Asthma and chronic spontaneous urticaria Back

Editorial

Welcome to Key Opinions in Medicine
This issue focuses on the role of Immunoglobulin E (IgE) in severe allergic asthma and chronic spontaneous urticaria / chronic idiopathic urticaria (CSU / CIU, hereafter CSU) and treatment of these diseases with anti-IgE therapy as based on clinical trial programs and further supported by real world experience as described in patient cases.
The present newsletter provides you with highlights of a satellite symposium during the European Academy of Allergy and Clinical Immunology (EAACI) yearly meeting in Barcelona, Spain (June 2015). The symposium was entitled: “Back to the future: the IgE journey in asthma, chronic spontaneous urticaria and beyond” and featured Professor Ana M. Giménez-Arnau, Professor Stephen Holgate, Professor Eugene Bleecker, and Professor Thomas Casale providing expert insights.

Executive Summary

Omalizumab, a humanized anti-IgE monoclonal antibody is known to improve asthma control by reducing symptoms especially exacerbations and the associated events such as hospitalization and/or an increased need for rescue medication. It received FDA regulatory approval in 2003 for moderate to severe persistent asthma, in patients 12 years of age and older, with a positive skin test or in vitro reactivity to a perennial aeroallergen and symptoms that are inadequately controlled with inhaled corticosteroids. In 2009 EMEA approved the use of omalizumab in children from 6 years and above. After its launch in asthma, reports surfaced on its potential use in CSU, and after a full development program, omalizumab received in 2014 EMA and FDA authorisation for CSU in adults and adolescents 12 years of age and above who remain symptomatic despite H1 antihistamine treatment.
Immunoglobulin E (IgE) interacts with its high affinity receptor FceRI and is traditionally considered a major contributing factor to most types of allergic disease such as allergic asthma, food allergy and other non-allergic afflictions such and chronic spontaneous urticaria/chronic idiopathic urticaria (CSU / CIU, hereafter CSU).
Asthma is heterogeneous disease. However, a number of identified biomarkers, such as IgE, eosinophils and neutrophils, have been linked to specific patient subgroups and disease severity. CSU is characterized by the sudden appearance of hives (wheals), angioedema or both. It is defined as chronic because it is continuously, or intermittently, present for at least 6 weeks, without an identified external trigger. The active episodes of CSU can last from few months to many years. Its pathophysiology remains poorly understood. Treatment of CSU remains a challenge as many patients do not adequately respond to antihistamines (even at higher dose).
Updated guidelines for the definition, classification, diagnosis, and management of urticaria including CSU enhance its management proposing routine diagnostic measures and an easy-to-follow treatment algorithm.

Introduction

Presented by Stephen T Holgate, MD, FAAAAI, University of Southampton, Southampton, UK
Recent advances in research confirmed that IgE plays a sentinel role in allergic diseases (Figure 1), and also mediates non-allergic diseases such as CSU1-13.
Immunoglobulin E (IgE) interacts with its high affinity receptor FceRI14. Depending on the type of allergy, a subgroup of patients displays common symptoms and yet lacks elevated levels of total serum IgE and/or antigen-specific IgE15. In asthma, IgE antibodies play a major role, together with Th2 derived cytokines andeosinophils, in the development of chronic airway inflammation, which is observed even in subjects with mild disease16-20.
The pathophysiology of CSU is yet not fully characterised21-26. However, it is known that similar types of cells have been implicated in the CSU skin lesions as those in the context of asthma. It is known that IgE plays a central role in mast cell activation, which causes CSU symptoms in the form of itchy hives and / or angioedema27.
The following reports an update on the role of IgE in asthma and CSU, completed with case studies for both conditions, from a symposium held at the 2015 EAACI meeting in Barcelona.

