Anti-IgE therapy

INTRODUCTION — Immunoglobulin E (IgE) plays a central role in the pathogenesis of allergic diseases, including asthma [1].

This review will examine IgE neutralization therapy with anti-IgE monoclonal antibody, with a focus on the treatment of asthma. Other promising approaches to reducing IgE, as well as investigational applications of anti-IgE to other disorders, will be discussed briefly.

The role of anti-IgE therapy in the overall management of asthma, as recommended by national and international asthma guidelines, is presented separately. The use of anti-IgE in the management of chronic spontaneous urticaria is also discussed in greater detail elsewhere. (See "An overview of asthma management" and "Chronic spontaneous urticaria: Treatment of refractory symptoms", section on 'Omalizumab'.)

ROLE OF IgE IN ASTHMA — Most asthmatic patients have elevated circulating IgE concentrations when levels are adjusted for age [2]. Allergic sensitization results from the formation of specific IgE in response to common inhalant allergens, such as those derived from house dust mites, pollens, animal dander, molds, and cockroaches.

Production and functions of IgE — IgE is produced by B lymphocytes under the direction of two cytokines: interleukin (IL)-4 and the closely related IL-13, which are produced by several cell types including T helper type 2 (Th2) cells (a subset of T helper lymphocytes prevalent in atopy) [3,4]. IgE formation is markedly enhanced by the interaction of two costimulatory molecules: CD40 ligand expressed on Th2 cells and CD40 expressed on B cells. Appropriately stimulated B cells mature into plasma cells that secrete allergen-specific IgE, which circulates and binds to high-affinity receptors (Fc-epsilon-RI) on the surface of mast cells, basophils, and other cells. (See "Mast cells: Surface receptors and signal transduction", section on 'High-affinity IgE receptor'.)

Bridging of IgE molecules on mast cells and basophils by protein allergens results in the activation of these cells. Activation leads to release of preformed mediators, such as histamine, and increased synthesis of lipid mediators, such as prostaglandins and cysteinyl-leukotrienes, which in turn results in bronchoconstriction and plasma exudation [5]. Subsequently, mast cells and basophils synthesize and release a number of cytokines important in allergic inflammation. Thus, IgE plays a central role in the mechanism of immediate bronchoconstriction and the late inflammatory response after allergen inhalation challenge of allergic asthmatic subjects. (See "The biology of IgE" and "The relationship between IgE and allergic disease".)

Circulating IgE also binds to high-affinity receptors on dendritic cells and to low-affinity IgE receptors (Fc-epsilon-RII or CD23) found on B lymphocytes, monocytes, macrophages, and dendritic cells [6]. Allergen may also interact with bound IgE on these cells, although higher concentrations of allergenic proteins may be required to result in cell activation.

Atopy is the strongest risk factor for developing asthma [2,7,8]. Up to 80 percent of asthmatic patients in the United States and other developed countries are atopic, with one or more positive skin tests to common allergens and detectable allergen-specific IgE concentrations in serum [9,10]. Exposure to allergens to which patients are sensitive can lead to acute and chronic asthma symptoms. A small proportion of asthmatic patients have "intrinsic" asthma with negative skin tests, normal levels of total IgE, and no circulating specific IgE. Others lose their atopic status over time but not their asthma. However, some of these patients may have local mucosal formation of IgE or may have IgE directed against unrecognized environmental allergens, suggesting that IgE may be abnormal in nearly all asthmatic patients, irrespective of whether they are atopic [11]. (See "Risk factors for asthma" and "Pathogenesis of asthma".)

Effects of other therapies on IgE — Glucocorticoids do not inhibit IgE synthesis by B lymphocytes and may even increase circulating IgE by enhancing the expression of CD40 ligand [12,13]. (See "Glucocorticoid effects on the immune system", section on 'B cells and immunoglobulin levels'.)

Immunotherapy is an option for patients with allergic asthma. Subcutaneous immunotherapy is associated with significant risk of systemic reactions in those with moderate-to-severe persistent asthma. However, immunotherapy should be considered in some atopic patients with clear allergic triggers. Successful immunotherapy is associated with a suppression of the usual postseasonal rise in allergen-specific IgE. In some countries, sublingual immunotherapy is preferred for patients with asthma, as the risk of anaphylaxis is less than for injection immunotherapy. (See "Subcutaneous immunotherapy (SCIT) for allergic rhinoconjunctivitis and asthma: Indications and efficacy".)

OMALIZUMAB THERAPY IN ASTHMA — Omalizumab is a recombinant humanized IgG1 monoclonal antibody that binds IgE with high affinity and has been developed for the treatment of allergic diseases [14-17]. Omalizumab is the only available anti-IgE therapy in use. (See 'Other novel strategies to reduce IgE' below.)

Indications and patient selection — In the United States and many other countries where it is available, omalizumab is approved for use in patients with all of the following characteristics [18,19]:

●Six years of age and older.

●Moderate-to-severe persistent asthma (in the United States).

●Asthma symptoms that are inadequately controlled with inhaled glucocorticoids (in the United Kingdom, patients must have symptoms despite high doses of inhaled glucocorticoids).

