1. Efficacy of Montelukast in Asthma Patients with Allergic Rhinitis
Contents
One Airway, One Disease, One Approach
Slide 1 Efficacy of Montelukast in Asthma Patients with Allergic Rhinitis
Slide 2 One Airway, One Disease
Slide 3 Asthma and Allergic Rhinitis: Two Related Conditions Linked by One Common Airway
Slide 4 Allergic Rhinitis and Asthma Have Similar Prevalence Patterns
Slide 5 Many Patients with Asthma Have Allergic Rhinitis
Slide 6 Allergic Rhinitis Is a Risk Factor for Asthma
Slide 7 Allergic Rhinitis Increased the Risk of Asthma Attacks
Slide 8 Allergic Rhinitis Doubled the Risk of ER Visits in Patients with Asthma
Slide 9 Allergic Rhinitis Increased the Odds of Hospitalization for Asthma by 50%
Slide 10 Allergic Rhinitis Increased the Number of Prescriptions for Rescue Therapy (SABA) in Patients with Asthma
Slide 11 Both Asthma and Allergic Rhinitis Are Inflammatory Conditions 
Slide 12 Allergic Rhinitis and Asthma Have Common Triggers
Slide 13 Allergic Rhinitis and Asthma Share Common Inflammatory Cells and Mediators
Slide 14 Allergic Rhinitis and Asthma Share a Common Inflammatory Process and Occur in the Same Mucosa
Slide 15 Symptoms Correlate with the Early- and Late-Phase Responses in Allergic Rhinitis and Asthma
Slide 16 Patients with Allergic Rhinitis Experience Increased Bronchial Hyperresponsiveness
Slide 17 Allergen Challenge to the Nose Increases Bronchial Hyperresponsiveness
Slide 18 Many Patients with Asthma Have Nasal Inflammation
Slide 19 Inflammatory Changes in the Nasal and Bronchial Mucosa Are Correlated
Slide 20 Bronchial Allergen Challenge Increases a Marker of Inflammation (Eosinophils) in Nasal and Bronchial Tissues
Slide 21 Bronchial Allergen Challenge Increases Systemic Markers of Inflammation
Slide 22 Summary
Slide 23 ARIA Guidelines Recommend a Combined Approach to Managing Asthma and Allergic Rhinitis
Slide 24 Cysteinyl Leukotrienes—Important Mediators of Both Asthma and Allergic Rhinitis
Role of Cysteinyl Leukotrienes
Slide 25 Montelukast Combined with a Steroid Affects the Dual Pathways of Inflammation
Slide 26 Inhaled Corticosteroids Do Not Affect Sputum Leukotriene Levels in Patients with Asthma
Slide 27 Cysteinyl Leukotrienes Are Important Mediators of Nasal Obstruction
Slide 28 Cysteinyl Leukotriene Challenge Increases Rhinorrhea in Allergic Rhinitis
Slide 29 Role of Cysteinyl Leukotrienes in Early- and Late-Phase Allergic Response
Slide 30 Correlation of Cysteinyl Leukotriene Release with Symptoms in Allergic Rhinitis
Slide 31 Efficacy of Montelukast in Asthma Patients with Seasonal Allergic Rhinitis
Clinical Study of Asthma Patients with Concomitant Seasonal Allergic Rhinitis
Slide 32 Study Design and Objective
Slide 33 Inclusion Criteria: Active Asthma and Daily Rhinitis Symptoms
Slide 34 Endpoints
Slide 35 Baseline Characteristics of Patients
Slide 36 Montelukast Significantly Reduced Daily Rhinitis Symptoms Scores
Slide 37 Montelukast Reduced Daily Rhinitis Symptoms Regardless of Asthma Status at Study Start
Slide 38 Montelukast Improved Global Evaluations of Clinical Status and Quality of Life
Slide 39 Montelukast Improved Asthma Control
Slide 40 Conclusions
COMPACT Subanalysis (Asthma Patients with Concomitant Allergic Rhinitis)
Slide 41 Objective of COMPACT Study and Subanalysis
Slide 42 COMPACT Study Design
Slide 43 Montelukast + Budesonide Improved Morning PEF Progressively over 12 Weeks
Slide 44 Statistical Analysis
Slide 45 Definition of Groups in Analysis
Slide 46 Baseline Characteristics of Patients
Slide 47 Montelukast Provided Greater Improvements in Morning PEF in Asthma Patients with Concomitant Allergic Rhinitis
Slide 48 Conclusion
Slide 49 Summary
Slides 50–53 References
Efficacy of Montelukast in Asthma Patients with Allergic Rhinitis
One Airway, One Disease, One Approach
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2. One Airway, One Disease
Slide 2
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3. Frequently overlapping conditions Involvement of the same tissues
One Airway, One Disease Asthma and Allergic Rhinitis: Two Related Conditions Linked by One Common Airway
Frequently overlapping conditions
Involvement of the same tissues
Common inflammatory processes
Common inflammatory cells
Common inflammatory mediators
Slide 3
In recent years there has been growing recognition of the epidemiologic, pathologic, and clinical links between asthma and allergic rhinitis. These diseases are frequent comorbidities, resulting in additional symptomatic burdens and higher socioeconomic costs in patients with both conditions.1 Both conditions are characterized by a strikingly similar underlying pathology; i.e., inflammation of the respiratory mucosa associated with the same allergic and pro-inflammatory mediators and cells.1,2
This slide kit will discuss the epidemiologic and pathologic links between these diseases and present data from clinical studies aimed at treating both conditions concomitantly.
Adapted from Phillip G et al Curr Med Res Opin 2004;20(10):1549–1558.
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4. Allergic Rhinitis Asthma
Epidemiologic Links between Allergic Rhinitis and Asthma Allergic Rhinitis and Asthma Have Similar Prevalence Patterns
Allergic Rhinitis
Asthma UK
Australia
Canada
Brazil
USA
South Africa
Germany
France
Argentina
Algeria
China
Russia UK
Australia
Canada
Brazil
USA
South Africa
Germany
France
Argentina
Algeria
China
Russia
Slide 4
Allergic rhinitis and asthma are highly prevalent worldwide, particularly in more developed countries that follow a “Western” lifestyle where the prevalence of both conditions is greatest.3-5 This slide shows 12-month prevalences of asthma and allergic rhinoconjunctivitis for selected participating centers in the International Study of Asthma and Allergies in Childhood (ISAAC). ISAAC is a systematic international comparison of the prevalence of asthma and allergies.3 This analysis looked at the relationship between asthma, allergic rhinoconjunctivitis, and atopic eczema by analyzing responses on one-page questionnaires completed by 463,801 children aged 13–14 years in 156 collaborating centers across 56 countries. The questionnaires included questions about symptoms over the previous 12 months. In addition, a video asthma questionnaire was used to ask children if their breathing had been like the breathing in the video.3
The association between atopic diseases and Western lifestyle may be attributable to a decreased incidence of certain infections in early childhood.4,5 It is thought that during early life, viral infections may selectively enhance the development of T-helper (Th)-1–type cells and thus inhibit proliferation of Th2 cells, which promote allergic sensitization.6 Because children in Western societies do not typically contract these early viral infections, normal maturation of the immune response is impaired while allergy-promoting Th2 responses persist.5,6 5 10 15 20 25 30 35 40 5 10 15 20 25 30 35 40
% prevalence
% prevalence
Study of worldwide prevalence of atopic diseases in 463,801 children 13–14 years of age. Children self-reported symptoms over 12 months using questionnaires.
Adapted from the International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee Lancet 1998;351:1225–1232.
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5. All asthmatic patients
Epidemiologic Links between Allergic Rhinitis and Asthma Many Patients with Asthma Have Allergic Rhinitis
Up to 80% of all asthmatic patients have allergic rhinitis
Slide 5
Epidemiologic studies support the results of pathophysiologic and clinical studies showing an association between asthma and allergic rhinitis, demonstrating that among patients with asthma, 60% to 80% also have allergic rhinitis.7-10
Therefore, allergic rhinitis should be suspected, and treated if necessary, in patients with a diagnosis of asthma.7
All asthmatic patients
Adapted from Bousquet J et al J Allergy Clin Immunol 2001;108(suppl 5):S147–S334; Sibbald B, Rink E Thorax 1991;46:895–901; Leynaert B et al J Allergy Clin Immunol 1999;104:301–304; Brydon MJ  Asthma J 1996:29–32.
