Targeting Immune Pathways for Therapy in Asthma ... - ATS Journals

TRANSATLANTIC AIRWAY CONFERENCE Targeting Immune Pathways for Therapy in Asthma and Chronic Obstructive Pulmonary Disease Guy Brusselle1,2 and Ken Bracke1 1

Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium; and 2Departments of Epidemiology and Respiratory Medicine, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands

Abstract Asthma and chronic obstructive pulmonary disease (COPD) are highly prevalent chronic inflammatory diseases of the airways, with differences in etiology, pathogenesis, immunologic mechanisms, clinical presentation, comorbidities, prognosis, and response to treatment. In mild to moderate early-onset allergic asthma, the Th2-driven eosinophilic airway inflammation and the ensuing disease can be well controlled with maintenance treatment with inhaled corticosteroids (ICS). In real-life settings, asthma control can be improved by facilitating adherence to ICS treatment and by optimizing inhaler technique. In patients with uncontrolled severe asthma, old and novel therapies targeting specific immunologic pathways should be added according to the underlying endotype/

phenotype. In COPD, there is a high unmet need for safe and effective antiinflammatory treatments that not only prevent exacerbations but also have a beneficial impact on the course of the disease and improve survival. Although several new approaches aim to target the chronic neutrophilic pulmonary inflammation per se in patients with COPD, strategies that target the underlying causes of the pulmonary neutrophilia (e.g., smoking, chronic infection, and oxidative stress) might be more successful. In both chronic airway diseases (especially in more difficult, complex cases), the choice of the optimal treatment should be based not only on arbitrary clinical labels but also on the underlying immunopathology. Keywords: asthma; chronic obstructive pulmonary disease; phenotypes; treatment; monoclonal antibodies

(Received in original form March 18, 2014; accepted in final form June 17, 2014 ) Although G.B. is currently guideline director of the European Respiratory Society, this manuscript only reflects his personal opinions and ideas. Correspondence and requests for reprints should be addressed to Guy Brusselle, M.D., Ph.D., Ghent University Hospital, Respiratory Medicine, De Pintelaan 185, B-9000 Ghent, Belgium. E-mail: [email protected] Ann Am Thorac Soc Vol 11, Supplement 5, pp S322–S328, Dec 2014 Copyright © 2014 by the American Thoracic Society DOI: 10.1513/AnnalsATS.201403-118AW Internet address: www.atsjournals.org

Asthma and chronic obstructive pulmonary disease (COPD) are chronic inflammatory diseases of the airways, which share clinical symptoms (shortness of breath, wheezing, coughing, and sputum production), pathophysiological mechanisms (airflow limitation and bronchial hyperresponsiveness), and pathogenetic mechanisms (i.e., interactions between environmental exposures and genetic susceptibility) (1). Although asthma has been classically considered as caused by an allergic eosinophilic airway inflammation, most frequently starting in early life (childhood and adolescence), it has become evident that asthma is a very heterogeneous syndrome, encompassing other phenotypes of asthma, such as nonallergic asthma, noneosinophilic asthma (characterized by

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neutrophilic or paucigranulocytic airway inflammation), and asthma that starts only in adulthood (adult-onset/late-onset asthma) (2–4). Unfortunately, some patients with asthma do smoke and thereby respond less well to maintenance treatment with inhaled corticosteroids (ICS). At the other end of the spectrum of chronic airway disease, COPD has been classically defined as an irreversible airflow limitation in smokers or ex-smokers, which is associated with chronic neutrophilic inflammation of the small airways (bronchiolitis) and progressive destruction of the lung parenchyma (emphysema) (5). However, COPD is also a heterogeneous disease that encompasses multiple phenotypes (e.g., airway-predominant vs. emphysema-predominant phenotypes)

and can occur in never-smokers (caused by exposure to biomass fuel smoke, outdoor air pollution, and/or occupational exposures) (6, 7). Moreover, the airflow limitation is partially reversible in approximately one-half of the patients with COPD (8). In this opinion paper, we focus on asthma in nonsmoking adults and on COPD in (ex)smokers, because most randomized clinical trials (RCTs) systematically exclude current smokers (or ex-smokers with a smoking history of .10 pack-years) in trials of asthma, and never-smokers (or smokers with a smoking history of ,10 pack-years) in trials of COPD. Apparently, for pharmaceutical companies and regulators, the magic number of 10 (pack-years of smoking) is the critical cut-off point for

AnnalsATS Volume 11 Supplement 5 | December 2014

TRANSATLANTIC AIRWAY CONFERENCE the differential diagnosis between asthma and COPD.

