REVIEW URRENT C OPINION Omalizumab in chronic urticaria Martin Metz and Marcus Maurer Purpose of review The current EAACI/GA2LEN/EDF/WAO treatment guidelines for the management of urticaria recommend omalizumab as fourth-line therapy. Within the last year, many reports of omalizumab treatment in chronic urticaria have been published. Recent findings Two multicenter, randomized, placebo-controlled trials in chronic spontaneous urticaria have shown excellent efficacy of omalizumab. Furthermore, in various case series and case reports, omalizumab has been shown to be effective also in inducible urticarias; however, no randomized placebo-controlled trial has been performed yet to thoroughly investigate the efficacy of omalizumab in inducible urticarias. Summary In this review, all published information on the use of omalizumab in urticaria will be summarized and discussed with special emphasis on reports published within the last year. The available data indicate that omalizumab is an effective and well tolerated drug in antihistamine-resistant chronic urticaria. Keywords anti-immunoglobulin (Ig) E, mast cell, physical urticaria, spontaneous urticaria, Xolair INTRODUCTION Urticaria is a frequent skin condition, which is characterized by transient pruritic wheal and flare type skin reactions and, in some patients, the occurrence of angioedema. In Europe alone, more than 5 million patients are thought to suffer from persisting urticaria symptoms [1 ], which either occur spontaneously, that is in chronic spontaneous urticaria, or can be induced, for example as a result of environmental physical stimuli such as pressure, ultraviolet irradiation, heat or cold (physical urticaria), or by other means (Fig. 1). Patients with chronic urticaria are often severely impaired in their quality of life , with negative effects on sleep, daily activities, school/work life and social interactions. Therefore, the current guidelines of the European Academy of Allergy and Clinical Immunology (EAACI)/Global Allergy and Asthma European Network (GA2LEN)/European Dermatology Forum (EDF)/World Allergy Organization (WAO) state that the aim of treatment for all types of urticaria is to achieve complete symptom relief . To accomplish complete symptom control, specific underlying causes can be identified and eradicated in some patients with chronic spontaneous urticaria . However, most patients with chronic spontaneous urticaria and all patients with inducible urticaria require symptomatic treatment for effective symptom control. & www.co-allergy.com The current EAACI/GA2LEN/EDF/WAO treatment guidelines for the management of urticaria recommend the use of second-generation nonsedating oral H1-antihistamines as first-line therapy. In more than 50% of the patients, symptoms persist with standard dosing of antihistamines [1 ]. In these patients, it is recommended to increase the dose of the nonsedating H1-antihistamines up to four-fold . Thereafter, among several other third-line and fourth-line options including ciclosporin A, the guidelines suggest the possibility of using omalizumab. Omalizumab (Xolair, Novartis, Switzerland and Genentech, USA) is a recombinant humanized monoclonal antibody that binds to immunoglobulin (Ig) E. It is specific for circulating free IgE and cannot bind to cell-bound IgE or IgG, as it is engineered to bind to the CH3 domain of the e chain, which is close to the binding site of IgE for FceRI and CD23. Omalizumab has been approved in the & Allergie-Centrum-Charite´, Department of Dermatology and Allergy, Charite´ – Universita¨tsmedizin Berlin, Berlin, Germany Correspondence to Professor Dr med. Marcus Maurer, MD, Department of Dermatology and Allergy, Charite´ – Universita¨tsmedizin Berlin, Charite´platz 1, D-10117 Berlin, Germany. Tel: +49 30 450 518043; fax: +49 30 450 518972; e-mail: [email protected] Curr Opin Allergy Clin Immunol 2012, 12:406–411 DOI:10.1097/ACI.0b013e328355365a Volume 12 Number 4 August 2012 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Omalizumab in chronic urticaria Metz and Maurer KEY POINTS Omalizumab has been shown in two multicenter, randomized, placebo-controlled trials to be highly effective and well tolerated in patients with chronic spontaneous urticaria. urticaria patients exhibit on average higher total IgE levels as compared with healthy controls . A transferable serum factor has been demonstrated in some forms of inducible urticaria [6–8] and autoallergic mechanisms can be identified as a potential underlying cause in up to 50% of chronic spontaneous urticaria patients [9 ]. && In various case series and case reports, omalizumab has been reported to be effective in patients with inducible urticaria including cholinergic urticaria, urticaria factitia, solar, cold, heat and delayed pressure urticaria. Removal