¹Dalhousie University, Halifax, NS, Canada
²Lynderm Research Inc., Markham, ON, Canada
³University Health Network, Toronto Western Hospital, Toronto, ON, Canada
⁴Department of Medicine, University of Toronto, Toronto, ON, Canada
⁵Gordon Sussman Clinical Research, Toronto, ON, Canada
⁶Division of Allergy and Clinical Immunology, St. Michael’s Hospital, Toronto, ON, Canada

Conflict of interest:
Erin Westby has no conflicts to report. Charles Lynde has been a speaker, principal investigator and consultant for Novartis and Pfizer, a speaker and consultant for Aralez, and a consultant for PediaPharm. Gordon Sussman is an advisor for Novartis and Aralez and gives funded lectures for them.

Abstract
Histamine is a key inflammatory player in the pathogenesis of urticaria, a mast-cell-driven disease characterized clinically by the development of wheals, angioedema, or both. Changes to the management of chronic spontaneous urticaria have recently been adopted due to increasing literature surrounding the efficacy and safety of up-dosing modern second-generation H₁-antihistamines and the use of omalizamub, a biologic agent, as a third-line treatment. Given the prevalence of chronic urticaria and its impact on quality of life, this editorial aims to provide a summary of the proposed updated guidelines for the management of chronic urticaria as agreed upon at the 5th Consensus Conference on the Update and Revision of the EAACI/GA²LEN/EDF/WAO Guideline for Urticaria in Berlin in December 2016. The chronic urticaria treatment algorithm outlined here reflects the updates and revisions made by 43 international experts representing 40 societies from 25 countries. These guidelines have yet to be published and therefore will require approval by respective national and international boards before adoption.

Key Words:
chronic spontaneous urticaria, chronic idiopathic urticaria, urticaria, antihistamines, biologics, omalizumab, monoclonal, anti-IgE antibody, up-dosing

Introduction

Urticaria is a common, mast-cell-driven disease, characterized clinically by the development of wheals, angioedema, or both. Histamine and other inflammatory mediators, including leukotrienes and prostaglandins, are considered major players in the development of symptoms. Intermittent urticaria and angioedema lasting greater than 6 weeks is defined as chronic urticaria and differentiates it from acute urticaria. The prevalence of chronic urticaria in the general population has been estimated to range between 0.5-1%.¹ Chronic urticaria has been shown to decrease quality of life and negatively impact performance at work and school. It has also been associated with increased levels of anxiety and depression, independently affecting quality of life.^2,3 Although self-limiting, the disease course can last longer than 5 years in an estimated 10-25% of people affected.⁴ As such, current management aims to improve quality of life and reduce impairment through symptom relief. Urticaria guidelines have promoted changes in the classification, approach to diagnosis, and management of chronic urticaria. These evidenced based guidelines are updated every 4 years by a joint initiative of the European Academy of Allergy and Clinical immunology (EAACI) Dermatology Section, Global Allergy and Asthma European Network (GA2LEN), the European Dermatology Forum (EDF), the World Allergy Organization (WAO), and by the Canadian Society of Allergy and Clinical Immunology (CSACI). The most recently proposed guidelines were updated and presented at the URTICARIA 2016, GA2LEN Global Urticaria Forum: 5th Guideline Consensus Conference in Berlin in December 2016.⁵ These updates and revisions reflect the work and collaboration made by a group of 43 international experts representing 40 societies from 25 countries. This review will summarize the current proposed consensus guidelines for the treatment algorithm of chronic urticaria. These guidelines have yet to be published and will require approval by respective national and international boards before adoption.

Classification

Urticaria can be arbitrarily divided into an acute condition wherein wheals, angioedema or both last less than 6 weeks versus a chronic process wherein wheals, angioedema or both last greater than 6 weeks. Generally, acute urticaria may be associated with identifiable causes, most notably an acute viral infection or an allergic reaction to medications, insects or foods. Alternatively, chronic urticaria can be further subdivided into two groups based on whether an inducible cause can be identified; induced urticaria and chronic spontaneous urticaria.^6-8

It should be noted that urticarial-related disease such as Schnitzler’s syndrome, Gleich’s syndrome, Well’s syndrome, bradykinin-mediated angioedema, cutaneous mastocytosis, and urticarial vasculitis are not considered subtypes of urticaria as they reflect distinctly different pathophysiology.

