Dermatology Online Journal

Omalizumab: A recombinant humanized monoclonal IgE-blocking antibody
Noah Scheinfeld MD JD
Dermatology Online Journal 11 (1): 2

Department of Dermatology St Lukes Roosevelt Hospital. Scheinfeld@Earthlink.net

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Abstract

Omalizumab (Xolair) is a recombinant humanized monoclonal antibody that blocks the high-affinity Fc receptor of immunoglobulin E (IgE). It is used to treat patients with moderate-persistent to severe-persistent asthma; patients must be older than 12 years, have a positive skin test to a perennial aeroallergen (e.g., dust mites, cats, dogs, and mold), and be symptomatic with inhaled corticosteroids. Omalizumab has a low incidence of side effects, and it is very expensive. The exact dosage of omalizumab dosage is determined by body weight and pretreatment serum total IgE levels. Omalizumab may have a role in the treatment of atopic dermatitis when IgE plays a causal role.

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Introduction

Omalizumab (Xolair, Novartis Pharmaceuticals, East Hanover, NJ; Genentech Inc., South San Francisco, CA) is a recombinant humanized monoclonal antibody that blocks immunoglobulin E's (IgE) high-affinity Fc receptor [1]. Omalizumab stops free-serum IgE from attaching to mast cells and other immune cells and prevents IgE-mediated inflammatory changes.

Omalizumab is used to treat asthma, which is part of the atopic triad with atopic dermatitis and allergic rhinitis. As such, omalizumab is of interest to dermatologists (1) because patients might be taking it; and (2) because of its immunological effects on IgE, it might be a treatment of atopic dermatitis. This review discusses the dosage, indications, effectiveness, immunology, and possible use in dermatology of omalizumab.

Mechanism of action

A variety of studies have found that omalizumab decreases inflammatory mediators. The result of blocking the immunoglobulin E (IgE) high-affinity Fc receptor are manifold. Omalizumab treatment downregulates dendritic cell FcεRI expression [2]. The combined effect of specific immunotherapy (SIT) and omalizumab is associated with prevention of nasal eosinophilic cationic protein increase and decreased tryptase levels in nasal secretions [3]. Anti-IgE therapy reduces leukotriene release of peripheral leukocytes stimulated with allergen in children with allergic rhinitis undergoing allergen immunotherapy independent of the type of SIT allergen used [4]. In a study assessing the immunologic effects of omalizumab on airway inflammation in allergic asthma, the mean percentage sputum eosinophil count decreased significantly (p < 0.001) from 6.6 percent to 1.7 percent in the omalizumab group, a reduction significantly (p = 0.05) greater than with placebo (8.5 % to 7.0 %); this was associated with a significant reduction in tissue eosinophils, FcεRI+ cells, CD3+, CD4+ and CD8+ T lymphocytes, B lymphocytes, and cells staining for IL-4+, but not with improvement in airway hyperresponsiveness to methacholine [5]. Treatment with omalizumab normalized the number of myeloid dendritic cells during the grass-pollen season [6].

Omalizumab induces complex changes in interleukin levels and does not decrease all Th-2-related interleukins. In a study of asthmatics, circulating levels of IL-5, IL-6, IL-8, IL-10, IL-13, and s-ICAM were measured before and after 16 weeks of treatment [7]; in addition, IL-13 and s-ICAM were measured before and after 16 weeks of treatment. The results of the aforementioned study were interesting: IL-13 decreased significantly (p < 0.01), IL-5 and IL-8 decreased in the omalizumab group compared to baseline, and other circulating mediators did not change.

Clinical trials

In approving omalizumab, The FDA considered two 52-week phase-3 trials involving 1,071 asthma patients, along with data from several supportive safety and efficacy studies [8]. When used as add-on therapy to inhaled corticosteroids, omalizumab reduced mean asthma exacerbations per patient by 33-75 percent during the stable-steroid phase and by 33-50 percent during the steroid-reduction phase. In clinical studies of asthma patients, it improved peak response, reduced exacerbations, and improved quality of life scores. Treatment with intravenous and subcutaneous omalizumab resulted in a 98-99 percent reduction in free IgE, reductions that were not observed following placebo treatment [9].

Side effects

Omalizumab has a low incidence of side effects. Common adverse events in clinical trials included injection-site reaction, viral infection, upper respiratory tract infection, sinusitis, headache, and pharyngitis. The most serious adverse reactions reported in clinical studies were malignancies (0.5  %) and anaphylaxis (0.1  %). The difference in malignancy between patients treated with omalizumab and placebo was not statistically significant. It is unknown whether IgE plays a surveillance role in cancer prevention and whether blocking IgE is associated with an increase in cancer incidence. In one study of 287 subjects, omalizumab was generally well tolerated, but two patients withdrew from treatment because of drug-related adverse events (rash and nausea; facial erythema and edema) [10].

Dosage range

The exact dosage of omalizumab dosage is determined by body weight and pretreatment serum total IgE levels [11]. The dosage schedule is given in Table 1. Doses greater than 150 mg are to be divided among more than one injection site. Slowly absorbed after subcutaneous administration and with a mean elimination half-life is 26 days, omalizumab (0.016 mg/kg/IgE [IU/mL] per 4 weeks) can be administered fortnightly or monthly. The bioavailability of omalizumab is 62 percent after subcutaneous administration. It reaches a peak concentration within 7-8 days after subcutaneous administration and has a half-life of approximately 26 days. Omalizumab is eliminated by the liver through the reticuloendothelial system [12]. It is a very expensive medication, costing $10,000-15,000 for a course of treatment.

Indications

On the basis of clinical trials, the FDA approved only very specific indications for omalizumab. Patients must have moderate-persistent to severe-persistent asthma, be older than 12 years, have a positive skin test to a perennial aeroallergen (e.g., dust mites, cats, dogs, and mold), and be symptomatic with inhaled corticosteroids [13]. Omalizumab does not have any specific drug interactions and is used with corticosteroids in most cases.

A recent evaluation by the Cochran group involved an evidence-based survey of omalizumab's utility for asthma (Table 2) [14]. This review found that omalizumab led to a significant reduction in inhaled steroid consumption compared with placebo: -114 mcg/day (95 % CI -150 to -78.13, two trials). Studies seemed to show increased health of patients and decreased steroid need, although the control groups had greater than expected responses. The Cochran reviewers believed the long-term clinical significance of the decrease of IgE induced by omalizumab has to be defined more fully.

A variety of off-label uses for omalizumab is being explored. It is being studied for the treatment of allergic rhinitis and peanut allergies. One study suggests it can be used to treat health-care workers with occupational latex allergy [15].

Conclusions

For dermatologists, insofar as atopic dermatitis is caused by IgE, omalizumab might be a promising treatment. IgE participates both in immediate-hypersensitivity response and in the induction of chronic allergic inflammation, probably because it enhances allergen capture and Th-2 cell activation and may trigger other modes of immune regulation [16]. Patients suffering from severe manifestations of atopy mount IgE autoantibodies against a variety of human proteins, and the levels of IgE autoantibodies correspond with disease severity with the variety of effects IgE-related autoimmunity perhaps contributing to the pathogenesis of atopic dermatitis [17]. Children with very high serum IgE levels are at risk for anaphylactic reactions and more severe atopic dermatitis [18]. It must be noted that a subgroup of atopic patients exhibits normal IgE levels and mechanisms contributing to the so-called "intrinsic" or "nonallergic" form [19].

Omalizumab has found a role in treating in treating patients with severe asthma. Its role in dermatology and for atopic dermatitis is probably best directed toward patients with high levels of IgE in whom the IgE is an etiologic factor for their disease.

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