Management of Bronchial Asthma in Adults..emerging role of anti-leukotriene

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1 Management of Bronchial Asthma in Adults..emerging role of anti-leukotriene Han-Pin Kuo MD, PhD Department of Thoracic Medicine Chang Gung University Chang Gung Memorial Hospital Taipei, Taiwan

2 Bronchial Asthma Chronic persistent Airway inflammation Structural change Pro-inflammatory cells Eosinophils T lymphocytes Macrophages Mast cells Pro-inflammatory mediators Airway Hyperresponsiveness Trigger s Episodic Bronchospasm Airway remodelin g Epithelial shedding Smooth muscle hypertrophy/hyperplasi a Mucus metaplasia Subepithelial fibrosis

3 Acute and Chronic Persistent Airway Inflammation Eosinophils: ECP, EDN, MBP CD4+ T lymphocyte (Th2): IL-3, IL-4, IL-5, GM-CSF, IL-13 macrophages Sloughing epithelium Endothelin-1 (bronchoconstrictor RANTES. (chemotaxis) GM-CSF. Eo CD8+ T lymphocyte neutrophi ls Airway smooth muscle GM-CSF, IL-8, RANTES, Eotaxin COX-2, NO, ROS

4 Neuropeptides released from sensory nerve endings (C-fiber) Toxic particles Noxious gas Mucus plug Nerve activation Epithelial shedding Mucus hypersecretion hyperplasia Vasodilatation New vessels Plasma leak Oedema Subepithelia fibrosis Sensory nerve activation Cholinergic reflex Bronchoconstriction Hypertrophy/hyperplasia

5 Airway Inflammation in Asthma IgE related immunological inflammation Antigen eliciated mast cell activation (early phase), Eosinophil, basophil, Th2 lymphocyte secreted cytokines mediated responses (late phase) Pro-inflammatory mediators released from structural cells Neurogenic inflammation: sensory C-fiber released neuropeptides (tachykinins) Irritant induced non-immunological inflammation (RADS)

6 Smooth muscle Dendritic cells β2-receptor Monocytes Epithelium sloughing Corticosteroids Mast cells Vascular permeability Basophils Eosinophil T-lymphocyte B-Lymphocyte Mucus secretion

7 Airway Inflammation Persists Despite Corticosteroid Use In a clinical study of 74 patients p<0.01 Eosinophil 10 3 /g sputum 20,000 10,000 1, p<0.01 p<0.001 p< Control group ICS low-dose (n=10) ICS high-dose (n=15) Mild to moderate OCS (n=10) OCS ± ICS (n=7) Severe asthma ICS=inhaled corticosteroids; OCS ± ICS=received oral corticosteroids with or without ICS Adapted from Louis R et al Am J Respir Crit Care Med 2000;161:9-16. Residual airway inflammation (corticosteroid insensitive)

8 Airway Inflammation in Asthma IgE mediated immunological inflammation Antigen eliciated Corticosteroid mast cell activation Sensitive (early phase), Eosinophil, basophil, Th2 lymphocyte secreted cytokines mediated responses (late phase) Neurogenic inflammation: sensory C-fiber released tachykinins Corticosteroid Sensitive Irritant induced non-immunological inflammation Corticosteroid Insensitive Pro-inflammatory mediators Varies with individuals released from structural cells Corticosteroid Insensitive

9 ICS vs Airway Hyperresponsiveness [Mch mg/ml] ICS fails to completely reverse airway hyperresponsiveness 1. Structural factors 2. Residual inflammation 3. Autonomic dysfunction 0 Before ICS Normal Kuo et al., Eur Respir J 1994

10 Structural change and Airway Hyperresponsiveness Concerning about airway remodeling is increasing.. Airway smooth muscle Hypertrophy/hyperplasia Subepithelial fibrosis Enhanced contractility Loss of compliance Synthesis of Proinflammatory mediators Enhanced Airway Hyperresponsiveness Exaggerate Clinical responses

11 Variation of Airway Structure Collagen 1 Collagen 3 Similar severity of asthma Different level of airway remodeling

12 Diversity of Asthma Variable in structural changes Variable in airway inflammation magnitude and composition Variable in the nature of triggers Individualized treatment