Diagnosis

A thorough history is the critical component of any initial patient evaluation, urticaria being no exception. Duration and frequency of intermittent symptoms will help establish chronicity of disease, whereas duration of individual urticarial lesions can help distinguish underlying pathogenesis, i.e. lasting greater than 24 hours would suggest vascular component rather than an immunoglobin E (IgE)-mediated phenomenon. When patients report identifiable triggers that would suggest chronic inducible urticaria, i.e., cold urticaria, delayed pressure urticaria, solar urticaria, heat urticaria, vibratory angioedema, cholinergic urticaria, contact urticarial, or aquagenic urticaria, specific provocation and threshold testing should be performed. If chronic spontaneous urticaria is suspected, initial blood work should be limited to complete blood count with differential and erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP). Omission of suspected drugs [e.g., nonsteroidal antiinflammatory drugs (NSAIDS)] should also be trialed. The American Joint Task Force on Practice Parameters (JTFPP) also include liver enzymes, renal function and thyroid-stimulating hormone (TSH) testing in their initial workup and recommends these laboratory investigations for all patients presenting with chronic spontaneous urticaria. Unless strongly suggested by history, extensive and costly screening programs for causes of urticaria are not recommended, which could include investigating for underlying infectious etiology (e.g., Helicobacter pylori), type I allergy, functional autoantibodies, thyroid hormones and autoantibodies, pseudoallergen-free diet for 3 weeks, tryptase, autologous serum skin test, and lesional skin biopsy (Table 1).^9-12

Management

Prevention of mast-cell degranulation through blockade of histamine on H₁-receptors remains the mainstay of treatment for chronic urticaria. Modern second-generation non-impairing, non-sedating H₁-antihistamines have been widely adopted as first-line treatment of chronic urticaria and have essentially replaced older first-generation antihistamines (Figure 1). They are effective and safe and do not possess the significant anticholinergic and sedating side effects that plague the first-generation antihistamines. Furthermore, current guidelines recommend against the use of first-generation H₁-antihistamines in the treatment of chronic urticaria, especially in the pediatric and geriatric populations, given their side effect profile.^6,7

If adequate control is not attained after 2-4 weeks or earlier if symptoms are intolerable, a trial of up to a fourfold increase in the standard therapeutic dose of modern second generation H₁– antihistamine is suggested. This has been proven to be safe and effective and is preferred over alternative treatments as second-line treatment based on recommendations by the updated and revised international guidelines.^5,6,13-15 First generation H₁-antihistamines are not recommended, but can still be used as adjunct therapy. H₂-antihistamines are not recommended as first-, second- or third-line therapy.^6,8,15-17 Similarly, antidepressants with potent H₁– and H₂-antagonism, such as hydroxyzine or doxepin, are not recommended given their sedating and anticholinergic nature, as well as the multiple drug-drug interactions.^18,19

The third-line treatment for resistant chronic urticaria, i.e., inadequate control after 2-4 weeks or earlier if symptoms are intolerable, includes the addition of omalizumab, an anti- IgE humanized monoclonal antibody (Figure 1).^1,5,6 In large, randomized, double-blind, placebo-controlled trials, omalizumab has been demonstrated to be efficacious, safe, and well-tolerated. ^20-24 Omalizumab has been shown to have few side effects and requires minimal ongoing monitoring. Omalizumab should be trialed for 6 months, unless symptoms are intolerable, before moving on to fourth-line therapy, cyclosporin A. Although trials using cyclosporin A have shown promising results when treating refractory chronic urticaria, continuous monitoring of blood pressure, renal function, serum drug levels, and other metabolic factors is important, in order to avert possible toxicity.^25,26 It is important to note that leukotriene receptor antagonists are no longer in the treatment algorithm for chronic spontaneous urticaria.⁵