of autoreactive immunoglobulin (Ig) E is hypothesized to be one potential mechanism of action in chronic spontaneous urticaria. In other diseases such as bullous pemphigoid, similar mechanisms and similar efficacy of omalizumab may be observed. United States in 2003 for the treatment of moderate to severe asthma in patients 12 years and older and in Europe in 2005 for the treatment of severe allergic asthma in patients 6 years and older. The postulated mechanism of action accounting for the reduction of exacerbations and symptoms of allergic asthma is the fall in free IgE levels and the associated downregulation in the expression of FceRI receptors on basophils and mast cells. In chronic urticaria, there is general consent that the underlying cause is never an allergy. Nevertheless, various lines of evidence indicated that antiIgE might still be beneficial in the treatment of chronic urticaria: for example, chronic spontaneous Spontaneous Inducible OMALIZUMAB IN CHRONIC SPONTANEOUS URTICARIA On the basis of the above-mentioned findings of a potential role of IgE in urticaria and some initial case reports, we therefore performed a first proof-ofconcept randomized, placebo-controlled doubleblind multicenter trial with omalizumab in chronic spontaneous urticaria (Table 1 [10 ,11 ,12,13,14 , 15–20,21 ,22 ,23–26]). In this study, a total of 49 patients with chronic spontaneous urticaria who exhibit IgE against thyroperoxidase have been treated. Omalizumab treatment resulted in rapid and significant reductions in weekly urticaria activity scores (UASs), and, most strikingly, in complete protection against the appearance of wheals in 70.4% of the omalizumab versus 4.5% of the placebo-treated patients [11 ]. The dose of omalizumab given to the patients in this trial has been determined according to the dosing scheme used in asthma patients, that is based on total IgE levels and body weight. However, we and others have observed within this trial as well as in a number of case series and case reports (Table 1 [10 ,11 ,12,13,14 ,15–20,21 ,22 ,23–26]) that treatment response to omalizumab appears to && & && & & && && && Spontaneous urticaria Acute spontaneous urticaria Physical urticaria Cold urticaria & & & Chronic spontaneous urticaria Heat urticaria Pressure urticaria Solar urticaria Urticaria factitia/dermographic urticaria Other forms of urticaria Aquagenic urticaria Cholinergic urticaria Contact urticaria Exercise-induced urticaria FIGURE 1. Classification of urticaria. 1528-4050 ß 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins www.co-allergy.com 407 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Pharmacotherapy and evidence based medicine Table 1. Trials and reports of omalizumab treatment in patients with chronic spontaneous urticaria Reference No. of patients Comment Saini et al. [10 ] 90 (21 placebo, 69 omalizumab) Dose finding: 75, 300, 600 mg; significant improvement with 300 and 600 mg Maurer et al. [11 ] 49 (22 placebo, 27 omalizumab) Complete protection from wheal development in 70.4% of omalizumab vs. 4.5% placebotreated patients 14 Significant improvement in urticaria activity and quality of life in all patients Randomized controlled multicenter trials && && Small trials/case series Bu¨yu¨ko ¨ ztu¨rk et al.  Godse  Ferrer et al. [14 ] & 5 Significant improvement in all patients 9 All patients responded, seven of nine showed complete response Groffik et al.  9 All patients responded Al-Ahmad  3 All patients responded Magerl et al.  8 All patients responded, six of eight showed complete response Kaplan et al.  12 Placebo controlled, seven complete response, four significant improvement, one nonresponder Spector and Tan  3 All with complete response Case reports Rodriguez-Trabado et al.  Response correlates with reduction in basophil activation Sa´nchez-Machin et al. [21 ] Increased activity of CD4þ T cells associated with effective treatment Saavedra and Sur [22 ] Successful treatment associated with FceRI down regulation Korkmaz et al.  Complete response Iemoli et al.  Complete response associated with normalization of B-cell activation and homing Vestergaard and Deleuran  Two patients with complete response Romano et al.  