Asthma Asthma is characterized by chronic airway inflammation, which is associated with bronchial hyperresponsiveness, leading to variable airflow limitation and respiratory symptoms (cough, wheezing, chest tightness, and/or shortness of breath) on exposure to specific allergens or nonspecific triggers. In the past decades, asthma has been considered as a homogeneous disease caused by an allergen-induced, Th2-driven eosinophilic airway inflammation, which has been modeled extensively in mice using ovalbumin or house dust mite as allergens (9, 10). However, clinical and translational research in recent years has demonstrated that asthma is a heterogeneous disease encompassing many different endotypes and phenotypes (Figure 1) (2, 3). Although several classification schemes of asthma have been proposed, for the purpose of this paper we will focus on the different inflammatory phenotypes of asthma, encompassing eosinophilic asthma, neutrophilic asthma, mixed granulocytic asthma, and paucigranulocytic asthma. Importantly, whereas allergy has been regarded as the main driver in asthma pathogenesis, it has become clear that a large proportion of adult patients, even those with eosinophilic asthma, are nonallergic (defined by negative skin prick tests and serum allergen-specific radioallergosorbent tests) (11, 12). The current mainstay treatment of persistent asthma is inhaled corticosteroids (ICS), with or without long-acting b2agonists (LABA). Treatment with ICS for 1 month or more significantly reduces the pathological signs of airway inflammation in asthma, decreasing the number of Th2 lymphocytes and eosinophils and improving progressively the bronchial hyperresponsiveness with prolonged treatment (13, 14). Classical RCTs have provided overwhelming evidence of the efficacy and safety of ICS in children and adults with persistent asthma, leading to well-controlled disease in the majority of patients with mild to moderate asthma. However, observational real-life studies throughout the world have shown that many patients with asthma have uncontrolled disease due to a combination

of factors: mainly noncompliance with maintenance treatment (ICS), incorrect inhalation technique, the presence of comorbidities (e.g., chronic rhinosinusitis, gastroesophageal reflux, obesity, obstructive sleep apnea syndrome, and depression), and persistent exposure to allergens and/or irritants (e.g., cigarette smoke) (15, 16). The implication of this discrepancy is that—at the population level—major gains in asthma control could be obtained by facilitating adherence to chronic ICS treatment and by optimizing inhalation devices and techniques (17). However, a subgroup of patients with refractory severe asthma remain uncontrolled despite optimal adherence to treatment with highdose ICS and even oral corticosteroids, implicating a high unmet medical need. Although ICS are an efficacious antiinflammatory treatment in patients with mild to moderate asthma, they do not modify the course of the disease and thus do not cure asthma. In the past decade, several large RCTs and Cochrane reviews have proven that (subcutaneous) specific immunotherapy with the appropriate allergen is efficacious and safe in wellselected patients with allergic rhinitis. Due to the increased risk of severe allergic reactions, including anaphylaxis and severe asthma attacks, specific allergen immunotherapy has been contraindicated in patients with uncontrolled asthma. Targeting specific immune pathways is becoming an attractive approach in patients with uncontrolled severe asthma (9). Because severe asthma is a heterogeneous syndrome, the specific immunologic add-on therapies (on top of high-dose ICS1LABA) should be targeted to the appropriate severe asthma phenotype (18). The classic example is the anti-IgE monoclonal antibody omalizumab, which is indicated in patients with severe allergic asthma with frequent exacerbations and persistent airflow limitation. Omalizumab has been shown to attenuate eosinophilic airway inflammation in subjects with allergic asthma and to reduce the frequency of exacerbations in severe allergic asthma (19). Moreover, an increased fractional excretion of nitric oxide in the exhaled air, an increased blood eosinophilia, and increased serum levels of periostin, a protein produced by airway epithelial cells under the influence of the Th2-cytokine IL-13, are predictors of response to treatment with omalizumab (20). In

