Aims
To explore the safety, tolerability, pharmacokinetics and pharmacodynamics (PD) of GSK2646264 using skin challenge models.
Methods
Healthy volunteers (HV) with a positive allergen skin prick ...test received GSK2646264 (0.5% or 1% ww) and placebo creams on up to 10% body surface area (BSA). Cold (ColdU) or chronic spontaneous (CSU) urticaria patients received 1% GSK2646264 or placebo on up to 10% BSA. PD assessments included weal characteristics after skin allergen challenge, critical temperature threshold (CTT) in ColdU patients and defined area urticaria activity score in CSU patients.
Results
Thirty‐four patients were randomised (17 HV, 12 ColdU, 5 CSU). Topical application of GSK2646264 and placebo was well tolerated. Systemic pharmacokinetics (AUC 0–24 h*ng/mL) was similar between HVs (Geomean 97.9 %CV 37) and ColdU patients (Geomean 68.2 %CV 14; 3.5% BSA or 167 %CV 120; 10% BSA). Whilst in HVs a similar reduction in skin allergen challenge weal area was observed following 3 applications of GSK2646264 and placebo, a trend towards a greater reduction was seen in ColdU with GSK2646264 compared to placebo. A clinically meaningful reduction in CTT, in ColdU patients treated with GSK2646264, was observed in 4 of 9 patients, who demonstrated either a complete inhibition of ColdU to ≤4°C (n = 2) or partial response (reduction by >4°C, n = 2). Due to the small number of CSU patients recruited, no meaningful conclusions could be drawn from the defined area urticaria activity score PD endpoint.
Conclusion
This Phase 1/1b study confirms that GSK2646264 cream applied topically penetrates the skin and some reduction in CTT was observed.
(NCT02424799)
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.
The ColdUAS development process was directed by PROM guidelines. For item generation 47 interviews with ColdU patients and a comprehensive literature research was performed. By conducting an impact analysis, cognitive debriefings, and an expert review final items were selected. The 4‐item ColdUAS is the first self‐administered questionnaire for the prospective assessment of disease activity in ColdU patients. Abbreviations: ColdU, Cold urticaria; ColdUAS, Cold Urticaria Activity Score; PROM, patient‐reported outcome measures
Mast cell-activating signals in cold urticaria are not yet well defined and are likely to be heterogeneous. Cold agglutinins and cryoglobulins have been described as factors possibly associated with ...cold urticaria, but their relevance has not been explained. We performed a single-center prospective cohort study of 35 cold urticaria patients. Cold agglutinin and cryoglobulin test results, demographics, detailed history data, cold stimulation test results, complete blood count values, C-reactive protein, total immunoglobulin E levels, and basal serum tryptase levels were analyzed. Forty six percent (
= 16) of 35 tested patients had a positive cold agglutinin test and 27% (
= 9) of 33 tested patients had a positive cryoglobulin test. Cold agglutinin positive patients, when compared to cold agglutinin negative ones, were mainly female (
= 0.030). No gender-association was found for cryoglobulins. A positive cold agglutinin test, but not a positive cryoglobulin test, was associated with a higher rate of reactions triggered by cold ambient air (
= 0.009) or immersion in cold water (
= 0.041), and aggravated by increased summer humidity (
= 0.007). Additionally, patients with a positive cold agglutinin test had a higher frequency of angioedema triggered by ingestion of cold foods or drinks (
= 0.043), and lower disease control based on Urticaria Control Test (
= 0.023). Cold agglutinin levels correlated with erythrocyte counts (r = -0.372,
= 0.028) and monocyte counts (r = -0.425,
= 0.011). Cryoglobulin concentrations correlated with basal serum tryptase levels (r = 0.733,
= 0.025) and cold urticaria duration (r = 0.683,
= 0.042). Results of our study suggest that cold agglutinins and cryoglobulins, in a subpopulation of cold urticaria patients, are linked to the course and possibly the pathogenesis of their disease.
Treatments of cold urticaria: A systematic review Kulthanan, Kanokvalai; Hunnangkul, Saowalak; Tuchinda, Papapit ...
Journal of allergy and clinical immunology,
April 2019, 2019-04-00, 20190401, Letnik:
143, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Several treatment options for cold urticaria (ColdU) have been studied and reported, but systematic reviews and meta-analyses are limited.
