Asthma affects more than 300 million people worldwide. Characterized by variable symptoms of shortness of breath, cough, and chest tightness, asthma is associated with chronic airway inflammation, reversible expiratory airflow limitation, and airway hyperresponsiveness.1
In difficult-to-treat asthma, poor control may be related to poor adherence to inhaled glucocorticoids, incorrect inhalation technique, and coexisting conditions, including exposure to allergens and irritants.2
Asthma that is difficult to treat is considered severe when control remains poor despite measures that adequately address each of these three variables.3,4
Up to 10% of adults and 2.5% of children with asthma have severe asthma, with reduced quality of life and increased risk of fixed airflow limitation, exacerbations, use of healthcare resources, hospitalization and death.5
Patients with severe asthma have persistent symptoms or frequent exacerbations requiring repeat glucocorticoids, maintenance therapy with oral glucocorticoids, or both, despite adequate treatment with high-dose inhaled glucocorticoids, long-acting β2-agonists, and long-acting muscarinic antagonists. prolonged.1 In these patients, additional treatment, which may include biological therapies, is necessary to reduce the disease burden.
Severe asthma is a heterogeneous syndrome that encompasses several clinical phenotypes that differ according to the age of asthma onset (childhood onset vs. adult onset), presence or absence of allergy and other coexisting conditions, severity of asthma limitation, airflow, frequency of exacerbations, response to treatment and prognosis.6
Severe asthma is also biologically heterogeneous, with distinct patterns of airway inflammation defined by predominant granulocytes in sputum or bronchial biopsy specimens and often identified by blood or exhaled breath biomarkers.
High-inflammation type 2 asthma ( type 2-high) is characterized by eosinophilic inflammation of the airways, which is associated with elevated blood eosinophil counts or elevations of fractional exhaled nitric oxide (FENO), while type 2 asthma low inflammation (type 2-low) encompasses neutrophilic asthma and paucigranulocytic asthma; The coexistence of eosinophilic and neutrophilic inflammation of the airways characterizes mixed granulocytic asthma.7
Approximately 50% of mild to moderate asthma cases and probably a higher proportion of severe asthma cases are type 2-high asthma.8,9 This review describes recent knowledge on type 2 inflammation in asthma and biological treatments. currently available, including their mechanism of action, efficacy and safety in children and adults with severe asthma.
| Type 2 inflammation in asthma |
Type 2 cytokines include interleukin-5, interleukin-4, and interleukin-13.10 Interleukin-5 promotes the proliferation, differentiation, activation, and survival of eosinophils. The number of eosinophils in peripheral blood, bronchoalveolar lavage fluid, and bronchial biopsy samples directly correlates with the severity of asthma.11
Interleukin-4 and interleukin-13, which share the interleukin-4 α receptor (interleukin-4Rα), have many overlapping functions. Interleukin-4 plays a key role in the differentiation of CD4+ type 2 helper T cells and drives IgE isotype switching into B cells. Interleukin-13 induces contraction of airway smooth muscle cells and stimulates inducible nitric oxide synthetase in bronchial epithelial cells, leading to increased FENO.
Type 2 inflammation in asthma is generally suppressed by glucocorticoids , as evidenced by a rapid decrease in FENO (mediated by airway interleukin-13) when inhaled glucocorticoid treatment is initiated and an immediate decrease in counts occurs. of blood eosinophils (mediated by systemic interleukin-5) with the use of oral glucocorticoids. However, in a subgroup of patients with severe asthma, airway eosinophilia persists despite the use of high-dose inhaled glucocorticoids or oral glucocorticoids.12
Type 2 cytokines and Ig E have been highlighted as therapeutic targets for asthma based on preclinical models of eosinophilic allergic airway inflammation. 10 However, successful translation into asthma treatments required two crucial insights into the pathogenesis of asthma: an appreciation of the clinical and biological heterogeneity of the disorder (type 2–high versus type 2–low)7 and the discovery of the strong association between eosinophilic airway inflammation and the risk of exacerbations.13 These insights led to the selection of medications for patients with eosinophilic asthma and for those with a history of exacerbations.
