Lancaster Medical Practice, Lancaster, UK.
Nottingham Business School, Nottingham Trent University, Nottingham, UK.
Cochrane Database Syst Rev. 2021 Oct 19;10(10):CD012929. doi: 10.1002/14651858.CD012929.pub2.
Targeting the immunoglobulin E pathway and the interleukin-5 pathway with specific monoclonal antibodies directed against the cytokines or their receptors is effective in patients with severe asthma. However, there are patients who have suboptimal responses to these biologics. Since interleukin-4 and interleukin-13, signalling through the interleukin-4 receptor, have multiple effects on the biology of asthma, therapies targeting interleukin-4 and -13 (both individually and combined) have been developed.
To assess the efficacy and safety of anti-interleukin-13 or anti-interleukin-4 agents, compared with placebo, anti-immunoglobulin E agents, or anti-interleukin-5 agents, for the treatment of children, adolescents, or adults with asthma.
We identified studies from the Cochrane Airways Trials Register, which is maintained by the Information Specialist for the Group and through searches of the US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform. The search was carried out on the 16 October 2020.
We included parallel-group randomised controlled trials that compared anti-interleukin-13 or -4 agents (or agents that target both interleukin-13 and interleukin-4) with placebo in adolescents and adults (aged 16 years or older) or children (younger than 16 years), with a diagnosis of asthma; participants could receive their usual short- or long-acting medications (e.g. inhaled corticosteroids (ICS), long-acting beta adrenoceptor agonists (LABA), long-acting muscarinic antagonists (LAMA), and/or leukotriene receptor antagonists) provided that they were not part of the randomised treatment.
We used standard methods expected by Cochrane.
We identified and included 41 RCTs. Of these, 29 studies contributed data to the quantitative analyses, randomly assigning 10,604 people with asthma to receive an anti-interleukin-13 (intervention) or anti-interleukin-4 agent (intervention), or placebo (comparator). No relevant studies were identified where the comparator was an anti-immunoglobulin agent or an anti-interleukin-5 agent. Studies had a duration of between 2 and 52 (median 16) weeks. The mean age of participants across the included studies ranged from 22 to 55 years. Only five studies permitted enrolment of children and adolescents, accounting for less than 5% of the total participants contributing data to the present review. The majority of participants had moderate or severe uncontrolled asthma. Concomitant ICS use was permitted or required in the majority (21 of 29) of the included studies. The use of maintenance systemic corticosteroids was not permitted in 19 studies and was permitted or required in five studies (information not reported in five studies). Regarding the most commonly assessed anti-interleukin-13/-4 agents, four studies evaluated dupilumab (300 mg once every week (Q1W), 200 mg once every two weeks (Q2W), 300 mg Q2W, 200 mg once every four weeks (Q4W), 300 mg Q4W, each administered by subcutaneous (SC) injection); eight studies evaluated