Reference: April 2024 | Issue 4 | Vol 10 | Page 8
Despite severe asthma affecting only up to 10 per cent of all individuals diagnosed with the disorder, it significantly contributes to the overall healthcare burden associated with the condition. An improved understanding of underlying pathophysiology, allowing the identification of phenotypes and endotypes, has led to development of specific biologic therapies, which in turn, has rapidly revolutionised the management of severe asthma.
While it is important to consider patient characteristics, predictive biomarkers, phenotypes, and endotypes to improve management of severe asthma, future research is crucial to understand pathophysiological mechanisms and aid in the development of further targeted treatment options in the future.
Background
According to Global Initiative for Asthma 2023 guidelines (GINA), asthma is a heterogenous disease characterised by chronic airway inflammation leading to clinical symptoms of wheeze, dyspnoea, chest tightness, and cough. These symptoms vary considerably, temporally and from person-to-person in intensity, and variable expiratory airflow limitation is frequently present – but not universal, as a significant number of patients with asthma can develop irreversible or fixed airflow obstruction.
Airway hyper-responsiveness and inflammation is usually present, but is not either necessary nor sufficient to make the diagnosis of asthma. We now understand that there are clusters of clinical and/or pathophysiological traits – asthma phenotypes – and these can correspond to specific pathological processes and/or treatment responses.
Asthma affects up to 334 million people worldwide, with increasing prevalence noted over the last three decades. There is no single diagnostic test for the condition and diagnosis is made clinically, with supporting evidence from either pulmonary function testing (PFTs), variable peak flow or PFTs over time, airway challenge testing, and documented expiratory airflow limitation.
In Ireland, it is estimated that one-in-13 adults have asthma, with a prevalence of one-in-five children. Ireland currently has the second highest rate of asthma hospital admissions and among the highest prevalence rate in Europe (about 380,000 persons). The disorder is estimated to cost the Irish State almost €500 million annually and with one death occurring every six days due to asthma, it remains a significant public health concern.
History of asthma treatment
The term asthma was first described by Hippocrates around 450BC. In the early 1900s, asthma began to be treated with adrenergic bronchodilators, such as adrenaline, initially intravenously, but by 1947 via metered dose inhaler. In the 1910s, belladonna and D. stromonium cigarettes were used to deliver alkaloids with bronchodilator properties. They were sold commercially for asthma treatment until just before the middle of the 20th Century. Corticosteroids as a class were introduced in the late 1940s, initially systemically, and in inhaler form post Brown’s pivotal publication in 1972.
Those of us treating patients with asthma recognise it as a perplexing disease to manage. The goals of asthma treatment are to achieve and maintain full control of symptoms, maintain normal activity levels, maintain pulmonary function, prevent asthma exacerbations, avoid adverse effects from medication, and prevent asthma deaths.
Patients experience varying responses to various treatment options. Multiple comorbid ailments muddy the diagnostic and treatment ‘waters’. Adherence to treatment varies widely from patient to patient and remains a significant barrier to effective care. Seminal data from the respiratory group at Beaumont Hospital, led by Prof Richard Costello, has underpinned the issues surrounding compliance and ways to measure it.
Asthma treatment has centred around inhaled therapies, inhaled corticosteroids (ICS), short- and long-acting beta agonists (SABA/LABA), short- and long-acting anti-muscarinic (SAMA/LAMA), and oral leukotriene receptor antagonists (LTRA) – which have been in the media recently due to simmering ongoing concerns over an increased risk of neuropsychiatric reactions, especially in adolescents. The macrolide azithromycin can also be utilised as an add-on therapy to help reduce asthma exacerbations. Now, combination maintenance single inhalers containing ICS, LABA, and LAMA are available alongside ICS/LABA reliver inhalers called ‘maintenance and reliever therapy’ (MART). When these fail to address a patient’s asthma control the patient has severe asthma.
Severe asthma
Severe asthma accounts for a large proportion of the disease and economic burden caused by the condition, despite accounting for only 3.7-to-10 per cent of patients with asthma. Severe asthma is a subtype of difficult-to-treat asthma that remains uncontrolled despite adherence to high dose ICS-LABA and management of contributing factors, or importantly, asthma that worsens when high-dose treatment is reduced. This essentially means the diagnosis of severe asthma is retrospective.