At any stage of the disease, a short course of an oral corticosteroid could be added for treating acute exacerbations. Long-term treatment with corticosteroids should be avoided (Figure 1).^7,13,27

Use of other pharmacologic agents, such as sulfasalazine, hydroxychloroquine, colchicine, tacrolimus, mycophenolate mofetil, intravenous immunoglobulin, and dapsone have been used in the treatment for chronic urticaria with inconsistent results. These agents have limited utility because of their side effect profile, modest benefit seen in clinical trials, or lack of available data.^6,27,28

Conclusion

National and international guidelines recommend avoidance of intensive and costly general screening for causes of urticaria, relying largely on history, physical examination, and appropriate follow-up. Recently updated and revised international guidelines suggest a step-wise approach to the management of chronic spontaneous urticaria. These proposed recommendations have yet to be published but represent a framework for further review by respective national and international boards before adoption. In sum, these guidelines suggest that first-line therapy includes second-generation non-impairing, non-sedatingH₁-antihistamines. If no response by 2-4 weeks, up-dosing with second-generationH₁-antihistamines, up to fourfold increase, has been widely adopted as a safe and efficacious second-line therapy when treatment is inadequate with standard therapeutic dosages. A large body of data has demonstrated that omalizumab, a biologic agent, is safe and effective in the treatment of H₁– antihistamine refractory urticaria and should be considered as a third-line agent, with cyclosporin A reserved for fourth-line therapy.

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Introduction

In use for more than 75 years, first generation antihistamines (AH) are now widely available over the counter.¹ However, first generation AH, including diphenhydramine and hydroxyzine, are associated with significant adverse effects. Given the improved risk/benefit profiles of second generation AH, Global Allergy and Asthma European Network (GA²LEN) has recommended that first generation AH should no longer be available for purchase over the counter. In this article, we examine the safety and efficacy data of the novel, second generation AH bilastine and its role in the treatment of nasal and non-nasal symptoms of seasonal allergic rhinitis and of symptoms associated with chronic spontaneous urticaria (CSU) (e.g. pruritus and hives).

First Generation Antihistamines

• First generation antihistamines (AH), such as diphenhydramine and hydroxyzine, cause significant adverse effects related to their nonselective sedative and anticholinergic activity.²
• These adverse effects include impairment related to reduced rapid eye movement (REM) sleep, which cause hangover or “morning-after” effects, which impair learning, memory and work efficiency.³
• Based on these risks and the availability of newer, second generation AH with improved risk/benefit profiles, GA²LEN now recommends that older, first generation AH should no longer be available for purchase over the counter.⁴
• Additionally, the Allergic Rhinitis and Its Impact on Asthma (ARIA) Guidelines do not recommend first generation AH for the treatment of allergic rhinitis.²
• Overall, there is very limited use for first generation AH given the availability of newer, more efficacious and much safer, non-sedating, non-impairing AH.

Second Generation Antihistamines

• Second generation AH are available both over-the-counter and by prescription.
• Second generation AH selectively act on histamine 1 receptors, have low penetration of the central nervous system (CNS), and do not interact with adrenergic, muscarinic and dopaminergic receptors.¹
• However, while second generation AH have improved side effect profiles, cetirizine causes sedation and most of these agents are metabolized by cytochrome P450, increasing the risk for drug interactions.⁵
• There is a need for non-sedating second generation AH that do not interact with cytochrome P450, as recommended by the ARIA Guidelines.²

