Mukherjee Manali, Forero David Felipe, Tran Stephanie, Boulay Marie-Eve, Bertrand Mylène, Bhalla Anurag, Cherukat Jayant, Al-Hayyan Hajar, Ayoub Anmar, Revill Spencer D, Javkar Tanvi, Radford Katherine, Kjarsgaard Melanie, Huang Chynna, Dvorkin-Gheva Anna, Ask Kjetil, Olivenstein Ronald, Dendukuri Nandini, Lemiere Catherine, Boulet Louis-Philippe, Martin James G, Nair Parameswaran
Dept of Medicine, Division of Respirology, McMaster University, Hamilton, ON, Canada.
Firestone Institute for Respiratory Health, St Joseph's Healthcare, Hamilton, ON, Canada.
Eur Respir J. 2020 Oct 8;56(4). doi: 10.1183/13993003.00117-2020. Print 2020 Oct.
In clinical trials, the two anti-interleukin (IL)-5 monoclonal antibodies (mAbs: mepolizumab and reslizumab) approved to treat severe eosinophilic asthma reduce exacerbations by ∼50-60%.
To observe response to anti-IL-5 mAbs in a real-life clinical setting, and to evaluate predictors of suboptimal response.
In four Canadian academic centres, predefined clinical end-points in 250 carefully characterised moderate-to-severe asthmatic patients were collected prospectively to assess response to the two anti-IL-5 mAbs. Suboptimal response was determined based on failure to reduce maintenance corticosteroid (MCS) or asthma symptoms scores (Asthma Control Questionnaire (ACQ)) or exacerbations, in addition to persistence of sputum/blood eosinophils. Worsening in suboptimal responders was assessed based on reduced lung function by 25% or increase in MCS/ACQ. A representative subset of 39 patients was 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.
Suboptimal responses were observed in 42.8% (107 out of 250) patients treated with either mepolizumab or reslizumab. Daily prednisone requirement, sinus disease and late-onset asthma diagnoses were the strongest predictors of suboptimal response. Asthma worsened in 13.6% (34 out of 250) of these patients. The majority (79%) of them were prednisone-dependent. Presence of sputum anti-eosinophil peroxidase immunoglobulin (Ig)G was a predictor of suboptimal 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.
A significant number of patients who meet currently approved indications for anti-IL5 mAbs show suboptimal response to them in real-life clinical practice, particularly if they are on high doses of prednisone. 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.
在临床试验中，两种被批准用于治疗重度嗜酸性粒细胞性哮喘的抗白细胞介素（IL）-5单克隆抗体（mAb：美泊利单抗和瑞利珠单抗）可使病情加重次数减少约50 - 60%。
观察在实际临床环境中对抗IL-5 mAb的反应，并评估反应欠佳的预测因素。
在加拿大的四个学术中心，前瞻性收集了250例特征明确的中重度哮喘患者的预定义临床终点指标，以评估对这两种抗IL-5 mAb的反应。除痰液/血液嗜酸性粒细胞持续存在外，若未能降低维持性皮质类固醇（MCS）或哮喘症状评分（哮喘控制问卷（ACQ））或病情加重次数，则判定为反应欠佳。根据肺功能下降25%或MCS/ACQ升高来评估反应欠佳者的病情恶化情况。对39例患者的代表性亚组进行了痰液中炎症介质、自身抗体和补体激活情况（通过酶联免疫吸附测定（ELISA））的评估，以及通过对福尔马林固定石蜡包埋的痰液栓子进行免疫染色来评估免疫复合物沉积情况。
接受美泊利单抗或瑞利珠单抗治疗的患者中，42.8%（250例中的107例）出现反应欠佳。每日泼尼松需求量、鼻窦疾病和迟发性哮喘诊断是反应欠佳的最强预测因素。这些患者中有13.6%（250例中的34例）哮喘病情恶化。其中大多数（79%）依赖泼尼松。痰液中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 mAb反应欠佳的一个预测因素。在治疗中病情恶化的患者痰液中观察到痰液C3c升高（补体激活标志物）以及C1q结合/IL-5结合IgG的沉积，提示存在潜在的自身免疫介导的病理过程。
在实际临床实践中，大量符合目前抗IL-5 mAb批准适应证的患者对其反应欠佳，尤其是那些正在使用高剂量泼尼松的患者。监测血液嗜酸性粒细胞计数对识别这些患者并无帮助。一小部分此类患者中与免疫复合物介导的补体激活相关的症状恶化问题凸显了识别气道自身免疫现象的重要性，这需要进一步评估。