It is important to note that neither LAMA, LTRA, or azithromycin treatments are mentioned in the GINA 2023 definition of severe asthma. There is no universally accepted definition of the features that constitute severe asthma. Patients with severe asthma not only place significant demand upon the healthcare and wider economic systems, but also face increased emergency hospital and unscheduled GP visits, reduced health-related quality-of-life, multimorbidity related costs, and both absenteeism and presenteeism.
Severe asthma is a heterogenous condition and thus, an increasing variety of phenotypes and endotypes have been discovered. Endotypes are more specific and delve into the pathophysiological mechanisms driving a disease, while phenotypes focus on shared observable characteristics and manifestations of a disease, and response to particular treatments.
The phenotypes include atopic or allergic asthma, late onset asthma, aspirin exacerbated respiratory disease, and non-atopic or non-allergic asthma (not an exhaustive list). The two main endotypes are based on the inflammatory Type 2 T-helper response: T2-high asthma (markers of this include elevated blood eosinophil count and/or elevated fraction of exhaled nitric oxide (FeNO)) and T2-low asthma.
The understanding of these endotypes has revolutionised the management of severe asthma. It is important to note that the T2-low asthma endotype is felt to represent a much smaller number of patients with asthma than previously thought and likely represents a suppressed T2-high endotype due to ICS/ oral corticosteroids (OCS) usage and other as yet unidentified processes.
Biologic therapies
Biologic therapies for asthma were first introduced in 2003. These represent a new era that has revolutionised the treatment of severe asthma. They are designed to target individual mediators of inflammation and are patient selective depending on the predominant phenotype identified. Accurately identifying the pathway involved in promoting active inflammation in each patient individually is crucial.
Clinical trials have demonstrated significant benefits across various biologic agents including a reduction in the frequency of exacerbations, improved lung function, and improved quality-of-life. Patients generally report less symptoms, a reduced reliance on the use of reliever inhalers, and improved overall health. Common targets for biologic agents currently (April 2024) include IgE (immunoglobulin E), interleukin (IL) -4, IL-5, IL-13, and thymic stromal lymphopoietin (TSLP). Biologic therapies are noted to be generally well tolerated with little in the way of adverse reactions.
At present five biologic agents are approved for the treatment of severe asthma. These include omalizumab (humanised recombinant monoclonal anti-IgE antibody), mepolizumab (human monoclonal antibody against IL-5), benralizumab (monoclonal antibody that binds IL-5 receptor), reslizumab (humanised monoclonal antibody anti-IL-5), and dupilumab (human monoclonal antibody that binds to IL-4 receptor). All are subcutaneous injections except reslizumab, which is given by intravenous infusion.
Any patient considered for biologic therapy should have a confirmed diagnosis of severe asthma, which in practice can be difficult to confirm as per GINA guidelines. They also need to be on maximal inhaled therapy, with confirmed adequate compliance, which is technically and logistically difficult to prove, with persistent symptoms and a minimum number of exacerbations requiring treatment with at least OCS (in Ireland, two or more per year and in the UK, four or more per year).
Anti-IgE
IgE is produced by B-cells in response to allergen activation. Omalizumab is a monoclonal antibody that binds to IgE to prevent it from combining with IgE receptors on mast cells and basophils, and thus prevents the release of inflammatory mediators when IgE is activated by allergens. Omalizumab reduces the number of asthma exacerbations, reduces maintenance OCS use, improves asthma symptoms, and reduces the need for reliever medication. In addition, some studies have reported some improvement in lung function. Efficacy is estimated at 60-to-70 per cent and omalizumab is generally well tolerated.
Anti-IL-5
IL-5 is the cytokine involved in the recruitment, activation, and survival of eosinophils. Mepolizumab is a monoclonal anti-IL-5 antibody. In clinical trials it has been proven to reduce asthma exacerbations and maintenance OCS required, improve lung function (modestly), symptoms, and quality-of-life.
Reslizumab has a similar mechanism of action against IL-5. Benefits are similar to those of mepolizumab, with reduction in exacerbations, reduced sputum eosinophils, improved lung function, symptoms, and quality-of-life.
Benralizumab differs in that it binds to the alpha subunit of the IL-5 receptor, inhibiting the proliferation and activation of eosinophils. Its benefits are largely similar to those of the other anti-IL-5 antibodies. In a global meta-analysis of randomised controlled trials of mepolizumab, reslizumab, and benralizumab, no clear superiority was observed and there have been no head-to-head trials.
