Samah Al Tawil

Examinateur Rapporteur Petra

Staubach

Examinateur Rapporteur Khaled

Salameh Pascale

 Tawil

Ezzedine K Les

Physiological and psychological distress associated with chronic urticaria

Keywords: urticaria, validation, auto-diagnostic, risk factors, quality of life, psychological Scientific

Although not related to an increase in mortality, mast cell driven diseases, namely urticaria, may have devastating effects on patients' quality of life. At the international level, there are still major unmet needs in many research aspects, such as the lack of insight into prevalence, risk factors and quality of life tools. The objectives of this project were the cross-validation of Urticara Activity Score (UAS-7) and Chronic urticaria Quality of Life (Cu-Q2oL) (Phase 1-A), the validation of self reportedurticaria diagnostic tool (SRUD) for epidemiological studies, the assessment of the prevalence and the risk factors of urticaria (phase 1-B), and its effect on the quality of life and psychological wellbeing of the patients in the Middle Eastern region (phase 2). This project included studies that were conducted between July 2018 and June 2021 in multicentered settings. During the first phase, the validity and reliability of the Arabic versions of the UAS-7 and the CU-Q2oL were investigated and the correlation between them was estimated. More patients with urticaria and other control patients with other dermatological conditions were recruited and asked to fill an auto-diagnostic questionnaire that was validated. Assessment of the prevalence of urticaria and its risk/triggering factors were also studied. The second phase focused on the evaluation of the impact of chronic urticaria (CU) on QoL and mental health. A prospective follow-up was performed on 152 patients with CU in phase 1. Both the Arabic UAS-7 and CU-Q2oL demonstrated high internal consistency (Cronbach alpha of 0.95 and 0.82 respectively) and moderate-to-high test-retest reliability (Intraclass coefficient of 0.61 and 0.91 respectively). Mild-to-moderate correlation was found between the Arabic UAS-7 and CU-Q2oL (r=0.52) as well as the dermatology life Quality Index (DLQI) (r=0.51). Recruitment of 402 patients with any dermatological disease continued and validation of the SRUD was done. It was found to have an excellent internal consistency (Cronbach alpha=0.8), a sensitivity of 89.1% and a specificity of 77.7% when compared with the physician's diagnosis. Prevalence of chronic urticaria was 44.5% and most important risk factors were asthma and prior allergy. Phase 2 included 295 patients with CU. A moderate negative correlation was detected between Urticaria Control Test (UCT) scores and Heath-related Quality of Life (HRQoL) assessments as well as Patient Health questionnaire-9 (PHQ-9) and Beirut Distress Score (BDS-22) (p<0.001). Patients with the lowest UCT score had the highest impairment in HRQoL scores and depression level. Our findings demonstrate that the Arabic versions of the UAS-7 and the CU-Q2oL are valid and reliable. In addition, the newly self-reported urticaria diagnostic tool (SRUD) demonstrated sufficient validity and can be used for further epidemiological research. It was also clearly demonstrated that CU compromises patients' quality of life and psychological health. Keeping that in mind, further larger controlled clinical trials are a must and local registries are essential for the global management of urticaria.

Résumé (Français)

Bien qu'elles ne soient pas liées à une augmentation de mortalité, les maladies provoquées par les mastocytes, notemment l'urticaire, peuvent avoir des effets néfastes sur la qualité de vie des patients. Au niveau international, il existe encore d'importants besoins non satisfaits dans de nombreux aspects de la recherche, tels que le manque de connaissance sur la prévalence, les facteurs de risque et les outils de qualité de vie concernant cette maladie. Les objectifs de ce projet étaient la validation croisée du score d'activité de l'urticaire (UAS-7) et de la qualité de vie de l'urticaire chronique (Cu-Q2oL) (Phase 1-A), la validation de l'outil de l'auto-diagnostic de l'urticaire (SRUD) pour des études épidémiologiques, et l'évaluation de la prévalence et des facteurs de risque de l'urticaire (phase 1-B), ainsi que son effet sur la qualité de vie et le bien-être psychologique des patients dans la région du Moyen-Orient (phase 2). Ce projet comprenait plusieurs études menées entre juillet 2018 et juin 2021 dans des contextes multicentriques. Au cours de la première phase, la validité et la fiabilité des versions arabes de l'UAS-7 et du CU-Q2oL ont été étudiées et la corrélation entre ces deux scores a été estimée. Le recruitement des patients atteints d'urticaire et d'autres cas témoins atteints d'autres maladies dermatologiques a continué et les participants ont été invités à remplir un questionnaire d'autodiagnostic qui a été validé. L'évaluation de la prévalence de l'urticaire et de ses facteurs de risque a également été évaluée. La deuxième phase était concentrée sur l'évaluation de l'impact de l'urticaire chronique (UC) sur la qualité de vie et la santé mentale des patients atteints. Un suivi prospectif a été réalisé sur 152 patients atteints de UC en phase 1. Les versions arabes de l'UAS-7 et CU-Q2oL ont démontré une cohérence interne élevée (alpha de Cronbach de 0,95 et 0,82 respectivement) et une fiabilité test-retest modérée à élevée (Coefficient intraclasse de 0,61 et 0,91 respectivement). Une corrélation légère à modérée a été trouvée entre le UAS-7 et le CU-Q2oL (r=0,52) ainsi que l'indice de qualité de vie dermatologique (DLQI) (r=0,51). Le recrutement de 402 patients atteints d'une maladie dermatologique s'est poursuivi et la validation de SRUD a été effectuée. Il s'est avéré avoir une excellente cohérence interne (alpha de Cronbach=0,8), une sensibilité de 89,1 % et une spécificité de 77,7 % tout en étant comparé au diagnostic du médecin traitant. La prévalence de l'urticaire chronique était de 44,5 % et les facteurs de risque les plus importants étaient l'asthme et la présence d'une allergie antérieure. La phase 2 a inclus 295 patients atteints de UC. Une corrélation négative modérée a été détectée entre les scores du test de contrôle de l'urticaire (UCT) et les évaluations de la qualité de vie reliée à la santé (HRQoL) ainsi que le questionnaire de santé du patient-9 (PHQ-9) et le score de détresse de Beyrouth (BDS-22) (p<0,001). Les patients avec le score UCT le plus bas présentaient la plus grande altération des scores HRQoL et PHQ-9. Nos résultats démontrent que les versions arabes du UAS-7 et du CU-Q2oL sont valides et fiables. En outre, le nouvel outil d'auto-diagnostic de l'urticaire (SRUD) a démontré une validité suffisante et peut être utilisé pour d'autres recherches épidémiologiques. Il a également été démontré que la UC a un effet négatif sur la qualité de vie et la santé psychologique des patients. En gardant cela à l'esprit, d'autres essais cliniques plus contrôlés sont indispensables à conduire et les registres locaux sont essentiels pour la prise en charge mondiale de l'urticaire.

Mots-clés: urticaire, validation, auto-diagnostic, facteurs de risque, qualité de vie, psychologique

Résumé Substantiel (Français)

Au niveau international, malgré le grand nombre d'études menées pour évaluer les maladies provoquées par les mastocytes (MCDD) en particulier l'urticaire, il existe encore d'importants besoins non satisfaits tels que les études sur sa prévalence ainsi que ses facteurs de risque et son impact sur la qualité de vie et la santé psychologique à l'aide d'outils spécifiques validés. De plus, il y a un manque de questionnaires spécifiques pour évaluer l'urticaire chronique (UC) et une connaissance limitée de l'impact de la relation médecin/patient au cours du traitement. De plus, aucun outil spécifique n'a jamais été généré ni validé dans la région du Moyen-Orient pour évaluer la sévérité de l'urticaire ni son effet sur la qualité de vie des patients. Par conséquent, nous avons conçu ce projet pour avoir une connaissance plus approfondie de l'urticaire afin d'évaluer sa prévalence, l'utilisation appropriée de ses outils de diagnostic et de leur processus de validation, et son fardeau sur les patients ainsi que leurs activités quotidiennes.

Ce projet a été mené entre juillet 2018 et juin 2021 dans des contextes multicentriques, qu'il s'agisse des cliniques de dermatologie ou d'allergie/immunologie de tous les gouvernerats du Liban, et a inclus des patients qui ont présenté une affection dermatologique en particulier l'urticaire. Ce projet a été divisé en deux phases. La première phase s'est concentrée sur la validation croisée des versions arabes des outils d'évaluation de l'activité de la maladie et de l'altération de la qualité de vie (QdV) ainsi que la validation d'un outil d'autodiagnostic pour l'urticaire «SRUD» à utiliser dans d'autres études épidémiologiques. Cette phase a également été conçue pour estimer la prévalence de l'urticaire chez les patients visitant les cliniques externes ou privées ainsi que les facteurs de risque qui y sont liés. La deuxième phase s'est concentrée sur son impact sur la Qdv et la santé mentale des patients concernés. Les critères d'évaluation secondaires de la première phase de l'étude se sont concentrés sur la comparaison entre les diagnostics des dermatologues et des allergologues pour évaluer leur concordance avec les résultats du questionnaire auto-diagnostic. Les critères d'évaluation secondaires de la phase 2 étaient 1) l'évaluation des corrélations entre les différents scores de qualité de vie et de détresse psychologique et 2) la distribution des scores vis-a-vis des différents facteurs affectant l'urticaire. Dans la première phase de l'étude, une étude prospective a été effectuée pour 152 patients diagnostiqués avec une UC afin d'étudier la validité et la fiabilité des versions arabes de l'Urticaria Activity Score 7 (UAS7) et du questionnaire sur la qualité de vie de l'urticaire chronique (CU-Q2oL) et d'estimer la corrélation entre eux. Les deuxième et troisième visites ont été fixées à une intervalle de deux semaines chacune, et les patients ont été informés du processus d'achèvement de l'UAS7, du CU-Q2oL ainsi que l'indice de vie dermatologique (DLQI) et ont été invités à remplir l'UAS7 au cours des 7 jours précédant la visite. Au quatorzième jour, le questionnaire UAS7 a été collecté et les versions arabes du CU-Q2oL et du DLQI ont été à nouveau complétées par les patients. Un autre UAS7 a été partagé avec chaque patient afin de le compléter avant la troisième visite (jour 28), et le CU-Q2oL et le DLQI ont à nouveau été remplis. Au cours de la première phase également, les patients atteints d'urticaire ont été invités à remplir un questionnaire d'auto-diagnostic avec d'autres patients témoins souffrant d'autres maladies dermatologiques (402 patients au total) dans une méthode transversale pour évaluer la prévalence de l'urticaire ainsi que son association avec certains facteurs de risque. L'existence d'interaction entre les facteurs personnels et environnementaux dans l'exacerbation de cette maladie a été aussi évaluée. La deuxième phase s'est concentrée sur le recrutement de plus de patients atteints de UC pour aboutir à un échantillon de 295 patients afin d'évaluer l'impact de l'UC sur la qualité de vie des patients affectés en utilisant des outils précédemment validés tels que CU-Q2oL, Dermatology life Index (DLQI) et le test de contrôle de l'urticaire (UCT). Les patients étaient inclus s'ils avaient plus de 18 ans. Ceux qui avaient un trouble psychiatrique diagnostiqué ou une déficience cognitive due à une maladie cérébrale ou psychotique actuelle, ou même une maladie maligne ou une maladie du système nerveux central ont été exclus. Un questionnaire spécifique a été préparé en trois langues : arabe, français et anglais. Le questionnaire comportait de nombreuses sections: les caractéristiques sociodémographiques et de santé, le diagnostic dermatologique antérieur, la plainte principale, les facteurs de risque, les scores de sévérité [UCT, UAS7, Angioedema Activity Score (AAS)], les scores pour mesurer la détresse psychologique ou la dépression [Beirut Distress et Patient Health Questionnaire (PHQ-9)], ainsi que les indices de qualité de vie (DLQI et CU-Q2oL). À la fin, une section pour le diagnostic du médecin, les résultats des tests de laboratoire et l'autodiagnostic du patient avec des images illustrées étaient disponibles. Le questionnaire auto-administré a été modélisé sur la base de plusieurs références et directives et a été utilisé pour identifier si le patient pense avoir la maladie d'intérêt (papules, gonflement, démangeaisons, début et durée de chacune et site d'apparition).

Parmi les 152 patients inclus dans la première phase, la fiabilité test-retest des scores UAS7 et CU-Q2oL a été réalisée sur 44 patients. L'UAS7 arabe et le CU-Q2oL ont démontré une cohérence interne élevée (alpha de Cronbach de 0,95 et 0,82 respectivement) et une fiabilité test-retest modérée à élevée (coefficient intraclasse (ICC) de 0,61 et 0,91 respectivement). L'analyse factorielle exploratoire du CU-Q2oL arabe a révélé cinq composantes qui expliquaient 81,8% de la variance totale. Les ICCs pour le score total CU-Q2oL et chacun des cinq scores de domaine entre la deuxième et la troisième visite ont été calculés pour les 44 patients dont leur état médical était considéré stable révélant une fiabilité moyenne à forte. Des corrélations significatives ont été trouvées entre le CU-Q2oL et DLQI (r=0,86), et des corrélations légères à modérées entre l'UAS7 et CU-Q2oL (r=0,52) ainsi que le DLQI (r=0,51). Cela prouve que la Qdv des patients souffrant de l'UC n'est pas seulement influencée par l'activité de la maladie, mais aussi par des facteurs supplémentaires tels que la privation de sommeil et les comorbidités psychiatriques existentes. Quant à la validation de l'outil d'autodiagnostic, sa cohérence interne s'est avérée élevée (alpha de Cronbach=0,8) avec une sensibilité acceptable de 89,5% et une spécificité de 75,7% ce qui indique que le questionnaire est simple et facilement adapté par les patients. Pour confirmer la validité du questionnaire, une analyse factorielle a été réalisée à l'aide d'une analyse en composantes principales. Deux facteurs ont été créés dont leur somme a constitué une nouvelle variable appelée « Diagnostic auto-déclaré de l'urticaire (SRUD) » avec une médiane de 4,00 [3,00 -5,00]. La version finale de ce nouvel outil d'autodiagnostic validé comprenait sept items avec une réponse « Oui » ou « Non » avec Oui =1 et Non =0. Pour que le patient puisse se diagnostiquer comme ayant une urticaire, le score devait être 4 ou plus. 355 patients (65,1%) avaient un score SRUD >4, par conséquent, se sont diagnostiqués eux-mêmes comme ayant une urticaire alors qu'un nombre inférieur (52,7%) a eu un diagnostic final d'urticaire lorsqu'il a été diagnostiqué par un médecin spécialiste. En outre, la prévalence de l'UC était de 44,5% qui est une valeur beaucoup plus élevée que le taux de prévalence indiqué dans les études de recherche précédentes (environ 0,5 à 1,8%). Ceci peut s'expliquer par le fait que la population cible principale était celle affectée par l'urticaire. En effet, depuis le début de ce projet, l'objectif principal était de recruter des patients atteints d'UC uniquement afin de valider de manière croisée les scores liés à son activité et son impact sur Qdv. De plus, une analyse multivariée utilisant la régression logistique dans laquelle l'urticaire était utilisée comme variable dépendante et les facteurs sociodémographiques, médicaux et autres facteurs environnementaux étaient considérés comme des variables indépendantes, a conclu que les facteurs de risque les plus importants associés à l'urticaire étaient l'asthme et les antécédents d'allergie. En effet, les patients qui souffrent de crises d'urticaire sévères rapportent fréquemment des sensations de «détresse respiratoire» et beaucoup d'entre eux souffrent de la présence concomitante d'allergie. De plus, le coefficient de Cohen Kappa a été calculé pour évaluer la concordance entre les patients et le diagnostic final du médecin selon l'interprétation de McHugh de Kappa, et était égal à 0,61, ce qui indique une bonne concordance entre les deux types de diagnostic. Le pourcentage de concordance entre les deux évaluateurs était de 81,7% (290/355 au total) qui est une valeur acceptable relativement. Une association statistiquement significative a été trouvée entre «SRUD» et le diagnostic du médecin (p<0,001). La majorité des patients (81,4%) se sont diagnostiqués en concordance avec le diagnostic final de leur médecin quelle que soit leur spécialité. La phase 2 a inclus 295 patients atteints d'UC. Une corrélation négative modérée a été détectée entre le contrôle de l'urticaire qui a été évalué par le score UCT et les évaluations de la qualité de vie ainsi que PHQ-9 et BDS-22 (p<0,001). Les patients ayant le score UCT le plus bas (i.e. un très mauvais contrôle de la CU) présentaient la plus forte altération des scores de la Qdv et de PHQ-9. Les patients qui avaient un bon contrôle de leur maladie (UCT ≥12) avaient les scores médians DLQI et CU-Q2oL les plus bas (4,00±4,75 et 34,00±14,00; p<0,001) ce qui indique que leur Qdv a été mois affectée. De plus, les patients avec des scores UCT<8 (très mauvais contrôle de l'uticaire) avaient les scores médians les plus élevés de PHQ-9 et BDS-22 (17,5±8,75 et 39,0±18,5 respectivement) indiquant qu'ils étaient plus sujets à la dépression et à la détresse psychologique car une augmentation du score des questionnaires sur la qualité de vie et la santé psychologique est révélatrice des résultats moins satisfaisants. Pour ajouter, l'analyse MANCOVA des scores CU-Q2oL et PHQ-9 a été effectuée parmi différentes catégories de caractéristiques sociodémographiques et de facteurs de risque en utilisant le sexe et l'âge comme covariables. Des variables tels que l'urticaire spontanée et le stress émotionnel ont été associées à une augmentation de la CU-Q2oL indiquant que la présence de ces facteurs affectait négativement la qualité de vie des patients atteints d'urticaire. Cela fait preuve que le stress a un grand impact sur la qualité de vie des patients atteints d'urticaire et peut influencer négativement leur Qdv. De plus, le fait d'avoir moins qu'un diplôme universitaire était associé à une augmentation du score PHQ-9 indiquant ainsi un niveau de dépression plus élevé que les autres catégories d'éducation.

En résumé, les versions arabes des scores UAS7 et CU-Q2oL se sont avérées montrer une performance psychométrique robuste chez les patients atteints de l'UC dans la pratique clinique habituelle. Les deux outils sont adaptés pour évaluer l'activité de la maladie et l'impact sur la qualité de vie, respectivement, chez les patients arabophones. La fiabilité et la validité des versions arabes UAS7 et CU-Q2oL sont similaires à celles rapportées pour les autres versions linguistiques. De plus, le nouvel outil d'autodiagnostic SRUD a fait preuve d'une grande fiabilité et peut être utilisé pour aider à poursuivre les prochaines recherches épidémiologiques évaluant la prévalence réelle de l'urticaire, son effet sur la qualité de vie et la santé mentale des patients, spécialement dans la région du Moyen-Orient. La concordance diagnostique prouvée dans notre étude n'est que la première étape d'un continuum de soins et servira également une base à des études plus larges afin d'améliorer les connaissances sur l'urticaire, son diagnostic et les différents types de traitement. De plus, l'évaluation de la Qdv est fondamentale pour mieux évaluer la progression de la maladie et l'efficacité du traitement. Cela devrait être pris en compte dans la pratique clinique ainsi que dans d'autres essais expérimentaux et cliniques. Sachant que ce projet est l'un des plus rares menés dans la région concernant l'urticaire, nos résultats stimulent la poursuite des recherches concernant le diagnostic de MCDD en particulier l'urticaire et l'implication du patient dans le processus medical. Cela pourrait être accompli par le développement et la validation d'outils de diagnostic simples utilisés par les médecins et les patients, tels que l'outil d'auto-diagnostic SRUD. De plus, des recherches plus élargies doivent être munies pour évaluer les obstacles qui interdisent l'accès aux soins essentiels. De point de vue global, l'élaboration de directives locales fait également partie de la prise en charge de la maladie pour évaluer les essais scientifiques publiés et fournir des recommandations basées sur les caractéristiques spécifiques de la population ainsi que l'évaluation régionale concernant les caractéristiques de la maladie, les facteurs de risque et les différents choix de traitement.

Dedications

I would like to express my genuine appreciation to Professors Khaled Ezzedine and Pascale Salameh for their continuous support, and helpful comments in completing this thesis. I dedicate this work to my husband and my two children who have helped me complete my work with a lot of understanding. They have made me stronger, better and more fulfilled than I could have ever imagined. And to my family, the accomplishment of this thesis would not have been possible without your continuous love and support, thank you for the encouragement that you provided me and the sacrifices you made during these past two years. I love you! Finally, I am grateful to have had the privilege of attending the prestigious Paris-Est University. This experience has granted me the opportunity to work with some of the best and brightest teachers, and the resources for me to achieve great success.

ABBREVIATIONS Abbreviation Definition

AAS

LIST OF TABLES

I. INTRODUCTION

The mast cell is a tissue resident granulocyte, active in the allergic response but also playing a vital role in immune tolerance, wound healing, angiogenesis and the innate immune response [1].

Mast cells can be found in virtually all organs and are abundantly present in skin and mucosal tissues.

They are strategically localized in close proximity to blood vessels, neurons, and lymphatic vessels, which gives them the ability to relay local inflammatory signals to distant target cells and tissues [2].

With respect to normal physiological functions, mast cells are known to control vasodilation, vascular homeostasis, angiogenesis, and innate and adaptive immune responses [3]. On the other hand, mast cells have also been implicated in the pathophysiology of many diseases through antigen-mediated activation of mast cells, which initiates signaling events leading to Calcium response and the release of inflammatory and allergic mediators from granules [4]. These diseases are known as Mast Cell Driven Disorders (MCDD) and they include urticaria, mastocytosis, type I allergies, as well as other inflammatory and autoimmune illnesses in addition to malignant tumors [2].