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6. Allergic rhinitis increased the risk of asthma about threefold
Epidemiologic Links between Allergic Rhinitis and Asthma Allergic Rhinitis Is a Risk Factor for Asthma
Allergic rhinitis increased the risk of asthma about threefold 12 10 8 6 4 2
p<0.002
10.5
% of patients who developed asthma
Slide 6
Allergic rhinitis is an important risk factor for asthma. In one long-term follow-up study, first-year college students with allergic rhinitis were approximately three times more likely to develop asthma over the ensuing 23 years than individuals without allergic rhinitis. This observed difference in the relative risk of developing asthma was significant between the two groups (p<0.002).11
In fact, allergic rhinitis may be an early manifestation of asthma. One large population-based study in Finland showed that the diagnosis of hay fever was almost always made before or concurrent with a diagnosis of asthma, but rarely thereafter.12
These associations reflect the shared atopy that underlies allergic rhinitis and asthma, thus explaining, at least in part, the frequent coexistence of these disorders.9
3.6
No allergic rhinitis at baseline (n=528)
Allergic rhinitis at baseline (n=162)
23-year follow-up of first-year college students undergoing allergy testing; data based on 738 individuals (69% male) with average age of 40 years
Adapted from Settipane RJ et al Allergy Proc 1994;15:21–25.
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7. + allergic rhinitis (n=893)
Post Hoc Resource Use Analysis of IMPACT Allergic Rhinitis Increased the Risk of Asthma Attacks 25 20 15 10
p=0.046
% of patients
21.3
17.1
Slide 7
The IMProving Asthma Control Trial (IMPACT) was a double-blind, multicenter clinical study of 1490 adults with chronic asthma who received montelukast plus fluticasone or salmeterol plus fluticasone for 48 weeks after an initial four-week run-in period with fluticasone alone. The primary objective was to compare the effect of therapy on the percentage of patients experiencing at least one asthma attack. This trial showed that 20% of patients treated with montelukast and fluticasone had at least one asthma exacerbation, compared to 19% in the salmeterol plus fluticasone group.13
A post hoc resource use analysis of IMPACT showed that over the one-year study period, the incidence of asthma attacks was significantly (p=0.046) higher among patients with both asthma and allergic rhinitis (21.3%) than among patients with asthma alone (17.1%).14
This difference represented an odds ratio of 1.3 for the group of patients with comorbid asthma and allergic rhinitis versus the group with asthma alone, with a 95% confidence interval (CI) of 1.04–
Patients
with asthma
(n=597)
Patients with asthma
+ allergic rhinitis (n=893)
Post hoc analysis of medical resource use/asthma attacks in asthmatic patients with and without concomitant allergic rhinitis over 52 weeks
Adapted from Bousquet J et al. Poster presented at the European Academy of Allergology and Clinical Immunology (EAACI), June 12–16, 2004, Amsterdam. Poster 141.
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8. Patients with asthma + allergic rhinitis
Allergic Rhinitis Worsens Asthma Allergic Rhinitis Doubled the Risk of ER Visits in Patients with Asthma
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
p=0.029
1.7
3.6
% of patients
Slide 8
The post hoc resource use analysis of the IMPACT study revealed that over the one-year study period, the incidence of emergency room visits was more than twice as high among patients with both asthma and allergic rhinitis (3.6%) than among patients with asthma alone (1.7%).14
This significant (p=0.029) difference represented an odds ratio of 2.2 for the group of patients with comorbid asthma and allergic rhinitis versus the group with asthma alone (95% CI 1.1–4.5).14
Patients
with asthma
(n=597)
Patients with asthma + allergic rhinitis
(n=893)
Post hoc analysis of medical resource use/asthma attacks in asthmatic patients with and without concomitant allergic rhinitis over 52 weeks
ER=emergency room
Adapted from Bousquet J et al. Poster presented at the European Academy of Allergology and Clinical Immunology (EAACI), June 12–16, 2004, Amsterdam. Poster 141.
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9. Patients with asthma + allergic rhinitis
Retrospective Cohort Study of UK Mediplus Database Allergic Rhinitis Increased the Odds of Hospitalization for Asthma by 50%
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
p<0.006
0.76
% of patients
hospitalized
annually
0.45
Slide 9
A retrospective cohort study was conducted to determine the incremental effect of allergic rhinitis on health-care resource use in adults with asthma. Data were analyzed from 27,303 adolescent or adult patients (16 to 55 years of age) with asthma who had one or more asthma-related office visits to a general practice in the UK. Medical resource use data were obtained from a database including more than 500 general practitioners.15
During the 12-month follow-up period, patients with documented allergic rhinitis were significantly more likely to be hospitalized for asthma than were patients with asthma alone (p=0.0058). Specifically, 0.76% of patients with comorbid asthma and allergic rhinitis required asthma-related hospitalizations, versus 0.45% of patients with asthma alone. Multivariate analysis demonstrated that this difference represented an odds ratio of 1.52 (95% CI 1.03–2.24), indicating that concomitant allergic rhinitis increased the odds of hospitalization for asthma by 50%.15
Patients
with asthma
(n=22,692)
Patients with asthma + allergic rhinitis
(n=4611)
Analysis of health-care resource use in adults 16 to 55 years of age with asthma and allergic rhinitis in a general practice in the UK
Adapted from Price D et al Clin Exp Allergy 2005, in press.
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10. + allergic rhinitis (n=4611)
Retrospective Cohort Study of UK Mediplus Database Allergic Rhinitis Increased the Number of Prescriptions for Rescue Therapy (SABA) in Patients with Asthma
3.3
3.2
3.1
3.0
2.9
2.8
2.7
2.6
2.5
2.4
Annual
prescriptions
per patient
p<0.0001
Slide 10
The retrospective cohort study of 27,303 patients with asthma revealed that over the 12-month follow-up period, patients with allergic rhinitis filled significantly more prescriptions for short-acting beta2-agonists (SABA) than did patients with asthma alone (p<0.0001). The mean number of SABA prescriptions for patients with comorbid asthma and allergic rhinitis was 3.15 during the years, compared with a mean of 2.71 for patients with asthma alone.15
Correspondingly, multivariate analysis showed that a concomitant diagnosis of allergic rhinitis was a significant predictor of higher annual costs for asthma medications (p=0.0001).15
Patients with asthma
(n=22,692)
Patients with asthma
+ allergic rhinitis (n=4611)
Analysis of health-care resource use in adults 16 to 55 years of age with asthma and allergic rhinitis in a general practice in the UK
SABA=short-acting beta2-agonists
Adapted from Price D et al Clin Exp Allergy 2005, in press.
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11. Asthma is fundamentally a disease of inflammation
One Airway, One Disease Both Asthma and Allergic Rhinitis Are Inflammatory Conditions
Asthma is fundamentally a disease of inflammation
Inflammation of the lower airways causes bronchoconstriction and airway hyperresponsiveness, resulting in asthma symptoms
Allergic rhinitis is an IgE-mediated inflammatory disorder
Inflammation of the nasal membranes in response to allergen exposure results in nasal symptoms
Slide 11
Asthma is a chronic inflammatory disorder in which exposure to various stimuli results in airway obstruction and airflow limitation.16 Allergic rhinitis is an immunoglobulin E (IgE)–mediated inflammatory disorder in which exposure of the nasal membranes to allergens leads to nasal symptoms.7 Although allergic rhinitis and asthma traditionally have been diagnosed and managed as distinct upper- and lower-airway diseases, respectively, recent insights into their underlying pathophysiology have identified a continuum of inflammation within the upper and lower airways.17
Several new terms have been proposed to describe the ubiquitous airway inflammation observed in patients with concurrent allergic rhinitis and asthma. These include “one airway disease,”17 “allergic rhinobronchitis,”18 “united airways,”19 and “one linked airway disease,”20 among others.
IgE=immunoglobulin E
Adapted from National Institutes of Health Global Initiative for Asthma: Global Strategy for Asthma Management and Prevention: A Pocket Guide for Physicians and Nurses. Publication No B. Bethesda, MD: National Institutes of Health, 1998; Bousquet J et al J Allergy Clin Immunol 2001;108(suppl 5):S148–S149.
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12. Insects (e.g., cockroach allergen) NSAIDs (e.g., aspirin)
One Airway, One Disease Allergic Rhinitis and Asthma Have Common Triggers
Outdoor allergens
Pollens
Molds
Indoor allergens
House-dust mites
Animal dander
Insects (e.g., cockroach allergen)
NSAIDs (e.g., aspirin)
Slide 12
Several of the same agents are known to trigger exacerbations of both allergic rhinitis and asthma.21 Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) can induce bronchospasm or rhinitis in susceptible individuals.16,22 Sensitivity to indoor allergens is highly correlated with the presence of both allergic rhinitis and asthma.23 Exposure to house-dust mites can lead to sustained inflammation of the bronchi24 and perennial allergic rhinitis.25 Animal dander is another important indoor allergen implicated in both conditions.8,26 Insects such as cockroaches are often involved in both allergic rhinitis and asthma.16,27 Tobacco smoke, a major source of indoor pollution, can trigger asthma or allergic rhinitis whether the patient smokes or breathes in smoke from others.16,27 Common outdoor allergens in both conditions are pollens and molds.16,27
Adapted from National Institutes of Health Global Initiative for Asthma: Global Strategy for Asthma Management and Prevention: A Pocket Guide for Physicians and Nurses. Publication No B. Bethesda, MD: National Institutes of Health, 1998; Workshop Expert Panel Management of Allergic Rhinitis and its Impact on Asthma (ARIA) Pocket Guide. A Pocket Guide for Physicians and Nurses, 2001.
