Urticaria and angioedema lasting more than 6 weeks have been designated as chronic urticaria (CU). It encompasses two major subtypes: chronic spontaneous urticaria (CSU) (previously known as chronic idiopathic urticaria) (CIU) and chronic inducible urticaria. CSU has been defined as wheals and/or angioedema that are endogenous and independent of any external physical stimulus. It affects 0.5 to 1% of the population [1]. In 40 to 45% of patients with CSU autoantibodies to the high affinity IgE receptor (FcϵRI) or to IgE itself are thought to play a psathogenic role, whereas 55 to 60% of cases are considered idiopathic [2]. Inducible urticarias include all forms of physical urticarias (cold-induced, heat-induced, solar, and pressure urticaria).
According to the International Guidelines for the management of urticaria and angioedema non-sedating, second generation antihistamines (NSAHs) are recommended for the treatment of CU [3]. Nevertheless, a considerable proportion of patients do not respond sufficiently to NSAHs. According to Humphreys and Hunter up to 40% of patients with CU may not achieve good control with antihistaminic therapy [4]. They reported that out of 390 CU patients who were treated with antihistamines 44% responded well, 29% became asymptomatic, and 15% showed partial improvement. In a recent paper from Japan it was observed that the improvement rates (defined as a urticaria symptom score UAS ≤ 3) in 117 CU patients who received standard doses of AHs were 36.6% at 12 months, 51.2% at 24 months, and 66.1% at 60 months, while the remission rates were 11.5%, 13.9%, and 27.7%, respectively [5].
In patients that do not respond to standard doses, the next step in guideline-based therapy is to increase AH doses up to 4 times [3]. Investigations assessing the response to various NSAHs have demonstrated that up-dosing is significantly more effective in reducing symptoms of CU than standard-dose treatment [6]. According to Kaplan, high-dose antihistamines are effective in 45-60% of patients with CSU [7], while about one third are antihistamine resistant regardless of which dose is used [8, 9].
The present article is a review of the literature on the treatment of CU with increased doses of NSAHs in order to investigate if there are differences in efficacy between the various second generation AHs that have been studied in controlled protocols. It must be noticed, however, that it is difficult to find clinical investigations that strictly follow the criteria recommended by the guidelines on the management of urticaria, and therefore studies included in this review were those in which higher doses of NSAHs were used regardless of the clinical response to conventional doses.
AHs included in this review are desloratadine, levocetirizine, fexofenadine, and the recently introduced NSAHs rupatadine and bilastine. Bilastine belongs to the piperidine class of antihistamines as do loratadine, desloratadine, and fexofenadine. Like other antihistamines bilastine is an H1 receptor inverse agonist. In vitro studies have shown that bilastine has a high specific affinity for the H1-receptor but it has no or very low affinity for 30 other tested receptors. The affinity for the H1 receptor is 3 and 6 times higher than for cetirizine and fexofenadine, respectively [10, 11]. Rupatadine fumarate is a new potent, long acting, orally active dual antagonist of both histamine H1 and Platelet-Activating Factor (PAF) receptors. In in vivo and in vitro studies rupatadine was as potent or even more potent than other second generation antihistamines (loratadine, terfenadine and cetirizine) or selective PAF antagonists [12].
