A Case-Control Study Comparing the General Characteristics of Patients with Symptomatic Dermographism and Chronic Spontaneous Urticaria: Is Atopy a Risk Factor for Symptomatic Dermographism?

INTRODUCTION: Symptomatic dermographism (SDerm) is the most common chronic inducible urticaria (CIndU) subtype. There is still limited information in the literature about clinical features, triggering factors, and accompanying comorbidities of SDerm. The aim of this study was to compare the clinical features and laboratory data of patients with SDerm and chronic spontaneous urticaria (CSU). METHODS: The clinical features and laboratory data of patients with SDerm and CSU were compared retrospectively. The laboratory data and general characteristic features of the patients were obtained from the medical records. RESULTS: The study included a total of 361 patients (CSU: 220, SDerm: 141). The rates of asthma (odds ratio [OR]: 1.79, p = 0.036), allergic rhinitis (OR: 6.03, p < 0.001), and thyroid disease (OR: 1.78, p = 0.039) were higher in patients with SDerm. The disease duration (median 12 months, p < 0.001) and regular antihistamine use (OR: 0.31, p < 0.001) were lower in patients with SDerm. Total IgE level (median: 193, p < 0.001), thyroid antibody positivity (OR: 1.93, p = 0.039), and atopy (OR: 8.81, p < 0.001) were higher in patients with SDerm. Dermatophagoides pteronyssinus (OR: 17.72, p < 0.001), Dermatophagoides farinae (OR: 17.20, p < 0.001), grass pollen (OR: 2.50, p < 0.026), cat epithelium (OR: 3.68, p < 0.023), and cockroach (OR: 4.93, p < 0.009) allergen positivity rates were higher in patients with SDerm. CONCLUSION: Atopic diseases such as asthma and allergic rhinitis and the sensitization rate to aeroallergens seem to be higher in patients with SDerm than in patients with CSU. The results of this study should be supported by multicenter studies of patients from different geographical regions.

Anti-KIT antibody, barzolvolimab, reduces skin mast cells and disease activity in chronic inducible urticaria.

BACKGROUND: Chronic inducible urticaria (CIndU) is characterized by mast cell (MC)-mediated wheals in response to triggers: cold in cold urticaria (ColdU) and friction in symptomatic dermographism (SD). KIT receptor activation by stem cell factor (SCF) is essential for MC function. Barzolvolimab (CDX-0159) is a humanized antibody that inhibits KIT activation by SCF and was well tolerated in healthy volunteers with dose-dependent plasma tryptase suppression indicative of systemic mast cell ablation. METHODS: This is an open-label, trial in patients with antihistamine refractory ColdU or SD, receiving one IV dose of barzolvolimab (3 mg/kg), with a 12-week follow-up. Primary endpoint was safety/tolerability; pharmacodynamic (PD)/clinical endpoints included serum tryptase, plasma SCF, skin MC histology, provocation tests, urticaria control test (UCT), and dermatology life quality index (DLQI). RESULTS: Analysis populations were safety (n = 21) and pharmacodynamics/clinical activity (n = 20). Barzolvolimab was well tolerated; most adverse events were mild and resolved. Treatment resulted in significant depletion of skin MCs, decreased tryptase (

Long-Term Omalizumab in Elderly Patients with Chronic Urticaria: Is It a Safe Therapy?

