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1 Management of Severe Asthma Heung-Woo Park Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea How to define severe asthma At least 3 of the following criteria: - Have been seen by a consultant in asthma for 2 yrs - Have persistent symptoms & decreased QOL - Have received maximal usual asthma therapy &/or medications(high doses of inhaled corticosteroids) with documented adherence to therapy - Have previous respiratory failure/intubations/near-fatal episodes - Have repeated low FEV1 < 70% predicted ENFUMOSA (European Network for Understanding Mechanisms of Severe Asthma) 1
2 How to define severe asthma Asthma severity Impairement of lung function Symtpoms Frequency Treatment requirement for control of asthma symptoms How to overcome severe asthma Is it really effective? Asthma heterogeneity Treatment requirement for control of asthma symptoms Phenotype dissection Biomarker/PGx approach Corticosteroid Is it only effective? Different approach Reassessing known drugs New drug development 2
3 Phenotype dissection Asthma heterogeneity The elephant metaphor of reality Lancet 2006;368: Biomarker-driven approach Anti-IL13 antibody treatment for asthma N Engl J Med 2011;365:
4 Pharmacogenomics approach Molecular phenotyping for asthma Am J Respir Crit Care Med 2009;180: In this presentation... Our recent works focused on the strategy to overcome severe asthma - Pharmacogenetic approach (reassessing known drug) Arg16Gly in ADRB2 vs. Tiotropium bromide - Biomarker-driven approach (overcoming steroid insensitivity) FKBP51 expression in PBMC vs. steroid response - Different treatment approach (overcoming steroid insensitivity) Singalings via TLR vs. steroid response - Newer modality for phenotyping Xenon ventilation computed tomography 4
5 Arg16Gly in ADRB2 vs. Tiotropium bromide Role of anti-cholinergic in the asthma management N Engl J Med 2010;363: Arg16Gly in ADRB2 vs. Tiotropium bromide Genetic variations in ADRB2 vs. anticholinergics Arg 16 /Arg 16 Gly 16 /Gly 16 Lancet 2004;364:
6 Arg16Gly in ADRB2 vs. Tiotropium bromide Additive role of tiotropium in severe asthmatics and Arg16Gly in ADRB2 as a potential marker to predict response 138 severe asthmatics - decreased lung function - on conventional medications 11 SNPs in CHRM1-3, Arg16Gly & Gin27Glu in ADRB2 scored in 80 of the 138 asthmatics Tiotropium 18µg once a day lung functions every 4 weeks Responders - FEV1 improvement : 15% & 200 ml : maintained for at least 8 successive weeks Park HW, et al. Allergy 2009:64: Arg16Gly in ADRB2 vs. Tiotropium bromide Additive role of tiotropium in severe asthmatics and Arg16Gly in ADRB2 as a potential marker to predict response # Main findings - As many as 30% of severe asthmatics on conventional medications with reduced lung function were found to respond to adjuvant tiotropium - Logistic regression analyses (controlled age, gender and smoking status) showed that Arg16Gly in ADRB2 [P = 0.003, OR (95% CI) = 0.21 ( ) in a minor allele dominant model] was significantly association with response to tiotropium Park HW, et al. Allergy 2009:64:
7 Arg16Gly in ADRB2 vs. Tiotropium bromide Crosstalk between muscarinic receptor & adrenergic receptor Proc Am Thorac Soc 2005;2: Arg16Gly in ADRB2 vs. Tiotropium bromide Tiotropium improves lung function in patients with severe uncontrolled asthma: A randomized controlled trial J Allergy Clin Immunol 2011;128:
8 Arg16Gly in ADRB2 vs. Tiotropium bromide Tiotropium is noninferior to salmeterol in maintaining improved lung function in B16-Arg/Arg patients with asthma J Allergy Clin Immunol 2011;128: FKBP51 expression vs.. steroid response 1 st Step Changes in gene expression during steroid treatment (murine model of asthma & dexamethasone treatment) Park HW, et al. J Clin Immunol 2011:31:
9 FKBP51 expression vs.. steroid response Park HW, et al. J Clin Immunol 2011:31: FKBP51 expression vs.. steroid response FKBP51 in cluster Park HW, et al. J Clin Immunol 2011:31:
10 FKBP51 expression vs.. steroid response 2 nd Step Evaluations using human PBMC - FKBP51 expression on PBMC (controls vs. asthamtics) Controls Asthmatics Asthmatics (mild-to-moderate vs. severe) Park HW, et al. J Clin Immunol 2011:31: FKBP51 expression vs.. steroid response 2 nd Step Evaluations using human PBMC - FKBP51 expression on PBMC (steroid response) R=-0.821, P= Park HW, et al. J Clin Immunol 2011:31:
11 Signaling via TLS vs.. steroid response The expressions of TLRs on PBMCs Park HW, et al. J Clin Immunol 2010:30: Signaling via TLS vs.. steroid response The changes in TNF-α production after in vitro stimulation with TLR-specific ligands according to asthma severity Park HW, et al. J Clin Immunol 2010:30:
12 Signaling via TLS vs.. steroid response The changes in the expression of TLRs on PBMCs of asthmatics after oral prednisolone administration Park HW, et al. J Clin Immunol 2010:30: Signaling via TLS vs.. steroid response The changes in TLRspecific ligands induced TNF-α and IFN-γ production after oral prednisolone administration Park HW, et al. J Clin Immunol 2010:30:
13 Xenon ventilation computed tomography Xenon ventilation CT (Functional imaging) Emphysema & bullae Xenon ventilation computed tomography Xenon ventilation CT (Functional imaging) Wash-in phase Wash-out phase Wash-in phase Wash-out phase Asthmatics Controls 13
14 Xenon ventilation computed tomography Clinical meanings of air trapping within the lungs of asthmatics (A promising role of Xenon ventilation CT) Park HW, et al. Manuscript in preparation Xenon ventilation computed tomography Park HW, et al. Manuscript in preparation 14
15 Xenon ventilation computed tomography Baseline characteristics associated with dyspnea measured by visual analogue scale Park HW, et al. Manuscript in preparation Xenon ventilation computed tomography Baseline characteristics associated with % increase in FEV1 after treatment Park HW, et al. Manuscript in preparation 15
16 Conclusion Pharamcogenetic approach - help the positioning of tiotropium in asthma management Dexamethasone-induced FKBP51 expression in PBMCs - a reliable & practical biomarker in predicting the response to corticosteroids in asthmatics A TLR-specific antagonist & glucocorticoid - required for the effective control of airway inflammation in asthmatics Xenon ventilation CT - an objective & promising tool in identifying specific subset of asthma & treatment responses 16
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