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13. Inflammatory mediators
One Airway, One Disease Allergic Rhinitis and Asthma Share Common Inflammatory Cells and Mediators
Membrane-bound
IgE
Mast cell
Preformed Mediators
Cysteinyl leukotrienes
Prostaglandins
Platelet-activating factor
Early-phase response
Allergen
Slide 13
The same immunologic processes are involved in the early- and late-phase responses seen in allergic rhinitis and asthma. The basis of both reactions is immediate hypersensitivity caused by a cascade of events that begins with sensitization and the generation of allergen-specific IgE when an allergen interacts with membrane-bound IgE on the surface of mast cells. This interaction triggers mast-cell degranulation; i.e., the release of preformed mediators (histamine and tryptase), cysteinyl leukotrienes, prostaglandins, and platelet-activating factor (PAF), which are directly responsible for the early-phase response. The late-phase response is provoked primarily by activation of mast cells or T cells, resulting in cytokine release. Cytokines influence a wide range of events associated with chronic inflammation, including eosinophil recruitment and the consequent release of cysteinyl leukotrienes and other newly generated inflammatory mediators.21,28,29
Whereas preformed and newly generated mediators of inflammation are similar in the upper and lower airway, their effects may differ in the different target organs.18
Eosinophils
T cells
Inflammatory mediators
Late-phase response
Cytokines
Adapted from Casale TB et al Clin Rev Allergy Immunol 2001;21(1):27–49; Kay AB N Engl J Med 2001;344:30–37.
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14. Eosinophil infiltration
Shared Pathophysiology of Allergic Rhinitis and Asthma Allergic Rhinitis and Asthma Share a Common Inflammatory Process and Occur in the Same Mucosa
Allergic rhinitis
Asthma
Slide 14
Nasal and bronchial tissues share histologic similarities, including a pseudostratified epithelium with columnar, ciliated cells resting on a basement membrane in normal individuals.7 Not surprisingly, the inflammatory process is strikingly similar in these tissues: they are subject to eosinophil infiltration arising from the release of mediators such as cysteinyl leukotrienes and cytokines during the allergic or asthmatic response. Eosinophils may mediate the tissue damage observed in both conditions and may sustain and further potentiate the allergic and inflammatory response.29
Because there are differences in the structure of the mucosa in the upper and lower airways (i.e., the greater vascularity of nasal tissue, the presence of smooth muscle in the bronchi, and the greater degree of epithelial shedding in the lungs), inflammation in these target tissues induces the expression of a different set of symptoms in allergic rhinitis and asthma. These include bronchoconstriction in the lungs and vascular engorgement leading to nasal obstruction in the nose.29
Nasal Mucosa
Bronchial Mucosa
Eosinophil infiltration
Eos=eosinophils; neut=neutrophils; MC=mast cells; Ly=lymphocytes; MP=macrophages
Adapted from Bousquet J et al J Allergy Clin Immunol 2001;108(suppl 5):S148–S149.
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15. Score for nasal symptoms
One Airway, One Disease Symptoms Correlate with the Early- and Late-Phase Responses in Allergic Rhinitis and Asthma
Score for nasal symptoms
Sneezing
Nasal pruritus
Congestion
Rhinorrhea
Time postchallenge (hours) 1
Antigen challenge
3–4
8–12 24
Immediate (early) phase
Late phase
Upper Airways
(Allergic rhinitis)
Slide 15
The slide illustrates the similar pattern and time course of early- and late-phase responses in allergic rhinitis and asthma. Approximately one hour after allergen provocation, patients with allergic rhinitis experience a peak in symptoms, while patients with asthma experience a steep decline in lung function (measured by forced expiratory volume in one second [FEV1]). Several hours later, a sustained period of symptoms occurs in patients with allergic rhinitis and reduced lung function affects patients with asthma. Within 12 to 24 hours, both types of reactions typically resolve.30,31
During the early-phase response, symptoms in patients with allergic rhinitis typically consist of sneezing, rhinorrhea, and conjunctivitis;28 patients with asthma experience wheezing, coughing, and shortness of breath in addition to objectively demonstrable changes in lung function.30 During the late-phase response, patients with allergic rhinitis experience sustained nasal congestion,28 and patients with asthma experience a fall in lung function similar to that observed in the early-phase response.30
FEV1 (% change)
Time (hours) 50
100 1 10 24 2 3 4 5 6 7 8 9
Lower Airways
(Asthma)
Adapted from Varner AE, Lemanske RF Jr. In: Asthma and Rhinitis. 2nd ed. Oxford: Blackwell Science, 2000:1172–1185; Togias A J Allergy Clin Immunol 2000;105(6 pt 2):S599–S604.
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16. Prevalence of bronchial hyperresponsiveness*
Clinical Links between Allergic Rhinitis and Asthma Patients with Allergic Rhinitis Experience Increased Bronchial Hyperresponsiveness
Prevalence of bronchial hyperresponsiveness* 60 50 40 30 20 10
(n=27)
p<0.02
% of patients 48
Slide 16
Many examples of “communication” between the nose and lungs link allergic rhinitis and asthma. One such example is the bronchial hyperresponsiveness observed in patients with allergic rhinitis. The prevalence of bronchial hyperresponsiveness (defined as a provocation dose [PD] of carbachol causing a 20% decrease in FEV1 [PD20] <1 mg) was evaluated during and out of pollen season in 27 nonasthmatic patients with seasonal allergic rhinitis plus hay fever. Bronchial hyperresponsiveness increased significantly, from 11% out of pollen season to 48% during pollen season (p<0.02). Thus, the expression of allergic symptoms, even when confined to the nose, is associated with bronchial hyperreactivity in the lungs.32 11
Out of season
In season
Study of bronchial hyperreactivity in patients (mean age 20 years) with hay fever; challenges were performed in the fall of one year and approximately six months later.
*PD20 <1 mg after carbachol challenge
PD=provocation dose
Adapted from Madonini E et al J Allergy Clin Immunol 1987;79:358–363.
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17. Geometric mean PC20 (methacholine, mg/ml)
Clinical Links between Allergic Rhinitis and Asthma Allergen Challenge to the Nose Increases Bronchial Hyperresponsiveness
Change from baseline in PC20*
Placebo (n=5) Allergen (n=5) 3 2
p=0.0009
Geometric mean PC20 (methacholine, mg/ml)
p=0.011
Slide 17
A crossover study further established the relationship between allergic rhinitis and lower-airway dysfunction. Patients were studied on two days separated by two weeks. On the first study day, 10 patients with allergic rhinitis and asthma randomly received nasal challenge with either allergen or placebo. Thirty minutes and 4.5 hours after challenge, bronchial hyperresponsiveness was determined through methacholine-challenge testing. The endpoint of PC20 measures the methacholine dose required to decrease FEV1 by 20%. Therefore, lower PC20 values denote greater hyperresponsiveness. Two weeks later, patients were crossed over to the alternate challenge group (allergen or placebo). Lower-airway responsiveness to methacholine was comparable at baseline on both study days. The geometric mean log2 PC20, however, was significantly lower in patients receiving allergen challenge to the nose than in the group receiving placebo 30 minutes (p=0.011) and 4.5 hours postchallenge (p=0.0009).33
This finding supports the observations described on the previous slide by demonstrating a causal relationship between nasal allergen challenge and the onset of bronchial hyperresponsiveness. The persistent changes in bronchial reactivity in this study most likely reflect the action of inflammatory products that reached the lower airways through either postnasal drainage or the systemic circulation.33
Baseline
0.5 hr postchallenge
4.5 hr postchallenge
Randomized, crossover two-day investigation of the relationship between allergic rhinitis and lower airway dysfunction in patients with allergic rhinitis and asthma (mean age 31.4 years)
PC=postchallenge
*Lower PC20 values indicate greater hyperresponsiveness
Adapted from Corren J et al J Allergy Clin Immunol 1992;89:611–618.
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18. Eosinophils/ field of nasal biopsy
Clinical Links between Allergic Rhinitis and Asthma Many Patients with Asthma Have Nasal Inflammation
Eosinophil counts in the nasal mucosa 18 16 14 12 10 8 6 4 2
(n=9)
(n=8)
(n=10)
Eosinophils/ field of nasal biopsy
Slide 18
In a recent study of 27 non-atopic patients, eosinophil counts in nasal biopsy specimens from asthmatic patients (with or without rhinitis symptoms) were consistently and significantly greater than those in normal controls (p<0.001). Of the 27 patients who participated, nine patients had both asthma and allergic rhinitis, eight had asthma without allergic rhinitis, and 10 were healthy non-atopic control subjects. These findings support the hypothesis that asthma and rhinitis are clinical expressions of the same entity.34
p<0.001
p<0.001
Rhinitis
No rhinitis
Control
Asthmatic
Study of whether nasal mucosal inflammation exists in asthma regardless of the presence of allergic rhinitis in atopic subjects 20 to 66 years of age
Bars represent median values.
