The potential pharmacologic mechanisms of omalizumab in patients with chronic spontaneous urticaria Tse Wen Chang, PhD,a Christina Chen, BS,a Chien-Jen Lin, PhD,a Martin Metz, MD,b Martin K. Church, PhD, DSc,b and Marcus Maurer, MDb Taipei, Taiwan, and Berlin, Germany In patients given a diagnosis of chronic spontaneous urticaria (CSU), there are no obvious external triggers, and the factors that initiate the clinical symptoms of wheal, flare, and itch arise from within the patient. Most patients with CSU have an autoimmune cause: some patients produce IgE autoantibodies against autoantigens, such as thyroperoxidase or doublestranded DNA, whereas other patients make IgG autoantibodies against FcεRI, IgE, or both, which might chronically activate mast cells and basophils. In the remainder of patients with CSU, the nature of the abnormalities has not yet been identified. Accumulating evidence has shown that IgE, by binding to FcεRI on mast cells without FcεRI cross-linking, can promote the proliferation and survival of mast cells and thus maintain and expand the pool of mast cells. IgE and FcεRI engagement can also decrease the release threshold of mast cells and increase their sensitivity to various stimuli through either FcεRI or other receptors for the degranulation process. Furthermore, IgEFcεRI engagement potentiates the ability of mast cells to store and synthesize de novo inflammatory mediators and cytokines. Administration of omalizumab, by virtue of its ability to deplete IgE, attenuates the multiple effects of IgE to maintain and enhance mast cell activities and hence reduces the ability of mast cells to manifest inflammatory mechanisms in patients with CSU. (J Allergy Clin Immunol 2015;135:337-42.) Key words: Chronic urticaria, omalizumab, IgE, FcεRI, autoantibodies, mast cells, activation/release threshold, IgE–FcεRI–mast cell axis

Chronic spontaneous (idiopathic) urticaria (CSU) is characterized by the presentation of itchy wheal-and-flare skin reactions, angioedema, or both for a period of greater than 6 weeks.1 For most patients with severe CSU, damage to their appearance and the unbearable itching extend beyond a physical ailment to psychological disorders, including anxiety and depression, and severely impair the patient’s quality of life.2 Although the From athe Genomics Research Center, Academia Sinica, Taipei, and bthe Department of Dermatology and Allergy, Charit
e-Universit€atsmedizin Berlin. Disclosure of potential conflict of interest: T. W. Chang has received research support grant no. NSC-2320-B-001-005 from Nation Science Council Taiwan. M. Metz has consultant arrangements with and has received research support and honoraria for lectures from Novartis, Switzerland. M. K. Church has received payment for lectures from Novartis, Switzerland. M. Maurer has received honoraria for lectures and consulting, and funding for research from Novartis, Switzerland and Genentech. The rest of the authors declare that they have no relevant conflicts of interest. Received for publication February 24, 2014; revised April 26, 2014; accepted for publication April 30, 2014. Available online June 17, 2014. Corresponding author: Martin K. Church, PhD, DSc, Allergie-Centrum-Charit
e, Department of Dermatology and Allergy, Charit
e-Universit€atsmedizin Berlin, Charit
eplatz 1, D-10117 Berlin, Germany. E-mail: [email protected]. 0091-6749/$36.00 Ó 2014 American Academy of Allergy, Asthma & Immunology http://dx.doi.org/10.1016/j.jaci.2014.04.036

