Author's personal copy REVIEW ARTICLE Treatment of Refractory Chronic Urticaria: Current and Future Therapeutic Options Riccardo Asero • Alberto Tedeschi • Massimo Cugno Published online: 2 October 2013 Ó Springer International Publishing Switzerland 2013 Abstract 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-gener- ation 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 corti- costeroids, leukotriene receptor antagonists, several dif- ferent anti-inflammatory drugs (dapsone, sulfasalazine, hydroxychloroquine), various immunosuppressive drugs (calcineurin inhibitors, methotrexate, cyclophosphamide, azathioprine, mycophenolate mofetil), intravenous immu- noglobulin, and newer treatment options, such as oma- lizumab 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 recom- mend their routine use; as a consequence, such compounds should be considered only in specific cases and in adequate settings. 1 Introduction Chronic urticaria (CU), a skin disorder characterized by the continuous or intermittent eruption of short-lived wheals, which can be associated with angioedema, for more than 6 weeks [1], may heavily impair the quality of life [2, 3]. Second-generation H 1- antihistamines, either at the licensed dosage or at higher than the licensed dosage, represent unquestionably the mainstay of CU treatment and are able to control the disease in the majority of patients. However, a significant pro- portion of patients with CU remain poorly controlled despite treatment with elevated doses of second-gener- ation H 1 -antihistamines. These subjects often represent a severe challenge for the clinician. This article critically reviews the available treatments for antihistamine- resistant patients with CU, providing some information about the quality of evidence and the strength of rec- ommendation (Table 1)[4]. The rationale for the use of most immunomodulatory and anti-inflammatory drugs that are reviewed comes from the detection of hista- mine-releasing autoantibodies [5–7], as well as from the demonstration of an increase in inflammation and coagulation biomarkers [8–10]. These treatments have R. Asero (&) Ambulatorio di Allergologia, Clinica San Carlo, Paderno Dugnano, Milan, Italy e-mail: r.asero@libero.it A. Tedeschi U.O. Allergologia e Immunologia Clinica, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy M. Cugno Medicina Interna, Dipartimento di Fisiopatologia Medico- Chirurgica e dei Trapianti, Universita ` degli Studi di Milano, IRCCS Fondazione Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy Am J Clin Dermatol (2013) 14:481–488 DOI 10.1007/s40257-013-0047-3