We sought to meta-analyze and review the efficacy and safety ...of ColdU treatments.
We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations. Suitable reports were identified by searching PubMed, Scopus, and Web of Science. Our systematic review included 16 studies, 9 of which met the eligibility criteria for the meta-analysis. We analyzed the effects of treatments on critical temperature thresholds (CTTs) and critical stimulation time thresholds (CSTTs), as well as on rates of complete response and adverse events.
Our pooled meta-analyses showed that nonsedating second-generation H1-antihistamines (nsAHs) are effective in the treatment of ColdU and that updosing of nsAHs significantly reduced CTTs relative to their own standard doses and placebos. In 4 studies involving CSTTs, updosing of nsAHs also resulted in significantly better CSTTs than their own standard doses or placebos. Omalizumab resulted in a marked reduction of CTTs in H1-antihistamine–resistant patients. Of 118 adverse events in 8 studies, standard-dose nsAHs, updosed nsAHs, and omalizumab produced lower numbers of adverse events than first-generation antihistamines.
Our study showed that greater dosages of nsAHs were more effective than standard dosages in controlling ColdU symptoms. Increasing the dosages was not significantly associated with higher adverse event rates. Omalizumab at 150 and 300 mg every 4 weeks was shown to be effective for patients with ColdU refractory to antihistamines.
La urticaria por frío (UF) es un tipo de urticaria crónica inducible (CIndU) donde aparecen ronchas pruriginosas recurrentes y/o angioedema tras la exposición a estímulos fríos. Aunque normalmente ...solo afecta a áreas expuestas, pueden producirse reacciones sistémicas. Nuestro objetivo es caracterizar los casos de UF de nuestro hospital.
Estudio retrospectivo de casos de UF seguidos en nuestra consulta de urticaria en Portugal hasta octubre de 2020.
Se incluyeron 52 pacientes, de ellos 40 mujeres. La edad media fue de 35años. En 19 pacientes, los síntomas comenzaron antes de los 18años de edad. La UF se clasificó como adquirida en todos los pacientes. Las pruebas de provocación por frío fueron negativas en 9 pacientes, clasificados como UF atípica. No se encontraron diferencias con respecto al inicio en edad pediátrica o adulta. Más de la mitad de los pacientes (52%) tenían una UF localizada. A pesar de no ser estadísticamente significativa, la temperatura umbral evaluada con TempTest® 4.0 fue más alta y el tiempo de estimulación más corto en los pacientes con síntomas más graves. Todos los pacientes fueron tratados con antihistamínicos y uno con omalizumab. Los pacientes controlados con dosis estándar de antihistamínicos tenían temperatura umbral más baja que los que necesitaban dosis más altas (p<0,01).
La UF es una enfermedad heterogénea que, en algunos casos, puede poner en peligro la vida del paciente. Las pruebas de provocación con frío pueden ser útiles en el manejo e identificación de grupos de gravedad.
Cold Urticaria (ColdU) is a type of chronic inducible urticaria (CIndU) where recurrent pruritic wheals and/or angioedema occur after exposure to cold stimulus. Although it usually only affects exposed areas, systemic reactions can occur in severe cases. In this study, we seek to characterize the ColdU cases within our Centre's population of patients.
Retrospective study based on clinical files of patients diagnosed with ColdU followed in an urticaria outpatient clinic in Portugal prior to October 2020.
We included 52 patients total (40 women) with median age of 35 years, 19 patients with symptom onset before 18 years-old. ColdU was classified as acquired in all patients. Cold provocation tests were negative in 9 patients and these were classified as atypical ColdU. No significant differences were found between those with pediatric or adult onset of disease. Most of the patients had a localized form of the disease (52%). Despite not being statistically significant, it was found that patient's temperature threshold, assessed with TempTest® 4.0, was higher and stimulation time was shorter in more severe groups. All patients were treated with non-sedating antihistamines (daily or on-demand), finding that those controlled with standard dosages had lower temperature thresholds than those needing higher dosages (p<0.01). One patient was under treatment with omalizumab.
ColdU is an heterogenous disease that can have life-threatening event consequences. Cold provocation tests and threshold assessment can be an important tool in the management treatment and in identifying severity groups.
