**Abstract**

Chronic urticaria, a common mast cell driven disease, has been considered so far an underestimated and difficult to treat disease, very often resulting in high physical, psychological and socio-economic burden. More than 60% of these patients are unresponsive to second generation H1 antihistamines, the first-line symptomatic treatment for urticaria. However, anti-IgE drugs (omalizumab and ligelizumab) showed improved activity in urticaria-treated patients with inadequate symptom control. Omalizumab has been widely proven to be very effective and well-tolerated in patients with antihistamine-refractory chronic spontaneous urticaria and inducible urticaria and is currently licensed for these indication as third-line treatment. Ligelizumab, a next-generation monoclonal anti-IgE antibody with higher affinity to IgE compared to omalizumab and a similar safety profile, has recently demonstrated to be even more effective than omalizumab. This review is focused on the role of anti-IgE antibodies in chronic urticaria.

**Keywords:** Urticaria, Chronic Spontaneous Urticaria, Chronic Inducible Urticaria, Anti-IgE antibodies, Omalizumab, Ligelizumab

### **1. Introduction**

Urticaria is a common mast cell-driven disease characterised by wheals (1–24 hours) and/or angioedema (up to 72 hours) (**Figure 1**), defined as acute when symptoms last <6 weeks or chronic if they occur continuously or intermittently for ≥6 weeks [1]. Approximately 50% of patients have both hives and angioedema, whereas 40% have wheals alone, and 10% have angioedema alone [2]. Moreover, Chronic Urticaria (CU) can be further classified as Chronic Inducible Urticaria (CIndU) when appear in response to specific eliciting factors, such as thermal agents, vibration, cholinergic factors, aquagenic, and delayed pressure or as Chronic Spontaneous Urticaria (CSU) if the above mentioned triggers have been excluded [1].

#### **1.1 The prevalence of Chronic Urticaria**

Both children and adults may develop urticaria, with the peak age of onset in adults being between 20 and 40 years [2]. The lifetime prevalence of Acute Urticaria (AU) ranges from <1% to 24% (12% to 24% in Europe), depending on the age range, method of sampling, and geographic location [3]. Instead, CU is estimated at 1% but there is no reliable data regarding its prevalence due to the lack of crosssectional studies [4]. About 20% to 45% of patients with AU develop into CU.

**Figure 1.** *(a–h): Urticaria is characterised by an outbreak of swollen, pale red bumps or plaques on the skin (wheals) and can also manifest as deep swelling around the eyes, lips, and face (angioedema) that appears suddenly.*

CSU occurs in 0.5–1% of the population at any point in time, with its incidence peaking between 20 and 40 years of age [5]. CSU is considered more common in adults than in children and women are affected twice as often as men. However, recent studies have suggested that the prevalence of CSU in the paediatric population is similar to that of the adult population [6].

Finally, the CIndU prevalence is lower than other types of urticaria (e.g., acquired cold urticaria in Europe is extimated around 0.5%) [3].

#### **1.2 The burden of Chronic Urticaria**

In 1997 O'Donnel et al. compared the Quality of Life (QoL) scores in 142 patients with CU and 98 patients with life-threatening heart disease, finding similar QoL scores in both groups [7]. Indeed, many CU patients exhibit a severe impairment of their quality of life. The long disease duration (on average aorund two to five years) and the lack of curative therapy have been underlined as the two main aspects that contribute to the high physical, psychological and socio-economic burden of CU [8, 9]. The last EAACI/GA<sup>2</sup> LEN/EDF/WAO guideline recommends "aiming at complete symptom control in urticaria, considering as much as possible the safety and the QoL of each individual patient" [1]. Currently, two specific QoL questionnaires are available for evaluating the burden of CU on patients: Chronic Urticaria Quality of Life (CU-Q2oL) and Angioedema Quality of Life (AE-QoL). Moreover, in order to collect quality, real-life data on CU patient characteristics, the course of disease, underlying causes, comorbidities, treatment responses, quality of life impairment and health care costs the Chronic Urticaria Registry was recently set up [10].