Urticaria remains a major problem in terms of etiology, investigation, management and causes as well as the high cost to the health care system. At the international level, despite the large numbers of studies conducted to assess urticaria as well as the prevalence of many inflammatory skin diseases such as atopic dermatitis (AD), psoriasis, alopecia areata, vitiligo and hidradenitis suppurativa in many regions of the world and their burden on patients [5][6][7][8][9], many research aspects regarding this disease are still scarce, especially in the Middle Eastern region, such as the paucity of standardized prevalence studies and the lack of insight into the risk factors and the quality of life (QoL) tools and as well as relationship with psychological variables. Moreover, few studies were conducted in Lebanon on the prevalence and etiology of urticaria although some have tackled the validation of scores for the assessment of the control of chronic urticaria (CU) [START_REF] Irani | Chronic urticaria in most patients is poorly controlled[END_REF] and others have shown a link between CU and auto-immune thyroid diseases [START_REF] Irani | Chronic urticaria and autoimmune thyroid disease in lebanon[END_REF]. However, there is yet a major need to answer many aspects in regards to MCDD research in general, such as the scarcity of standardized global incidence and prevalence studies [START_REF] Zuberbier | The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria[END_REF], the absence of specific tools that could evaluate CU, the lack of assessment of the impact of the physician/patient relationship during therapy, the cross-cultural validation of the available tools throughout the world, the estimation of the risk factors associated with urticaria, and the unavailability of specific tools that can help determine the quality of life (QoL) effects of MCDD on the affected patients in the Middle Eastern region.

I.1. LITERATURE REVIEW I.1.1. DEFINITIONS

MCDDs are common in the general population, specifically spontaneous and inducible urticaria. Urticaria is a group of diseases characterized by mast cell-mediated and histaminedependent wheal and flare responses associated with severe pruritus [START_REF] Maurer | Practical algorithm for diagnosing patients with recurrent wheals or angioedema[END_REF]. Other mediators such as platelet-activating factor and cytokines are also released from activated mast cells, and may result in vasodilatation, sensory nerve activation, and plasma extravasation as well as cell recruitment towards urticarial lesions [START_REF] Zuberbier | The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria[END_REF]. These findings underline the complex nature of the pathogenesis of urticaria and makes it notoriously hard to treat [START_REF] Maurer | Practical algorithm for diagnosing patients with recurrent wheals or angioedema[END_REF].

Urticaria is characterized by the sudden appearance of wheals (hives), angioedema, or both. 30 to 40% of patients present with isolated hives, 10 to 20% with isolated angioedema and one-third present with both hives and angioedema [START_REF] Antia | Urticaria: A Comprehensive review: epidemiology, diagnosis, and work-up[END_REF]. Urticarial wheals can be a few millimetres or several centimetres in diameter, colored white or red, with or without a red flare. Each wheal may last a few minutes or several hours and may change in shape. Wheals may be round, or form rings, a map-like pattern, or giant patches. They are accompanied by itching or sometimes a burning sensation, with the skin returning to its normal appearance, usually within 1-24 hours, although sometimes wheals resolve even more quickly. Angioedema is more often localised. It commonly affects the face (especially eyelids and perioral sites), hands, feet, and genitalia. It may involve tongue, uvula, soft palate, or larynx. It is usually characterized by a swift, pronounced erythematous or skin-colored swelling of the lower dermis and subcutis with frequent involvement below mucous membranes and sometimes pain is encountered more than itching, its resolution is slower than that for wheals and can take up to 72 hours. Both urticaria and angioedema often coexist as relapsing and remitting episodes [START_REF] Zuberbier | The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria[END_REF][START_REF] Godse | Consensus statement for the diagnosis and treatment of urticaria: A 2017 update[END_REF]. 'urticatio' (derived from the Latin urere; to burn), and 'scarlatina urticaria' are all names that decribed urticaria. In the 18th century, urticaria was compared with the stinging and burning of a nettle (Urtica dioica). The first scientist who used the term "urticaria" in 1769 was William Cullen [START_REF] Rook | The historical background[END_REF][START_REF] Czarnetzki | The history of urticaria[END_REF].

I.1.2. HISTORICAL BACKGROUND

I.1.3. EPIDEMIOLOGY

Urticaria is a common worldwide disease that has a prevalence of an average of 0.05% to 23.6% in the general population, but a range of 1-5% seems more realistic depending on the age range, method of sampling, and geographic location, with point prevalence being 0.5-1.0%. The prevalence for acute urticaria is approximately 20% while the annual prevalence of CU is 0.5 to 2.3%, and its lifetime prevalence is 1.8% across several countries [START_REF] Min | Emerging Therapies in Chronic Spontaneous Urticaria[END_REF]. Chronic spontaneous urticaria (CSU) constitutes the most common form of CU and was statistically significantly higher to be happening in the presence of the following variables: obesity; anxiety, dissociative and somatoform disorders; malignancies; use of immunosuppressive drugs; and chronic use of systemic corticosteroids [START_REF] Godse | Consensus statement for the diagnosis and treatment of urticaria: A 2017 update[END_REF][START_REF] Lapi | Epidemiology of chronic spontaneous urticaria: results from a nationwide, population-based study in Italy[END_REF]. In general, urticaria appears to be more common in adults than children (3.4 to 5.4%) and in females with 0.48% prevalence rate versus 0.23% in males constituting a ratio of 2:1 and an incidence in females of 1.6 versus 0.8 per 1000 person-years in males [START_REF] Antia | Urticaria: A Comprehensive review: epidemiology, diagnosis, and work-up[END_REF][START_REF] Radonjic-Hoesli | Urticaria and Angioedema: An Update on Classification and Pathogenesis[END_REF]. According to the systematic review with meta-analysis that was conducted by Fricke, J. and his colleagues in 2019, it was shown that CU affects a considerable part of the population around the globe with overall lifetime and point prevalence rates of 1.4% and 0.7% respectively. CU seems to be more prevalent in Asia than Europe and Northern America. Regarding sex-specific analyses, women seemed to be more affected than men.

In children less than 15 years old, a sex-specific difference was not detected. Varying time trend evaluations showed an increasing prevalence of CU in recent years [START_REF] Fricke | Prevalence of chronic urticaria in children and adults across the globe: Systematic review with meta-analysis[END_REF].

I.1.4. HISTOPATHOLOGY

Edema is usually present in the superficial portion of the dermis in urticaria. Dilated veins with endothelial swelling with minimal inflammatory cells are seen in acute urticaria, while a perivascular and interstitial infiltration of lymphocytes, eosinophils and neutrophils is seen in chronic urticaria. The major basic protein, a cytotoxic molecule from eosinophilic granules, is found in the dermis of skin lesions of chronic urticaria, delayed pressure urticaria, and solar urticaria [START_REF] Mobini | Noninfectious erythematous papular, and squamous disease[END_REF]. Moreover, an early leukocytoclastic vasculitis characterized by neutrophilic infiltration in and around dermal blood vessels, minimal fibrin deposits and extravasation of erythrocytes is seen in urticarial vasculitis. Necrotizing vasculitis of venules has been found in dermographism, cold urticaria, pressure urticaria and solar urticaria. Direct immunofluorescence test shows prominent granular deposits of immune complexes along with dermoepidermal junction and perivascular areas [START_REF] Peters | Extracellular deposition of eosinophil major basic protein in pressure urticaria[END_REF]24].

I.1.5. PATHOGENESIS

The Mast Cell

The cutaneous mast cells have been deeply implicated in urticaria. Upon activation, they liberate mediators, resulting in vasodilatation and increase in the local permeability of capillaries and venules. Both the phenotypes of mast cells (MCTC, mast cells of the skin and intestinal mucosa containing tryptase and chymase; and MCT, mast cells of the bowel mucosa, alveolar wall and nasal mucosa containing only tryptase) usually express high affinity IgE receptors on their cell surface and are able to take part in IgE-dependent allergic reactions [START_REF] Church | Effector cells of allergy[END_REF]. anaphylotoxin, further enhancing degranulation [START_REF] Grattan | Urticaria and angioedema[END_REF].

Mediators

The mast cells contain preformed mediators (histamine, heparin, proteases like tryptase, chymase) as well as newly formed mediators [leukotrienes (LTs), platelet activating factors (PAF), and prostaglandin D2]. Those mast cells may also contain cytokines [tumor necrosis factor (TNF-α), interleukins (IL-3, -4, -5, -6, -8, and -13) and granulocyte-macrophage-colony stimulating factor].

Upon stimulation, histamine, which is the most important preformed mediator, binds to H1 receptors in the skin and induces itching, flare, erythema and wheal, and to H2 receptors to lead to erythema and wheal. Chymase and tryptase help in the cleavage of C3 to C3a and C3b, which activate mast cells and the alternative complement pathway respectively. Stimulation of FcRI upregulates the secretion of the cytokines mentioned above and release of TNF-α induces expression of adhesion molecules (such as E-selectin) on the endothelial cells of post-capillary venules. Prostaglandin E2 has been found to be an inhibitor of degranulation and thus may have a protective role in urticaria [START_REF] Kobayasi | Degranulation and regranulation of human mast cells[END_REF].

Leukocytes

Upon IgE stimulation, basophils release less histamine and are greatly reduced. Eosinophils play a role in the persistence of wheals by generating leukotrienes C4, D4 and E4 and by releasing major basic protein. Neutrophils and lymphocytes may also enhance and perpetuate the wheal response [START_REF] Kaminer | Extracellular localization of human connective tissue mast cell granule contents[END_REF].

Blood Vessels

Vasodilation is caused by the binding of histamine and other mediators to post-capillary venules, causing vasodilatation, edema and increase in permeability to plasma proteins like albumin and immunoglobulin which leads to what is called clinically a 'wheal'. The expression of adhesion molecules on the endothelial cells of these venules results in the attachment of blood leukocytes to the endothelial luminal membrane and their entrance into the cutaneous compartement [START_REF] Klein | Degranulation of human mast cell induces an endothelial antigen central to leukocyte adhesion[END_REF].

Other Pathomechanisms (Mast Cell Independent)

Not all mechanisms of urticaria are known to be mast cell dependents. In some cases, C1

esterase inhibitor deficiency urticarias may be complement and kinin dependent. In other cases, the exact pathogenesis may be not well known such as in patients suffering from many physical urticarias [START_REF] Christofiden-Solomidon | Induction of E selectin-dependent leukocyte recruitment by mast cell degranulation in human skin grafts transplanted as SCID mice[END_REF].

I.2. CLINICAL CLASSIFICATION

Urticaria is classified as either acute or chronic based on the duration of illness. Acute urticaria is defined as the presence of evanescent wheals with or without angioedema which completely resolve within six weeks and routine diagnostic measures are not recommended. It becomes evident a few minutes after the person has been exposed to an allergen. The outbreak may last several weeks, but usually the hives are gone in six weeks. Acute urticaria usually does not require a diagnostic workup, as it is usually self-limiting, whereas, the recurrence of lesions over more than 6 weeks is considered as chronic urticaria. CU has an unpredictable course; its treatment is based on controlling clinical symptoms until spontaneous remission [START_REF] Radonjic-Hoesli | Urticaria and Angioedema: An Update on Classification and Pathogenesis[END_REF][START_REF] Eun | Natural course of new-onset urticaria: Results of a 10-year follow-up, nationwide, population-based study[END_REF] and it is estimated that 80 to 90% of patients with CU have no identifiable cause of the disease [START_REF] Doong | Chronic idiopathic urticaria: systemic complaints and their relationship with disease and immune measures[END_REF]. Chronic urticaria comprises both CSU and chronic inducible urticaria (CIU) that includes physical (symptomatic dermographism/urticaria factitia, cold-and heat-induced urticarias, delayed pressure urticaria, solar urticaria) and non-physical urticarias (cholinergic urticaria, contact urticaria, and aquagenic urticaria) [START_REF] Radonjic-Hoesli | Urticaria and Angioedema: An Update on Classification and Pathogenesis[END_REF]. Acute and chronic hives are visually indistinguishable. Details about the different types of urticaria are summarized in Table 1. Intensive and costly general screening programs for causes of urticaria that look for the causes of urticaria, and stress on relying largely on patient's history, physical examination, and appropriate follow-up are strongly advised against [START_REF] Westby | Chronic urticaria: Following practice guidelines[END_REF]. Therefore, unless strongly proposed by the thorough history checkup, it is not recommended to execute a costly screening program in order to investigate the underlying etiologies which could include infectious causes, type I allergy, functional autoantibodies, thyroid hormones and autoantibodies, tryptase, and autologous serum skin [START_REF] Zuberbier | The EAACI/GA 2 LEN/EDF/WAO guideline for the definition, classification, diagnosis, and management of urticaria: The 2013 revision and update[END_REF]. Consequently, diagnosis should be made by a specific detailed patient history, physical examination, and also some routine laboratory investigations in order to rule out any autoimmune or auto inflammatory disease [START_REF] Godse | Consensus statement for the diagnosis and treatment of urticaria: A 2017 update[END_REF]. Period and frequency of intermittent symptoms will help define the chronicity of the disease, whereas duration of the patient's lesions can assist in deciding underlying pathogenesis. When patients report recognizable triggers that would indicate CIU, threshold testing should be done. If CSU is suspected, complete blood count (CBC) with differential and erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) should be completed.

I.2.1. TYPES OF URTICARIA AND CAUSATIVE AGENTS

Urticaria may be either spontaneous or inducible. If spontaneous, the causative agent cannot be known. However, some of the risk factors may be associated with inducible urticaria and may be listed according to the type of urticaria involved:  Infections and infestations including influenza, the common cold, glandular fever, hepatitis B, bacterial infections such as dental sepsis, sinusitis, urinary tract and gallbladder infections may cause urticaria. Helicobacter pylori infection of the stomach has also been associated with chronic urticaria. Intestinal parasites may also fall under this category. Linear wheals may follow migration of Ancylostoma and Strongyloides worms.

I.2.
 Autoimmune component may be associated with CU such as in the case of chronic illnesses, thyroid diseases or systemic lupus eythematouses (SLE). About 40% cases of chronic urticaria have an autoimmune basis. There are circulating anti-IgE antibodies and also antibodies to the subunit of the high affinity IgE receptor (FcRI) located on the outer surface of all mast cells and basophils in 10% and 30% patients of chronic idiopathic urticaria respectively.

Basophils have been found in a reduced number in the peripheral blood in autoimmune urticaria because of their recruitment in wheals.

 Inhalants including fumes and odors from some chemicals and detergents, grass pollen, mould spores, animal dander and house dust mites.

 Aggravating factors: Extreme temperatures or changes in temperature, sunlight exposure, overheating, exercise, scratching, pressure, alcohol, stress, contact with water, and premenstrual period in women.

I.2.1.2. INDUCIBLE URTICARIA

 Physical urticarias [41]

Physical urticaria occurs due to a specific stimulus which causes whealing that appears within minutes and lasts approximately 30 to 60 minutes. This type of urticaria may sub-classified according to the causative agent behind its appearance and can be summarized according to the list below:

 Mechanical force:

o Dermographism: It is a rapid appearance of a linear wheal with flare at the site where scratching occurred or a brisk and firm stroke was made with a firm object. It can be classified into two major forms: simple and symptomatic. Simple dermographism is seen in 5% of normal people and may be considered as an exaggerated physiological response. Symptomatic dermographism is the most common form of physical uricarias and the patients, most frequently young adults, complain of pruritus before the wheals appear [START_REF] Horiko | Dermographism (mechanical urticaria) mediated by IgM[END_REF][START_REF] Breathnach | Symptomatic dermographism: natural history, clinical features, laboratory investigations and response to therapy[END_REF].

o Pressure urticaria: This type of urticaria may be immediate or delayed. The Immediate Pressure Urticaria consists of wheals that occur within minutes after applying pressure to the skin. Its duration is usually 30 minutes to few hours. Delayed Pressure Urticaria occurs within 30 minutes to 12 hours after pressure and is often pruritic and painful. It usually persists for 12 to 72 hours. Lesions may appear after sitting on hard surfaces on the buttocks for example on the buttocks, or on the soles of the feet after standing for a long time on a ladder, or appear at the site of tight clothing especially the waistline, or even on the hands after manual work [START_REF] Barlow | Diagnosis and incidence of delayed pressure urticaria in patients with chronic urticaria[END_REF][START_REF] Lawlor | Delayed pressure urticaria, objective evaluation of a variable disease using a dermographometer and assessment of treatment using colchicine[END_REF].

o Vibratory angioedema is also one type of Pressure urticaria and occurs after any vibratory stimulus such as jogging or vigorous towelling that induces a localized, red, itchy swelling within minutes and lasting less than a few hours [START_REF] Ting | vibration-induced angioedema[END_REF].

 Temperature changes [47]:

o Heat urticaria: It is a rare form of physical urticaria where wheals appear on warmed areas within usually 2 to 15 minutes and last for 1 to 3 hours. Upon contact with heat, they may show a delayed appearance and disappearance of wheals, with even 10 hours required for complete resolution.

o Cold Urticaria: This type of urticaria is associated with cold exposure that leads to wheals within minutes.

o Cholinergic Urticaria: Characterized by the appearance of micropapules due to sweating (induced by high temperatures or emotional stress). Redness and flushing appear and may persist on the neck and upper thorax for few minutes to 1-2 hours.

Gradually other areas may get involved and lesions become confluent, resembling angioedema. Sometimes, some peppery or sour foods can lead to this type of urticaria as well as cholinergic stimuli such as lacrimation, salivation and diarrhea. Systemic symptoms like abdominal cramping, diarrhea or even fainting may accompany this type of urticaria [START_REF] Mayou | Cholinergic dermographism[END_REF].

 Other urticarias [22]:

o Solar Urticaria: It is a rare type of urticaria where itching, erythema and wheals appear rapidly within minutes after sun exposure and disappear within an hour when exposure to sun ends.

o Aquagenic Urticaria: Characterized by the appearance of pruritic wheals upon contact with all types of water (tap, swimming pool, distilled water, high humidity, tears, sweat and saliva) which disappear after 30 to 60 minutes after the contact with water ends.

 Non-Physical Urticarias [49]

 Stress-induced Urticaria: This rare type is also called adrenergic urticaria which is characterized by multiple small wheals that are induced by stress not related to heat nor exercise.

It is different from cholinergic urticaria by the presence of blanching and vasoconstriction surrounding the wheals. It can be reproduced by intradermal injections of epinephrine and norepinephrine, but not by acetylcholine.

 Exercise-induced Urticarias: This type is produced by exercise (jogging or active sports) that is not related to an increase in core temperature associated with cholinergic urticaria. In this type, the typical wheals of cholinergic urticaria are not encountered; but the first symptom that characterizes it is itching that occurs at the beginning, followed by urticaria and angioedema, which usually persist for 30 minutes to 4 hours.

 Contact Urticaria: This kind of urticaria is immediate. Local wheals and flares appear within minutes to an hour after contact with the provoking substance. It can be sub-classified into immunologic and non-immunologic. Immunologic contact urticaria is a type I hypersensitivity reaction (IgE-mediated) in a previously sensitized person to one protein who can react to another protein due to the presence of a chemically related allergen in both proteins.

Provoking agents for this type of uricaria may be: dairy foods such as milk, egg, and cheese; fruits (apple, banana, mango, orange, watermelon, peanut) or vegetables (beans, carrot, cabbage, cucumber, garlic, onion, tomato, soybean); meat (chicken, pork, lamb, beef) or even drugs such as aspirin, ampicillin, bacitracin, gentamicin, and rifamycin. Non-immunologic contact urticaria is caused by other types of foods such as fish or capsicum or preservatives (benzoic acid, chlorocresol, capsaicin, camphor, chloroform); some fragrance and flavoring agents like menthol, vanilla and cinnamon; some plants like nettles and chrysanthemum; some medications (benzocaine, dimethyl sulfoxide, methyl salicylate); and some animals (arthropods, caterpillars and moths) [START_REF] Bourrain | Occupational contact urticaria[END_REF].

 Urticarial Vasculitis: Characterized by the presence of wheals lasting more than 24 hours and vasculitis in the form of vessel inflammation and leukocytoclasis [START_REF] Chang | Urticarial vasculitis[END_REF].

I.3. CLINICAL FEATURES AND SYMPTOMS

Hives resulting from urticaria are usually red, itchy, and erythematous. There may be associated angioedema in 50% of patients with ordinary urticaria. These welts vary in size and appear and fade repeatedly as the reaction disappears. They occur anywhere on the body in variable numbers and sizes, ranging from a few millimeters to large lesions, of varying shapes including rounded, annular, serpiginous and bizarre patterns. The condition is considered chronic if the welts appear for more than six weeks and recur frequently over months or years which may be very uncomfortable and may interfere with sleep and daily activities. It may be associated with systemic symptoms of malaise, loss of concentration, low mood, feeling hot and cold, headache, abdominal pain or diarrhea.

In summary, signs and symptoms of chronic hives include:

 Batches of red or skin-colored welts (wheals), which can appear anywhere on the body  The bumpsred or skin-colored "wheals" with clear edgesusually appear suddenly and go away  Itching, which may be severe  Painful swelling (angioedema) of the lips, eyelids and inside the throat  A tendency for signs and symptoms to flare with triggers such as heat, exercise and stress  A tendency for signs and symptoms to persist for more than six weeks and to recur frequently and unpredictably, sometimes for months or years [START_REF] Zuberbier | The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria[END_REF][START_REF] Godse | Consensus statement for the diagnosis and treatment of urticaria: A 2017 update[END_REF]

I.4. INVESTIGATIONS AND DIAGNOSIS

Acute urticaria usually does not require a diagnostic workup since it is self-limiting. Exceptions to this are types of urticaria due to type I food allergy in sensitized patients or the existence of other eliciting factors such as NSAIDs. In this case, allergy tests may be useful to avoid re-exposure to eliciting factors. On the other hand, many advances have been made in identifying causes of different types and subtypes of urticaria especially chronic urticaria (Table 2) [7,[START_REF] Zuberbier | Urticaria: current opinions about etiology, diagnosis and therapy[END_REF][START_REF] Asero | Chronic urticaria: a focus on pathogenesis[END_REF]. Some of these tests are autoimmunity-mediated by functional auto-antibodies directed against the high-affinity IgE receptor or IgE-auto-antibodies to auto-antigens, pseudo-allergy to foods or drugs, or acute or chronic infections. In patients who display only wheals without angioedema, urticarial vasculitis and autoinflammatory disorders such as Schnitzler syndrome need to be ruled out. On the other hand, in patients who suffer only from recurrent angioedema without any wheal, bradykinin-mediated angioedema, ACE inhibitor-induced angioedema or hereditary angioedema should be considered as differential diagnoses (Figure 4). Intensive and costly general screening programs for causes of urticaria as well as tests for malignancies are strongly advised against. The factors named in Table 2 should only be investigated based on patient history [START_REF] Zuberbier | The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria[END_REF].