BACKGROUND: Biologics have revolutionized the treatment of many diseases. In this regard, omalizumab (OMA), an anti-IgE monoclonal antibody, is the recommended therapeutic option for patients with chronic spontaneous urticaria (CSU) refractory to second-generation H1-antihistamines. Several studies confirm the efficacy and safety of the drug. However, the literature focusing on the elderly population is scarce, as this age group is often excluded from clinical trials. Therefore, the pharmacological treatment of CSU in elderly patients is a challenge that is increased by their comorbidities and consequent polypharmacy. OBJECTIVES: We describe the real-life safety profile of OMA in elderly patients (≥70 years) with CSU and chronic inducible urticaria (CIndU). We aimed to provide data for daily clinical practice in this vulnerable patient group. METHOD: A retrospective review was performed of the records of patients with CSU/CIndU from May 2003 to December 2019 in the Hospital Universitario La Paz. We describe qualitative and quantitative data according to measures of central tendency. Comparisons between qualitative and quantitative data were performed with the Mann-Whitney U test and the Fisher's test for qualitative variables. A p value <0.05 was considered statistically significant. RESULTS AND CONCLUSIONS: Eighty-nine patients were included, divided into two groups (<70 vs. ≥70 years). The overall rate of adverse events (AEs) was 48%, mainly mild. No association between age and AE was found (p = 0.789). No serious AE such as anaphylaxis was detected. CSU predominated in both groups. CIndU was less prevalent in the elderly (p = 0.017). There was no association between age and the other variables. Although the frequency of neoplasms was slightly higher in the elderly with OMA, we found no difference compared to the incidence of neoplasms in the general population. Therefore, our data suggest that OMA may be a safe treatment in elderly people with CSU/CIndU for prolonged periods of treatment, although further studies with larger samples are needed to corroborate our observations.

Biomarkers of Autoimmune Chronic Spontaneous Urticaria.

PURPOSEOF REVIEW: Chronic spontaneous urticaria and chronic inducible urticaria (CSU/CindU) are caused by mast cell and basophil activation leading to degranulation and the release of histamine and several other mediators. Three kinds of factors can trigger mast cells in CSU: (1) activation of stimulating receptor(s) on the mast cell membrane, (2) upregulation of certain receptor(s), and (3) intracellular dysregulation in signaling with overexpression of the spleen tyrosine kinase (SYK) or reduced activation of the inhibitory Src homology 2 (SH2)-containing inositol phosphatases (SHIP)-related pathways. In CSU, two major endotypes exist based on the primary receptor activating mechanism: type I hypersensitivity (IgE-mediated, directed against auto-allergens) and type IIb (autoimmune, via IgG autoantibodies directed against IgE or the IgE-receptor). Their treatment responses vary. We discuss in vitro and in vivo biomarkers. RECENT FINDINGS: Patients with auto-allergic CSU have clinical characteristics that can distinguish them partly from those with autoimmune CSU. Most importantly, their disease generally presents a less aggressive course, a better response to second generation (up-dosed) antihistamines and a good response to omalizumab, if necessary. Meanwhile, autoimmune CSU/CindU patients fare less well and often need immunosuppressive drugs. Biomarkers that might help endotype CSU/CindU patients and select the most appropriate treatment, dose, and duration, e.g., for autoallergic CSU, high total IgE and IgE against auto-allergens; for autoimmune CSU, low IgE, basopenia, and IgG against autoantigens like thyroid peroxidase and a positive autologous serum skin test (but sometimes also positive in autoallergy). Some biomarkers are easily accessible but of low specificity; others are highly specific but more futuristic.

Food-dependent and food-exacerbated symptomatic dermographism: New variants of symptomatic dermographism.

BACKGROUND: Symptomatic dermographism (SD) is the most common form of chronic inducible urticaria. The criterion standard for diagnosing SD and disease activity assessment in SD is provocation testing. As of now, if and what cofactors have an impact on provocation test results is unknown. OBJECTIVE: We sought to determine whether the induction of signs and symptoms of SD is affected by the intake of food. METHODS: We performed standardized skin provocation testing with a dermographometer (FricTest) before and after the intake of food. Patients were off antihistamine treatment for at least 3 days before testing. In total, 17 patients were tested after not having eaten for at least 4 hours (preprandial) on one volar forearm and 60 minutes after a carbohydrate-rich meal (postprandial) on the other. FricTest responses (wheals, itch) at trigger thresholds were assessed at 5 and 30 seconds as well as at 1, 2, 5, and 10 minutes. RESULTS: We identified 7 patients with SD who showed faster onset of FricTest-induced whealing and/or lower trigger thresholds after the intake of food, that is, food-exacerbated SD. In 5 other patients, FricTest provocation testing resulted in a positive response only after the intake of food, but not before. Three of these 5 patients with food-dependent SD had comorbid chronic spontaneous urticaria and 1 had cholinergic urticaria. CONCLUSIONS: We describe 2 previously unknown subtypes of SD, food-exacerbated SD and food-dependent SD. The prevalence and underlying pathomechanisms of food-exacerbated SD and food-dependent SD need to be investigated, and the impact of food intake on other forms of chronic inducible urticaria should be explored.

