Kocatürk E.; Kovalkova E.; Kulthanan K.; Kuznetsova E.; Makris M.; Mukhina O.; Pesqué D.; Peter J.; Salameh P.; Siebenhaar F.; Sikora A.; Staubach P.; Tuchinda P.; Zamłyński M.; Weller K.; Maurer M.; Kolkhir P.; Pyatilova P.; Mahidol UniversityBackground: Chronic spontaneous urticaria (CSU) can present with non–skin related symptoms (NSRS), including recurrent unexplained fever, joint, bone, or muscle pain (JBMP), and malaise, which also occur in other conditions that manifest with wheals (eg, urticarial vasculitis or autoinflammatory disorders) or without wheals (eg, 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 of 2,521 patients with CSU who were aged 16 years or older. Results: One third of CSU patients (31.2%; 786 of 2,521) had one or more NSRS, including recurrent fever (5.3%), JBMP (19.1%), and/or malaise (18.6%). In a multivariable analysis, having one or more 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 or greater 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 (weekly Urticaria Activity Score, median: 21 vs 14; P = .009), longer disease duration (years, median: 2 vs 1; P = .001), the presence of angioedema (74.6% vs 58.7%; P < .001), worse quality of life (Chronic Urticaria Quality of Life Questionnaire, median: 42 vs 29; P < .001) and more frequent poor control of CSU (78% vs 69%; P < .001). Conclusions: The presence of NSRS in a subpopulation of patients with CSU points to the need for better control of the disease, exclusion of comorbid conditions, and/or exclusion of urticarial vasculitis and urticarial autoinflammatory diseases.Item Metadata only The Benefit of Complete Response to Treatment in Patients With Chronic Spontaneous Urticaria—CURE Results(2023-02-01) Kolkhir P.; Laires P.A.; Salameh P.; Asero R.; Bizjak M.; Košnik M.; Dissemond J.; van Doorn M.; Hawro T.; Kasperska-Zajac A.; Zajac M.; Kocatürk E.; Peter J.; Parisi C.A.S.; Ritchie C.A.; Kulthanan K.; Tuchinda P.; Fomina D.; Kovalkova E.; Khoshkhui M.; Kouzegaran S.; Papapostolou N.; Du-Thanh A.; Kamegashira A.; Meshkova R.; Vitchuk A.; Bauer A.; Grattan C.; Staubach P.; Bouillet L.; Giménez-Arnau A.M.; Maurer M.; Weller K.; Mahidol UniversityBackground and Objective: Chronic spontaneous urticaria (CSU) is a distressing disease. We report real-world data from the global Chronic Urticaria Registry (CURE) about associations between various CSU states and sleep impairment, plus important health-related quality-of-life (HRQoL) outcomes and compared different methods to assess CSU states. Methods: CURE data were collected at baseline and 6-monthly follow-ups (FU). Assessments included CSU states using the Urticaria Control Test (UCT), weekly Urticaria Activity Score (UAS7), and Physician Global Assessment (PhyGA) of treatment response. Complete response to treatment (CR, UAS7 = 0), complete control of disease (CC, UCT = 16), and PhyGA = CR were assessed, plus the Dermatology Life Quality Index and the Chronic Urticaria Quality-of-Life Questionnaire (CU-Q2oL) sleep domain. Results: Overall, 2078 patients were included. At baseline, 9.8%, 17.9%, and 42.3% of patients had UCT = 16, UAS7 = 0, or PhyGA = CR, respectively, which increased at FU1 and FU2. Patients with higher UCT scores had better sleep and HRQoL. The presence of angioedema without wheals, episodic disease, omalizumab treatment, and male sex were associated with CC (P <.05). Among 469 patients who achieved CC or CR, 16.4% (n = 77) showed CC or CR with all 3 instruments. Agreement between UCT = 16 and UAS7 = 0 measurements was moderate (κ = 0.581), but poor between UCT = 16 and PhyGA = CR (κ = 0.208). Conclusions: Few patients had CR/CC of their CSU at baseline entry. Disease control strongly related to good sleep and better HRQoL; therefore, it is important to aim for CR in CSU treatment. Patient-reported UCT and UAS7 assessments demonstrated a more accurate measurement of CSU state versus physician assessments.