 Initial workup [54]

It is a thorough history, taking the following items into consideration:



I.4.1. ASSESSMENT OF DISEASE ACTIVITY AND CONTROL

Patient-reported outcome measures (PROMs) are of key importance for the management of CU. PROMs for CSU management assess disease activity, impact and control and include the Urticaria Activity Score (UAS) [START_REF] Hawro | The urticaria activity scorevalidity, reliability, and responsiveness[END_REF][START_REF] Hollis | Comparison of Urticaria Activity Score over 7 days (UAS7) values obtained from once-daily and twice-daily versions: Results from the ASSURE-CSU study[END_REF][START_REF] Hawro | Comparison and interpretability of the available urticaria activity scores[END_REF][START_REF] Mathias | Evaluating the minimally important difference of the urticaria activity score and other measures of disease activity in patients with chronic idiopathic urticaria[END_REF], the Angioedema Activity Score (AAS) [START_REF] Kulthanan | Angioedema activity score (AAS): a valid and reliable tool to use in Asian patients[END_REF][START_REF] Weller | Development, validation, and initial results of the angioedema activity score[END_REF], and the Urticaria Control Test (UCT) [START_REF] Irani | Chronic urticaria in most patients is poorly controlled[END_REF][START_REF] Ohanyan | Responsiveness and minimal important difference of the urticaria control test (UCT)[END_REF][START_REF] Kulthanan | Validity, reliability and interpretability of the Thai version of the urticarial control test (UCT)[END_REF][START_REF] Kocatürk | Validation of the Turkish version of the Urticaria Control Test: Correlation with other tools and comparison between spontaneous and inducible chronic urticaria[END_REF][START_REF] Weller | Development and validation of the urticaria control test a patient reported outcome instrument for assessing urticaria control[END_REF]. Diagnostic algorithm for patients presenting with wheals, angioedema or both. AAE, acquired angioedema due to C1inhibitor deficiency; ACE-Inh, angiotensin-converting enzyme inhibitor; AE, angioedema; AID, auto-inflammatory disease; HAE, hereditary angioedema; RAS, renin-angiotensin system 1. Apart from ACE-inhibitors, other renin inhibitors and sartans have been described to induce angioedema but much less frequently. 2. Patients should be asked for a detailed family history and age of disease onset. 3. Test for elevated inflammation markers (C-reactive protein, erythrocyte sedimentation rate), test for paraproteinemia in adults, look for signs of neutrophil-rich infiltrates in skin biopsy; perform gene mutation analysis for hereditary periodic fever syndromes (eg, cryopyrin-associated periodic syndrome), if strongly suspected. 4. Patients should be asked: "For how long does each individual wheal last?". 5. Test for complement C4, C1-INH levels and function; in addition, test for C1q and C1-INH antibodies, if AAE is suspected; do gene mutation analysis, if former tests are unremarkable but patient's history suggests hereditary angioedema. 6. If there is no remission after 6 months of ACE-inhibitor discontinuation C1-inhibitor should be tested for. 7. Does the biopsy of lesional skin show damage of the small vessels in the papillary and reticular dermis and/or fibrinoid deposits in perivascular and interstitial locations suggestive of urticarial vasculitis? 8. Patients should be asked: "Can you make your wheals come? Can you bring out your wheals?". 9. In patients with a history suggestive of inducible urticaria standardized provocation testing according to international consensus recommendations should be performed. 10. Acquired auto-inflammatory syndromes include Schnitzler0s syndrome as well as systemic-onset juvenile idiopathic arthritis (sJIA) and adult-onset Still's disease (AOSD); hereditary auto-inflammatory syndromes include Cryopyrin-associated periodic syndromes (CAPS) such as familial cold auto-inflammatory syndromes (FCAS), Muckle-Wells syndrome (MWS) and neonatal-onset multisystem inflammatory disease (NOMID), more rarely hyper-IgD syndrome (HIDS) and tumour necrosis factor receptor alpha-associated periodic syndrome (TRAPS). 11. In some rare cases, recurrent angioedema is neither mast cell mediator-mediated nor bradykinin-mediated, and the underlying pathomechanisms remain unknown. These rare cases are referred to as "idiopathic angioedema" by some authors.

Urticaria Activity Score (UAS)

The UAS is the gold standard for measuring disease activity in patients with CSU [START_REF] Mathias | Development of a daily diary for patients with chronic idiopathic urticaria[END_REF]. It was developed specifically for the use in patients with CSU, and it is the recommended method for assessing disease activity including changes in disease activity in response to treatment according to the international guideline for urticaria [START_REF] Zuberbier | The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria[END_REF]. UAS-7 records, over 7 days, the numbers of wheals and the intensity of itch based on either a twice-daily or once-daily documentation. Items are scored individually, the daily UAS is a sum of the daily Itch Severity Score (3 points) and the daily Number of Hives Score (3 points), giving a range of 0 to 6 points per day and 0 to 42 over one week, with higher scores indicating more severe symptoms. As for the UAS-7, it is calculated as the sum of pruritus and number of hives over 7 days (Table 3) [START_REF] Zuberbier | Definition, classification, and routine diagnosis of urticaria: a consensus report11this consensus report is the result of a panel discussion during the international clinically oriented ESDR symposium 'Urticaria 2000[END_REF][START_REF] Mathias | Evaluating the minimally important difference of the urticaria activity score and other measures of disease activity in patients with chronic idiopathic urticaria[END_REF].

Urticaria Control Test (UCT)

The UCT is the first valid and reliable tool to assess disease control in patients with chronic urticaria (spontaneous and inducible). It is a patient-reported outcome tool that retrospectively assesses urticaria control. It is a simple scoring system that works as a daily diary to quantify wheals and itching. Although it was proved to be a useful tool and became the gold standard for measuring disease control in patients with CSU, it has some major limitations. First, its assessment becomes difficult if the patient forgets its completion on the same day. Second, it works only prospectively and therefore cannot be used during the first patient contact. Third, it does not cover angioedema.

Fourth, it is not designed for patients with other urticaria subtypes. Each UCT item has 5 answer options (scored with 0-4 points). Low points indicate high disease activity and low disease control.

The UCT score is calculated by adding individual item scores. Accordingly, the minimum and maximum UCT scores are 0 and 16, with 16 points indicating complete disease control (Figure 5) [START_REF] Weller | Development and validation of the urticaria control test a patient reported outcome instrument for assessing urticaria control[END_REF].

Scoring of mastocytosis (SCORMA)

SCORMA index is used to clinically assess the extent of cutaneous mastocytosis and is composed of 3 parts:

-In the first part (A) the extent of the skin involvement was assessed and represented by a marked surface.

-In the second part (B), the activity of the lesions was estimated where 4 items of the chosen lesion are scored semi-quantitatively: pigmentation/erythema, vesiculation, elevation and Darier's sign. The score for each item is 0-3.

-In the third part (C), the subjective symptoms were recorded where the severity of the symptoms was scored from 0 to 10.

Each part was rated separately on a semi-quantitative scale. The combined scores of A, B and C formed the SCORMA index. The resulting scores of each item are incorporated in the SCORMA index formula: A + 3B+ C or A/5 + 5B +2C/5 and ranges from 5.2 to 100.8 (Figure 6) [START_REF] Heide | Serum Tryptase and SCORMA (SCORing MAstocytosis) index as disease severity parameters in childhood and adult cutaneous mastocytosis[END_REF][START_REF] Heide | Mastocytosis Study Group Rotterdam. Clinical scoring of cutaneous mastocytosis[END_REF].

Angioedema Activity Score (AAS)

AAS is the first specific patient-reported outcome instrument to assess disease activity in recurrent angioedema patients. The AAS tool is designed as a daily diary with an opening question concerning whether or not the patient has had any angioedema in the past 24 hours followed by five specific AAS questions to determine the severity and impact of the angioedema episode. The patients were only asked to complete the additional items if the answer to the opening question was affirmative.

Each AAS item is scored between 0 and 3 points, that is, the minimum and maximum daily AASs are 0 and 15 points. The daily AASs are summed up to 7-day scores and range from 0 to 105, questionnaires such as Dermatology Life Quality Index (DLQI) [START_REF] Finlay | Dermatology Life Quality Index (DLQI)-a simple practical measure for routine clinical use[END_REF], the Children's DLQI [START_REF] Salek | Clinical experience and psychometric properties of the Children's Dermatology Life Quality Index (CDLQI), 1995-2012[END_REF], and the Dermatology Quality of Life Scales [START_REF] Tondury | The Pictorial Representation of Illness and Self Measure (PRISM) instrument reveals a high burden of suffering in patients with chronic urticaria[END_REF]. Some of them like CU quality of life questionnaire (CU-Q2oL) [START_REF] Baiardini | Minimal important difference of the Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL)[END_REF][START_REF] Brzoza | Adaptation and initial results of the polish version of the GA²LEN chronic urticaria quality of life questionnaire (CU-Q2oL)[END_REF][START_REF] Młynek | The German version of the chronic urticaria quality-oflife questionnaire (CU-Q2oL): Factor analysis, validation and initial clinical findings[END_REF][START_REF] Baiardini | A new tool to evaluate the impact of chronic urticaria on quality of life: Chronic Urticaria Quality of Life Questionnaire (CU-QoL)[END_REF] and the Angioedema Quality of Life Questionnaire (AE-QoL) [START_REF] Kulthanan | Angioedema quality of life questionnaire (AE-QoL) -interpretability and sensitivity to change[END_REF][START_REF] Weller | The angioedema quality of life questionnaire (AE-QoL)assessment of sensitivity to change and minimal clinically important difference[END_REF][START_REF] Weller | Development and construct validation of the angioedema Quality of Life Questionnaire (AE-QoL)[END_REF] were specifically generated to assess the impact of chronic urticaria on the affected patients. Baseline assessment of disease activity (UAS, AAS), quality of life (CU-Q2oL, AE-QoL) and disease control (UCT) are indispensable for guiding treatment decisions, providing better insights into the patients' disease burden, as well as facilitating, improving and standardizing the increasingly important documentation work.

Dermatology Life Quality Index (DLQI)

The DLQI is the first dermatology-specific Health-related QoL (HRQoL) questionnaire that was published in 1994 [START_REF] Finlay | Dermatology Life Quality Index (DLQI)-a simple practical measure for routine clinical use[END_REF]. The DLQI consists of 10 questions that relate ''to the last week'' and relating to symptoms and feelings, daily activities, school, leisure, work, personal relationships and treatment. Each question is answered by a tick box: "Not relevant", ''not at all'', ''a little'', ''a lot'' or ''very much''. Each question is scored from 0 to 3 and DLQI is calculated by summing the score of each question resulting in a maximum of 30 and a minimum of 0. The higher the score, the more quality of life is impaired. The DLQI was designed to be used in adults over the age of 18 years (Table 4) [START_REF] Lewis | 10 years experience of the Dermatology Life Quality Index (DLQI)[END_REF].

I.4.3. CONSEQUENCES OF THE DISEASE ON PSYCHOLOGICAL AND MENTAL WELLBEING

Many previous studies have demonstrated that patients with CU suffer from a prolonged mental and psychological burden such as depression and anxiety, that may in turn influence QoL [START_REF] Balp | The impact of chronic urticaria from the patient's perspective: a survey in five European countries[END_REF][START_REF] Weldon | Quality of life in patients with urticaria[END_REF][START_REF] Baiardini | Quality of life and patients' satisfaction in chronic urticaria and respiratory allergy[END_REF][START_REF] Engin | The levels of depression, anxiety and quality of life in patients with chronic idiopathic urticaria[END_REF][START_REF] Staubach | Quality of life in patients with chronic urticaria is differentially impaired and determined by psychiatric comorbidity[END_REF]. In this regard, CU is still considered to be of the most poorly controlled inflammatory conditions.

In fact, several previous studies suggested the role of stress within CU [START_REF] Papadopoulou | Corticotropin-releasing hormone receptor-1 and histidine decarboxylase expression in chronic urticaria[END_REF][START_REF] Lindsay | Treating chronic spontaneous urticaria using a brief 'whole person' treatment approach: a proof-of-concept study[END_REF]. A recent survey examining the controversial influence of psychological factors in CU showed that the majority of Canadian allergists reported psychosocial parameters playing a notable role in the pathogenesis of this disease [START_REF] Ben-Shoshan | Psychosocial factors and the pathogenesis of chronic hives: a survey of Canadian physicians[END_REF]. A recent meta-analysis showed that the overall prevalence of any psychopathological condition among patients with CU was estimated to be 31.6%, significantly higher than in healthy subjects [START_REF] Konstantinou | Psychiatric comorbidity in chronic urticaria patients: a systematic review and meta-analysis[END_REF]. Moreover, an online survey in Germany (ATTENTUS), in which data were collected from 9055 participants diagnosed with CU in real-life setting, reported the existence of a highly burdened population outside specialized centers [START_REF] Maurer | ATTEN-TUS, a German online survey of patients with chronic urticaria highlighting the burden of disease, unmet needs and real-life clinical practice[END_REF]. Some of the questionnaires that are used to assess psychological, depression and mental wellbeing are Patient health questionnaire-9 (PHQ-9) and Beirut Distress Score 22 (BDS-22).

Patient health questionnaire-9 (PHQ-9)

PHQ-9 includes 9 items which focus on the Diagnostic and Statistical Manual of Mental Disorders, 4th edition for Major Depressive Disorder [START_REF] Wolkerstorfer | Scoring the severity of atopic dermatitis: three item severity score as a rough system for daily practice and as a pre-screening tool for studies[END_REF]. The questionnaire assesses how often the subjects had been disturbed by any of the 9 items during the immediately preceding 2 weeks. Each item of PHQ-9 was scored on a scale of 0-3 (0 =not at all; 1=several days; 2=more than a week;

3=nearly every day). The PHQ-9 total score ranges from 0 to 27 (scores of 0-9 are classified as mild depression; 10-14 as moderate depression; 15-19 as moderately severe depression; ≥20 as severe depression) (Figure 8) [START_REF] Kroenke | The PHQ-9: validity of a brief depression severity measure[END_REF]. up by adding all the items on and the higher the score, the greater the risk of psychological distress is [START_REF] Abbas | Development and initial validation of a brief scale for assessing psychological distress in obese adults[END_REF][START_REF] Barbour | Psychological distress in lebanese young adults: constructing the screening tool "BDS-22[END_REF]. In acute urticaria, there should be an arduous attempt to identify the initiating stimulus and avoid it.

Some patients may require an oral H1 antihistamine. Systemic corticosteroids are sometimes useful in resistant cases. In case of anaphylaxis, subcutaneous epinephrine injections should be given immediately. The treatment of CU includes several drugs that have anti-inflammatory or immunosuppressant effect that must be individualized. The therapeutic approach to CU involves the identification and elimination of underlying causes, the avoidance of eliciting factors, tolerance induction, and/or the use of pharmacological treatment to prevent mast cell mediator release [START_REF] Zuberbier | The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria[END_REF].

I.5.2. PHARMACEUTICAL MANAGEMENT

 First Line Therapies

Antihistamines

H1 antihistamines are the cornerstone of pharmacological therapy in all patients with CU. The third generation H1-antihistamines such as desloratadine and fexofenadine are preferred over the first generation ones because they are associated with less sedation and less cholinergic side effects. A drug of a different pharmacological class may be used to replace the initial drug if there is no response or can be added to the initial agent in case of partial response. Escalation of the dose or the addition of a sedating antihistamine (first or second generation like hydroxyzine, chlorpheniramine, or cetirizine) at night may be considered if no response is seen. A combination of H1 and H2 antihistamines may also be considered for significant wheals. Before changing to an alternative therapy, it is recommended to wait for 1-4 weeks to allow full effectiveness of the antihistamines before considering referral to a specialist [START_REF] Grob | How to prescribe antihistamines for chronic idiopathic urticaria: desloratadine daily vs PRN and quality of life[END_REF][100].



TNF alpha-inhibitors

TNF-α has been shown to be upregulated in the epidermis skin of CU patients. TNF inhibitors, including etanercept, adalimumab, and infliximab, have been studied in the treatment of CU but reports of effectiveness are limited in addition to their association with several adverse effects including injection-site or infusion-related reactions, and infectious complications [106].

Leukotriene Antagonists

Many studies have reported the efficacy of anti-LTs Montelukast and Zafirlukast in CU. They may be especially useful in urticaria induced by food additives and/or aspirin and other NSAIDs. A few studies in the literature have reported no benefit with anti-LTs, and no improvement of symptoms in chronic idiopathic urticaria patients with montelukast monotherapy. However, a short trial with these agents may be recommended in all patients with refractory urticaria, before considering other therapeutic agents [107-108].

 Last Line Therapies:

Immunoglobulins

Immunoglobulin is an immunomodulatory agent that alters cell adhesion, cytokine levels, and autoantibody production. It can be administered intravenously (intravenous immune globulin) or subcutaneously (subcutaneous immune globulin) [109].

Dapsone, sulfasalazine, hydroxychoroquine, interferon, methotrexate

Dapsone, a uslfone antimicrobial agent is perceived to have little evidence to maintain health in CU along with sulfasalazine, methotrexate, hydroxychloroquine, and interferon as they have lowquality evidence that is published but they may still have relevance as they are very affordable [START_REF] Zuberbier | Definition, classification, and routine diagnosis of urticaria: a consensus report11this consensus report is the result of a panel discussion during the international clinically oriented ESDR symposium 'Urticaria 2000[END_REF].

Colchicine, androgens, cyclophosphamide

Colchicine may act to relieve CU by suppressing LTs generation or by decreasing leukocyte adhesiveness and migration. Androgens have been studied in chronic idiopathic urticaria and angioedema. Short-term adverse effects were reported as "infrequent," and included elevations in transaminases that normalized without treatment cessation. Cyclophosphamide is suggested for treatmentresistant patients, but its use is limited by expense, inconvenience, need for monitoring, and risk of serious adverse effects like delayed secondary neoplasia and hemorrhagic cystitis [START_REF] Zuberbier | The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria[END_REF].

Autologous Serum Skin Test

I.5.3. NON-PHARMACEUTICAL MANAGEMENT  Eradication of infectious agents and treatment of inflammatory processes

Chronic spontaneous urticaria is often reported to be associated with a variety of inflammatory or infectious diseases. These infections may include those of the gastrointestinal tract like Helicobacter pylori [111][112] or bacterial infections of the nasopharynx. Apart from infectious diseases, chronic inflammatory processes have also been identified as potentially causative for CU such as gastritis, reflux oesophagitis or inflammation of the bile duct or gall bladder [113][114].

 Dietary management

IgE-mediated food allergy is rarely associated with CU [113-115]. However, if identified, the specific food allergens need to be omitted [116]. In these cases, a diet containing only low levels of natural as well as artificial food pseudoallergens should be instituted and maintained for a prolonged period, at least 3-6 months.

 Phototherapy

Phototherapy efficacy was proven in the management of solar urticaria and other types of phys-

 Plasmapheresis

Plasmapheresis acts by removing proteins and functional antibodies of inflammation, which serve the function of immune modulation, from the blood system of the patient. Various studies showed either complete resolution or at the least improvement in symptoms [120].

I.6. AIMS AND OBJECTIVES

At the international level, despite the large numbers of studies conducted to assess MCDD [5][6][START_REF] Weller | Development and validation of the urticaria control test a patient reported outcome instrument for assessing urticaria control[END_REF] as well as the prevalence of many inflammatory skin diseases internationally [9,[START_REF] Weller | Development and validation of the urticaria control test a patient reported outcome instrument for assessing urticaria control[END_REF]121], there are still major unmet needs in projects studying urticaria, such as prevalence and incidence studies as well as the triggering factors and its impact on the quality of life using specific tools and as well as its relationship with psychological variables and its effect on mental health [122-123]. Moreover, there is lack of specific tools to evaluate chronic and inducible urticaria and knowledge of the impact of the doctor/patient relationship during the treatment course. In addition, in parallel to the research needs at the international level, no specific tools to measure the risk factors of MCDD neither its effect on the patients' QoL have ever been generated nor validated in the Middle Eastern region specifically. Therefore, there is a necessity to have a deeper knowledge regarding MCDDs especially urticaria in order to assess their prevalence, the appropriate use of their diagnostic tools and the validation process, and their burden on the patients and their daily life activities.

 Objectives of the project:

This project was divided into two phases. The first phase focused on the cross-validation of Arabic versions of tools for assessment of disease activity and QoL impairment and the validation of an auto-diagnostic tool for urticaria to be used in further epidemiological studies. The second phase focused on its impact on the quality of life and mental health of the affected patients. Secondary endpoints of the first phase of the study focused on the 1) assessment of the prevalence of urticaria as well as 2) the study of risk factors associated with the disease and finally 3) the comparison between dermatologist and allergist diagnoses for their rates of agreement with the results of self-diagnostic tool. Secondary endpoints of phase 2 were 1) the assessment of correlations among different QoL and psychological distress scores and the known-group validity among them and 2) the distribution of scores among different factors affecting urticaria.

II. METHODOLOGY

Some of the scores for the measurement of urticaria activity and its effect on the QoL were validated and cross-validated in many languages but not in Arabic. Knowing that these scores are essential to be used in the whole management of urticaria, it was mandatory to translate UAS-7 and CU-Q2oL to Arabic and cross-validate them. Moreover, an appropriately validated self-diagnostic tool for epidemiological studies is lacking in the general population. For this sake, a specific questionnaire was generated to include many detailed aspects about the patients' dermatological disease that is capable to prove whether the patients were able to self-diagnose their disease or not.

After the validation and the cross-validation phases ended, the validated tools were used among diagnosed patients with urticaria to assess its impact on their QoL and mental health and estimate the association of urticaria with different risk factors. The first phase of this project started in October 2018 and was implemented in October 2019 after the initiation of the second phase of the study (Table 8).

II.1. STUDY DESIGN AND SETTING

A descriptive cross-sectional study was conducted in multi-centered settings, whether dermatology and/or allergy/immunology clinics from all districts of Lebanon, in outpatients' clinics or in private clinics, by patients who presented with any dermatological condition especially urticaria.

In the first phase of the study, a prospective follow-up was performed for the patients with CU in order to investigate the validity and reliability of the Arabic versions of the UAS-7 and the CU-Q2oL

in Lebanon and estimate the correlation between them.

During the first phase as well, those urticaria patients were asked to fill an auto-diagnostic questionnaire along with other control patients presenting with other dermatological conditions in a cross-sectional method to assess the prevalence of urticaria in adults and its association with risk/triggering factors and the existence of interactions between personal and environmental factors in the exacerbation of this disease. The second phase was also a cross-sectional study that focused on the recruitment of patients with chronic urticaria that continued until June 2021 in order to evaluate the impact of chronic urticaria on the QoL of the affected patients using previously validated tools such as CU-Q2oL, DLQI, and UCT.