Adapted from Gaga M et al Clin Exp Allergy 2000;20:663–669.
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19. Asthmatic nasal mucosa eosinophils
Clinical Links between Allergic Rhinitis and Asthma Inflammatory Changes in the Nasal and Bronchial Mucosa Are Correlated 40 35 30 25 20 15 10 5
(n=17)
Asthmatic nasal mucosa eosinophils
Slide 19
A recent study included 27 non-atopic patients: nine patients had both asthma and allergic rhinitis, eight had asthma without allergic rhinitis, and 10 were healthy non-atopic control subjects. There was a strong linear correlation between eosinophilia in the nasal mucosa and in the bronchial mucosa of the 17 asthmatic patients (r=0.851, p<0.001). The airway epithelium in patients with asthma therefore appears to be inflamed all along its length, further supporting the hypothesis that asthma and rhinitis are clinical expressions of the same entity.34
r=0.851, p<0.001 5 10 15 20 25 30
Asthmatic bronchial mucosa eosinophils
Study of whether nasal mucosal inflammation exists in asthma regardless of the presence of allergic rhinitis in atopic subjects 20 to 66 years of age
Adapted from Gaga M et al Clin Exp Allergy 2000;20:663–669.
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20. Clinical Links between Allergic Rhinitis and Asthma Bronchial Allergen Challenge Increases a Marker of Inflammation (Eosinophils) in Nasal and Bronchial Tissues
Nasal tissue (lamina propria)
Bronchial tissue (subepithelial layer) b
100 80 60 40 20 a
1600
1200
800
400
Eosinophils (number cells/
mm2) d c
Slide 20
Allergic rhinitis and asthma are linked by clinical evidence of an inflammatory response in the lower airways, as well as by inflammation of the nasal mucosa after bronchial allergen challenge in nonasthmatic patients with allergic rhinitis. In a recent study, nasal and bronchial biopsy and blood samples were obtained from eight nonasthmatic patients with allergic rhinitis (age 21–31 years) and eight nonasthmatic, nonallergic controls (age 18–29 years) immediately before and 24 hours after segmental allergen bronchoprovocation. Nasal biopsies were obtained at baseline and at 1 and 24 hours after challenge. Eosinophils, markers of mucosal allergic inflammation, were counted in the biopsy specimens and blood samples.35
In the nasal lamina propria, eosinophil counts did not differ significantly in the allergic and control groups at baseline. Twenty-four hours after bronchial allergen challenge, however, eosinophils in the nasal tissues of allergic patients had increased significantly from baseline (p=0.04). In the bronchial subepithelium, the number of eosinophils in the allergen-challenged segment also rose significantly from baseline 24 hours after challenge (p=0.002).35
In this study, segmental allergen bronchoprovocation produced a widespread allergic response that included the nose and bronchial tissue in patients with allergic rhinitis.35 a T0
T24 T0
Unchallenged left lung
Allergen- challenged right middle lobe
Control patients (n=8)
Allergic patients (n=8)
T24
Evaluation of allergic inflammation in the upper and lower airways after bronchial challenge in nonasthmatic allergic rhinitis patients vs. controls (age range 18–31 years)
T0= before challenge; T24=24 hours postchallenge; ap<0.05; bp<0.01; cp=0.001; dp=0.002
Adapted from Braunstahl G-J et al Am J Respir Crit Care Med 2000;161:2051–2057.
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21. Peripheral blood eosinophils (106 cells/L)
Clinical Links between Allergic Rhinitis and Asthma Bronchial Allergen Challenge Increases Systemic Markers of Inflammation *
Control patients (n=8)
Allergic patients (n=8)
600
500
400
300
200
100 **
Peripheral blood eosinophils (106 cells/L)
Slide 21
The study discussed on the previous slide also showed that bronchial allergen challenge in individuals with allergic rhinitis increased inflammatory cells (eosinophils) in the blood from baseline (p<0.05) and compared with nonallergic controls (p<0.01). Together with the inflammatory response observed throughout the upper and lower respiratory tract in allergic patients, this finding suggests a systemic inflammatory effect.35 T0
T24
Evaluation of allergic inflammation in the upper and lower airways after bronchial challenge in nonasthmatic allergic rhinitis patients vs. controls (age range 18–31 years)
T0= before challenge; T24=24 hours postchallenge; *p<0.05; **p<0.01
Data presented as median ± range
Adapted from Braunstahl G-J et al Am J Respir Crit Care Med 2000;161:2051–2057.
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22. Shared Pathophysiology of Allergic Rhinitis and Asthma Summary
Allergic rhinitis and asthma share several pathophysiologic characteristics
Common triggers
Similar inflammatory cascade on exposure to allergen
Cysteinyl leukotrienes are common mediators in upper and lower airway diseases
Similar pattern of early- and late-phase responses
Infiltration by the same inflammatory cells (e.g., eosinophils)
Several potential connecting pathways, including systemic transmission of inflammatory mediators
Slide 22
Many potential mechanisms may link allergic rhinitis and asthma. These conditions share several common triggers, including both indoor and outdoor allergens.16,27 The same immunologic process underlies the inflammatory cascade on exposure to allergen,28 resulting in a similar pattern of early- and late-phase responses.30,31 Histologic studies have confirmed that nasal and bronchial tissues have a similar structure. Both tissues are subject to infiltration by the same inflammatory mediators during the allergic or asthmatic response.29 Several potential connecting pathways between these two diseases have been proposed, including the systemic transmission of inflammatory mediators between the upper and lower airways.36 Leukotrienes play a role in both upper (allergic rhinitis) and lower (asthma) airway disease.21
Adapted from National Institutes of Health Global Initiative for Asthma: Global Strategy for Asthma Management and Prevention: A Pocket Guide for Physicians and Nurses. Publication No B. Bethesda, MD: National Institutes of Health, 1998; Casale TB, Amin BV Clin Rev Allergy Immunol 2001;21(1):27–49; Workshop Expert Panel Management of Allergic Rhinitis and its Impact on Asthma (ARIA) Pocket Guide. A Pocket Guide for Physicians and Nurses. 2001; Kay AB N Engl J Med 2001;344:30–37; Varner AE, Lemanske RF Jr. In: Asthma and Rhinitis. 2nd ed. Oxford, UK: Blackwell Science, 2000:1172–1185; Togias A J Allergy Clin Immunol 2000;105(6 pt 2):S599–S604; Togias A Allergy 1999; 54(suppl 57):94–105.
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23. Patients with allergic rhinitis should be evaluated for asthma
One Airway, One Disease ARIA Guidelines Recommend a Combined Approach to Managing Asthma and Allergic Rhinitis
Patients with allergic rhinitis should be evaluated for asthma
Patients with asthma should be evaluated for allergic rhinitis
A strategy should combine the treatment of upper and lower airways in terms of efficacy and tolerability
Slide 23
In light of the associations between asthma and allergic rhinitis, recent guidelines developed by the Allergic Rhinitis and its Impact on Asthma (ARIA) Workshop Expert Panel, in collaboration with the World Health Organization, recommended strategies to integrate the diagnosis and treatment of allergic rhinitis and asthma. Specific emphasis was placed on the need to evaluate patients with allergic rhinitis for asthma and to evaluate patients with asthma for allergic rhinitis. When these diseases coexist, a combined treatment strategy should be used.7
Because optimal management of rhinitis may improve coexisting asthma, consideration should be given to the effectiveness of treatment for both conditions.7 For example, corticosteroids and antileukotrienes have efficacy in both conditions; alpha-adrenergic antagonists are effective only in the treatment of allergic rhinitis; beta-adrenergic antagonists are effective only in the treatment of asthma; and antihistamines are less effective in asthma than in allergic rhinitis.7 The route of administration also deserves consideration; orally administered drugs may affect both nasal and bronchial symptoms.7 Caution should be exercised in the use of intranasal plus inhaled corticosteroids because of possible additive side effects.7 The ARIA guidelines acknowledge that the prevention or early treatment of nasal inflammation may help to control asthma, but this possibility requires further study.7
Adapted from Bousquet J et al J Allergy Clin Immunol 2001;108(suppl 5):S147–S334.
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24. Cysteinyl Leukotrienes—Important Mediators of Both Asthma and Allergic Rhinitis
Slide 24
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25. Steroid-sensitive mediators (e.g., cytokines) Cysteinyl leukotrienes
Cysteinyl Leukotrienes in Asthma: Dual Pathways of Inflammation Montelukast Combined with a Steroid Affects the Dual Pathways of Inflammation
Steroid-sensitive mediators (e.g., cytokines)
Cysteinyl leukotrienes
Montelukast
Inhaled steroids
Slide 25
Cysteinyl leukotrienes and steroid-sensitive mediators are two important pathways of inflammation in asthma.37,38
• Airway inflammation and asthma symptoms often persist despite treatment with inhaled steroids and long-acting beta2-agonists.39-42
• Steroids do not block the formation of leukotrienes in asthmatics.40,43-45
Therefore, treating dual pathways may provide complementary benefits—better control of inflammation and effective asthma control—compared with treating only the steroid-sensitive pathway.46
Inhibit steroid- sensitive mediators (e.g., cytokines)
Inhibits cysteinyl leukotrienes
The slide represents an artistic rendition.
