Chronic spontaneous urticaria (CSU) is a debilitating inflammatory disorder of the skin, characterized by a fluctuating natural history, a complex mechanism of action, and a significant burden on patients, including effect on quality of life, development of psychosocial disorders, and a range of comorbidities. Recent international guidelines recommend a therapeutic approach of first-line treatment with second generation H1-antihistamines and second-line treatment with the biologic omalizumab. Here, the salient aspects of CSU and current status of data for omalizumab for patients with CSU are reviewed, with a focus on mechanism of action, efficacy and real-world effectiveness (including patient outcomes, response, relapse, and remission), and safety (including consideration of the risk of anaphylaxis). The review also considers recent data on COVID-19, CSU, and omalizumab and presents our perspective on future needs. Overall, the data suggest that omalizumab is an effective and well-tolerated treatment for patients with CSU that provides benefits for a wide range of patients.
Key Summary Points
This review article presents a summary of the current evidence for the biologic omalizumab as a treatment for patients with chronic spontaneous urticaria (CSU).
Omalizumab is a beneficial treatment for appropriate patients with CSU as it improves both itch and wheals and quality of life, is supported by a well-established safety profile, and provides an opportunity for self-administration.
Given this information is now easily accessible for clinicians, this review may improve treatment for patients with CSU.
What is CSU?
Chronic spontaneous urticaria (CSU, previously chronic idiopathic urticaria [CIU]) is a debilitating inflammatory disorder of the skin characterized by the occurrence of itchy wheals (hives) and/or angioedema for more than 6 weeks with no specific trigger [1] (and recently reviewed by Lang [2] and Kolkhir et al. [3]). CSU affects approximately 1–3% of individuals (lifetime prevalence) [4‐6], is twice as prevalent in women than men [5, 6], more prevalent among patients aged 40–59 years than for other ages [5] (although prevalence is similar across childhood [7]), and there is limited evidence of racial or ethnic differences worldwide [8].
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Accurate diagnosis of CSU is important, especially as wheals and angioedema also occur in patients with other diseases, and includes factors such as exclusion of differential diagnoses, identification of underlying causes, and identification of conditions that may modify disease activity [9]. Once diagnosed, clinicians find a variable natural history of the disease: CSU is a fluctuating condition marked by spontaneous remissions and relapses that requires frequent re-evaluation. For example, a small study (N = 72) found the duration of CSU ranged from 2 to 204 months, with 31% with relapsing/remitting disease [10], and a review of the literature found the proportion of patients achieving remission within 5 years ranged from 29% to 71% [11]. The presence or absence of angioedema also complicates CSU as angioedema is reported in approximately 50% of patients and leads to more severe and prolonged disease [10, 12, 13], and is an isolated finding in around 10% of cases [14]. In addition, prognosis in terms of duration and activity is predicted by certain factors: an observational study (N = 549) found worse prognosis is associated with multiple episodes of CSU, late-onset, concomitant chronic inducible urticaria (CIndU), and serum autoreactivity [15].
Given the complexity of CSU, many factors need to be considered before, during, and after treatment. Here, we review the salient aspects of CSU and highlight treatment with the primary (and only) biologic option, omalizumab.
Pathogenesis
The pathogenesis of CSU is complicated and not completely understood. However, the driving process of mast cell activation has been elucidated and reviewed recently by Dobrican et al. [16], Hide and Kaplan [17], and Kaplan et al. [18], and briefly summarized herein. In most patients with CSU, mast cell activation and degranulation are driven by autoimmunity—either immunoglobulin (Ig)E-mediated type I autoimmunity (or autoallergy) or type IIb autoimmunity by IgG autoantibodies to IgE and/or the IgE receptor FcεRI on mast cells [19] (and reviewed by Hennino et al. [20] and Kolkhir et al. [21] and considered in recent articles [22, 23]). Mast cells may also be activated by other non-immunologic pathways including complement, stem cell factor, Toll-like receptors, Mas-related G protein-coupled receptor X2, and pathogen-associated and damage-associated molecular patterns; this aspect has been reviewed by Ansotegui et al. [24].