13 Therapeutic Approach to Bronchial Asthma Persistent heightened Anti-inflammatory Airway inflammation agents Steroid sensitive Steroid insensitive Avoid Specific or Treat triggering concomitant factors Concomitant diseases diseases Allergic rhinitis/sinusitis GERD Aspirin sensitive asthma Virus infection etc., Persistent Bronchial heightened protective Airway agents Hyperresponsiveness (LABA) Structural factors (airway remodeling)

14 Effect of Salmeterol on glucocorticoid receptors Fluticason Salmeterol ß 2 adrenoceptor Glucocorticoid receptor + cyclic AMP PKA Synergistic Effect Nucleus MAPK Enhance anti-inflammation Provide bronchodilator effect on airway hyperresponsiveness mrna protein Modified from P J Barnes GRE Steroid-responsive gene

15 Combination therapy is more effective than a higher dose of ICS 30 Change in morning PEF (L/min) p< Most effective decreasing acute -5 exacerbation stabling clinical course Treatment days Symbicort 160/4.5 µg bid fluticasone DPI 250 µg bid Bateman et al, Am J Respir Crit Care Med 2001

16 Combination therapy Rescue bronchodilators Severe moderate mild persistent mild intermittent Systemic steroids Inhaled steroids

17 Despite ICS or ICS plus LABA therapy, 74% of patients used rescue therapy each day (INSPIRE study ) 21 SABA use (inhalations/day in the last week) Number of inhalations/day SABA = short-acting β 2 -agonist Base: all respondents (n=3,415) Patients (%) Partridge MR, et al. BMC Pulm Med 2006

18 Despite ICS or ICS plus LABA therapy, only 28% of patients were well controlled according to the Asthma Control Questionnaire (ACQ) 22 51% uncontrolled (poor) 28% well controlled 21% not well controlled ACQ-6 summary score Well controlled: 0.0 to 0.74 Not well controlled: 0.75 to 1.5 Uncontrolled: >1.5 Partridge MR, et al. BMC Pulm Med 2006

19 3 GINA 2006 guidelines Outcome: Asthma Control Outcome: best possible results Step 1 Intermittent None Step 2 Mild persistent Low-dose ICS (theophylline, leukotriene modifier, cromolyn) ICS = inhaled corticosteroid; LABA = long-acting β 2 -agonist Step 3 Moderate persistent Low-to-mediumdose ICS + LABA (theophylline, leukotriene modifier, oral β 2 -agonist) Step 4 Severe persistent High-dose ICS + LABA plus if needed Anti-IgE Leukotriene modifier Oral β 2 -agonist Oral corticosteroid Theophylline-SR Leukotriene modifier Effective in some patients Decrease dosage of ICS Adapted from GINA Workshop Report 2006

20 CASIOPEA Study Montelukast + Budesonide Significantly Reduced Asthma-Exacerbation Days Median percentage of asthmaexacerbation days % p= Budesonide + placebo (n=308) Montelukast + budesonide (n=317) Adapted from Vaquerizo MJ et al Thorax 2003;58:

21 CASIOPEA Study Montelukast + Budesonide Significantly Increased Asthma-Free Days Median percentage of asthmafree days % p= Budesonide + placebo (n=308) Montelukast + budesonide (n=317) Adapted from Vaquerizo MJ et al Thorax 2003;58:

22 CASIOPEA Study Montelukast + Budesonide Significantly Reduced Nocturnal Awakenings Least square mean % of patients with nocturnal awakenings* % p= Budesonide + placebo (n=308) Montelukast + budesonide (n=317) *The percentage of patients who awoke during the night because of asthma Adapted from Vaquerizo MJ et al Thorax 2003;58:

23 CASIOPEA Study Montelukast + Budesonide Significantly Reduced Beta 2 -Agonist Use* Budesonide + placebo (n=313) Montelukast + budesonide (n=326) % change from baseline in beta 2 -agonist use A more rapid onset of action than budesonide + placebo 40 Basal First 7 days in active treatment *p = 0.05 vs. budesonide alone Adapted from Vaquerizo MJ et al Thorax 2003;58:

