Effects of an Oral CRTh2 Antagonist (AZD1981) on Eosinophil Activity and Symptoms in Chronic Spontaneous Urticaria.

BACKGROUND: Approximately 50% of patients with chronic spontaneous urticaria (CSU) experience symptoms that are not fully controlled by antihistamines, indicating an unmet clinical need. OBJECTIVE: To evaluate the effects of the selective CRTh2 antagonist AZD1981 on symptoms and targeted leukocytes in adults with persistent CSU despite treatment with H1-antihistamines. METHODS: We performed a single-center, randomized, placebo-controlled study involving adult CSU subjects with symptoms despite daily antihistamines. The subjects underwent a 2-week placebo run-in and 4 weeks of double-blinded therapy with either AZD1981 40 mg TID or placebo, followed by a 2-week placebo washout. The primary objective was to assess the effect of AZD1981 on CSU signs and symptoms. Secondary objectives included the effects of AZD1981 on prostaglandin D2 (PGD2)-induced eosinophil shape change, circulating leukocyte subsets, CRTh2 expression on blood leukocytes, and total blood leukocyte histamine content. RESULTS: Twenty-eight subjects were randomized to AZD1981 or placebo, with 26 subjects completing the study. The urticaria activity scores declined during the treatment phase in both groups, and they were significantly reduced in the AZD1981 group at the end of washout. AZD1981 treatment increased circulating eosinophils and significantly impaired PGD2-mediated eosinophil shape change. CRTh2 surface expression rose significantly on blood basophils during active treatment. No serious adverse events were observed. CONCLUSIONS: This is the first study to examine the efficacy of a CRTh2 antagonist in antihistamine-refractory CSU. AZD1981 treatment was well tolerated, effectively inhibited PGD2-mediated eosinophil shape change, shifted numbers of circulating eosinophils, and reduced weekly itch scores more than hives during treatment and into washout. Further studies are needed to determine whether inhibition of the PGD2/CRTh2 pathway will be an -effective treatment for CSU.

Chronic Idiopathic Urticaria: Systemic Complaints and Their Relationship with Disease and Immune Measures.

BACKGROUND: Patients with chronic idiopathic urticaria (CIU)/chronic spontaneous urticaria sometimes report systemic complaints (SCs). OBJECTIVE: We sought to determine the frequency and characteristics of SCs among patients with CIU, as well as the association of SCs with disease measures, basophil histamine release, and serum tryptase. METHODS: Adult patients with CIU were recruited from a university allergy clinic. Patients completed a disease symptom survey and underwent blood sampling for subsequent basophil histamine release and serum tryptase measurement. RESULTS: A total of 155 patients with CIU were surveyed, with 103 reporting SCs with concomitant hives as follows: joint pain or swelling (55.3%), headache/fatigue (47.6%), flushing (42.7%), wheezing (30.1%), gastrointestinal complaints (26.2%), and palpitations (9.7%). Patients with SCs (CIU-SC) were compared with those with no SCs (CIU-NSC). Both groups had similar demographic characteristics (average age in 40s, majority female and white) and basophil histamine release profiles. CIU-SC had significantly greater disease duration (51.5% CIU-SC vs 30.8% CIU-NSC had >4 years duration), emergency department visits (41.7% vs 23.1% had >1 visit in the last year), CIU-related work absences (65% vs 27.5% had >1 day), oral corticosteroid use (84.5% vs 59.6%), quality-of-life impairment (76.1 vs 59.2 SkinDex score), and serum tryptase levels (5.1 ng/mL vs 3.9 ng/mL). CONCLUSIONS: Despite similar demographic characteristics and basophil profiles as patients with CIU-NSC, patients with CIU-SC have features of greater disease burden (work absences, emergency department visits, and corticosteroid use), quality-of-life impairment, and baseline serum tryptase levels.