Two patients with complete response & & be largely independent of total IgE. Therefore, a larger dose-finding multicenter trial with a total of 90 chronic spontaneous urticaria patients from the United States or Germany has been performed with 75, 300 and 600 mg omalizumab or placebo [10 ]. In this study, patients received a single dose of omalizumab and efficacy was assessed by comparing urticaria activity at baseline to week 4. Here, the overall excellent and rapid response to omalizumab has been confirmed and 300 mg omalizumab has been identified as the optimal dose for the treatment of urticaria symptoms. In currently ongoing clinical trials, the additional dose of 150 mg of omalizumab, which has been shown to be effective in a number of patients reported in case series and case reports, will also be evaluated. In both multicenter trials, treatment with omalizumab was found to be safe and well tolerated and the incidence of adverse events was found to be similar across all treatment groups. && 408 www.co-allergy.com Furthermore, a total of 63 patients with chronic spontaneous urticaria treated with omalizumab have been reported in the literature to date (Table 1 [10 ,11 ,12,13,14 ,15–20,21 ,22 ,23–26]). Overall, a significant clinical response has been described in 62 out of the 63 patients, with no report of relevant adverse events. Most of the patients reported in these case series and reports have been treated according to the escalating treatment scheme recommended in the EAACI/GA2LEN/EDF/ WAO treatment guidelines, that is with high-dose H1-antihistamines, H2-antihistamines, leukotriene antagonists, dapsone and/or ciclosporin A. The patients then received omalizumab because of failure of the previous treatment or because of intolerable side effects, such as kidney failure after cyclosporine treatment. Taken together, based on the results from two multicenter placebo-controlled trials and numerous && && & & & Volume 12 Number 4 August 2012 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Omalizumab in chronic urticaria Metz and Maurer patients treated individually, omalizumab appears to be a highly effective and well tolerated treatment option in severe and antihistamine-resistant chronic spontaneous urticaria. OMALIZUMAB IN INDUCIBLE URTICARIA Similar to chronic spontaneous urticaria, a classical allergy is never the underlying cause of an inducible urticaria disease. Nonetheless, IgE has often been speculated to play a role in the pathomechanisms underlying inducible urticarias. For example, early work by Houser et al.  and Kaplan et al.  have shown that in some patients with cold urticaria, a transferable serum factor consistent with IgE may exist [27,28]. Similarly, passive transfer experiments have indicated the existence of a mast cell-activating IgE serum factor in some patients with urticaria factitia , and in solar urticaria, the production of a photoallergen in the skin and the subsequent IgE-mediated activation of mast cells is often hypothesized to be the relevant underlying mechanism . A critical mast cell-activating factor such as a photoallergen in solar urticaria or a cold-induced allergen in cold urticaria has, however, not yet been identified. The first report of a successful treatment of urticaria with omalizumab by Boyce in 2006 described a complete symptom control in a girl with persistent asthma and severe cold urticaria . Based on this case report and the considerations of a potential role of IgE in inducible urticarias we and others have described successful treatment of patients with urticaria factitia, cholinergic, solar, cold, heat, and delayed pressure urticaria (Table 2 && [32 ,33–40]). Overall, a total of 16 patients have been reported with 11 patients showing a complete response. Interestingly, not all patients responded; some patients did not show any effect at all, indicating different pathomechanisms in some patients. As of now, no randomized placebo-controlled trial has been performed to thoroughly investigate the efficacy of omalizumab in inducible urticarias. OUTLOOK AND OPEN QUESTIONS THAT NEED TO BE ADDRESSED In moderate to severe asthma, omalizumab has been shown to effectively improve symptoms and to reduce the rate of exacerbations and emergency visits . The response to treatment in these patients differs, however, considerably from the one in patients with urticaria. For example, in asthmatic patients, low levels of total IgE are associated with a smaller treatment benefit, and the response to omalizumab is described as a progressive onset, with 38% of patients responding within 4 weeks of initiating treatment, and 64% after 16 weeks [42,43]. In contrast, treatment benefit in urticaria patients appears to be independent of total IgE levels and significant clinical improvement was observed already after a few days of initiating treatment [11 ]. These differences raise the question whether the omalizumab-induced symptom improvement in both asthma and urticaria follow similar underlying mechanisms. The main mechanism of omalizumab is the reduction of free IgE to less than 10% of baseline levels. Associated with the rapid reduction in free && Table 2. Reports of omalizumab treatment in patients with inducible urticaria Reference No. of patients Comment 7 Complete response in solar (2), cold (1), delayed pressure urticaria (1) and urticaria facitita (1), no response in heat urticaria (1) Case series Metz et al. [32 ] && Case reports Duchini et al.  