●A total serum IgE level between 30 and 700 (1300 for children 6 to 11 years old and 1500 in Europe) international units/mL, which is the range over which the drug can reduce enough free IgE to ensure a therapeutic effect, provided the patient's body weight is within a specified range. (See 'Mechanisms of action' below.)

●Allergic sensitization demonstrated by positive skin testing or in vitro testing for allergen-specific IgE to an allergen that is present year-round (a perennial allergen), such as house dust mites, animal danders, cockroaches, or molds.

The 2021 Global Initiative for Asthma (GINA) guidelines recommended omalizumab for patients with moderate or severe allergic asthma uncontrolled on step 4 to 5 treatment. (See "Treatment of severe asthma in adolescents and adults", section on 'Anti-IgE therapy (omalizumab)'.)  

Predictors of response — Among patients who meet all of the criteria for approved use, there are limited characteristics that predict a positive response to omalizumab, although preliminary findings suggest a pretreatment circulating eosinophil count >300 cells/microL may predict a better clinical response.

A possible correlation between pretreatment peripheral blood eosinophil counts and response to omalizumab was demonstrated in some studies [20,21]. One randomized trial included 328 patients with normal lung function aged 12 to 75 years with incompletely controlled atopic asthma despite inhaled glucocorticoids [20]. An analysis of responses in patients with high (≥300/microL) versus low (≤300/microL) absolute peripheral eosinophil counts was planned at the study outset. The primary endpoint of the study was a reduction in the rate of asthma exacerbations during the six-month treatment period. Although the exacerbation rate was reduced in the omalizumab group compared with placebo, the difference was not statistically significant in the group as a whole, and thus, the primary endpoint was not met. However, in the high eosinophil group, the exacerbation rate was reduced by 45 percent (0.4 to 0.22 exacerbations/patient during the treatment period [95% CI 0.25-1.22]), while there was no change in the low eosinophil group. However, a real-world study did not show an enhanced effect in patients with elevated eosinophils [22].

In a previous randomized trial of 1070 patients with allergic asthma performed to assess clinical predictors of responsiveness to omalizumab, only impaired baseline lung function or frequent exacerbations despite high-dose inhaled glucocorticoid therapy was correlated to a good response [23]. This study did not evaluate peripheral eosinophil count as a predictor of omalizumab responsiveness.

The importance of allergic triggers in a patient's disease may also be a factor, although the best means of assessing this beyond clinical history has not been determined:

●A randomized trial of 419 inner-city children, adolescents, and young adults (6 to 20 years of age) found the greatest benefit in patients with allergy to prevalent indoor allergens (cockroach and dust mite) [24]. Unexpectedly, this study also found that omalizumab reduced seasonal exacerbations in the fall and spring, without altering rates of positive cultures for common respiratory viruses. These findings indicate that omalizumab does not prevent viral infection, although it can alter the patient's tendency to develop an asthma exacerbation as a result of a viral infection. (See 'Virus-induced asthma exacerbations' below.)

●Patients with low total IgE (ie, below 30 international units/mL) who have a relatively high proportion of allergen-specific IgE also respond to omalizumab [22,25,26].

Occupational asthma — Omalizumab has been reported to ameliorate occupational asthma in patients who are unable to change their work environment [27,28]. (See "Occupational asthma: Management, prognosis, and prevention", section on 'Management'.)

Nonatopic asthma — Patients with nonallergic (intrinsic) asthma also have local IgE synthesis in the airways, and omalizumab can be beneficial in these patients as well, although it is not a treatment of choice in this subgroup because there are more appropriate therapies [29,30]. In a small randomized trial, 18 patients with non-atopic asthma were administered omalizumab or placebo in addition to existing therapy for 20 weeks, and existing asthma medications were withdrawn in a step-wise manner after 14 weeks. Bronchial biopsies were collected at various time points. Omalizumab but not placebo therapy significantly reduced median total bronchial mucosal IgE+ cells and resulted in improvement in lung function [29].

Virus-induced asthma exacerbations — Several studies have found that omalizumab decreases the rate of asthma exacerbations associated with viral infections [24,31,32]. In inner-city children with asthma and recent exacerbations, the addition of omalizumab prior to the start of school in the fall was more effective in preventing exacerbations than doubling inhaled glucocorticoids [31]. Possible mechanisms for this effect are reviewed below. (See 'Reduction of exacerbations related to viral infections' below.)

Mechanisms of action — Omalizumab binds to the third constant domain of the IgE heavy chain (C-epsilon-3), which is the same site at which IgE normally binds to both high- and low-affinity IgE receptors on mast cells, basophils, and other cell types. Thus, omalizumab forms complexes with free IgE and prevents its interaction with these receptors. The omalizumab-IgE complexes are subsequently cleared by the hepatic reticuloendothelial system (figure 1). The antibody is specific to IgE and does not bind to IgG or IgA. An important property of omalizumab is that it cannot bind to IgE receptors or to IgE already attached to the alpha chain of Fc-epsilon-RI and therefore does not interact with cell-bound IgE or activate mast cells or basophils [33]. (See 'Hypersensitivity reactions' below.)