Brusselle and Bracke: Targeting Immune Pathways for Therapy in Asthma and COPD

patients with refractory eosinophilic asthma, add-on treatment with the anti– IL-5 monoclonal antibody mepolizumab has been shown to significantly reduce the rate of severe asthma exacerbations (11, 21). Importantly, approximately half of the patients with severe eosinophilic asthma in the Does Ranging Efficacy And safety with Mepolizumab in severe asthma (DREAM) study were nonallergic, suggesting that besides the classical Th2 pathway other immunologic mechanisms, such as the epithelial–innate lymphoid cell type 2 (ILC2) pathway, might be involved in this asthma phenotype (12). We put forward the hypothesis that patients with adult-onset (late-onset), nonallergic severe eosinophilic asthma with repetitive exacerbations are the best responders to add-on treatment with anti–IL-5 or anti–IL-13 monoclonal antibodies. Our hypothesis that innate lymphocytes such as ILC2s and natural killer T cells drive eosinophilic airway inflammation in severe nonallergic asthma is based on the following observations: (1) patients with this severe asthma phenotype have frequently chronic rhinosinusitis with nasal polyps as comorbidity, (2) ILC2s are strongly increased in eosinophilic nasal polyposis, and (3) ILC2s are able to produce high amounts of IL-5 and IL-13 (22, 23). However, this hypothesis needs to be tested appropriately by basic, translational, and clinical research in patients with (nonallergic and allergic) severe asthma. If our hypothesis is confirmed, the ILC2s pathway might explain the unusual pharmacology of nonallergic severe asthma, which is poorly responding to topical treatment with ICS but responds well to systemic corticosteroids and the cytokine blockers anti–IL-5 and anti–IL-13. Because the monoclonal antibody dupilumab targets the IL-4a receptor, which is a subunit common to the IL-4 and IL-13 receptors, it has the ability to interfere with both the Th2 pathway (including IL-4 signaling and IgE synthesis) as well as the ILC2 pathway. In an ICStapering RCT, dupilumab significantly prevented mild asthma exacerbations compared with placebo (24). However, at least two caveats should be underlined before extrapolating these promising results to the treatment of patients with severe asthma in clinical practice. First, the pathogenesis of exacerbations elicited by S323

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neutrophilic asthma ICS ± LABA add-on treatment: • macrolides (azithromycin) • anti-lL-17 • anti-lL-17R (brodalumab)

Figure 1. Simplified scheme of three different types of chronic airway inflammation in patients with asthma. In allergic eosinophilic asthma, Th2 lymphocytes and mast cells drive eosinophilic airway inflammation in an allergen-specific, IgE-dependent manner. In nonallergic eosinophilic asthma, innate lymphocytes such as natural killer T cells (NKT cells) and innate lymphoid cells type 2 (ILC2) might contribute to airway eosinophilia via the production of IL-5. The mechanisms underlying neutrophilic asthma need to be elucidated, but the IL-17 pathway and CXCL8 have been associated with airway neutrophilia. GM-CSF = granulocyte/macrophage colony-stimulating factor; ICS = inhaled corticosteroids; LABA = long-acting b2-agonist; MHC = major histocompatibility complex; TCR = T cell receptor; TSLP = thymic stromal lymphopoietin.

