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Neurology
Introduction
CIDP is a rare, often progressive, immune-mediated neuromuscular disorder of the peripheral nervous system.1
As an acquired inflammatory demyelinating neuropathy, it can lead to both distal and proximal weakness, along with sensory deficits.1 The condition typically causes motor and sensory impairment in the upper and lower limbs.2
References & Abbreviations
XXXXX | XXXX 2025
Respiratory
IL-33 Is Not Just IL-33: There Is More Than One Side to the COPD Story
Interview Summary
What does dysfunctional reduced IL-33 (IL-33RED) primarily drive in COPD?
What does dysfunctional oxidised IL-33 (IL-33OX) primarily drive in COPD
How well do you understand the role of IL-33 in controlling multiple downstream pathways in COPD?
Very well
How well do you understand the role of IL-33 in controlling multiple downstream pathways in COPD?
What does dysfunctional reduced IL-33 (IL-33RED) primarily drive in COPD?
What does dysfunctional oxidised IL-33 (IL-33OX) primarily drive in COPD
Introduction
Transforming Care in COPD
The Unmet Need for Novel Therapies in COPD
The Role of Mucus Dysfunction in COPD Progression
The Distinct Pathways of IL-33 driving COPD Pathogenesis
EXPLORING CLINICAL DEVELOPMENT OF IL-33 TARGETED BIOLOGICS
Panel discussion
CONCLUSION
Adequate management of COPD is important because hospitalisation for an acute exacerbation of COPD (AECOPD) is associated with high rates of:1
Pooled 365-day hospital readmission: 38.2%
In-hospital mortality: 6.2%
Pooled 365-day post-discharge mortality: 12.2%
However, despite optimisation of maintenance treatment with combination inhalers, many patients continue to experience exacerbations,2 highlighting an unmet need for additional treatments. Biologics targeting immune system components, including IL-33 signalling, have been developed as potential new COPD therapies.3
The main objectives of the symposium described in this article were to:
Raise awareness of the current unmet need for biologic therapy in COPD despite optimised standard-of-care treatment
Explore the roles of IL-33RED and IL-33OX in COPD pathogenesis
Review new biologics for COPD that target IL-33 pathways
Lung disease is a major driver of health inequalities.5,6 The number of deaths, disability-adjusted life years, and hospitalisations due to chronic respiratory diseases has increased during the past 3 decades.4,7,8
Healthcare systems have similar barriers to care for chronic respiratory diseases, including delayed diagnosis and fragmented care pathways.9-11 As a result, many individuals with chronic lung diseases are undiagnosed or undertreated.12,13
The main stakeholders in healthcare delivery, including healthcare providers, pharmaceutical companies, professional societies, and patient advocacy groups, need to work together to provide proactive, integrated, patient-centred care for chronic respiratory diseases, as early diagnosis and initiation of guideline-directed medical therapy decreases the rates of AECOPD and hospital admissions, and may reduce the rate of premature deaths.
Rebecca D’Cruz Guy’s and St Thomas’ NHS Foundation Trust, London, UK
COPD affects millions of people worldwide, but many patients receive suboptimal therapy and continue to experience moderate-to-severe exacerbations.14 Exacerbations have profound effects on patients’ disease progression,15 their physical and mental wellbeing,16,17 and their caregivers’ lives.18
Exacerbations are a key component of cardiopulmonary risk in COPD and associated with premature death.21,22 Source: Singh D et al.22 Licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/).
