Real-life impact of anti-IL5 therapy on exacerbation types in patients with obstructive lung disease

Authors: Lowie E G W Vanfleteren, Delphine Vauterin, Lies Lahousse

Abstract

Background

While anti-interleukin (IL) 5 therapy has been shown to be efficacious to reduce exacerbation rates (ERs) in patients with severe eosinophilic asthma and might also benefit patients with coexisting chronic obstructive pulmonary disease (COPD), it is unknown whether anti-IL5 therapy reduces all types of exacerbations in heterogeneous (smoking) real-life patients.

Methods

Adults initiating mepolizumab or benralizumab between 2017 and 2019 were identified in Belgian nationwide data. The ER in the year before anti-IL5 therapy initiation was compared to the year after. Exacerbations were classified as severe (hospitalised) exacerbations or moderate (outpatient) exacerbations treated with antibiotics, oral corticosteroids (OCS) or the combination.

Results

Among 807 patients initiating anti-IL5 therapy, severe ER was 40±4 exacerbations per 100 patient years pretreatment versus 17±3 post-treatment initiation (p<0.001, relative risk reduction (RRR) −56%, number needed to treat (NNT)=4) and significantly reduced both in patients without COPD (n=616, ERpre=15±2, ERpost=6±1, p<0.001, NNT=11) as with coexisting COPD (n=191, ERpre=119±12, ERpost=53±9, p<0.001, NNT=2). For moderate exacerbations, ERs were significantly reduced for all types of exacerbations in both patients with or without COPD, except for OCS only-treated exacerbations in patients with coexisting COPD (p=0.288). Current smoking reduced anti-IL5 effectiveness on OCS-treated exacerbations (NNT >1), although current smokers with coexisting COPD still had a great reduction in hospitalisations (ERpre=152±23, ER post=55±18, p<0.001, NNT=1, RRR=-64%).

Conclusions

In this nationwide cohort study, treatment targeting eosinophilic inflammation was significantly associated with reduced moderate and severe exacerbations, with seemingly less impact on corticosteroid-treated exacerbations in (current smoking) patients with coexisting COPD, but still a large number of hospitalisations were prevented.

Introduction

Asthma and chronic obstructive pulmonary disease (COPD) are common lung diseases with substantial morbidity and mortality worldwide.13 Exacerbations add to significant personal, social and economic burden in both.24 Monoclonal antibodies targeting the interleukin (IL) 5 pathway have been shown to be efficacious in reducing real-life exacerbation rates (ERs) in patients with severe eosinophilic asthma.58 A subgroup of patients with (coexistent) COPD and frequent exacerbations has elevated eosinophils which could also make them eligible for anti-IL5 treatment.911 However, in clinical trials, the relative decrease in the annual ER was around 45% in severe asthma patients,^12 13^ while it was around 20% in patients with COPD.^10 11 14^ Therefore, characteristics of responding eosinophilic COPD patients need to be further determined.^15^

While most clinical trials exclude smoking adults with asthma, up to half of adult patients with asthma are cigarette smokers worldwide.^16^ Smoking may add to corticosteroid insensitivity as it has been shown to affect response to maintenance therapy differently.^17^ While smoking in asthma is more likely to induce predominately non-T2 inflammation, T2-high eosinophilic inflammation may coexist.^16^ Little is known about how smoking may affect response to biologics targeting eosinophilic inflammation in real-life asthma with or without coexistent COPD. Furthermore, the exacerbation phenotype might influence the effectiveness of biologic treatment. Indeed, cluster analysis previously identified biologically distinct infection-related and eosinophil-associated exacerbation types in COPD.^18^ Differential treatment response not only to inhaled corticosteroids (ICS)/long-acting β2-agonists (LABA) but also to anti-IL5 therapy has been demonstrated according to oral corticosteroid (OCS) treated and/or antibiotic (AB) treated exacerbations.^19 20^

We hypothesised that exacerbation subtypes, defined by the treatment decisions of physicians in real life, may be differentially responsive to specific inhibition of eosinophilic airway inflammation. We further hypothesised that coexistent COPD and/or smoking history could influence the treatment response. Therefore, we aimed to compare in a Belgian nationwide cohort the impact of initiating anti-IL5 therapy on severe and moderate ERs. We explored the impact of coexistent COPD and smoking, and additionally stratified on exacerbation type.