Regardless of the mechanism of mast cell degranulation, intracellular signaling triggers the release of multiple immunological mediators, including histamine, platelet activating factor, proteases, lipid metabolites, cytokines, and chemokines (tumor necrosis factor-α, interleukin [IL]-1, IL-4, IL-6, IL-13, and platelet activating factor) [24, 25]. Vascular permeability is increased via the activation of endothelial cells, leading to wheals and angioedema [25]. Of note, the pathogenic role of infiltrating cells, such as neutrophils, eosinophils, basophils, and monocytes, remains unclear, but has recently been considered by Giménez-Arnau et al. [26], and other mediators reviewed by Nettis et al. may also play a role [25]. For example, substance P action through the G protein-coupled receptor MRGPRX2 may release histamine in a subset of patients with CSU [27].
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Patient Burden
CSU places a substantial burden on the patient, compromising quality of life (QoL) [8, 28] and interfering with activities of daily living including sleep, work productivity, and social functioning. For example, pruritus, painful and unsightly wheals, angioedema, and reduced sleep quality all contribute to diminished QoL [29‐31]. In addition, sexual functioning of women may be impaired by CSU [32]. With regard to overall patient burden, the 2016 Global Burden of Disease Study found that the disability-adjusted life years rate for urticaria was 55.5/100,000 people in the general population, which ranked fourth among dermatological conditions, but the rate varied by geography, sex, and age [33]. Furthermore, the economic burden of CSU is substantial, and includes productivity loss because of absence from work and reduced work performance: in the ASSURE-CSU observational study (N = 673), mean (SD) overall work productivity loss was 43.6% (28.4%) in patients with more disease activity versus 11.9% (21.6%) in those with less disease activity, mostly because of presenteeism [34].
Of importance, patients with CSU are predisposed to develop psychosocial disorders. A systematic analysis of 114 studies found a prevalence estimate of 46% for psychosocial factors in patients with symptomatic CSU [35]. Patients with CSU experience higher rates of anxiety and depression relative to healthy controls [36, 37], which is linked to emotional distress [38] and increased impairment in QoL [39]. As an explanation, a mediation model proposed that anxiety and depression develop because itching associated with CSU leads to sleep disturbance [40], which is associated with risk of depression [41] and anxiety [42].
The burden on patients with CSU is also complicated by the association of CSU with a wide range of comorbidities. Comorbidities that are overrepresented among patients with CSU include atopic diseases such as allergic rhinitis and asthma, thyroid disease, rheumatic diseases, and inflammatory diseases [8], and there is a correlation between the frequency of comorbidities and the duration of urticaria [43]. In addition, patients with CSU (especially adult female patients and those with a positive family history) have an increased risk of autoimmune diseases, particularly vitiligo, pernicious anemia, and Hashimoto’s thyroiditis [44].
Overall, patients provide a very negative perspective of living with CSU. A non-interventional qualitative study found that patients with CSU commonly experienced anxiety, frustration, helplessness, and powerlessness, and reported feelings of loss of normalcy and identity, social stigmatization, shame, and distress [45].
Unmet Needs
Physicians often underestimate the true impact of CSU as it is fluctuating and non-life-threatening. However, the impact of CSU on health-related QoL is similar to that experienced by patients with other severe, disabling dermatological diseases such as atopic dermatitis and psoriasis [46, 47] and patients with coronary artery disease [29]. Furthermore, CSU is often underdiagnosed. For example, a self-report survey (N = 1037) found that patients suffered from urticaria symptoms for around 3 years before diagnosis [48], and time to diagnosis is highly variable—even a small study (N = 25) found that time to diagnosis ranged from 1 week to 15 years [45]. Diagnosis is also complicated by the presence/absence of angioedema, which is often underreported [12]. Finally, CSU is often undertreated. For example, in an observational study, only 57.6% of patients diagnosed with H1-antihistamine-refractory CSU (N = 1539) were receiving pharmacological treatment [49], and a self-report survey (N = 1037) reported that 60.3% of patients were not currently receiving any treatment [48]. Maurer et al. [49] concluded that “the majority of CSU patients were undertreated, had uncontrolled urticaria and moderately or largely affected QoL [and there was a] need for improved patient care and adherence to the latest treatment guidelines.” However, although guidelines are available for the management of CSU, not all physicians are aware or follow the recommended path [50].
