**1. Introduction**

Chronic spontaneous urticarial (CSU) with or without angioedema, is a condition which lasts more than 6 weeks, without an apparent trigger. It results from a pathogenic over-activation of dermal mast cells and basophils, followed by their degranulation and the release of pro-inflammatory mediators (mainly histamine) inducing the appearance of transient itchy wheals, and occasionally episodes of angioedema. The prevalence of CSU is estimated to be between 0.5-1percent in the general population, with an incidence of 0.10 to 1.50 per 1000 person-years. It predominantly affects female, with symptom onset occurring mainly between 20 and 40 years [1]. Earlier studies reported on CSU lasting over one year in more than 70% of cases and continuing to exist in 14% of them after five years. CSU duration was associated with the presence of angioedema and disease severity. In a recent study, younger CSU patients (22 ± 16 years) tended to have a significantly longer course, were in 16% of patients, CSU symptoms lasted over ten years [2, 3]. In addition to its prolonged duration, CSU severely affects quality of life and is associated with comorbidities such as lack of sleep, impairments in work productivity, and depression/anxiety. In one study about 50% of patients with CSU were diagnosed with one or more psychosomatic disorders, the most frequent of which was anxiety, followed by depressive and somatoform disorders [4, 5]. The prevalence of rheumatoid arthritis, systemic lupus erythematosus, thyroiditis and vitiligo were found to be significantly increased in CSU patients [6]. Patients without any evidence of comorbidities at the time of their CSU diagnosis had an increased risk of developing mast cell-mediated diseases including atopic diseases [7]. Many studies have focused on the importance of clinical and laboratory biomarkers for the assessment of CSU severity and the evaluation of treatment efficacy. Clinical manifestations such as asthma and thyroid disease were associated

with higher disease severity and duration [8]. Laboratory markers, namely, C-reactive protein (CRP), autologous serum skin test (ASST), basophil activation test (BAT, D-dimer levels and total serum IgE are all potential blood biomarkers that are useful for CSU management [9]. Many CSU patients continue to suffer from symptoms of pruritus, urticaria, and angioedema despite the acceptable up dosing of second-generation antihistamines (up to fourfold) [10]. Recurrent short courses of steroids were also reported to have only a short-term beneficial effect in severe CSU patients. Current treatments are considerably effective in achieving good response and favorable remission, however, many CSU patients are still refractory to these available treatments. This is why, it is extremely important to identify and understand underlying disease mechanisms, in order to achieve better therapeutic outcomes. In addition to a brief summary covering the pathogenesis of CSU, and the currently used therapies, this chapter will focus on emerging new therapies, some of which are being studied in on-going clinical trials, and others that are being assessed as potential candidates for treatment.