24 Central Role of CysLTs in Asthma Decreased Mucus Transport Cationic Protein Release, Epithelial-Cell Damage Airway Epithelium Increased Mucus Secretion Blood Vessel Edema Inflammatory Cells (mast cells, eosinophils) Eosinophil Influx CysLTs Sensory Nerves (C fibers) Contraction and Proliferation Airway Smooth Muscle Adapted from Hay DWP et al Trends Pharmacol Sci 1995;16:

25 Pro-inflammatory cells Stable Acute exacerbation Am J Respir Cell Mol Biol 2005, 531-

26 Residual Airway Inflammation (Steroid insensitive) Cells: Neutrophil Cytotoxic T cells (CD8, Tc2 cells) Structural cells Pro-Inflammatory mediators: Leukotrienes Neuropeptides Growth factors Reactive oxygen species

27 Effect of Inhaled Fluticasone Propionate on Urinary LTE 4 Excretion Urinary LTE 4 excretion (ng/mmol creatinine) Fluticasone propionate Placebo p = NS between groups Adapted from O Shaughnessy KM et al Am Rev Respir Dis 1993;147:

28 Effect of Oral Prednisone on Urinary LTE 4 Excretion 0.3 Control Prednisone * Urinary LTE 4 (ng/mg creatinine) * 0 Baseline Post-allergen challenge *p<0.05 vs. baseline Adapted from Dworski R et al Am J Respir Crit Care Med 1994;149:

29 Oral Prednisone Did Not Suppress CysLT Levels Recovered from BAL Fluid Eicosanoids in Asthmatics Before prednisone After prednisone BAL levels (pg/ml) LTC 4 LTE 4 n=14 BAL = bronchoalveolar lavage Adapted from Dworski R et al Am J Respir Crit Care Med 1994;149:

30 When low dose ICS fails to control asthma.. (n=75) Budesonide 800 µg/day 2 weeks Incomplete control Budesonide 1600 µg/day Budesonide 800 µg/day+ Montelukast 10 mg 12 weeks Respiratory Medicine 2007 online

31 ICS+Montelukast vs DS ICS Anti-leukotriene Vs High dose steroids * Compared with baseline 30 * Equal efficacy in PFT & QoL ampefr (L/min) No change in inflammatory markers 15 ICS+Montelukast Leukotriene: A major DS ICS mediator in heightened airway inflammation 6 12 weeks Eosinophilia 29% 26% On sputum Respir Med 2007, online

32 Diverse Immune and Inflammatory stimuli Leukotrienes BLT1 Leukocyte BLT2 LTA4 hydrolase LTB4 Inflammatory cells PLA2 Arachidonic acid LTA4 FLAP 5-LO LTC4 synthase LTC4 LTD4 LTE4 Bronchospasm Mucus production Vascular permeability Tissue edema Chemotaxis for pro-inflammatory cells CysLT1 Smooth muscle Macrophages CysLT2 Ubiquitous cell Endothelium

33 Specific Forms of Persistent Asthma Allergic rhinitis and Asthma Eosinophils Aspirin sensitive asthma Exercise induced asthma Sinusitis complicated asthma Pre-menstruation asthma Monocytes

34 Allergic rhinitis aggravates Asthma severity Asthma alone Coexisting AR 50% β2-agonist ICS symptoms moderate/severe% Asthma symptoms Moderate/severe AR > One attack/week Noctural attack Inable to work Moderate/severe asthma mild to nil AR Vinuya: Ann Allergy Asthma Immunol, Volume 88(4) Supplement 1.April

35 Similar Immunological Responses between Allergic Rhinitis and Asthma Allergen IgE Mast cells Histamine New synthesis Leukotrienes, PGs, PAF Allergic rhinitis Asthma sneezing bronchospasm rhinorrhea mucus secretion nasal stuff airway edema CysLT1 receptor On nasal mucosa Eosinophils Cytokines Chronic allergic responses Lymphocytes edema Inflammatory cells hyperresponsiveness CysLTs=cysteinyl leukotrienes; PGs=prostaglandins; PAF=platelet activating factor Based on and modified from Casale TB, Amin BV Clin Rev Allergy Immunol 2001;21(1):27-49; Kay AB N Engl J Med 2001;344:30-37.