Development of the Cold Urticaria Activity Score.

BACKGROUND: Cold urticaria (ColdU) is a form of inducible urticaria where cold induces wheals and/or angioedema. The burden of disease is high and linked to trigger thresholds, exposure, and avoidance. There are presently no validated patient-reported outcome measures (PROMs) to assess and monitor disease activity. Our objective was to develop a disease-specific activity score for ColdU that is easy to administer and evaluate. METHODS: A Cold Urticaria Activity Score (ColdUAS) questionnaire was developed, directed by PROM developing guidelines. After the generation of a conceptional framework, the item generation phase included the literature research on ColdU signs and symptoms and on comparable tools for similar diseases and 47 ColdU patient interviews. Subsequently, an impact analysis for content validity was performed. The final selection of items underwent expert review for face validity and cognitive debriefing. RESULTS: The ColdUAS, a self-administered questionnaire for the prospective assessment of disease activity in patients with ColdU, consists of 4 items: 1. the frequency and severity of the signs (wheals and/or angioedema), 2. the frequency and severity of the symptoms (e.g., itch and burn), 3. the exposure to specific triggers, and 4. the avoidance of these triggers. The recall period for each item is the last 24 h. CONCLUSIONS: The ColdUAS is the first disease-specific PROM to assess ColdU disease activity. It may help to better assess patients' disease status in routine clinical practice as well as in clinical trials. Anchor-based approaches are currently used to validate the ColdUAS.

Cold urticaria in a pediatric cohort: Clinical characteristics, management, and natural history.

BACKGROUND: Cold urticaria (coldU) is associated with substantial morbidity and risk of fatality. Data on coldU in children are sparse. We aimed to evaluate the clinical characteristics, management, risk of associated anaphylaxis, and resolution rate of coldU in a pediatric cohort. Additionally, we sought to compare these metrics to children with chronic spontaneous urticaria (CSU). METHODS: We prospectively enrolled children with coldU from 2013-2021 in a cohort study at the Montreal Children's Hospital and an affiliated allergy clinic. Data for comparison with participants with solely CSU were extracted from a previous study. Data on demographics, comorbidities, severity of presentation, management, and laboratory values were collected at study entry. Patients were contacted yearly to assess for resolution. RESULTS: Fifty-two children with cold urticaria were recruited, 51.9% were female and the median age of symptom onset was 9.5 years. Most patients were managed with second-generation H1-antihistamines (sgAHs). Well-controlled disease on sgAHs was negatively associated with concomitant CSU (adjusted odds ratio (aOR) = 0.69 [95%CI: 0.53, 0.92]). Elevated eosinophils were associated with cold-induced anaphylaxis (coldA; aOR = 1.38 [95%CI: 1.04, 1.83]), which occurred in 17.3% of patients. The resolution rate of coldU was 4.8 per 100 patient-years, which was lower than that of CSU (adjusted hazard ratio = 0.43 [95%CI: 0.21, 0.89], p < 10-2 ). CONCLUSION: Pediatric coldU bears a substantial risk of anaphylaxis and a low-resolution rate. Absolute eosinophil count and co-existing CSU may be useful predictive factors.

Omalizumab on Chronic Spontaneous Urticaria and Chronic Inducible Urticaria: A Real-World Study of Efficacy and Predictors of Treatment Outcome.

BACKGROUND: Omalizumab is a very important drug for the treatment of chronic urticaria. Although omalizumab's therapeutic efficacy has been demonstrated, data on real-world experiences in Korea, especially regarding chronic inducible urticaria (CIndU), are limited. This study attempted to compare the efficacy of omalizumab in Korean chronic spontaneous urticaria (CSU) and CIndU patients. METHODS: Fifty-two CSU and 29 CIndU patients were included and Urticaria Activity Score 7 (UAS7) at baseline, week 4, and week 12 was assessed retrospectively. RESULTS: Omalizumab 150 mg significantly decreased UAS7 in both patients with CSU and CIndU with only one dose (P < 0.001). The significant decrease in the UAS7 scores of both groups of patients continued from weeks 4 to 12. Although there was no significant difference in treatment efficacy between the two groups, the symptoms of patients with CSU tended to improve faster; furthermore, the number of antihistamines administered daily reduced more significantly in this patient group (P = 0.047). Additionally, the decrease in the UAS7 score between baseline and week 12 and the response rate were higher in patients with CSU. CONCLUSION: Omalizumab may be slightly more effective against CSU than against CIndU. Regarding the CIndU subtypes, dermatographic urticaria was associated with the greatest reduction in the UAS7 score, and patients with this condition showed the highest response rate, indicating the best effect of omalizumab. The duration of chronic urticaria was greater in non-responders than in responders (P = 0.025). Conversely, baseline immunoglobulin E levels were significantly higher in responders (P = 0.039).