Guidelines for Treatment of CSU
An update to the international EAACI/GA2LEN/EuroGuiDerm/APAAACI guideline for the definition, classification, diagnosis, and management of urticaria was published in 2021 [1] (and recently reviewed by Zuberbier et al. [51]). The guidelines recommend that the therapeutic approach for CSU should aim for a complete response (complete control and normalization of QoL) and include elimination of possible underlying causes, avoidance of eliciting factors, tolerance induction, and the use of pharmacological treatment. The recommended first-line treatment is a second-generation H1-antihistamine. The recommended second-line treatment for patients who do not show benefit from H1-antihistamines is the biologic therapy omalizumab (300 mg every 4 weeks, independent of IgE levels) [1]. For patients with severe CSU, refractory to any dose of antihistamine or omalizumab, cyclosporin (3.5–5.0 mg/day) may be given.
As the only biologic approved and recommended for treatment of patients with CSU, a review of the current status of omalizumab data is warranted. This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.
Omalizumab
Our review of omalizumab will focus on the mechanism of action, efficacy, and real-world effectiveness, including patient outcomes, response, relapse, and remission, and safety, for treatment of patients with CSU.
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Of note, omalizumab is also beneficial (although not currently approved in the USA) for patients with CIndU, including cholinergic urticaria, cold urticaria, solar urticaria, heat urticaria, symptomatic dermographism, and delayed pressure urticaria [1, 52, 53]. This is likely because expression of FcεRI receptors on basophils and serum IgE levels are both elevated in patients with CindU, similar to CSU and independent of subtype [54].
Omalizumab is indicated for CSU “in adults and adolescents 12 years of age and older who remain symptomatic despite H1-antihistamine treatment” [55].
Mechanism of Action
Omalizumab is a humanized, recombinant, monoclonal anti-IgE antibody, originally developed for the treatment of allergic respiratory disorders such as asthma. The antibody binds to free IgE at the site of FcεRI binding [56], thus blocking free IgE from binding to FcεRI on mast cells (principally) and thereby preventing the immunological cascade. The potential of omalizumab to treat CSU associated with autoimmunity was proposed as early as 2005 [57], as the role of autoantibodies to FcεRI or IgE in CSU became clear [58]. The efficacy of omalizumab for auto-allergic CSU was confirmed in phase II efficacy studies in patients with CSU and IgE autoantibodies to thyroperoxidase [59].
The mechanism of action of omalizumab for CSU is not completely understood. In patients with CSU omalizumab not only reduces free IgE levels but also downregulates the expression of FcεRI on skin cells in the dermis of both lesional and non-lesional skin, and on basophils [60]. However, these pathways do not fully explain the clinical effects of omalizumab. Potential mechanisms of action that contribute to efficacy have been considered by Kaplan et al. [61] and include changes in mast cells, IgG and IgE autoantibodies, coagulation abnormalities, and a recent study found a possible link to vasoactive intestinal protein [62]. In addition, cross talk between mast cells and other immune cells creates complex systems in the microenvironment [63], which may further explain the action of omalizumab. Another clue to the mechanism of action is that patients with type IIb autoimmunity with IgG and IgM antibodies directed against IgE receptors on mast cells have more severe and prolonged CSU and a poorer response to omalizumab [64]. However, regardless of the intricacies of omalizumab action, the antibody is both efficacious and effective for many patients with CSU.
