Role of Endothelial Cells in the Pathogenesis of Chronic Urticaria.

Study Overview
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Brief Summary
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Chronic urticaria (CU) is a disease that usually affects a large visible amount of surface of the skin. It is accompanied by severe itch and feeling of burned skin. Therefore the disease has a big impact on the quality of life of patients. Unfortunately, to date CU is not easily controlled by its few existing treatment options (i.e. antihistamines, omalizumab, cyclosporine). This research's main perspective is to improve quality of life for CU patients by first of all focusing on a good clinical diagnosis of (different subtypes of) CU in a CU reference center, and secondly by gaining more insight on the pathogenesis of the disease to expand knowledge on potential new targeted treatments for the patients.

Detailed Description
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Chronic urticaria (CU) is an inflammatory skin disease that is defined by the presence of urticaria (hives), on most days of the week, for a period of six weeks or longer. About 40 percent of patients with CU have accompanying episodes of angioedema. It is classified as chronic inducible urticaria (CIU) in which urticaria is induced by one or more environmental stimuli (such as heat, cold, pressure applied to the skin, exercise, water, vibration, and sunlight) and chronic spontaneous urticaria (CSU) which refers to CU in which appearance of lesions is not triggered by consistent or identifiable factors. At any given time, CU affects up to 1 percent of the general population in the United States, and the prevalence is believed to be similar in other countries. So far, epidemiological studies for a Belgian population haven't been performed yet. It is generally proposed that patients with CU have defects in mast cell and/or basophil trafficking, signaling and/or function. Nevertheless more recently also other cells seem to be involved: lymphocytes, eosinophils, endothelial cells (ECs). The integrity of EC structure and function is important in the maintenance of the vessel wall and circulatory function. As a barrier, the endothelium is semi-permeable and controls molecular transport between the blood and the tissues. Under basal conditions, ECs are involved in maintaining the anti-thrombotic blood-tissue interface by regulating thrombosis, thrombolysis, platelet adherence, vascular tone and blood flow. In CU, mast cells are activated and histamine release occurs. This histamine binds to its receptor on the ECs causing vasodilation and extravasation. This endothelial function/dysfunction can be characterized by several biological markers from different signalization/activation pathways. Vascular injury induces release of vascular endothelial growth factor (VEGF) to stimulate angiogenesis. Cytokine stimulation triggers the expression and release of adhesion molecules (e.g., E-selectin, ICAM-1, VCAM-1), making transendothelial migration of lymphocytes possible. In particular, E-selectin is expressed only by activated endothelium; however, its circulating form (sE-selectin) can be found in the plasma after enzymatic cleavage or from shedding by damaged or active ECs. Furthermore it is known for ECs to interact with mast cells through the production of Stem Cell Factor (SCF; c-kit ligand) to influence mast cell proliferation and differentiation. Asero et al (2003) determined serum SCF levels in 65 CIU patients and found no difference from those found in healthy controls. Nevertheless, the increase in mast cells in skin biopsy specimens, along with the absence of systemic eosinophilia in CIU patients suggests a possible role for stem cell factor (SCF) in CU pathogenesis. Endothelial progenitor cells (EPC) normally have the ability to develop into fully mature EC and contribute to neovascularization by targeting sites of endothelial injury. Furthermore it is shown that acute exercise-induced nitric oxide production contributes to upregulation of circulating endothelial progenitor cells in healthy subjects. Since exercise is a known trigger for CU, it would be interesting to investigate the effect of exercise on EPC recruitment and EC activation in CSU. Microvascular damage and EC injury is described in multiple diseases such as diabetes and scleroderma. This can be evaluated by nail fold videocapillaroscopy (NVC). The integrity of vessel walls is compromised in CU, of which the appearance of wheals due to the extravasation process seems to be the most obvious symptom clinically. It would be interesting to examine if there are microscopical abnormalities on NVC that could help identify (certain subtypes of) CU. If present, correlations between these abnormalities and disease severity can be further investigated. The objectives of the study are: To determine the incidence of CU (CSU and CIU) in a Belgian city center hospital To investigate the role of ECs in CSU on a clinical and molecular level

Official Title
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Prospective, Observational, Longitudinal Cohort Study on the Role of Endothelial Cells in the Pathogenesis of Chronic Urticaria.

Conditions
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Chronic Urticaria

Intervention / Treatment
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* Procedure: Punch Biopsy
* Procedure: Blood sampling


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All patients diagnosed with chronic urticaria receiving medical care within the CHU Brugmann Hospital. Diagnose performed according to the European Academy of Allergy and Clinical Immunology (EAACI) guidelines. Exclusion Criteria: None

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Chronic urticaria<br>50 consecutive chronic urticaria patients receiving medical care within the CHU Brugmann Hospital. Diagnose according to the European Academy of Allergy and Clinical Immunology (EAACI) guidelines. | Procedure: Punch Biopsy<br>* A 3 mm punch biopsy will be taken from lesional and non-lesional skin as a routine procedure.<br>Procedure: Blood sampling<br>* Blood sampling<br>|
| Control<br>20 healthy control patients, without chronic urticaria. Patients coming to the CHU Brugmann hospital for the excision of atypical naevi. | Procedure: Punch Biopsy<br>* A 3 mm punch biopsy will be taken from lesional and non-lesional skin as a routine procedure.<br>Procedure: Blood sampling<br>* Blood sampling<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Stem cell factor expression | Immunohistochemistry performed on cryostat sections with a monoclonal antibody | 6 months | 
| E-selectin expression | Immunohistochemistry performed on paraformaldehyde fixed sections with a monoclonal antibody | 6 months | 
| Vascular endothelial growth factor (VEGF) expression | Immunohistochemistry performed with a monoclonal antibody on paraffin sections | 6 months | 
| C5B9 complement complex expression | Immunofluorescence staining performed on paraffin-embedded tissue blocks | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of chronic inducible urticaria | Incidence of chronic inducible urticaria within the CHU Brugmann Hospital. Diagnose established by means of provocation tests. | 6 months | 
| Incidence of chronic spontaneous urticaria | Incidence of chronic spontaneous urticaria within the CHU Brugmann Hospital. Diagnose established by means of provocation tests. | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic Urticaria, Endothelial cells