| Anti-IgE monoclonal antibodies |
The anti-IgE monoclonal antibody omalizumab was the first biological agent approved by the Food and Drug Administration (FDA) for the treatment of asthma. By targeting the Fc fragment of IgE, omalizumab reduces free IgE levels in serum and inhibits the binding of IgE to its high-affinity receptor on mast cells and basophils. In allergen challenge models in patients with mild allergic asthma, omalizumab limits allergen-induced early and late phase asthmatic responses.14
Omalizumab is approved for subcutaneous administration in people 6 years of age or older who have moderate to severe allergic asthma, with a positive skin prick test or allergen-specific IgE to a perennial aeroallergen, and whose symptoms are not controlled with glucocorticoids inhaled.
A review evaluating 25 clinical trials concluded that omalizumab reduced asthma exacerbations and hospitalizations, with small improvements in quality of life and lung function.15 Anaphylaxis occurs in 0.1 to 0.2% of patients, most frequently with one of the first three doses, and a black box warning recommends precautions, including administering the agent in a healthcare setting and providing patients with epinephrine auto-injectors.
Most studies of omalizumab involved patients with moderate to severe asthma who were receiving inhaled glucocorticoids, with only a few studies involving patients with severe asthma.
Almost all studies included patients with allergic asthma and used threshold serum levels of total IgE as an inclusion criterion. Although the dose of omalizumab (75 to 375 mg administered subcutaneously every 2 to 4 weeks) is based on body weight and pretreatment serum total IgE level, the absolute level of total IgE does not accurately predict a therapeutic response.
In a post hoc analysis, reductions in asthma exacerbations were greater in subgroups of patients with FENO, blood eosinophils, and high serum periostin levels than in subgroups with low values.16 However, identification of biomarkers that accurately predict a therapeutic response to omalizumab.17
| Antibodies against Interleukin-5 and Interleukin-5R |
Mepolizumab and reslizumab , humanized monoclonal antibodies directed against the interleukin-5 ligand, and benralizumab, which reduces eosinophils by binding to the interleukin-5 receptor (interleukin-5R), are biologic agents approved by the FDA for the treatment of patients with asthma severe eosinophilia. Although the initial studies, which enrolled patients who had moderate asthma without evidence of eosinophilic airway inflammation, failed to show a benefit from anti-interleukin-5 antibodies, subsequent investigator-initiated trials showed significant reductions in exacerbations among patients with eosinophilic asthma.12,18
In phase 3 studies, additional treatment with mepolizumab (given subcutaneously or intravenously) or reslizumab (given intravenously) reduced exacerbation rates by approximately 50% and improved health-related quality of life in patients with severe eosinophilic asthma prone to exacerbations (i.e., patients with severe eosinophilic asthma who have recurrent exacerbations), regardless of the presence or absence of allergy.19-21 Although different cut-off values for blood eosinophil counts were used in these studies , blood eosinophilia was a better predictor of a therapeutic response to anti-interleukin-5 antibody than sputum eosinophil counts or FENO. 22,23
In real-world observational studies, adolescents and adults with severe eosinophilic asthma who were treated with mepolizumab (100 mg administered subcutaneously every 4 weeks) had fewer exacerbations and hospitalizations, a lower oral glucocorticoid burden, and better symptom control and quality of life. life than in the previous year.24
In adults with uncontrolled severe eosinophilic asthma , treatment with reslizumab (3 mg per kilogram of body weight, administered intravenously every 4 weeks) was associated with fewer exacerbations, both in randomized controlled trials (RCTs) and real-world studies .20,25
The most frequently reported adverse events in long-term safety studies of mepolizumab and reslizumab were respiratory infections, headache, and worsening asthma.26,27 Among 1,028 patients receiving intravenous reslizumab, three cases of anaphylaxis were observed, which led to a black box warning from the FDA.27
Benralizumab is a humanized, afucosylated monoclonal antibody that targets the alpha subunit of interleukin-5R in eosinophils, inducing apoptosis through antibody-dependent, cell-mediated cytotoxicity.