Abbreviations used ASST: Autologous serum skin test CSU: Chronic spontaneous urticaria CU: Chronic urticaria dsDNA: Double-stranded DNA HC: Highly cytokinergic ssDNA: Single-stranded DNA TPO: Thyroperoxidase

symptoms of the majority of patients can be adequately treated with antihistamines, in many cases they cannot. In these cases it is necessary to consider second-line treatments.3 Between 2006 and 2008, a number of physician-initiated case reports and pilot studies on CSU,4 chronic autoimmune urticaria,5 idiopathic angioedema,6 cold-induced urticaria,7 cholinergic urticaria,8 and solar urticaria9 showed that the humanized anti-IgE antibody omalizumab was efficacious against urticarial diseases not adequately treated with other medications. These reports spurred subsequent broader investigation of the effects of omalizumab in patients with chronic urticaria (CU). To date, 2 phase II10,11 and 4 phase III multicenter, randomized, placebo-controlled clinical trials12,13 have convincingly established that omalizumab is efficacious and safe for treating recalcitrant CSU that cannot be adequately treated with current standard care. Furthermore, a retrospective clinical analysis of 51 patients in Germany has shown omalizumab to be a rapidly acting, highly effective, and safe drug in both patients with CSU and those with chronic inducible urticaria.14 A summary of the clinical studies of omalizumab in patients with urticaria is shown in Table E1 in this article’s Online Repository at www.jacionline.org. Omalizumab, which has been conceptualized for treating IgEmediated allergic diseases15 and approved for treating patients with severe persistent allergic asthma in many countries, can neutralize IgE, impede the IgE allergic pathway, and render mast cells and basophils insensitive to activation through IgE/ FcεRI.16,17 Although reports showing the therapeutic effects of omalizumab on CSU have suggested a mechanism by which it attenuates the pathology of CSU with an autoimmune cause, such analyses are largely simplistic and incomplete. Furthermore, there is a nearly complete void of explanation in the literature on how omalizumab might achieve its therapeutic effects in patients with CSU and chronic inducible urticaria. This review will focus on CSU and the possible mechanism or mechanisms by which omalizumab might be effective in its treatment.

HISTAMINE, MAST CELLS, AND CSU The activation of mast cells and their release of inflammatory mediators are regarded as the ‘‘final common pathway’’ for a myriad of proinflammatory factors, including those involved in 337

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FIG 1. The inflammatory manifestation of mast cells in affected skin is the final common pathway in various types of urticaria. For the inducible subtypes, there are identifiable external triggers. For physical urticaria, the internal pathologic factors that transduce external triggers to mast cell activation have not been identified. For the spontaneous type, the primary causative factors that cause the urticarial manifestation arise internally. In one large subtype the patients have an autoimmune cause. For the remaining cases of the spontaneous type, the internal abnormalities have not been identified.

the various types of urticaria,18,19 as shown in Fig 1. The clinical response of CSU to H1-antihistamines and the finding of increased concentrations of histamine in skin tissue fluid underscore the role of histamine derived from dermal mast cells as a major mediator of urticaria.20 But what stimulates mast cells to degranulate, and why does this happen in the skin? Although highly unlikely, it cannot be excluded that in some cases of CSU, the primary abnormality lies in the mast cells themselves (eg, because of intrinsic or genetic alterations that cause altered activities of signal transduction pathways, as occurs in mastocytosis).21 If this were the case, it would be likely that the condition would be systemic rather than confined to the skin. Therefore it is more likely that skin mast cells in patients with CSU are not intrinsically abnormal but become increasingly sensitive or ‘‘unstable’’ or activated as the result of certain abnormal factors present in their surroundings. Although there are many nonimmunologic factors that might influence mast cell function in the skin, such as components of the complement system22 and neuropeptides, particularly those related to stress,23 because this review is primarily concerned with the mechanisms by which omalizumab might be effective, nonimmunologic factors will not be considered in detail.

A STATE OF MAST CELL ACTIVATION WITHOUT DEGRANULATION: PRIMING MAST CELLS FOR FULL ACTIVATION Accumulating evidence in the literature suggests that the IgE– FcεRI–mast cell axis does not merely exist in idled and triggered states. Before mast cells become productively activated for mediator release, they exist at some point along a spectrum of activation states of increasing potency. In other words, the activation of mast cells does not necessarily lead to their degranulation but might serve to prime them for subsequent activation. We will consider 2 possible mast cell–priming pathways for urticaria, namely the heterogeneous effects of

monomeric IgE and the consideration of CSU as an autoreactive disease (Fig 2).