II.2. STUDY POPULATION II.2.1. PHASE 1A -CROSS-VALIDATION OF UAS-7 AND CU-Q2OL

The first phase of the study was a pilot study that was conducted on a cluster sample of Lebanese patients suffering from CSU in order to accomplish the cross-validation of the previously translated Arabic versions of UAS-7 and CU-Q2oL scores. Patients were included if they were >18 years old and if they had a diagnosis of CSU at the time of the first study visit, defined as the daily or almost daily spontaneous occurrence of hives with or without angioedema for at least 6 weeks prior to inclusion. Patients were excluded if they had acute urticaria (<6 weeks of hives), urticaria vasculitis or other urticaria symptoms not considered chronic, angioedema as a sole symptom, dermatitis or skin diseases other than CSU.

II.2.2. PHASE 1B -VALIDATION OF CU SELF-DIAGNOSTIC TOOL

For the validation of the self-diagnostic tool, cases were patients aged 18 years or older, with the most commonly encountered MCDD, namely acute and chronic urticaria, whether spontaneous or induced. These patients were asked to fill a questionnaire and make their own diagnosis, while waiting for their check-up. They were also asked to select their particular symptoms from a list of features, indications and descriptions, and to identify their skin disorder from the pictorial album provided to them. After applying the latest diagnosis criteria and laboratory testing if applicable, the disease was then confirmed by the specialized physician. This permitted the selection of the most appropriate diagnosing combination of symptoms and photographical representations. Controls were patients in the same age range with other dermatological illnesses namely eczematous and exanthematic skin lesions, pruritus and angioedema, such as atopic dermatitis, psoriasis, prurigo, rosacea, and chronic pruritus with secondary skin lesions. Moreover, patients with other infections presenting with hives that were deemed of a non-urticarial nature were also included as controls.

II.2.3. PHASE 2 -IMPACT OF CU ON QOL AND MENTAL HEALTH

Skin diseases other than chronic urticaria were afterwards excluded and only patients with CU were included in the second phase of the study in order to measure the effect of the disease on the QoL of affected patients. Recruitment continued for the patients with CU who were >18 years old, defined as the daily or almost daily occurrence of hives, with or without angioedema, for at least 6 weeks prior to inclusion. Patients were excluded if they had acute urticaria (<6 weeks of hives), urticaria vasculitis or other urticaria symptoms not considered chronic, angioedema as a sole symptom (absence of hives), dermatitis or skin diseases other than CU. We also excluded patients who had a diagnosed psychiatric disorder, a cognitive impairment due to a current cerebral or psychotic illness, a malignant or a central nervous system disease.

II.3. SAMPLE SIZE CALCULATION

Since the project was divided into three different phases, three different techniques for sample size calculation were adopted. The recruitment of patients was divided into three temporal segments as shown in the diagram below (Figure 10).

II.3.1. PHASE 1A -CROSS-VALIDATION OF UAS-7 AND CU-Q2OL

Based on previous study data and taking into consideration high Cronbach alpha values for UAS-7 and CU-Q2oL ranging from 0.78 [START_REF] Hawro | The urticaria activity scorevalidity, reliability, and responsiveness[END_REF] to 0.86 [START_REF] Młynek | The German version of the chronic urticaria quality-oflife questionnaire (CU-Q2oL): Factor analysis, validation and initial clinical findings[END_REF], and based on the fact that a minimum of 5-10 participants per scale item would be adequate for establishing sufficient evidence of scale validity and reliability [START_REF] Mathias | Development of a daily diary for patients with chronic idiopathic urticaria[END_REF], the minimum target sample size for validation was set to be 120 participants. At the end, 152 patients with chronic urticaria accepted to participate in the first pilot study of the cross-validation of Arabic UAS-7 and CU-Q2oL.

II.3.2. PHASE 1B -VALIDATION OF CU SELF-DIAGNOSTIC TOOL

Along with the patients who were first recruited in the first phase of the study and taking into consideration the study conducted by Taal, A. and coworkers, which showed that 82% of the cases were correctly diagnosed as having chronic urticaria [124], and using GPower version 3.1.9.

II.3.3. PHASE 2 -IMPACT OF CU ON QOL AND MENTAL HEALTH

After the validation of the self-diagnostic tool was done, recruitment of only CU patients continued in a multi-centered cross-sectional study until June 2021, using a random cluster sample of Lebanese patients with CU visiting dermatology and immunology clinics from all districts of Lebanon.

Using Epi-info TM 7 for the calculation of the sample size for cross-sectional studies and population survey in which the primary endpoint is the worldwide prevalence of urticaria, a total number of 264 participants were required to participate in the study (taking into account a prevalence of 0.5-1% and a precision measure of 1.2% [8]. At the end, a total sample size of 295 participants was adopted in the epidemiological study of CU and its impact of QoL in order to account for any missing value.

II.4. PHYSICIANS' NETWORK

A list of specialized practicing physicians was obtained from the Order of Physicians in Lebanon, a total of fifteen dermatologists, allergists and clinical immunotherapists representing the physicians' repartition on the Lebanese territory were contacted and asked whether they would like to be part of this research.

II.4.1. STANDARDISATION AND EVALUATORS'EXPERIENCE

Before the start of the study, physicians met with the research personnel to familiarize themselves with the study protocol in order to improve concordance. All involved healthcare professionals in this study (physicians, nurses, and assistants) participated in the standardization of the data collection technique, the interpretation of the physical tests and the definition of the related diagnoses and all agreed to conform to the suggested definitions.

II.5. TRAINED RESEARCH ASSISTANTS

Data were collected using a self-administered structured questionnaire, both open ended and closed questions were used. Two trained researchers individually assisted all patients while waiting in the waiting room at the clinics in order to deliver the questionnaire without her direct interference and only answered when a question was deemed incomprehensible in order to efficiently fill the

II.6.1.3. PSYCHOLOGICAL AND DEPRESSION SCORES

The two scores used to measure depression and psychological distress associated with urticaria were PHQ-9 and BDS-22. PHQ-9 validity was well established in a sample of Lebanese adults and can therefore be a useful screening tool for depression not only in psychiatric clinics but also in settings that lack sufficient psychiatric care to determine the need for psychiatry referral [126].

Beirut Distress Score 22 is a 22-item questionnaire that differentiates among core symptoms of depression, anxiety, and perceived stress. It was initially created in Arabic and tested for internal consistency and validity among Lebanese population [START_REF] Barbour | Psychological distress in lebanese young adults: constructing the screening tool "BDS-22[END_REF].

II.6.1.4. SELF-DIAGNOSTIC QUESTIONNAIRE

The self-administered questionnaire was modeled based on different references [START_REF] Maurer | Practical algorithm for diagnosing patients with recurrent wheals or angioedema[END_REF][START_REF] Grattan | Urticaria and angioedema[END_REF][START_REF] Weller | Chronic urticaria: tools to aid the diagnosis and assessment of disease status in daily practice[END_REF]127] namely EAACI/GA(2) LEN/EDF/WAO Guideline [START_REF] Zuberbier | The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria[END_REF]. Items were also based on the UAS-7 which is the gold standard for measuring disease activity in patients with chronic spontaneous urticaria [START_REF] Mathias | Development of a daily diary for patients with chronic idiopathic urticaria[END_REF] and included 3 sections: (i) a declarative section (Questions (Q) 1-8) that helps to identify whether the patient thinks he/she has the disease of interest, (wheals, swelling, itching, onset and duration of each and site of occurence), (ii) a section (Q1, Q2, and Q8), offering a photographic panel of the disease of interest and/or questions regarding the features of disease in its most common phenotypes with a score of three different categories (mild, moderate, severe) and/or questions regarding differential diagnosis; and (iii) descriptive questions that help identify the different types of urticaria, if applied (solar, pressure-induced, aquagenic, exercise-induced, cholinergic, heat-induced, druginduced, and contact urticaria). These questionnaires may therefore contain redundant items, but they enable assessment to be carried out with the optimum comprehension by patients between the pictures and text.

II.6.1.5. PICTORIAL AIDS

There were 1-3 photographs per item that reflected different body areas involved such as the arms, elbows, legs, and scalp. The value of pictorial aids for epidemiological studies has been previously demonstrated for other skin conditions such as hidranitis supporitiva [128], vitiligo [129],

psoriasis [130], as well as atopic dermatitis [START_REF] Wolkerstorfer | Scoring the severity of atopic dermatitis: three item severity score as a rough system for daily practice and as a pre-screening tool for studies[END_REF] where an increase in the specificity and the sensitivity were observed compared to the specialized physician diagnosis that was considered the golden standard. Therefore, we hypothesized a similar value for MCDDs. Pictorial aids included images that are colorful and clear that helped the patients identify their condition correctly whenever they asked about the meaning of a certain ailment by showing the manifestation of each of the following MCDDs in three different languages (Appendix D).

II.6.1.6. TRANSLATION AND VALIDATION PROCESS OF DIFFERENT SCORES

 UCT

The Arabic version of UCT that was used in our study was previously linguistically validated to screen Arabic-speaking patients for poorly versus well controlled disease [START_REF] Irani | Chronic urticaria in most patients is poorly controlled[END_REF] which means that no translation was needed at this stage.

 DLQI

The DLQI is available in 55 languages and was used in 32 countries including Arabic-speaking ones such as Morocco and Egypt to assess the impact of different skin diseases and their treatment on patients' lives. The Arabic DLQI was shown to be reliable and valid in multiple studies, for example in psoriasis, vitiligo, atopic dermatitis, viral warts, and acne vulgaris [131][132][133].

 PHQ-9

The PHQ-9 was previously validated in a sample of Lebanese patients and it was shown to be a sensitive measure of depressive symptoms if used in its Arabic version [126].

 BDS-22

The original version of BDS-22 was in Arabic since it was first tested on a sample of Lebanese population, therefore no translation was needed for this score [START_REF] Abbas | Development and initial validation of a brief scale for assessing psychological distress in obese adults[END_REF][START_REF] Barbour | Psychological distress in lebanese young adults: constructing the screening tool "BDS-22[END_REF].

 UAS-7 and CU-Q2oL

Over the last decade, the UAS-7 has been validated in many different languages, but not in Arabic [134][135]. Similarly, the CU-Q2oL's validity, reliability, and responsiveness to change have been demonstrated in several different languages, including German, Greek, Iranian, Persian, Polish, Spanish, and Turkish [START_REF] Kocatürk | Validation of the Turkish version of the Urticaria Control Test: Correlation with other tools and comparison between spontaneous and inducible chronic urticaria[END_REF][START_REF] Brzoza | Adaptation and initial results of the polish version of the GA²LEN chronic urticaria quality of life questionnaire (CU-Q2oL)[END_REF][136][137][138], but not Arabic. For this reason, a translation and a crossvalidation of these two scores was a necessity before the initiation and continuation of the whole project.

The original versions of UAS-7 and CU-Q2oL were translated into Arabic by a professional translator. The face and content validity and comprehensibility of the items of the translated instruments were reviewed by two physicians with immunology and dermatology specializations.

Minor changes in the naming of some risk factors and scores were done. After reaching consensus, the Arabic versions were back translated into their original languages by another professional translator with scientific background. A total of three original and back-translated versions were reviewed by the original translator and the Arabic research team to detect any misinterpretation before being distributed to patients.

II.6.1.7. QUESTIONNAIRE PILOT TESTING

The questionnaire was first tested on a pilot sample of 10 individuals with different age groups for each different language to ensure completeness and appropriateness of the questions as well as the efficiency of the data collection method for the intention of finalizing the details. Modifications of the questionnaire content such as the addition of some risk factors such as specific types of food or latex allergy were done.

II.7. STUDY CONDUCT AND MEASUREMENTS

II.7.1. PHASE 1A -CROSS-VALIDATION OF UAS-7 AND CU-Q2OL

At the first visit, patients were informed by the research personnel about the aims of the study.

Then, participants completed the questionnaire in Arabic (local language) comprising the CU-Q2oL Then, the second and the third visit at an interval of two weeks each were set, and patients were informed about the completion process of the UAS-7, CU-Q2oL, and DLQI and asked to complete UAS-7 during the 7 days before the second and third visit. On the second visit (day 14), the UAS-7

questionnaire was collected, and the Arabic versions of the CU-Q2oL and the DLQI were completed again by the patients. Another UAS-7 was given to each patient to complete before the third visit (day 28), when it was collected and the CU-Q2oL and the DLQI were again completed by the patients.

II.7.2. PHASE 1B -VALIDATION OF CU SELF-DIAGNOSTIC TOOL

The same participating patients of the first study were handed the self-administered questionnaire in Arabic and answered it by themselves for once in a cross-sectional manner. To them were added the patients with other dermatological diseases used as controls.

All patients without exemption provided information on their socio-demographic characteristics as well as their medical information. This phase of the project also assessed the prevalence of the disease as well as its association with allergy triggering factors including food, medications, seasonal pollen, cold, heat, contact substances, insect bites, and animals with urticaria.

II.7.2.1. PHYSICIAN DIAGNOSIS OF CASES AND CONTROLS

Each patient's condition was diagnosed by a specialized physician: none of the physicians was aware of the results on the questionnaire at the time of the visit. They used necessary individualized investigations for complete work-up, at their discretion, until they reached a final diagnosis. A complete history of possible causes, physical exam, and laboratory tests was performed.

Individualized diagnostic tools such as simple dermographism test, basophil activation test, ASST, and skin prick testing were used when needed.

Based on the physician diagnosis, cases were patients with urticaria while controls were patients in the same age range with other dermatological illnesses (n=190), namely eczematous and exanthematic skin lesions, pruritus, atopic dermatitis, psoriasis, prurigo, rosacea, and chronic pruritus with secondary skin lesions. Moreover, patients with other infections presenting with hives that were deemed of a non-urticarial nature were also included as controls.

II.7.3. PHASE 2 -IMPACT OF CU ON QOL AND MENTAL HEALTH

Only cases of patients with chronic urticaria were included in this cross-sectional phase of the project. All controls and patients with acute forms of urticaria were excluded. All participants were asked to provide their contact information for further follow-up in case of any missing or erroneous information.

In this phase, patients also provided information on their socio-demographic characteristics, but the main focus was the impact of the disease on the quality of life of the affected patients as well as its effect on their psychological and mental health.

II.8. STATISTICAL ANALYSIS

Two independent observers double-checked the quality of the questionnaire and an additional audit was performed on a randomized 5% of the questionnaires. The data collected was analyzed using the Statistical Package for Social Sciences (SPSS, IBM Corporation, Somers, NY) version 23.0 and all data were examined for accuracy before entry.

II.8.1. DESCRIPTIVE STATISTICS

Descriptive statistics were calculated using mean and standard deviation (SD) for normally distributed continuous variables, median and interquartile range for continuous variables lacking a normal distribution, and counts and percentages for categorical variables. Continuous data were tested for normality using the Shapiro-Wilk test.

II.8.2. BIVARIATE ANALYSIS

Bivariate analysis was done to measure the association of the different patients' characteristics and the incidence of having urticaria and/or its effect on QoL and pshychological wellbeing as well as with the various scores that are available in the questionnaire (AAS, UAS, UCT, SCORMA, BDS-22, PHQ-9, DLQI, and CU-Q2oL). For normally distributed variables, Student's t-test and Analysis of variance (ANOVA) test were used to compare means between two groups and more than two groups, respectively. Alternatively, for continuous non-normally distributed variables, the Mann-Whitney test was applied to compare means of two groups and the Kruskall-Wallis test for more than two groups. As for categorical variables, the Pearson chi-square test was used, and when the expected values within cells were <5, the Fisher exact test was the substitute. In all cases, a p-value ≤0.05 was considered significant.

II.8.3. MULTIVARIABLE ANALYSIS

A multivariable analysis was performed using logistic regression models where urticaria is the dependent variable and only including selected independent variables, all of which had a p-value ≤0.1 in the bivariate analysis in order to assess the predictive factors associated with urticaria. A pvalue ≤0.05 was considered statistically significant.

For phase 2, the Multivariable Analysis of Variance MANCOVA was performed where CU-Q2oL and PHQ-9 were the dependent variables, age and gender the covariates and socio-demographics and risk factors the independant variables in order to assess the effect of the different factors associated with urticaria on both QoL and depression. A p-value ≤0.05 was considered statistically significant.

II.8.4. INTERNAL CONSISTENCY AND RELIABILITY

Cronbach alpha coefficients were computed to characterize the internal consistency reliability of the Arabic UAS-7 and CU-Q2oL as well as the auto-diagnostic questionnaire. Its interpretation was defined as follows: A coefficient <0.6 was considered as unacceptable, 0.60-0.65 as undesirable, 0.65-0.70 as minimally acceptable, 0.70-0.80 as respectable, 0.80-0.90 as excellent, and >0.9 as excessive consistency [START_REF] Brzoza | Adaptation and initial results of the polish version of the GA²LEN chronic urticaria quality of life questionnaire (CU-Q2oL)[END_REF]139].

Test-retest reliability was measured to check the consistency of UAS-

II.8.5. FACTOR ANALYSIS

To confirm the cross-cultural validity of the CU-Q2oL, an exploratory factor analysis was launched using the principal component analysis (PCA) technique, with a Promax rotation, since the extracted factors were found to be significantly correlated. However, the validity of the selfdiagnostic tool was confirmed using a factor analysis that was performed using the principal PCA technique with a varimax rotation since the extracted factors were not found to be correlated. The retained number of factors corresponded to Eigen values higher than one. The Kaiser-Meyer-Olkin (KMO) measure of sampling adequacy and Bartlett's test of sphericity were ensured to be adequate.

The KMO measures sampling adequacy for each variable in the model and for the complete model, whereas Bartlett's test would indicate if the variables are unrelated and therefore unsuitable for structure detection. Out of all the items, we assessed whether they are over-correlated to each other (R>0.8), whether they have a low loading on factors (R<0.4), or whether they have a low communality (R<0.3).

Both factors generated from the factor analysis of the self-diagnostic tool were created, and In addition, the variation of different QoL scores as well as scores to measure mental and psychological distress was also evaluated among three different disease control levels (classified as very poorly controlled (UCT<8), poorly controlled (UCT=8-11), or well-controlled (UCT≥12) using the Kruskal-Wallis test. The relationship between disease control and all remaining scores were evaluated using Pearson's or Spearman's correlation analysis.

their

II.8.7. CONCORDANCE AND AGREEMENT OF SRUD

The new self-reported diagnosis was compared with that of the physician by conducting a concordance analysis and calculating the percentage of agreement and Cohen's Kappa coefficient (κ)

stating that any kappa below 0.6 indicates inadequate agreement among the raters and little confidence should be placed in the results [143][144]. In all cases, a p-value ≤0.05 was considered significant.

II.9. ETHICAL CONSIDERATION

All phases of this research project were completely observational, with no breach of patients' confidentiality and no animal nor genetic experiments were involved. Nevertheless, patients gave their verbal informed consent to participate in the research and were assured about the anonymity of

III. RESULTS

III.1. SOCIO-DEMOGRAPHIC CHARACTERISTICS

III.1.1. SOCIO-DEMOGRAPHIC CHARACTERISTICS -PHASE 1-A

Of the 152 patients with CSU, 81 (53.3%) were male and 71 (46.7%) were female. The mean age of the participants was 36±12 years. 44 patients have completed CU-Q2oL, UAS-7, and DLQI at the third visit. Fifteen patients (10%) had angioedema along with their hives, and 22% of them had other forms of allergy. Antihistamines were the most commonly used medication (85%). The sociodemographic characteristics of the participants are summarized in Table 9.

III.1.2. SOCIO-DEMOGRAPHIC CHARACTERISTICS -PHASE 1-B III.1.2.1. PATIENTS CHARACTERISTICS

A total of 402 patients were enrolled in this study with a mean age of 38.7±14.9 years old . The female: male ratio was 214:188 (female: 53.2%), the majority were married (57.5%), and almost half had a university degree (46.8%). Most of the patients were employed (72.5%), and one third of patients considered their financial status to be "Fine" (33.2%). Details about the sociodemographic characteristics of the participants are listed in Table 10.

III.1.2.2. SELF-REPORTED CHARACTERISTICS OF THE DISEASE

The majority of the patients did not have any positive family history of dermatological disease (72.9%). Nine of ten patients (358 of 402) reported to have active skin disease at the time of participation. 84 (36.4%) described their condition as mild, 58 (25.1%) as moderate and 36 (15.6%) as severe, based on the pictorial aids provided. Antihistamines were the most commonly used treatment in patients with urticaria (55%) followed by corticosteroids (8%), leukotriene receptor antagonists (3.5%) and antibiotics (1.7%).

III.1.2.3. PHYSICIAN-DIAGNOSED CHARACTERISTICS OF THE DISEASE

Out of 402 patients, 212 (52.7%) were diagnosed with urticaria by their physician, while 190 (47.3%) were considered controls with other dermatological diseases. Types of urticaria including physical (5.9% symptomatic dermographism; 25.5% contact urticaria and 18.6% delayed pressure urticaria,) and non-physical urticarias (6% cold-induced urticaria; 27.1% heat-induced urticaria; 26.6% cholinergic urticaria, and 12.7% solar urticaria). More detailed characteristics are listed in Table 11. . The female: male ratio was 161:134 (female: 54.6%), the majority were married (67.1%), and half of the participants had a university degree (51%). Most of the patients were employed (81.6%), and one third of patients considered their financial status to be "Just as needed" (31.5%). More details about the socio-demographic characteristics of the participants are listed in

III.2 PRIMARY ENDPOINTS III.2.1. PHASE 1-A: CROSS-CULTURAL VALIDATION OF UAS-7 AND

CU-Q2OL

As said before, the participants completed the questionnaire in Arabic (local language) comprising the CU-Q2oL and the DLQI at the first visit. Then, they were informed to fill out the same scores for their second and the third visits along with UAS-7 (separated by an interval of two weeks each). On the second visit (day 14), the UAS-7 questionnaire was collected, and the Arabic versions of the CU-Q2oL and the DLQI were completed again by the patients for the second time. Another UAS-7 was given to each patient to complete before the third visit (day 28) and the CU-Q2oL and the DLQI were again completed by the patients for the third time. This was essential to assess the test-retest reliability and the ICC of both Arabic UAS-7 and CU-Q2oL.

