伴气道自身免疫的严重嗜酸性哮喘患者对抗IL-5单克隆抗体疗效欠佳
2020/06/11
摘要
背景：在临床试验中，两种抗IL-5单克隆抗体（mAb，mepolizumab和reslizumab）已被批准用于治疗严重嗜酸性粒细胞性哮喘，可将病情加重减少约50-60％。
目的：在真实的临床环境中观察对抗IL-5 单克隆抗体的反应，并评估疗效欠佳的预测因子。
方法：在加拿大的四个学术中心中，前瞻性收集250个中重度哮喘患者的预定义临床终点来评估对两种抗IL-5单克隆抗体的反应。 除了持续存在痰/血嗜酸性粒细胞外，还根据未能降低维持性皮质类固醇（MCS）或哮喘症状评分（ACQ）或急性发作而确定疗效欠佳。根据肺功能降低25％或MCS / ACQ升高评估疗效欠佳者的病情恶化。通过ELISA评估代表性亚集39例患者的的痰中炎症介质、自身抗体和补体激活情况，通过福尔马林固定石蜡包埋的痰栓免疫染色评估免疫复合物沉积情况。
结果：Mepolizumab/reslizumab治疗的患者中，42.8％（107/250）观察到疗效欠佳。每日泼尼松需求量、鼻窦疾病和迟发性哮喘是疗效欠佳的最强预测因子。这些患者中有13％（34/250）的患者出现病情恶化。其中大多数（79％）依赖于泼尼松。痰中的抗嗜酸性粒细胞过氧化物酶免疫球蛋白（Ig）G的存在是对抗IL-5单抗反应欠佳的预测指标。在治疗恶化的患者的痰中观察到痰中C3c（补体激活标记）的增加和与C1q结合/ IL-5结合的IgG沉积，提示潜在的自身免疫介导的病理学。
结论：在真实临床实践中，满足当前批准的抗IL5 单克隆抗体适应症的大量患者显示出疗效欠佳。监测血液嗜酸性粒细胞计数无助于识别这些患者。这些患者中有一小部分出现与免疫复合物介导的补体激活相关的症状恶化强调认识气道自身免疫现象的相关性，这需要进一步评估。
Sub-optimal Treatment Response to anti-IL-5 Monoclonal Antibodies in Severe Eosinophilic Asthmatics With Airway Autoimmune Phenomena.
Manali Mukherjee, David Felipe Forero, Stephanie Tran, Marie-Eve Boulay, Mylène Bertrand, Anurag Bhalla, Jayant Cherukat, Hajar Al-Hayyan, Anmar Ayoub, Spencer D Revill, Tanvi Javkar, Katherine Radford, Melanie Kjarsgaard, Chynna Huang, Anna Dvorkin-Gheva, Kjetil Ask, Ronald Olivenstein, Nandini Dendukuri, Catherine Lemiere, Louis-Philippe Boulet, James G Martin, Parameswaran Nair.
Abstract
BACKGROUND:In clinical trials, the two anti-IL-5 monoclonal antibodies (mAbs, mepolizumab and reslizumab) that are approved to treat severe eosinophilic asthma, reduce exacerbations by approximately 50-60%.
OBJECTIVE:To observe response to anti-IL-5 mAbs in real-life clinical setting, and to evaluate predictors of sub-optimal response.
METHODS:In four Canadian academic centres, pre-defined clinical end-points in 250 carefully characterised moderate-to-severe asthmatics were collected prospectively to assess response to the two anti-IL-5 mAbs. Sub-optimal responses was determined based on failure to reduce maintenance corticosteroid (MCS) or asthma symptoms scores (ACQ) or exacerbations, in addition to persistence of sputum/blood eosinophils. Worsening in suboptimal responders were assessed based on reduced lung function by 25% or any increase in MCS/ACQ. A representative sub-set of 39 patients were evaluated for inflammatory mediators, autoantibodies and complement activation in sputum (by ELISA) and for immune-complex deposition by immunostaining formalin-fixed paraffin-embedded sputum plugs.
RESULTS:Sub-optimal responses were observed in 42.8% (107/250) patients treated with either mepolizumab/reslizumab. Daily prednisone requirement, sinus disease, and late-onset asthma diagnoses were the strongest predictors of sub-optimal response. Asthma worsened in 13% (34/250) of these patients. Majority (79%) of them were prednisone-dependent. Presence of sputum anti-eosinophil peroxidase immunoglobulin (Ig)G was a predictor of sub-optimal response to an anti-IL-5 mAb. An increase in sputum C3c (marker of complement activation) and deposition of C1q-bound/IL-5-bound IgG were observed in the sputa of those patients who worsened on therapy, suggesting an underlying autoimmune-mediated pathology.
CONCLUSIONS:A significant number of patients who meet currently approved indications for anti-IL5 mAbs show sub-optimal response to them in real-life clinical practice. Monitoring blood eosinophil count is not helpful to identify these patients. The concern of worsening of symptoms associated with immune-complex mediated complement-activation in a small proportion of these patients highlights the relevance of recognising airway autoimmune phenomena and this requires further evaluation.