Clinical Characteristics, Management, and Natural History of Chronic Inducible Urticaria in a Pediatric Cohort.

BACKGROUND: Some forms of chronic urticaria (CU) can be specifically attributed to a response to a definite trigger, referred to as chronic inducible urticaria (CIndU). We aimed to assess the demographics, clinical characteristics, comorbidities, natural history, and management of pediatric patients with CIndU. METHODS: Over a 6-year period, children presenting to the allergy clinic at the Montreal Children's Hospital (MCH) with CIndU were prospectively recruited. CU was defined as the presence of wheals and/or angioedema, occurring for at least 6 weeks. A standardized diagnostic test was used to establish the presence of a specific form of urticaria. Resolution was defined as the absence of hives for 1 year without treatment. RESULTS: Sixty-four patients presented with CIndU, of which 51.6% were male, with a median age of 12.5 (interquartile range 7.3, 15.9) years. Cold CU and cholinergic CU were the most common subtypes (60.3 and 41.3%, respectively). Basophil counts were undetectable in 48.4% of the cases, and C-reactive protein levels were elevated in 7.8% of patients. Of all cases, 71.4% were controlled with second-generation antihistamines. The resolution rate was of 45.3% (95% confidence interval 33.1-57.5%), based on per-protocol population within the 6-year course of the study. Resolution was more likely in patients who presented with well-controlled urticaria control test scores and elevated CD63 counts and in those suffering from thyroid comorbidity. CONCLUSION: The natural history of CIndU resolution in pediatric patients was relatively low and was associated with elevated CD63 levels, as well as thyroid comorbidity.

Chronic inducible urticaria subtypes in children: Clinical features and prognosis.

BACKGROUND: Chronic inducible urticaria (CIndU) is a subtype of chronic urticaria induced by a physical stimulus. OBJECTIVE: To evaluate the clinical features, prognostic factors, and natural course of childhood CIndU subtypes. METHODS: Patients (1-18 years old, n = 117) diagnosed with CIndU between March 2011 and March 2019 were analyzed. Patients (n = 101) were re-evaluated for the status of their CIndU at least 6 months after the initial evaluation. RESULTS: The study population comprised of 117 children with a median (inter-quartile range) age of 10.3 (6-14.8) years at admission and a male predominance (53%). Symptomatic dermographism was the most common type of CIndU, affecting 65% of the group, followed by cold urticaria and cholinergic urticaria, which affected 17% and 15.4%, respectively. Baseline serum tryptase levels in cholinergic urticaria and cold urticaria were higher than those in symptomatic dermographism [7.0 (3.3-10.7) µg/L, 4.2 (2.8-9.3) µg/L, and 2.7 µg/L (1.8-5.9), respectively; P = .020]. Recovery was observed in 9.6%, 25.3%, and 34.7% of the CIndU children after 12, 36, and 60 months, respectively. Of the patients with symptomatic dermographism, 40% had remission in 5 years, whereas this rate was only one-fifth in patients with cold urticaria. The worst prognosis was observed in patients with cholinergic urticaria. CONCLUSION: This study concluded that nearly one-third of children with CIndU recovered within 5 years and symptomatic dermographism has the best prognosis. Cholinergic urticaria is the CIndU type with the worst prognosis, male dominance, and highest baseline serum tryptase levels.

Spiritual well-being and quality of life are impaired in chronic urticaria.