III.2.1.1. UAS-7: INTERNAL CONSISTENCY AND TEST-RETEST RELIABILITY

The internal consistency of the UAS-7 score was found to be excessive with a Cronbach alpha coefficient equal to 0.95. The ICC between the second and third visit was 0.61 [95% CI (0.4-0.81); p<0.001] indicating an acceptable test-retest reliability.

III.2.1.2. CU-Q2OL: FACTOR ANALYSIS, INTERNAL CONSISTENCY AND TEST-RETEST RELIABILITY

During factor analysis, none of the 23 items of the original CU-Q2oL score had to be removed.

All items could be extracted from the list, since no items over-correlated to each other (r>0.8), had a low loading on factors (<0.3) or because of a low communality (<0.3). The exploratory factor analysis was run over the whole patient sample (n=152) and demonstrated a five domain structure of the Arabic CU-Q2oL, which described 81.9% of the variance of the 23 items. The KMO measure of sampling adequacy was found to be 0.811, with a significant Bartlett's test of sphericity (p<0.001),

indicating the adequacy of the factor analysis. According to the promax rotated matrix, the five domains are summarized in Table 14. As for the internal consistency of CU-Q2oL, it was considered to be excellent (Cronbach alpha=0.82) in both second and third time administrations. The ICCs for the CU-Q2oL total score and each of the five domain scores between the second and third visit were calculated for 44 stable patients revealing average to strong reliability (Table 15). In contrast, the CU-Q2oL total score strongly correlated with the DLQI score (r=0. 86, p<0.001).

Correlations between each corresponding domain of the CU-Q2oL and the DLQI were found to be moderate to strong (≥0.5, p<0.001) (Table 16). The mean UAS-7 and DLQI scores were 22.7±10.3 [0-42] and 7.3±5.5 [0-25], respectively.

As shown in Figure 11, statistically significant differences in UAS-7 score was found among all DLQI categories except no effect and small effect on patients' quality of life (p<0.001) This was also similar for the CU-Q2oL total score, where statistically significant differences were found among the three predefined UAS-7 groups and five DLQI groups (Figure 12, p<0.001),

i.e. there was a statistically significant difference in CU-Q2oL median scores between patients with mild versus moderate disease as well as between patients with mild versus severe disease while a statistically significant difference in CU-Q2oL scores was seen among all the five categories of DLQI.

III.2.2. PHASE 1-B: VALIDATION OF SELF-DIAGNOSTIC TOOL

The self-diagnostic questionnaire was filled by the same participating patients of the first study to which were added the patients with other dermatological diseases used as controls. Factor analysis was done, and validity, sensitivity and specificity of the new tool were calculated.

III.2.2.1. VALIDITY AND INTERNAL CONSISTENCY

To confirm the validity of the self-diagnostic questionnaire, a factor analysis was performed using the PCA technique. A varimax rotation was used since the extracted factors were found not to be correlated (R<0.8); the KMO was found to be 0.717, which indicates that the sample is adequate.

Bartlett's test of sphericity was significant (p<0.001), which ensures further adequacy. Anti-image correlation was >0.5 confirming good quality of variables. The communalities were all >0.3 indicating a good proportion of each variable's variance that can be explained by the factors. Seven items of the questionnaire were included in the analysis, after the removal of redundant questions.

The number of factors was determined by scree plot/Kaiser's rule and by the table of total variances explained, which showed that 2 factors had eigenvalues above 1 and these extracted components explained 72.4% of the variance (Table 17). Moreover, Cronbach's alpha was done to check for internal consistency and it was found to be 0.8 indicating a high value.

III.2.2.2. SCORING, SENSITIVITY AND SPECIFICITY

Both factors generated from the factor analysis were created, and their sum constituted a new variable called SRUD. It was not normally distributed; it had a median of 4.00 [3.00-5.00]. 355 patients (65.1%) had SRUD score >4, therefore, diagnosed themselves as having urticaria whereas a lower number (52.7%) had a final diagnosis of urticaria when diagnosed by a specialty physician.

More details about "SRUD" and its comparison with that of the physicians are shown in Table 18. Moreover, and as shown in Figure 13, a ROC curve was done and it has shown a sensitivity of 89.5% and a specificity of 75.7% (Area under the curve=0.85 and 95% CI [0.81-0.90]). shown between the patients with a UCT score <8 and UCT score 8-11. However, the well-controlled group had the lowest DLQI median score (4.00±4.75; p<0.001; Figure 14a). The same trend was also seen in the variation of CU-Q2oL median scores where no statistically significant difference was detected between the very poorly controlled and poorly controlled group, whereas those who were well controlled showed the lowest CU-Q2oL median score (34.00±14.00; p<0.001; Figure 14b). Out of these 212 patients with urticaria, 179 patients (84.4%) were confirmed to have the chronic type, and out of these, 41 patients (29.7%) were considered to have CSU. Moreover, it is worth to mention that 16 patients had both chronic urticaria associated with angioedema.

III.3.1.2. ASSOCIATION BETWEEN PATIENTS' DEMOGRAPHICS AND URTICARIA: BIVARIATE ANALSYIS

Results showing the socio-demographic characteristics of the patient population in phase 1-B and their association with urticaria are presented in Table 19 where the prevalence of urticaria did not appear to differ with patients' marital status, level of education, household income, number of individuals living in the same house, province, financial status, smoking, nor drinking alcohol. On the other hand, gender appeared to be significantly associated with urticaria, where a higher number of male patients (n=112) had urticaria verus females (n=100). Age was also significantly associated with urticaria where among patients with urticaria, the majority were between 25-49 years of age.

The presence of urticaria appeared to be related to the geographical location of the patients, whereby, those who lived in Beirut and South appeared to be affected by a higher risk of having urticaria (68.3% and 67.7%) compared to those who lived in Bekaa (60%), Mount-Lebanon (44.7%), and finally North (42.9%), but this finding was not shown to be statistically significant. It is also important to mention that the work status of the patients enrolled had a statistically significant difference, by which 56.8% of those with urticaria were employed whereas 35% were not.

BIVARIATE ANALYSIS

Results have shown that among patients who suffer from urticaria, 57.3% have other current diseases whereas 15.9% did not (p<0.001). Also, a statistically significant difference was found in patients who have angioedema: 85.7% patients experienced urticaria compared to 50.9% who did not (p<0.001). The same trend was also seen between asthma and urticaria where a statistically significant difference was seen among those who had asthma where 73.5% of them had also urticaria whereas 26.5% didn't have. Moreover, a statistically significant difference was noticeable with other current diseases such as diabetes, acne, eczema, and atopic dermatitis where patients who have diabetes mellitus had less urticaria than those who did not have diabetes (18.8% vs. 54.1%), and those who had acne also had less urticaria than those who did not (0.0% vs. 53.3%); as well as patients who had eczema, have shown to be less affected by urticaria (15.8% vs. 54.6%) and finally, patients suffering from atopic dermatitis presented with less urticaria than those without atopic dermatitis (0% vs.

54.4%) (Table 20).

III.3.1.4. ASSOCIATION BETWEEN ALLERGY TRIGGERING FACTORS AND URTICARIA: BIVARIATE ANALYSIS

The association between patient's allergy and urticaria is elaborated in Table 21 in details.

Among the patients who stated having urticaria, 138 turned out to have an allergy compared to only 10 patients who did not have an allergy (p<0.001).

In the questionnaire, allergic patients have stated their triggers but remarkably, most of them were not statistically associated with urticaria except the patients who revealed having an allergy triggered by an infection, as well as by pollen. Environmental factors like hot bath and humidity as well as emotional stress also were significantly associated with urticaria. What was noteworthy is the high percentage of people affected by urticaria but still don't know the triggering factor. In fact, 64.8% of the patients with urticaria don't actually know the trigger of their disease (p=0.025)

III.3.1.5. FACTORS ASSOCIATED WITH URTICARIA: MUTIVARIABLE ANALYSIS

A likelihood ratio logistic regression using 'enter' method was performed for multivariable analysis where urticaria was used as the dependent variable and only selected independent variables were included, all of which had a p-value ≤0.1 in the bivariate analysis in order to assess the predictive factors correlated with urticaria. Such a restrictive criterion was considered because of the small sample size of the study. A p-value ≤0.05 was considered statistically significant.

The Omnibus Tests of Model Coefficients was found significant (p<0.001) suggesting that the model is fit and suitable to the data and that at least one of the independent variables was considered as significant in explaining urticaria. The Hosmer and Lemeshow goodness-of-fit test was used to assess the overall fit of the model, it was found to be non-significant (p=0.24), thus further emphasizing that the model is fit with its data and that the observed event rates match the expected ones. The overall percentage from the classification table was 78.5% suggesting that the entered variables could explain more than 50% of the variability of urticaria. The Nagelkerke R square was equal to 0.6217 which indicates that 62.7% of the variation of urticaria is due to the variation of the independent variables included in the model.

These results, as shown in Table 22, demonstrate that being older than 50 years old was associated with a higher risk of having urticaria (ORa=2.829). Moreover, urticaria seems to occur more when associated with other concomitant diseases and allergies (ORa=3.513 and 4.681 respectively). Furthermore, patients who are diagnosed as having eczema or diabetes were less likely to have urticaria with respective ORa=0.077 and ORa=0.175.

AND URTICARIA

When comparing BDS-22 for the assessment of psychological distress and mental health perception in both patients with and without urticaria, student t test (independent t test) was used for analysis of this continuous independent variable with our dependent dichotomous one. Results

showed a mean of 13.2±10.89 in patients with urticaria compared to 10.54±10.1 in patients without urticaria. This mean difference is indicative of a higher risk of psychological distressin patients with urticaria compared to those without (p=0.012) (Table 23).

A significant difference was also seen with the PHQ-9 score as well where our analysis showed that urticaria patients had a mean PHQ-9 score of 5.57±4.3 whereas patients who did not have urticaria had a mean of 4.03±3.9 (p=0.003). This concludes that there was a statistically significant difference showing that patients with urticaria experienced a higher risk of depression than those without urticaria.

DIAGNOSIS

A statistically significant association was found between "SRUD" and the physician's diagnosis (p<0.001) (Table 25). The majority of the patients diagnosed themselves in concordance with the final diagnosis of their corresponding physician. In fact, 81.4% of the patients correctly diagnosed themselves as having urticaria and was confirmed by the physician at a later stage (positive predictive value). In addition, the calculated sensitivity was 69.63%, specificity was 70.35%, and negative predictive value was 55.4%. The percentage of agreement between both raters was 81.7% (290/355 total), which indicates an acceptable value. Cohen's Kappa was equal to 0.61, which is indicative of a good agreement between both types of diagnosis. 26a). Percentage of agreement when comparing both allergists' and dermatologists' diagnosis with that of the patient was not statistically significant. Among allergists, the agreement percentage was 82.4% compared to 80.2% for dermatologists (p=0.61) (Table 26b). Moreover, having less than university degree was associated with an increase in PHQ-9 score therefore indicating higher depression than other educational categories. More details about scores differences are presented in Table 27. IV. DISCUSSION

IV.1. GENERAL REVIEW

Although important pathophysiologic advances and research studies have been accomplished in recent years, there is limited data on the prevalence of urticaria in the Middle East and its impact on daily life activities; the data from Arabic world and Mediterranean region are even more scarce [START_REF] Irani | Chronic urticaria in most patients is poorly controlled[END_REF][START_REF] Irani | Chronic urticaria and autoimmune thyroid disease in lebanon[END_REF]146]. Our study has shown that UAS-7 and CU-Q2oL are valid, reliable and easily adapted by urticaria patients. Therefore, their use should be more common in the region in order to assess the disease severity and its effect on QoL. In addition, epidemiological studies vary among different geographic regions of the world and there are still few information regarding many research studies and lack of evaluation of the implication of the patient in the whole treatment process as well doctor/patient relationship during the treatment course. Not to forget the scarcity of the specific tools to measure the risk factors of the disease, its impact on the patients' quality of life and psychological wellbeing [120-121]. The newly created auto-diagnostic tool SRUD opens the door for the involvement of the patient in the treatment process and his/her implication in the management of urticaria. In fact, by diagnosing themselves as having urticaria, patients may have a clearer idea about their disease and can predict their prognosis. Although not related to an increase in mortality, chronic urticaria may have devastating effects on patients' quality of life and mental health, as shown in our project, and represents an important burden that compromises patient's quality of life, interferes with routine daily activities, and is frequently associated with psychiatric comorbidities (depression and/or anxiety) [START_REF] Baiardini | Quality of life and patients' satisfaction in chronic urticaria and respiratory allergy[END_REF][START_REF] Engin | The levels of depression, anxiety and quality of life in patients with chronic idiopathic urticaria[END_REF]. Consequently, it is worth to focus more on this disease and be enlighted about its details, risk factors and effect on daily activities which consisted the main objectives of this work.

Without comprehensive data on the clinical aspect of MCDD, namely urticaria, it will be impossible to develop appropriate local diagnostic tools and avoid its negative consequences. A clear understanding of this disease will help public health services to be reactive rather than proactive. For these reasons, it was essential to conduct this research project which was divided into two basic phases.

The main focus of the first phase was the cross-validation of Arabic versions of tools for assessment of disease activity and QoL impairment as well as the validation of an auto-diagnostic tool for urticaria to be used in further epidemiological studies in order to be able to use these specific tools in the Middle-eastern region. The second phase, on the other hand, focused on the impact of this disease on the quality of life and mental health of the affected patients. Not to forget that we also assessed the association of this disease with the main triggering factors especially those considered to be of significance in the region.

IV.2. SUMMARY OF THE MAIN RESULTS

Our project was conducted between October 2018 and June 2021 in multi-centered dermatology and/or allergy/immunology settings from all districts of Lebanon, in outpatients' clinic or in private clinics. The first phase consisted in recruiting 152 patients diagnosed with chronic urticaria in a prospective method and conducting a follow-up of two intervals of two weeks for the patients with CU in order to investigate the validity and reliability of the Arabic versions of the UAS-7 and the CU-Q2oL and estimate the correlation between them. This phase clearly demonstrated that the Arabic verisons of both severity and QoL scores related to urticaria were reliable and valid. This indicates that these versions can be generalized and circulated among Arabic-speaking patients, whether Lebanese or not, since the Arabic language used in this work was not limited to Lebanese-Arabic but also to the general grammar Arabic that is usually understood and spoken by most Arabicspeaking countries.

For the second part of the first phase, patients were also asked to fill an auto-diagnostic questionnaire along with other recruited control patients suffering from other dermatological conditions in a crosssectional method to assess whether the patients are capable of diagnosing themselves or not. The association of urticaria with the main risk factors was also evaluated in this phase. 402 patients were recruited and a validation of an auto-diagnostic tool "SRUD" was accomplished. SRUD was shown to be reliable and a readily used tool for the patients presenting to dermatology clinics to self-diagnose themselves with urticaria. This accomplished, the patients will be more involved in the general treatment process and will have a clearer idea about their condition before being officially diagnosed by their heathcare professional. As such, they will know more about their disease, its risk factors, and diverse treatment options and will eventually reach better prognosis results. Moreover, this phase assessed also the different risk factors and their association with urticaria. In fact, it was clearly shown that a previous history of asthma and prior allergies increased the odds of urticaria since they share a similar inflammatory pathophysiology [4,[START_REF] Imbalzano | Association between Urticaria and Virus Infections: A Systematic Review[END_REF]. Moreover, the specific association of pollen allergy with urticaria was one of the noteworthy findings in the Middle-Eastern region since pollen allergy is abundant and consist one of the risk factors of seasonal allergic rhinitis.

The second phase was also a cross-sectional study that focused on the recruitment of 295 patients with only chronic urticaria (either recruited in phase 1 or newly recruited participants) in order to evaluate its impact on the quality of life and psychological as well as mental wellbeing of the affected patients using previously validated tools such as CU-Q2oL, DLQI, and UCT along with PHQ-9 and BDS-22. This phase clearly demonstrated the negative impact of CU on the QoL of the affected patients as well as its effect on the deterioration of mental health. Patients with CU were more prone to depression whereas those who had a family history of urticaria or a higher educational level had less PHQ-9 scores. This explains that urticaria is considered to be a socio-dermatological disease affected by other social or psychological factors.

Overall, this study mainly targeted adult patients who were >18 years old and excluded the pediatric population. In fact, there is little data on the prevalence of chronic urticaria in children [5,147] while previous studies reported that the prevalence of acute urticaria to be 1% to 14.5% [147][148].

Specifically, the study conducted by Dilek, F. and his colleagues concluded that the prevalence of urticaria in pediatric patients is thought to be approximately one-tenth that in adults so chronic urticaria is considered to be less prevalent in children than in adults [149][150]

IV.2.1 PHASE 1-A: CROSS-CULTURAL VALIDATION OF UAS-7 AND

CU-Q2OL

The first phase of our study demonstrated that both Arabic UAS-7 and the Arabic CU-Q2oL have a very good reliability and construct validity with mild-to-moderate correlation between the two scores. Although the UAS-7 is widely used to assess CU activity, there is not, to date, any published information on the psychometric properties of the Arabic version of the once-daily version of the instrument. Thus, the results of our study indicate that the Arabic version of the UAS-7 has a very good reliability and construct validity.

The internal consistency of the UAS-7 is supported by the Cronbach alpha coefficient exceeding a value of 0.7. This may be due to the fact that the UAS-7 is a simple and easy score that is readily adapted and used in many languages [134]. In terms of test-retest reliability, acceptable ICCs were noticed and data was obtained prior to two subsequent visits that were close to each other, i.e. 2 weeks.

This was done to minimize the influence of a possible fluctuation in CU activity that may occur over a longer period of time.

As for CU-Q2oL, it was shown to be semantically equivalent to the original version of the questionnaire [START_REF] Lewis | 10 years experience of the Dermatology Life Quality Index (DLQI)[END_REF]. This is similar to the outcome of the study conducted by Kulthanan Although we used the official Arabic for translation instead of the lay language of each country and knowing that the Arabic language may slightly differ from country to another, the adapted versions of the UAS-7 and CU-Q2oL were particularly useful to assess disease activity and HRQoL in Lebanon and they may constitute a good starting point for further adaptations in other Arabic countries.

The correlation between UAS-7 and HRQoL instruments was only moderate in our study. Notably, similar findings were also reported by other authors [START_REF] Konstantinou | Psychiatric comorbidity in chronic urticaria patients: a systematic review and meta-analysis[END_REF]154] disease activity and HRQoL impairment. In fact, patients with higher CU-Q2oL scores tend to have higher disease activity and higher impairment in QoL. These findings were also highlighted in the last phase where it was clearly stated that patients with poor urticaria control had a greater impact on their QoL and psychological health.

IV.2.2 PHASE 1-B: VALIDATION OF SELF-DIAGNOSTIC TOOL

When it comes to the self-diagnostic tool "SRUD", our results demonstrated a good validity of the patients' self-reported history of urticaria with acceptable-to-good sensitivity and specificity.

Moreover, the internal consistency of the questionnaire is supported by the Cronbach alpha coefficient exceeding a value of 0.7. This may be due to the fact that the items in the self-diagnostic questionnaire were simple, easy, and understandable. Similarly, previous studies found that self- there is an acceptable agreement between the patients' and the physicians' diagnosis. This proves again the simplicity of the questions and the fact that a minimal number of questions may be sufficient to capture most of the diagnostic accuracy benefits. It is also worth to mention that the concordance of patients' and the physicians' diagnosis was less accentuated when we assessed whether the specialty of the physicians had a different outcome. In fact, allergists/clinical immunologists showed Kappa value of 0.41 while dermatologists showed a lesser agreement with a kappa value of 0.35 and was not statistically significant when comparing both. Thus, this scale can be used for any population with skin disorder regardless of the specialty of the treating physician. This again aligns with the simplicity and accuracy of the diagnostic tool.

Moreover, the visual features and pictorial aids that were used would have been very helpful in detecting the severity of the disease and ensuring reasonable diagnostic accuracy. This is comparable to the study conducted by Han, S. et al. who developed a region-based classifier for identification of onychomycosis using clinical images [159]. However, on the other hand, this autodiagnostic scale was shown to have a relatively low negative predictive value (55.4%), which might affect its validity in the clinical settings; although we expect it to have a higher negative predictive value in more epidemiological realistic settings where the prevalence of urticaria is lower.

Among all interviewed patients, almost half of them turned out to have chronic urticaria which demonstrates that the prevalence of chronic urticaria in our sample was 44.5%. This percentage is much higher than the prevalence rate shown in previous research studies [START_REF] Fricke | Prevalence of chronic urticaria in children and adults across the globe: Systematic review with meta-analysis[END_REF]. This can be explained by the fact that our main target population was the patients affected by urticaria whereby in the beginning of our study, the main focus was to recruit patients with CU only in order to cross-validate the scores related to its activity and impact on QoL. Once done, recruitment of patients with other skin diseases continued in order to be used as controls in the validation of the self-diagnostic tool (SRUD). Thus, the control patients participated in the study in order to balance the results and reach equilibrium. Consequently, our findings do not reveal the real lifetime prevalence of chronic urticaria in the Lebanese population.

Even though the rate of female to male patients in this phase of the study was high, urticaria was more prevalent in the male population in the bivariate analysis. Furthermore, our regression excluded the gender from the model proving that this difference in percentage between the female and male patients having the disease is not significant which supports the prior published evidence which states that the prevalence of urticaria is usually higher in females than males [START_REF] Antia | Urticaria: A Comprehensive review: epidemiology, diagnosis, and work-up[END_REF][START_REF] Radonjic-Hoesli | Urticaria and Angioedema: An Update on Classification and Pathogenesis[END_REF]160].

There is little information in the literature about the association of urticaria with the patients' socio-economic status, exposure to secondary smoke, and other lifestyle factors that are of particular importance in other allergic diseases. Our project did not show any association between household income, level of education, marital status, smoking or alcohol but it showed a relationship with work status which revealed that almost half of the patients who are employed have urticaria.