reducing and stopping ICS and LABA in patients with (partially) controlled asthma might be fundamentally different from naturally occurring asthma exacerbations in patients on persistent ICS1LABA treatment. Second, because we hypothesize that Th2 lymphocytes are very sensitive to ICS, in contrast to ILC2s, the relative contribution of these immunologic mechanisms/pathways might differ according to whether the patient is on high-dose ICS or not. In patients with neutrophilic asthma, add-on treatment with the macrolide azithromycin has been shown to decrease the rate of exacerbations (25). In addition, a metaanalysis of RCTs of macrolides in moderate to severe asthma has demonstrated that macrolides improve the quality of life compared with placebo (26). These clinical data are in agreement with the proven efficacy and safety of macrolides in other neutrophilic chronic airway diseases, such as cystic fibrosis, S324

non–cystic fibrosis bronchiectasis, diffuse panbronchiolitis, COPD, and bronchiolitis obliterans after lung transplantation. However, the fact that neutrophilic airway inflammation appears to be a predictor of response to treatment with macrolides does not prove that neutrophils are the main target in these diseases. First, more specific antineutrophildirected therapies such as brodalumab, a human anti–IL-17 receptor monoclonal antibody, have failed in patients with moderate to severe asthma, although the investigators did not enrich the enrolled patient population for the neutrophilic phenotype (27). Second, macrolides have both immunomodulatory, antiinflammatory effects and antibiotic effects, encompassing the direct killing of microbes (e.g., Haemophilus influenzae), the prevention of biofilm formation through interfering with quorum sensing (e.g., Pseudomonas aeruginosa), and the stimulation of phagocytosis of microbes

by alveolar macrophages (28). Because population antimicrobial resistance due to chronic treatment with macrolides is a concern, the development of nonantibiotic macrolides is an attractive approach (29). It will be crucial to compare the effects of the newer nonantibiotic macrolides in severe (neutrophilic) asthma not only with placebo but also with the classical macrolide antibiotics, such as azithromycin. If azithromycin appears to be more efficacious than the newly developed nonantibiotic macrolide(s), this would suggest that the chronic bacterial colonization and infection of the lower airways with microbes such as H. influenzae and Haemophilus parainfluenzae is contributing to the pathogenesis of severe asthma.

COPD The mainstay of current therapy for COPD is long-acting bronchodilators, including


TRANSATLANTIC AIRWAY CONFERENCE LABAs and long-acting muscarinic receptor antagonists (30). Although LABAs and long-acting muscarinic receptor antagonists have additive effects on improvement of lung function and symptoms in patients with COPD, they do not affect the underlying pulmonary inflammation (Figure 2). Although a longitudinal study with bronchial biopsies has demonstrated that combination therapy with ICS and LABA significantly reduced the number of CD81 T lymphocytes in the bronchial mucosa of patients with COPD, the antiinflammatory effects on other adaptive and innate immune cell numbers were much less than seen in asthma (31). The chronic airway inflammation in (ex)smokers with COPD thus appears to be resistant to treatment with ICS (32). The latest version of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategic document recommends adding ICS to long-acting bronchodilator therapy in patients with COPD with frequent exacerbations (30). However, this recommendation

is an oversimplification. First, COPD exacerbations are heterogeneous in nature and etiology, encompassing exacerbations that are eosinophil-predominant, requiring treatment with systemic corticosteroids, and exacerbations that are caused by bacterial lower respiratory tract infections, needing treatment with antibiotics (33). Second, the use of ICS in patients with COPD has been associated with a significantly increased risk of pneumonia, including severe pneumonia and fatal pneumonia (34, 35). Therefore, it seems logical to tailor the add-on therapy in the frequent COPD exacerbator to the predominant underlying phenotype of exacerbations and concomitant comorbidities. In patients with frequent exacerbations due to bacterial respiratory infections and/or bronchiectasis, ICS should be avoided—or stopped—and maintenance treatment with macrolides such as azithromycin during winter season is an effective alternative (36). In contrast, adding ICS to single or dual bronchodilator therapy will be beneficial in patients with frequent eosinophil-predominant COPD

exacerbations requiring repetitive bursts of oral corticosteroids. The ultimate goal is to develop a safe and effective antiinflammatory treatment for COPD that has a disease-modifying effect (i.e., preventing the accelerated decline in lung function and reducing mortality). The community of respiratory researchers and clinicians can learn a lot from the rheumatology field, where several diseasemodifying antirheumatic drugs have been developed in the past 2 decades. The classical example of disease-modifying antirheumatic drugs is biologics targeting tumor necrosis factor (TNF)-a, such as the monoclonal antibodies infliximab, adalimumab, or golimumab and the soluble TNF-a receptor etanercept (37). Treatment of patients with rheumatoid arthritis with anti–TNFa biologics—most frequently in combination with methotrexate—has revolutionized the management of this disease, not only providing symptomatic benefit but also and most importantly preventing the relentless destruction of joints. Because TNF-a is elevated in sputum and bronchoalveolar lavage of

