口服CRTh2拮抗剂（AZD1981）对慢性自发性荨麻疹患者嗜酸性粒细胞活性及症状的影响
Effects of an Oral CRTh2 Antagonist (AZD1981) on Eosinophil Activity and Symptoms in Chronic Spontaneous Urticaria.
作者信息
Oliver Eric Tyrell, Chichester Kris, Devine Kelly, Sterba Patricia Meghan, Wegner Craig, Vonakis Becky Marie, Saini Sarbjit Singh
机构信息
Division of Allergy and Clinical Immunology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA,
Division of Allergy and Clinical Immunology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
出版信息
Int Arch Allergy Immunol. 2019;179(1):21-30. doi: 10.1159/000496162. Epub 2019 Mar 15.
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.
背景
约50%的慢性自发性荨麻疹（CSU）患者的症状无法通过抗组胺药得到充分控制，这表明存在未满足的临床需求。
目的
评估选择性CRTh2拮抗剂AZD1981对尽管接受H1抗组胺药治疗但仍患有持续性CSU的成年人的症状和靶向白细胞的影响。
方法
我们进行了一项单中心、随机、安慰剂对照研究，纳入了尽管每日服用抗组胺药仍有症状的成年CSU受试者。受试者先进行了为期2周的安慰剂导入期，然后接受4周的双盲治疗，分别给予40 mg tid的AZD1981或安慰剂，随后是为期2周的安慰剂洗脱期。主要目的是评估AZD1981对CSU体征和症状的影响。次要目的包括AZD1981对前列腺素D2（PGD2）诱导的嗜酸性粒细胞形态变化、循环白细胞亚群、血液白细胞上CRTh2表达以及全血白细胞组胺含量的影响。
结果
28名受试者被随机分为AZD1981组或安慰剂组，26名受试者完成了研究。两组在治疗阶段荨麻疹活动评分均下降，在洗脱期末AZD1981组显著降低。AZD1981治疗增加了循环嗜酸性粒细胞，并显著损害了PGD2介导的嗜酸性粒细胞形态变化。在积极治疗期间，血液嗜碱性粒细胞表面的CRTh2表达显著升高。未观察到严重不良事件。
结论
这是第一项研究CRTh2拮抗剂在抗组胺药难治性CSU中的疗效的研究。AZD1981治疗耐受性良好，有效抑制了PGD2介导的嗜酸性粒细胞形态变化，改变了循环嗜酸性粒细胞数量，并且在治疗期间和洗脱期降低每周瘙痒评分的效果优于降低荨麻疹评分。需要进一步研究以确定抑制PGD2/CRTh2途径是否将是CSU的有效治疗方法。
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