Prior research have stated that there is a relationship between urticaria and pseudo-allergy and other concurrent diseases such as autoimmune diseases [START_REF] Ferrer | healthcare, resources, use and clinical features of different types of urticaria. Alergológica 2005[END_REF] but this relationship was seen in our study only for some of the co-morbidites, where, out of the current diseases that 89.1% of the patients were suffering from, only diabetes, asthma, acne, eczema, atopic dermatitis and concurrent allergy showed an association with urticaria whereas autoimmune diseases like inflammatory bowel diseases, rheumatoid arthritis, and SLE did not. Only the presence of asthma was shown to be siginificantly correlated wih urticaria in the regression model. Researchers from previous studies suspect that asthma is linked to uricaria and that they frequently occur in the same patient due to similarities in regards to their pathophysiology and treatment process [161-163]. These findings were also proven in our work where it was shown that the odds of urticaria increased by 4-fold with asthma and that both diseases frequently occured in the same patient. Indeed, patients who suffer from severe attacks of urticaria frequently report sensations of 'respiratory distress', although this is mostly not real asthma [164][165]. Moreover, a positive association was seen between allergy and urticaria which highlights the results of prior research stating that an allergic reaction is usually associated with CU and is even one of the predictive factors [4,[166][167]. On the other hand, although a large population study reported that the odds of having urticaria in type 1 diabetes was 7.703 [168], our study showed a protective effect for diabetes regarding urticara. This may be explained by the fact that mainly adult patients with type 2 diabetes were recruited instead of other patients suffering from diabetes type 1.

This latter is considered to have an auto-immune nature more than the second type that is linked to other environmental and dietary triggering factors which might explain the negative relationship between diabetes type 2 and urtcaria in our sample. Concerning the presence of eczema or atopic dermatitis, these diseases seem to be negatively associated with urticaria in our model where it was demonstrated that the presence of eczema decreases the odds of urticaria by almost 30%. One explanation could be that both dermatological conditions are similar in nature and appearance as they share almost the same risk factors. In fact, eczema plays a role in the differential diagnosis of urticaria and it is very rare to detect the presence of both diseases at the same time. On the other side, the opposite of this finding was found in a pediatric population with atopic dermatitis in a recent published study conducted by Paller, A. et al. where it was noted that the prevalence of urticaria was higher in children suffering from atopic dermatitis [169]. In this regard, further studies with larger sample size are a must to be conducted to prove this association.

Furthermore, former studies have also shown that some allergy triggers such as infections and pollen exposure as well as other environmental factors such as humidity and emotional stress can sometimes precede the onset of urticaria and once established can exacerbate the symptoms [START_REF] Imbalzano | Association between Urticaria and Virus Infections: A Systematic Review[END_REF]170].

Although there was a statistically significant association between urticaria triggered by an infection or pollen exposure as well as emotional stress in our study, this significant association did not persist throughout the regression and these variables cannot be considered to be direct risk factors for urticaria. Although not seen in the regression model, one of the noteworthy findings of this study is that a high percentage of patients with urticaria (64.8%) admit that they don't know the trigger of their disease which is similar to the results of many previous research projects demonstrating that around 80% to 90% of chronic urticaria cases are idiopathic [171][172].

It has been demonstrated in previous research that psychological factors, anxiety and depression are associated with urticaria onset and aggravation [START_REF] Engin | The levels of depression, anxiety and quality of life in patients with chronic idiopathic urticaria[END_REF]164,173]. This was also proven in this study since both BDS-22 and PHQ-9 scores were higher in patients suffering from urticaria than those who don't.

Both phase 1-B and the second phase of the project demonstrated that chonic urticaria was detected mostly in the middle age category (25-50) which is consistent with some of the previous findings [8,[START_REF] Maurer | ATTEN-TUS, a German online survey of patients with chronic urticaria highlighting the burden of disease, unmet needs and real-life clinical practice[END_REF]. Furthermore, around 90% of the patients with CU were diagnosed by an allergist/immunolgist compared to only 10% by a dermatologist. This maybe either due to the fact that patients are more aware of their condition requiring an allergist intervention or because most of them had an allergy already confirmed by a doctor (76.5%). These results were not surprising as most probably, the majority of the cases were sent by primary care providers to an allergy/immunology service, and presumably general practitioners had found diagnostic difficulty for a significant proportion of these cases. In fact, it is estimated that diagnostic accuracy of non-specialists is only 24

IV.2.3. PHASE 2: IMPACT OF CU ON QOL AND MENTAL HEALTH

The second phase of the project was conducted to collect data on the CU burden on HRQoL and psychological wellbeing in the real-life clinical practice. The demographic characteristics of the 295 recruited patients suffering from chronic urticaria are mostly comparable with the findings reported in previous publications [181-182] and as stated before, CU occurrence was mostly detected in the category of age 20 and 40 years, which is consistent with previous literature [8].

This phase evaluated disease control of chronic urticaria using UCT and revealed that approximately Our findings have proven that CU patients with lower UCT scores showed higher CU-Q2oL and DLQI total scores compared with patients with high UCT scores. It is worth to mention here that although some references in the literature use the cut-off of 12 to differentiate between patients who have controlled disease from those with less controlled symptoms [START_REF] Irani | Chronic urticaria in most patients is poorly controlled[END_REF][START_REF] Ohanyan | Responsiveness and minimal important difference of the urticaria control test (UCT)[END_REF], we preferred to use the cut-off of 8 in reference to other previous studies in order to have a more detailed description of HRQoL and psychological scores among the patients who are considered to have poor control over their disease [START_REF] Weller | Development and validation of the urticaria control test a patient reported outcome instrument for assessing urticaria control[END_REF]. Furthermore, it has been shown that chronic urticaria affects the QoL of most affected patients where 50.3% of them suffered from moderate to very large effect. Unsurprisingly, similar studies revealed that chronic urticaria is compromising the patients' QoL indicating the need To add, this study has shown that patients with CU suffered from depression and psychological distress which were considered to be more serious when urticaria was less controlled. It is noteworthy to mention that in the literature, there are many studies about psychiatric comorbidity in chronic urticaria but fewer studies that specifically address depression exist. An early study by Sperber, J. and co-authors performed a psychological assessment to 19 patients with chronic inducible urticaria and found that these patients had significantly higher scores on somatization, obsessive-compulsive disorder, depression and anxiety scales when compared to the control group [190]. However, Sperber's study was limited by its small sample size unlike our study that showed a significant impairment in psychological health in a bigger sample of patients affected by CU.

The goal of this phase of the project was to provide proof of concept for the potential utility of PHQ-9 and BDS-22 scales in allergy/immunology clinics in the management of CU patients in regards to depression and psychological distress. Given the unpredictable nature of individual urticaria episodes (i.e., frequency, duration, intensity) and the adverse impact they can have on an individual's life, it is not surprising to detect an association between chronic urticaria and symptoms of depression. This was also highlighted in many previous works showing the association between urticaria and psychologic impairment [START_REF] Engin | The levels of depression, anxiety and quality of life in patients with chronic idiopathic urticaria[END_REF]191].

It is also important to mention that scores of QoL and depression did not differ significantly among different groups of patients with urticaria in regards to different demographic characteristics or medical conditions, unlike many other diseases that have a prevalence standard that is dependent on socio-economic and educational levels [189]. With respect to urticaria, there is little data available on this issue. Our study is similar to several previous studies that were not able to show a difference in the QoL associated with urticaria in terms of gender differentiation, income, age, and marital status, etc. [152]. Only emotional stress and the spontaneous type of urticaria were associated with an increase in CU-Q2oL score while lower educational level was associated with more depression. This proves that stress has a great impact on the QoL of the patients affected with urticaria and may influence it negatively. In fact, CU is also classified as a psychodermatological disorder. It was proved that factors, such as stress, can affect urticaria wheals onset and exacerbation and emotional distress can also be related to itch intensity that is one of the strongest symptoms with a negative influence on patients' QoL [192][193]. It seems also that the patients who didn't know the exact trigger behind their disease had worse impact on their QoL than those who did. This finding is logical since it is usually better to cope with the disease whenever the cause is well defined and in some cases avoidable.

When it comes to educational level, it is very common to expect that patients with lower degrees to be more depressed than those with higher education since more employment chances and better lifestyle would be associated with those who have normally better educational level. Improvements in the education system lead to a greater understanding of health issues and better health choices. In fact, education seems to have a significant effect on HRQoL. This was highlighted in the study conducted by Baumann, M. et al. on 355 students from Europe which showed that the psychological dimension of quality of life was positively associated with academic skills and more knowledge regarding employability and daily life activities [194].

IV.3. MAIN STRENGTHS AND LIMITATIONS OF THE STUDY

This project is considered to be novel in the Middle-East since it was intended to study all aspects of MCDD, namely urticaria, from the validation of diagnostic and related tools, to the assessment of its risk factors and its impact on daily life activitites and mental health. It is important to mention that studies on the same subject are still scarce regionally which allows this project to initiate and guide many future studies on the same subject. This study is descriptive conducted in multi-centered settings all over Lebanon, whether in outpatients' clinic or in private clinics, and allows analysis of a wide variety of patient population, from different geographical locations therefore enabling comparison of feedback between sites and providing insight related to generalizability of effect and external validity of the results. Moreover, the fact that we studied all patients who have any skin disorder at a certain point without any exclusions also improves the representability of our adult population and the generalizability of our results. The presence of trained research assistants to help the patients with any question was ambiguous as well as the availability of pictorial aids made it very easy and clear for the patients to correctly answer questions about the severity of the disease without any discrepancies.

Moreover, our study studied the validation of a novel auto-diagnostic tool named SRUD which is simple, easily understandable and user-friendly. Knowing that no previous tools were created for such a purpose in the same region, this tool can help carry on more epidemiological researches assessing the prevalence of urticaria and the calculation of its effect on patients' quality of life and mental health in the Middle Eastern region. In addition, SRUD can also be used in many diagnostic search engines or softwares for the patients to be more involved in their treatment process.

This study provides, for the first time, the validation data for both the Arabic UAS-7 and CU-Q2oL and their internal consistency and reliability in patients with CU. Because of the very simple linguistic structure of the UAS-7 and its straightforward questions, no significant cross-linguistic and cross-cultural differences are to be expected in different populations. However, it cannot be excluded that the disease activity of the patients in the setting of this study (tertiary care clinics) is not fully comparable with other patient groups treated in other medical settings. However, this may have an effect on the UAS-7 values rather than on its validity and reliability. Therefore, although the study was conducted in a relatively homogenous population, we believe that the results can be generalized to other populations.

To the best of our knowledge, this is the first study to evaluate agreement between patients and physicians regarding the diagnosis of urticaria. Despite the importance of doctor-patient agreement and its significant effect on health outcome, there are very few validated tools that are used for assessing this major medical aspect and none of them is implemented for diagnostic purposes in Lebanon. Being a study that was conducted in a multi-center setting, it allows analysis of a wide variety of patient population, enhancing generalizability of effect and therefore increasing the external validity of the results. Moreover, the fact that all patients with any skin disorder were included with immune biomarkers as well as the use of diagnostic interviews. Furthermore, this study was an uncontrolled, open trial conducted in a relatively small sample of patients, which would have reduced power to find significant differences. Therefore, future studies that involve a larger sample of participants may be needed. Moreover, researchers also did not have access to medical records beyond initial screening for eligibility. As such, we lack knowledge regarding changes in medical care or urticaria-directed health behaviors or any effects such changes may have had on the outcome measures and impact on the QoL. Finally, the percent of patients with urticaria that was found in the first phase of the project doesn't really reflect the actual prevalence of this disease in the region since we aimed at involving all the patients who were first recruited in Phase 1-A in order to increase the sample size and get better results. This said, more cross-sectional studies will be needed in order to evaluate the true prevalence of urticaria in the Middle-eastern region.

IV.4. PERSPECTIVES AND FUTURE IMPLICATIONS

Our study opens the door for further research projects regarding MCDD specifically urticaria especially that this disease is heterogeneous, persistent, severely debilitating and often poorly controlled. Recent findings suggest that the prevalence of CU and its subforms may be more heterogeneous than previously thought and in need of further studies, across all age groups. Knowing that our study is one of the few ones conducted in the region regarding urtcaria, our findings stimulate further research regarding the diagnosis of MCDD in primary care regarding patient involvement. This could be accomplished by the development and validation of simple diagnostic tools used by doctors and patients, such as the auto-diagnostic tool SRUD, to help the patients be more involved in the treatment process, especially that an increasing body of evidence shows that patients who are more engaged enjoy better health outcomes at lower cost compared with those who are less engaged in their care [195]. In fact, a recently published study has accomplished to help parents diagnose molluscum contagiosum in their children [196] which makes it more convenient and easier for patients to have an idea about their proper or their children's condition, get ready and imagine the therapy afterwards.

Effective communication and respect for patients' values and preferences allow patients to become informed and involved in the process of decision making, facilitating information disclosure. Being actively included in treatment decisions helps build more confidence, which may alleviate some of the psychological burden and negative impact of the disease on daily activities. Motivational interviewing technique and disease registries that respect the patient's autonomy and active listening may help strengthen the patient-physician relationship to achieve better outcomes in disease management.

This was mainly highlighted in the EAACI/GA²LEN/EDF/WAO 2017 guideline that acknowledges the effects of CSU on QoL, and the burden of the disease for patients, their family and friends, and for the healthcare system [START_REF] Zuberbier | The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria[END_REF] Indeed, the psychosocial and mental impact of CU warrants further study. It is a must for all healthcare professionals to examine further the social and emotional aspects of living with CU. Additional research on referral for counseling could be valuable, as this is something that is not covered in depth in the available guidelines. Moreover, further research of the barriers to accessing timely care would be of value. The choice of the right physician and orientation of the patients to visit allergists/immunologists should be considered. This was a main focus in our study to highlight the importance of avoiding months or even years of frustration, anxiety and/or depression before finding the 'right' physician to meet patients' needs. In addition, as it was obvious from our study and many other previous research projetcs [START_REF] Hawro | The urticaria activity scorevalidity, reliability, and responsiveness[END_REF][START_REF] Hollis | Comparison of Urticaria Activity Score over 7 days (UAS7) values obtained from once-daily and twice-daily versions: Results from the ASSURE-CSU study[END_REF][START_REF] Hawro | Comparison and interpretability of the available urticaria activity scores[END_REF][START_REF] Mathias | Evaluating the minimally important difference of the urticaria activity score and other measures of disease activity in patients with chronic idiopathic urticaria[END_REF][START_REF] Kulthanan | Angioedema activity score (AAS): a valid and reliable tool to use in Asian patients[END_REF][START_REF] Weller | Development, validation, and initial results of the angioedema activity score[END_REF], PROMs are of key importance for optimizing the management of CU and assessing treatment effects. Patients should be familiarized with the use of each PROM and should be encouraged to use them in order to record the progress of their disease and be more engaged in the whole treatment process. On the global level of the country, a general guideline development is also part of disease management which may evaluate published scientific evidence and provide recommendations based on the specific characteristics of the population and the overall assessment of the region concerning the disease features, risk factors and treatment options. For this reason, disease and patients' data registries obtained from real-life patients and databases constitute key instruments for setting health care policies, and may provide the background for clinical research [197]. Registries in allergology have allowed investigators to obtain data that is inaccessible with other methodologies and helped in determining standards of care. In 2007, Young, A. et al. performed a systematic review on the usefulness of having integrated clinical information. The main recommendation was that interactive (disorder-specific) pathways should be implemented to quickly provide clinicians with patient clinical status, treatment history, and decision support [198]. The use of such registries for CU is considered to be very valuable especially in the Middle East where information regarding urticaria is very little. For instance, online academia-driven, investigator-initiated registries on chronic urticaria may be initiated to unravel the understanding and knowledge of CU in that region.

A summary of the future implications regarding urticaria management are presented in Table 28.

V. CONCLUSION

Despite many important recent insights on the pathogenesis of CU, the endotypes and pathomechanisms and causes of CU are still insufficiently characterized or unknown.

Our study is the first step of many phases to come that shall make a difference in the future epidemiological studies to cover all the major unmet needs in urticaria research.

Despite the development of novel guidelines and treatment options for urticaria internationally, more efforts are needed to develop and validate tools for all forms of CU and extend the existing tools to children, in addition to making urticaria and angioedema PROMs more available for routine practice on a global scale. The Arabic versions of the UAS-7 and CU-Q2oL scores were found to show a robust psychometric performance in patients with CU in usual clinical practice. Both tools are suitable to assess disease activity and quality of life, respectively, in Lebanese Arab-speaking patients since their reliability and validity results were similar to those reported for other language versions.

Moreover, the newly developed self-diagnostic tool SRUD showed a high reliability and can be used to help carry on the next phases of an epidemiological research to assess the prevalence of MCDD, their effect on patients' quality of life and mental health in the Middle Eastern region, as well as the evaluation of the physicians' management, disease activity and the level of treatment control of MCDDs. The proven diagnostic concordance in our study is only the first step in a continuum of care and shall also be the basis for larger studies in order to improve the knowledge about urticaria, its diagnosis, and treatment options.

To add, the evaluation of quality of life is fundamental to better assess disease progression and treatment efficacy. This should be taken into account in routine clinical practice as well as further experimental and clinical trials in addition to the evaluation of psychological health of patients with CU in routine clinical practice.

It is crucial to mention that patients with CU need to be investigated for improvement of emotional distress levels as well as QoL after psychosomatic therapy when indicated by means of larger controlled clinical trials.

Figure 14 . 78 Figure 15 79 Figure 16 88 Figure 17

 14781579168817 Figure 14. a) DLQI median scores differences among UCT categories ............................................ b) CU-Q2oL median scores differences among UCT categories…………………….….78 Figure 15. a) PHQ-9 median scores differences among UCT categories .......................................... b) BDS-22 median scores differences among UCT categories………………………….79 Figure 16. a) Correlation between DLQI total score and UCT; p <0.001 ......................................... b) Correlation between CU-Q2oL total score and UCT…………………………………88 c) Correlation between PHQ-9 total score and UCT…………………………………….88 d) Correlation between BDS-22 total score and UCT…………………………………...88 Figure 17. a) DLQI median scores differences among PHQ-9 categories......................................... b) CU-Q2oL median scores differences among PHQ-9 categories……………………...90

Figure 1 .

 1 Figure 1. Mast cell dependent mechanism

Figure 2 .

 2 Figure 2. Mast cell dependent mechanism -Degranulation

Figure 3 .

 3 Figure 3. Different types of urticaria



  Time of onset of disease  Shape, size, frequency and duration of wheals  Occurrence of angioedema  Other related symptoms (bone/joint pain, fever, diarrhea, abdominal cramps, etc.)  Family and personal history regarding wheals and angioedema  Stimulation by causative agents: physical agents or exercise, foods or drugs (NSAIDs, ACE inhibitors), infections, stress, heat, water, etc. Previous or current allergies, infections, internal/autoimmune diseases, gastric/intestinal problems or other disorders  Social and occupational history, leisure activities  Medication history and response to therapy including dosage and duration  Previous diagnostic procedures/results

Figure 4 .

 4 Figure 4. Recommended diagnostic algorithm for chronic urticaria (Zuberbier, T. et al. 2018)

Figure 5 .

 5 Figure 5. Urticaria Control Test (UCT)

Figure 6 .

 6 Figure 6. SCORMA Index

Figure 8 .

 8 Figure 8. PHQ-9 score

A

  placebo-controlled trial by Staubach, P. et al. in 2006 suggested that ASST positive chronic urticaria patients can benefit from autologous serum therapy [110].

Figure 9 .

 9 Figure 9. Recommended treatment algorithm for urticaria (Zuberbier, T. et al. 2018)

  ical urticarias. It acts by targeting the cells and inflammatory mediators in parts of the skin by direct irradiation [117]. Several types of phototherapy such as Psoralen combined to UV-A, narrow band UV-B and UV-A have been shown to effective [118-119].

Figure 10 .

 10 Figure 10. Recruitment of patients in different phases

•

  2. [125]with the following parameters: power of 0.8, type I error of 0.05, an odds ratio of 2 and proportion of discordant pairs of 0.2 (the expected proportion of responses that differ between patient self-diagnosis and physician's diagnosis) assuming a two-tailed null hypothesis, a minimum number of 360 participants was required to participate in the study aiming at the validation of the auto-diagnostic with chronic urticaria from phase 1-A participated• 60 more patients with urticaria (all types) included • Controls: 190 patients with other dermatological conditions recruited Phase 2; N= 295 All patients with chronic urticaria from phase 1 were included• Recuitment continued to include new patients with chronic urticaria who haven't participated in phase 1 before tool. To avoid misleading withdrawals, 402 patients were finally recruited, of which 212 patients had CU and 190 patients had other types of dermatological conditions according to the final diagnosis of the treating physician.

  and the DLQI, by themselves or via interview. Illiterates, geriatrics, and those who have reading difficulties or visual problems were interviewed by a team of scientific researchers trained in dermatological diseases, especially MCDDs, who had received interview training ahead of time. Each questionnaire took approximately 10 to 15 minutes to complete. Patients were interviewed to obtain information on their socio-demographic characteristics, as well as their medical information like the main reason for doctor's visit, current and past medical history as well as medications history, any family history of dermatological diseases, symptoms of the disease and the main triggering factor. A complete history of possible causes, physical exam, and laboratory tests such as CBC, urinalysis, ESR, CRP, tryptase levels (to rule out mastocytosis), and other investigations that were necessary on individual basis for complete diagnosis of the disease. Various types of allergies were investigated including food, medications, seasonal pollen, cold, heat, contact substances, mites, insect bites, and animals. Skin prick testing and drug provocation tests were performed when necessary.

Figure 11 .

 11 Figure 11. Differences in the UAS-7 scores among the five DLQI groups ⃰ and °: outlier values

Figure 12 .

 12 Figure 12. Differences in CU-Q2oL scores among DLQI and UAS-7 groups(a) Correlation between Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL) and Dermatology Life Quality Index (DLQI) (b) Correlation between Chronic CU-Q2oL and Urticaria Activity Score-7 (UAS-7) (a) ⃰ and °: outlier values

Figure 13 .

 13 Figure 13. ROC curve of Self-reported Urticaria Diagnosis (SRUD)

Figure 14 .

 14 Figure 14. a) DLQI median scores differences among UCT categories b) CU-Q2oL median scores differences among UCT categories ⃰ and °: outlier values

Figure 15 . 1 .

 151 Figure 15. a) PHQ-9 median scores differences among UCT categories b) BDS-22 median scores differences among UCT categories °: outlier value

Figure 16 .

 16 Figure 16. a) Correlation between DLQI total score and UCT; p<0.001 b) Correlation between CU-Q2oL total score and UCT; p<0.001 c) Correlation between PHQ-9 total score and UCT; p<0.001 d) Correlation between BDS-22 total score and UCT; p<0.001

Figure 17 .III. 3 . 2 . 3 .