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Efficacy and Effectiveness
The strength of evidence for omalizumab in CSU comes from the pivotal phase III studies ASTERIA I, ASTERIA II, and GLACIAL [65‐67]. These phase III studies, as well as proof-of-concept and phase II studies, were reviewed by Giménez-Arnau [68]. All studies confirmed the efficacy of omalizumab versus placebo (by reduction of urticaria activity scores and itch severity score) in patients 12–75 years of age with H1-antihistamine-refractory moderate-severe CSU [68]. Furthermore, a meta-analysis of seven randomized controlled trials (N = 1312) found that omalizumab significantly reduced itch and wheal scores compared with placebo, with the strongest reduction at 300 mg every 4 weeks, and significantly improved rates of complete response (relative risk 4.55) [69]. Of note, in patients from the phase III clinical trials, omalizumab was also able to increase the proportion of angioedema-free days [13].
Importantly, omalizumab is well tolerated and effective in a range of patients with CSU, including children [70, 71], adolescents [72, 73], and older people [74]. Moreover, despite higher CSU prevalence in female individuals, response to omalizumab is similar in both sexes although relapse is most common in male patients [75]. Omalizumab is also efficacious in patients in the East Asian population—the phase III POLARIS study found significant decreases in itch severity score for omalizumab versus placebo [76], and in patients with comorbid CIndU [77]. However, there is little or no information on omalizumab treatment in patients with CSU who are pregnant [78], have a malignancy, or are being treated with other systemic or biologic therapies for a comorbid condition [79].
Patient Outcomes
Omalizumab clinical trial results are supported by the phase IV SUNRISE study (N = 136), which found that by week 12 most patients on omalizumab achieved disease control (74.6%, by Urticaria Control Test score) and well-controlled disease (67.7%, by 7-day Urticaria Activity Score) [80]. Furthermore, omalizumab improves QoL, sleep, sexual function, anxiety, and work-related productivity in patients with CSU. For example, post hoc analyses of phase III clinical trials found that omalizumab improved Dermatology Life Quality Index versus placebo and provided initial and ongoing improvements in sleep [81‐83], and a retrospective chart review found that omalizumab may play a role in enhancing sexual function [84]. In the phase IV EXTEND-CIU study, improvements following omalizumab initiation were observed at week 12 (first reported measurement) and were sustained for the study duration (48 weeks), and occurred in a range of patient-reported outcomes, including the perception of skin disease and control, sleep, work productivity, and anxiety [85, 86]. Overall, these findings highlight the ability of omalizumab to improve QoL outcomes in addition to urticarial lesions and pruritus.
Omalizumab also improves QoL in patients with CSU with angioedema. The X-ACT study (N = 91) found that by week 28, omalizumab was superior to placebo for improvement in Chronic Urticaria Quality of Life Questionnaire scores, and also improved angioedema-burdened days/week, median time to first recurrence of angioedema, and angioedema-specific quality of life [87]. However, to date, few studies have specifically assessed whether omalizumab is effective for patients with CSU with isolated angioedema, even though there is some evidence of effectiveness from case reports [79] and one small placebo-controlled trial [88]—this should be a focus of future work.
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Patients completing a qualitative questionnaire describe that omalizumab treatment led to dramatic changes in multiple aspects of their QoL [89]. Quotes from the participants in response to the question “Please can you kindly tell us how your life has changed since starting your omalizumab treatment for urticaria/angio-oedema?” included “My life has become normal again… I think this treatment saved my life” and “It has given me my life back… for me this was a hugely beneficial and life-transforming treatment.”