In a bronchoscopic study, benralizumab reduced the eosinophil count in the airway mucosa and sputum by 90% or more and completely suppressed the number of eosinophils in the blood.28 In two pivotal phase 3 trials involving adolescents and adults with tendency to severe asthma exacerbations, additional treatment with benralizumab (30 mg administered subcutaneously every 4 to 8 weeks) significantly reduced the exacerbation rate and improved prebronchodilator forced expiratory volume in 1 second (FEV1), compared with placebo, in patients with baseline blood eosinophil counts of 300 per microliter or higher.29,30
Because the every 8-week benralizumab regimen also rapidly improved asthma symptoms and health-related quality of life,31 this dosing regimen has been chosen for market authorization. Open-label, real-world extension studies have confirmed the real-life efficacy and long-term safety of benralizumab in patients with severe eosinophilic asthma.32,33
More exacerbations in the past year and a higher blood eosinophil count at baseline are predominant predictors of an improved response to anti-interleukin-5 and anti-interleukin-5R antibodies.34,35 However, a single eosinophil measurement , particularly when low, may be insufficient to establish a diagnosis of severe eosinophilic asthma.36,37
Studies have shown that patients with adult eosinophilic asthma or concomitant nasal polyposis have a good response to anti-interleukin-5 or anti-interleukin-5R antibodies.38,39 In contrast, in patients with an eosinophilic disease phenotype Chronic Obstructive Pulmonary Disease (COPD) and a history of exacerbations, additional therapy with mepolizumab only modestly reduces exacerbations, compared with placebo; Benralizumab does not reduce exacerbations.40,41 Therefore, it is important to differentiate severe asthma from COPD.
| Anti Interleukin 4 receptor antibody |
Dupilumab , a fully human monoclonal antibody, inhibits interleukin-4 and interleukin-13 signaling by binding to interleukin-4Rα, which they share. In the pivotal Phase 3 trial in patients with uncontrolled moderate to severe asthma, dupilumab significantly reduced severe exacerbations, including those leading to emergency department visits or hospitalization, compared with placebo.42
Dupilumab also improved asthma control, as well as pre-bronchodilator and post-bronchodilator FEV1. 43 Reductions in exacerbation frequency and improvements in lung function were most pronounced among patients with blood eosinophil counts of 150 per microliter or higher or FENO values of 25 parts per billion (ppb) or higher at baseline. 42.44
In phase 3 trials, patients with eosinophil counts above 1500 per microliter at baseline were excluded. In a real-life retrospective cohort study of adults with severe asthma (primarily dependent on oral glucocorticoids), additional dupilumab therapy was associated with improved asthma and lung function control, as well as reductions in glucocorticoid use. oral administration and the rate of exacerbations.45
The most common adverse events with dupilumab are injection site reactions (occurring in 15% of patients).42,45 Hypereosinophilia (eosinophil count ≥1500 per microliter) is seen in 4 to 25% of patients ; it persists after 6 months in 14% of these patients. Although dupilumab-induced hypereosinophilia is most frequently asymptomatic, rare cases of eosinophilic granulomatosis with polyangiitis have been reported.46
Dupilumab is effective and approved by the FDA for the treatment of atopic dermatitis and chronic rhinosinusitis with nasal polyposis, both of which are driven by type 2 inflammation.47,48 Therefore, dupilumab is a suitable treatment for patients with any of these conditions. and severe asthma.