 17323 Figure 17. a) DLQI median scores differences among PHQ-9 categories b) CU-Q2oL median scores differences among PHQ-9 categories °: outlier value

  , K. and coworkers, who found the Thai CU-Q2oL to have a good-to-excellent Cronbach alpha value and a remarkable test-retest reliability [142]. Interestingly, the Arabic CU-Q2oL has only five domains, whereas the original Italian version, as well as the German, Greek, and Polish version of the CU-Q2oL [134-138] have six domains. In terms of internal consistency, the Cronbach alpha values of the five identified CU-Q2oL domains as well as for the total score were found to be good, i.e. over the recommended 0.70 threshold [142]. Moreover, the Arabic version of the CU-Q2oL was shown to be reliable and valid for use in Lebanese patients with CU. This is of particular importance since disease-specific questionnaires like CU-Q2oL are more useful in measuring HRQoL than general measurement scales for dermatology [153]; thus a reliable and valid translated version of the CU-Q2oL will allow its use in Lebanese patients with CU specifically.

  report and parental report of most skin conditions have good validity [157-158]. For instance, Flohr, C. and co-workers demonstrated good diagnostic precision for the question used in the International Study of Asthma and Allergies in Childhood about "persistent flexural eczema" in the past 12 months that was diagnosed by the parents of children suffering from eczema [157] supporting the fact that patients' self-diagnosis may be somehow specific and correct. In addition, the results revealed an inter-rater reliability of a kappa value 0.61 and a percentage of agreement of 81.7% showing that

  to provide appropriate treatment options to the patients with uncontrolled symptoms[185][186][187]. In a study conducted by Alzahrani, N. et al in Saudi arabia, it was proven that CU has a negative effect on patients' quality of life and disease severity had markedly affected the self-perception, mental status, and leisure activities[188]. Moreover, another comparative study of atopic dermatitis, psoriasis and chronic urticaria effect on QoL was done in France which showed that all of the three disorders impaired the QoL of the affected patients and underlined the fact that this impairment is often underestimated. [189].

Table 28 .

 28 List of future implications for urticaria management in the Middle-eastern region 1. Perform larger research projects studying the prevalence, risk factors and impact on QoL as well as psychological health 2. Develop more self-diagnostic tools to encourage the patient recognize his/her condition 3. Assess social and economical consequences of the disease from a patient and societal perspective 4. Develop virtual search engines and/or diagnostic databases for urticaria to involve the patient remotely in the treatment process 5. Encourage the use of PROMs in routine practice for the assessment of disease control, activity and impact on QoL 6. Develop urticaria-specific PROMs for use in children and adolescents since none of them was validated nor assessed in this specific population in the region 7. Raise public awareness about the disease and its effects on daily activities and encourage patients with urticaria to regularly visit immulogists/allergists 8. Promote motivational interviews and active listening to help strengthen the patient-physician relationship and achieve better outcomes in disease management 9. Encourage clinicians to differentiate between spontaneous and inducible urticaria and perform routine counseling for the patients to avoid triggering or exacerbating factors 10. Encourage long-term monitoring and frequent consultations of patients with chronic urticaria to assess disease control and prognosis 11. Encourage clinicians to follow the guidelines, utilize validated PROMs and diagnostic tests for disease diagnosis, and use medications with proven efficacy and safety 12. Perform large controlled multi-centered studies on the possible novel treatment options of urticaria to assess their efficacy and possible side effects 13. Develop a general guideline for the global management of urticaria in the region and provide recommendations based on the specific characteristics of the population 14. Maintain disease registries in allergology to obtain baseline data for further research projects and determine standards of care

Table 1 .

 1 Classification of urticaria .....................................................................................................

Table 2 .

 2 Recommended diagnostic tests in different urticaria subtypes ............................................

Table 3 .

 3 Urticaria activity Score (UAS) .............................................................................................

Table 4 .

 4 DLQI questionnaire .............................................................................................................

Table 5 .

 5 CU-Q2OL questionnaire ......................................................................................................

Table 6 .

 6 BDS-22 score .......................................................................................................................

Table 7 .

 7 Summary of scores and indexes ...........................................................................................

Table 8 .

 8 Calendar of project phases ...................................................................................................

Table 9 .

 9 Sociodemographic characteristics -Phase 1-A ...................................................................

Table 10

 10

. Socio-demographic characteristics -Phase 1-B ................................................................ Table 11. Characteristics of participants' disease -Phase 1-B ..........................................................

Table 12. Sociodemographic characteristics -Phase 2 ..................................................................... Table 13. Disease characteristics -Phase 2 ....................................................................................... Table 14. Promax rotated matrix of the CUQ2oL score .................................................................... Table 15. Internal consistency and test-retest reliability of the Arabic CU-Q2oL ............................ Table 16. Correlation of each domain of Arabic CU-Q2oL with UAS-7 and DLQI scores ............. Table 17. Varimax rotated matrix of SRUD and scoring .................................................................. Table 18. Difference between SRUD and physician's diagnosis ...................................................... Table 19. Association of patients' socio-demographic characteristics and urticaria ......................... Table 20. Association of patients' present illnesses and urticaria ..................................................... Table 21. Association between patient's allergy triggers and urticaria ............................................. Table 22. Factors associated with urticaria ........................................................................................ Table 23. Association between the patient's psychological health and urticaria ...............................

Table 24 .

 24 Patient

's quality of life indexes .......................................................................................... Table 25. Concordance between the physician's diagnosis and SRUD ............................................ Table 26. a) Diagnosis based on physician's specialty and concordance .......................................... b) Agreement depending on physician's specialty……………………………………….86

Table 27 .

 27 MANCOVA multivariable analysis ...................................................................................

Table 28 .

 28 List of future implications for urticaria management in the Middle-eastern region…..…105 Figure 1. Mast cell dependent mechanism .........................................................................................Figure 2. Mast cell dependent mechanism -Degranulation ...............................................................Figure 3. Different types of urticaria .................................................................................................Figure 4. Recommended diagnostic algorithm for chronic urticaria. ................................................Figure 5. Urticaria Control Test (UCT) .............................................................................................Figure 6. SCORMA Index .................................................................................................................Figure 7. AAS scale ...........................................................................................................................Figure 8. PHQ-9 score .......................................................................................................................Figure 9. Recommended treatment algorithm for urticaria ................................................................

	LIST OF FIGURES

Figure 10. Recruitment of patients in different phases ......................................................................

Figure 11. Differences in the UAS-7 scores among the five DLQI groups .......................................

Figure 12. Differences in CU-Q2oL scores among DLQI and UAS-7 groups ..................................

Figure 13. ROC curve of Self-reported Urticaria Diagnosis (SRUD) ...............................................

Table 1 . Classification of urticaria Type Subtype Definition Spontaneous urticaria

 1

		Acute spontaneous	Wheals and / or angioedema <6 weeks
		Chronic spontaneous	Wheals and / or angioedema >6 weeks
		Continuous	Daily or most days of the week
		Recurrent	Symptoms free intervals
	Inducible urticaria	Subtype	Precipitating factors
	Physical urticaria	Cold urticaria	Cold objects, air, fluid, wind
		Delayed pressure urticaria	Vertical pressure (wheals in 3-12 hrs.)
		Heat urticaria	Localized hear
		Solar urticaria	Ultraviolet, visible light
		Dermographic urticaria	Mechanical shearing force (wheals within 1-5 min)
		Vibratory urticaria/	Vibratory forces (wheals within 1-2 hrs)
		angioedema
		Aquagenic urticaria	Water
	Non-physical	Cholinergic urticaria	Increase core body temperature (due to exercise,
	urticaria		spicy food)
		Exercise-induced urticaria	Physical exercise
		Contact urticaria	Substance contact
	Other disease related	Urticaria pigmentosa
	urticaria	(mastocytosis)
		Urticaria vasculitis
			(Zuberbier, T. et al. 2018)

1.1. SPONTANEOUS URTICARIA  Acute and Chronic Urticarias [36-40]

	 Idiopathic: No cause can be identified. This form of urticaria is found in almost 50% of
	acute urticaria cases.
	 Allergic: This type of allergic urticaria is common. It typically occurs within minutes to
	hours depending on the causative agent. For instance, in case of allergy to food, for example,
	it occurs within minutes and no more than 30 minutes, whereas in the case of allergy to a
	certain medication, symptoms may appear after 36 hours of drug administration. In this cat-
	egory, we may find the following agents:
	o Medications including some antibiotics and non-steroidal anti-inflammatory
	drugs (NSAIDs), aspirin and Angiotensin Converting Enzyme (ACE) inhibitors, etc.
	 Non-allergic: These may be due to direct histamine release from mast cells or due to other
	mechanisms (pseudoallergic). These reactions may lead to severe anaphylaxis. Here, mast-
	cell histamine release is not immunological and may occur after the first exposure to a sub-
	stance. Examples include morphine, codeine, atracurium and antibiotics, such as polymyxin
	and vancomycin. Iodine-based radiocontrast dyes may also cause non-allergic anaphylaxis.

o Foods such nuts, shellfish, food additives, eggs, strawberries, wheat products, etc. o Pet dander from dogs, cats, horses, etc. o Seasonal pollen o Some plants, including nettles, poison ivy, and poison oak o Dust and dust mites o Latex o Insect bites and stings o Contact with some chemicals or detergents

Table 2 . Recommended diagnostic tests in different urticaria subtypes

 2

CSU: Chronic Spontaneous Urticaria; CBC: Complete Blood Count; ESR: Erythrocyte Sedimentation Rate; TSH: Thyroidstimulating Hormone; UV: Ultraviolet (Godse, K. et al, 2018)  Physical examination [27]  Morphology of the lesion (small papules, plaques, combination of lesions, thickness)  Distribution (localized, generalized, sun exposed skin, other sites)  Tests for physical urticarias (exercise, ice cube test)  Features of systemic syptoms (fever, arthralgia)  Evidence of any infection (sinusitis, cystitis, vaginitis)  Laboratory work up and special tests [55]  Initial screening tests: CBC, ESR, platelet count, Liver Function Tests, Thyroid hormone T4, Thyroid-stimulating hormone, urinalysis, stool for ova and parasites.  Disease-specific focused tests: o Autoimmune Urticaria: Peripheral basophil count, functional release assays with basophils and mast cells and immunoassay. An Autologous Serum Skin Test (ASST) may also be used. A positive ASST is indicated by a red wheal with a diameter of 1.5mm greater than at the control site (saline injected site) at 30 minutes when 0.05ml autologous serum is injected intradermally during disease activity. ASST is usually negative in physical urticarias and healthy individuals. o Physical urticarias: Dermographometer for symptomatic dermographism. o Cholinergic urticaria: Provocation test by intradermal injection of methacholine. o Cold urticaria: Ice cube test, passive transfer of cold urticaria test, serum cryoprotein estimation. o Food and exercise induced anaphylaxis: Prick test for specific IgE-dependent anaphylaxis. o Solar urticaria: Spectrodermograph, solar simulator. o Aquagenic urticaria: Wet swab test at body temperature. o Contact urticaria: Open patch test, prick test, scratch test. o Urticarial vasculitis: C3, skin biopsy. o Angioedema (Hereditary): C4, C1 esterase inhibitor.

Table 3 . Urticaria activity Score (UAS)

 3

	Score a Wheals

2 Moderate (21-50 wheals/24 h) Moderate 3 Intense (>50 wheals/24 h, or large confluent areas of wheals) Intense a Sum of score: (0-6)

Table 4 . DLQI questionnaire

 4

	Factor

9

. Over the last week how embarrassed were you? 10. Over the last week, how much has your skin influenced the clothes you wear?

Chronic

Urticaria Quality of Life Questionnaire (CU-Q2oL)

  HRQoL evaluation of patients with chronic urticaria is essential for a better assessment of disease progression and treatment response. Most studies on QoL concerning chronic urticaria have used generic questionnaires or those for dermatological diseases, such as the DLQI which was validated as a useful instrument to evaluate the HRQoL of patients with chronic urticaria. However, the DLQI can be used for any dermatological disease, since it was not developed specifically for CU patients and may not measure important factors concerning them.

	In 2005, Baiardini, I. et al. developed and validated a specific questionnaire to evaluate the HRQoL
	in CU; The Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL); which has been shown to
	have satisfactory psychometric properties [77]. The CU-Q2oL, originally written in Italian, was
	successfully validated in many languages including Spanish, German, Polish, Turkish, Brazilian

Portuguese, Korean, Greek and Persian

[START_REF] Tondury | The Pictorial Representation of Illness and Self Measure (PRISM) instrument reveals a high burden of suffering in patients with chronic urticaria[END_REF][START_REF] Baiardini | Minimal important difference of the Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL)[END_REF][START_REF] Brzoza | Adaptation and initial results of the polish version of the GA²LEN chronic urticaria quality of life questionnaire (CU-Q2oL)[END_REF][START_REF] Młynek | The German version of the chronic urticaria quality-oflife questionnaire (CU-Q2oL): Factor analysis, validation and initial clinical findings[END_REF]

. CU-Q2oL includes 23 items that are includes six QoL dimensions: pruritus, swelling, impact on life activities, sleep problems, limits, and looks. Each item is scored on a 5-point Likert scale ranging from 1="not at all" to 5="very much". The individual items are summed to generate the overall CU-Q2oL score, which are then converted to a 0-to-100 scale; higher scores indicate greater QoL impairment (Table

5

)

[START_REF] Jáuregui | Assessment of severity and quality of life in chronic urticaria[END_REF][84]

.

Table 5 . CU-Q2OL questionnaire

 5

	Factor

12. Do you wake up during the night? 13. Are you tired during the day due to lack of sleep? 14. Do you have difficulties in concentration? 15. Do you feel nervous/irritable? 16. Do you feel in a bad mood? 17. Do you put limits to food choices? 18. Do you have limits to your sport activity? 19. Are you affected by medications side effects? 20. Do you usually feel embarrassed? 21. Do you feel embarrassed to go in public? 22. Do you any problem in using cosmetics? 23. Do you have any limits in choosing clothes?

Table 6 . BDS-22 score Factor Not applicable Never A little Moderately A lot

 6

	1. I am in a bad mood
	2. My mood changes for tiny things
	3. I feel despaired
	4. I think life has no meaning
	5. I feel empty
	6. I feel on the edge
	7. I feel I don't recognize myself
	8. I isolate myself
	9. I lost the desire to learn
	10. I lack enthusiasm
	11. I don't know what I want
	12. My ideas are puzzled
	13. I have constipation or diarrhea
	14. I have stomach cramps
	15. I have stomach heartburn
	16. I find it difficult to relax
	17. I get angry for ridiculous reasons
	18. I have memory troubles
	19. I have difficulty concentrating
	20. I don't know what values to adopt
	21. I have panic attacks
	22. I worry about little things

Table 7

 7

is a summary of the questionnaires used in the assessment of disease activity, control, and burden on the quality of life of affected patients and it shows tha range of each score indicating its severity.

Table 7 . Summary of scores and indexes

 7

	Scores Range	Measures
	DLQI 0-30	Dermatology-specific health-related quality of life questionnaire
	CU-Q2oL 0-100	Specific to chronic urticaria not just any dermatological disease
	BDS-22 0-66	Assess psychological distress and psychological health perception
	UAS 0-42	Outcome measure for patients with chronic idiopathic urticaria
	UCT 0-16	Assess disease control in patients with chronic urticaria
	AAS 0-105	Assess recurrent angioedema
	SCORMA 5.2-100.8	Clinically assess the extent of cutaneous mastocytosis
	PHQ-9 0-27	Assess degree of depression severity

Second and Third Line Therapies: Omalizumab

  Some immunosuppressants may be effective especially in patients who are steroid-dependent and suffering from toxicity. Agents used in the treatment of CU include cyclosporine, tacrolimus, sirolimus, and mycophenolate. Ciclosporin A also has a moderate, direct effect on mast cell mediator release. Efficacy of ciclosporin A in combination with a modern 2nd-generation H1-antihistamine has been shown in many clinical trials in CSU, but the use of this medication is limited due to the high incidence of adverse effects. Ciclosporin A is off label for urticaria and is recommended only for patients with severe disease refractory to any dose of antihistamine and omalizumab in combina-

	Immunosuppressant agents

Omalizumab, a monoclonal antibody directed against IgE, is effective for chronic spontaneous and inducible urticaria patients older than 12 years of age who are not controlled on H1 antihistamine therapy. Omalizumab is effective at doses from 150 to 300 mg per month and no laboratory monitoring is needed during therapy [101-102]. tion [103-104]. Experience with the use of tacrolimus, sirulimus and mycophenolate in CU is limited where data of their use in CU is limited to case reports and series. Corticosteroids A short course of oral corticosteroids for a maximum of up to 10 days may be helpful to reduce disease duration/activity. The remissions achieved result in disease control with only antihistamines at licensed doses [105].

Table 8 . Calendar of project phases Phases of the project October 2018 October 2019 October 2020 June 2021 November 2021

 8

	Phase 1a: Cross-validation of	Implementation	Follow up
	Arabic UAS-7 and CU-Q2oL
	scores
	Phase 1b: Validation of self-	Implementation	Follow up
	diagnostic tool for
	epidemiological studies and
	assessment of the prevalence
	of urticaria in the Middle East
	and estimation of risk factors
	Phase 2: Assessment of the	Implementation	Follow up
	effect of MCDD on patients'
	quality of life and mental
	health in the Middle Eastern
	region

  For the patient to diagnose him/herself as having urticaria regardless of the type, the score has to be 4 or above. Self-report diagnosis was compared with physician diagnosis of urticaria. Sensitivity, specificity, positive and negative predictive values as well as the respective 95% CI were calculated. Moreover, cronbach alpha was recorded for reliability analysis for the different domains of CU-Q2oL score.

	II.8.6. CONSTRUCT AND KNOWN GROUP VALIDITY
	Construct validity indicates the correlation with other standard measurements. Spearman and
	Pearson's correlation coefficients of <0.3, 0.3-0.6, and >0.6 were considered to indicate weak,
	moderate, and strong correlations, respectively [142]. Known-group validity demonstrates the ability
	to discriminate groups that are assumed to be different. Known-group validity and the ability of the
	Arabic CU-Q2oL to distinguish patients with three different disease activity levels and different

sum constituted a new variable called "Self-reported Urticaria Diagnosis (SRUD)". The final version of this new validated self-diagnostic tool was created and consisted of seven items with a "Yes" or "No" answer with Yes=1 and No=0.

HRQoL impairment were investigated using the Kruskal-Wallis test. For easiness of calculation and because only two patients fell under the well-controlled category, three categories of UAS-7 were used to classify disease severity of the patients as follows: mild (score of 0-14), moderate (score of

[START_REF] Godse | Consensus statement for the diagnosis and treatment of urticaria: A 2017 update[END_REF][START_REF] Rook | The historical background[END_REF][START_REF] Czarnetzki | The history of urticaria[END_REF][START_REF] Min | Emerging Therapies in Chronic Spontaneous Urticaria[END_REF][START_REF] Lapi | Epidemiology of chronic spontaneous urticaria: results from a nationwide, population-based study in Italy[END_REF][START_REF] Radonjic-Hoesli | Urticaria and Angioedema: An Update on Classification and Pathogenesis[END_REF][START_REF] Fricke | Prevalence of chronic urticaria in children and adults across the globe: Systematic review with meta-analysis[END_REF][START_REF] Mobini | Noninfectious erythematous papular, and squamous disease[END_REF][START_REF] Peters | Extracellular deposition of eosinophil major basic protein in pressure urticaria[END_REF][24][START_REF] Church | Effector cells of allergy[END_REF][START_REF] Grattan | Urticaria and mastocytosis[END_REF][START_REF] Grattan | Urticaria and angioedema[END_REF]

, or severe (score of

[START_REF] Grattan | Urticaria and angioedema[END_REF][START_REF] Kobayasi | Degranulation and regranulation of human mast cells[END_REF][START_REF] Kaminer | Extracellular localization of human connective tissue mast cell granule contents[END_REF][START_REF] Klein | Degranulation of human mast cell induces an endothelial antigen central to leukocyte adhesion[END_REF][START_REF] Christofiden-Solomidon | Induction of E selectin-dependent leukocyte recruitment by mast cell degranulation in human skin grafts transplanted as SCID mice[END_REF][START_REF] Eun | Natural course of new-onset urticaria: Results of a 10-year follow-up, nationwide, population-based study[END_REF][START_REF] Doong | Chronic idiopathic urticaria: systemic complaints and their relationship with disease and immune measures[END_REF][START_REF] Westby | Chronic urticaria: Following practice guidelines[END_REF][START_REF] Zuberbier | The EAACI/GA 2 LEN/EDF/WAO guideline for the definition, classification, diagnosis, and management of urticaria: The 2013 revision and update[END_REF][START_REF] Van Arsdel | Classification and risk factors for drug allergy[END_REF][START_REF] Grattan | A serological mediator in chronic idiopathic urticaria: A clinical, immunological and histological evaluation[END_REF][START_REF] Hide | Skin mast cell activation by autoantibodies in urticaria and therapeutic implications[END_REF][START_REF] Imbalzano | Association between Urticaria and Virus Infections: A Systematic Review[END_REF][START_REF] Ferrer | healthcare, resources, use and clinical features of different types of urticaria. Alergológica 2005[END_REF][START_REF] Illig | Physical urticaria: its diagnosis and treatment[END_REF][START_REF] Horiko | Dermographism (mechanical urticaria) mediated by IgM[END_REF]

.

Table 9 . Sociodemographic characteristics -Phase 1-A

 9

	Frequency (%)

Table 10 . Socio-demographic characteristics -Phase 1-B

 10

	Socio-demographic characteristics	Frequency	Percentage
	Gender	Male Female	188 214	46.8 53.2
		18-24	60	14.9
	Age	25-49	251	62.4
		>50	91	22.6
		Married	231	57.5
	Marital status	Divorced/ widowed	23	5.7
		Single	135	34.7
		Beirut	104	25.9
		Mount-Lebanon	210	52.2
	Province	Beqaa	15	3.7
		North	42	10.4
		South	31	7.7
		No diploma	9	2.3
		Baccalaureate	143	36.1
	Highest level of education	University degree	188	46.8
		Higher education	42	11.1
		Technical education	13	3.0
		<750000	10	4.6
		750000-1500000	25	11.5
	Household income per	1500000-2250000	35	16.1
	month (LBP)	2250000-5000000	70	32.1
		>5000000	74	35.8
		1-2	67	19.5
	Individuals per household	3-4 5-6	172 101	50.0 29.4
		>7	4	1.2
		Unemployed	84	23.0
	Current work status	Employed Retired	264 16	72.5 4.4
		Full-time	139	68.1
		Yes	75	27.1
		Occasionally	31	11.2
	Smoking status	Previously	19	6.9
		No	139	50.2
		No, but in contact with smokers	13	4.7
		Yes	23	8.7
	Alcohol	Occasionally Previously	106 2	40.2 0.8
		No	133	50.4

Table 11 . Characteristics of participants' disease -Phase 1-B

 11

	Allergy

III.1.3. SOCIO-DEMOGRAPHIC CHARACTERISTICS -PHASE 2 III.1.3.1. PATIENTS CHARACTERISTICS

A total of 295 patients with CU were screened for enrolment in this phase. The mean age was 35.7±11.33 years old

Table 12 .