Adapted from Diamant Z, Sampson AP Clin Exp Allergy 1999;29:1449–1453; Barnes PJ Am J Respir Crit Care Med 1996;154:S21–S27;
Claesson H-E, Dahlén S-E J Intern Med 1999;245:205–227; Price DB et al Thorax 2003;58:211–216.
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26. All patients with asthma
Cysteinyl Leukotrienes—Mediators of Asthma Inhaled Corticosteroids Do Not Affect Sputum Leukotriene Levels in Patients with Asthma 14 12 10 8 6 4 2
13*
Sputum cysteinyl
leukotriene
levels (ng/ml)
11.4**
9.4*
Slide 26
A study in healthy and asthmatic non-smoking adults investigated concentrations of cysteinyl leukotrienes (LTC4, LTD4, and LTE4) in the sputum. Leukotriene levels were significantly higher in asthmatic patients (9.4 ng/ml) than in normal individuals (6.4 ng/ml). Moreover, the levels increased with disease severity (11.4 ng/ml in patients with persistent asthma and 13.0 ng/ml in patients with recent acute exacerbations) despite the daily use of inhaled corticosteroids.47
These results support other evidence that corticosteroids do not block the formation of leukotrienes in asthmatics.40,43-45
6.4
Controls (n=10)
All patients with asthma
(n=26)
Patients with persistent asthma (n=10)
Patients with acute attacks (n=12)
Study of the use of induced sputum to assess airway eicosanoid production in 10 healthy and 26 asthmatic adults (mean age 40 to 57 years in each treatment group)
*p<0.02 vs. normal individuals; **p<0.05 vs. normal individuals
 Adapted from Pavord ID et al Am J Respir Crit Care Med 1999;160:1905–1909.
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27. Cysteinyl Leukotrienes—Mediators of Asthma Cysteinyl Leukotrienes Are Important Mediators of Nasal Obstruction
150
125
100 *
% change in NAR *
Slide 27
A nasal-provocation study was conducted to examine the role of LTD4 in the nasal symptoms of allergic rhinitis. Sixty adult patients with house dust–induced allergic rhinitis were assigned to nasal provocation with LTD4 (n=14), histamine (n=14), antigen (n=18), or a nonactive control solution (n=14). Nasal airway resistance (NAR) was expressed as the ratio of peak NAR with the active agent to peak with the control solution. The endpoint of concentration (threshold) was the minimum concentration of the active agent required to produce an increase of at least 20% in sneezing, nasal secretion, or NAR compared with nonactive control provocation.48
LTD4 had longer-lasting effects on NAR than histamine. After histamine challenge (n=11), NAR increased once at 1 hour (p<0.05 vs. baseline) and returned to baseline between one and three hours on average. After LTD4 challenge (n=7), in contrast, NAR increased significantly at 30 minutes (p<0.05) and did not return to baseline for 11 hours. Moreover, LTD4 was a stronger mediator of nasal response than histamine, as reflected by a threshold concentration approximately 5000-fold lower than that of histamine. Thus, LTD4 plays an important role in nasal allergy by inducing strong and long-lasting nasal blockage.48
Challenge
(n=7) 1/
Hour
LTD4 was approximately 5000 times more potent than histamine in mediating nasal responses
Study to examine the clinical significance of LTD4 versus antigen and histamine in adult patients (mean age 25.0–26.4 in each group). Nasal provocations were carried out with serially increasing doses of LTD4, histamine, or antigen.
*p<0.05 vs. baseline
NAR=nasal airway resistance
Adapted from Okuda M et al Ann Allergy 1988;60:537–540.
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28. Nasal secretion (10-2 g/min)
Cysteinyl Leukotrienes—Mediators of Both Asthma and Allergic Rhinitis Cysteinyl Leukotriene Challenge Increases Rhinorrhea in Allergic Rhinitis
1.00
0.75
0.50
0.25
(n=8)
Nasal secretion (10-2 g/min)
Slide 28
A nasal-provocation study was conducted to examine the role of LTD4 in the nasal symptoms of allergic rhinitis. Sixty adult patients with house dust–induced allergic rhinitis were assigned to nasal provocation with LTD4 (n=14), histamine (n=14), antigen (n=18), or a nonactive control solution (n=14). Nasal airway resistance (NAR) was expressed as the ratio of peak NAR with the active agent to peak with the control solution. The endpoint of concentration (threshold) was the minimum concentration of the active agent required to produce an increase of at least 20% in sneezing, nasal secretion, or NAR compared with nonactive control provocation.48
LTD4 was also shown to play a role in nasal secretion (rhinorrhea) in these patients with allergic rhinitis. While the average amount of secretion was less with LTD4 (0.28±0.36 g with a threshold concentration of 210–1.4 µg/ml) than with antigen or histamine, the duration of nasal secretion was comparable to that with topical antigen and longer than that observed with histamine.48 ~5
~10
~15
~20
Time (minutes)
Study to examine the clinical significance of LTD4 versus antigen and histamine in adult patients (mean age 25.0 – 26.4 in each group). Nasal provocations were carried out with serially increasing doses of LTD4, histamine, or antigen.
Adapted from Okuda M et al Ann Allergy 1988;60:537–540.
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29. Score for nasal symptoms Time postchallenge (hours)
Cysteinyl Leukotrienes—Mediators of Asthma Role of Cysteinyl Leukotrienes in Early- and Late-Phase Allergic Response
Early phase
Histamine, cysteinyl leukotrienes, prostaglandins, thromboxanes,
heparin, proteases, PAF
Late phase
Cysteinyl leukotrienes, cytokines (predominant)
Score for nasal symptoms
Sneezing
Nasal pruritus
Congestion
Rhinorrhea
Cysteinyl leukotrienes
Slide 29
Initial exposure to an allergen leads to the formation of allergen-specific IgE antibodies, which bind to high-affinity receptors on mast cells and basophils.20 Allergic inflammation is subsequently triggered when the IgE molecules on the surface of mast cells become crossbound by allergen, resulting in mast cell degranulation.20 This early phase of the allergic response is characterized by the release of inflammatory mediators, e.g., histamine, leukotrienes (including cysteinyl leukotrienes), prostaglandins, thromboxanes, as well as heparin, proteases, and platelet-activating factor.49 Among these mediators, the cysteinyl leukotrienes and histamine are particularly important.16 Within an hour of allergen exposure, cysteinyl leukotrienes and histamine increase in nasal secretions, corresponding to the emergence of symptoms.31, While the role of histamine is well known, clinical studies now indicate that cysteinyl leukotrienes also mediate the characteristic symptoms of allergic rhinitis, including nasal congestion, sneezing, and rhinorrhea.48,50,53,54
Several hours after the early allergic response, a late-phase reaction may also occur.49 This phase is characterized by the influx of inflammatory cells and the release of mediators (including leukotrienes and cytokines) that promote and prolong the inflammatory response.49,50,55 During the late-phase reaction, the release of cysteinyl leukotrienes coincides with the recurrence of nasal symptoms.50
Cysteinyl leukotrienes are therefore involved in both early- and late-phase reactions.
Antigen challenge 1
3–4
8–12 24
Time postchallenge (hours)
PAF=platelet-activating factor
Adapted from Togias A J Allergy Clin Immunol 2000;105(6 pt 2):S599–S604; Rachelevsky G J Pediatr 1997;131:348–355; Rouadi P, Naclerio R. SRS-A to Leukotrienes: The Dawning of a New Treatment. S Holgate, S Dahlen, eds. Oxford, England: Blackwell Science, 1997; Creticos PS et al N Engl J Med 1984;31:1626–1630.
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30. Early-phase allergic response Late-phase allergic response
Cysteinyl Leukotrienes—Mediators of Asthma Correlation of Cysteinyl Leukotriene Release with Symptoms in Allergic Rhinitis
Early-phase allergic response
(within minutes)
Late-phase allergic response
(within 4+ hours)
Predominant mediator types
Cysteinyl leukotrienes
Histamine
Cytokines
Most commonly associated allergy symptoms
Sneezing
Nasal itching
Rhinorrhea
Nasal obstruction
Prolonged nasal obstruction
Slide 30
The slide shows the correlation of cysteinyl leukotriene release with symptoms in allergic rhinitis.7,20,48,51, The early phase of an allergic response begins within minutes of exposure to an allergen.7,20 During this phase, numerous inflammatory mediators are released in nasal secretions, most importantly cysteinyl leukotrienes and histamine.7,16,49,59,60 The most common early-phase symptoms are sneezing, nasal itching, rhinorrhea, and nasal obstruction.7,31,59 The late-phase allergic response, which occurs in 30% to 40% of patients, begins within at least four hours and peaks six to 12 hours after the initial response.7,20 This phase is characterized by the release of cysteinyl leukotrienes and cytokines in nasal secretions,7,49,50 and is associated with prolonged nasal obstruction.7
Adapted from Philip G et al Curr Med Res Opin 2004;20(10):1549–1558; Bousquet J et al J Allergy Clin Immunol 2001;108(suppl 5):S147–S334; Sibbald B, Rink E Thorax 1991;46:895–901; Leynaert B et al J Allergy Clin Immunol 1999;104:301–304; Brydon MJ  Asthma J 1996:29–32; Vignola AM et al Allergy 1998;53:833–839; Meltzer EO Ann Allergy Asthma Immunol 2000;84(2):176–185; Casale TB, Amin BV Clin Rev Allergy Immunol 2001;21(1):27–49; Settipane GA Arch Intern Med 1981;141:328–332; Magnan A et al Eur Respir J 1998;12:1073–1078; Yssel H et al Clin Exp Allergy 1998;5:104–109, discussion 17–18.