A retrospective USA cohort study (SIRIUS I) included 4,920 patients with COPD on triple therapy with a history of ≥2 moderate or ≥1 severe exacerbations per year:14
During the first year of follow-up, 69% of participants experienced ≥1 moderate and/or severe exacerbation.19
69%
OCS exposure is associated with significantly elevated risks of various adverse outcomes, including:
Notably, relative all-cause mortality rates were 74% higher for patients exposed to cumulative OCS doses of 0.5–<1.0 g (aHR: 1.74; 95% CI: 1.65–1.83) and 145% higher for patients exposed to cumulative OCS doses of 1.0–<2.5 g (aHR: 2.45; 95% CI: 2.33–2.58), in comparison to those exposed to <0.5 g of OCS.20
Pneumonia (adjusted hazard ratio [aHR]: 2.90; 95% CI: 2.77–3.03 versus no exposure)
D’Cruz emphasised that patients with COPD frequently die of cardiovascular disease, and the management of cardiopulmonary risk in patients with COPD remains suboptimal. An AECOPD increases the risks of subsequent exacerbations and cardiovascular events, both of which are associated with premature death.21,22
Mucus plugs occlude the lumen of airways.31,32,40 Furthermore, there is evidence that mucus plugs are more common in severe COPD.29,41
A retrospective UK cohort study of 213,466 patients with COPD concluded that, during the first 14 days after a moderate/severe exacerbation there was:23
An approximately two-fold increase in the risk of acute coronary syndrome (aHR: 2.07; 95% CI: 1.39–3.09)
Nearly a three-fold elevation in the risks of arrhythmia (aHR: 2.86; 95% CI: 2.36–3.47)
Nearly a three-fold increase in heart failure (aHR: 2.87; 95% CI: 2.36–3.50)
Patients with COPD continuing to experience exacerbations on triple therapy have a severe and under-recognised disease burden.
In an analysis of data (drawn from an international cross-sectional study) for 399 patients on triple therapy with productive cough and ≥2 moderate/≥1 severe exacerbations in the prior year:25,26
54% exhibited severe-to-very-severe airway obstruction
78% had breathlessness with a Modified Medical Research Council (mMRC) Dyspnoea Scale score ≥2
35% required O2 therapy
Unfortunately, the devastating implications of COPD are under-recognised by clinicians: a recent survey revealed that 73% of physicians considered their patients’ COPD to be somewhat/well/completely controlled, despite these patients exhibiting exacerbations on triple therapy.26 This highlights an incongruence between patients’ experiences and clinicians’ perceptions.
Physician-reported COPD control (past 4 weeks), % of patients (n=399)*
*Data for the CAPELLA study (n=4,372) were drawn from the Adelphi Real World COPD Disease Specific Programme; a previously validated cross-sectional physician survey with retrospective elements assessing patient COPD-related characteristics in EU, China and the US. Data depicted are from CAPELLA SET cohort (n=399), which comprised patients who were current or former smokers and symptomatic with frequent productive cough within 4 weeks of the analysis cut-off date.26
Mucus dysfunction is central to COPD pathology and includes mucus hypersecretion and mucus plugging.27-31
The COPDGene study (Figure 1) was an observational prospective cohort study that included 4,363 patients with COPD at 21 centres in the USA.35 Click on Figure 1 to explore.
Figure 1: Mucus dysfunction is common in COPD, with a poor correlation between mucus hypersecretion and mucus plugs.
COPDGene study,* approximately 75% of patients had signs of mucus dysfunction.† of these patients:
*Based on data from 4,363 patients with COPD (current or former smokers) across the full spectrum of COPD severity. Patients were recruited from the COPDGene study, an observational prospective cohort study conducted across 21 centres in the USA, and included 45–80-year-old non-Hispanic White or non-Hispanic Black patients with COPD and with a ≥10 pack-year smoking history.29,35 †Signs of mucus dysfunction included cough, phlegm, and/or mucus plugs. Created from Mettler SK et al.,35 licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/).
This suggests that although mucus dysfunction is common in patients with COPD, mucus hypersecretion and mucus plugs may be distinct, and there is a poor correlation between the two.
Productive cough and excess sputum are associated with numerous negative outcomes.36-39
Airflow limitation, exacerbations, dyspnoea
Fatigue and physical activity limitations
Depression, anxiety, and social isolation
Although some patients with COPD exhibit resolution of mucus plugging, others have persistent plugs or develop new mucus plugs. In a subgroup of 2,118 patients with COPD in the COPDGene study, who were followed up for 5 years including CT and spirometry assessments, the annual mean decline in forced expiratory volume in 1 second was faster in participants with persistent (60.4 mL/year) or newly formed (54.9 mL/year) mucus plugs than in those with resolved mucus plugs (39.3 mL/year) or absent mucus plugs (reference group; 37.2 mL/year).42
There is evidence that mucus plugs are associated with elevated risks of AECOPD and death.