| Anti-epithelial cytokine antibodies |
The epithelial cytokines TSLP (thymic stromal lymphopoietin), interleukin-25, and interleukin-33 are released by airway epithelial cells in response to allergens, air pollutants, and viruses, increasing downstream inflammation.49
It has been hypothesized that by interfering upstream in the inflammatory cascade, biologic agents targeting epithelial cytokines, compared with antibodies specific to type 2 cytokines, could improve asthma outcomes in a broader patient population. .49.50
RCTs have recently demonstrated the efficacy of a human monoclonal anti-TSLP antibody (tezepelumab), a human monoclonal anti-interleukin-33 antibody (itepekimab), and a human monoclonal antibody that inhibits the interleukin-33 receptor (also known as tumorigenicity suppressor 2 [ST2]) (astegolimab) in patients with severe asthma.51-53
In a phase 3 RCT involving adolescents and adults with severe uncontrolled asthma, adjunctive therapy with the human anti-TSLP monoclonal antibody tezepelumab , at a dose of 210 mg administered subcutaneously every 4 weeks, significantly reduced the rate annualized rate of asthma exacerbations by 56%, and among patients with blood eosinophil counts of less than 300 per microliter at baseline, the rate was reduced by 41%.51
Compared with placebo, tezepelumab reduced exacerbations in patients with type 2-high asthma and in patients with type 2-low asthma and also improved lung function, asthma control, and health-related quality of life. Tezepelumab rapidly reduced blood eosinophil and FENO counts, gradually reduced total serum IgE levels, and attenuated airway hyperreactivity to mannitol.54,55
Safety findings were similar for active treatment and placebo.51 In a mechanical bronchoscopy study, tezepelumab significantly reduced the number of eosinophils, but not the number of neutrophils, mast cells, or T cells, in the submucosa of the airways. 55
Itepekimab , at a dose of 300 mg administered subcutaneously every 2 weeks, prevented loss of asthma control and improved lung function, compared with placebo, in a phase 2 study involving patients who had moderate to severe asthma and were reducing their maintenance therapy with inhaled glucocorticoids plus long-acting beta-agonists.52
The combination of itepekimab and dupilumab did not provide benefits beyond the individual treatments. Astegolimab (70 mg or 490 mg, but not 210 mg, administered subcutaneously every 4 weeks) reduced exacerbations, compared with placebo, in a phase 2b RCT involving patients with asthma, including those with low levels of asthma. eosinophil counts.53
Astegolimab did not improve lung function. Confirmatory phase 3 RCTs of antibodies against interleukin-33 and ST2 in patients with severe asthma, particularly type 2-low, are necessary.
| Biological therapies as oral glucocorticoid-sparing agents |
Systemic glucocorticoids are commonly used for the treatment of severe asthma, as short-term treatment courses or long-term daily oral regimens, but are associated with acute and chronic adverse effects.56
The burden of disorders associated with oral glucocorticoids increases with dose accumulation and increases the burden of severe asthma.
Furthermore, while asthma is not associated with increased severity of coronavirus disease 2019 (Covid-19),57 the use of oral glucocorticoids for severe uncontrolled asthma has been linked to increased Covid-related mortality. 19.58
In clinical trials, several anticytokine antibodies allowed tapering of oral glucocorticoids with the use of predefined schedules while asthma control was maintained in adults with severe glucocorticoid-dependent asthma.
Mepolizumab (100 mg administered subcutaneously every 4 weeks) reduced glucocorticoid dosage by a median of 50% compared with placebo, while reducing the annualized exacerbation rate by 32% and improving asthma control,59 findings that were supported by real-life observational studies.60
Mepolizumab has been approved by the FDA at a higher dose (300 mg administered subcutaneously every 4 weeks) for the treatment of eosinophilic granulomatosis with polyangiitis in patients with uncontrolled asthma.61
Benralizumab (30 mg administered subcutaneously every 4 to 8 weeks) significantly reduced the mean oral glucocorticoid dose from baseline to 28 weeks compared to placebo (75% reduction vs. 25% reduction). 62 The annual exacerbation rate was also reduced, although there was no sustained effect on FEV1. Adding dupilumab treatment (300 mg administered subcutaneously every 2 weeks) reduced the oral glucocorticoid dose by 70%, compared with 42% with placebo, while reducing severe exacerbations and improving lung function.63 Although the magnitude Although the glucocorticoid-sparing effect of dupilumab treatment was greater in patients with a higher blood eosinophil count at baseline, dupilumab provided benefits even in the low eosinophil subgroup.
