Urticaria is characterized by the development of wheals with or without angioedema. Chronic urticaria (CU) is defined as lasting for more than 6 weeks [1]. The prevalence of CU is estimated to be between 0.1 and 1.4% across different areas of the world ^[2][3][2,3].

Different triggers can elicit urticaria, such as cold, heat, contact, infections, and others. However, in 75% of the patients suffering from CU, the causal factor cannot be detected [4]. Accordingly, urticaria is defined as spontaneous when no specific trigger is identified [1].

Mast cells are primarily involved in the pathogenesis of chronic spontaneous urticaria (CSU) through the release of pro-inflammatory mediators, which, in turn, recruit neutrophils, eosinophils, and T lymphocytes ^[5][6][5,6]. Impaired intracellular signaling pathways, and type II and type I autoimmunity have been suggested as pathogenic mechanisms [7]. It has been found that 30–50% of patients with CSU produce immunoglobulin (Ig)G autoantibodies against IgE or its receptor (FcεRI), causing the degranulation of cutaneous mast cells and basophils, and thus histamine release ^[8][9][8,9]. Regarding type I autoimmunity, in a cluster of CSU patients, researcheuthors reported evidence of IgG and IgE against thyroperoxidase (TPO), defining this mechanism as “autoallergy”. Patients with CSU had a six-fold higher risk of TPO antibodies positivity than controls (odds ratio (OR) 6.72; 95% confidence interval (CI) 4.56, 9.89). However, their pathogenic role is still under debate ^{[10][11][12][13]}[10,11,12,13]. More recently, the activation of cascade coagulation has been proposed as an alternative pathogenic mechanism, initiated by tissue factors expressed on eosinophils in lesional skin. This event leads to thrombin-mediated increased vascular permeability and mast-cell degranulation [14].

CU can significantly affect the health-related quality of life (HRQoL) of patients, as it has been reported to interfere with sleep quality, and school and work performance, especially in patients with uncontrolled disease, with subsequent high health care and indirect costs ^[15][16][15,16]. Notably, it has also been associated with psychiatric disorders, such as anxiety and depression [15].

The treatment of CU has been based on the avoidance or elimination of triggering factors and, when identified, on the treatment of the underlying causes, such as infection. The treatment of CSU is based on symptomatic drugs and, among these, second-generation H1-antihistamines (H1AH) represent the current mainstay of treatment according to guidelines [1]. Nevertheless, the percentage of non-responders to H1AH is around 60%, which remains high, despite the possibility of increasing the dose to four-fold the licensed dose (40–45% of non-responders to standard dose) ^[17][18][19][17,18,19]. Furthermore, the up-dosing of H1AH is not free from potential adverse effects in children [19]. Therefore, in the last two decades, new treatment approaches, including monoclonal antibodies (mAbs) and immunosuppressants (e.g., cyclosporine), have been introduced to optimize symptom control and improve HRQoL [20]. The identification of different molecular pathways underlying CSU has made them potential therapeutic targets ^[6][8][6,8]. In this context, mAbs represent targeted therapies directed towards specific molecular pathways, being potentially more efficacious and avoiding toxicity and/or side effects of immunosuppressants [21]. They have proven to be effective in other inflammatory and allergic diseases, such as rheumatoid arthritis and asthma ^[21][22][23][21,22,23]. In CSU, their use is currently restricted to moderate-to-severe forms refractory to standard treatment, and only omalizumab, an anti-IgE mAb, is labelled as an add-on treatment for CSU [24].