*Mucus plug score calculated as the number of lung segments with mucus plugs.
Results are from an observational retrospective analysis of prospectively collected data from patients with a diagnosis of COPD, aged 45–80 years, who smoked at least 10 pack-years. Participants were enrolled at 21 centres across the US between November 2007 and April 2011 and were followed up through August 31, 2022. 4,363 patients were included in the primary analysis.
Figure developed using Table 2 from Diaz AA et al.28
Furthermore, an observational retrospective analysis of COPDGene data found that the presence of mucus plugs was associated with significantly higher hazards of all-cause mortality: aHR 1.15 (95% CI: 1.02–1.29) for plugs in 1–2 lung segments and aHR 1.24 (95% CI: 1.10–1.41) for plugs in three or more segments versus none.29
Many patients with COPD continue to experience exacerbations on triple therapy, indicating an unmet need for novel approaches that target the broader mechanisms underlying COPD pathogenesis.43-46
Dave Singh University of Manchester; Medicines Evaluation Unit an IQVIA Business, Manchester, UK
IL-33-mediated signalling is a key pathway driving COPD pathogenesis. IL-33 is highly expressed in lung tissue homogenate from patients with severe COPD: IL-33 levels were significantly higher in patients with GOLD Stage III/IV COPD (forced expiratory volume in 1 second: <50% predicted) than in healthy controls (p<0.001).41,47 IL-33 levels correlate with an increased risk of future COPD exacerbations and prevalence of productive cough.48,49
Figure 2: IL-33 is highly expressed in lung tissue of patients with severe COPD.47
Lung biopsy images used with permission of Elsevier Inc. from Kearley J et al.47
IL-33 is found in two forms in the body: IL-33RED and IL-33OX. IL‑33RED is stored in the nuclei of structural cells such as epithelial and endothelial cells, and is rapidly released upon tissue injury and cell damage induced by trauma, infections, pollutants, and allergens, for example.46,50,51 IL-33RED undergoes a conformational switch to IL-33OX upon exposure to the extracellular environment.51
IL-33 dysregulation is a key driver of COPD pathogenesis, with IL-33RED-mediated pathways causing inflammation, and IL-33OX-mediated signalling leading to mucus hypersecretion and impaired epithelial repair.44,46,50
IL-33RED
IL-33OX
EGFR: epidermal growth factor receptor; IL-33OX: oxidised IL-33; IL-1RAP: IL-1 receptor accessory protein; IL-33RED: reduced IL-33; RAGE: receptor for advanced glycation end-products; ST2: serum-stimulated-2.