MONOMERIC IgE POTENTIATES THE ACTIVITIES OF MAST CELLS IN THE ABSENCE OF ALLERGEN CROSS-LINKING In conventional thinking the involvement of IgE in mast cell activation requires the cross-linking of FcεRI-bound IgE by antigen or anti-IgE antibodies. This initiates the aggregation of FcεRI, leading to tyrosine kinase activation and subsequent mast cell activation for secretion. However, in 2001, it was suggested independently by 2 groups24,25 that monomeric IgE in the absence of antigen can have multiple effects in murine mast cells, including differentiation, proliferation, survival, and mediator and cytokine generation. These effects, which involve the binding of IgE to FcεRI and the aggregation of FcεRI, occur without the mast cells undergoing degranulation.24 The finding that monomeric IgE can augment mast cell activity has been confirmed by studies using various techniques. In a transcriptome analysis of 8793 genes, sensitization of mast cells with monoclonal IgE alone, without FcεRI cross-linking, was found to upregulate 58 genes more than 2-fold compared with their levels in unsensitized mast cells.26 These genes included those for cytokines, such as IL-1b, IL-6, and colony-stimulating factor 1; chemokines, such as IL-8 (CXCL8), CCL4, and monocyte chemoattractant protein 1 (CCL7); and cytokine and chemokine receptors. The genes for various immune regulators, adhesion molecules, antiapoptosis proteins, and cytoskeletal elements, such as RAS protein activator like 1 (RASAL1) and fibronectin leucine-rich transmembrane protein 2 (FLRT2), were also upregulated. Other studies have followed the suggestion that mouse monoclonal IgE molecules are heterogeneous with respect to their ability to induce survival and activation events in mast cells.27 At one end of the spectrum, highly cytokinergic (HC)

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FIG 2. The potentiating effects of IgE on mast cell activity. Binding of monomeric IgE to FcεRI, without IgE cross-linking, potentiates the activities of mast cells in the absence of degranulation. Compared with mast cells without IgE engagement, the IgE-engaged mast cells become more sensitive as the thresholds for activation and degranulation (release thresholds) by various factors through their receptors are decreased. The mast cells also become more potent because they store more mediators and can synthesize more mediators on degranulation. The mast cells also synthesize an array of factors and cytokines, which promote both differentiation of progenitors to become mast cells and survival of mast cells, thus augmenting the pool of mast cells. In subjects with anti-IgE autoantibodies, IgE autoantibodies, or both, the anti-IgE autoantibodies and presence of cross-reactive self-antigens can cause subthreshold levels of IgE cross-linking and FcεRI aggregation and augment the IgE-potentiating effect of mast cells.

IgEs induce enhanced survival, degranulation, adhesion, migration, and expression of cytokines, such as IL-6 and TNF-a; at the other extreme, poorly cytokinergic IgEs mediate these effector functions inefficiently.28 Interestingly, most murine monoclonal HC IgEs exhibit polyreactivity to autoantigens, such as double-stranded DNA (dsDNA), single-stranded DNA (ssDNA), b-galactosidase, thyroglobulin, and histaminereleasing factor. Autoantibodies to such autoantigens are often found in patients with autoimmune diseases. By contrast, poorly cytokinergic IgEs do not react with these antigens.29 This IgE heterogeneity is not restricted to murine antibodies: Kashiwakura et al29 recently reported that a human monoclonal HC IgE also shows polyreactivity to dsDNA, ssDNA, and histamine-releasing factor. Furthermore, sera from patients with atopic dermatitis showed increased reactivity to ssDNA and b-galactosidase and increased levels of histaminereleasing factor, suggesting a relationship between HC IgE and atopic disease.