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smooth muscle cells Bronchodilators • LABA • LAMA

Figure 2. Overview of pathogenic pathways and possible therapeutic targets in patients with chronic obstructive pulmonary disease. Please see text for discussion. ASC = apoptosis-associated speck-like protein containing a caspase activation and recruitment domain; BAFF = B-cell–activating factor belonging to the tumor necrosis factor family; HEV = high endothelial venules; ICS = inhaled corticosteroids; LABA = long-acting b2-agonist; LAMA: long-acting muscarinic antagonist; NLRP = nucleotide-binding oligomerization domain-like receptor, pyrin domain-containing; NF = nuclear factor; TLR = Toll-like receptor.


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TRANSATLANTIC AIRWAY CONFERENCE patients with COPD and increases further during exacerbations, TNF-a blockers have been investigated in placebo-controlled RCTs in COPD. Treatment of patients with moderate to severe COPD with the anti– TNF-a monoclonal antibody infliximab for 24 weeks did not improve symptoms, lung function, exercise capacity, or the rate of exacerbations (38). In contrast, infliximab treatment in COPD was associated with numerical increases in malignancies, especially lung cancer, and pneumonias, implicating major safety concerns. Two lessons are to be learned from this landmark study. First, TNF-a appears to play an important role in tumor immunosurveillance in the respiratory tract. Smokers with COPD and/or emphysema have indeed a significant increased risk of lung cancer compared with smokers without airflow limitation and without emphysematous destruction of the lung parenchyma (39). Second, in contrast to the sterile inflammation of the joints in rheumatoid arthritis, the airways and lungs of smokers, and especially patients with COPD, are colonized with pathogenic bacteria, which might not only cause acute exacerbations of COPD and/or pneumonias but also amplify the chronic pulmonary inflammation in stable COPD (40–42). Several studies using non–culturebased techniques (e.g., 16S ribosomal RNA sequencing) have demonstrated that the airway microbiome is altered in patients with COPD compared with healthy control subjects, including an increase in Proteobacteria such as H. influenzae and P. aeruginosa (43). It is worthwhile to investigate the efficacy and safety of tocilizumab and other anti–IL-6 therapies in COPD, because tocilizumab has proven to be efficacious in other chronic immune diseases such as rheumatoid arthritis and because IL-6 levels are significantly increased in patients with COPD, both locally in the lungs and systemically in the blood (in a COPD subgroup with persistent systemic inflammation). Chronic treatment with the macrolides azithromycin and erythromycin has been shown to significantly prolong the time to the first exacerbation and reduce the exacerbation rate in patients with moderate to very severe COPD and a history of repeated exacerbations (36, 44). Caution is warranted because patients with COPD are elderly people with multimorbidities (including cardiovascular disease) and S326

