Wechsler M E, Pauwels R, Drazen J M
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Drug Saf. 1999 Oct;21(4):241-51. doi: 10.2165/00002018-199921040-00001.
Zafirlukast, montelukast and pranlukast are all cysteinyl leukotriene receptor antagonists that have recently been approved for the treatment of asthma. Within 6 months of zafirlukast being made available on the market, 8 patients who received the agent for moderate to severe asthma developed eosinophilia, pulmonary infiltrates, cardiomyopathy and other signs of vasculitis; the syndrome that these patients developed was characteristic of the Churg-Strauss syndrome. All of the patients had discontinued systemic corticosteroid use within 3 months of presentation and all developed the syndrome within 4 months of zafirlukast initiation. The syndrome dramatically improved in each patient upon reinitiation of corticosteroid therapy. Since the initial report, there have been multiple similar cases reported to the relevant pharmaceutical companies and to federal drug regulatory agencies in association with zafirlukast as well as with pranlukast, montelukast, and with use of high doses of inhaled corticosteroids, thus leading to an increased incidence rate of the Churg-Strauss syndrome. Many potential mechanisms for the association between these drugs and the Churg-Strauss syndrome have been postulated including: increased syndrome reporting due to bias; potential for allergic drug reaction; and leukotriene imbalance resulting from leukotriene receptor blockade. However, careful analysis of all reported cases suggests that the Churg-Strauss syndrome develops primarily in those patients taking these asthma medications who had an underlying eosinophilic disorder that was being masked by corticosteroid treatment and unmasked by novel asthma medication-mediated corticosteroid withdrawal, similar to the forme fruste of the Churg-Strauss syndrome. It remains unclear what the exact mechanism for this syndrome is and whether this represents an absolute increase in cases of vasculitis, but it appears that none of the asthma medications implicated in leading to the development of Churg-Strauss syndrome was directly causative of the syndrome. These agents remain well tolerated and effective medications for the treatment of asthma, although physicians must be wary for the signs and symptoms of the Churg-Strauss syndrome, particularly in patients with moderate to severe asthma in whom corticosteroids are tapered.
扎鲁司特、孟鲁司特和普仑司特均为半胱氨酰白三烯受体拮抗剂，最近已被批准用于治疗哮喘。在扎鲁司特上市后的6个月内，8名接受该药物治疗中度至重度哮喘的患者出现了嗜酸性粒细胞增多、肺部浸润、心肌病及其他血管炎体征；这些患者所患的综合征具有变应性肉芽肿性血管炎综合征的特征。所有患者在就诊前3个月内均已停用全身性皮质类固醇，且均在开始使用扎鲁司特后的4个月内出现该综合征。在重新开始皮质类固醇治疗后，每位患者的综合征均显著改善。自最初报告以来，已有多起类似病例报告给相关制药公司及联邦药品监管机构，这些病例与扎鲁司特以及普仑司特、孟鲁司特有关，也与高剂量吸入性皮质类固醇的使用有关，从而导致变应性肉芽肿性血管炎综合征的发病率上升。关于这些药物与变应性肉芽肿性血管炎综合征之间关联的许多潜在机制已被提出，包括：因偏倚导致综合征报告增加；药物过敏反应的可能性；以及白三烯受体阻断导致的白三烯失衡。然而，对所有报告病例的仔细分析表明，变应性肉芽肿性血管炎综合征主要发生在那些服用这些哮喘药物的患者中，这些患者存在潜在的嗜酸性粒细胞疾病，此前被皮质类固醇治疗所掩盖，而因新型哮喘药物介导的皮质类固醇撤药而被暴露出来，类似于变应性肉芽肿性血管炎综合征的顿挫型。目前尚不清楚该综合征的确切机制是什么，以及这是否代表血管炎病例的绝对增加，但似乎没有一种与变应性肉芽肿性血管炎综合征发生相关的哮喘药物是该综合征的直接病因。这些药物仍然是耐受性良好且有效的哮喘治疗药物，尽管医生必须警惕变应性肉芽肿性血管炎综合征的体征和症状，尤其是在中度至重度哮喘患者中，这些患者的皮质类固醇正在逐渐减量。