背景：在临床试验中，两种抗IL-5单克隆抗体（mAb，mepolizumab和reslizumab）已被批准用于治疗严重嗜酸性粒细胞性哮喘，可将病情加重减少约50-60％。
目的：在真实的临床环境中观察对抗IL-5 单克隆抗体的反应，并评估疗效欠佳的预测因子。
方法：在加拿大的四个学术中心中，前瞻性收集250个中重度哮喘患者的预定义临床终点来评估对两种抗IL-5单克隆抗体的反应。 除了持续存在痰/血嗜酸性粒细胞外，还根据未能降低维持性皮质类固醇（MCS）或哮喘症状评分（ACQ）或急性发作而确定疗效欠佳。根据肺功能降低25％或MCS / ACQ升高评估疗效欠佳者的病情恶化。通过ELISA评估代表性亚集39例患者的的痰中炎症介质、自身抗体和补体激活情况，通过福尔马林固定石蜡包埋的痰栓免疫染色评估免疫复合物沉积情况。
结果：Mepolizumab/reslizumab治疗的患者中，42.8％（107/250）观察到疗效欠佳。每日泼尼松需求量、鼻窦疾病和迟发性哮喘是疗效欠佳的最强预测因子。这些患者中有13％（34/250）的患者出现病情恶化。其中大多数（79％）依赖于泼尼松。痰中的抗嗜酸性粒细胞过氧化物酶免疫球蛋白（Ig）G的存在是对抗IL-5单抗反应欠佳的预测指标。在治疗恶化的患者的痰中观察到痰中C3c（补体激活标记）的增加和与C1q结合/ IL-5结合的IgG沉积，提示潜在的自身免疫介导的病理学。
结论：在真实临床实践中，满足当前批准的抗IL5 单克隆抗体适应症的大量患者显示出疗效欠佳。监测血液嗜酸性粒细胞计数无助于识别这些患者。这些患者中有一小部分出现与免疫复合物介导的补体激活相关的症状恶化强调认识气道自身免疫现象的相关性，这需要进一步评估。
(中日友好医院呼吸与危重症医学科 王瑞茵 摘译 林江涛 审校)
(Eur Respir J. 2020 May 22; 2000117.)
(Eur Respir J. 2020 May 22; 2000117.)
Sub-optimal Treatment Response to anti-IL-5 Monoclonal Antibodies in Severe Eosinophilic Asthmatics With Airway Autoimmune Phenomena.
Manali Mukherjee, David Felipe Forero, Stephanie Tran, Marie-Eve Boulay, Mylène Bertrand, Anurag Bhalla, Jayant Cherukat, Hajar Al-Hayyan, Anmar Ayoub, Spencer D Revill, Tanvi Javkar, Katherine Radford, Melanie Kjarsgaard, Chynna Huang, Anna Dvorkin-Gheva, Kjetil Ask, Ronald Olivenstein, Nandini Dendukuri, Catherine Lemiere, Louis-Philippe Boulet, James G Martin, Parameswaran Nair.
Abstract
BACKGROUND:In clinical trials, the two anti-IL-5 monoclonal antibodies (mAbs, mepolizumab and reslizumab) that are approved to treat severe eosinophilic asthma, reduce exacerbations by approximately 50-60%.
OBJECTIVE:To observe response to anti-IL-5 mAbs in real-life clinical setting, and to evaluate predictors of sub-optimal response.
METHODS:In four Canadian academic centres, pre-defined clinical end-points in 250 carefully characterised moderate-to-severe asthmatics were collected prospectively to assess response to the two anti-IL-5 mAbs. Sub-optimal responses was determined based on failure to reduce maintenance corticosteroid (MCS) or asthma symptoms scores (ACQ) or exacerbations, in addition to persistence of sputum/blood eosinophils. Worsening in suboptimal responders were assessed based on reduced lung function by 25% or any increase in MCS/ACQ. A representative sub-set of 39 patients were evaluated for inflammatory mediators, autoantibodies and complement activation in sputum (by ELISA) and for immune-complex deposition by immunostaining formalin-fixed paraffin-embedded sputum plugs.
RESULTS:Sub-optimal responses were observed in 42.8% (107/250) patients treated with either mepolizumab/reslizumab. Daily prednisone requirement, sinus disease, and late-onset asthma diagnoses were the strongest predictors of sub-optimal response. Asthma worsened in 13% (34/250) of these patients. Majority (79%) of them were prednisone-dependent. Presence of sputum anti-eosinophil peroxidase immunoglobulin (Ig)G was a predictor of sub-optimal response to an anti-IL-5 mAb. An increase in sputum C3c (marker of complement activation) and deposition of C1q-bound/IL-5-bound IgG were observed in the sputa of those patients who worsened on therapy, suggesting an underlying autoimmune-mediated pathology.
CONCLUSIONS:A significant number of patients who meet currently approved indications for anti-IL5 mAbs show sub-optimal response to them in real-life clinical practice. Monitoring blood eosinophil count is not helpful to identify these patients. The concern of worsening of symptoms associated with immune-complex mediated complement-activation in a small proportion of these patients highlights the relevance of recognising airway autoimmune phenomena and this requires further evaluation.
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