Bilastine (BLEXTEN^®): a novel second generation antihistamine

Indications and Use Around the World

• Bilastine (BLEXTEN^®) is a novel second generation AH that has been used by more than 71 million patients in 104 countries.
• In December 2016, bilastine became available in Canada with indications for:⁶
  • The symptomatic relief of nasal and non-nasal symptoms of seasonal allergic rhinitis in patients 12 years of age and older.
  • The relief of symptoms associated with chronic spontaneous urticaria (CSU) (e.g. pruritus and hives) in patients 18 years of age and older.
• In Europe, bilastine was recently approved for use in children 6 to 11 years of age (>20 kg) for seasonal and perennial allergic rhinoconjunctivitis and urticaria.⁷
  • This approval was based on a pivotal phase 3 trial by Novak et al⁸ that demonstrated no statistically significant differences between bilastine and placebo with respect to adverse events.
• In Japan, bilastine is also indicated for the treatment of pruritus.
  • This approval was based on a 52-week open-label trial that showed a significant improvement in the itch score from 2 weeks to the end of the study.⁹

Dosage of Bilastine

• In Canada, bilastine is indicated for use at 20 mg, once per day. For maximum absorption, it should be taken 1 hour before eating or 2 hours after.⁶
• Since bilastine is not metabolized, no dose adjustment is required in patients with hepatic impairment.⁶
• No dosage adjustments are required in patients with renal impairment; bilastine has not been studied in end stage renal failure.⁶

Bilastine Pharmacodynamics

• Bilastine has a rapid onset of action of 1 hour after treatment and lasts for 26 hours.⁶
• Bilastine does not interact with cytochrome P450 and therefore has no metabolic interaction with other drugs metabolized via P450.¹⁰

Safety of Bilastine

• • At the recommended dose of 20 mg daily, treatment-emergent adverse reactions with bilastine, including somnolence, were equal to placebo.⁶
  • Bilastine does not cross the blood brain barrier¹¹ and therefore, at the 20 mg dose it does not:
    • • Affect functional performance⁶
      • Affect the ability to drive⁶
      • Potentiate the effects of alcohol or lorazepam⁶
    • Cause sleepiness or impair performance of tasks related to flying under hypobaric conditions¹²

• In clinical trials with bilastine administered at doses of up to 40 mg once daily (double the recommended dose), it did not affect psychomotor performance and did not affect the subjects’ driving performance in a standard car driving test.^13,14
• Bilastine safety was assessed with no significant concerns in patients older than 65.^6,15

Cardiovascular QT Safety Data

• • The potential for QT prolongation is considered a class effect for all AH and bilastine, along with other second generation AH, is contraindicated in patients with a history of QT prolongation and/or torsades de pointes including congenital long QT syndromes.⁶
  • Unlike first generation AH, which were introduced decades before clinical pharmacology studies and randomized controlled trials of medication efficacy and safety were required by regulatory agencies⁵, most second generation AH have been thoroughly evaluated in pharmacology studies and phase 3 trials.

• The cardiac safety of bilastine was assessed in a robust QT study and showed no clinically significant impact on the QTc interval at both therapeutic and supratherapeutic doses.¹⁶
• Bilastine, dosed at up to 100 mg, has been shown to have no effect on QT interval.¹⁷
• All AH should be avoided in patients with known QT prolongation and used with caution in patients with cardiac arrhythmias.

The Use of Bilastine for the Treatment of Allergic Rhinitis (AR)

• AR occurs after exposure to an air-borne allergen and is characterized by nasal congestion, rhinorrhea, sneezing and nasal itching.
• The prevalence of AR is estimated at 20% of the Canadian population.¹⁸
• There are two phase 3 registration studies that support the use of bilastine for the treatment of seasonal AR (SAR).
• The Kuna et al. trial¹⁹ was a double-blind, randomized, controlled study performed in patients suffering from SAR to determine the efficacy and safety of bilastine 20 mg, cetirizine 10 mg, and placebo.
• The mean total symptom scores were reduced in the bilastine and cetirizine treated groups to a similar, and significantly greater extent, compared with placebo (Figure 1).
• Bilastine demonstrated a significantly lower incidence of somnolence and fatigue compared to cetirizine (Figure 2):
  • Somnolence rate was 1.8% with bilastine vs 7.5% with cetirizine
  • Fatigue rate was 0.4% with bilastine vs. 4.8% with cetirizine