36 Anti-leukotriene concomitantly improves Allergic rhinitis & Asthma Allergic rhinitis Asthma 0 15 Change from baseline score (LS mean) Placebo (n=352) Morning FEV 1 mean % change from baseline 10 5 Montelukast 10 mg once daily (n=408) Placebo (n=273) 0.5 Montelukast 10 mg once daily at bedtime (n=348) *p<0.001 montelukast vs. placebo Weeks *p<0.001 montelukast vs. placebo Adapted from Reiss TF et al Arch Intern Med 1998;158: Multicenter, randomized, 12-week double-blind trial of montelukast vs. placebo in patients 15 years and older with asthma Adapted from Malmstrom K et al. Poster presentation at the 57th AAAAI Annual Meeting, March 16 21, Multicenter, 12-week double-blind, randomized trial in patients 15 to 81 years with seasonal allergic rhinitis.

37 Aspirin Sensitive Asthma Severe asthma attack min-3 hrs after taking aspirin or NSAIDs 15-20% of asthmatics Usually with nasal polyps, sinusitis Anaphylactic reaction No latency

38 Aspirin Sensitive Asthma Arachidonic acid Aspirin Cyclooxygenase-1 Lipooxygenase NSAIDs Thromboxane PGE4 LTC4 LTD4 Leukotrienes Histamine release LTE4

39 Montelukast protects from Aspirin Challenge Montelukast Placebo

40 Aspirin (or NSAID) sensitive Asthma Masked by URI Severe attack after anti-pyretics Chronic persistent asthma Rheumatoid arthritis Degenerative arthritis

41 EIA % Change from Preexercise FEV 1 Max % Fall in FEV End of Exercise AUC 0-60min Time to Recovery from Max % Fall in FEV 1 to within 5% of Pre-exercise FEV Time (Minutes) Return to 5% of Pre-exercise FEV 1

42 Effect of anti-leukotriene therapy on exercise-induced induced bronchoconstriction Accolate 20 mg bd Placebo FEV 1 as % baseline Time (minutes) post-exercise Significant difference in mean maximum fall in FEV 1, p<0.01 Finnerty et al (1992)

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44 Leukotrienes and Airway Remodeling

45 Airway smooth muscle proliferation Airway fibrosis Am J Respir Crit Care Med 2006, 173:

46 Control +Montelukast Control +Steroid Allergen challenge +Steroid OVA challenge +MK+Steroid +Montelukast Mucus metaplasia/hyperplasia Am J Respir Crit Care Med 2006, 173:718-

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48 Synergistic Effect between TGF-β1 and Leukotrienes

49 TGF-β1 TGF-β1 LTD4 TGF-β1 Fibrosis Int Arch Allergy Immunol 2005, 137(suppl 1)17-20

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51 Patients with rapid decline in FEV1 within 5 years of follow up Circulating fibrocyte A n=9, r=0.812, p= p< Percentage of fibrocyte in NANT cells, % p< p< p< Decline of FEV1 in 5 years (%) Fibrocytes in NANT cells (10 4 cells /ml) 0 Normal Asthma Chronic Asthma with Subjects Normal PFT Obstuctive asthma AE

52 A E BM B C * * * D * E F E BM G H

53 Culture for 14 days 85 p= p=0.001 Cell count of myofibroblast (10 4 cells/ml) p= myofibroblasts Montelukast 0 Normal Asthma Chronic Normal Asthma Chronic Subjects Normal PFT Obstructive Subjects Normal PFT Obstructive Asthma Asthma 30% FCS +Montelukast Adipose cells

54 When asthma symptoms persists despite of use of inhaled corticosteroid. Long-acting β2-agonists or Leukotriene modifiers (especially when specific triggers exists) are the best-fit add-on therapy.