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Which biologic therapy should I use in patients who have moderate to severe asthma with associated comorbidities?
Dr. Hossri and Dr. Ivashchuk are with UTHealth Houston –Texas Medical Center, Department of Internal Medicine; Division of Pulmonary, Critical Care, and Sleep Medicine.
As new treatments for specific moderate to severe asthma phenotypes have been developed, management decisions have grown more complicated. The treatment indications for asthma are clear; however, there is overlap with certain therapeutics that target the same pathway with similar end results. because it is not a one-size-fits-all approach that follows a rigid algorithm. Instead, it is a customized treatment plan that accounts for patient-specific risk factors and comorbidities.
Comorbidities commonly associated with asthma include atopic dermatitis, chronic rhinosinusitis with nasal polyposis, eosinophilic granulomatosis with polyangiitis, eosinophilic esophagitis, bronchiectasis and allergic bronchopulmonary aspergillosis. While we lack consensus or a universally accepted treatment algorithm for treating asthma when these comorbidities are present, recent evidence helps guide us to which therapies work best.
Atopic dermatitis
There is a higher prevalence of asthma in patients with atopic dermatitis. A concept called the “atopic march” refers to the progression of childhood atopic dermatitis to manifestations such as asthma, food allergies, and hay fever. The more severe the atopic dermatitis is in childhood, the higher the risk for asthma later on in life. The data on the biologic pathogenesis of atopic dermatitis point to the involvement of interleukins – interleukin (IL)-4 and IL 13 (Silverberg JI. Ann Allergy Asthma Immunol. 2019;123[2]:144-51).
These same interleukins are active in what is called “Th2-high” asthma. The activation of Th2 cells in the inflammatory pathway occurs in atopic dermatitis and asthma irrespective of immunoglobulin E levels. Preliminary data show therapies that target IL-13 alone are effective for treating asthma with comorbid atopic dermatitis but those blocking both IL-4 and IL-13, like dupilumab, are superior. Both interleukins are considered pivotal in the Th-2 pathway. This suggests that dual inhibition is an integral component in the treatment of moderate to severe atopic dermatitis with asthma. Analysis of other Th2 mediators, such as mepolizumab (IL-5 antagonist) and omalizumab (anti-IgE) have shown minimal efficacy, further supporting the use of dupilumab (Guttman-Yassky E, et al. J Allergy Clin. Immunol. 2019 Jan;143[1]:155-72).
Chronic rhinosinusitis with nasal polyposis
The “unified airway” concept holds that because the upper airways (nasal mucosa, pharynx, and larynx) are in direct communication with the lower airways (bronchi and bronchioles). This would explain the correlation between chronic rhinosinusitis with nasal polyposis (CRSwNP) and asthma. Many studies also show the severity of one disease increases the severity of the other.
Patients with both CRSwNP and asthma typically experience a more treatment-resistant course characterized by higher rates of corticosteroid dependence and nasal polyposis recurrences when compared with asthma alone (Laidlaw TM, et al. J Allergy Clin Immunol. 2021 Mar;9[3]:1133-41). They typically have Th2-high asthma and are usually eosinophilic. The optimal treatment approach is mindful of the unified airway concept. Large-scale studies demonstrate significant benefit when targeting IL-5, especially in those with bilateral nasal polyps, need for systemic steroids in the past 2 years, significant impairment in quality of life, loss of smell, and a concomitant diagnosis of asthma (Fokkens WJ, et al. Allergy. 2019 Dec;74[12]:2312). Although data are inconsistent, there is enough evidence to suggest dupilumab be considered for those with eosinophilic asthma and CRSwNP along with atopy, atopic dermatitis, and/or high FeNO levels. In those without atopic symptoms, an anti-IL5/anti-IL5R (mainly mepolizumab and benralizumab) is preferred. Having said this, direct comparative analyses between biologics are lacking, and the above approach relies on an indirect assessment of existing data coupled with clinical experience. The approach may change as new data become available.