 12

	Infection	10	2.5
	Viral	2	0.5
	Bacterial	2	0.5
	Fungal	6	1.5
	Contact	73	18.2
	Detergents	37	9.2
	Paint/Dye	3	0.7
	Mites	14	3.5
	Dust	2	0.4
	Perfumes	4	0.9
	Animals	12	2.9
	Pollen	99	24.6
	Insect bites	6	1.5
	Sunlight	14	3.5
	Heat	13	3.2
	Cold	4	1.0
	Water	4	1.0
	Pressure	4	1.0
	Emotional stress	27	6.7
	Hot bath	7	1.7
	Sweating	15	3.7
	Exercise	7	1.7

Table 12 . Sociodemographic characteristics -Phase 2

 12 or dermatologist (8.1%), or physicians with other specialties such as otolaryngology, cardiovascular, pulmonologist, etc. (4.8%). As shown in Table13, 226 patients (81%) complained mainly from symptoms involving the skin only (red papules, itching, or swelling alone or combined) while 53 patients (19%) had both skin and respiratory problems. Both spontaneous and induced types of urticaria were encountered including physical (17.3% contact urticaria and 1.7% delayed pressure

	Frequency (%)

III.1.3.2. DISEASE CHARACTERISTICS

The majority of the patients did not have any positive family history of dermatological disease (75.8%). The final diagnosis was mainly confirmed an allergist/immunotherapist (87.1%) in most of the cases,

Table 13 . Disease characteristics -Phase 2

 13

	Frequency (%)

Table 14 . Promax rotated matrix of the CU-Q2oL score Extraction Sums of Squared Loadings Rotation Sums of Squared Loadings

 14 UAS-7 score was moderately correlated with HRQoL measurements, i.e. a moderate correlation was found between the UAS-7 score and the CU-Q2oL total score (r=0.52, p<0.001) and the UAS-7 and the DLQI total score (r=0.51, p<0.001) respectively.

	Domain	Total	% of Variance	Cumulative %	Total
	I 12.832		55.79	55.79		10.58
	II 2.117		9.20	65.00		9.83
	III 1.507		6.55	71.54		8.61
	IV 1.376		5.98	77.53		3.07
	V 1.000		4.35	81.88		3.19
					Domains
	Item No. Item		I	II	III	IV	V
	12 Wake up at night	0.93
	11 Difficulty falling asleep	0.86
	7 Affect sleep	0.85
	21 Embarrassed in public	0.76
	13 Tired		0.71
	20 Usually embarrassed	0.62
	5 Interference with work	0.58
	19 Medications side effects	0.58
	22 Problem with cosmetics	0.58
	10 Limits in eating behavior		0.83
	17 Limits to food choices		0.80
	23 Limits in clothes choices		0.79
	9 Social relationships		0.68
	8 Spare time			0.66
	16 Bad mood			0.59
	14 Problem in concentration			0.89
	18 Limits to sport activity			0.73
	15 Nervous/irritable			0.68
	6 Limits to activities			0.52
	3 Swelling of eyes			0.87
	4 Swelling of lips			0.83
	1 Itching					0.86
	2 Wheals					0.54

Table 15 . Internal consistency and test-retest reliability of the Arabic CU-Q2oL

 15

	Scale	Items	Mean Score	SD*	Cronbach	Intraclass coefficients
			(0-100)*		alpha	(n=44) **
					(n=152) *
	Total Score		39.57	14.22	0.823	0.91
	Domain I	12,11,7,21,13,20,5,	14.46	6.47	0.952	0.93
		19,22
	Domain II	10,17,23,9,8,16	10.44	4.29	0.941	0.97
	Domain III	14,18,15,6	7.44	2.92	0.879	0.75
	Domain IV	3,4	3.26	1.59	0.931	0.95
	Domain V	1,2	4.87	1.50	0.962	0.93

* Values derived from the data of 152 patients who completed the CU-Q2oL for the first time ** ICC values analyzed from the data of 44 patients who had stable disease severity and completed both questionnaires again in two intervals of 2-week interval each between second and third time visit

Table 16 . Correlation of each domain of Arabic CU-Q2oL with UAS-7 and DLQI scores

 16

	Scale	Items	DLQI Total Score*	UAS-7 Total Score*
	CU-Q2oLTotal Score*		0.86**	0.52**
	Domain I	12,11,7,21,13,20,5,19,22	0.81**	0.32**
	Domain II	10,17,23,9,8,16	0.75**	0.58**
	Domain III	14,18,15,6	0.71**	0.41**
	Domain IV	3,4	0.51**	0.38**
	Domain V	1,2	0.58**	0.61**

* Values derived from the data of 152 patients who completed the CU-Q2oL for the first time; **p<0.001

Table 17 . Varimax rotated matrix of SRUD and scoring

 17

Table 18 . Difference between SRUD and physician's diagnosis

 18

	*Defined as SRUD score >4

Table 19 . Association of patients' socio-demographic characteristics and urticaria Socio-demographic characteristics No urticaria Urticaria P value

 19

	Gender	Male Female	76 (40.4%) 114 (53.3%)	112 (59.6%) 100 (46.7%)	0.012
		18-24	33 (55.0%)	27 (45.0%)	0.001
	Age	25-49	101 (40.2%)	150 (59.8%)
		>50	56 (61.5%)	35 (38.5%)
		Married	102 (44.2%)	129 (55.8%)	0.362
	Marital status	Divorced/ Widowed	11 (47.8%)	12 (52.2%)
		Single	70 (51.9%)	65 (48.1%)
		Beirut	33 (31.7%)	71 (68.3%)	0.053
		Mount-Lebanon	117 (55.7%)	93 (44.3%)
	Province	Bekaa	6 (40.0%)	9 (60.0%)
		North	24 (57.1%)	18 (42.9%)
		South	10 (32.3%)	21 (67.7%)
		No diploma	5 (55.6%)	4 (44.4%)	0.063
		Baccalaureate	67 (46.9%)	76 (53.1%)
	Level of education	University degree	78 (41.5%)	110 (58.5%)
		Higher education	25 (56.8%)	19 (43.2%)
		Technical education	10 (76.9%)	3 (23.1%)

III.3.1.3. ASSOCIATION BETWEEN PATIENTS' CURRENT ILLNESS AND URTICARIA:

Table 20 . Association of patients' present illnesses and urticaria

 20

	Present illness		No urticaria	Urticaria	P value
	Angioedema	Yes No	3 (14.3%) 187 (49.1%)	18 (85.7%) 194 (50.9%)	0.002
	Allergic rhinitis	Yes No	16 (38.1%) 174 (48.3%)	26 (61.9%) 186 (51.7%)	0.209
	Drug or other allergy	Yes No	58 (55.8%) 132 (44.3%)	46 (44.2%) 166 (55.7%)	0.052
	Asthma	Yes No	9 (26.5%) 181 (49.2%)	25 (73.5%) 187 (50.8%)	0.011
	Inflammatory Bowel Disease	Yes No	1 (16.7%) 189 (47.7%)	5 (83.3%) 207 (52.3%)	0.219
	Diabetes	Yes No	13 (81.3%) 177 (45.9%)	3 (18.8%) 209 (54.1%)	0.005
	Hypertension	Yes No	25 (56.8%) 165 (46.1%)	19 (43.2%) 193 (53.9%)	0.179
	Thyroid disease	Yes No	10 (50.0%) 180 (47.1%)	10 (50.0%) 202 (52.9%)	0.801
	Rheumatoid arthritis	Yes No	4 (80.0%) 186 (49.7%)	1 (20.0%) 211 (50.3%)	0.154
	Systemic lupus erythematouses	Yes No	1 (25.0%) 189 (47.5%)	3 (75.0%) 209 (52.5%)	0.354
	Acne	Yes	4 (100.0%)	0 (0.0%)	0.049
		No	186 (46.7%)	212 (53.3%)
	Atopic dermatitis	Yes No	12 (100.0%) 178 (45.6%)	0.0 (0.0%) 212 (54.4%)	0.001
	Eczema	Yes No	16 (84.2%) 174 (45.4%)	3 (15.8%) 209 (54.6%)	0.001

Table 21 . Association between patient's allergy triggers and urticaria

 21

	Patient's allergy		No urticaria	Urticaria	P value
	Allergy	Yes No	105 (43.2%) 68 (87.2%)	138 (56.8%) 10 (12.8%)	<0.001
	Allergy type	Respiratory	18 (66.7%)	9 (33.3%)	0.001
		Skin	68 (37.6%)	113 (62.4%)
		Hay fever	4 (66.7%)	2 (33.3%)
		Anaphylaxis	2 (100.0%)	0 (0.0%)
		Respiratory and skin	27 (27.3%)	72 (72.7%)
		Eye	1 (20.0%)	4 (80.0%)
	Allergy triggers
	Food	Yes No	19 (38.0%) 171 (48.6%)	31 (62.0%) 181 (51.4%)	0.161
	Alcohol	Yes No	0 (0.0%) 190 (47.5%)	2 (100%) 210 (52.2%)	0.277
	Medications	Yes No	12 (46.2%) 178 (47.3%)	14 (53.8%) 198 (52.7%)	0.907
	Infections	Yes No	8 (80.0%) 182 (46.7%)	2 (20.0%) 208 (53.3%)	0.037
	Contact	Yes No	38 (52.1%) 152 (46.2%)	35 (47.9%) 177 (53.8%)	0.365
	Animals	Yes No	6 (66.7%) 184 (46.8%)	3 (33.3%) 209 (53.2%)	0.318
	Pollen	Yes No	28 (28.3%) 162 (53.5%)	71 (71.7%) 141 (46.5%)	<0.001
	Insect bites	Yes No	5 (83.3%) 185 (46.7%)	1 (16.7%) 211 (53.3%)	0.105
	Environmental factors
	Sunlight	Yes No	7 (53.8%) 183 (47.2%)	7 (46.2%) 205 (53.0%)	0.629
	Heat	Yes No	7 (66.7%) 183 (47.0%)	6 (33.3%) 206 (51.1%)	0.225
	Cold	Yes No	1 (25.0%) 189 (47.5%)	3 (75.0%) 209 (52.5%)	0.625
	Water	Yes No	3 (75.0%) 187 (47.0%)	1 (25.0%) 211 (53.0%)	0.348
	Hot bath	Yes No	7 (100.0%) 183 (46.3%)	0 (0.0%) 212 (53.7%)	0.003
	Emotional stress	Yes No	19 (70.4%) 167 (46.1%)	8 (29.6%) 195 (53.9%)	0.005
	Pressure	Yes	2 (50.0%)	2 (50.0%)	1

Table 22 . Factors associated with urticaria

 22

	Independent variables	ORa	95% CI	P-value
	Age categories
	18-24			0.007
	25-49	1.962	0.350-2.648	0.94
	>50	2.667	1.268-5.610	0.01
	Current asthma	5.067	1.571-16.34	0.007
	Current Diabetes mellitus	0.175	0.033-0.928	0.035
	Current disease eczema	0.077	0.015-0.381	0.002
	Allergy	8.987	4.22-19.136	0.000
	ORa= Adjusted odds ratio; CI= Confidence interval

III.3.1.6. ASSOCIATION BETWEEN PATIENT'S PSYCHOLOGICAL HEALTH

Table 23 . Association between the patient's psychological health and urticaria

 23 Student t test (independent t test) was also used for analyzing DLQI and CUQ2oL in patients with urticaria. The mean DLQI and CUQ2oL score are elaborated in Table24below. These results are indicative of a nonsignificant difference of urticaria impact on patients' HRQoL, in comparison with other dermatological diseases.

	Patient's severity score	N	Mean (SD)	P value
	BDS-22	Urticaria No urticaria	212 189	13.2 (10.10) 10.54 (10.89)	0.012
		Urticaria	107	5.57 (4.30)
	PHQ-9	No urticaria	155	4.03 (3.90)	0.003

SD standard deviation; BDS-22 Beirut Distress Score-22; PHQ-9 Patient Health Questionnaire III.3.1.7. ASSOCIATION BETWEEN QOL INDICATORS AND URTICARIA

Table 24 . Patient's quality of life indexes

 24

	Patient's quality of life indexes	N	Mean (SD)	P value
	DLQI	Urticaria No urticaria	211 189	7.84 (6.05) 7.48 (5.85)	0.550
	CU-Q2oL	Urticaria No urticaria	210 148	40.41 (16.97) 38.16 (14.71)	0.193
	SD: standard deviation; DLQI: Dermatology Life Quality Index; CU-Q2oL: Chronic Urticaria Quality of Life
	Questionnaire
	III.3.1.8. CONCORDANCE BETWEEN PHYSICIANS' AND PATIENTS'

Table 25 . Concordance between the physician's diagnosis and SRUD Physician's diagnosis

 25

	Patient's self-diagnosis	No urticaria	Urticaria	P value	Kappa
	No urticaria Urticaria	102 (55.4%) 43 (18.6%)	82 (44.6%) 188 (81.4%)	<0.001	0.610

Table 26 . a) Diagnosis based on physician's specialty and concordance

 26

		Dermatologist N (%)	Allergist N (%)	P value
	No urticaria	105 (57.1%)	79 (42.9%)
	Urticaria	22 (10.4%)	190 (89.6%)	<0.001
	Total	127 (32.1%)	269 (67.9%)
	b)

Agreement depending on physician's specialty III.3.2. PHASE 2 III.3.2.1. CORRELATION BETWEEN QOL AND PSHYCHOLOGICAL DISTRESS SCORES AND URTICARIA CONTROL

		Allergist	Dermatologist	P value
		N (%)	N (%)
	No Agreement	41 (17.6%)	23 (19.8%)	0.61
	Agreement	192 (82.4%)	93 (80.2%)
	All scales were shown to be negatively correlated to UCT. The HRQoL measurement scores
	were shown to have a moderate negative correlation with UCT. i.e. a moderate correlation was found
	between DLQI total score and UCT (rho=-0.51, p<0.001) and CU-Q2oL total score and UCT (rho =-
	0.55, p<0.001) respectively. The same was also noticed between the psychological distress scores and
	UCT (PHQ-9: rho =-0.55 and BDS-22: rho =-0.61, p<0.001). More details about correlation
	measurements are presented in Figure 16.

Table 27 . MANCOVA multivariable analysis

 27

	CU-Q2oL	PHQ-9

  . Although, a change in UAS-7 may indicate a change in the patient's HRQoL as seen in our study similarly to the study conducted by Stull, D. and his colleagues [135], the moderate correlation can be explained by the fact that disease activity and HRQoL constitute different concepts. HRQoL is influenced by not only disease activity but also additional factors such as sleep deprivation and psychiatric comorbidities [93], and other psychosocial variables in other chronic skin diseases such as psoriasis [155-156]. However, it was demonstrated that the Arabic CU-Q2oL could clearly differentiate patients with different levels of

  This was proven in previous studies such as the one conducted by Weller, K. et al. in which it was reported that the screening accuracy of the UCT to identify CU patients with insufficiently controlled disease was high[START_REF] Weller | Development and validation of the urticaria control test a patient reported outcome instrument for assessing urticaria control[END_REF]. Notably, similar findings were also reported by other authors who highlighted the large proportion of CU patients with a UCT score of less than 12 and the higher DLQI dissatisfaction among those[183]. Although a change in UCT may indicate a change in the patient's HRQoL as seen in our study similarly to the study conducted by Stull, D. and his colleagues [184], the moderate correlation can be explained by the fact that disease control and HRQoL don't fall under the same category. As previously mentioned concerning disease activity and its association with QoL, HRQoL is not influenced only by disease control itself but other psychological and environmental factors may also play a role. This again was highlighted in our study by the change of HRQoL scores among different categories of PHQ-9.

68.6% of CU patients at the time of survey displayed a UCT score less than 12, indicating uncontrolled symptoms. Also, a moderate negative correlation between UCT scores and HRQoL assessments such as CU-Q2oL and DLQI has been proven.

Acknowledgments

with higher scores indicative of a higher disease activity (Figure 7) [START_REF] Kulthanan | Angioedema activity score (AAS): a valid and reliable tool to use in Asian patients[END_REF][START_REF] Weller | Development, validation, and initial results of the angioedema activity score[END_REF][START_REF] Staubach | Omalizumab rapidly improves angioedema-related quality of life in adult patients with chronic spontaneous urticaria: X-ACT Study Data[END_REF].

I.4.2. BURDEN OF THE DISEASE

The burden of CU for patients as well as the healthcare system and society is substantial.

PROMs are of key importance for the management of CU [6,[START_REF] Weller | Chronic urticaria: tools to aid the diagnosis and assessment of disease status in daily practice[END_REF]. In addition to the assessment of disease activity and control, PROMs define the impact of CU on the patients' QoL [START_REF] Baiardini | Recommendations for assessing patient-reported outcomes and health-related quality of life in patients with urticaria: a GA(2) LEN taskforce position paper[END_REF] using general questionnaire. Each patient filled the questionnaire within approximately 20 minutes. At the end of the process, the completed questionnaires were collected back for data entry.

II.6. TOOLS FOR DATA COLLECTION

II.6.1. QUESTIONNAIRE

A specific questionnaire was prepared in three languages: Arabic, French and English. During the first phase of the study, only the Arabic version of the questionnaire was provided for the patients for the sake of cross-validation of urticaria-related questionnaires (UAS-7, CU-Q2oL and DLQI).

For the second phase, the versions with the three languages were distributed and offered to the patient based on his/her preference in order to ensure the best comprehension and therefore to get the most appropriate answers without any discrepancies. The questionnaire consisted of many sections including: sociodemographic and health characteristics, previous dermatological diagnosis, chief complaint, risk factors, severity scores such as UCT and UAS-7, AAS, SCORMA, BDS-22, and PHQ-9, as well as Quality of life Indexes (DLQI and CU-Q2oL). At the end, a section for physician's diagnosis, laboratory testing results, and patient self-diagnosis with pictorial aids were available (Appendix A, B, C).

II.6.1.1. SOCIO-DEMOGRAPHIC/MEDICAL CHARACTERISTICS

The socio-demographic characteristics that were asked for in the questionnaire consisted of: age, gender, highest educational level, marital status, household income per month, financial status, employment status, cigarette smoking and alcohol consumption. The past and present medical history were also taken into account by asking about the following items: all known current diseases and past surgical procedures, list of current medication(s), family history of dermatological diseases (parents, brothers/sisters and children), previously diagnosed or reported skin disease/allergies and concomitant diseases, allergies and their types, triggers or aggravating factors of the disease, any prick tests done, allergens and IgE levels, and the main chief compliant for the doctor's visit.

II.6.1.2. SEVERITY AND QOL SCORES

The questionnaire comprised PROMs for CSU management assess disease activity, impact and control such as UAS-7, the UCT, the AAS, and the SCORMA index. AAS was only used if angioedema was suspected and SCORMA in case of mastocytosis. As for the HRQoL scores, the CU-Q2oL and the DLQI were used.

questionnaires and that investigators shall maintain the privacy and confidentiality of all information collected. The Lebanese University ethics committee gave an official waiver for approval, as the study was observational and respected participants' confidentiality; there was no traceability of the patient and data was analyzed anonymously. The three core principles of Belmont report regarding the research on human subjects were abided by: respect for persons, beneficence, and justice. All included patients gave their oral informed consent to participate [147].

no exclusions also improves the representability of our adult population.

We enforced our concordance analysis by using more than one value, relying on both the percentage of agreement and Cohen's kappa. While Cohen's kappa is one of the most frequently used statistical measure to assess inter-rater reliability, it has some limitations. Choosing an acceptable level of kappa in health studies is questioned. If for example in healthcare research, a kappa of 0.4 was used to measure reliability, it could lead to recommendations for changing practice based on faulty evidence. Therefore, we did not rely on Cohen's proposed lenient interpretation but instead we used the one suggested by McHugh which is stricter in order to have a more solid revelation [143].

Moreover, this is one of few studies in the region to evaluate the impact of urticaria on QoL and psychological health. In addition, it is worth to note that the CU-Q2oL was used which is a valid and specific instrument to evaluate the HRQoL in CU on the contrary of most studies that used generic questionnaires for dermatological diseases, such as the DLQI alone. To add, the fact that all patients with all types of chronic urticaria were included also improves the representability of our adult population. In fact, patients with both types of chronic urticaria (induced and spontaneous) participated in the study because we aimed to prove our objectives under real-life conditions. Despite this, some limitations may be implied. Actually, the present study was conducted only in an observational mode and neither its aim nor design were meant to assess responsiveness which needs to be done in future studies in different settings, e.g. before and after changing a treatment regimen. Moreover, the collection of retrospective information about factors that might have been important in our analysis such as previous diseases, allergies, medication names and family history, may have increased the risk of recall bias. Another limitation is the lack of thorough objective diagnostic criteria such as laboratory tests as a reference for testing validity. Furthermore, although the test-retest reliability analysis was supposed to be done in patients without change in disease activity, some treatment regimens have been changed for some participants in between visits, e.g. some patients couldn't have been kept without any treatment after the first visit.

In addition, the self-diagnostic tool was not designed to differentiate between inducible and spontaneous urticaria, but this may be of relevance since we aimed to test the validity of the patients' self-diagnostic capacity under real-life conditions. Moreover, items and questions that may help in differential diagnosis of other dermatological conditions were lacking. To add, the number of patients seen by allergists are more than those seen by dermatologists which may influence the results of agreement in diagnosis of urticaria in favor of allergists; but this may in turn be favorable, since we may conclude that most patients are aware of their condition being an allergic reaction rather than a sole dermatological one. Not to forget that all outcome measures were self-reported, which may be open to bias, such as social desirability or limited awareness of internal states. Thus, future studies would benefit from the inclusion of more objective measures of disease severity and control, such as