2. MoCurrenoclonal Antibodiest Work

Although omalizumab still remains the only approved mAb in treating CSU, other biologics have shown promising results and are currently under investigation in several trials ^{[24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57]}[24,37,38,39,40,42,43,44,45,46,47,48,49,50,51,52,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71]. Regarding omalizumab, a number of performed trials with a consistent number of enrolled patients have shown that omalizumab is effective, improving disease control and QoL, and safe, thus representing a well-established add-on treatment in refractory CSU, as stated by the updated EAACI guidelines ^{[1][58][59][60][61][62][63][64][65][66][67][68][69]}[1,25,26,27,28,29,30,31,32,33,34,35,36]. Nevertheless, a limitation is the lack of RCTs on children. The only data refer to adolescents (≥12 years of age), who have been included in RCTs with adults, where they represent a marginal percentage, and they are not analyzed separately. A prospective open-label researchtudy on 29 adolescents with refractory CSU confirmed the effectiveness of omalizumab, with 58% of patients reaching a complete response (UAS = 0) at week 12. Three patients had a relapse after several months (from 4 to 12) following omalizumab withdrawal ^[70][120]. A resviearchw including 13 children reported a complete response in 12 of them after omalizumab 150 mg or 300 mg ^[71][121]. Nevertheless, around 30–40% of patients do not achieve disease control (UAS ≤ 6) with omalizumab ^[59][60][72][26,27,125]. This might be due to the standard dose of omalizumab, not adapted to weight and IgE levels, as seen in asthma, and/or high IgE levels (>1500 IU/mL), and/or different pathogenic mechanisms ^{[32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][70][71][72][73][74][75][76][77][78][79][80][81][82][83][84][85][86][87][88][89][90][91][92][93][94][95][96][97][98][99][100][101][102][103][104][105][106][107][108][109][110][111][112][113][114][115][116][117][118][119][120][121][122][123][124][125]}[45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126]. Omalizumab up-dosing to 600 mg reduced the proportion of non-responders to 7% ^[126][127]. With the aim of optimizing a treatment, high total serum IgE levels have been suggested as a biomarker predictive of the response to omalizumab ^[127][128]. Indeed, patients who exhibited a poor response to omalizumab had lower pre-treatment IgE levels compared with responders, who also showed an increase in IgE levels at week 4, and the IgE level at week 4/IgE level at baseline ratio revealed its superiority as a predictor of the response to treatment ^[128][129]. Blood basophils and histamine, which both increased in patients treated with omalizumab 300 mg, could represent other biomarkers predictive of the response to treatment ^[129][130]. Serum transglutaminase-2 activity may be a more reliable monitoring biomarker of the response to omalizumab, being less influenced by other comorbidities than IgE ^[130][131]. Another unanswered question concerns the optimal duration of treatment. RCTs have reported CSU-relapses after the interruption of omalizumab, with a subsequent response when treatment was re-started ^[66][33]. Therefore, omalizumab cannot be defined as a disease-modifying drug, and long-term treatments seem to be needed to control the disease. Ligelizumab (240 mg), another anti-IgE, drug has shown superiority to omalizumab, probably due to its slightly different mechanism of action and higher affinity to IgE ^[25][37]. However, at the end of 2021, Novartis announced that ligelizumab showed superiority to a placebo, but not versus omalizumab at week 12 in two ongoing trials (NCT03580369 and NCT03580356), although the data are not yet available ^{[44][45][131]}[58,59,132]. Contrary to this, quilizumab did not improve symptoms ^[132][41]. Currently, several experimental and clinical research studies are ongoing with the aim to provide further evidence on the pathogenesis of CSU. Understanding the close relationship between pathogenic pathways and clinical features will allow the identification of novel predictive biomarkers helpful in selecting the best candidate to receive targeted therapies with mAbs, and, consequently, the achievement of better clinical outcomes. In addition to IgE, other investigated targets have included IL-5/IL-5R, through the development of anti-IL-5 mAbs (mepolizumab, reslizumab, and benralizumab), showing efficacy in 14 patients ^{[29][30][31][47][48]}[42,43,44,61,62]. The IL-4 and IL-17 pathways, targeted by dupilumab and secukinumab, respectively, seem to play a remarkable role in the pathogenesis of CSU; thus, they could be an additional therapeutic weapon in the treatment of refractory CSU ^[6][39][109][6,52,107]. Nevertheless, data on these mAbs, though encouraging, come from case series, thus no firm conclusions can be drawn about their efficacy ^{[32][33][34][39]}[45,46,47,52]. Ongoing and future RCTs on larger populations will clarify their potential therapeutic role in CSU. TSLP, IL-25, and IL-33, the so called “alarmins” probably represent one of the most intriguing targets because they are located upstream of the inflammatory cascade. Hence, blocking the alarmins pathway could potentially be more efficacious and modify the disease course ^[116][114]. Barzolvolimab, suppressing mast cells, could represent another disease-modifying drug ^[117][115]. Although it is not the purpose of this review, it is necessary to mention that, among biologic drugs, small molecule inhibitors such as remibrutinib (LOU064), a Bruton’s tyrosine kinase (BTK) inhibitor with a potential role in the treatment of CSU, represent an alternative to mAbs [133]. Remibrutinib, similar to other BTK inhibitors (fenebrutinib, tirabrutinib, rilzabrutinib, and TAS5315), targets BTK, which is involved in B-cell differentiation and proliferation and mast-cell activation, mediated by B-cell receptor and FcεRI activation, respectively ^{[133][134][135][136][137][138][139][140][141][142][143][144]}(Table 6 and Table 7) [133,134,135,136,137,138,139,140,141,142,143,144]. Remibrutinib at different doses showed superiority to a placebo in the NCT03926611 trial [133]. Similarly, the preliminary results of the NCT03137069 trial on fenebrutinib 150 mg daily and 200 mg twice a day showed a significant reduction from the baseline in UAS7 at week 8 compared with a placebo (−17.6 and −20.7, respectively, vs. −11.2) [145]. On the contrary, trials on tirabrutinib and etanercept, a TNF-α antagonist, have been stopped early ^[141][144][141,144]. Other trials are ongoing to investigate inhibitors acting on different targets, such as JAK1/TYK2 and prostaglandin D2 receptor 2 (DP2 or CRTH2) ^[146][147][146,147]. CRTH2 plays a role in the chemotaxis of Th2 cells and eosinophils, and Th2 cytokine synthesis. AZD1981, a CRTH2 antagonist, induced a significant reduction in UAS7 at the end of the drug wash out period compared with a placebo and with no safety concern [147]. To summarize, small molecule inhibitors may represent an alternative to mAbs as targeted therapies in refractory CSU, with the advantage for some of them of oral administration compared with mAbs. However, data on inhibitors, excepted for etanercept, whose use has been reported successfully in a case report of CSU, are limited to few trials, that, to date, do not allow reusearchers to draw conclusions on their efficacy and safety ^{[40][135][141][147]}[54,135,141,147].