Response, Relapse, and Remission
Response to omalizumab may vary and requires an individualized approach to maximize the potential for response and to prevent relapse. The time to response to omalizumab is an important consideration for clinicians: studies suggest that there are “early” and “late” responders to omalizumab, and many patients require multiple doses to achieve a response [90, 91]. For example, Kaplan et al. found that, although the median time to complete response was 8–10 weeks (300 mg omalizumab), some patients responded after the first injection, some patients achieved complete response before week 4, and some patients continued to achieve a complete response up to week 24 [90]. Indeed, about half of patients who were non-responders at week 12 had a response by week 24 [90]. The mechanism of action responsible for this differential response is unknown; however, early responders show a rapid decrease in IgE and basophil FcεRI receptor levels [90].
Therapeutic strategy may be guided by the initial response to omalizumab, e.g., non-responders and partial responders may require up-dosing and re-evaluation after 3 months, whereas good and complete responders may benefit from lower dosing after 3–6 months [92]. Metz et al. [93] reviewed real-world evidence for up-dosing of omalizumab and found that up-dosing (by increases in dose [to 450 mg then 600 mg] and/or frequency [to 2 weeks]) for refractory patients was safe and effective in up to 60% of patients. Up-dosing may be most valuable for patients with clinical factors such as angioedema, basophil activation, high body mass index, previously treated with cyclosporin A, older age, lower Urticaria Control Test score, or lower IgE levels [93, 94].
Although about 50% of patients with CSU enter long-term (> 4 years) remission following one to two courses of omalizumab [95], relapse may occur following discontinuation, especially in patients with high baseline Urticaria Activity Score or a slow decrease in symptoms [96]. However, a prospective, open-label study (N = 314) found that of the 18% of patients re-treated with omalizumab after relapse post-withdrawal, most (88%) regained symptomatic control, suggesting that re-treatment is as effective as initial treatment [97]. Of note, a retrospective study found that gradually extending the dosing interval in patients who responded to omalizumab may facilitate omalizumab discontinuation [98].
Predictors of Response
The most reliable predictor of response to omalizumab in patients with CSU or CIndU is IgE level [99‐104]. Consistent across studies, non-responders to omalizumab (generally assessed at around 12–14 weeks after initiation) have baseline total IgE levels less than 20 IU/mL (around 40 IU/mL is often used as a cutoff point). IgE levels for partial response, complete response, and early response varied across studies, but were consistently seen with an IgE level of greater than around 70 IU/mL. However, please note that assessment of responders by IgE levels is duration-dependent as the proportion of patients who respond to omalizumab will increase over time [86, 90]. Using another approach, Ertas et al. [99] found that the best predictor of response was the ratio of week 4 IgE levels to baseline IgE levels: a ratio of 1.0 was significantly associated with non-response to omalizumab and a ratio of around 4.0 was significantly associated with a partial or complete response to omalizumab.
Other markers that may predict response to omalizumab include trough concentrations of serum omalizumab [105], expression of FcεRI [100] (especially on basophils [106]), eosinopenia [107], antinuclear antibodies [108], basophil CD203c activity [109], previous immunosuppressant treatment, D-dimer, and IL-31 [100, 101]. In a retrospective study of patients with CSU from a single center, a good response to omalizumab was associated with patients who were atopic (high eosinophils, basophils, and IgE) and a poor response was associated with comorbid psychiatric disease and thyroid antibodies [110]. Predictors of relapse following omalizumab withdrawal include high IgE levels [111], baseline Urticaria Activity Score [101], and early treatment response [96].
Safety
Omalizumab has a well-established safety profile, attained over 20 years across multiple indications and doses [112], and based on clinical trials and real-world studies (such as for asthma [113]). For CSU, a meta-analysis of 67 real-world studies reported an adverse event rate of 4% with omalizumab and a safety profile similar to that observed in clinical trials [114]. Long-term safety data collected over 9 years (N = 91) in a real-world setting found that prolonged omalizumab treatment did not increase the risk of side effects [115].