Anti-IL-4/IL-13
Il-4 and IL-13 are mainly produced by Th2-cells and they promote the production of IgE and recruitment of inflammatory cells. Dupilumab is a monoclonal antibody to IL-4 receptor alpha subunit. It has been proven to significantly reduce the number of exacerbations, frequency of steroid use, and biomarkers of inflammation with good tolerability and limited side-effects. Use of dupilumab in patients with markedly elevated blood eosinophil counts (>1.5u/ul) is cautioned against.
DRUG | OMALIZUMAB | MEPOLIZUMAB | RESLIZUMAB | BENRALIZUMAB | DUPILUMAB |
---|---|---|---|---|---|
Target | IgE | IL-5 | IL-5 | IL-5R alpha | IL-4R alpha |
Mode of administration | Subcutaneous | Subcutaneous | Intravenous | Subcutaneous | Subcutaneous |
Eligibility criteria in asthma (all must be on high dose ICS/LABA therapy and adherent) |
Specific IgE or sensitisation to inhaled allergens and 2 or more exacerbations in the last 12 months or on maintenance OCS ≥5mg prednisolone daily or equivalent |
Serum eosinophils >300/μL* and 2 or more exacerbations in the last 12 months or on maintenance OCS ≥5mg prednisolone daily or equivalent |
Serum eosinophils >400/μL* and 1 or more exacerbations in the last 12 months |
Serum eosinophils >300/μL* and 2 or more exacerbations in the last 12 months or on maintenance OCS ≥5mg prednisolone daily or equivalent |
Serum eosinophils >300/μL* and <1500/μL and 2 or more exacerbations in the last 12 months and/or FeNO >25ppb Not smoking |
TABLE 1: Biologics for severe asthma in Ireland criteria (April 2024) *or historical pre OCS (or it should be argued a biologic) blood eosinophil count
TSLP
TSLP, IL-25, and IL-33 are epithelial derived cytokines also referred to as alarmins. These cytokines are produced upstream in the inflammatory cascade and are expressed by airway epithelial cells in response to allergens, airway pollutants, viruses, and various other environmental insults. They are implicated in both the pathogenesis of asthma and its disease severity. It has been hypothesised that by interfering upstream in the ‘asthma’ cascade, TLSP may, in contrast to IL-4, IL-5, or IL-13, affect disease activity more widely than a single further downstream cytokine.
Having been identified as a novel target for biologic therapy in severe asthma, randomised controlled trials have recently shown the efficacy of an anti-TSLP human monoclonal antibody called tezepelumab. Tezepelumab improves lung function, asthma control, and health-related quality-of-life, and reduces the number of exacerbations in patients with severe uncontrolled asthma. However, tezepelumab did not demonstrate a significant reduction in the daily OCS dose in patients with severe asthma in clinical trials.
Studies have demonstrated that the relief provided is sustained and appears to be regardless of asthma phenotype, therefore, including patients with T2-low asthma for whom at present there is no approved specific treatments. Though patients with a more T2-high phenotype have a more profound response to this who are T2-low.
Identifying appropriate patients for biologic therapy is paramount in the success of these treatment algorithms and to ensure cost-effectiveness, appropriate use of resources, and best clinical outcomes for patients. A more precise understanding of patient characteristics that would elucidate the greatest benefit from a specific biologic would be helpful. Use of predictive biomarkers could also help clinicians decide which biologic would lead to the most beneficial response. In addition, use of biomarkers and clinical indicators of response to biologic therapy earlier in the treatment course would allow for earlier adjustment to treatment regimens.
Summary
Asthma is a chronic disease comprising multiple clinical and inflammatory phenotypes. The mainstay of treatment has historically heavily relied on corticosteroids, which we understand can have devastating long-term sequelae. Biologic therapies represent a paradigm shift in the management of severe asthma, offering targeted approaches to control inflammation and improve quality-of-life for patients. By targeting specific inflammatory pathways, these medications have demonstrated significant reductions in exacerbations, improvements in lung function, and enhanced quality-of-life.
As our understanding of asthma phenotypes and endotypes deepens, the selection of biologic therapies becomes increasingly personalised. However, challenges remain including a lack of real world evidence, though registries such as the International Severe Asthma Registry or the European Severe Asthma Registry are tackling this. Identifying appropriate biomarkers to predict response to biologics and guide treatment decisions remains a challenge, as individual patient responses vary.
Hopefully, earlier identification of patients at high risk of developing severe asthma (recall it is a retrospective diagnosis) may also benefit from earlier access to biologics, which may alter the disease trajectory. These challenges underscore the need for ongoing research, personalised treatment approaches, and efforts to address economic and social barriers to optimise the use of biologics in managing severe asthma.
References on request
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