Clinical Reviews in Allergy & Immunology (2020) 59:38–45 https://doi.org/10.1007/s12016-020-08794-6 Omalizumab Updosing in Chronic Spontaneous Urticaria: an Overview of Real-World Evidence Martin Metz 1 & Zahava Vadasz 2 & Emek Kocatürk 3 & Ana M. Giménez-Arnau 4 Published online: 16 May 2020 # The Author(s) 2020 Abstract Chronic spontaneous urticaria (CSU) is defined as the spontaneous development of itchy hives and/or angioedema due to known or unknown causes that last for at least 6 weeks. At any given time, CSU is believed to affect 0.5–1% of the global population. Omalizumab (a recombinant, humanized anti-immunoglobulin-E antibody) is the only approved treatment for antihistamine refractory CSU. However, ~ 30% of patients remain symptomatic at licensed doses of omalizumab 150 mg and 300 mg, even after a treatment period of over 6 months. In the recent years, there have been several studies on updosing of the drug, suggesting that the individualized approach for urticaria treatment with omalizumab is useful. In this article, we provide an overview of these studies and the real-world data on omalizumab updosing as it became necessary to obtain complete CSU symptom control in a proportion of patients. Published observational studies (from June 2003 to October 2019) on the updosing of omalizumab in CSU were identified using PubMed and Ovid databases. Reports mainly show that updosing/dose adjustment evaluated with the assessment of disease activity (Urticaria Activity Score) and control (Urticaria Control Test) achieves better clinical response to omalizumab with a good safety profile in a pool of patients with CSU. These real-world data will provide an overview of updosing of omalizumab in CSU and aid in setting informed clinical practice treatment expectations. Keywords Chronic spontaneous urticaria . Chronic idiopathic urticaria . Refractory urticaria . Omalizumab . Updosing . Real-world evidence Introduction licensed dose [4–6]. Approximately 33–67% of CSU cases have both hives and associated angioedema [7–9]. A recent Chronic spontaneous urticaria (CSU), a subgroup of chronic investigation looking at differences in physician and patient urticaria, is defined as the spontaneous daily, or almost daily, reporting of angioedema showed that in 40% of inadequately occurrence of itchy hives (wheals), angioedema, or both, last- controlled CSU patients angioedema are reported by both ing for 6 weeks or more, with no apparent external trigger [1]. physicians and patients, but additionally, almost every third CSU presents a major burden of disease for patients and soci- patient reported about occurrence of angioedema while the ety with a significantly diminished quality of life [2, 3]. The physician did not [10]. estimated lifetime point prevalence of CSU is approximately Much progress has been made recently to delineate the 0.5–1% and nearly 60% of patients with CSU continue to underlying mechanisms of CSU and the pathogenesis therein, have the disease despite treatment with antihistamines at the and to use this understanding to develop better treatment op- tions including immunoglobulin E (IgE)–targeted therapies, which show benefit in patients [11, 12]. The EAACI/ * Ana M. Giménez-Arnau GA2LEN/EDF/WAO guidelines recommend following a anamariagimenezarnau@gmail.com stepwise approach to treat urticaria (Fig. 1) [1]. Treatment with second-generation H1-antihistamines (H1-AHs) are the 1 Department of Dermatology and Allergy, Charité – Universitätsmedizin Berlin, Berlin, Germany mainstay of symptomatic therapy of CSU, with treatment in 2 licensed standard dosing as first-line, and updosing to up to Division of Allergy and Clinical Immunology, Bnai-Zion Medical Center, Haifa, Israel four times the recommended standard dosing as the second- 3 line treatment. The guideline recommended third-line therapy Department of Dermatology, Koç University, Istanbul, Turkey 4 which is the use of omalizumab as third-line add-on therapy to Department of Dermatology, Hospital del Mar. IMIM, Universitat H1-AHs, if an inadequate response to H1-AHs is observed Autònoma de Barcelona, Barcelona, Spain Clinic Rev Allerg Immunol (2020) 59:38–45 39 how it is measured [25]. Commonly used categories for com- plete and well-controlled disease activity for CSU include Urticaria Activity Score (UAS) over 7 days (UAS7) of 0 and of ≤ 6 respectively. Omalizumab non-responders to treatment are generally considered to be those patients whose baseline UAS7 remains unchanged after treatment or who continue to present a UAS7 > 16 after six doses of omalizumab at 300 mg every 4 weeks. Partial responders are often defined by a reduc- tion of the UAS7 by at least 30%, but by less than 90% or