Methods

The source population was provided by two nationwide databases, namely the InterMutualistic Agency (IMA) database and Minimal Hospital Dataset (MHD). The IMA centralises all claims data from Belgian health insurance funds and manages three (1) a population database containing sociodemographic characteristics of all insured persons (eg, age and sex), (2) a healthcare database containing data on reimbursed ambulatory and hospital care (eg, medical procedures, inpatient medication and other reimbursed care) and (3) a pharmaceutical database containing outpatient medication dispensing claims (eg, dispensing date, Anatomical Therapeutic Chemical (ATC) Classification code, dose strength, number of pills and packages supplied and prescriber type).^21^ Since health insurance is legally mandatory in Belgium, the source population represents all legal residents with reimbursed medication or care. The MHD database, collected by the Belgian Ministry of Health, provides information on medical diagnoses since it aggregates hospital discharge diagnoses of every hospital admission in Belgium, coded in International Classification of Diseases (ICD) codes (ICD-10 from 2015 onwards).^22^

Within all adult (≥18 years) chronic users of medication for obstructive lung diseases (≥2 dispensing claims for a drug for obstructive airway diseases (ATC code R03) in 1 year) with at least 1 year coverage by a Belgian health insurance fund, we identified all new users of biologic treatment targeting the IL5 pathway (ATC code R03DX09 mepolizumab and R03DX10 benralizumab) in Belgium from 1 January 2017 to 1 March 2019 to exclude the COVID-19 period (online supplemental figure E1). Patients with ≥2 dispensing claims of different biologics at the treatment initiation date, or using anti-IgE biological treatment (omalizumab) in the year before IL5-therapy, were excluded. Follow-up ended in case of death, emigration out of Belgium or end of the study period (1 March 2020), whichever came first.

Patient and public involvement

Patients or the public were not involved in the design, conduct, reporting or dissemination of our research.

Exacerbations

Among all adult patients initiating mepolizumab or benralizumab between 2017 and March 2019, the ER in the year after biologic treatment initiation was compared with the rate in their year before. Percentage responders were defined by the proportion of patients having at least a 50% reduction in their ER. Exacerbations were classified into severe (hospitalised) and moderate (outpatient treated) exacerbations in line with 2024 Global Initiative of Asthma^3^ and 2024 Global Initiative of Chronic Obstructive Lung Disease reports.^2^ Severe exacerbations were defined as hospital admissions (including emergency department visits) with a primary diagnosis of asthma or (acute) COPD exacerbation (ICD-10: J44.0, J44.1, J45.X1, J45.X2, J45.901 or J45.902) or with a primary diagnosis code for chronic lower respiratory disease (ICD-10: J40 – J47) or respiratory failure (ICD-10: J96) and a secondary diagnosis code for asthma or (acute) COPD exacerbation. Hospitalisations with a pneumonia or acute lower respiratory infection diagnosis (ICD-10: J09-J22) were separately explored. Moderate exacerbations were defined as an outpatient prescription fill for OCS (ATC code H02AB04, except parenteral use) and/or guideline-recommended AB (ATC code J01CA, J01CR, J01DC, J01FA and J01MA, except continuous azithromycin therapy).^23^ Prescription fills needed to be separated by at least 14 days to be considered as separate events. Outpatient exacerbations were classified as AB-treated, OCS-treated or OCS+AB-treated. Outpatient exacerbations followed by a hospital admission for a severe exacerbation within 14 days were counted only as severe exacerbation, to avoid counting exacerbations twice.

Covariates

Baseline characteristics were assessed at the date of biologic treatment initiation and included age, sex, smoking status, socioeconomic status, frailty and comorbidities (including the age-adjusted Charlson comorbidity index) (see online supplemental table E1). Increased reimbursements to which low-income Belgians are entitled were assessed as indicators of low socioeconomic status. In the case of missing data, medical coverage was derived from copayments for medication on the index date. Frailty was identified using the claims-based Frailty Indicator.^24 25^ Comorbidities and medication history were identified up to 1 year before treatment initiation using ICD-coded diagnoses, medical procedure codes and/or ATC-coded medication dispensing claims. Patients were categorised as ever smoking if any ICD code related to (history of) tobacco use or nicotine dependence, a nomenclature code for smoking cessation counselling or medication for smoking cessation, was registered in the database (1 January 2010–2022). Current smokers were ever smokers with (still) active smoking ICD-coding or smoking cessation attempts after the index date. Patients were defined to have (coexistent) COPD based on a hospital discharge diagnosis of COPD (ICD-10 J44) registered between 1 January 2016 at the earliest and the treatment initiation date. Chronic users of OCS were defined as users of ≥6 packages of OCS (equivalent to ≥180 days of 5 mg prednisolone/day) in the year preceding treatment initiation.

