Prospective Double-blind Placebo-controlled Study of the Effect of Xolair (Omalizumab) in Chronic Urticaria Patients

Background

Chronic urticaria (CU) is a frequent disease with a lifetime incidence of up to 25-30% of the population. Currently, CU treatment relies mainly on second generation antihistamines and is purely symptomatic. The disease tends to have a cyclical nature with spontaneous disappearance and frequent relapses. Some patients show a sufficient response to standard second generation antihistamines like (levo)cetirizine 10mg, (des)loratadine 5mg or terfenadine 120-180mg. Others need higher doses (up to 4-fold usual daily dose), often accompanied by sedation. Treatment may last for months, even years. If this first-line therapy is insufficient, the next step (sometimes even before use of excessively high doses of antihistamines) is to add first generation, even more sedating antihistamines, some of which have additional modes of action (e.g. anticholinergic effects in doxepin treatment). A considerable number of patients with CU need treatment escalations with leukotriene receptor blocking agents (e.g. montelukast), systemic corticosteroids (5-20mg prednisolon/d) or even cyclosporine (daily dose 3-5 mg/kg) or other immunosuppressive drugs used off-label. Such patients are often investigated more in detail to find an infection or autoimmune disease - often still without clear results.

Different clinical findings suggest that the mast cell system in many patients with CU is "overactive" with increased releasability. Minor stress like scratching can already induce degranulation resulting in wheal-and-flare skin reactions. Therefore, a therapy directly aiming at a decrease in this mast cell "hyperreleasability" would be optimal. Omalizumab binds selectively to free IgE in plasma, inhibits its binding to Fc-IgE receptor on the surface of mast cells and basophils and reduces the number of Fc-IgE receptors on basophils in atopic patients. Significant reduction of Fc-IgE receptor density on the surface of circulating basophils has been found as early as 1 week after administration of omalizumab. In contrast to this, the onset of clinical efficacy of omalizumab in asthma is considered to take place relatively late, namely about 4 months after start of treatment. The pathophysiologic concepts of omalizumab treatment in allergic asthma are focused on the neutralisation of IgE, and less on the Fc-IgE receptor density. In allergology, free IgE in plasma is only relevant regarding Fc-IgE receptor density on effector cells. Therefore, Fc-IgE receptor density measurement might be an important parameter for mast cell and basophil "releasability" and therefore a good in vitro surrogate marker for their reactivity. E.g. it is well known that only about 50% of IgE-sensitized individuals show clinically relevant allergic symptoms. This difference between sensitization and allergy may also be due to Fc-IgE receptor density on mast cells and basophils. Flowcytometric determination of Fc-IgE receptor density on the surface of basophils and additional testing for the functional consequences of a change in this density (ability to crosslink Fc-IgE receptors by autoantibodies and allergens) raise the possibility to evaluate this hypothesis - using omalizumab as a drug being able to decrease Fc-IgE receptor density:

1. Study data show that a fixed dose of 300 mg omalizumab is useful for the treatment of CU. The investigators assume that this effect is due to the decrease of Fc-IgE receptor density. Thus, the basophil Fc-IgE receptor density should be monitored quantitatively and functionally (see below) and correlated to clinical response.
2. 30-40% of patients with CU have autoantibodies against Fc-IgE receptor or IgE itself, which can be measured in vitro (already via ELISA, flowcytometric via CD63 and CD203c upregulation on basophils). Decrease of Fc-IgE receptor density may decrease basophil reactivity and explain or be correlated to the clinical response in CU patients. At least three patients will be followed for reactivity to autoantibodies over the study period.
3. Some patients with CU may also have an accompanying IgE-mediated allergy, which is most probably irrelevant for the CU, but offers the possibility of a functional test of basophil responsiveness to low concentrations of allergens - before (with presumably high Fc-IgE receptor density) and after omalizumab treatment (low Fc-IgE rec. density). At least three patients will be followed for allergen reactivity of basophils.

Objective