by patients showing a UAS7 > 6 but with an improvement in UAS7 as compared with baseline [25]. Using the Urticaria Control Test (UCT), the cutoff values for “controlled disease” is ≥ 12 which is often considered as a complete response to treatment (complete control = 16, controlled urticaria ≥ 12, no control < 12) [25]. As per the current EAACI/GA2LEN/EDF/ WAO guideline, the third line of treatment is recommended for the partial and non-responders to updosed AH treatment [24]. The licensed dose of omalizumab is 300 mg in Europe and either 150 mg or 300 mg in the USA by subcutaneous injection every 4 weeks [26]. Some reports have shown examples of the optimization of omalizumab treatment in patients who show inadequate response by increasing the dose or decreasing the Fig. 1 EAACI/GA 2 LEN/EDF/WAO International Guideline: dosing intervals [27]; a more flexible treatment regimen rather recommended treatment algorithm for urticaria. Short course (maximum than a constant regimen including shortening dosing interval or of 10 days) of corticosteroids may also be used at all times if augmenting dose based on the patient’s symptoms is also like- exacerbations demand this. EAACI, European Academy of Allergology ly to provide better symptom control [28, 29]. Although there and Clinical Immunology; EDF, European Dermatology Forum; GA2LEN, Global Allergy and Asthma European Network; H1-AH, H1 is currently no algorithm for the individualized management of antihistamine; WAO, World Allergy Organization omalizumab treatment that is agreed on, treatment algorithms based on specific response profiles of patients refractory to after 2–4 weeks (or earlier if symptoms are intolerable). AHs have been proposed to facilitate clinical management of Patients who remain inadequately controlled with omalizumab and enable clinicians to assess therapeutic strate- omalizumab after 6 months (or earlier if symptoms are intol- gy [2, 30, 31]. The aim of this article is to provide a summary erable) are recommended to receive add-on therapy with cy- of the published real-world evidences for the updosing of closporin A as a fourth-line agent. omalizumab in the treatment of CSU. Omalizumab (a recombinant, humanized anti-IgE antibody) is an effective and well-tolerated treatment option for CSU and the first drug approved for use in patients with CSU who re- Overview on Omalizumab main symptomatic despite H1-AH treatment. Omalizumab is shown to be safe and effective across randomized placebo- Omalizumab is a recombinant humanized IgG1 monoclonal controlled trials [13–15] and several real-world studies antibody that binds to IgE-specific epitopes within the C3 [16–20], with a total patient exposure of 1,328,183 patient (FcεRI binding) region of the IgE molecule, with low immu- years (Novartis data on file, Dec 2019). Omalizumab binds nogenicity, that inhibits binding of IgE to FcεRI on the surface IgE and rapidly reduces levels of free IgE by > 90%, resulting of mast cells and basophils [32–34]. On continued therapy, in a subsequent reduction of FcεRI, the high affinity IgE re- omalizumab is associated with downregulation of cell surface ceptor, on blood basophils and mast cells in the skin [21]. Both IgE receptors, further preventing IgE-mediated histamine re- of these mechanisms are thought to importantly contribute to lease and inflammation. the efficacy of omalizumab in urticaria [22]. Additional modes of action of omalizumab may exist in urticaria and further research will be necessary to fully clarify the potential of Omalizumab in the Treatment of Refractory omalizumab in CSU [23]. The definition of response to treat- CSU ment in CSU differs between clinical trials, real-world studies and daily practice of individual physicians globally [24], and, Positive results from investigator-reported use of omalizumab therefore, the response to treatment in CSU also depends upon for chronic urticaria provided an impetus for therapeutic 40 Clinic Rev Allerg Immunol (2020) 59:38–45 treatment in CSU. Successful use of omalizumab in chronic disease control, disease course, and patient-reported symp- urticaria began to appear in the literature as early as 2006 as toms that were observed at month 6 and continued beyond case reports [35, 36]. The first controlled clinical trials in 24 months, particularly when AHs alone failed to control chronic spontaneous urticaria followed some years later and symptoms [45]. Across real-world settings, treatment with included the X-CUISITE trial [37] which showed a high effi- omalizumab was thus associated with improved clinical re- cacy of omalizumab in patients with CSU pre-selected for the sponse and clinical improvement [46]. presence of anti-thyroid