lebrikizumab (37.5 mg Q4W, 125 mg Q4W, 250 mg Q4W each administered by SC injection); and nine studies (3259 participants) evaluated tralokinumab (75 mg Q1W, 150 mg Q1W, 300 mg Q1W, 150 mg Q2W, 300 mg Q2W, 600 mg Q2W, 300 mg Q4W, each administered by SC injection; 1/5/10 mg/kg administered by intravenous (IV) injection); all anti-interleukin-13 or-4 agents were compared with placebo. The risk of bias was generally considered to be low or unclear (insufficient detail provided); nine studies were considered to be at high risk for attrition bias and three studies were considered to be at high risk for reporting bias. The following results relate to the primary outcomes. The rate of exacerbations requiring hospitalisation or emergency department (ED) visit was probably lower in participants receiving tralokinumab versus placebo (rate ratio 0.68, 95% CI 0.47 to 0.98; moderate-certainty evidence; data available for tralokinumab (anti-interleukin-13) only). In participants receiving an anti-interleukin-13/-4 agent, the mean improvement versus placebo in adjusted asthma quality of life questionnaire score was 0.18 units (95% CI 0.12 to 0.24; high-certainty evidence); however, this finding was deemed not to be a clinically relevant improvement. There was likely little or no difference between groups in the proportion of patients who reported all-cause serious adverse events (anti-interleukin-13/-4 agents versus placebo, OR 0.91, 95% CI 0.76 to 1.09; moderate-certainty evidence). In terms of secondary outcomes, there may be little or no difference between groups in the proportion of patients who experienced exacerbations requiring oral corticosteroids (anti-interleukin-13/-4 agents versus placebo, rate ratio 0.98, 95% CI 0.72 to 1.32; low-certainty evidence). Anti-interleukin-13/-4 agents probably improve asthma control based on asthma control questionnaire score (anti-interleukin-13/-4 agents versus placebo, mean difference -0.19; 95% CI -0.24 to -0.14); however, the magnitude of this result was deemed not to be a clinically relevant improvement. The proportion of patients experiencing any adverse event was greater in those receiving anti-interleukin-13/-4 agents compared with those receiving placebo (OR 1.16, 95% CI 1.04 to 1.30; high-certainty evidence); the most commonly reported adverse events in participants treated with anti-interleukin-13/-4 agents were upper respiratory tract infection, nasopharyngitis, headache and injection site reaction. The pooled results for the exploratory outcome, the rate of exacerbations requiring oral corticosteroids (OCS) or hospitalisation or emergency department visit, may be lower in participants receiving anti-interleukin-13/-4 agents versus placebo (rate ratio 0.71, 95% CI 0.65 to 0.77; low-certainty evidence). Results were generally consistent across subgroups for different classes of agent (anti-interleukin-13 or anti-interleukin-4), durations of study and severity of disease. Subgroup analysis based on category of T helper 2 (TH2) inflammation suggested greater efficacy in patients with higher levels of inflammatory biomarkers (blood eosinophils, exhaled nitric oxide and serum periostin).