AUTOREACTIVITY PROBABLY PLAYS A LARGER ROLE IN CSU THAN CURRENTLY APPRECIATED There is a strong correlation between CSU and autoimmune diseases. In a study involving 12,778 patients with CU using data spanning 17 years,30 it was shown that the odds of patients with CU to have 1 or more autoimmune diseases, mostly within 10 years of their diagnosis of CU, were 7.7 to 28.8 times higher than control subjects. These autoimmune diseases include hypothyroidism, thyroiditis, rheumatoid arthritis, systemic lupus erythematosus, Sj€ogren syndrome, celiac disease, and type 1 diabetes, among others, which involve autoantibodies. The data indicate that patients with CU have a propensity to autoimmunity and that in many patients with CU, urticaria appears to be the first or only manifestation of pathologic autoimmunity.

The autoreactivity in patients with CSU can be described in 2 subtypes. In the first subtype, which is essentially a Coombs and Gell type II hypersensitivity reaction, affected patients produce IgG autoantibodies against FcεRI, IgE, or both, which can cross-link IgE-occupied or barren FcεRI to activate mast cells and basophils.31 This was originally reported by Grattan et al32 in 1986 after the observation that serum from some patients with CSU produced a wheal at the site of intradermal injection. This is the so-called autologous serum skin test (ASST). Interestingly, the IgG subclasses that appear to be pathogenic are IgG1 and IgG3,22 both of which are capable of activating complement C5a, an established stimulator of skin mast cells, but not other mast cells, in human subjects.33 In adults the prevalence of positive ASST reactivity in patients with CSU is approximately 45%.34 Although this IgG autoreactivity is not definitively proved to be a trigger for urticaria, it is linked to longer duration of disease and the need for more intensive treatment.3 In the second subtype patients produce IgE antibodies against autoantigens. Work in this area stems from the observation that patients with CSU frequently exhibit increased total IgE levels35 and have autoimmune conditions, especially thyroid autoimmune disorders, such as Hashimoto thyroiditis.36 Several independent studies have reported that a significant number of patients with CSU (up to 33% in some studies) exhibit high levels of autoantibodies to thyroid antigens.37,38 In a study of 478 patients with CSU, 54% of sera were found to contain significant amounts of IgE directed against thyroperoxidase (TPO).39 Interestingly, IgE anti-TPO1 patients also had significantly higher IgG anti-TPO levels than IgE anti-TPO1 patients. However, there were no differences in disease activity and duration between IgE antiTPO1 and IgE anti-TPO2 patients. More recently, significantly higher levels than normal of IgE against dsDNA (IgE anti-dsDNA) have also been found in some

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patients with CSU.40 No differences between patients with CSU and healthy subjects were seen in IgG anti-dsDNA levels or IgE and IgG levels against thioredoxin, peroxiredoxin, and thyroglobulin. There was also no significant difference in levels of IgE antidsDNA between patients with positive and those with negative ASST results.40 These findings suggest that the ASST cannot reveal the presence of all autoreactive antibodies and that autoantibodies, such as IgE anti-dsDNA, other than the welldocumented IgG autoantibodies against IgE and FcεRI and IgE autoantibodies against TPO can also activate basophils to degranulate and play substantial roles in the pathogenesis of CSU. These findings suggest that this type of autoreactivity is one of the underlying causes of CSU and that IgE against self-allergen and the corresponding autoallergen might play important auxiliary roles in the priming of mast cells for activation (without degranulation) or be a direct stimulus of skin mast cell degranulation in patients with CSU. If this is the case, then it might be expected that therapies that reduce autoantibody levels would be effective in the treatment of CSU. The effectiveness of omalizumab (anti-IgE) is discussed below. Furthermore, there are case reports41,42 that rituximab, which binds to B-cell CD20 and reduces the levels of all classes of antibodies, including autoantibodies, and cyclophosphamide,43,44 which targets B cells producing autoantibodies, might be effective for treating autoimmune CSU.