peroxidase-specific IgE autoanti- Despite our understanding of the long-term treatment of bodies [37, 38] and the MYSTIQUE study [39] which showed CSU, it is known that only a minority of patients have symp- improvement in CSU symptoms with omalizumab 300 mg tom control with standard-dosed H1-AH treatment. Updosing and formed the basis of further investigations of efficacy and of second-generation AHs as recommended by the EAACI/ safety of omalizumab in CSU at this particular dose. Overall, GA2LEN/EDF/WAO urticaria guideline as second-line thera- there is much evidence for the efficacy and safety of py can improve response, but many patients remain symptom- omalizumab and treatment with 300 mg omalizumab every atic. Although omalizumab in licensed dosing has been prov- 4 weeks in patients with CSU [40]. Clinical trials for treatment en to be effective in H1-AH refractory patients, there are pa- of CSU with omalizumab generally provide data for up to tients who do not achieve complete control. Here, we 6 months; there are ongoing trials with omalizumab treatment reviewed the published evidence for the use and safety of for up to 1 year and for re-treatment effectiveness. updosing omalizumab from the standard monthly 300 mg dose to higher doses of monthly 450 mg or 600 mg. From the first report in 2014 by Fiorino et al. [27] in Italy to Literature Search Methodology the most recent report in 2019 from Aghdam et al. [47] in the Netherlands, there have been a growing number of publica- A literature search was performed in PubMed and Ovid (from tions reporting real-world evidence for updosing of June 2003 to October 2019) for the identification of relevant omalizumab in CSU (Table 1). studies on the updosing of omalizumab in CSU. The following Fiorino et al. [27] reported a case for the long-term treat- search terms were used: “omalizumab” OR “omalizumab 450 ment of refractory severe CSU by omalizumab with a mg” OR “omalizumab 600 mg” and “chronic spontaneous UAS7 > 38. The patient was not responding to omalizumab urticaria” OR “chronic idiopathic urticaria” OR “urticaria” 300 mg for 9 months and achieved complete symptom control OR “angioedema” AND “real-world evidence” AND/OR after updosing to the higher dose of 450 mg/month. “updosing.” The search was also restricted to English language Metz et al. [17] from Germany published a retrospective and studies in humans. Out of the total 87 hits obtained from analysis of 30 patients with CSU not sufficiently treated with the search, 17 publications with omalizumab updosing were updosed H1-AH. Complete symptom control and remission identified. Of these, nine publications were finally included in of their symptoms (reduction of 90% or more in UAS7) was the review. Publications on inter-dose updosing from 150 to observed in 25 of 30 (83%) patients, without the requirement 300 mg were excluded. Reference lists of the articles included of any other drugs after the first treatment with omalizumab. were manually searched for additional relevant studies. Among 25 patients who achieved complete remission, one patient was updosed from 150 to 300 mg/3 weeks. In a further 5 (of the 30) patients, the minimum effective dose of Real-World Evidence of Omalizumab omalizumab was 300 mg every 3 or 4 weeks. Two of these Treatment and Updosing in CSU patients showed significant improvement when updosed from 150 to 450 mg every 4 weeks. The findings suggest that pa- Several studies from real-life clinical practice have reported tients who may not respond to omalizumab show complete the safety and efficacy of omalizumab at approved dosing. In a response upon updosing. systematic review of 84 publications, Bernstein et al. [41] Barron et al. [48] from Canada reported a prospective anal- reported the real-world effectiveness of omalizumab for treat- ysis of 149 patients refractory to treatment of CSU who were ment of CSU. The most common initiation dose was 300 mg treated with omalizumab 150 mg every 4 weeks. The dose and (in 62.7% of patients), whereas 34.5% of patients received dose interval of omalizumab was adjusted based on UAS and 150 mg and 2.8% received other regimens [41]. The most physician assessment. A total of 21 patients were updosed common dosing frequency (83.9%) was every 4 weeks. with omalizumab (two patients updosed to 375 mg, ten pa- There is also much evidence on the long-term effectiveness tients to 450 mg, and nine patients to 600 mg). From the total and safety, including long-term omalizumab treatment from 1 149 patients observed, 52% achieved complete remission, to 5 years or longer [42–44]. Long-term outcomes in a real- 29% showed significant improvement, and 17% were refrac- world study from a