Free IgE must be reduced to extremely low levels to achieve clinical efficacy. This is because there are 10,000 to 1,000,000 Fc-epsilon-RIs on mast cells and basophils, and nearly all are occupied by IgE. Only 2000 IgE molecules are needed for half-maximal release of histamine from basophils. Therefore, a marked reduction in IgE is needed to prevent mast cell and basophil activation [34].

Omalizumab therapy causes a marked downregulation of Fc-epsilon-RI on the surface of basophils and mast cells, although the time course of this change may differ in the two cell types [35-40]:

●In a study of ragweed-allergic patients with allergic rhinitis, Fc-epsilon-RI on the surface of basophils was reduced by 73 percent after seven days of treatment and correlated with a decreased clinical response to allergen on nasal challenge [41].

●In contrast, the downregulation of receptors on cutaneous mast cells occurs more slowly. In a study of dust mite-allergic patients with allergic rhinitis treated with intravenous omalizumab, the expression of Fc-epsilon-RI on cutaneous mast cells was unchanged after 7 days of treatment but 90 percent reduced at 70 days [37]. The number of cells staining positive for tryptase was unchanged, demonstrating that the mast cells were still present but receptor expression had decreased. These mast cell changes correlate to a gradual reduction in cutaneous skin test responses [37,42]. A decrement in the late-phase cutaneous response is seen by two weeks, followed by a decrease in the early phase at eight weeks of therapy [42,43]. However, the subtlety of this reaction questions its usefulness in clinical practice.

There is usually little to no improvement in FEV₁ when omalizumab is added to pre-existing therapy [44,45]. Similarly, airway hyper-reactivity, as measured by methacholine responsiveness, improves little or not at all [46,47].

Several studies have demonstrated anti-inflammatory effects from omalizumab treatment [47-52]. In one, bronchial biopsies show decreased eosinophils, reduced numbers of CD3+, CD4+, and CD8+ T lymphocytes, B lymphocytes, and interleukin 4-positive cells. IgE-positive cells in the bronchial mucosa were decreased 10-fold.

Efficacy — In patients with moderate-to-severe asthma, treatment with omalizumab (compared with placebo) can decrease the incidence of exacerbations and result in a significant reduction in the dose of inhaled or oral glucocorticoids required to control symptoms [48,49,53,54]. Omalizumab has never been compared directly in a controlled clinical trial with other asthma therapies, such as inhaled glucocorticoids with long-acting beta-agonists, antileukotriene agents, or allergen immunotherapy.

Moderate-to-severe asthma — A 2014 systematic review included 25 randomized trials of patients with moderate or severe asthma receiving inhaled glucocorticoids, to which subcutaneous omalizumab was added [55]. Most of the studies involved patients with moderate asthma. The addition of omalizumab had the following effects:

●Reduced the risk of experiencing an exacerbation from 26 to 16 percent over 16 to 60 weeks of treatment.

●Reduced the risk of hospitalization for asthma from 3 to 0.5 percent over 28 to 60 weeks.

●Allowed for a small but significant reduction in inhaled glucocorticoid dose (weighted mean difference -118 mcg beclomethasone dipropionate equivalent per day [95% CI -154 to -84]).

In addition, subjects receiving omalizumab were significantly more likely to be able to withdraw inhaled glucocorticoids completely compared with those receiving placebo (40 versus 21 percent). However, omalizumab did not appear to increase the likelihood that subjects could discontinue oral glucocorticoids. A systematic review of three trials of children and adolescents reached similar conclusions [56].

Severe asthma — Fewer studies have been performed on patients with severe asthma (rather than moderate-to-severe) [57,58]:

●In a randomized trial of 850 patients (aged 12 to 75 years) with uncontrolled symptoms despite both high-dose inhaled glucocorticoids (ie, doses ≥500 mcg fluticasone twice daily) and long-acting beta-agonist therapy, treatment with omalizumab or placebo was administered for 12 months, during which other controller therapies were not changed [57]. All patients had IgE levels within the specified range and sensitization to a perennial allergen. The primary endpoint was number of exacerbations requiring systemic glucocorticoids for more than three days or requiring an increase in daily dose of ≥20 mg of prednisone (or equivalent) for patients on chronic oral glucocorticoids. The rates of exacerbations per subject were 0.66 and 0.88 in the omalizumab and placebo groups, respectively, which corresponded to a 25 percent reduction in the incidence rate. The difference was statistically significant. Recommendations for the treatment of severe asthma are reviewed elsewhere. (See "Treatment of severe asthma in adolescents and adults".)

●Another study of patients with severe asthma was performed in 34 children, one-half of whom were 5 to 11 years of age [58]. In this prospective, nonrandomized trial, consecutive children were chosen to receive four months of omalizumab therapy if they required daily prednisolone during the preceding three months. Allergy testing was not performed. Baseline serum IgE levels ranged from 119 to 1193 international units/mL (note that the higher values are outside the range approved in the United States) with a median of 411 international units/mL. Primary endpoints were reduction in prednisolone dose and changes in quality of life, Childhood Asthma Control Test (ACT), and FEV₁. After four months of treatment, during which all other therapies were kept constant, 85 percent of the children were able to reduce their doses of prednisolone, with a median dose reduction from 20 mg to 5 mg daily. Dramatic reductions were seen in about 20 percent of subjects. Quality of life and ACT scores improved significantly. However, the lack of a placebo group and small size limit the conclusions that can be drawn from this study, and controlled trials are needed. Omalizumab is not approved for use in children younger than six years of age in the United States.