Treatment failure in solar urticaria Krause et al.  Successful treatment in urticaria factitia Waibel et al.  Partial improvement in solar urticaria Bullerkotte et al.  Complete response in heat urticaria Sabroe  Treatment failure in cholinergic urticaria Bindslev-Jensen and Skov  Complete response in delayed pressure urticaria Gu¨zelbey et al.  Complete response in solar urticaria Metz et al.  Complete response in cholinergic urticaria Boyce  Complete response in cold urticaria 1528-4050 ß 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins www.co-allergy.com 409 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Pharmacotherapy and evidence based medicine IgE levels, a subsequent down regulation of the IgE receptor FceRI on mast cells and basophils occur, which is also thought to contribute to the clinical response . In chronic spontaneous urticaria, additional mechanisms may be relevant. For example, we have recently identified a possible novel pathogenic pathway in chronic spontaneous urticaria. In more than 50% of chronic spontaneous urticaria patients elevated levels of IgE autoantibodies against thyroperoxidase (TPO) can be detected [9 ]. These IgE-anti-TPO autoantibodies, when bound and activated on the surface of mast cells, could cause an autoallergic mast cell degranulation. It can be speculated that in addition to IgEanti-TPO other IgE autoantibodies exist in chronic spontaneous urticaria patients. Anti-IgE treatment could result in the rapid reduction of these IgE and thus to the suppression of urticaria symptoms. Chronic spontaneous urticaria is not the only disease in which IgE autoantibodies have been shown to exist. For example, autoreactive IgE have been detected in a large number of patients with atopic dermatitis, especially in those with severe disease [44,45 ]. Similarly, pathogenic autoreactive IgE can be found in patients with bullous pemphigoid [46 ]. Interestingly, omalizumab treatment has been reported to be effective in some patients with atopic dermatitis  as well as in patients with bullous pemphigoid . These findings suggest that IgE autoantibodies might be a relevant pathogenic pathway in several diseases and anti-IgE treatment could be beneficial in those diseases. Further research has to confirm the existence and to identify the relevance of other IgE auto antibodies. Another open question that needs to be addressed in the future is the required dosing and treatment scheme of omalizumab in urticaria. In the initial trials, case series and case reports in urticaria the dosing scheme for omalizumab treatment in asthma patients has been used, that is based on total IgE levels and body weight. Currently available data however indicate that efficacy of omalizumab in urticaria is independent of these parameters and that 150–300 mg every 4 weeks is sufficient in most patients [10 ,17,32 ]. Future investigations will have to confirm this and detailed treatment schemes need to be developed. For example, optimal treatment intervals, and modes of up dosing and tapering of dosing should be defined. Furthermore, it is has not been studied in detail yet whether omalizumab treatment can have a disease-modifying effect and may lead to a remission of urticaria in some patients. The currently published studies as well as our personal experience argue against this possibility as the large majority of patients return to similarly severe urticaria && symptoms usually 4–8 weeks after the last omalizumab injection. CONCLUSION More than 50% of patients with chronic spontaneous urticaria and a large proportion of patients with inducible urticarias such as solar or cold urticaria are resistant to standard antihistamine treatment. In these patients, treatment with the monoclonal anti-IgE antibody omalizumab has been found to be a highly effective and well tolerated therapy. Further investigations have to be carried out to identify the exact mechanisms underlying the excellent efficacy, to provide the optimal dosing scheme in urticaria and to identify other diseases in which anti-IgE treatment might be beneficial. Acknowledgements The development of this paper was supported in part by Novartis; we thank Jodie Urcioli for medical writing services including proofreading. & & && 410 && www.co-allergy.com Conflicts of interest There are no conflicts of interest. The authors disclose the following activities as speaker and/or advisor for pharmaceutical companies: Abdi Ibrahim, Almirall Hermal, Bayer Healthcare, Biofrontera, Dr R. Pfleger, Essex Pharma, Genentech, JADO Technologies, Jerini, Merckle Recordati, Novartis, Sanofi Aventis, ScheringPlough, Leo Pharma, MSD, Merck, Shire, Symbiopharm, UCB, Uriach. 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