IL-33RED binds to the serum-stimulated 2 (ST2) receptor on immune and endothelial cells, which recruits IL-1 receptor accessory protein (IL-1RAP) to form a heterodimer that activates various inflammatory pathways, including Type 1 inflammation via cell types such as Th1 cells, Type 2 inflammation via cell types such as eosinophils, and Type 3 inflammation via cell types such as neutrophils and macrophages.45,50,52,53 IL-33 can also stimulate endothelial cells to release cytokines involved in Type 1 and Type 3 inflammation.54,55
IL-33RED is a potent inflammatory cytokine, and multiple homeostatic mechanisms regulate its activity. Firstly, IL-33RED is retained in the nuclei of airway epithelial cells and is inactivated by caspase 3/7 during apoptosis to prevent initiation of an immune response.56 Secondly, ST2 is found not only as a membrane-bound form but also as a soluble form (sST2) that acts as a ‘decoy’ receptor to dampen the immune response to IL-33RED.56 sST2 acts as an endogenous regulator of inflammation, and it is thought that reduced sST2 levels may cause an imbalance between IL-33RED and sST2 that promotes uncontrolled inflammation.57-59 Thirdly, the conformational switch that occurs on oxidation of IL-33RED to IL-33OX prevents it from binding to membrane-bound ST2 receptors.46,51
In vitro experiments have shown that IL-33OX signals via the receptor for advanced glycation end-products (RAGE)/epidermal growth factor receptor (EGFR) and is involved in mucus hypersecretion and airway remodelling.46 Experiments using human bronchial epithelial cells cultured in an air-liquid interface revealed that goblet cell MUC5AC/B expression was upregulated by IL-33OX, inducing a human epithelial mucin hypersecretion phenotype similar to that observed in COPD.46 MUC5AC secretion was also increased by IL-33OX but not by an oxidation-resistant form of IL-33RED (p≤0.01).46
The effects of IL-33OX and IL-33RED were also evaluated in a model of airway epithelial wound healing, which measured the extent of wound closure 24 hours after a scratch injury to cultured primary human bronchial epithelial cells. IL-33OX, but not IL-33RED, inhibited wound closure, indicating that IL-33OX impairs epithelial repair mechanisms.46
Smoking status has complex effects on IL-33 signalling. A recent study reported significantly higher sputum IL-33 levels for 80 people with COPD than for 20 healthy controls (median [interquartile range]: 38.7 [16–80] versus 14.1 [8–37] pg/mL; p<0.05).61 Interestingly, among patients with COPD, active smokers had significantly lower sputum IL‑33 concentrations than former smokers (median [interquartile range]: 23 [11–53] versus 64 [32–108] pg/mL; p=0.002).61 Nonetheless, patients with severe COPD (GOLD Stage III/IV) had higher airway
IL-33 levels compared to healthy controls, irrespective of their smoking status.61
An analysis of the association between smoking status and IL-33 gene expression across eight different studies also provided evidence of lower IL-33 levels in current smokers with COPD than in former smokers with COPD.62 However, there also appeared to be a trend toward lower ST2 expression in active smokers than in former smokers.62
Notably, further analyses of gene set variation in bronchial epithelial air-liquid interface cultures have indicated that IL-33OX signalling is higher in patients with COPD than in healthy controls, and higher in current smokers than in former smokers, irrespective of COPD status.46 These data raise the possibility that active smoking may be associated with enhanced activation of IL-33OX signalling relative to former smokers.
IL-33 as a strategic therapeutic target
Given its role as a key orchestrator of the inflammatory cascade (Figure 3), IL-33 is a strategic therapeutic target for COPD.45,46,50,51,63,64 Several novel biologics have been developed that inhibit IL-33 activity with differing mechanisms of action. Phase II and Phase III studies of these biologics are either completed or ongoing, and the results of these studies will provide important insights into the potential of these agents as novel COPD therapies.
Figure 3: IL-33 is a key orchestrator of the inflammatory cascade in COPD and a strategic therapeutic target.45,46,50,51,63-66
*Damage induced by smoke, pollutants, and viral or bacterial exposure.
†Eosinophils are elevated in 10–40% of patients with COPD.45
CD4+/8+: cluster of differentiation 4/8-positive; EGFR: epidermal growth factor receptor; IL-33OX: oxidised IL-33; IL-1RAP: IL-1 receptor accessory protein; IL-33RED: reduced IL-33; RAGE: receptor for advanced glycation end-products; sST2: soluble serum-stimulated 2; ST2: serum-stimulated 2; Th1/2/17: T helper 1/2/17 cell.
Stephanie Christenson University of California, San Francisco, USA
Phase II and Phase III clinical trials have been undertaken to evaluate the different types of biologics targeting IL-33 pathways in the management of COPD.67-83 Christenson began by summarising the clinical development programmes for the three types of biologics described above by Singh. They went on to present data from some of the Phase II studies that have been published.67,68,72,77,82,83
Although the primary endpoint was not met in the Phase II clinical trials for these biologics, important signals of clinical efficacy were observed, supporting the initiation of large Phase IIb/III programmes. The results of these Phase IIb/III studies have yet to be published, so Christenson focused on describing the important features of the design of each of these clinical trials.69,70,73,74,78-80 The results from the Phase IIb/III studies will help to better understand these molecules and elucidate the impact of their different mechanisms of action.