Reduction of exacerbations related to viral infections — The mechanism by which omalizumab reduces asthma exacerbations due to viral illness appears to involve the normalization of an impaired response to viral infection that can be seen in patients with asthma. In such patients, higher serum levels of IgE are associated with increasing severity of viral-induced exacerbations, and production of interferon-alpha (IFN-alpha) in response to viral infection is diminished [59,60]. Cross-linking of IgE on the surface of plasmacytoid dendritic cells (pDCs) suppresses IFN-alpha production, which explains the relationship between exacerbation severity and serum IgE levels. Omalizumab treatment reduces free serum IgE, reduces the number of IgE receptors on the surface of pDCs (and other cell types), and augments the production of IFN-alpha by these cells in the setting of viral infection [61]. In addition, omalizumab has been shown to decrease the duration of rhinovirus infections, viral shedding, and the risk of rhinoviral illnesses in asthmatic children [32].

Impact on acute allergen exposures — A multicenter study evaluated the effect of 16 weeks of omalizumab treatment on 68 patients acutely exposed to high levels of allergen in the form of a cat chamber challenge [62]. Subjects were cat-allergic adults with moderate asthma and a history of cat-induced exacerbations, taking a mean daily dose of inhaled fluticasone of 340 to 380 mcg. They were randomized to omalizumab therapy or placebo and challenged in the chamber at week 0 and week 16. The primary endpoint was the area under the curve of the percentage decrease from prechallenge FEV₁ per hour of exposure. Patients receiving omalizumab demonstrated a significantly smaller reduction in FEV₁ compared with those receiving placebo (15 versus 27 percent). Both chest and nasal symptoms were also significantly lower in the treatment group, and treated patients tolerated a median of 50 minutes in the chamber, compared with 22 minutes in the placebo group.

Other changes with therapy — The following changes are typically observed during omalizumab treatment, although these are not considered outcomes for assessing response to treatment:

●Total serum IgE levels increase three- to sixfold (due to the presence of immune complexes of omalizumab and IgE) and are not useful for monitoring clinical response [11,49,63].

●Allergen skin testing responses are significantly reduced but are not useful as a marker of efficacy, as the inhibition is incomplete and difficult to appreciate on individual patients in a clinical setting [43].

●Free serum IgE levels decrease dramatically, although measurement of free IgE is not available outside of research settings [64]. One study found that free serum IgE levels did not predict clinical response to treatment with omalizumab [65].

●Therapy may also interfere with the performance of most allergen-specific IgE assays, although the ImmunoCAP system appears to retain accuracy [66].

●Blood eosinophils decreased in a study of patients with asthma [67]. However, in a study of patients with chronic urticaria, blood eosinophils were unchanged but neutrophils were decreased [68].

●Levels of IgG, IgA, and IgM are not affected by omalizumab [68].

Cost — The cost is USD $10,000 to $12,000 per year for patients who require the minimum dose (150 mg every four weeks) and approximately USD $60,000 to $70,000 per year for those requiring the maximum dose (375 mg every two weeks), which far exceeds that of other approved asthma therapies [18,19,69]. Several analyses have questioned the cost-effectiveness of omalizumab therapy [70,71]. On the other hand, a few centers have concluded that omalizumab has a favorable cost to utility ratio in adult cohorts with severe asthma [72-74]. In the United States, information about cost for health care providers and patients is available through the manufacturer [75].

Administration

Dosing — For the treatment of asthma, the dosing of omalizumab is weight-based (0.016 mg/kg per international units/mL of IgE per month). The dose and interval that achieves this is determined for each patient based upon body weight and the levels of serum IgE. Doses range from 150 to 375 mg injected subcutaneously every two to four weeks. Detailed dosing tables are available in the linked drug monograph on omalizumab. Therapy should not be initiated during an acute exacerbation of asthma, due to the risk of anaphylaxis. (See 'Anaphylaxis' below.)

Peak serum concentration is reached in seven to eight days [19]. A maximum amount of 150 mg should be administered at a single injection site to avoid local reactions. The elimination half-life of the drug is one to four weeks after subcutaneous administration.

Dosing for the treatment of chronic spontaneous urticaria is reviewed elsewhere. (See "Chronic spontaneous urticaria: Treatment of refractory symptoms", section on 'Omalizumab'.)

Pretreatment testing — Total serum IgE levels should be between 30 and 700 international units/mL (or 1300 in children 6 to 11 years of age), although reports describe benefit in patients with IgE levels below this level, and omalizumab is approved above this range in Europe [76,77]. For all patients with serum IgE levels above 300 international units/mL, there are upper limits of body weight beyond which administration is not recommended. Sensitization to a perennial aeroallergen (eg, house dust mite, animal danders, cockroaches, molds) must be demonstrated by positive skin testing or by in vitro-specific serum IgE testing. Baseline FEV₁, peak flow, or other pulmonary function testing is recommended.