Statistical analysis

Mean and SD were presented for continuous variables, and counts and percentages for categorical variables. Exacerbation event rates (incidence rates) were presented as the total number of exacerbations per 100 patient years with their standard errors (SEM). P values were derived from paired samples t tests comparing event rates within individuals prebiologic and postbiologic treatment initiation and considered significant when less than 0.05. The relative risk reduction (RRR) in ER was calculated as the absolute risk reduction (difference in event rates between the year before and the year after biologic treatment initiation), divided by the event rate in the year before initiation. The number needed to treat (NNT) was calculated as the inverse of the absolute risk reduction. Analysis was repeated after stratification by having coexistent COPD, smoking status and OCS-dependence. A two-sided p value of <0.05 was considered statistically significant. All analyses were undertaken using R (R V.4.3.0, Vienna, Austria).^26^

This study was reported following the Strengthening the Reporting of Observational Studies in Epidemiology guideline (see online supplemental table E2).^27^

Results

Baseline characteristics

Among 807 asthma patients (mean age 58 years, 51% females) in this study, 78.2% were initiated on mepolizumab and 21.8% on benralizumab (anti-IL5/IL5R treatment).(table 1, see online supplemental figure E1) Coexistent COPD was present in 191 (23.7%) of patients and these patients were older, more frequently male, frail and ever smokers and were more frequently on triple therapy (ICS/LABA/long-acting muscarinic antagonists (LAMA)) before initiation of biologic treatment.

The severe ER in the overall population was 40±4 exacerbations per 100 patient years in the year before anti-IL5 treatment initiation versus 17±3 after (table 2, p<0.001, RRR=−56%, NNT=4). The severe ER in the 616 patients without COPD was 15 exacerbations per 100 patient years in the year before anti-IL5 treatment initiation, while it was 119 exacerbations per 100 patient years among patients with coexistent COPD (table 2, figure 1). Given the high severe ER in patients with coexistent COPD, the NNT and percentage of patients at least halving their ER appear to be very favourable in this patient population (NNT=2 and 41% responders respectively). The total moderate ER in the overall population was 396±9 events per 100 patient years before and 281±10 after anti-IL5 treatment initiation (p<0.001, RRR=-29%, NNT=1) and was visualised per exacerbation type for patients with or without COPD in figure 1. The RRR seemed overall more pronounced for OCS-treated exacerbations (RRR=-35%, NNT=1) than AB-only-treated exacerbations (RRR=-19%; NNT=4). Table 2 also demonstrates that reduced rates of OCS-treated exacerbations were largely driven by the rate reductions in asthma patients without COPD. Interestingly, OCS-only treated exacerbations were not significantly reduced after anti-IL5 therapy initiation when COPD coexisted (p=0.288, NNT=7, RRR=-8%), although these exacerbations were as frequent as AB-only treated exacerbations in the year prior to initiation.

Table 3 demonstrates that current smoking reduced the effectiveness of anti-IL5 therapy on OCS-only-treated exacerbations both in asthma patients with or without COPD. While the NNT was 1 to reduce OCS-treated exacerbations in all never or former smokers, higher numbers were needed in current smokers. Severe ERs were high in former and current smokers with coexistent COPD (116 and 152 per 100 patient years compared with 62 in never smokers with coexistent COPD) and significantly reduced (p<0.001, RRR −53%, NNT=2 for former smokers and p<0.001, RRR −64%, NNT=1 for current smokers) in the year after initiation of anti-IL5 therapy in those with coexistent COPD.