• The Bachert et al. trial²⁰ was a double-blind, randomized controlled study performed in patients suffering from SAR which sought to determine the efficacy and safety of bilastine 20 mg, desloratadine 5 mg, and placebo.
• There was no significant difference in change in total symptom score between the bilastine and desloratadine treatment arms and both active arms were significantly better than placebo.²⁰
• Bilastine was equally effective for nasal and non-nasal symptoms.²⁰
• The bilastine and desloratadine safety profiles were comparable to placebo:
  • The incidence of somnolence was 3.9% with bilastine, 3.7% with desloratadine and 2.4% with placebo.²⁰
• A phase 3 registration study in a Japanese patient population has also shown bilastine to be effective in the treatment of perennial allergic rhinitis.²¹
• Since bilastine is not metabolized and does not cause somnolence, it is an excellent fit for the ARIA Guidelines recommendation of a second generation AH that does not cause sedation and does not interact with cytochrome P450.²

The Use of Bilastine for the Treatment of Chronic Spontaneous Urticaria (CSU)

• Spontaneous urticaria results from mast cell activation, with the release of histamine and pro-inflammatory mediators; in the majority of cases no allergy is found.³
• CSU occurs intermittently for at least six weeks, characterized by pruritic wheals, deeper swelling termed angioedema or both.²²
• CSU has a prevalence of 0.5-1% of the general population, occurring mostly in women; peak age of onset is 20-40 years, and 10-50% have the disease longer than 5 years.³
• The EAACI/GA²LEN/EDF/WAO 2016 guideline for the treatment of CSU is shown in Figure 3.
• The use of bilastine for CSU is supported by a double-blind, randomized placebo- and active-controlled parallel group study of 516 subjects with chronic spontaneous urticaria.²³
  • Subjects were randomized to bilastine 20 mg, levocetirizine 5 mg (similar to cetirizine) or placebo.²³
  • Bilastine significantly improved total symptom score including itch severity and wheal number and size over a 28-day period, with no significant difference between bilastine and levocetirizine.²³

• The differences in overall and drug-related incidence of adverse events were not significant between the treatment groups and both agents were well tolerated as compared to placebo.²³
• The efficacy and safety of bilastine up-dosing in urticaria has been demonstrated in a 12-week randomized, double-blind, cross-over, placebo-controlled study in adults with cold contact urticaria.²⁴
  • 20 patients with cold contact urticaria received each of the following, 20 mg, 40 mg, 80 mg bilastine or placebo for 7 days with 14-day washout periods between treatments.²⁴
  • The primary endpoint was the change in critical temperature threshold (CTT) to induce cold urticaria.²⁴
  • Key secondary endpoints were changes in pruritus and the safety and tolerability of bilastine.²⁴
  • The median CTT was significantly lowered by all doses of bilastine compared to placebo.²⁴
  • Bilastine 80 mg was significantly better than the two lower doses.²⁴
  • Pro-inflammatory mediators, IL-6 and IL-8 were significantly decreased following up-dosing with 80 mg bilastine, suggesting an anti-inflammatory effect of bilastine at 4 times the therapeutic dose.²⁴
  • Pruritus was also significantly lowered by all doses and 13 of the 20 patients reported no itch at a dose of 20 mg daily, demonstrating that bilastine is particularly effective against pruritus.²⁴

• This data shows that bilastine is a fast-acting, effective antihistamine for CSU that can be safely up-dosed when needed.

Conclusion

Bilastine has a proven, long-term safety record with use by over 71 million patients in over 104 countries. This novel, second generation antihistamine is non-sedating due to the fact that it does not cross the blood brain barrier. As well, bilastine is not metabolized and does not interact with CYP450.

Bilastine is available by prescription in Canada for the treatment of seasonal allergic rhinitis and chronic spontaneous urticaria. The efficacy data in allergic rhinitis and chronic spontaneous urticaria are comparable to other second generation AHs with a rapid onset of action that lasts for over 24 hours.

