Review question
We assessed 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.
Background
Immunoglobulin E and interleukin-5 are chemicals in the body that promote allergy (or an allergic response) in the airways and cause the symptoms of asthma. Some people with severe asthma take drugs that target immunoglobulin E or interleukin-5, but these drugs don't work for everyone. Since interleukin-4 and interleukin-13 are also chemicals in our body that promote allergy (or an allergic response) in the airways, we looked at whether drugs that target interleukin-4 and interleukin-13 are safe and effective (compared with placebo - a substance that has no therapeutic effect) for improving the symptoms or quality of life of people with asthma.
Study characteristics
We found 41 studies that compared anti-interleukin-4 or anti-interleukin-13 agents (or agents that target both interleukin-13 and interleukin-4) with placebo in people with asthma. No relevant studies were identified where anti-interleukin-4 or -13 agents were compared with either anti-interleukin-5 or anti-immunoglobulin agents. Twenty-nine of the included studies (10,604 participants) reported information that fed into this review. The evidence presented is current up to October 2020. Most of the people who took part in the included studies had moderate or severe, uncontrolled asthma and the average age of people in each study ranged from 22 to 55 years. Only four studies allowed recruitment of children and adolescents and participants in this age group accounted for less than 5% of those contributing data to his review. Most studies tested whether dupilumab, an interleukin-4 agent (four studies), or the anti-interleukin-13 agents lebrikizumab (eight studies) or tralokinumab (nine studies), were better than placebo.
Key results
When we pooled the information provided by the 29 studies, we showed that these drugs reduced the number of people having asthma attacks and improved lung function to a level where a person would feel the benefit. Small improvements in health-related quality of life and asthma control were also seen, but the size of these effects was not great enough for a person with asthma to feel the benefit. A 16 per cent reduction in the dose of oral corticosteroids was also observed, although our confidence in this finding is low. Although no increase in serious side effects was found (i.e. any untoward medical occurrence that results in death; is life threatening; requires hospitalisation; results in persistent or significant disability/incapacity; or is a birth defect), the number of people who had any side effect was increased compared with people who took placebo. The most commonly reported side effects in participants treated with anti-interleukin-13/-4 agents were upper respiratory tract infections, colds, headaches or injection site reactions. The results also showed that information about blood markers (blood eosinophils and serum periostin) and the exhaled nitric oxide levels may help predict the efficacy of these medications in an individual with asthma. In summary, these drugs are likely helpful for some people with severe or uncontrolled asthma when other treatments have not worked and the purpose of the treatment is to reduce the number of asthma attacks experienced.
Quality of the evidence
The included studies were generally well designed and well reported. People in the studies and those performing the research did not know which treatment people were receiving, which ensures a fair evaluation of the treatments. Overall, we can be confident in the conclusions of this review.
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.
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).