Eosinophilic granulomatosis with polyangiitis
Eosinophilic granulomatosis with polyangiitis (EGPA) is a vasculitis characterized by disseminated necrotizing eosinophilic granulomas. EGPA is driven by a response similar to that seen in Th2-high asthma. Adult-onset asthma with sinusitis and allergic rhinitis is the most common EGPA presentation. Of all the biologics, mepolizumab has been best studied as treatment for those with EGPA and asthma symptoms. One small study demonstrated disease remission in 8 of 10 cases (Moosig F, et al. Ann Intern Med. 2011 Sep 6;155[5]:341-3). However, many of these patients relapsed after discontinuing therapy.
Eosinophilic esophagitis
Recent reports demonstrated a large portion of adults with a
diagnosis of eosinophilic
esophagitis (EoE) also have a history of asthma. Currently, standard treatment is proton pump
inhibitors and diet modifications. The prevalence of EoE has increased with growing awareness of the disease. Unrecognized and untreated EoE can lead to devastating complications such as esophageal fibrosis, strictures, and food impaction. Similar to some of the above-mentioned syndromes,
EoE is also driven by a Th2 response and eosinophilic inflammation. A recent study in 2022 showed that 31% to 38% of
people with EoE had concomitant asthma (Dellon ES, et al. N Engl J Med. 2022 Dec 22;387 [25]:2317-30). In this population, a weekly dose of dupilumab, 300 mg, led
to a significant improvement in dysphagia symptoms and
histology when compared with placebo.
Allergic bronchopulmonary aspergillosis
Despite its low prevalence worldwide, allergic bronchopulmonary aspergillosis (ABPA) is frequently encountered when managing severe asthma. Current treatment is long-term, relatively high dose systemic corticosteroids. In light of their unfavorable side effect profile, steroid-sparing approaches are being sought. Dupilumab, omalizumab, mepolizumab, and benralizumab have all been tested for their effects on ABPA. Thus far, mepolizumab has the most convincing evidence to support its use for asthma with concomitant ABPA, mainly because it has the most rapid onset of action. Up to 90% of patients with ABPA were able to stop systemic steroids between 2 and 14 months after starting mepolizumab (Schleich F, et al. J Allergy Clin Immunol. 2020 Jul-Aug;8[7]:2412-3.e2).
Bronchiectasis
Asthma and bronchiectasis can coexist in up to 77% of patients. Typically, the pathophysiology behind bronchiectasis is focused around neutrophilic inflammation. New evidence suggests some patients with bronchiectasis, usually in the setting of comorbid adult-onset asthma, demonstrate an eosinophilic Th-2 response. The association is seen more commonly in female patients, the elderly, and nonsmokers. A small prospective study with four patients with severe asthma and bronchiectasis showed significant improvement with less exacerbations, increased pre-bronchodilator FEV1, and a reduction of serum and sputum eosinophils after starting mepolizumab treatment (Carpagnano GE, et al. J Asthma Allergy. 2019 Mar 5;12:83-90). Clinical trials designed to clarify the role for biologics for asthma with co-morbid bronchiectasis are currently underway.
Dr. Hossri and Dr. Ivashchuk are with UTHealth Houston –Texas Medical Center, Department of Internal Medicine; Division of Pulmonary, Critical Care, and Sleep Medicine.
As new treatments for specific moderate to severe asthma phenotypes have been developed, management decisions have grown more complicated. The treatment indications for asthma are clear; however, there is overlap with certain therapeutics that target the same pathway with similar end results. because it is not a one-size-fits-all approach that follows a rigid algorithm. Instead, it is a customized treatment plan that accounts for patient-specific risk factors and comorbidities.
Comorbidities commonly associated with asthma include atopic dermatitis, chronic rhinosinusitis with nasal polyposis, eosinophilic granulomatosis with polyangiitis, eosinophilic esophagitis, bronchiectasis and allergic bronchopulmonary aspergillosis. While we lack consensus or a universally accepted treatment algorithm for treating asthma when these comorbidities are present, recent evidence helps guide us to which therapies work best.
Atopic dermatitis
There is a higher prevalence of asthma in patients with atopic dermatitis. A concept called the “atopic march” refers to the progression of childhood atopic dermatitis to manifestations such as asthma, food allergies, and hay fever. The more severe the atopic dermatitis is in childhood, the higher the risk for asthma later on in life. The data on the biologic pathogenesis of atopic dermatitis point to the involvement of interleukins – interleukin (IL)-4 and IL 13 (Silverberg JI. Ann Allergy Asthma Immunol. 2019;123[2]:144-51).