Route of administration — Omalizumab is approved for administration by subcutaneous injection. Initial trials demonstrated that aerosolized omalizumab was ineffective in protecting against allergen challenge and had no effect on circulating IgE [78]. In contrast, both intravenous and subcutaneous administration induce a rapid fall in free serum IgE, although subcutaneous administration is more practical [79-81].  

Home administration — Omalizumab may be self-administered at home in many countries, including the United States [82]. The US Food and Drug Administration (FDA) outlined selection criteria for home administration: No prior history of anaphylaxis, successful administration of three separate doses of omalizumab in the office, ability to recognize and treat symptoms of anaphylaxis, and ability to follow the prescribed dosing regimen and utilize proper injection technique for omalizumab. Patients should be prescribed omalizumab in prefilled syringes and instructed on correct administration.

Time to effect — A minimum of 12 weeks of treatment is needed to determine the efficacy of anti-IgE therapy for asthma [23]. A three- to six-month trial is appropriate, although some patients may respond only after weeks of treatment, but this appears to be atypical [83].

Monitoring therapy — No specific laboratory tests are suggested for monitoring patients who are responding clinically to anti-IgE therapy. Total serum IgE levels increase three- to sixfold in all individuals on therapy and are not useful for monitoring clinical response [11,49,63]. However, if therapy is interrupted for more than one year, the manufacturer states that serum IgE levels may be measured again and dosing based on the new measurement. Dosing should be adjusted for significant changes in body weight. (See 'Other changes with therapy' above.)

Duration of treatment — The optimal duration of therapy in patients with asthma who experience clinical benefit has not been determined and consensus is lacking. Patients who respond are generally continued on the drug long term. However, if after two years the patient's asthma is well-controlled with low- to medium-dose inhaled corticosteroids, it is reasonable to extend the dosing interval gradually. Dosing should also be adjusted for changes in bodyweight.

Observations post-treatment — Once omalizumab therapy is discontinued, serum-free IgE levels [84], skin test responses [43], and basophil surface Fc-epsilon-RI and mediator release levels [36] gradually return to baseline.

Data are accumulating to suggest that, after several years of treatment, there may be persistent benefit after the drug is discontinued [85-87]:

The largest study evaluated over 19,000 patients with asthma (2453 children older than six and 16,750 adults) who were treated with omalizumab for at least 16 weeks from 2009 to 2019, using the French national health care database [85]. The median treatment period was 54 (95% CI 51-56) months in children and 51 (95% CI 49-53) months in adults. Therapy was effective, reducing rates of asthma hospitalizations by 75 percent after two years of treatment, and reducing use of oral corticosteroids by 30 percent in all ages. Among patients whose asthma was controlled during treatment, asthma remained controlled in a significant number one, two, and three years after discontinuation (ie, 76, 44, and 33 percent of children, respectively, and 70, 39, and 24 percent of adults, respectively).

Thus, there appears to be lasting benefit in a significant fraction of patients who are treated with omalizumab for several years. A possible explanation for this observation is the effect of prolonged administration on the production of IgE. A pharmacokinetic study found that omalizumab reduced the production of IgE gradually over time, resulting in a new equilibrium after about five years [88]. Based on the models used, the authors concluded that it could take years after discontinuation for IgE production to reach pretreatment levels. However, controlled studies are needed before recommendations can be made regarding the optimal duration of therapy.

ANTI-IgE THERAPY IN OTHER DISEASES — IgE plays a critical role in other allergic diseases, and it might be expected that omalizumab may be beneficial in the treatment of these disorders as well (table 1).

Chronic urticaria — Omalizumab has been shown in randomized trials to be effective for chronic spontaneous urticaria refractory to antihistamine therapy and for some forms of inducible urticaria. In 2014, omalizumab was approved in the United States for the treatment of adults and adolescents (12 years and older) with chronic spontaneous urticaria who remain symptomatic despite H1 antihistamine treatment. The recommended dosing is different from that used for asthma. It is either 150 or 300 mg given subcutaneously every four weeks and is not determined by serum IgE level or body weight. This is reviewed in detail separately. (See "Chronic spontaneous urticaria: Treatment of refractory symptoms", section on 'Omalizumab' and "Cold urticaria", section on 'Other pharmacotherapy' and "Physical (inducible) forms of urticaria".)

Other allergic disorders — Omalizumab has been reported to be helpful in the management of food allergy, nasal polyposis, idiopathic anaphylaxis, allergic rhinitis, venom hypersensitivity, atopic dermatitis, and several other disorders (table 1).

●Omalizumab is approved for the treatment of chronic rhinosinusitis with nasal polyposis. (See "Chronic rhinosinusitis with nasal polyposis: Management and prognosis", section on 'Anti-IgE (omalizumab)'.)