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31. Efficacy of Montelukast in Asthma Patients with Seasonal Allergic Rhinitis
Slide 31
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32. Double-blind treatment
Clinical Study of Asthma Patients with Concomitant Seasonal Allergic Rhinitis Study Design and Objective
Period I
Single-blind run-in
Period II
Double-blind treatment
Montelukast* (n=415)
Placebo
Placebo (n=416)
Slide 32
Based on evidence of the linked pathophysiology of allergic rhinitis and asthma, and the role of cysteinyl leukotrienes in both conditions, recent investigations have focused on the effects of cysteinyl leukotriene blockade in the treatment of patients with both conditions.1
Recently, a prospective, randomized, double-blind, multicenter, parallel-group study was conducted during the spring and fall in the United States and Europe to evaluate the efficacy of montelukast in improving the symptoms of seasonal allergic rhinitis in patients with asthma and seasonal allergic rhinitis.1
After a three- to five-day single-blind placebo run-in period, patients were randomized to receive two weeks of treatment with oral montelukast 10 mg (n=415) or placebo (n=416) once daily at bedtime.1 Short-acting beta2-agonists were permitted in both groups.1
–3 to 5 days
2 weeks
To evaluate the efficacy of montelukast in improving the symptoms of allergic rhinitis in patients with active asthma and active allergic rhinitis during the allergy season
*10 mg once daily at bedtime
Short-acting beta2-agonists were used as needed in both groups.
Adapted from Philip G et al Curr Med Res Opin 2004;20(10):1549–1558.
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33. 1-year history (dyspnea, wheezing, chest tightness, cough)
Clinical Study of Asthma Patients with Concomitant Seasonal Allergic Rhinitis Inclusion Criteria: Active Asthma and Daily Rhinitis Symptoms
Asthma
1-year history (dyspnea, wheezing, chest tightness, cough)
1 of 4 criteria for active asthma
Asthma symptoms  once weekly
Reversible airway obstruction
History of methacholine hyperresponsiveness
1-year history of exercise-induced bronchoconstriction
Stable dose of inhaled corticosteroid and/or long-acting beta2-agonist use
Allergic Rhinitis
2-year clinical history (rhinitis symptoms worsening during allergy season)
Daily rhinitis symptoms at least mild to moderate during placebo run-in
Positive skin test to 3 allergens active during study season
Slide 33
The study enrolled patients 15 to 85 years of age with a clinical history of active asthma of at least one year and a clinical history of seasonal allergic rhinitis of at least two years. Eligible patients met at least one of four criteria for active asthma: asthma symptoms at least once weekly, reversible airway obstruction (>12% increase in FEV1 after inhaled short-acting beta2-agonist), a history of methacholine airway hyperresponsiveness, or at least a one-year history of exercise-induced bronchoconstriction. Patients on a stable dose of inhaled corticosteroid and/or inhaled long-acting beta2-agonist were eligible. During the placebo run-in period, patients had to demonstrate at least mild to moderate daily rhinitis symptoms (daytime nasal congestion, rhinorrhea, sneezing, and itching and nasal congestion upon awakening, difficulty going to sleep, and nighttime awakenings). Additionally, patients were required to demonstrate a positive skin test (wheal diameter 3 mm greater than control) to at least three allergens that were active during the study season.1
Adapted from Philip G et al Curr Med Res Opin 2004;20(10):1549–1558.
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34. Composite Daily Rhinitis Symptom Score
Clinical Study of Asthma Patients with Concomitant Seasonal Allergic Rhinitis Endpoints
Composite Daily Rhinitis Symptom Score
Daytime nasal symptoms
Congestion
Rhinorrhea
Pruritus
Sneezing
Nighttime symptoms
Difficulty falling asleep
Nighttime awakenings
Nasal congestion on awakening
Slide 34
During the run-in and treatment periods, patients completed a daily diary in which they assigned a score to each of their allergic rhinitis symptoms on a four-point scale in which 0=none, 1=mild, 2=moderate, and 3=severe. The mean changes in these symptoms from pretreatment baseline values were analyzed over the two-week treatment period.1
The primary endpoint in this trial was the daily rhinitis symptoms score, a composite of daytime nasal symptoms scores (average of scores for nasal congestion, rhinorrhea, sneezing, and itching, each rated on a 0 to 3 scale), nighttime symptoms scores (average of nasal congestion upon awakening, difficulty going to sleep, and nighttime awakenings, each rated on a 0 to 3 scale).1 Additional endpoints included global evaluations of asthma, in which patients and physicians individually assessed the clinical status of asthma at the end of the treatment period, and the frequency of as-needed use of short-acting beta2-agonists during treatment.1
Secondary allergic rhinitis endpoints were the rhinoconjunctivitis quality-of-life score, completed before randomization and at the end of treatment, which consisted of the average of scores of seven individual domains (nasal symptoms, eye symptoms, non–nose/eye symptoms, activity, sleep, emotions, and practical problems) graded by patients on a six-point scale, and global evaluations of allergic rhinitis, in which patients and physicians individually assessed the clinical status of allergic rhinitis at the end of the treatment period relative to study entry on a six-point scale.1
(0–3 scale, mild to severe)
Secondary/other endpoints
Rhinoconjunctivitis quality of life
Patients’ and physicians’ global evaluations of allergic rhinitis
Patients’ and physicians’ global evaluations of asthma
As-needed beta2-agonist use
Adapted from Philip G et al Curr Med Res Opin 2004;20(10):1549–1558.
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35. Clinical Study of Asthma Patients with Concomitant Seasonal Allergic Rhinitis Baseline Characteristics of Patients
Montelukast
(n=415)
Placebo
(n=416)
Age (years)
Mean±SD
Range
33.013.2
15–78
33.613.7
15–80
Gender (% of patients)
Male
Female
36%
64%
35%
65%
Duration of allergic rhinitis (years)
19.611.9
19.012.2
Duration of asthma (years)
17.512.2
16.511.9
Inhaled corticosteroid therapy at baseline (% of patients)
38%
43%
Asthma symptoms once weekly (% of patients)
90%
93%
Asthma symptoms twice weekly (% of patients)
57%
62.5%
Season studied (% of patients)
Spring
Fall
84%
16%
85%
15%
FEV1 (% predicted)
Daily rhinitis symptoms score
1.750.42
1.770.42
Slide 35
The treatment groups were similar at baseline with respect to demographic and clinical characteristics. The mean age of patients was approximately 33 years in each group; approximately two-thirds of each group were female, and the vast majority of patients in each group were studied in the spring. Mean duration of allergic rhinitis was 19.3 years and mean duration of asthma was 17.0 years at baseline. Patients had mild to moderate asthma, with mean FEV1 in each group of 84%. About 41% of patients were using inhaled corticosteroids. Mean daily rhinitis symptoms scores were similar in the two groups.1
Adapted from Philip G et al Curr Med Res Opin 2004;20(10):1549–1558.
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36. Daily rhinitis symptoms Daytime nasal symptoms Nighttime symptoms
Clinical Study of Asthma Patients with Concomitant Seasonal Allergic Rhinitis Montelukast Significantly Reduced Daily Rhinitis Symptoms Scores*
Daily rhinitis
symptoms
Daytime nasal
symptoms
Nighttime
symptoms
–0.1
–0.2
–0.3
–0.4
–0.5
Change
from
baseline
(mean)
–11.8%
–11%
–18.2%
Slide 36
During the two-week active treatment period, montelukast significantly improved the primary endpoint of daily rhinitis symptoms score (p0.001 vs. placebo), producing a mean reduction of 0.35±0.48 (18%) from baseline, versus a mean reduction of 0.25±0.46 (11%) from baseline with placebo. Montelukast also significantly reduced the two individual components of the primary endpoint; i.e., the daytime nasal symptoms score and the nighttime symptoms score (both, p0.001 vs. placebo).1
–10.5%
–18%
p0.001
–18.7%
p0.001
p0.001
Placebo (n=416) Montelukast (n=415)
Multicenter study of the effects of montelukast 10 mg on allergic rhinitis in asthmatic patients 15 to 85 years of age with allergic rhinitis during the allergy season
*Scored on a 4-point scale
Adapted from Philip G et al Curr Med Res Opin 2004;20(10):1549–1558.