Cold Urticaria (ColdU) is a type of chronic inducible urticaria (CIndU) where recurrent pruritic wheals and/or angioedema occur after exposure to cold stimulus. Although it usually only affects ...exposed areas, systemic reactions can occur in severe cases. In this study, we seek to characterize the ColdU cases within our Centre's population of patients.
Retrospective study based on clinical files of patients diagnosed with ColdU followed in an urticaria outpatient clinic in Portugal prior to October 2020.
We included 52 patients total (40 women) with median age of 35 years, 19 patients with symptom onset before 18 years-old. ColdU was classified as acquired in all patients. Cold provocation tests were negative in 9 patients and these were classified as atypical ColdU. No significant differences were found between those with pediatric or adult onset of disease. Most of the patients had a localized form of the disease (52%). Despite not being statistically significant, it was found that patient's temperature threshold, assessed with TempTest® 4.0, was higher and stimulation time was shorter in more severe groups. All patients were treated with non-sedating antihistamines (daily or on-demand), finding that those controlled with standard dosages had lower temperature thresholds than those needing higher dosages (p < 0.01). One patient was under treatment with omalizumab.
ColdU is an heterogenous disease that can have life-threatening event consequences. Cold provocation tests and threshold assessment can be an important tool in the management treatment and in identifying severity groups.
La urticaria por frío (UF) es un tipo de urticaria crónica inducible (CIndU) donde aparecen ronchas pruriginosas recurrentes y/o angioedema tras la exposición a estímulos fríos. Aunque normalmente solo afecta a áreas expuestas, pueden producirse reacciones sistémicas. Nuestro objetivo es caracterizar los casos de UF de nuestro hospital.
Estudio retrospectivo de casos de UF seguidos en nuestra consulta de urticaria en Portugal hasta octubre de 2020.
Se incluyeron 52 pacientes, de ellos 40 mujeres. La edad media fue de 35 años. En 19 pacientes, los síntomas comenzaron antes de los 18 años de edad. La UF se clasificó como adquirida en todos los pacientes. Las pruebas de provocación por frío fueron negativas en 9 pacientes, clasificados como UF atípica. No se encontraron diferencias con respecto al inicio en edad pediátrica o adulta. Más de la mitad de los pacientes (52%) tenían una UF localizada. A pesar de no ser estadísticamente significativa, la temperatura umbral evaluada con TempTest® 4.0 fue más alta y el tiempo de estimulación más corto en los pacientes con síntomas más graves. Todos los pacientes fueron tratados con antihistamínicos y uno con omalizumab. Los pacientes controlados con dosis estándar de antihistamínicos tenían temperatura umbral más baja que los que necesitaban dosis más altas (p < 0,01).
La UF es una enfermedad heterogénea que, en algunos casos, puede poner en peligro la vida del paciente. Las pruebas de provocación con frío pueden ser útiles en el manejo e identificación de grupos de gravedad.
Physical urticarias and cholinergic urticaria Abajian, Marina; Schoepke, Nicole; Altrichter, Sabine ...
Immunology and allergy clinics of North America,
02/2014, Letnik:
34, Številka:
1
Journal Article
Recenzirano
Physical urticarias are a unique subgroup of chronic urticaria in which urticarial responses can be reproducibly induced by different specific physical stimuli acting on the skin. These conditions ...include urticaria factitia/symptomatic dermographism, delayed pressure urticaria, cold contact urticaria, heat contact urticaria, solar urticaria, and vibratory urticaria/angioedema. Physical urticarias and cholinergic urticarias are diagnosed based on the patients' history and provocation tests including trigger threshold testing where possible. Treatment is mainly symptomatic. Many patients benefit from avoiding eliciting triggers, and desensitization to these triggers can be helpful in some physical urticarias and in cholinergic urticaria.
PLCG2 associated antibody deficiency and immune dysregulation (PLAID) is a complex dominantly inherited disease characterized almost universally by cold urticaria, and variably by recurrent bacterial ...infection, autoimmunty and skin granuloma formation. Several striking phenotypes can emerge from this disease, and the pathophysiology leads to a complex mix of loss and gain of function in cellular signaling. This review discusses the key phenotypic characteristics and pathophysiologic observations seen in PLAID, and contrasts PLAID to several related disorders in order to best contextualize this fascinating disease.
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