●Studies have explored the use of omalizumab and related anti-IgE antibodies for the treatment of food allergy (including children receiving oral immunotherapy), bullous pemphigoid, asthma associated with eosinophilic granulomatosis with polyangiitis (Churg-Strauss), and allergic bronchopulmonary aspergillosis [89-97]. Dosing in these disorders may not conform to approved standards, since some patients have extremely high IgE levels that do not fall within the ranges for recommended and approved dosing. (See "Experimental therapies for food allergy: Immunotherapy and nonspecific therapies", section on 'Anti-IgE' and "Management and prognosis of bullous pemphigoid", section on 'Other therapies' and "Eosinophilic granulomatosis with polyangiitis (Churg-Strauss): Treatment and prognosis", section on 'Anti-IgE therapy' and "Treatment of allergic bronchopulmonary aspergillosis", section on 'Anti-IgE therapy' and "Chronic rhinosinusitis with nasal polyposis: Management and prognosis", section on 'Anti-IgE (omalizumab)'.)

●Omalizumab has been used to treat anaphylaxis in patients with idiopathic anaphylaxis, mastocytosis, and mast cell activation disorders.

●Omalizumab is effective in reducing symptoms and decreasing the need for concomitant medical therapy in seasonal and perennial allergic rhinitis [98-102].

●Several reports have described the administration of omalizumab prior to or concomitant with subcutaneous allergen immunotherapy. Omalizumab has been administered in this manner for the purpose of reducing systemic allergic reactions to the injections in patients who were otherwise unable to tolerate immunotherapy with aeroallergens or Hymenoptera venoms [103,104]. In addition, omalizumab added to subcutaneous immunotherapy decreases rhinitis symptoms compared with immunotherapy alone [105]. It has also been used to help patients tolerate rapid desensitization protocols with fewer systemic allergic reactions [105] and/or to enhance the beneficial effects of immunotherapy [106]. (See "Hymenoptera venom immunotherapy: Technical issues, protocols, adverse effects, and monitoring", section on 'Recurrent systemic reactions'.)

●Vernal keratoconjunctivitis in children has been successfully treated with omalizumab [107]. (See "Vernal keratoconjunctivitis".)

ADVERSE EFFECTS — Omalizumab is generally well-tolerated [54,108,109]. However, there are case reports and series of adverse reactions, including the following.

Hypersensitivity reactions — Hypersensitivity reactions to omalizumab include anaphylaxis, urticaria, and injection site reactions. Severe hypersensitivity reactions to omalizumab or any ingredient of omalizumab are the only known contraindications for treatment.

Anaphylaxis — Anaphylaxis and anaphylactoid reactions that could not be ascribed to any other agent developed in approximately 1 to 2 in 1000 patients receiving omalizumab [110-113]. This rate of reaction is among the lowest of all biologics on the market. However, a boxed warning was added to the package insert in 2007 at the recommendation of the US Food and Drug Administration (FDA). The mechanism(s) in these reactions is not known, although a hypersensitivity reaction to the additive polysorbate 20 was implicated in a report of two cases [114]. Skin testing with the drug was negative, and IgE or IgG antibodies specific to omalizumab were not found in any of 30 cases in another series [115]. A self-reported history of anaphylaxis to foods, medications, or other causes has been identified as a potential risk factor.

Anaphylaxis after omalizumab may occur after any dose. In a review of 124 cases, 39 percent occurred with the first dose, and 19 percent occurred with the second dose. The reaction occurred after one of the first three doses in 68 percent of cases [111]. Approximately 70 percent of reported cases occurred within two hours of administration, although anaphylactic events beginning as late as four days after the injection and protracted anaphylaxis occurring over the course of one to two days have also been reported [116,117]. A later review of 30 additional patients found that 70 percent of reactions occurred within one hour [115].

Skin testing with omalizumab can be performed to evaluate apparent anaphylaxis to the drug, but the predictive value has not been established. Prick testing can be performed with undiluted drug. For intradermal testing, the drug can be diluted in normal saline. A concentration of 1:100,000 (1.2 micrograms/mL) has been determined to be nonirritating [118].

Recommended precautions — A joint task force of the American Academy of Allergy, Asthma, and Immunology and the American College of Allergy, Asthma, and Immunology convened in 2007 to review the clinical trials and postmarketing surveillance data regarding anaphylaxis associated with omalizumab. Their report included the following recommendations for clinicians prescribing omalizumab, which could be modified at the clinician's discretion [112]:

●Obtain informed consent from the patient after discussing the risks, benefits, and alternatives to omalizumab therapy.

●Educate the patient about the signs, symptoms, and treatment of anaphylaxis.

●Prescribe an epinephrine autoinjector(s) and instruct the patient on how and when to use it. Advise the patient to bring the autoinjector to every scheduled omalizumab injection and carry it for at least 24 hours afterward.

●Assess the patient's interim health status and pulmonary function prior to each injection and withhold omalizumab if the patient's status might place him/her at higher risk for a more serious outcome should anaphylaxis occur (eg, an active asthma exacerbation).

●Observe the patient for two hours after each of the first three injections and for 30 minutes after each subsequent injection.