Bilastine can be used without dose adjustments in patients with hepatic and renal impairment as well as in elderly patients. At up to double the recommended dose, bilastine did not affect psychomotor performance in clinical trials and did not affect driving performance in a standard car driving test.

¹Department of Internal Medicine, University of Chicago (Northshore University Health System), Evanston, IL, USA ²Division of Allergy and Clinical Immunology, St. Michael’s Hospital, University of Toronto, Toronto, ON, Canada

Conflict of Interest:
Dr. Naaman has no conflicts to report. Dr. Sussman wishes to disclose that he is a consultant for Novartis and has conducted one research study sponsored by Novartis on omalizumab. There are no other potential or actual conflicts.

ABSTRACT
Chronic idiopathic urticaria (CIU) is a common autoimmune skin condition characterized by spontaneously recurring hives for 6 weeks or longer. The new terminology used for CIU in most countries including Canada is chronic spontaneous urticaria (CSU). CSU is associated with significant psychosocial morbidity with a markedly negative impact on overall quality of life. Conventional approaches with antihistamines, even at high doses, is effective in about 50% of patients suffering from CSU. A new treatment option, omalizumab, a humanized monoclonal antibody against the Fc domain of IgE, has undergone the scrutiny of randomized research studies evaluating the efficacy in CSU. This editorial reviews mechanisms of action of omalizumab, efficacy, cost and potential side effect profile. Omalizumab has emerged as a very promising treatment option for patients with CSU. Future research is necessary to establish standardized protocols related to dosing as well as monitoring possible adverse effects of long-term treatment.

Key Words:
angioedema, antibodies, anti-allergic agents, autoimmune skin disorder, hives, hypersensitivity, immunoglobulin E, monoclonal antibody, omalizumab, urticaria, Xolair

Introduction

Chronic idiopathic urticaria (CIU), also known as chronic spontaneous urticaria (CSU), is a common autoimmune skin disease characterized by spontaneously recurring hives or welts, which may also be accompanied by deeper cutaneous swelling termed angioedema. The primary symptom causing significant disability is itchiness or pruritus.¹ The diagnosis is defined as urticarial skin lesions occurring intermittently or continuously for more than 6 weeks. A fairly common condition, urticaria occurs across all age groups and has a lifetime prevalence of about 20% with about 1% of the population suffering from the chronic form.² CSU occurs largely in young women between 20 and 40 years of age.^3,4 Notably, 70% of patients diagnosed with CSU report symptoms lasting more than 1 year and a significant 14% report non-remitting symptoms which have lasted for more than ⁵ years.5 This condition has been associated with significant psychosocial impairment; specifically impacting emotional and physical health-related quality of life indices; resulting in substantial disability and diminished productivity.^6-8 Notably, the negative impact on quality of life measures reported by patients with CSU is on par with the severity reported by patients with triple vessel ischemic coronary disease. Specifically, patients in both clinical populations report similar levels of emotional distress, social isolation and lethargy.^9,10

Treatment of Chronic Spontaneous Urticaria

Current practice guidelines for management of CSU describe a stepwise approach with non-sedating H1 oral antihistamines as the initial agents, these can be given in up to four times the FDA recommended dose.¹¹ However, close to half of all CSU patients do not achieve adequate symptom relief with H1 antihistamines alone.¹² Second-line therapies can involve addition of H2 blockers although these are not recommended as first, second or third-line treatment because of low evidence supporting their clinical efficacy. The H2 blocking agents and anti-leukotriene medications are often tried because of their excellent safety profiles. If remission is not induced, third-line treatments may be initiated; this includes use of immune modulators. To date, cyclosporine has been the best studied agent with demonstrated efficacy based on adequately powered studies of good quality. Its significant toxicity profile, however, has limited its widespread use in many patients, especially in the older population dealing with other comorbidities.¹¹ Other immune modulators which have been used in refractory CSU include tacrolimus, mycophenolate mofetil, hydroxychloroquine, sulfasalazine and even intravenous immunoglobulin. In addition to the limited data supporting use of these agents in managing CSU, many of them are associated with substantial and often unacceptable toxicities. Systemic glucocorticoids have also been used in refractory cases and while consensus guidelines recommend their use to be limited to exacerbations, clinical practice has often necessitated their longterm use in many patients, again posing less than desirable side effects.¹³