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37. Clinical Study of Asthma Patients with Concomitant Seasonal Allergic Rhinitis Montelukast Reduced Daily Rhinitis Symptoms Regardless of Asthma Status at Study Start
Treatment difference:
montelukast minus placebo (LS meanSE)
–0.1
Greater
Effect
Slide 37
Montelukast was effective in the patients with mild asthma included in this study. Analysis showed that the effects of montelukast on the daily rhinitis symptoms score were consistent across subgroups defined by asthma status at study entry (i.e., patients taking vs. not taking inhaled corticosteroids, patients with asthma symptoms twice weekly vs.<twice weekly; patients with FEV1 <80% vs. 80% of predicted; and patients with 12% vs. <12% beta2-agonist reversibility).1
–0.2
Yes No
 twice weekly
<twice weekly
<80%
80%
12%
<12%
–0.3
n=335
n=490
n=495
n=330
n=316
n=503
n=427
n=392
On inhaled corticosteroids
Asthma symptoms
FEV1 % predicted
Beta-agonist reversibility
Multicenter study of the effects of montelukast 10 mg on allergic rhinitis in asthmatic patients 15–85 years of age with allergic rhinitis during the allergy season
Adapted from Philip G et al Curr Med Res Opin 2004;20(10):1549–1558.
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38. Global evaluations of allergic rhinitis*
Clinical Study of Asthma Patients with Concomitant Seasonal Allergic Rhinitis Montelukast Improved Global Evaluations of Clinical Status and Quality of Life
Global evaluations of allergic rhinitis* 5 4 3 2 1
p0.001
p0.001
Placebo (n=416)
Montelukast (n=415)
Treatment
score
(mean±SD)
2.77
2.76
Slide 38
Montelukast had a significant effect on patient and physician global evaluations of the patients’ clinical status with respect to allergic rhinitis at the end of treatment. The effects of montelukast on these scores were significantly greater than those of placebo (both, p0.001).1
Montelukast significantly improved rhinoconjunctivitis quality-of-life scores, producing mean reductions from baseline of 0.73±1.14 versus 0.55±1.10 in the placebo group (p<0.01). These results reflect overall improvement in many aspects of daily life affected by allergic rhinitis, including symptoms, activity, sleep, emotions, and practical problems.1
2.39
2.41
Patients
Physicians
Montelukast significantly improved rhinoconjunctivitis quality-of-life scores versus placebo (p<0.01)
Multicenter study of the effects of montelukast 10 mg on allergic rhinitis in asthmatic patients 15–85 years of age with allergic rhinitis during the allergy season
*Scored on a 6-point scale
Adapted from Philip G et al Curr Med Res Opin 2004;20(10):1549–1558.
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39. Global evaluations of asthma*
Clinical Study of Asthma Patients with Concomitant Seasonal Allergic Rhinitis Montelukast Improved Asthma Control
Global evaluations of asthma*
2.8
2.6
2.4
2.2
Placebo (n=416) Montelukast (n=415)
Treatment
score
(mean)
p<0.01
p<0.05
2.52
2.52
Slide 39
As with global evaluations of allergic rhinitis, montelukast had significantly greater effects on global evaluations of asthma by patients (p<0.01) and physicians (p<0.05) versus placebo.1
During double-blind treatment, montelukast significantly reduced the number of puffs per day of as-needed short-acting beta2-agonist use in the complete study cohort of patients with mild asthma, and in the subgroup of patients who used beta2-agonists during the baseline run-in period (p0.005).1
Although the effects of therapy on FEV1 were not measured because the focus of the trial was relief of rhinitis symptoms, the results with these lung function endpoints show that montelukast provided relief from asthma in these comorbid patients.1
2.34
2.28
Patients
Physicians
Montelukast significantly reduced beta2-agonist use (p0.005 vs. placebo)
Multicenter study of the effects of montelukast 10 mg on allergic rhinitis in asthmatic patients 15–85 years of age with allergic rhinitis during the allergy season
*Scored on a 6-point scale
Adapted from Philip G et al Curr Med Res Opin 2004;20(10):1549–1558.
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40. In asthmatic patients with concomitant seasonal allergic rhinitis,
Clinical Study of Asthma Patients with Concomitant Seasonal Allergic Rhinitis Conclusions
In asthmatic patients with concomitant seasonal allergic rhinitis,
montelukast demonstrated significant improvements in
Allergic Rhinitis
Daily rhinitis symptoms score (average of the daytime nasal symptoms score and the nighttime symptoms score)a
Rhinoconjunctivitis quality of lifeb
Global evaluations of allergic rhinitis by patient and by physiciana
Asthma
Global evaluations of asthma by patientb and by physicianc
Beta2-agonist used
Slide 40
This randomized, parallel-group, double-blind study demonstrated that montelukast significantly improved seasonal allergic rhinitis symptoms in asthma patients with concomitant seasonal allergic rhinitis.1
Two weeks of treatment with montelukast produced significant improvements versus placebo in many of the study endpoints. Improvements in allergic rhinitis included the daily rhinitis symptoms score, an average of the daytime nasal symptoms score and the nighttime symptoms score (primary endpoint) (p0.001), the rhinoconjunctivitis quality-of-life score (p<0.01), as well as global evaluations of allergic rhinitis by patients and physicians (p0.001). Asthma endpoints were also improved, including global evaluations of asthma by patients (p<0.01) and physicians (p<0.05), and as-needed short-acting beta2-agonist use (p0.005).1
The beneficial effects of montelukast on allergic rhinitis endpoints observed in this study are consistent with the findings from previous studies of montelukast in the treatment of allergic rhinitis.1, The effects of montelukast on the symptoms of seasonal allergic rhinitis in patients with active asthma may be attributable to amelioration of the systemic inflammation that underlies both conditions.1 The authors of this study concluded that the use of montelukast in asthma patients with concomitant allergic rhinitis provides clinicians with an option that provides overall clinical benefits.1
ap0.001 vs. placebo; bp<0.01 vs. placebo; cp<0.05 vs. placebo; dp0.005 vs. placebo
Adapted from Philip G et al Curr Med Res Opin 2004;20(10):1549–1558.
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41. Objective of COMPACT Study and Subanalysis
To determine whether adding montelukast 10 mg to budesonide (800 µg) would provide greater benefits than doubling the dose of budesonide (to 1600 µg) in
Adult patients with asthma (OVERALL study)
Patients with asthma and allergic rhinitis (SUBGROUP analysis)
Slide 41
The Clinical Outcomes with Montelukast as a Partner Agent to Corticosteroid Therapy (COMPACT) study was a randomized clinical trial designed to compare the efficacy of adding the leukotriene receptor blocker montelukast to inhaled budesonide (400 µg twice daily) versus doubling the dose of budesonide (800 µg twice daily) in adults with chronic asthma.41
After the trial was completed, a post hoc analysis was conducted to determine whether treatment with montelukast plus budesonide, compared to budesonide alone, provided additional benefits in the subgroup of asthma patients who had concomitant allergic rhinitis.66
COMPACT=Clinical Outcomes with Montelukast as a Partner Agent to Corticosteroid Therapy
Adapted from Price DB et al Thorax 2003;58:211–216; Price DB et al. Presentation at the World Allergy Organization Biannual Meeting, September 2003, Vancouver, British Columbia, Canada.
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42. Period I Run-in (4 weeks) Single-blind Period II
COMPACT Study Design
Period I Run-in (4 weeks)
Single-blind
Period II
Active treatment (12 weeks)
Double-blind
Montelukast 10 mg once daily + Budesonide 400 µg twice daily (n=448)
Budesonide
400 µg twice daily
Slide 42
The COMPACT study began with a single-blind, four-week run-in period during which all patients received budesonide 400 µg twice daily. Patients were then randomized to receive 12 weeks of double-blind treatment with either montelukast 10 mg once daily plus budesonide 400 µg twice daily, or budesonide 800 µg twice daily plus oral placebo montelukast.41
Budesonide 800 µg twice daily + Oral placebo montelukast (n=441) 1 4 8 12 16
Weeks
Adapted from Price DB et al Thorax 2003;58:211–216.
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43. Days after randomization
COMPACT Study Montelukast + Budesonide Improved Morning PEF Progressively over 12 Weeks
440
430
420
410
400
390
380
Montelukast 10 mg + budesonide 800 µg (n=448) Budesonide 1600 µg (n=441)
Morning PEF*
(L/min)
Slide 43
Morning peak expiratory flow rate (PEF) was the prespecified primary endpoint of COMPACT. Both montelukast with budesonide and budesonide alone treatment groups showed progressive improvements in morning PEF over the 12-week trial. Addition of montelukast to budesonide was at least as effective as doubling the dose of budesonide over the last 10 weeks of the 12-week treatment period. In addition, changes in morning PEF during the first three days of treatment demonstrated a rapid onset of effect and significantly greater efficacy for the montelukast with budesonide group (p<0.001).41
–14 –7 7 14 21 28 35 42 56 63 70 77 84
Days after randomization
PEF=peak expiratory flow
*Mean measurement before administration of study medication
Adapted from Price DB et al Thorax 2003;58:211–216.