In contrast, neither fixed-dose subcutaneous reslizumab (110 mg every 4 weeks) nor fixed-dose subcutaneous tezepelumab (210 mg every 4 weeks) reduced the daily dose of oral glucocorticoid in glucocorticoid-dependent patients with severe asthma.64,65 Although Subgroup analyzes suggest that patients with severe asthma dependent on oral glucocorticoids have better asthma control when receiving omalizumab, prospective evaluation is required to determine whether omalizumab has glucocorticoid-sparing effects.
| Biological agents in children and adolescents with severe asthma |
The anti-IgE monoclonal antibody omalizumab has been extensively studied in moderate to severe pediatric asthma . A meta-analysis of three RCTs involving 1380 children with allergic asthma showed that omalizumab reduced exacerbations and hospitalizations, was associated with a greater reduction in inhaled glucocorticoids compared with placebo, and had an acceptable adverse event profile. 66
Some phase 3 trials of anti-cytokine type 2 antibodies have included adolescents (≥12 years of age). A post hoc meta-analysis involving 34 adolescents with severe eosinophilic asthma who were included in randomized trials suggested similar effects in this group and in the general population studied, but the small sample precluded drawing conclusions.
The safety profile among adolescents appeared to be similar to that of adults, although as noted, the number of patients that could be evaluated was small.67 A recent open-label observational study confirmed the safety of mepolizumab in children (6 to 11 years of age) with severe asthma and showed a reduction in exacerbations, compared to baseline.68 Since the type 2-high eosinophilic phenotype is often observed in children with severe asthma and recurrent exacerbations,69 it appears It is likely that anti-cytokine type 2 antibodies will be effective in children with severe asthma who are prone to exacerbations.70
In an RCT of 408 children (6 to 11 years of age) with uncontrolled moderate to severe asthma, dupilumab significantly reduced asthma exacerbations and improved lung function and asthma-related quality of life, with more pronounced effects in the population. of children with high type 2 asthma and baseline blood eosinophil counts of 150 per microliter or greater or FENO values of 20 ppb or greater.71
The safety profile was acceptable. In previous analyzes of predictors of response to benralizumab or reslizumab, older age (≥18 years vs <18 years) and later onset of eosinophilic asthma (adulthood onset vs. childhood) are associated with greater efficacy. 34,38 These observations underscore the need for RCTs that involve well-characterized children with severe asthma and include long-term follow-up for safety assessment.
| Choice of initial biological therapy |
As no head-to-head RCT data are available comparing the efficacy, real-life effectiveness and long-term safety of monoclonal antibodies in patients with severe asthma, high-level evidence to guide clinical decision-making is lacking.
Before starting biological therapy, the number of exacerbations in the last year, status with respect to the use of oral glucocorticoids, biomarkers (blood eosinophil count, FENO, and total and allergen-specific serum IgE), FEV1 should be recorded. , asthma control and quality of life.
Criteria are taken into account such as dosing frequency, route of administration (subcutaneous or intravenous), whether the administration of the drug requires monitoring by health personnel, age of onset of asthma, biomarkers, coexisting conditions (for example, atopic dermatitis and nasal polyposis). ), insurance coverage, cost, and patient preference in choosing an available therapy.35
Biomarkers and coexisting conditions should be integrated with clinical phenotyping in decision making regarding the choice of initial biological therapy.
| Monitoring of biological therapies |
Management should be individualized according to the “assess, adjust, and review response” cycle.1
A treatment period of 4 to 6 months is needed to evaluate the effectiveness of a biologic agent; Safety concerns may arise early in that interval (e.g., eosinophil elevations with dupilumab or injection site reactions with all treatments).
Although there are currently no well-defined criteria for a good response to a biologic agent, a reduction in the number of exacerbations and improvement in asthma symptoms and quality of life are key outcomes, which must be defined at a later date. priori by the doctor and the patient together.
In patients with severe asthma dependent on oral glucocorticoids, the percentage reduction in glucocorticoid dose with maintenance of asthma control is a critical outcome measure.73 In addition, the use of health services, the degree of improvement in Pulmonary function, effect on coexisting conditions, side effects and patient satisfaction must be taken into account.