Asthma heterogeneity and personalised medicine

Presented by Eugene R. Bleecker, MD, Centre for Genomics and Personalised Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA

Clinical asthma is characterised by a phenotypic variation with different levels of disease severity28, 29. In response to the question how to manage effectively asthma heterogeneity, current guidelines for asthma classification do not provide clear answers as they do not reflect the heterogeneity within and across asthma severity levels and assume that all patients within a severity level respond to the same therapy.
The initial NIH Severe Asthma Research Program (SARP) was a phenotyping analysis using mild, moderate and severe classifications of asthma severity showed overlapping phenotypes and identified asthma heterogeneity. The unbiased SARP cluster analysis identified different asthma subpopulations, each with similar clinical phenotype profiles and severity26, 30, 31.
As a result of this cluster analysis, 5 distinct clinical phenotypes were defined (Figure 2). Clusters 1 and 2 represent mild and moderate asthma severity (both with an early onset, atopic, minimal sputum eosinophilia from normal to minimal airflow limitation, low use of rescue medication and healthcare resources) while clusters 4 (early onset, atopic, severe decrease in FEV1, high frequency of symptoms, high health care utilization and sputum eosinophilia), 3 and 5 (older, less atopic, sputum eosinophilia and neutrophilia) define more severe asthma subpopulations32-34. For all clusters, the majority of patients were atopic, presenting high levels of IgE and Eos blood count. The percentage of the IgE serum concentration, the median eosinophil blood count and the median percentage of sputum eosinophila are considered as important descriptors in these clusters (Table 1).
Biomarkers such as IgE but also eosinophils, neutrophils are used to identify asthma subpopulation greater severity and poor asthma outcome. Molecular endpoints such as high periostin and the fraction of exhaled nitric oxide (FeNO) as well as pharmacogenetic markers are used to identify the high-risk asthma population. Biomarkers including IgE, eosinophils and neutrophils are used to identify more severe asthma populations29, 35. Despite these biomarkers, it is evident that biomarker strategies need to be defined when developing new severe asthma therapies to clearly predict individualized outcomes. In 1989 Burrows et al. investigated the association of  self-reported asthma or allergic rhinitis with serum IgE levels and skin-test reactivity to allergens in 2657 subjects in a general-population study (Figure 3)36. Results showed that regardless of the subjects’ status with respect to atopy or age group, asthma prevalence was closely related to the serum IgE level standardised for age and sex (p<0.0001). However, they also demonstrated that no asthma was present in the 177 subjects with the lowest IgE levels for their age and sex. In contrast, allergic rhinitis was associated primarily with skin-test reactions to common aeroallergens, independent of the serum IgE level. The authors concluded that asthma is almost always associated with allergic mechanisms IgE-related although not all the allergic stimuli that cause asthma may be included in the usual tested battery of common aeroallergens36.