OMALIZUMAB ABOLISHES THE ABILITY OF IgE TO POTENTIATE MAST CELL ACTIVITY In a patient with an allergic disease caused by type I hypersensitivity toward specific external antigens, omalizumab induces multifactorial therapeutic effects. Omalizumab depletes free IgE in the blood and interstitial space and inhibits IgE binding to FcεRI on basophils, mast cells, and dendritic cells. Omalizumab cannot bind to IgE that is already bound to FcεRI and does not have a direct effect on FcεRI levels. However, the depletion of free IgE results in the downregulation of FcεRI on cells bearing the receptor, making those cells insensitive to the stimulation by incoming allergens. It has also been suggested that the accumulation of omalizumab-IgE immune complexes might help sequester incoming allergen molecules.16,45 Omalizumab can also downregulate CD23 (also referred to as FcεRII) on B cells.46 There is also evidence that membrane-bound IgE-expressing B lymphoblasts and memory B cells can be downregulated, causing a reduction in the continual generation of IgE-secreting plasma cells.47,48 This is supported by the finding that IgE production decreases by 54% annually in omalizumab-treated asthmatic patients.49 Thus these effects of omalizumab inhibit the allergens to activate basophils and mast cells and their subsequent release of inflammatory mediators and cytokines. Omalizumab treatment ultimately brings down the overall inflammatory state in the body. But how does omalizumab exert its beneficial effects in patients with urticaria? As shown in Fig 2, there are 3 possible scenarios involving IgE. First, omalizumab sequesters monomeric IgE to reduce its priming effect on mast cells. This would be particularly relevant if HC IgE is involved in the pathogenesis of urticaria. Second, in patients with IgG autoantibodies against IgE or FcεRI, the depletion of mast cell–bound IgE by omalizumab and the subsequent downregulation of FcεRI on mast cells and basophils would lead to their decreased state of hyperexcitability.

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TABLE I. The potential pharmacologic mechanisms of omalizumab in patients with CSU Mechanisms

Binding of omalizumab to IgE Free IgE concentration in blood and interstitial space FcεRI on mast cells and basophils IgE-FcεRI engagement Potentiating of mast cells Secretion of cytokines (without degranulation) Mast cell pool Immune complexes of IgE-omalizumab Trapping of autologous antigens (eg, TPO) Trapping of IgE-specific IgG autoantibodies Binding of omalizumab to membrane-bound IgE on B lymphocytes Continual synthesis of IgE in extended periods IgE pool in the immune system Overall effects Release thresholds for mast cells for various degranulators Degranulation of mast cells Secretion of mediators, cytokines, and chemokines Recruitment of T cells, macrophages, and eosinophils Inflammatory manifestation in skin Vasopermeability, wheal, edema, itch, and erythema

Effects

Y Y Y Y Y Y [ [ [ Y Y [ Y Y Y Y Y

When IgE is bound by omalizumab, forming a complex, IgE cannot bind to FcεRI. This inhibits TPO-specific IgE autoantibody binding of FcεRI. Because IgE-specific IgG autoantibodies bind to IgE in accumulating IgE-omalizumab complexes, fewer of these autoantibodies can bind to IgE on FcεRI.

Third, in those patients with IgE autoantibodies against autoallergens, the inhibition of IgE binding to FcεRI by omalizumab and the downregulation of FcεRI would represent a central mechanism of omalizumab. Furthermore, accumulation of omalizumab-IgE immune complexes15 would sequester endogenous autoantigens, such as TPO and dsDNA, with which IgE reacts. In addition to these effects, the binding of omalizumab to IgE on B lymphocytes and memory cells would reduce the continual generation of IgE-producing plasma cells and hence IgE synthesis. The overall effect of omalizumab is that the IgE–FcεRI–mast cell axis is downgraded and the threshold for activation of mast cells to undergo degranulation by various factors is increased. This decrease in mast cell sensitivity and potency and thus increase in mast cell stability causes the mast cells to undergo less degranulation and secrete smaller amounts of pharmacologic mediators, thus decreasing the manifestation of urticarial symptoms. A summary of the possible effects is shown in Table I. Also, the decreased release of inflammatory cytokines and mediators from basophils in the vasculature as the result of omalizumab treatment would reduce the inflammatory manifestation in the skin. Such an effect might be important during the initial period of omalizumab treatment because the downregulation of FcεRI on basophils is faster than that on mast cells.