polypharmacy (including drugs that cause QT prolongation), increasing the risk of hearing decrements and cardiac arrhythmias (45, 46). An additional concern is the increase in macrolideresistant bacteria (and mycobacteria) within the COPD and general population (29), implicating that the development of nonantibiotic macrolides with antiinflammatory, immunomodulatory effects is much needed. Importantly, by comparing the clinical efficacy of the new nonantibiotic macrolides with azithromycin in patients with COPD with frequent exacerbations, we will get novel insights into the relative contribution of the antibiotic effects versus the antiinflammatory effects of azithromycin. These pivotal studies will offer us the opportunity to unravel the pathogenic role of bacteria such as H. influenzae in COPD and thus to test the vicious circle hypothesis of chronic infection and inflammation in COPD (40–42). In severe COPD, increased numbers of lymphoid follicles have been observed around the small airways and in the lung parenchyma (47–49). These peribronchiolar and intrapulmonary lymphoid follicles mainly contain B cells and plasma cells and are local factories producing antibodies in the mucosa (including immunoglobulin A, which is secreted into the airway lumen as secretory IgA after transport through bronchial epithelial cells via the polymeric immunoglobulin receptor). These locally produced antibodies might be directed against viral and bacterial microorganisms in the respiratory tract of patients with COPD and thus be protective (50). However, the lymphoid follicles might also produce autoantibodies against epithelial antigens, posttranslationally modified proteins, or degraded extracellular matrix proteins. Several autoantibodies have been detected in serum of a subgroup of patients with (severe) COPD (51–53), although the presence of elastin autoantibodies in COPD is controversial (54, 55). Oxidative stress, an essential component in the pathogenesis of COPD, can induce increased levels of highly reactive carbonyls in the lung, resulting in the formation of immunogenic carbonyl adducts on selfproteins. These carbonyl-modified proteins have been shown to promote autoantibody production (56). Because lymphoid follicles and autoantibodies are supposed

to play a pathogenic role in this severe COPD phenotype with autoimmune emphysema, anti–B-cell–directed therapies using monoclonal antibodies against CD20 (e.g., rituximab), CD22 (epratuzumab), IL-6 (tocilizumab), or BAFF (belimumab) merit investigation in well-designed RCTs (57). However, long-term studies will be required to demonstrate efficacy on exacerbations and disease progression, and close monitoring of infectious adverse events is warranted. An interesting new avenue in the treatment of chronic airway inflammation in COPD is targeting the inflammasomes, which are intracellular multiprotein complexes in myeloid and epithelial cells that facilitate the activation of the cysteine protease caspase-1 (58). Active caspase-1 subsequently cleaves the inactive pro–IL-1b and pro–IL-18 proteins into bioactive IL-1b and IL-18, two major proinflammatory cytokines recruiting additional innate immune cells and skewing adaptive T helper cell responses toward Th1 and/or Th17 (Figure 2). Interfering with the inflammasome/caspase-1/IL-1b/IL-18 pathway can be accomplished at several levels: by inhibiting nuclear factor-kB– dependent up-regulation of pro–IL-1b and pro–IL-18, by preventing the assembly of the inflammasome complex or the enzymatic activity of caspase-1, and by blocking the interaction between secreted IL-1b/IL-18 and their membrane receptors. Because IL-1a, a danger signal that is independent from the inflammasome/ caspase-1 axis, is also increased in sputum and lungs of patients with COPD (59), blocking the common IL-1RI (which binds both IL-1a and IL-1b) might be more efficacious than specific caspase-1 inhibitors or IL-1b blockers (e.g., the anti– IL-1b monoclonal antibody canakinumab). However, deficient mucosal inflammatory responses to microbes may predispose patients with COPD to respiratory tract infections and pneumonia.

Predictors of Therapeutic Response versus Therapeutic Targets Finally, it is important to bear in mind that a predictor of therapeutic response does not implicate that this predictor per se is a therapeutic target. The discordance between a predictor of response and


TRANSATLANTIC AIRWAY CONFERENCE a therapeutic target is elegantly illustrated in the following examples. First, an increased fraction of nitric oxide (NO) in the exhaled air of patients with asthma (either asthma-like symptoms such as chronic cough or a firm diagnosis of asthma) is a predictor of a good response to treatment with ICS (60). However, inhibiting inducible nitric oxide synthase (iNOS)—the enzyme responsible for the production of NO in the respiratory tract—did not improve lung function or symptoms in patients with asthma (61). Second, the presence of neutrophilic

chronic airway inflammation is a predictor of therapeutic response to azithromycin (see above). However, specific antagonists of mediators likely to be involved in the chemotaxis and accumulation of neutrophils into the airways have failed to show clinical benefit in RCTs in COPD: antagonists of leukotriene B4, a CXCR2 antagonist and a CXCL8 (formerly called IL-8)-specific monoclonal antibody, were ineffective (32). Although we are eagerly awaiting the results of clinical studies investigating monoclonal antibodies against IL-17, IL-17R, and IL-18 in COPD, the

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