Targeted anti-IgE therapy: Omalizumab

Omalizumab (Xolair®, Novartis, Switzerland) is a humanised monoclonal anti-IgE antibody containing small portions of murine complementarity determining regions (CDRs) directed against human IgE, grafted onto a human IgG1 framework. Its pharmacological properties allow omalizumab to form small immune complexes with IgE, thereby reducing circulating or unbound IgE and preventing it from binding and activating mast cells.
Omalizumab is known to improve asthma control by reducing symptoms especially exacerbations and the associated events such as hospitalization and/or an increased need for rescue medication. It received FDA regulatory approval in 2003 for moderate to severe persistent asthma in patients 12 years of age and older with a positive skin test or in vitro reactivity to a perennial aeroallergen and symptoms that are inadequately controlled with inhaled corticosteroids. In 2009 EMEA approved the use of omalizumab in children from 6 years and above37, 38.
In patients with allergic or atopic asthma, IgE inhibition with omalizumab results in a decreased number of basophils and reduced mediator release39, 40, a decreased Interleukin (IL)-5 expression and a reduced proliferation of eosinophils14, 41, inhibition of the degranulation of mast cells and the release of inflammatory mediators14 and, in dendritic cells, a reduced FcεRI expression and reduced presentation of the allergen to the T-cells42.
Other research work showed that omalizumab reduces plasma levels of multiple inflammatory markers, such as peripheral, sputum and submucosal eosinophilia43, IL-2, IL-4, IL-5, IL-13, granulocyte macrophage colony-stimulating factor receptor GM-CSF43-46 as well as T and B-lymphocytes47 and FeNO48. Furthermore, it downregulates the IgE receptor expression in dendritic cells, mast cells and basophils, reduces sputum eosinophil count (EC) in allergic asthma47, significantly decreases the bronchial biopsy EC in patients with asthma4 and improves lung function (Figure 4)49.
Humbert et al. showed that omalizumab significantly reduces the rate of clinically significant asthma exacerbations, severe exacerbations and emergency visits in patients with allergic severe asthma who are inadequately controlled despite ICS / LABA, and often additional therapy50. Table 2 shows a significant reduction in asthma exacerbation rates across seven different studies conducted with omalizumab in asthmatic patients compared to the control49-55.
The effects of omalizumab were evident in seasonal patterns of both symptoms and exacerbations (Figure 5)56-58. In a post hoc analysis, the average monthly rate of asthma exacerbations nearly doubled in the placebo group during the fall and spring compared with summer (9.0% and 8.1%, respectively, vs. 4.6%; p<0.001). This seasonal spike in exacerbations was not observed in the omalizumab group (4.3% in fall and 4.2% in spring vs. 3.3% in summer) and the difference between the placebo and omalizumab groups was significant (p<0.001 for interaction). A monthly exacerbation rate of approximately 4% remained throughout the year among participants in the omalizumab group. Finally, the daily dose of inhaled glucocorticoids varied little during the year in the omalizumab group, whereas in the placebo group, dose adjustments were required to achieve asthma control59.
The potential of FeNO, peripheral blood eosinophil count and serum periostin as biomarkers of Th2 inflammation and predictors of treatment effects of omalizumab was assessed in patients aged 12-75 years with uncontrolled severe persistent allergic asthma. Results showed that the difference in exacerbation frequency between omalizumab and the placebo was greatest in the 3 high-biomarker subgroups (Figure 6), probably associated with the greater risk for exacerbations in these subgroups48.
The anti-IgE antibody QGE031 (ligelizumab) and other treatments are currently under development in asthma and recent publications reported that the anti-IL-5 therapies mepolizumab , reslizumab and benralizumab reduce exacerbations by between 30 to 50% and improve the predicted percent FEV1 by at least 3% in patients with severe asthma with persistent eosinophilia and recent exacerbations despite treatment with high doses of inhaled corticosteroids and long-acting beta agonists60-63.
A recent post hoc analysis on pooled data from subpopulations of patients with allergic asthma with eosinophilia (Eos > 300) treated with omalizumab or placebo demonstrated that the reduction of the exacerbation rate in patients treated with omalizumab compared to those treated with placebo was 63% (data presented by Casale et al. at the Annual Scientific Meeting of the American Academy of Allergy, Asthma & Immunology, February 20-24, 2015, Houston, Texas), similar to the IL-5 antagonists (data presented by Ortega et al. at the American Thorax Society in May 2013, Philadelphia, Pennsylvania).

Chronic spontaneous urticaria

Chronic urticaria (CU) is defined by the recurrent occurrence of itchy hives, angioedema or both for 6 weeks or more26 (Figure 11 a and b). It may be further classified into chronic inducible urticaria (CINDU) and chronic spontaneous urticaria (CSU) depending on whether a specific trigger for the development of CU signs and symptoms can be identified or not64 (Figure 7).
CINDU comprises symptomatic dermographism, cold urticaria, delayed pressure urticaria, solar urticaria, heat urticaria, vibratory angioedema, cholinergic urticaria, contact urticaria and aquagenic urticaria26.
CSU must be differentiated from other medical conditions where wheals, angioedema, or both can also occur as a symptom, anaphylaxis, auto-inflammatory syndromes, or hereditary angioedema (bradykinin-mediated angioedema)26.
A wheal consists of three typical features: a central swelling of variable size, almost invariably surrounded by a reflex erythema, itching or sometimes a burning sensation and a fleeting nature, with the skin returning to its normal appearance, usually within 1 to 24 hours26.

Angioedema is characterized by a sudden, pronounced erythematous or skin-coloured swelling of the lower dermis and subcutis with frequent involvement below mucous membranes and sometimes pain rather than itching. Its resolution is slower than that for wheals and can take up to 72 hours26.
CSU causes a significant decrease in quality of life and overall well-being. Indirectly, it presents significant socioeconomic burden as a consequence26, 65. CSU, and CSU in general, are more common than previously thought; at any time up to 1% of the population suffers from the disease66.
The pathophysiology of CSU is not yet fully characterised21-26. However, an increased number of mast cells, basophils, neutrophils, eosinophils and T-lymphocytes can be observed in CSU skin lesions. In CSU, mast cells can be activated via a variety of mechanisms, including cross-linking of IgE receptors (FceRI) by IgG autoantibodies against the FceRI or the IgE13, 67. In CSU, mast cells can be activated via a variety of mechanisms, including cross-linking of IgE receptors (FceRI) by IgG autoantibodies against the FceRI or the IgE13,67. Not all the mechanisms of mast cell activation in CSU are clear.
Upon mast cell activation, degranulation and histamine release cause the development of CSU symptoms70, 71.
These mechanisms support the strong rationale for targeting IgE as a means to alleviate symptoms in patients with CSU.