DIFFERENCES IN RESPONSE TO OMALIZUMAB AMONG PATIENTS WITH CSU AND THOSE WITH ALLERGIC DISEASES In patients with CSU, omalizumab has a relatively rapid onset of action, usually within 4 weeks in most patients and more rapidly in some.14 Clearly, this is very different from the onset of action seen in asthmatic patients in whom, although free IgE is extensively and very rapidly suppressed after commencing

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omalizumab, optimal benefit with respect to symptoms takes 12 to 16 weeks.50 There are many reasons for this difference. In some allergic patients allergen-specific IgE accounts for substantial percentages (eg, >3% to 5%) of total IgE, and it is difficult to reduce these to levels at which they do not occupy sufficient FcεRI on basophils and mast cells to sensitize them. Also, during some episodes of allergic attacks, patients might be exposed to external allergens, such as dust mites, pollens, or food antigens, or triggers, levels of which are much greater than the activation threshold of basophils and mast cells. Furthermore, in asthmatic patients there is persistent allergic inflammation in the bronchi, with consequential tissue remodeling.51 The inflammation takes time to resolve before symptoms improve significantly.50 In contrast, the hives and angioedema that manifest in the skin of patients with CSU disappear after each episode. There is no long-lasting damage to the affected skin.

CONCLUSION In cases of CSU, in which autoreactive IgG antibodies against FcεRI, IgE, or both or autoreactive IgE antibodies against autoallergens are found, these autoantibodies are causative factors, and IgE, FcεRI, and mast cells are unambiguously at the center of the pathologic process. For the remaining cases of CSU, IgE, FcεRI, and mast cells are also likely to play essential pathologic roles, although the causative factors have not been identified. Because the potentiating effect of IgE on mast cell activity involves the binding of monomeric HC IgE or the aggregation of FcεRI to a subthreshold level without triggering degranulation, it is possible that the presence of IgE antibodies with crossreactivity to very low concentrations of self-antigens, such as dsDNA, ssDNA, and other self-components, might play an important role in CSU. It should be emphasized that IgG autoantibodies to IgE and FcεRI, IgE autoantibodies to TPO and other thyroid antigens, and IgE autoantibodies to dsDNA, ssDNA, and other self-antigens can all bind to and cross-link IgE/FcεRI. Although the autoantibodies to individual antigens are not detectable in immunoassays, their cumulative binding to IgE/FcεRI might be sufficient to prime mast cells for activation. If these concepts are correct, autoimmune response and autoreactive IgE antibodies might play a larger role in patients with CSU than previously appreciated. In other words, autoimmune processes might be the primary cause of most cases of CSU. Thus for those cases with a clear autoimmune cause, the attenuation of the IgE–FcεRI–mast cell axis by the action of omalizumab yields the observed therapeutic efficacy. Even for those cases that involve autoimmune response and autoreactive IgE antibodies subtly, they still involve the central pathologic axis of IgE–FcεRI–mast cells, as depicted in Fig 2, and omalizumab similarly renders therapeutic effects. The thesis presented here is based on multiple lines of research results from various investigators. Future studies examining the composition of autoantibodies and their effects on mast cells in patients with CSU should help in the evaluation of this thesis. In all, the development of the anti-IgE therapy has provided a badly needed therapy for those patients with CU who cannot be adequately treated with existing standard care. Furthermore, studies with omalizumab are also advancing our understanding of the disease process of CU.