Table 4 demonstrates that in severe OCS-dependent patients who initiated anti–IL5 therapy, severe exacerbation and OCS-treated ERs were also significantly reduced following anti-IL5 therapy. In contrast, rates of AB-treated exacerbations were not significantly reduced and rather increased. Moreover, the rates of hospitalised respiratory infections (including pneumonia) per 100 patient years remained stable following treatment in severe OCS-dependent patients, while these rates tended to decrease in the overall population (n=807) from 9±3 to 6±1 hospitalised respiratory infections per 100 patient years (p=0.051, RRR=-32%).

Discussion

In this large real-life study, we showed that initiating biologic treatment targeting eosinophilic inflammation effectively reduced moderate and severe exacerbations in patients with asthma, regardless of coexistent COPD. The RRR of moderate exacerbations treated with AB alone was approximately half the reduction obtained in exacerbations treated with OCS. While patients with (coexistent) COPD also perceived benefit on severe and OCS+AB or AB only-treated exacerbations, the reduction was less pronounced and no longer significant for OCS only-treated exacerbations. The effectiveness of anti-IL5 therapy on OCS-treated exacerbations seemed reduced in current smokers. Severe OCS-dependent patients had an increased risk of AB only-treated events, while OCS-treated exacerbations clearly diminished.

Although the RRR of severe exacerbations is similar in patients with and without coexistent COPD, the absolute number of hospitalisations prevented after treatment is much larger in those with coexistent COPD, which is interesting from a health-economic perspective.^2^ A quarter (24%) of treated patients had comorbid COPD, and 80% among those were ever smokers. Likewise, in a smaller retrospective cohort study, 23% had comorbid emphysema and 80% among those were ever smokers.^28^ Treatment response was not significantly different for patients with comorbid emphysema.^28^ Also in a post hoc analysis of the REALITI-A patient population at 1 year, mepolizumab reduced exacerbations in patients with severe asthma, irrespective of physician-labelled coexistent COPD.^29^ Patients with coexistent COPD when exacerbating are likely more prone to be hospitalised because of their higher frailty due to older age, more frequent comorbidities and likely worse lung function. Indeed, the number of moderate exacerbations (not requiring hospitalisation) is more similar in patients with and without coexistent COPD and is overall more effectively reduced in asthma without coexistent COPD.

Exacerbations of asthma and COPD are commonly treated with OCS or AB, or both, as decided by the treating physician based on clinical manifestations such as fever, productive cough, sputum purulence, wheezing, chest tightness and the severity of symptoms.^2 3^ If symptoms are clearly infectious in nature, patients might be treated with ABs alone and if symptoms are clearly related to worsening of asthma or COPD, with clear absence of infectious origin, patients might be treated with OCS alone.^2 3^ Often, patients have signs of both, and certainly when symptoms are more outspoken, patients are treated in combination.^2 3^ It is clear that the treatment decisions made by the physician relate to different phenotypes of exacerbations. Indeed, cluster analysis previously identified biologically distinct infection-related and eosinophil-associated exacerbation types in COPD.^18^ Interestingly, a differential treatment response to ICS/LABA has been demonstrated according to OCS-treated or AB-treated exacerbations in COPD.^20^

In the current study, we also observed a differential response of AB only-treated exacerbations compared with exacerbations treated with OCS. Although the RRR after initiation of biologics of AB only-treated exacerbations was half the reduction of OCS-treated exacerbations, still a clinically important effect was seen. Furthermore, a surprisingly high amount of events was treated with ABs alone. In clinical practice, disease severity and eligibility for biologic treatment are often evaluated by retrospectively evaluating exacerbations. While OCS-treated exacerbations respond to a greater extent to anti-IL5 treatment, it seems that AB-only-treated worsenings have relevant predictive value as well. Our findings largely align with the relatively larger ER reductions observed on anti-IL5 treatment in trials including severe asthma patients (~45%) than those in COPD (~20%).1014 In our real-world cohort, OCS-treated exacerbations specifically showed a stronger reduction than AB-only events in patients with asthma. Notably, the effect was less pronounced for OCS-only exacerbations in patients with comorbid asthma and COPD. The less pronounced reduction in OCS-only–treated exacerbations among patients with concomitant COPD is intriguing and may reflect several factors. OCSs may be more readily prescribed in this population, while blood eosinophils may not suffice as the sole biomarker of biologic responsiveness in COPD, as both inhaled corticosteroids in non-responders and smoking can elevate eosinophil counts.^30 31^ Smoking may further reduce corticosteroid prior studies (eg, SUMMIT, IMPACT) demonstrated reduced treatment effects in current versus former smokers,^32 33^ likely related to cigarette smoke induced steroid resistance.^34 35^ Current smoking indeed reduced treatment response to anti-IL5 treatment on OCS-treated exacerbations, but severe ERs in current smokers with coexistent COPD were still significantly reduced. Smoking is linked with worse clinical outcomes in patients with asthma, including more exacerbations and healthcare utilisation.^16^ While it has also been previously shown for patients with asthma who smoke that their treatment response to inhaled and OCSs is less, patients with coexistent COPD in our study clearly suffered more comorbidities and had substantially higher hospitalisation rates.3639 A Danish severe asthma register study also observed mepolizumab effectiveness in patients with severe asthma and smoking history, despite the fact that they were also older and had more coexistent COPD and cardiovascular disease.^40^ Although current smokers may have less chance to be super-responders to biologic therapy, still partly better control of their disease and chronic inflammatory processes may largely benefit their overall hospitalisation and mortality risk.^8 41^