Omalizumab in CSU

The history of omalizumab evidence for CSU started as individual case reports in 200672. To investigate in depth the potential benefit of omalizumab in CSU, two proof-of-concept studies were successfully completed in 200773, 74.
This was followed in 2009 and 2010 by the X‑CUISITE study66 and the phase II study MYSTIQUE75 which were completed with positive results.
In 2013, the phase III programme, including the ASTERIA I, ASTERIA II and GLACIAL trial, was completed76-78. These studies confirmed the fast onset of treatment effect of omalizumab and the dose-response relationship. Furthermore, they demonstrated that the clinical efficacy of omalizumab was maintained over a treatment period of 12 and 24 weeks. In all 3 studies (treatment period 12 or 24 weeks) CSU symptoms returned once treatment was stopped76-78.
Recently, Urgert et al. conducted a meta-analysis on results from 5 different clinical studies assessing omalizumab versus placebo79. Results showed that complete and partial response were more frequent after treatment with omalizumab with no difference in the proportion of participants reporting adverse events between the omalizumab and placebo treatment groups. The studies confirmed that there is high-quality evidence to support the effectiveness and safety of omalizumab 300mg per month for the treatment of CSU for up to 6 months.
In parallel, Casale et al.64 compared results from the pivotal Phase III trials ASTERIA I76 and II77 which included only approved doses of H1-antihistamine as background therapy, to those from GLACIAL78, which permitted higher doses of H1-antihistamines as well as other types of background therapy. As a result, this post hoc analysis showed that the efficacy with omalizumab in CSU was similar despite different background therapy (Figure 8).

Case studies of patients with asthma treated with omalizumab

Presented by Thomas B Casale, MD University of Medicine, University of South Florida, Tampa, FL
The following case reports describe the use of omalizumab in two different patients, one is about a teenager with a history of asthma and the second is about an adult with perennial allergic asthma and rhinitis.

• Asthma Case Study 1

A thirteen-year-old male presented with a fouryear history of asthma. As a child, he had atopic dermatitis and wheezed. Throughout the year he reported having rhinitis that worsened in springtime. Allergy tests indicated sensitivity to dust mite, cats, cockroaches and birch trees. In the last two years, he has had more than two exacerbations, requiring treatment with oral corticosteroids and requiring two hospitalisations. Recently, he woke up often during the night with asthma symptoms, which was affecting his performance at school. His symptoms prevented him from participating in physical activities and maintaining relationships with classmates.
His current medications included medium dose inhaled corticosteroids, a long-acting β2-agonist, a leukotriene receptor antagonist and a shortacting β2-agonist, as needed. Spirometry revealed FEV1 75% of predicted value with an 18% reversibility and a fractional exhaled nitric oxide of 26 ppb. Questioning to identify alternative reasons for his worsening symptoms revealed he had no pets, there were no smokers in the house, that he was compliant with medication and used his inhaler properly. However, he reported that viral infections in autumn and pollination in spring triggered exacerbation episodes.
Laboratory analysis showed elevated total IgE, 700 IU/mL and blood EC 300 cells/μL. This patient was at high-risk, polysensitised, with severe asthma and a history of both allergic comorbidities and virus-induced exacerbations. He was therefore considered for treatment with omalizumab. At the six-month follow-up, the patient reported fewer symptoms and no exacerbations.

 

• Asthma Case Study 2

This case concerns a forty-three-year-old woman, who presented with a 30-year history of asthma. She is allergic to dogs, cats, cockroaches and dust mite. She does not smoke or live with any animals. She is symptomatic around three times per year, requiring treatment with oral corticosteroids. Her current baseline therapy included high dose inhaled corticosteroids, and a short acting β2 agonist, as required. A long acting muscarinic antagonist was prescribed at her previous visit. Although she took her medication, she was frustrated by the amount of time she continued to lose from her work. On examination, nasal mucosa was pale and boggy with clear rhinorrhoea, and she had nasal polyps. The respiratory examination revealed a prolonged expiratory phase and wheezing throughout both lung fields. Her asthma control test score (ACT) was 16. Spirometric measurements showed an obstructive pattern, FEV1 68% of predicted value and a fractional exhaled nitric oxide of 54 ppb. Laboratory results showed a total IgE of 350 IU/mL and blood eosinophil count of 350 cells/μL. Having multiple allergies, uncontrolled asthma with frequent exacerbations, and T2 driven inflammation, this patient was treated with omalizumab.
Six months later, the patient reported using less rescue salbutamol, had had no exacerbations, and had not been absent from work. Her ACT score rose to 21, FEV1 was 79% of predicted value, fractional exhaled nitric oxide, 18 ppb, nasal polyps improved and symptoms of allergic rhinitis diminished. In conclusion, these two case studies showed that omalizumab reduces asthma exacerbations and improves asthma control in high-risk, polysensitised asthma patients.