large cohort of patients in the USA asso- tory. However, the analysis did not consider the updosed pa- ciated with omalizumab 300 mg use were improvements in tients separately. Clinic Rev Allerg Immunol (2020) 59:38–45 41 Table 1 List of all studies showing omalizumab updosing in Author (year) Country Total number Updose of omalizumab chronic spontaneous urticaria of patients, N Fiorino et al. (2014) Italy 2 450 mg/4 weeks Metz et al. (2014) Germany 30 300 mg/4 or 3 weeks; 450 mg/4 weeks Barron et al. (2017) Canada 149 450 mg/4 weeks; 600 mg/4 weeks Asher et al. (2017) Portugal 50 450 mg/4 weeks Vadasz et al. (2017) Israel 280 450 mg/4 weeks Kocatürk et al. (2018) Turkey 92 450 mg/4 weeks; Spain 80 600 mg/4 weeks Curto-Barredo et al. (2018) Spain 286 450 mg/4 weeks; 600 mg/4 weeks Salman et al. (2019) Turkey 72 450 mg/4 weeks Aghdam et al. (2019) Netherlands 166 450 mg/4 weeks; 600 mg/4 or 2 weeks Asher et al. [49] from Israel reported evidence from real- study for a large group of patients with refractory CSU. life experience on the beneficial effects of high-dose (450 mg After 12 weeks of therapy, response was defined as well- monthly) omalizumab for 50 patients with severe, unrespon- controlled if improvement was > 80% from baseline (urticaria sive CSU who did not respond to the standard 300 mg month- between 6 and 18 months; UAS7 12–18 points); 60–70%, fair ly omalizumab dose (Table 2). Response to the starting dose response; 40–50%, weak response; and < 30%, failure. Weak of omalizumab 300 mg was complete in 30 (60%), partial in responders and treatment failures had long-lasting urticaria, of 15 (30%), and failed in five (10%) patients. Patients who 24–60 months, and UAS7 between 20 and 32 points. While showed partial response/failed to respond to 6 or more fair responders continued only on AHs, weak responders re- omalizumab injections of 300 mg dose, improved with quired short courses of steroids. The dosage of omalizumab updosing to 450 mg; of the nine patients who were updosed was increased from 300 to 450 mg after 3 months if the re- to omalizumab 450 mg, only one patient failed to show a sponse to therapy was weak; further beneficial effect was seen response to the higher dose; while 8 patients improved signif- in 64.1% (50/78) of patients with an increase to omalizumab icantly. The mean time to response to the higher dose in these 450 mg. patients was 2.6 ± 0.9 months. A significant decrease in the Kocatürk et al. [51], in a retrospective analysis of patients UAS7 from 20 ± 9 to 7 ± 10 (P = 0.002) following treated with omalizumab for CSU, proposed a protocol for omalizumab treatment was reported in the updosed patients updosing patients from two urticaria centers from Istanbul, (Table 2). Turkey, and Barcelona, Spain. From a total of 92 patients Vadasz et al. [50] from Israel reported real-life experiences enrolled in Istanbul, 81 were treated with omalizumab of 280 patients, where updosing omalizumab from 300 to 300 mg while 11 received omalizumab 600 mg. Patients 450 mg in 78 patients was significantly beneficial in 64.1% who did not respond to omalizumab 300 mg achieved symp- of patients (Table 2). The usefulness of increasing the dose tom control after directly being updosed to 600 mg. Response above 300 mg was carefully assessed in this retrospective to updosing occurred in 8/11 patients (72.7%) who achieved a Table 2 Proportion of patients with chronic spontaneous urticaria achieving complete or partial response on updosing omalizumab from 300 to 450 or 600 mg every 4 weeks Study Updosed to 450 mg Updosed to 600 mg Efficacy parameter (UAS7/UCT) Complete/partial response, % Asher et al. 9 UAS7 ≤ 6 66.7 (n = 6)/22.2 (n = 2) Kocatürk et al. 17 11 UCT ≥ 12 and UAS7 ≤ 6 64.3 (n = 18) Barcelona 11 UCT ≥ 12 72.7 (n = 8) Istanbul Vadasz et al. 78 64.1 (n = 50) Curto-Barredo et al. 79 UAS7 ≤ 6 75.0 (n = 59)/25.0 (n = 20) Salman et al. 13 UCT ≥ 12 and UAS7 ≤ 6 46.2 (n = 6)/23.1 (n = 3) Aghdam et al. 11 33 UCT ≥ 12 and UAS7 ≤ 6 32.0 (n = 14)/30.0 (n = 13) UAS7 Urticaria Activity Score over 7 days; UCT, Urticaria Control Test 42 Clinic Rev Allerg Immunol (2020) 59:38–45 UCT score of ≥ 12 at week 12 of updosing (Table 2). From a Aghdam et al. [47] recently demonstrated that updosing total of 80 patients enrolled at the center in Barcelona, a step- omalizumab from 300 to 450 mg or 600 mg every 4 weeks wise dosing regimen was preferred, starting with 450 mg and (in 44 of 166 patients) resulted in a clinical benefit in 61% of updosed to 600 mg if there was no response. Urticaria control these patients who were not responsive to the initial dose of was achieved by 76.4% (13/17) of patients treated with 300 mg. If the treatment response after