Chronic urticaria is a distressing disease that affects up to 1 % of the general population at a time point in life and may severely worsen the quality of life. First-line treatment has been based on antihistamines, and presently relies on the use of non-sedating, second-generation antihistamines; following the recommendations of the recent international guidelines, in patients who do not respond to antihistamines at licensed doses, the daily dosage of these drugs can be increased up to fourfold. Nonetheless, a significant proportion of patients with chronic urticaria remain poorly controlled; in these cases, alternative therapeutic approaches have to be considered. This article critically reviews all of the third- and fourth-line treatment options suggested for patients whose disease is refractory to antihistamines, including systemic corticosteroids, leukotriene receptor antagonists, several different anti-inflammatory drugs (dapsone, sulfasalazine, hydroxychloroquine), various immunosuppressive drugs (calcineurin inhibitors, methotrexate, cyclophosphamide, azathioprine, mycophenolate mofetil), intravenous immunoglobulin, and newer treatment options, such as omalizumab and other biologic drugs. In addition, the article examines possible future treatment options based on recent findings about pathogenic mechanisms, and considers the treatment of antihistamine- unresponsive urticaria in special conditions such as children and pregnancy/lactation. The evidence supporting the use of several of the discussed drugs is presently limited and thus insufficient to recommend their routine use; as a consequence, such compounds should be considered only in specific cases and in adequate settings.
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