AUTHORS' CONCLUSIONS: Based on the totality of the evidence, compared with placebo, anti-interleukin-13/-4 agents are probably associated with a reduction in exacerbations requiring hospitalisation or ED visit, at the cost of increased adverse events, in patients with asthma. No clinically relevant improvements in health-related quality of life or asthma control were identified. Therefore, anti-interleukin-13 or anti-interleukin-4 agents may be appropriate for adults with moderate-to-severe uncontrolled asthma who have not responded to other treatments. These conclusions are generally supported by moderate or high-certainty evidence based on studies with an observation period of up to one year.
针对细胞因子或其受体的免疫球蛋白 E 途径和白细胞介素-5 途径的特异性单克隆抗体靶向治疗在严重哮喘患者中是有效的。然而，有些患者对这些生物制剂的反应不理想。由于白细胞介素-4 和白细胞介素-13 通过白细胞介素-4 受体信号传递对哮喘的生物学有多种影响，因此开发了针对白细胞介素-4 和白细胞介素-13（单独和联合）的治疗方法。
评估抗白细胞介素-13 或抗白细胞介素-4 药物与安慰剂、抗免疫球蛋白 E 药物或抗白细胞介素-5 药物相比，在治疗儿童、青少年或成人哮喘方面的疗效和安全性。
我们从 Cochrane 气道试验登记处（该登记处由信息专家为小组维护，并通过美国国立卫生研究院正在进行的试验注册ClinicalTrials.gov 和世界卫生组织国际临床试验注册平台进行搜索）中检索了研究。检索于 2020 年 10 月 16 日进行。
我们纳入了平行组随机对照试验，比较了抗白细胞介素-13 或 -4 药物（或同时针对白细胞介素-13 和白细胞介素-4 的药物）与安慰剂在青少年和成年人（年龄在 16 岁或以上）或儿童（年龄小于 16 岁）中的疗效，这些参与者被诊断为哮喘；参与者可以接受他们通常的短效或长效药物治疗（例如吸入皮质类固醇（ICS）、长效β肾上腺素受体激动剂（LABA）、长效毒蕈碱拮抗剂（LAMA）和/或白三烯受体拮抗剂），只要它们不是随机治疗的一部分。
我们使用了 Cochrane 预期的标准方法。
我们确定并纳入了 41 项 RCT。其中，29 项研究提供了定量分析的数据，随机分配了 10604 名哮喘患者接受抗白细胞介素-13（干预）或抗白细胞介素-4 药物（干预）或安慰剂（对照）治疗。没有发现安慰剂是抗免疫球蛋白药物或抗白细胞介素-5 药物的相关研究。研究的持续时间为 2 至 52 周（中位数为 16 周）。纳入研究的参与者平均年龄为 22 至 55 岁。只有五项研究允许儿童和青少年入组，占总参与者的不到 5%，这些参与者提供了本综述的数据。大多数参与者患有中度或重度未控制的哮喘。大多数（29 项中的 21 项）纳入研究允许或需要同时使用 ICS。19 项研究不允许使用维持性全身皮质类固醇，5 项研究（信息未报告）允许或需要使用维持性全身皮质类固醇。关于最常用的抗白细胞介素-13/-4 药物，四项研究评估了度普利尤单抗（每 1 周 300 mg（Q1W）、每 2 周 200 mg（Q2W）、每 2 周 300 mg（Q2W）、每 4 周 200 mg（Q4W）、每 4 周 300 mg（Q4W），均通过皮下（SC）注射给药）；八项研究评估了利布瑞单抗（每 4 周 37.5 mg、每 4 周 125 mg、每 4 周 250 mg，均通过 SC 注射给药）；九项研究（3259 名参与者）评估了特罗利单抗（每 1 周 75 mg、每 1 周 150 mg、每 1 周 300 mg、每 2 周 150 mg、每 2 周 300 mg、每 2 周 600 mg、每 2 周 300 mg、每 4 周 Q4W，每 1/5/10 mg/kg 通过静脉（IV）注射给药）；所有抗白细胞介素-13 或 -4 药物均与安慰剂进行比较。偏倚风险通常被认为是低或不清楚（提供的细节不足）；九项研究被认为有较高的失访偏倚风险，三项研究被认为有较高的报告偏倚风险。以下结果与主要结局有关。与安慰剂相比，特罗利单抗治疗组的住院或急诊室（ED）就诊的恶化率可能较低（率比 0.68，95%置信区间 0.47 至 0.98；中等确定性证据；仅特罗利单抗（抗白细胞介素-13）的数据可用）。接受抗白细胞介素-13/-4 药物治疗的患者，调整后的哮喘生活质量问卷评分的平均改善与安慰剂相比为 0.18 单位（95%置信区间 0.12 至 0.24；高确定性证据）；然而，这一发现被认为没有临床相关的改善。两组之间报告的所有原因严重不良事件（抗白细胞介素-13/-4 药物与安慰剂相比，比值比 0.91，95%置信区间 0.76 至 1.09；中等确定性证据）的比例可能差异不大或无差异。在次要结局方面，接受抗白细胞介素-13/-4 药物治疗的患者与安慰剂相比，经历需要口服皮质类固醇的恶化的比例可能差异不大或无差异（抗白细胞介素-13/-4 药物与安慰剂相比，率比 0.98，95%置信区间 0.72 至 1.32；低确定性证据）。基于哮喘控制问卷评分，抗白细胞介素-13/-4 药物可能改善哮喘控制（抗白细胞介素-13/-4 药物与安慰剂相比，平均差异 -0.19；95%置信区间 -0.24 至 -0.14）；然而，这一结果的幅度被认为没有临床相关的改善。与接受安慰剂治疗的患者相比，接受抗白细胞介素-13/-4 药物治疗的患者经历任何不良事件的比例更高（抗白细胞介素-13/-4 药物与安慰剂相比，比值比 1.16，95%置信区间 1.04 至 1.30；高确定性证据）；在接受抗白细胞介素-13/-4 药物治疗的患者中，最常见的不良事件是上呼吸道感染、鼻咽炎、头痛和注射部位反应。对于需要口服皮质类固醇（OCS）或住院或急诊室就诊的恶化率，接受抗白细胞介素-13/-4 药物治疗的患者可能低于接受安慰剂治疗的患者（率比 0.71，95%置信区间 0.65 至 0.77；低确定性证据）。结果在不同类别的药物（抗白细胞介素-13 或抗白细胞介素-4）、研究持续时间和疾病严重程度的亚组分析中基本一致。基于炎症生物标志物（血嗜酸粒细胞、呼气一氧化氮和血清前蛋白）水平的辅助 2（TH2）炎症类别的亚组分析表明，在炎症水平较高的患者中，药物疗效更高。
基于现有证据，与安慰剂相比，抗白细胞介素-13/-4 药物可能会降低哮喘患者需要住院或急诊室就诊的恶化率，但会增加不良反应，在中度至重度未控制的哮喘患者中，这些药物可能适合对其他治疗方法没有反应的患者。因此，抗白细胞介素-13 或抗白细胞介素-4 药物可能对未接受过其他治疗的中度至重度未控制哮喘患者有一定疗效。这些结论得到了中度或高度确定性证据的支持，这些证据来自于为期一年的观察期内的研究。