three doses of omalizumab 450 mg and by 45.4% (5/11) of patients given omalizumab 600 mg every 4 weeks was insufficient, the sub- 600 mg. The stepwise approach was thus recommended for sequent treatment interval was shortened to 2 weeks. patients with CSU starting from 450 mg and updosing to Omalizumab was discontinued if two consecutive doses of 600 mg who do not respond nor partially respond to 300 mg 600 mg at 2-week intervals yielded an insufficient response. of omalizumab after 3–6 months of treatment. Updosing was The effects of updosing were examined by comparing disease required more often in patients with a body mass index activity prior to starting omalizumab treatment and at the end (BMI) > 30 kg/m2 and with lower UCT scores at the baseline. of the high-dose treatment. UAS7 at the end of the high-dose Curto-Barredo et al. [52] from Spain, in a recent observa- treatment was improved compared with UAS7 before dose tional multicentre study, showed that upon updosing of increase (median of 20.0 vs 4.3, respectively). The additional omalizumab in 80% of partial or non-responders (of 286 pa- effect of updosing was shown by comparing the effect of tients with CSU treated with omalizumab 300 mg every standard dose with the high dose, with improved clinical treat- 4 weeks), 75% of patients achieved UAS7 ≤ 6 and disease ment after updosing observed in 61% of patients; 32% had a control. Fifty-five percent of these patients were updosed to complete response and 30% had a partial response. Patient and 450 mg every 4 weeks; 20% of patients who had received treatment characteristics did not differ significantly between omalizumab 450 mg every 4 weeks were further updosed to patients treated with standard-dosed and updosed 600 mg every 4 weeks. Patients with CSU were updosed with omalizumab. omalizumab if they were considered non-responder to standard-dosed omalizumab treatment. Here, non-response was defined as patients having a UAS7 > 6. Discussion It was shown in a bivariate analysis that 41% of the high- dose (450–600 mg/4 weeks) versus 21% of licensed-dose re- The objective of this review article was to summarize the sponders (300 mg/4 weeks) frequently used cyclosporin A published real-world evidence on the effects of updosing immediately before start of the anti-IgE therapy. In the multi- omalizumab for the clinical management of patients with variate analysis, patients with BMI ≥ 30 kg/m2 were associat- CSU who do not respond to the licensed dose or the prescribed ed with updosed omalizumab (odds ratio 1.14; P = 0.004) and initial dose of omalizumab. The results presented in this re- a predicted likelihood of greater success with omalizumab view article have been extracted from several published re- treatment in these patients. The variables included in the anal- ports, and provide comprehensive evidence that omalizumab ysis were baseline once-daily UAS7, inducible urticaria, an- updosing can result in improvements in UAS7, UCT, and gioedema, sex, age, BMI, total immunoglobulin (Ig) E, d-di- quality of life scores in patients who were not responding mer, and previous immunosuppressive treatments. Likewise, sufficiently to standard dose of omalizumab. This report also patients aged > 57 years old showed a significant association highlights evidence suggesting that omalizumab updosing is with omalizumab updosing (odds ratio 1.038; P = 0.013). associated with complete response rates in up to 60% of pa- Salman et al. [53] reported the effectiveness and safety of tients with refractory CSU. High dose of omalizumab is omalizumab 450 mg in a retrospective cohort study of 72 shown to be beneficial in patients with CSU who either failed patients treated with omalizumab 300 mg and 450 mg. Of or had partial response to the standard 300 mg dose of 13 patients with CSU who were unresponsive to omalizumab omalizumab treatment. 300 mg and updosed to 450 mg, six had complete response The reports assessed in this article suggest that updosing and three had good disease control with a mean UAS7 that omalizumab in patients with no response at any time during decreased from 18.6 to 5.1 and a mean UCT score that dosing intervals after three doses or with partial response after increased from 8.6 to 12.0. A partial response to 6 months of treatment at the maximum licensed dose of omalizumab updosing was noted in 2 patients, while 2 300 mg can be considered. There is also increasing evidence patients were non-responders. No adverse events were re- that updosing to omalizumab 600 mg either directly or with a ported during the entire study period. It was of interest to stepwise approach starting from 450 mg and then updosing to note that lower baseline total