The results in the subgroup of severe glucocorticoid-dependent patients are of special interest. Although a clear overall reduction in moderate and severe exacerbations was seen, the AB-treated ERs increased the year after initiation of biologic therapy initiation compared with the year before. In line, in another study following severe OCS-dependent patients initiating benralizumab during a median treatment period of 14 months, the incidence of respiratory infections significantly increased (from 0.62/patient to 2.01/patient).^42^ Also, low levels of circulating eosinophils (<100/μL) have been independently associated with a higher risk of pneumonia in patients treated with ICS.^43^ Sputum eosinophils have been attributed a potential protective role in innate responses to respiratory bacterial pathogens,^44^ and therefore it might be speculated that the targeted reduction of eosinophils in patients already exposed to systemic immunosuppressant therapy as OCS potentially further increases the risk of bacterial respiratory infections. In this context, stepping down OCS after introducing anti-IL5 therapy should always be considered, and failing to do so may hold potential warning.^45^

Strengths of the current study are the large sample size, the real-life setting, the elimination of all time-invariant confounding by the self-controlled design and complete information on dispensing and hospitalisation of patients 1 year before and after anti-IL5 treatment initiation. Notably, in this real-life study, discontinuation within the first year was rare (<3%), and all patients resumed therapy within the study period. We also identified several limitations, including the probability of coding errors, misclassification bias, unmeasured confounding, the inability to confirm if the patient actually used the dispensed medication and the lack of information about symptom control, blood (such as eosinophil and neutrophil counts) or lung function values. Therefore, we could not account for disease severity markers. Coexistent COPD may have been underestimated since it was defined by a registered ICD-coded (hospital discharge) diagnosis or it may indicate misclassified asthma at older age. However, our patients were in terms of characteristics in line with previously identified asthma patients with comorbid COPD as they were also clearly older and more frequently ever smokers.^28 29^ Despite rigorous attempts to ascertain smoking status, some degree of misclassification cannot be ruled out, potentially leading to an underestimation of the proportion of ever smokers. Furthermore, as ICD-code registration in Belgium is not obligated for emergency department visits, exacerbations leading to an emergency department visit but without the need for hospitalisation may have been missed or classified as an outpatient exacerbation. Additionally, only patients with complete 1 year follow-up were included, and therefore patients dying shortly after biologic treatment initiation were absent in this complete case analysis. Although data were available till 2022, we deliberately set the last patient with complete follow-up at 1 March 2020 to avoid including the influence of the COVID-19 pandemic on ERs after treatment initiation.

In conclusion, this real-life evaluation of the risk reduction after initiation of anti-IL5 treatment showed that anti-IL5 therapy effectively reduced exacerbations resulting in hospitalisation, with a large effect in absolute figures in those with a coexistent COPD diagnosis. Response on OCS-treated exacerbations was especially reduced in (currently smoking) patients with coexistent COPD. AB only-treated exacerbations responded to a lesser extent compared with OCS-treated exacerbations and rather increased in severe glucocorticosteroid-dependent patients after anti-IL5 therapy initiation.

Supplementary material