Claus Vogelmeier (Chair) University Hospital Marburg, Germany
Vogelmeier emphasised the unmet need for novel treatments targeting the mechanisms underlying COPD, including inflammation and mucus dysfunction. IL-33 is a potential therapeutic target for COPD because it promotes all these pathogenetic mechanisms through IL-33RED and IL-33OX. Novel biologics inhibiting the IL-33 pathway have differing mechanisms of action, and it will be interesting to establish whether these differences are reflected in the outcomes of Phase III trials.
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Z4-81533 | April 2026
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62. Faiz A et al. IL-33 expression is lower in current smokers at both transcriptomic and protein levels. Am J Respir Crit Care Med. 2023;208(10):1075-87. 63. Wechsler ME, Wells JM. What every clinician should know about inflammation in COPD. ERJ Open Res. 2024;10(5):00177-2024. 64. Zhou Y et al. Role of IL-33-ST2 pathway in regulating inflammation: current evidence and future perspectives. J Transl Med. 2023;21(1):902. 65. Marcuccio G et al. Endothelial dysfunction in chronic obstructive pulmonary disease: an update on mechanisms, assessment tools and treatment strategies. Front Med (Lausanne). 2025;12:1550716. 66. Gabryelska A et al. IL-33 mediated inflammation in chronic respiratory diseases-understanding the role of the member of IL-1 superfamily. Front Immunol. 2019;10:692. 67. Yousuf AJ et al. Astegolimab, an anti-ST2, in chronic obstructive pulmonary disease (COPD-ST2OP): a phase 2a, placebo-controlled trial. Lancet Respir Med. 2022;10(5):469-77. 68. University of Leicester. Anti-ST2 (MSTT1041A) in COPD (COPD-ST2OP). NCT03615040. https://clinicaltrials. gov/study/NCT03615040. 69. Genentech, Inc. A study to evaluate the efficacy and safety of astegolimab in participants with chronic obstructive pulmonary disease. NCT05037929. https://clinicaltrials.gov/study/ NCT05037929.
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Source: spiral of decline figure from Hurst JR et al.17 Licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). QoL: quality of life.
While 25% of patients experienced ≥1 severe exacerbation requiring hospitalisation for ≥2 days.19
These arresting statistics highlight COPD as a devastating disease with serious implications.
25%
Approximately 90% of patients in the SIRIUS I study received an oral corticosteroid (OCS) during baseline for a mean cumulative duration of 73 days.14
90%
Osteoporosis (aHR: 1.80; 95% CI: 1.70–1.92)
Type 2 diabetes (aHR: 1.44; 95% CI: 1.37–1.51)
Cardiovascular/cerebrovascular disease (aHR: 1.26; 95% CI: 1.21–1.30).20
D’Cruz described the importance of treating both inflammation and mucus dysfunction in COPD.
Although therapies are available to break down mucus and promote its expectoration, pharmacological interventions inhibiting mucus overproduction are lacking. Given the adverse effects of long-term OCS use,20 D’Cruz was of the opinion that new treatments are needed to reduce the risk of further exacerbations and steroid exposure in patients with COPD who exhibit exacerbations on triple therapy.
Christenson explained that IL-33 is a good therapeutic target for COPD because it is involved in driving heterogeneous types of inflammation as well as mucus dysfunction, all of which are relevant to COPD.
Discovering whether differences in mechanisms between biologics are reflected by differences in clinical trial outcomes will be enlightening. Christenson also stressed the importance of acquiring data for both current and former smokers in clinical trials.