Treating CSU is challenging, as there are often no identifiable indicators as to the responders to specific treatments. Cutaneous mast cell degranulation with release of histamine and other mediators are ascribed to urticaria, however, nonimmunoglobulin E (IgE) and non-immunologic mast cell activation is responsible for ongoing urticaria.¹⁴ In up to 50% of patients with CSU, an autoimmune mechanism is thought to mediate the disease process; this either involves autoantibodies to the alpha chain of the high affinity IgE receptor or intrinsic IgE immune modulation is believed to account for the pathophysiology.^15,16 Research-based assays have been developed to isolate an autoimmune etiology; however, at the present time, these are not readily available nor practical in a clinical setting.¹⁷

Omalizumab: Mechanism of Action

In the last few years, there has been a burgeoning interest in expanding the use of omalizumab beyond its originally approved use as adjunctive therapy for refractory asthma to CSU. Recently approved in Canada for CSU management, omalizumab is a fully humanized recombinant monoclonal antibody which binds to the fragment crystallizable (Fc) region of the IgE molecule which itself binds to FcεRI.^18,19 In theory, this structure precludes anaphylactogenic potential since the drug does not interact directly with IgE, which is already bound to cell surfaces. Therefore, mast cell or basophil degranulation would not be possible.^20,21 Functionally, omalizumab binds to circulating IgE, irrespective of allergen specificity. This results in circulating IgE-anti-IgE complexes, which are biologically inert and have specifically been shown not to activate the complement system.^19,20,22 Notably, reductions in circulating IgE reaching up to 99% have been reported in studies (that is free IgE not bound to omalizumab).^22,23 Interestingly, these serologic changes are seen within the very first administrations of the drug and are typically maintained throughout the duration of treatment; although the precise doses in CSU have not yet been established. Omalizumab has also been shown to down regulate FcεRI on basophils,²⁴ mast cells,²⁵ and dendritic cells.²⁶ A reduction in the expression of FcεRI on basophils and mast cells decreases the binding of circulating IgE, thus preventing the release of inflammatory mediators. Although most CSU patients have no identifiable allergy triggers, and there is not necessarily an increased incidence of atopy or high IgE levels, chronic urticaria may develop due to many stimuli. These include NSAIDs use, certain foods and even emotional stress. Omalizumab has also been shown to reduce the expression of FcεRI on dendritic cells; thereby attenuating the degree of allergen presentation and processing.

Evaluation of Efficacy

In addition to initial observation studies, case reports^27,28 and one proof-of-concept study²⁹, there have been four prospective randomized clinical trials which have directly evaluated the clinical efficacy of omalizumab in treatment of refractory CSU^30-33, in addition to one multicenter double-blinded placebo-controlled study³⁰. Omalizumab has been evaluated using a total pool of approximately 1,000 CSU patients across all studies to date.^27-32 Results have demonstrated clinically significant efficacy of omalizumab in decreasing pruritus and Urticaria Activity Scores (UAS – a widely used patient-reported outcome measure for patients with CSU) in comparison with conventional treatments. Specifically, studies have demonstrated symptom attenuation and improvement on quality of life measures in adult patients treated with omalizumab for 6-20 months.^27,34 In one study, which enrolled patients presenting with moderate to severe CSU who were unresponsive to antihistamines, omalizumab was associated with clinically relevant decreases in severity of hives and associated pruritus, as well as meaningful improvement on quality of life questionnaires.³² Notably, omalizumab often demonstrates an onset of action within 1 week of drug initiation, inducing complete remission; however, symptoms return when treatment is stopped, generally within 1 to 2 months. Also of relevance is the demonstrated efficacy of omalizumab in chronic inducible urticarial, such as cold and delayed pressure urticaria in small numbers of patients, for whom treatment options have generally been rather limited and outcomes unsatisfactory.³⁵