In the aforementioned 9-year real-world study, there were no reports of anaphylaxis following omalizumab administration in patients with asthma [115], which is similar to a single-center study of 22,000 doses of omalizumab [116]. Indeed, reports of anaphylaxis have been rare and inconsistent, and little information is available specifically for patients with CSU. In a comprehensive review of the literature and government databases in the USA, Canada, and Europe, Gulsen et al. found that the incidence of anaphylaxis following omalizumab ranged from 0% to 0.09%, which was lower than most other biologicals [117], and similar to clinical trials and initial post-marketing reports [55]. In an analysis of US Food and Drug Administration Adverse Events Reports, Li et al. found evidence of anaphylaxis following omalizumab, with incidence more life-threatening for patients with asthma versus urticaria [118]. Thus, although the boxed warning on the US omalizumab prescribing information provides awareness of anaphylaxis, we believe that the potential benefits outweigh the risk (although the risk should be considered for each individual and prescribing information should be adhered to, to ensure risk minimization). Others agree as self-administration of omalizumab is approved [55], and omalizumab is being considered as a preventative treatment for severe anaphylaxis, especially for people with food allergy [119].
COVID-19, CSU, and Omalizumab
Given the recent coronavirus disease 2019 (COVID-19) pandemic, it is relevant to consider any potential interactions between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, CSU, and treatment with omalizumab. A global survey study found that the COVID-19 pandemic substantially impacted care of patients with CSU because of reduced referrals and clinic hours, and face-to-face consultations decreased by over 60% [120]. The study also found that, although the presence of CSU did not affect the course of SARS-CoV-2 infection, SARS-CoV-2 infection did lead to urticaria exacerbations in many patients [120].
Regarding treatment of allergic and type 2 inflammatory conditions during the COVID-19 pandemic, a European position paper recommended continued use of biologicals but noted that the potential effects of biologicals on the immune response in patients with SARS-CoV-2 infection are unknown [121]. However, a recently published systematic review proposed that omalizumab may actually protect allergic patients against SARS-CoV-2 infection [122]. For treatment of CSU, the global survey study found that cyclosporine and systemic corticosteroids were used less during the pandemic, whereas use of antihistamines and omalizumab did not change [120]. Moreover, single-center studies have found no difference in SARS-CoV-2 positivity rate, or related pneumonia or hospitalizations for patients with CSU on omalizumab versus other treatments [123, 124]. Of note, a retrospective chart review study found that male patients, but not female patients, had increased urticaria activity during the COVID-19 pandemic and, as omalizumab treatment rates were similar, the authors concluded that omalizumab efficacy has decreased in male patients; however, this requires further investigation [125]. Importantly, patients on omalizumab were able to easily transition to home self-administration during the COVID-19 pandemic, enabling treatment to continue and fears regarding SARS-CoV-2 exposure to be lessened [126].
Of note, a single-center study found that 92% of patients with CSU currently on omalizumab did not show any exacerbation of urticaria following COVID-19 vaccination, and indeed acute adverse responses to the vaccine were decreased compared with patients on antihistamines [127] and anaphylactic reactions may have been prevented [128].
Clinicians’ Perspective
From our perspective, omalizumab is an effective and well-tolerated treatment for patients with CSU that provides benefits for a wide range of patients (see Fig. 1 for a summary). Moreover, omalizumab is approved for self-administration by appropriate patients with CSU and this has many practical and psychological benefits [129‐131] and could contribute to improvements in QoL.
Fig. 1
Omalizumab for CSU
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Although detailed guidelines are available for management of omalizumab [132], there are still unmet needs that should be addressed with future research. Areas that we believe could warrant more information to optimize use of omalizumab include the potential role of CSU pathogenesis in an individual (including autoallergy, anti-IgE antibodies, and angioedema) on the response to omalizumab; combination treatment (especially with other biologics [133]) for patients with comorbidities or slow responders; influence of pregnancy (by an initial analysis, pregnancy outcomes for patients with CSU treated with omalizumab were similar to patients with asthma where no increased risk was observed [134]); and the impact of race on access [135] and response.