These same interleukins are active in what is called “Th2-high” asthma. The activation of Th2 cells in the inflammatory pathway occurs in atopic dermatitis and asthma irrespective of immunoglobulin E levels. Preliminary data show therapies that target IL-13 alone are effective for treating asthma with comorbid atopic dermatitis but those blocking both IL-4 and IL-13, like dupilumab, are superior. Both interleukins are considered pivotal in the Th-2 pathway. This suggests that dual inhibition is an integral component in the treatment of moderate to severe atopic dermatitis with asthma. Analysis of other Th2 mediators, such as mepolizumab (IL-5 antagonist) and omalizumab (anti-IgE) have shown minimal efficacy, further supporting the use of dupilumab (Guttman-Yassky E, et al. J Allergy Clin. Immunol. 2019 Jan;143[1]:155-72).
Chronic rhinosinusitis with nasal polyposis
The “unified airway” concept holds that because the upper airways (nasal mucosa, pharynx, and larynx) are in direct communication with the lower airways (bronchi and bronchioles). This would explain the correlation between chronic rhinosinusitis with nasal polyposis (CRSwNP) and asthma. Many studies also show the severity of one disease increases the severity of the other.
Patients with both CRSwNP and asthma typically experience a more treatment-resistant course characterized by higher rates of corticosteroid dependence and nasal polyposis recurrences when compared with asthma alone (Laidlaw TM, et al. J Allergy Clin Immunol. 2021 Mar;9[3]:1133-41). They typically have Th2-high asthma and are usually eosinophilic. The optimal treatment approach is mindful of the unified airway concept. Large-scale studies demonstrate significant benefit when targeting IL-5, especially in those with bilateral nasal polyps, need for systemic steroids in the past 2 years, significant impairment in quality of life, loss of smell, and a concomitant diagnosis of asthma (Fokkens WJ, et al. Allergy. 2019 Dec;74[12]:2312). Although data are inconsistent, there is enough evidence to suggest dupilumab be considered for those with eosinophilic asthma and CRSwNP along with atopy, atopic dermatitis, and/or high FeNO levels. In those without atopic symptoms, an anti-IL5/anti-IL5R (mainly mepolizumab and benralizumab) is preferred. Having said this, direct comparative analyses between biologics are lacking, and the above approach relies on an indirect assessment of existing data coupled with clinical experience. The approach may change as new data become available.
Eosinophilic granulomatosis with polyangiitis
Eosinophilic granulomatosis with polyangiitis (EGPA) is a vasculitis characterized by disseminated necrotizing eosinophilic granulomas. EGPA is driven by a response similar to that seen in Th2-high asthma. Adult-onset asthma with sinusitis and allergic rhinitis is the most common EGPA presentation. Of all the biologics, mepolizumab has been best studied as treatment for those with EGPA and asthma symptoms. One small study demonstrated disease remission in 8 of 10 cases (Moosig F, et al. Ann Intern Med. 2011 Sep 6;155[5]:341-3). However, many of these patients relapsed after discontinuing therapy.
Eosinophilic esophagitis
Recent reports demonstrated a large portion of adults with a
diagnosis of eosinophilic
esophagitis (EoE) also have a history of asthma. Currently, standard treatment is proton pump
inhibitors and diet modifications. The prevalence of EoE has increased with growing awareness of the disease. Unrecognized and untreated EoE can lead to devastating complications such as esophageal fibrosis, strictures, and food impaction. Similar to some of the above-mentioned syndromes,
EoE is also driven by a Th2 response and eosinophilic inflammation. A recent study in 2022 showed that 31% to 38% of
people with EoE had concomitant asthma (Dellon ES, et al. N Engl J Med. 2022 Dec 22;387 [25]:2317-30). In this population, a weekly dose of dupilumab, 300 mg, led
to a significant improvement in dysphagia symptoms and
histology when compared with placebo.