SUMMARY: Background. Patients with chronic urticaria (CU) often report an impaired quality of life (QoL). Although a positive effect of addressing spirituality in health care has been proved in several chronic diseases, its potential role in CU has received no attention. Objective. We aim to evaluate spirituality and QoL in CU subjects. Methods. In a single-centre observational study, 100 CU subjects were investigated using Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being (FACIT-Sp-12) scale, Chronic Urticaria Quality of life Questionnaire (CU-Q2oL) and Urticaria Control Test (UCT). Results. Of 100 subjects, 82 were female and 18 were male. It was observed that subjects with poorly controlled CU presented FACIT Sp-12 meaning/peace (p = 0.004) significantly lower, and CU-Q2oL (p less than 0.0001) significantly higher (worst QoL) than subjects with controlled CU. There was no difference in the FACIT Sp-12 faith (p = 0.43) between groups. There was moderate direct correlation between FACIT Sp-12 faith and FACIT Sp-12 meaning/peace (r = 0.483; p less than 0.0001; n = 100). There was a significant strong inverse correlation between the CU-Q2oL and the UCT (r = - 0.762; p less than 0.0001; n = 100). No correlation was found between the FACIT Sp-12 faith and CU-Q2oL, neither with UCT. Conclusions. No study has ever investigated the role of spirituality in managing patients with urticaria. Our findings support the impact of poorly controlled urticaria in spiritual well-being and QoL. Therefore, clinicians should pay more attention to spirituality among CU patients. We suggest that urticaria guidelines should include specific recommendations on spirituality assessment.

Omalizumab in Chronic Urticaria: An Italian Survey.

Omalizumab is approved for use in chronic spontaneous urticaria (CSU); however, it is not approved for chronic inducible urticaria (CIndU). The aim of the present study was to assess the effectiveness of omalizumab in treating CSU and CIndU in Italy. This is a multicentre prospective observational real-life study involving patients with severe urticaria capable of undergoing omalizumab therapy. We enrolled 127 patients (59.1% females), ranging in age from 15 to 83 years, 69.3% had CSU alone, 26.8% had CSU and CIndU, and 3.9% had only CIndU (30.8% delayed pressure, 35.9% dermographic, 15.3% cholinergic, 12.8% cold, 5.1% aquagenic). After the first cycle of omalizumab (300 mg every 4 weeks for 24 weeks), 16 CSU patients and 10 patients (20.5%) with CIndU with or without CSU did not require a second cycle of omalizumab (300 mg every 4 weeks for 20 weeks). The patient with aquagenic urticaria achieved remission after the first cycle. None showed a lack of response to the second cycle of omalizumab. Omalizumab is a promising drug for both spontaneous and inducible chronic urticaria. Current evidence indicates that omalizumab may be approved also for CIndU.

Update on Omalizumab for Urticaria: What's New in the Literature from Mechanisms to Clinic.

PURPOSE OF REVIEW: Since omalizumab has been approved for urticaria, numerous randomized and real-life observational trials have been published. We reviewed the period January 2017-February 2018. RECENT FINDINGS: Omalizumab is effective for the control of urticaria recalcitrant to antihistamines in different populations globally. The ratio of total serum IgE 4-week/baseline ≥2 can predict response with a high likelihood. In observational real-life trials, doses have been adjusted on an individual basis: in some populations, up to two-thirds of the patients can be controlled with 150 mg/month; however, others are still not controlled with 300 mg/month. In these, 150 mg bimonthly could be tried, before up-dosing to 450 mg/month. On the long run (up to 3 years) omalizumab kept its efficacy. In many patients, dosing intervals could be augmented (6-8 weeks, some even more). After a 12-month treatment, about 20% showed long-term remission without relapse. Some biomarkers are being detected. Adjusting omalizumab doses in urticaria patients could enhance efficacy (shortening dosing interval and/or augmenting dose) and save costs (after 12 months: extending dosing interval and/or reducing dose).

Clinical and photobiological response in eight patients with solar urticaria under treatment with omalizumab, and review of the literature.