In addition to practical implications, research and clinical experience with omalizumab has benefited the development process for new treatments, particularly for patients with CSU that is refractory to omalizumab. Research and development is constantly changing but has focused on two main avenues: (i) identification of biomarkers as predictors of response and as therapeutic targets (recently reviewed [136, 137]) and (ii) use of alternative biologics (recently reviewed [137‐140]). The biologic furthest in development is the IL-4 and IL-13 antibody dupilumab. Although dupilumab reduced itch and hives in omalizumab-naïve patients (at 24 weeks), in patients refractory to omalizumab statistical significance was not reached [141], suggesting more research is needed. In addition, other potential future treatment options may have an inferior safety profile to that established for omalizumab over the past 20 years. Ultimately, new treatments for CSU are coming, but in the interim the optimization of omalizumab use is imperative.
Conclusion
Patients with CSU paint a negative picture of their lives and describe a debilitating disease with a fluctuating natural history that requires frequent re-evaluation and comes with a myriad of concomitant medical conditions. Here, we have provided a review of the current status of omalizumab—the primary and only biologic approved for treatment of CSU. In summary, omalizumab blocks free IgE and prevents the immune cascade (albeit via a complex mechanism of action), which translates to efficacy in clinical trials and effectiveness in the real world. A key feature is that the response to omalizumab varies by individual in terms of time to response, relapse after discontinuation, and remission after treatment. Importantly, we highlight a focus on patients as studies have investigated disease-specific patient outcomes, health-related QoL, patient perspectives, and the importance of self-administration. Finally, the consistent long-term safety profile of omalizumab across indications represents a positive benefit-to-risk ratio.
This review presents an opportunity to improve treatment for patients, as clinicians are now able to assess the body of evidence describing omalizumab as a therapy for patients with CSU.
Medical Writing, Editorial, and Other Assistance
Medical writing assistance was provided by Janelle Keys, PhD, CMPP of Envision Pharma Group, and was funded by Genentech, Inc., a member of the Roche Group. Envision’s services complied with international guidelines for Good Publication Practice.
Declarations
Conflict of Interest
Jonathan A. Bernstein has served as a consultant and speaker bureau member for Genentech, Inc. Thomas B. Casale has served as a consultant and speaker bureau member for Genentech, Inc., and a consultant for Novartis Pharmaceuticals Corporation. Ana Maria Giménez-Arnau is or recently was a speaker and/or advisor for and/or has received research funding from Almirall, Amgen, AstraZeneca, Avene, Celldex, Escient Pharmaceuticals, Genentech, GSK, Instituto Carlos III- FEDER, Leo Pharma, Menarini, Novartis, Sanofi–Regeneron, Servier, Thermo Fisher Scientific, Uriach Pharma/Neucor. Michael Holden is an employee of Genentech, Inc., and a stockholder in Roche. Marcus Maurer has been a speaker and/or advisor for and/or has received research funding from Allakos, Amgen, Aralez, ArgenX, AstraZeneca, Celldex, Centogene, CSL Behring, Eli Lilly, FAES, Genentech, GI Innovation, GSK, Innate Pharma, Kyowa Kirin, Leo Pharma, Menarini, Moxie, Novartis, Pfizer, Roche, Sanofi/Regeneron, Third Harmonic Bio, UCB Pharma, and Uriach. Torsten Zuberbier has received institutional funding for research and/or honoraria for lectures and/or consulting from AbbVie, ALK, Almirall, Amgen, Astellas, AstraZeneca, Bayer Health Care, Bencard, Berlin Chemie, FAES, HAL, Henkel, Kryolan, Leti, L’Oreal, Meda, Menarini, Merck, MSD, Novartis, Pfizer, Sanofi, Stallergenes Greer, Takeda, Teva, UCB Pharma, and Uriach, and is a member of ARIA/WHO, DGAKI, ECARF, GA2LEN, and WAO.
Ethical Approval
This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.
Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide 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 in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.
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