A critical appraisal of omalizumab as a therapeutic option for chronic refractory urticaria/angioedema.

Despite advances that have been made in our understanding of chronic urticaria/angioedema (CUA), many patients with CUA continue to experience poor control of their disease and severe impairment in their quality of life.1,2 More than half of patients may not achieve satisfactory control of CUA with antihistamine treatment.1,3 Urticaria and pruritus are promoted primarily by the action of histamine on H1 receptors located on endothelial cells (wheal) and on sensory nerves (flare); however, CUA is characterized by a nonnecrotizing perivascular infiltrate of CD4þ lymphocytes, monocytes, neutrophils, eosinophils, and basophils that can be recalcitrant to antihistamine therapydevenwhen advanced to high doses.1 Patients with CUA who do not respond to combination antihistamine therapy, with or without an antileukotriene, including dose advancement of a potent antihistamine (eg, doxepin at a dose of 75-125 mg/d) as tolerated, are considered to have antihistamine-resistant or refractory CUA.4 A number of therapeutic agents have been reported to be efficacious in patients with refractory CUA in case reports or case series.5,6 However, such studies may be subject to bias and do not provide high-quality evidence.7 Randomized controlled trials tend to be rated as high-quality evidence; however, the quality of evidence may be lowered based onmethodologic issues and other factors.8 Of the 4 agents for which randomized controlled trials in patients with refractory CUA have been reported (hydroxychloroquine,9 stanozolol,10 cyclosporine,11,12 and omalizumab13e16), cyclosporine and omalizumab are the only agents for which more than one randomized controlled trial has been published. In the 2014 update of the Urticaria/Angioedema Practice Parameter,4 a critical appraisal of the literature supporting the therapeutic utility of cyclosporine judged this evidence to be of low quality based on a number of methodologic shortcomings, leading to a weak recommendation for use of cyclosporine for refractory CUA. The weak recommendation does not imply that cyclosporine may not be of benefit in properly selected patients with refractory CUA or that it should not be prescribed. The weak recommendation signifies the need for clinicians to carefully consider whether administration of cyclosporine is favorable from the standpoint of balancing the potential for benefit with the potential for harm and discuss this with patients to determine that the decision to proceed with a trial of cyclosporine is consistent with their values and preferences. Omalizumab is a recombinant humanized monoclonal antibody approved by the US Food and Drug Administration (FDA) in 2003. It is the first monoclonal antibody approved for patients with allergic disorders. Omalizumab interrupts the allergic response at its primary step: the binding of allergen-specific IgE to mast cells.17 Its mechanism of action for asthma is thought to entail reduction of free IgE combined with down-regulation of expression of the high-affinity IgE receptor on basophils and mast cells.17 Salutary response to omalizumab in patients with refractory asthma has exhibited a gradual pattern of onset: 38% responding in 4 weeks and 62% after 16 weeks.18,19 This Clinical Perspective is intended to critically appraise the published evidence on omalizumab as a therapeutic intervention for patients with refractory CUA.