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44. All analyses of patient subgroups were post hoc
Subanalysis of Asthma Patients with Concomitant Allergic Rhinitis in COMPACT Statistical Analysis
All patients with a baseline and at least one on-treatment value were included in this intention-to-treat analysis
Treatment comparisons were based on an analysis of covariance (ANCOVA) model, with corresponding baseline value included as a covariate and the treatment group as a factor
All analyses of patient subgroups were post hoc
Slide 44
In the post hoc analysis of asthma patients with coexisting allergic rhinitis, all patients with a baseline and at least one on-treatment value were included in this intention-to-treat analysis. Treatment comparisons were based on analysis of covariance (ANCOVA); in this model, corresponding baseline values were included as a covariate and the treatment group as a factor.66
Adapted from Price DB et al. Presentation at the World Allergy Organization Biannual Meeting, September 2003, Vancouver, British Columbia, Canada.
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45. Subanalysis of Asthma Patients with Concomitant Allergic Rhinitis in COMPACT Definition of Groups in Analysis
Asthma+AR Patients with asthma and allergic rhinitis, defined by both positive patient history and confirmed physician diagnosis
Asthma–AR Patients with asthma but without both a patient history and physician diagnosis of allergic rhinitis
Slide 45
In this subanalysis of COMPACT, asthma patients were classified as having concomitant allergic rhinitis if they had both positive patient history and confirmed physician diagnosis of allergic rhinitis. Patients without both a history and physician diagnosis of allergic rhinitis were classified as asthma patients without allergic rhinitis.66
Adapted from Price DB et al. Presentation at the World Allergy Organization Biannual Meeting, September 2003, Vancouver, British Columbia, Canada.
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46. Subanalysis of Asthma Patients with Concomitant Allergic Rhinitis in COMPACT Baseline Characteristics of Patients
Asthma +
Allergic Rhinitis
(n=410)
Asthma
(n=479)
Age (years)
Median
Range 43
15–74 45
15–75
Gender (% of patients)
Male
Female 42 58 38 62
Duration of asthma (years) 15 13
Median morning PEF (L/min)
381
360
History of exercise-induced asthma
(% of patients) 83 80
Skin tested for allergies (% of patients) 74
History of atopic dermatitis (% of patients) 19 12
Slide 46
The subgroup analysis of COMPACT included patients with a history and diagnosis of asthma and allergic rhinitis (n=410), and patients with asthma but no history or diagnosis of allergic rhinitis (n=479). The treatment groups were similar at baseline with respect to demographic and clinical characteristics. The median age was 43 years in the comorbidity group and 45 years in the asthma group, both treatment groups had approximately the same proportion of male and female patients, and three quarters of each group were Caucasian. At baseline, lung function was similar in the two groups; i.e., a median morning PEF value of 381 L/min in the comorbidity group and 360 L/min in the asthma group. A history of exercise-induced asthma was noted in 83% of patients in the comorbidity group and 80% of the asthma group. Seventy-four percent of patient were skin tested for allergy in the asthma with allergic rhinitis treatment group and 58% were skin tested for allergy in the other group. A history of atopic dermatitis was noted in 19% of patients in the comorbidity group and 12% of the asthma group.66
Adapted from Price DB et al. Presentation at the World Allergy Organization Biannual Meeting, September 2003, Vancouver, British Columbia, Canada.
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47. Change from baseline (L/min, LS meanSEM)
Subanalysis of Asthma Patients with Concomitant Allergic Rhinitis in COMPACT Montelukast Provided Greater Improvements in Morning PEF in Asthma Patients with Concomitant Allergic Rhinitis
Montelukast (n=433)* Budesonide (n=425)**
Montelukast (n=216)* Budesonide (n=184)** 50 40 30 20 10 50 40 30 20 10
Change from baseline (L/min, LS meanSEM)
Slide 47
As shown on the graph on the left, in the total group of patients treated in the COMPACT study, montelukast + budesonide had effects on lung function similar to those of budesonide alone. Morning PEF increased by 33.5 L/min (8.6%) from baseline in the montelukast + budesonide group and by L/min (7.7%) in the budesonide alone group (p=0.36).66
In contrast, as shown in the graph on the right, in the subgroup of asthma patients with allergic rhinitis, the mean increase from baseline in morning PEF was significantly (p<0.03) higher in the montelukast + budesonide group (36.4 L/min; 9.2%) than in the budesonide alone group (24.1 L/min; 6.0%).66
p=0.36
p<0.03 4 8 12 4 8 12
Weeks
Weeks
*Montelukast 10 mg once daily + budesonide 400 µg twice daily; **Budesonide 800 µg twice daily
Adapted from Price DB et al. Presentation at the World Allergy Organization Biannual Meeting, September 2003, Vancouver, British Columbia, Canada.
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48. Subanalysis of Asthma Patients with Concomitant Allergic Rhinitis in COMPACT Conclusion
In the subgroup of asthma patients from the COMPACT study who had concomitant allergic rhinitis, the addition of montelukast to budesonide provided greater improvements in reducing airway obstruction than doubling the dose of budesonide
Improvements in morning PEF were similar in both treatment groups (primary endpoint)
Slide 48
The subgroup analysis of the COMPACT study showed that for asthma patients who had concomitant allergic rhinitis, adding montelukast to budesonide provided greater benefit in reducing airway obstruction than doubling the dose of budesonide. Improvements in morning PEF (primary endpoint) were similar in both treatment groups.66
Adapted from Price DB et al. Presentation at the World Allergy Organization Biannual Meeting, September 2003, Vancouver, British Columbia, Canada.
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49. Montelukast in Asthma Patients with Concomitant Allergic Rhinitis Summary
Allergic rhinitis and asthma are inflammatory disorders that have been linked epidemiologically, pathophysiologically, and clinically as “one airway disease”
Allergic rhinitis increases morbidity, therapeutic needs, and use of health-care resources in patients with asthma
ARIA recommends a combined strategy for the management of coexistent allergic rhinitis and asthma when possible
Cysteinyl leukotrienes are mediators of both allergic rhinitis and asthma
The cysteinyl leukotriene modifier montelukast has been shown to improve lung function, symptoms, and quality of life in asthma patients with concomitant seasonal allergic rhinitis
Slide 49
Allergic rhinitis and asthma are inflammatory disorders that have been linked epidemiologically, pathophysiologically, and clinically as “one airway disease.”7,16,21 The clinical importance of this association has been established in outcomes research showing that the presence of allergic rhinitis increases morbidity, drug costs, and use of health-care resources in patients with asthma.14,15 Therefore, current ARIA guidelines recommend a combined strategy for the management of coexistent allergic rhinitis and asthma.7
In light of the importance of cysteinyl leukotrienes as mediators of both allergic rhinitis and asthma, recent investigations have focused on the effects of cysteinyl leukotriene blockade in the treatment of patients with both conditions.1 In clinical studies, the cysteinyl leukotriene receptor antagonist montelukast was shown to improve lung function, symptoms, and quality of life in asthma patients with concomitant seasonal allergic rhinitis.1,66
Therefore, in asthma patients with seasonal allergic rhinitis, montelukast represents a therapeutic option that provides overall clinical benefits.1
Adapted from National Institutes of Health Global Initiative for Asthma: Global Strategy for Asthma Management and Prevention: A Pocket Guide for Physicians and Nurses. Publication No B. Bethesda, MD: National Institutes of Health, 1998; Bousquet J et al J Allergy Clin Immunol 2001;108(suppl 5):S148–S149; Casale TB, Amin BV Clin Rev Allergy Immunol 2001;21(1):27–49; Philip G et al Curr Med Res 2004;20(10): 1549–1558; Price DB et al. Presentation at the World Allergy Organization Biannual Meeting, September 2003, Vancouver, British Columbia, Canada.
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50. References Please see notes page. References
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53. References (continued)
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References (continued)
Please see notes page.
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54. Efficacy of Montelukast in Asthma Patients with Allergic Rhinitis
Before prescribing, please consult the manufacturers’ prescribing information.
Slide 49
Before prescribing, please consult the manufacturers’ prescribing information.
Copyright © 2004 Merck & Co., Inc., Whitehouse Station, NJ, USA.
All rights reserved SGA 2004-W-6776-SS Printed in USA
VISIT US ON THE WORLD WIDE WEB AT
Copyright © 2004 Merck & Co., Inc., Whitehouse Station, NJ, USA.
All rights reserved SGA 2004-W-6776-SS Printed in USA
VISIT US ON THE WORLD WIDE WEB AT
SGA 2004-W-6776-SS