Desensitization — A small number of patients with omalizumab-associated allergic reactions have been desensitized. One report describes a protocol performed successfully in three patients [119]. In another report, the patient initially tolerated omalizumab but later developed serum sickness [120].

Urticaria — Urticaria has been reported to develop in approximately 1 percent of patients [116]. The relationship between this limited reaction and risk for anaphylaxis has not been studied. Of note, omalizumab has proven to be an effective therapy for chronic spontaneous urticaria. This is reviewed separately. (See "Chronic spontaneous urticaria: Treatment of refractory symptoms", section on 'Omalizumab'.)

Injection site reactions — Injection site reactions appeared with equal frequency in approximately 44 percent of omalizumab- and placebo-treated patients. These were mostly described as mild-to-moderate and ranged in size from 1.5 to 3 cm. Most local reactions occurred within one hour of injection and lasted for 3 to 14 days [108].

Serum sickness — A small number of case reports describe serum sickness-like reactions following administration [120,121]. One case proved fatal.

Other issues — Several other issues have arisen with continued use of omalizumab therapy:

●Unclear association with cardiovascular disease – In a 2009 safety analysis by the FDA on the Evaluating the Clinical Effectiveness and Long-term Safety in Patients with Moderate-to-Severe Asthma (EXCELS) trial, a small apparent increase was noted in certain cardiovascular disorders in patients receiving omalizumab compared with the placebo group [122]. Disorders included transient ischemic attacks, cardiac ischemia, pulmonary hypertension, venous thrombosis, and pulmonary embolism. In 2014, the FDA released a statement based upon a combined analysis of 25 randomized trials comparing omalizumab with placebo, which did not detect an increased risk of thromboembolic events [123]. However, the FDA noted that the low number of events, young population, and short duration of follow-up could have impaired the ability of the analysis to detect an increase in risk and recommended alterations in the safety labeling. A 2017 analysis of EXCELS data reported a higher incidence of cardiovascular and cerebrovascular serious adverse events in omalizumab-treated patients, compared with non-omalizumab-treated patients (13.4 versus 8.1 per 1000 patient-years), with a hazard ratio of 1.32 (95% CI, 0.91-1.91) [124]. However, patients in the omalizumab group generally had more severe asthma than the control group. In addition, there are data indicating that asthma is a risk factor for cardiovascular disease and the more severe asthma in the omalizumab group may have confounded the results [125].

●Eosinophilic granulomatosis with polyangiitis – Cases of eosinophilic granulomatosis with polyangiitis (EGPA, Churg-Strauss) developing in temporal relationship with the use of omalizumab have been reported, although the coincident reduction in glucocorticoid therapy must also be considered as a possible contributing factor in expression of the disease. Reports about this association are reviewed separately. (See "Epidemiology, pathogenesis, and pathology of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)", section on 'Omalizumab'.)

Omalizumab has also been administered as an investigational therapy for the treatment of EGPA. (See 'Anti-IgE therapy in other diseases' above and "Eosinophilic granulomatosis with polyangiitis (Churg-Strauss): Treatment and prognosis", section on 'Less common therapies'.)

●Susceptibility to parasitic infection – Concerns that reducing IgE might impair immunity to parasitic infections were addressed experimentally in mice infected with Strongyloides and Schistosoma. Surprisingly, animals treated with anti-IgE therapy showed increased rather than decreased elimination of parasites [126,127]. However, a randomized trial of 137 people with allergic asthma who were at high risk for helminth infection and received omalizumab or placebo for one year found a trend toward more infections in the omalizumab subjects, although the difference was not statistically significant [128]. Response to appropriate anti-geohelminth treatment of infection was not different between treatment groups. This issue might warrant further investigation.

●Malignancy – Early data raised the possibility of an association between omalizumab treatment and malignancy, although this was not supported by subsequent analyses. The manufacturer submitted an initial report to the FDA in 2003 of adverse effects in all preclinical and clinical studies [108,109]. This reported that there were 16 malignancies (0.4 percent) in the omalizumab group and 2 (0.1 percent) in the control group, representing a 0.3 percentage point increase in the rate of malignancy per year. These were largely solid tumors that varied in location and cell type.

In 2012, a systematic review of 32 randomized trials identified 14 malignancies in 4254 omalizumab-treated patients and 11 in 3178 placebo-treated patients. No patterns in the type or histologic characteristics were detected, making it unlikely that there is an increased risk of malignancy with omalizumab treatment [129]. A prospective cohort study published in 2014, in which exposed and nonexposed patients were followed for five years, also found no increase in malignancy risk [130].

●Theoretical concerns – There are theoretical concerns about the therapy that have not been observed with clinical use. These include the following:

•Thrombocytopenia was noted in experiments in which cynomolgus monkeys received 3 to 27 times the maximum human clinical dose but has not been a significant problem in reported human trials [111].

•Loss of effect with continued treatment has not been observed.

SPECIAL POPULATIONS

Safety in pregnancy and lactation — The initiation of omalizumab in pregnant women is not recommended, although if a woman becomes pregnant while receiving omalizumab, it is suggested that therapy can be continued if the benefits are estimated to outweigh the potential harms. IgG crosses the placenta, so the fetus of a woman receiving omalizumab would be exposed to the drug. Studies of the safety of omalizumab in pregnancy are reviewed separately. (See "Management of asthma during pregnancy", section on 'Anti-immunoglobulin E'.)