Case studies: Omalizumab in chronic spontaneous urticaria

Presented by Ana M. Giménez-Arnau, MD PhD, Hospital del Mar, Universitat Autònoma de Barcelona, Barcelona, Spain
The incidence of CSU in women is almost twice as high then in men80. Treatment of CSU remains a challenge as many patients are inadequately controlled with antihistamines (even at higher doses, the currently recommended standard of care first-line treatments.
According to the current guidelines26, diagnosis of CSU should be based on the patient’s disease history, physical examination and a limited number of exploratory tests (Figure 9) while an easy-to-follow treatment algorithm (Figure 10) enhances the management of the disease.
The following case reports describe the use of omalizumab in two 37-year-old women suffering from inadequately controlled CSU.

• CSU Case study 1

This first case illustrates two issues when trying to manage CSU patients. The first is that “Different patterns of response to treatment are not necessarily only related to different patients, but also to different periods of the disease in the same patient”81. The second is that according to the current guidelines26, few extended diagnoses are necessary to assess correctly the diagnosis of the trigger and exacerbating factors involved in the CSU course.
In 2014, a 37-year-old female patient with a long history of CSU presented with a 6-month episode of itchy hives that covered the whole body and angioedema (Figure 11).
Her CSU started in 1991 and was treated until 1997 with sedative and non-sedative H1-antihistamines. The patient remained disease-free without treatment.
In 2003, she returned for a new episode of CSU with a concomitant delayed pressure urticaria with difficulties in wearing shoes, making it impossible for her to walk. She suffered from daily itchy wheals over the entire body surface including the face, palms and soles. She was not taking non-steroidal anti-inflammatory drugs (NSAIDs) or any other medication. No trigger factor was identified. A battery of tests were performed, including detection of omitted suspected drugs (such as nonsteroidal antiinflammatory drugs), erythrocyte sedimentation rate (ESR), c-reactive protein (CRP) testing the presence of Helicobacter pylori (H. pylori) or other infections, functional antibodies, abnormal thyroid hormones and presence of antibodies; skin tests, tryptase testing, autologous serum skin test (ASST) and lesional skin  biopsies, and ruled out any underlying vasculitis. The ASST was negative at that time. Delayed pressure urticaria defined as CINDU was confirmed using the standardized provocation test with the dermographometer (70 seconds in the back with a pressure of 100 g/cm2, reading time 4 hours after). This episode was controlled with high oses of second generation H1-antihistamine and sporadic oral corticosteroid use. The patient remained free of symptoms again during the two following years.
In 2009, she presented with a third episode with a weekly urticaria activity score (UAS7) reaching a score of 26*. Angioedema episodes were frequent with associated delayed pressure urticaria. The autologous serum skin test  (ASST) was positive. Her symptoms remained uncontrolled on high doses of second generation H1-antihistamine. An initial dose of cyclosporine A 300 mg/day was added; at that time, cyclosporine A was considered the third-line therapy of choice. The response was good with a UAS7 score of 0. When the dose was reduced to the commonly better tolerated dose of 200 mg/day,  symptoms worsened getting a UAS7 of 42, being worse than the initial score. Because the patient became refractory even to cyclosporine A at that time a compassionate access to omalizumab 300mg/month was obtained. The UAS7 score dropped back again to 0.
She was asymptomatic for two years with continuous treatment when she got pregnant in 2014. Due to lack of data on omalizumab in pregnancy, the treatment was stopped and loratidine 20mg was started but was unable to control her symptoms reaching within a few weeks an UAS7 of 42. The  patient felt extremely uncomfortable during her pregnancy. A normal life was impossible due to itch and angioedema that interfered with her life, during day and night. Following data from a pregnancy register of omalizumab in asthma (which showed no major anomalies or patterns of anomalies)82, omalizumab at a monthly dose of 300 mg was re-introduced after 3 months, which controlled her symptoms almost completely, resulting in an UAS7 of 10 until the end of pregnancy.