In real life studies omalizumab generally induces remissions in 50% of patients after the first dose.³⁵ Overall, more than 70% of patients achieve complete remission at some point within their treatment course. About 80% have a clinically significant response overall. The dose interval is generally between 4-8 weeks in most patients. More research is needed to more fully evaluate the dose interval and complete remission rate. The 300 mg dose was superior to the 150 mg dose in randomized clinical trials.³²

Treatment Cost

Omalizumab is substantially more expensive than mainstream therapies that have been traditionally used to treat CSU. Despite its high cost at the present time, it can be argued that using omalizumab in selected patients with refractory and chronic urticaria may in fact defray the potential long-term financial costs associated with conventional therapies; in addition to alleviating the psychosocial burden associated with loss of productivity.

Side Effect Profile

Use of omalizumab in the asthmatic population is more extensive compared to CSU. In asthma there are reports of anaphylactic reactions in about 1 in 50,000 injections. It should be noted, however, that omalizumab is designed to interact with the Fc region of the IgE molecule, making its anaphylactogenic potential very low and clinical experience confirms that it is safe.^20,21 There is still a recommendation for all patients to be observed for 2 hours after the first injection as well as carry epinephrine auto-injectors as some anaphylactic reactions have been reported as being delayed. Recently, the malignancy warning has been removed from the product monograph as patients with undiagnosed cancer were enrolled in one early trial.³⁴ The most common adverse side effects reported by patients include viral infections, headaches, sinus inflammation; however, these did not reach statistical significance when compared to patients enrolled in the placebo group. Notably, omalizumab is approved for children >12 years of age. The data available on its safety in children showed that that after 1 year of use, there was a slight increase in frequency of headaches and upper respiratory tract infections in the omalizumab group compared to placebo.³⁶

Future Directions

Omalizumab has emerged in recent years as a very effective treatment for refractory CSU. Future research should aim at investigating its mechanism of action and optimal dose schedule and treatment duration required for long-term remission. To date, the longest trial duration has been 24 months.³⁷

Conclusion

Chronic spontaneous urticaria (CSU) or CIU is a common autoimmune skin condition characterized by spontaneously recurring hives, occurring either intermittently or continuously for 6 weeks or longer. A significant association is a deeper localized swelling called angioedema, which is observed in about one-third of patients.¹ This is associated with significant psychosocial morbidity in the form of depression, social isolation and lethargy.^9,10 The impact of CSU on quality of life is notably substantial. There are recently developed standardized tools to assess the quality of life in CSU.³² A simple general test to assess disease severity is the Urticaria Activity Score (UAS7) that assesses pruritus and urticaria severity weekly, which should be used in clinical practice.³⁸ Conventional treatment guidelines prescribe a stepwise approach with non-sedating non-impairing antihistamines as first-line agents followed by increasing to four times the licensed doses as second-line treatment.² Thirdline treatments include cyclosporin, which is associated with toxicity and requires frequent monitoring.^11,12 Omalizumab, a fully humanized monoclonal antibody against the Fc domain of IgE, has gained widespread use as a new third-line treatment in CSU. A solid body of research including double-blinded, randomized clinical trials investigating its clinical utility in inducing remission in CSU has demonstrated robust efficacy.^27-33 Specifically, patients treated with omalizumab experienced clinically relevant decrements in severity of hives and associated pruritus, as well as meaningful improvement on quality of life measures.³² Omalizumab often demonstrated onset of action within 1 week of drug initiation, although the treatment generally appears to be given every 4 to 6 weeks. Two doses of 150 mg and 300 mg have been shown to be effective. As such, omalizumab has emerged as a very promising treatment option for patients with CSU. Future research will need to establish standardized protocols related to dosing and duration, as well as monitor possible longterm side effects, particularly in vulnerable clinical populations.

References

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