Singh discussed the COPDGene study35 and the fact that mucus plugs are associated with higher exacerbation and mortality rates.29,34 He highlighted how it will be important to establish whether interventions that reduce mucus plugging improve outcomes. Additionally, Singh addressed potential biomarkers for responders to anti-IL-33 therapy, highlighting exacerbation frequency as a disease severity measure that might help identify patients requiring more aggressive therapy.
Even a single moderate exacerbation may increase the risk of future exacerbations and is associated with a higher risk of premature mortality.
In an observational analysis of 340,515 patients with COPD in the UK, one moderate exacerbation was associated with:
17% increase in the adjusted incidence rate ratio (aIRR) for COPD-related death (1.17; 95% CI: 1.04–1.33 versus no exacerbation); and
23% higher aIRR for cardiovascular-related death (1.23; 95% CI: 1.07–1.42).24
Notably, the risks were even greater after one severe exacerbation, with aIRR increases of:
138% for COPD-related death (2.38; 95% CI: 2.08–2.73 versus no exacerbation); and
65% for cardiovascular-related death (1.65; 95% CI: 1.34–2.02).24
IL-33RED
IL-33OX
Figure developed using figure 5 forest plots from Graul EL et al. 23 Licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). *Moderate (requiring primary care management) or severe (requiring hospitalisation) exacerbation. †Results are from a retrospective cohort study conducted in 213,466 patients with COPD in the UK’s CPRD Aurum database, assessing risk of CV events in patients with any exacerbation compared with patients with no exacerbations
Not intended for US or UK healthcare professionals
Very well
Well
Well
Slightly well
Slightly well
Not well at all
Not well at all
Mucus hypersecretion and impaired epithelial repair
Mucus hypersecretion and impaired epithelial repair
Uncontrolled inflammation
Uncontrolled inflammation
No known effect
No known effect
Not sure
Not sure
Not sure
Not sure
No known effect
No known effect
Mucus hypersecretion and impaired epithelial repair
Mucus hypersecretion and impaired epithelial repair
Uncontrolled inflammation
Uncontrolled inflammation
Not sure
Not sure
No known effect
No known effect
Mucus hypersecretion and impaired epithelial repair
Mucus hypersecretion and impaired epithelial repair
Uncontrolled inflammation
Uncontrolled inflammation
Not sure
Not sure
No known effect
No known effect
Mucus hypersecretion and impaired epithelial repair
Mucus hypersecretion and impaired epithelial repair
Uncontrolled inflammation
Uncontrolled inflammation
Not well at all
Not well at all
Slightly well
Slightly well
Well
Well
Very well
Very well
What does dysfunctional oxidised IL-33 (IL-33OX) primarily drive in COPD
What does dysfunctional reduced IL-33 (IL-33RED) primarily drive in COPD?
How well do you understand the role of IL-33 in controlling multiple downstream pathways in COPD?
What does dysfunctional oxidised IL-33 (IL-33OX) primarily drive in COPD
What does dysfunctional reduced IL-33 (IL-33RED) primarily drive in COPD?
How well do you understand the role of IL-33 in controlling multiple downstream pathways in COPD?
EGFR: epidermal growth factor receptor; IL-33OX: oxidised IL-33; IL-1RAP: IL-1 receptor accessory protein;
IL-33RED: reduced IL-33; RAGE: receptor for advanced glycation end-products; ST2: serum-stimulated 2
approaches
The prevalence of ≥1 mucus plug in CT images of 18 lung segments increased progressively from 22.1% in patients with mild COPD (Global Initiative for Chronic Obstructive Lung Disease [GOLD] Stage I) to 63.1% in patients with very severe disease (GOLD Stage IV). 29,41
IL-33 dysregulation is a key driver of inflammation and mucus dysfunction in COPD44,46,50,60
IL-33 dysregulation is a key driver of inflammation and mucus dysfunction in COPD44,46,50,60
Support: The ERS symposium was organised and funded by AstraZeneca. This article was commissioned and funded by AstraZeneca.
Disclaimer: The opinions expressed in this article belong solely to the speakers. This article refers to investigational products that are not currently approved for the treatment of COPD in any country.