If a patient has an inadequate response, with persistent symptoms or exacerbations, lack of adherence to background control therapy or the biologic itself should be evaluated. While several biologic agents are available as an autoinjector pen, potential poor adherence with home dosing should be considered and adherence should be improved before switching to a different biologic agent.
Inadequate management of coexisting conditions (e.g., obesity and rhinosinusitis) and the development of neutralizing antidrug antibodies may also underlie suboptimal responses to biologic therapy.
Finally, the asthma phenotype, including biomarkers (blood eosinophil count, FENO, and serum IgE level), should be reevaluated before switching to another biologic agent. The addition of a second biologic is currently not recommended due to incremental costs and lack of high-quality evidence supporting this approach.
| Future perspectives |
For uncontrolled, severe, type 2-high asthma, data are required to better inform the choice of biologic therapy.74 There is an urgent need for biomarkers that accurately predict therapeutic response (predictive biomarkers) and early markers of response. to therapy (monitoring biomarkers).
Adaptive platform testing is anticipated to facilitate rapid evaluation of new interventions in subgroups of patients with severe asthma defined by biomarkers.75 Additionally, pragmatic trial platforms are needed to conduct head-to-head RCTs of different biologics to determine their comparative effectiveness. in patients with severe asthma.76,77
Responses to biologic agents in such patients differ, from excellent response to no response.33,34,77 Because biologic therapies are expensive, targeted use of these antibodies in patients most likely to benefit from them is warranted.
Several other research questions need to be asked. First, what is the immunogenicity risk of monoclonal antibodies in patients with severe asthma? The development of neutralizing antidrug antibodies could affect the efficacy of the agent.33 Therapeutic drug monitoring should be explored in patients with suboptimal responses.37
Second, how long should patients with severe asthma be treated with these biologic agents? There is a need for long-term studies investigating the effect of agents on disease course, such as change in underlying asthma endotype, whether the target of biologic therapy occurs after an inciting event, or perhaps even improvement in asthma severity or remission.78
Third, more data are needed on the efficacy and safety of biologic therapies in special populations (e.g., children, adolescents, and pregnant women79,80; populations whose genetic ancestry was not well represented in clinical trial registration). ; and in elderly patients). Severe asthma disproportionately affects black populations who, along with other more affected groups, have been underrepresented in clinical studies. 81,82 Future studies are needed to improve the evaluation of appropriate and equitable measures to care for all communities affected by asthma.83
Finally, there are currently no biological treatments available for type 2-severe asthma,7 which is characterized by neutrophilic or paucigranulocytic inflammation of the airways and is associated with advanced age, adult asthma, obesity, metabolic syndrome, hypertension, and increased resistance. to treatment with glucocorticoids.84 Although the pathophysiological characteristics of type 2-low asthma still need to be clarified, several molecular mechanisms have been implicated, including interleukin-6, CXCL8 (CXC chemokine ligand 8), interleukin-17A, interleukin-23, interferon -γ, tumor necrosis factor α, interleukin-33, and TSLP.85
Recently, the anti-TSLP antibody tezepelumab was shown to reduce exacerbation rates among patients with severe, uncontrolled asthma, regardless of baseline blood eosinophils,51 while the anti-interleukin-23 monoclonal antibody Risankizumab did not provide a clinical benefit in patients with severe asthma.86
Conclusions
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| Comment |
The present review highlights the essential role of establishing an adequate diagnosis of the type of asthma that patients present, differentiating difficult-to-treat asthma from severe asthma, in addition to determining the phenotype of severe asthma.
It is necessary to integrate clinical characteristics, biomarkers, and coexisting conditions to choose the appropriate initial biologic therapy and then monitor therapeutic response and adverse effects to decide whether to continue or change the administered agent.
Criteria for a good response to treatment are a reduction in the number of exacerbations and an improvement in asthma symptoms and patients’ quality of life.
More RCTs will be necessary to make generalizable recommendations to different populations of patients with asthma.