IgG is excreted into human milk, so it would be expected that a breastfeeding infant would be exposed to omalizumab to some degree. Data in humans are not available [131].

Safety in children between the ages of 6 and 11 years — Studies in this patient population with asthma did not identify significant increased risks of serious adverse events, including cardiovascular problems or malignancy. However, long-term experience in the pediatric population is limited.

OTHER NOVEL STRATEGIES TO REDUCE IgE

Higher-affinity anti-IgE — Another anti-IgE monoclonal antibody, ligelizumab, with approximately 50-fold greater affinity for IgE, has been shown to inhibit allergen-induced skin test responses and reduce IgE levels to a greater degree than omalizumab [132,133]. However, in a field study of asthma patients, it did not have any better effects than omalizumab, and further development for asthma has been discontinued [134]. Ligelizumab is being evaluated for the treatment of chronic spontaneous urticaria.

Cytokine modulators — IgE synthesis is suppressed by inhibition of the cytokines interleukin (IL)-4 or IL-13, which are needed for class-switching. IgE production is also inhibited by the cytokines interferon-gamma and IL-12, which switch the balance from T helper type 2 toward T helper type 1 [4]. Several efforts have been made to influence IgE production at these upstream steps [135-140]. Dupilumab, an anti-IL-4-alpha receptor monoclonal antibody, has demonstrated some suppression of IgE levels of unclear clinical significance and has exhibited positive results in trials for atopic dermatitis, asthma, and chronic rhinosinusitis with nasal polyposis [141-144]. Dupilumab is approved for the treatment of severe atopic dermatitis in patients age 18 years and above, as well as for chronic rhinosinusitis with nasal polyposis. (See "Chronic rhinosinusitis with nasal polyposis: Management and prognosis", section on 'Anti-IL-4RA (dupilumab)' and "Treatment of atopic dermatitis (eczema)", section on 'Dupilumab'.)

SUMMARY AND RECOMMENDATIONS

●IgE in asthma – Immunoglobulin E (IgE) plays a central role in the mechanism of immediate bronchoconstriction and the influx of inflammatory cells in allergic asthmatic patients after inhalation of allergen. Most asthmatic patients are atopic and have elevated circulating IgE concentrations when levels are adjusted for age. (See 'Role of IgE in asthma' above.)

●Mechanism of omalizumab – Omalizumab is a recombinant humanized IgG1 monoclonal antibody that binds circulating IgE, forming immune complexes that are subsequently cleared by the hepatic reticuloendothelial system (figure 1). This binding inhibits the attachment of IgE to IgE receptors on mast cells, basophils, and other cell types, thereby reducing surface IgE receptor levels and the ability of these cells to be activated by allergens. (See 'Omalizumab therapy in asthma' above.)

●Indications in asthma – Omalizumab is approved for use as an add-on therapy in patients six years of age and above with inadequately controlled moderate-to-severe asthma despite the use of inhaled glucocorticoid therapy at appropriate doses. The 2021 Global Initiative for Asthma (GINA) guidelines recommended that omalizumab be considered as adjunctive therapy in step 5 care for patients with severe persistent asthma. (See 'Indications and patient selection' above.)

●Patient selection – In the United States, patients receiving omalizumab for asthma should be six years of age or older, have total serum IgE levels between 30 and 700 international units/mL in adults and 30 and 1300 international units/mL in 6- to 11-year-old children, and have evidence of sensitization to a perennial aeroallergen either by allergen skin testing or in vitro IgE testing. However, other biomarkers or clinical features that reliably identify patients who are likely to respond to therapy have not been definitively identified, but pretreatment blood eosinophil counts might prove useful. (See 'Indications and patient selection' above.)

●Impact on asthma Randomized trials of patients with moderate and severe persistent asthma showed that anti-IgE therapy significantly reduces severe exacerbations. Many patients can also significantly reduce their need for inhaled glucocorticoids. (See 'Efficacy' above.)

●Use in other disorders – Omalizumab is also effective for the treatment of chronic urticaria that is refractory to antihistamine therapy and several other disorders. (See 'Anti-IgE therapy in other diseases' above.)

●Administration – Omalizumab is administered by subcutaneous injection. No specific laboratory tests are suggested for monitoring patients who are responding (or not responding) clinically to anti-IgE therapy. Total serum IgE levels are not helpful, because these do not distinguish free IgE from IgE complexed to the drug, and total IgE levels typically increase three- to sixfold on therapy. (See 'Administration' above.)

●Adverse effects – Omalizumab is generally well-tolerated. Anaphylaxis occurs in approximately 1 to 2 per 1000 patients and can develop after any dose, including the first one, or have a delayed onset or a protracted course. Professional allergy societies in the United States have proposed observing patients for two hours after the initial three doses and for 30 minutes after each subsequent dose. (See 'Adverse effects' above and 'Hypersensitivity reactions' above.)