Reviews and feature article
The potential pharmacologic mechanisms of omalizumab in patients with chronic spontaneous urticaria

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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 double-stranded 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, IgE-FcεRI 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.

Section snippets

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 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

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

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

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, Sjögren syndrome, celiac disease, and type 1

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

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 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

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

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    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.

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