Allergic bronchopulmonary aspergillosis
Despite its low prevalence worldwide, allergic bronchopulmonary aspergillosis (ABPA) is frequently encountered when managing severe asthma. Current treatment is long-term, relatively high dose systemic corticosteroids. In light of their unfavorable side effect profile, steroid-sparing approaches are being sought. Dupilumab, omalizumab, mepolizumab, and benralizumab have all been tested for their effects on ABPA. Thus far, mepolizumab has the most convincing evidence to support its use for asthma with concomitant ABPA, mainly because it has the most rapid onset of action. Up to 90% of patients with ABPA were able to stop systemic steroids between 2 and 14 months after starting mepolizumab (Schleich F, et al. J Allergy Clin Immunol. 2020 Jul-Aug;8[7]:2412-3.e2).
Bronchiectasis
Asthma and bronchiectasis can coexist in up to 77% of patients. Typically, the pathophysiology behind bronchiectasis is focused around neutrophilic inflammation. New evidence suggests some patients with bronchiectasis, usually in the setting of comorbid adult-onset asthma, demonstrate an eosinophilic Th-2 response. The association is seen more commonly in female patients, the elderly, and nonsmokers. A small prospective study with four patients with severe asthma and bronchiectasis showed significant improvement with less exacerbations, increased pre-bronchodilator FEV1, and a reduction of serum and sputum eosinophils after starting mepolizumab treatment (Carpagnano GE, et al. J Asthma Allergy. 2019 Mar 5;12:83-90). Clinical trials designed to clarify the role for biologics for asthma with co-morbid bronchiectasis are currently underway.
Dr. Hossri and Dr. Ivashchuk are with UTHealth Houston –Texas Medical Center, Department of Internal Medicine; Division of Pulmonary, Critical Care, and Sleep Medicine.
As new treatments for specific moderate to severe asthma phenotypes have been developed, management decisions have grown more complicated. The treatment indications for asthma are clear; however, there is overlap with certain therapeutics that target the same pathway with similar end results. because it is not a one-size-fits-all approach that follows a rigid algorithm. Instead, it is a customized treatment plan that accounts for patient-specific risk factors and comorbidities.
Comorbidities commonly associated with asthma include atopic dermatitis, chronic rhinosinusitis with nasal polyposis, eosinophilic granulomatosis with polyangiitis, eosinophilic esophagitis, bronchiectasis and allergic bronchopulmonary aspergillosis. While we lack consensus or a universally accepted treatment algorithm for treating asthma when these comorbidities are present, recent evidence helps guide us to which therapies work best.
Atopic dermatitis
There is a higher prevalence of asthma in patients with atopic dermatitis. A concept called the “atopic march” refers to the progression of childhood atopic dermatitis to manifestations such as asthma, food allergies, and hay fever. The more severe the atopic dermatitis is in childhood, the higher the risk for asthma later on in life. The data on the biologic pathogenesis of atopic dermatitis point to the involvement of interleukins – interleukin (IL)-4 and IL 13 (Silverberg JI. Ann Allergy Asthma Immunol. 2019;123[2]:144-51).
These same interleukins are active in what is called “Th2-high” asthma. The activation of Th2 cells in the inflammatory pathway occurs in atopic dermatitis and asthma irrespective of immunoglobulin E levels. Preliminary data show therapies that target IL-13 alone are effective for treating asthma with comorbid atopic dermatitis but those blocking both IL-4 and IL-13, like dupilumab, are superior. Both interleukins are considered pivotal in the Th-2 pathway. This suggests that dual inhibition is an integral component in the treatment of moderate to severe atopic dermatitis with asthma. Analysis of other Th2 mediators, such as mepolizumab (IL-5 antagonist) and omalizumab (anti-IgE) have shown minimal efficacy, further supporting the use of dupilumab (Guttman-Yassky E, et al. J Allergy Clin. Immunol. 2019 Jan;143[1]:155-72).
Chronic rhinosinusitis with nasal polyposis
The “unified airway” concept holds that because the upper airways (nasal mucosa, pharynx, and larynx) are in direct communication with the lower airways (bronchi and bronchioles). This would explain the correlation between chronic rhinosinusitis with nasal polyposis (CRSwNP) and asthma. Many studies also show the severity of one disease increases the severity of the other.