* To assess disease severity in patients with CSU, patients record the severity of their itch and the number of hives once a day, in the evening. Each component of the UAS (itch severity and number of hives) is scored on a scale of 0 (none) to 3 (severe); the 2 scores are added together for a daily total of 0 to 6. The UAS7 is the sum of the average daily UAS over 7 days. After 7 days, average daily scores from the morning and evening assessments are added together. Values can range between 0 to 21 for weekly itch severity, and 0 to 21 for weekly hive count. The UAS7 ranges from 0 to 4226.

• CSU Case study 2

This case study concerns a 37-year-old woman with severe CSU (UAS7 of 30, indicating severe symptoms). The treatment objective was to obtain complete relief of symptoms, as outlined in the current treatment guidelines26. She had an atopic profile with a history of rhino-conjunctivitis and allergy to dust mites, parietaria (nettles), olives, cat, food (peaches). The first time she presented herself in the hospital with a complex episode of CSU, with angioedema, inducible urticaria, symptomatic dermographism and delayed pressure urticaria with an UAS7 of 30. This episode of CSU started four years before her baseline visit at the Hospital del Mar. The episode was treated with intermittent courses of oral corticosteroids and sedative anti-H1 antihistamines without any improvement. She never obtained a complete relief of symptoms. No specific CSU approach was conducted during the four years and finally she decided to be examined in a specific consultation for urticaria in a tertiary centre.

According to the extended personalized diagnostic program, the ASST was negative, she had a high total IgE (909 kU/L) level and as sign of an ongoing inflammation (high D Dimer = 1016 ng/ml). She was sideropenic and the urticaria was exacerbated by the intake of NSAIDs (ibuprofen). She had an active H pylori infection which was controlled. Initially, she was treated with 2nd generation anti-H1-antihistamines four fold time the licenced doses, subsequently. The second step of the urticaria treatment algorithm was initiated according the International guidelines. As symptoms remained uncontrolled at this high dose, a 3rd line treatment with cyclosporine A at 300 mg/day was chosen. Symptoms reappeared when the dose was decreased to commonly better tolerated dose of 200 mg/day, and the initial obtained UAS7 of 0 turned to 35 (severe). Additionally, she wanted to reduce the amount of medication she was taking each day, a total of four pills of H1-antihistamine and three pills of cyclosporine A. Omalizumab at 300 mg monthly was added. Hives had disappeared by the 4th day of treatment with no recurrence during the treatment period. Since July 2014, the patient receives continuously omalizumab 300 mg per month.
The decrease of the UAS7 parallels that of the decreased expression of the FceRI on the surface of the blood basophils assessed by flow cytometry. When trying to prolong the interval of the 300mg omalizumab doses,  symptoms reappeared and the level of the IgE receptor increased.
In conclusion, these two severe uncontrolled cases of CSU required a longer treatment course than those currently reported in published trials. Hence, choosing a safe and effective treatment, to manage a long lasting CSU  episode until it has been resolved, is mandatory to improve the patient’s conditions and daily quality of life.
Furthermore, these case studies confirm the International guideline recommendations on the management of CSU 26: the clinical diagnosis of CSU should be based on clinical history and examination and that if treatment with antihistamines is not able to control the disease, omalizumab may be added to efficiently control symptoms.

Summary

Presented by Stephen Holgate MD, FAAAAI and Ana M. Giménez-Arnau, MD PhD.
It is acquired that IgE plays a central role in the pathophysiology of allergic asthma.
The humanised monoclonal anti-IgE antibody omalizumab reduces cellular and molecular biomarkers of uncontrolled asthma and exacerbation and has been shown to be an effective treatment option across several asthma phenotypes.
There is evidence that anti-IgE therapy also affects non-allergic diseases such as CSU. Hence, it seems as if IgE may play a much broader role beyond the classical allergy concept.
Current guidelines for the definition, classification, diagnosis, and management of urticaria, issued in 2014, show a clear and simple management of CSU patients. Omalizumab is proposed as a third line add-on treatment in patients with CSU in adults and adolescents 12 years of age and above who remain symptomatic despite H1-antihistamine treatment.

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