IgE levels were used as a 600 mg if there is no response after omalizumab treatment predictor of non-response to omalizumab and the need results in better disease control. for higher doses. Patients were grouped according to base- In addition, there is some evidence that other factors may line IgE levels as high or low; updosed patients generally be seen to influence the updosing of omalizumab. Better clin- had lower IgE levels. ical response with regard to disease severity for instance could Clinic Rev Allerg Immunol (2020) 59:38–45 43 be achieved by updosing omalizumab along with adjustments Compliance with Ethical Standards to the frequency of omalizumab treatment. Patients with higher BMI are more likely to require higher doses of the drug Conflict of Interest Martin Metz has received honoraria as speakers and/ or consultant from Aralez, Argenx, Bayer, Celgene, Moxie, Novartis, for treatment and achieve greater success with updosing with Roche, Sanofi, and Uriach. Zahava Vadasz has received honoraria as omalizumab. Also, patients previously treated with cyclospor- speaker from Novartis, RAFA, and Sanofi; and has received research in A and older patients (> 57 years of age) who may be non- grants supported from Novartis. Emek Kocatürk has received honoraria responders to the standard dose can be expected to have great- as speaker and consultant for Bayer, Novartis, and Sanofi. Ana M Giménez-Arnau has served as medical advisor for Uriach Pharma, er success with updosing omalizumab [52]. Patients with low- Genentech, Novartis, FAES, GlaxoSmithKline (GSK), and Sanofi; has er IgE levels are more likely to be non-responders to received research grants from Uriach Pharma, Novartis, and Instituto omalizumab and therefore required updosing more often than Carlos III—La Federación Española de Enfermedades Raras (FEDER); the patients without [53]. Overall, it was observed that and is involved in educational activities for Uriach Pharma, Novartis, Genentech, Menarini, LEO Pharma, GSK, Merck Sharp & Dohme, updosing in suboptimal responders was safe and effective. Almirall, and Sanofi. Patients receiving updosed omalizumab in general had higher BMI, lower pre-omalizumab UCT scores, and lower IgE Ethical Approval This article does not contain any studies with human levels. There was also no particular association with gender, participants or animals performed by any of the authors. associated angioedema, baseline UAS7 scores or inducible Open Access This article is licensed under a Creative Commons urticaria, and increased treatment success rate with updosing. Attribution 4.0 International License, which permits use, sharing, adap- Omalizumab has a well-established safety profile at higher tation, distribution and reproduction in any medium or format, as long as doses in severe allergic asthma and has been extensively used you give appropriate credit to the original author(s) and the source, pro- to treat adult and pediatric populations in clinical trials and in vide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included real-world practice [54, 55]. The benefits of omalizumab in the article's Creative Commons licence, unless indicated otherwise in a updosing reported in the real-world treatment of CSU exceed credit line to the material. If material is not included in the article's those reported in clinical trials, while the real-world safety Creative Commons licence and your intended use is not permitted by profile is similar to that reported in clinical trials. The real- statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this world treatment setting offers benefit to a heterogeneous pop- licence, visit http://creativecommons.org/licenses/by/4.0/. ulation of patients affected by CSU and real-life data on their safety and efficacy profiles. The experiences on the use of doses higher than the licensed dose of omalizumab 300 mg provide support to recommend these higher doses for patients who are partial/non-responders and refractory to treatment. References One of the current limitations with omalizumab treatment in patients with CSU is the fixed dosing schedule without op- 1. Zuberbier T, Aberer W, Asero R, Abdul Latiff AH, Baker D, tions to adapt the therapy to individual patients. Dose optimi- Ballmer-Weber B, Bernstein JA, Bindslev-Jensen C, Brzoza Z, Buense Bedrikow R, Canonica GW, Church MK, Craig T, zation with omalizumab with the potential for updosing in Danilycheva IV, Dressler C, Ensina LF, Giménez-Arnau A, patients not achieving complete remission is shown to provide Godse K, Gonçalo M, Grattan C, Hebert J, Hide M, Kaplan A, clinical benefit in a considerable number of patients. 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