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TABLE E1. Case reports, case series, and clinical trials of omalizumab in patients with CSU Patients

3 with CSU (2 autoimmune) 12 with CSU 1 with CSU 1 CSU 8 with CSU 1 with CSU 2 with CSU 2 with CSU 3 with CSU 9 with CSU 9 with nonautoimmune CSU 49 with CSU, with IgE anti-TPO (phase II trial) 5 with CSU 90 with CSU (phase II trial) 14 (2 with chronic angioedema) 19 (6 with CSU, 1 delayed pressure) 51 with CSU 16 with severe CSU 323 with CSU (phase III trial) 14 (3 autoimmune) 15 with CSU 336 with CSU (phase III trial) 110 with CSU (real-life practice collection) 19 with CSU 1 (CSU 1 CIndU)

Omalizumab treatments

Varying dosages every 2 wk Ranging from 150 mg every 4 wk to 300 mg every 2 wk; 16 wk 300 mg every 4 wk; 8 wk 150 mg every 4 wk; for 12 mo Ranging from 150 mg every 4 wk to 300 mg every 2 wk 300 mg every 2 wk for 6 mo 150 or 300 mg every 4 wk for 32 wk Ranging from 150 mg every 4 wk to 300 mg every 2 wk 300 mg every 4 wk for 16 wk Ranging from 150 mg every 4 wk to 300 mg every 2 wk 300 mg bimonthly, monthly, or every 3 mo Two treatment groups (placebo and OM between 75-375 mg every 2 wk or every 4 wk) for 24 wk 300 mg every 2 wk or every 4 wk Four groups (placebo and 75, 300, and 600 mg; single dose) Ranging from 150 mg every 4 wk to 375 mg every 2 wk for 6 mo 150 mg every 2 wk for 1 y Ranging from 150 mg every 2 wk to 300 mg every 4 wk for 8 wk 150 mg every 2 wk or every 4 wk for various periods Four groups (placebo or 75, 150, or 300 mg OM every 4 wk) for 12 wk 150 mg every 4 wk, 300 mg every 2 wk, or 300 mg every 4 wk; for 2-37 mo Ranging from 150 mg every 4 wk to 350 mg every 4 wk for 6 mo Two groups (placebo and OM 300 mg every 4 wk for 24 wk) 150 mg every 4 wk or 300 mg every 4 wk for various periods Ranging from 150 mg every 2 wk to 300 mg every 4 wk for 1-16 mo 150 mg every 4 wk or 150 mg every 2 wk

Results

Reference

All CR 7 CR, 4 PR, 1 NR

Spector and TanE1 Kaplan et alE2

Positive response Positive response Seven positive responses

GodseE3 Maspero et alE4 Magerl et alE5

Positive response Both positive responses Both positive responses

Iemoli et alE6 Vestergaard et alE7 Romano et alE8

All positive response All positive response

Al-AhmadE9 Groffik et alE10

All positive response Significant improvement in OM group All positive response Significant improvement in 300- and 600-mg groups All positive response

Ferrer et alE11 Maurer et alE12

58% CR, 26% PR, 16% NR 83% CR, 10% PR, 7% NR (30 CAU) 88% positive response

Ivyanskiy et alE16 Metz et alE17

Significant improvement in 150- and 300-mg groups 93% positive response

Maurer et alE19 Lefevre et alE20

87% CR or PR

Armengot-Carbo et alE21

Significant improvement in OM group 82% CR, 11% PR, 7% NR

Kaplan et alE22 Labrador-Horrillo et alE23

47% CR, 42% PR, 11% NR

Viswanathan et alE24

CR

Vieira Dos Santos et alE25

GodseE13 Saini et alE14 Buyukozturk et alE15

Song et alE18

The order of the list is according to the publication dates of the studies. CAU, Chronic autoimmune urticaria; CIndU, chronic inducible urticaria; CR, complete response; NR, no response; OM, omalizumab; PR, partial response.