BACKGROUND: Solar urticaria (SU) is a rare photodermatosis. Treatment is challenging, and outcomes are often disappointing. Omalizumab is an anti-IgE, currently approved for treatment of chronic spontaneous urticaria. We sought to evaluate therapy with omalizumab in refractory SU and describe predictive factors for response. MATERIALS/METHODS: Patients with refractory SU under treatment with omalizumab were included in this study. Clinical outcome was evaluated using the Urticaria Activity Score 7 (UAS7), Dermatology Life Quality Index (DLQI) and Pruritus Visual Analogue Scale (VAS). Complete clinical response (CCR) was defined as having an UAS7 = 0, DLQI <6 and VAS = 0. Phototesting was performed and compared to baseline. We performed a PubMed search to identify reported cases of SU in adults treated with omalizumab, analysing their characteristics in order to predict response to omalizumab. RESULTS: Eight patients were included. Median age was 45.5 years (range, 23-64). Light spectrum most commonly implicated was UV-A. Clinical outcomes: 89% (7/8) achieved CCR with omalizumab. Phototesting was normal in 42.8% (3/7) of them. In our review, we identified 38 patients (including the current case series), and 68.4% showed favourable outcomes with omalizumab. Median time since onset of SU was lower in responders. CONCLUSIONS: Omalizumab can be an effective treatment in refractory SU.

Omalizumab in chronic spontaneous and inducible urticaria: a 9 year retrospective study in Portugal.

Summary: Objective. Describe the safety and long-term use of omalizumab in chronic urticaria (CU), both spontaneous (CSU) and inducible (CIndU). Methods. Retrospective chart-review (2006-15) of CU patients treated with omalizumab for ≥ 6 months. Statistical analyses: descriptive statistics, Mann-Whitney, generalized linear models. Results. 23 patients with CSU (3 men), 3 with CIndU (2 men). Generalized linear models showed UAS reduction per omalizumab administration of 16% in CIndU and CSU and UAS7, of 15% in CIndU, and 20% in CSU. DLQI score at baseline had a median of 19 (CIndU and CSU) and after omalizumab a median of 0 (in both). Seven CSU patients stopped omalizumab and remain asymptomatic. No side-effects were observed. Conclusion. Omalizumab is safe and efficacious in CU. Stopping omalizumab can be tried, as some patients achieve remission.

[Chronic urticaria in childhood : Rational diagnostics and treatment]. / Chronische Urtikaria im Kindesalter : Rationale Diagnostik und Therapie.

Chronic urticaria (CU) is defined by episodes of urticaria with or without angioedema, which recur daily or nearly daily over more than 6 weeks. Sudden manifestations of CU with or without known causes are termed chronic spontaneous urticaria, which is differentiated from chronic inducible urticaria. The differential diagnoses of CU in childhood range from self-limiting dermatoses to severe systemic diseases. Further targeted steps are taken to detect potential trigger factors or underlying illnesses only if suspicion arises on anamnestic grounds and CU is best treated in accordance with international guidelines. First-line therapy consists of non-sedating H1-antihistamines at approved or even higher doses. If symptoms persist, additional treatment with omalizumab, cyclosporine or montelukast can be initiated after careful individual consideration.

Omalizumab in the Treatment of Chronic Inducible Urticaria. / Omalizumab en el tratamiento de la urticaria crónica inducible.

Omalizumab is a recombinant humanized monoclonal antibody that inhibits immunoglobulin E. It has been approved for the treatment of severe asthma and chronic spontaneous urticaria refractory to other treatments. Its use in the management of chronic inducible urticaria (a type triggered by certain stimuli) is still considered off-label, although this use has been discussed in some consensus papers. This review brings together case reports and case series describing the use of omalizumab to treat chronic inducible urticaria. We analyze the most important aspects of the cases and the outcomes reported. The results seem to position omalizumab as a potentially effective, safe treatment alternative in some cases of chronic inducible urticaria.

The definition, diagnostic testing, and management of chronic inducible urticarias - The EAACI/GA(2) LEN/EDF/UNEV consensus recommendations 2016 update and revision.

These recommendations for the definition, diagnosis and management of chronic inducible urticaria (CIndU) extend, revise and update our previous consensus report on physical urticarias and cholinergic urticaria (Allergy, 2009). The aim of these recommendations is to improve the diagnosis and management of patients with CIndU. Our recommendations acknowledge the latest changes in our understanding of CIndU, and the available therapeutic options, as well as the development of novel diagnostic tools.