Patients with both CRSwNP and asthma typically experience a more treatment-resistant course characterized by higher rates of corticosteroid dependence and nasal polyposis recurrences when compared with asthma alone (Laidlaw TM, et al. J Allergy Clin Immunol. 2021 Mar;9[3]:1133-41). They typically have Th2-high asthma and are usually eosinophilic. The optimal treatment approach is mindful of the unified airway concept. Large-scale studies demonstrate significant benefit when targeting IL-5, especially in those with bilateral nasal polyps, need for systemic steroids in the past 2 years, significant impairment in quality of life, loss of smell, and a concomitant diagnosis of asthma (Fokkens WJ, et al. Allergy. 2019 Dec;74[12]:2312). Although data are inconsistent, there is enough evidence to suggest dupilumab be considered for those with eosinophilic asthma and CRSwNP along with atopy, atopic dermatitis, and/or high FeNO levels. In those without atopic symptoms, an anti-IL5/anti-IL5R (mainly mepolizumab and benralizumab) is preferred. Having said this, direct comparative analyses between biologics are lacking, and the above approach relies on an indirect assessment of existing data coupled with clinical experience. The approach may change as new data become available.
Eosinophilic granulomatosis with polyangiitis
Eosinophilic granulomatosis with polyangiitis (EGPA) is a vasculitis characterized by disseminated necrotizing eosinophilic granulomas. EGPA is driven by a response similar to that seen in Th2-high asthma. Adult-onset asthma with sinusitis and allergic rhinitis is the most common EGPA presentation. Of all the biologics, mepolizumab has been best studied as treatment for those with EGPA and asthma symptoms. One small study demonstrated disease remission in 8 of 10 cases (Moosig F, et al. Ann Intern Med. 2011 Sep 6;155[5]:341-3). However, many of these patients relapsed after discontinuing therapy.
Eosinophilic esophagitis
Recent reports demonstrated a large portion of adults with a
diagnosis of eosinophilic
esophagitis (EoE) also have a history of asthma. Currently, standard treatment is proton pump
inhibitors and diet modifications. The prevalence of EoE has increased with growing awareness of the disease. Unrecognized and untreated EoE can lead to devastating complications such as esophageal fibrosis, strictures, and food impaction. Similar to some of the above-mentioned syndromes,
EoE is also driven by a Th2 response and eosinophilic inflammation. A recent study in 2022 showed that 31% to 38% of
people with EoE had concomitant asthma (Dellon ES, et al. N Engl J Med. 2022 Dec 22;387 [25]:2317-30). In this population, a weekly dose of dupilumab, 300 mg, led
to a significant improvement in dysphagia symptoms and
histology when compared with placebo.
Allergic bronchopulmonary aspergillosis
Despite its low prevalence worldwide, allergic bronchopulmonary aspergillosis (ABPA) is frequently encountered when managing severe asthma. Current treatment is long-term, relatively high dose systemic corticosteroids. In light of their unfavorable side effect profile, steroid-sparing approaches are being sought. Dupilumab, omalizumab, mepolizumab, and benralizumab have all been tested for their effects on ABPA. Thus far, mepolizumab has the most convincing evidence to support its use for asthma with concomitant ABPA, mainly because it has the most rapid onset of action. Up to 90% of patients with ABPA were able to stop systemic steroids between 2 and 14 months after starting mepolizumab (Schleich F, et al. J Allergy Clin Immunol. 2020 Jul-Aug;8[7]:2412-3.e2).
Bronchiectasis
Asthma and bronchiectasis can coexist in up to 77% of patients. Typically, the pathophysiology behind bronchiectasis is focused around neutrophilic inflammation. New evidence suggests some patients with bronchiectasis, usually in the setting of comorbid adult-onset asthma, demonstrate an eosinophilic Th-2 response. The association is seen more commonly in female patients, the elderly, and nonsmokers. A small prospective study with four patients with severe asthma and bronchiectasis showed significant improvement with less exacerbations, increased pre-bronchodilator FEV1, and a reduction of serum and sputum eosinophils after starting mepolizumab treatment (Carpagnano GE, et al. J Asthma Allergy. 2019 Mar 5;12:83-90). Clinical trials designed to clarify the role for biologics for asthma with co-morbid bronchiectasis are currently underway.