Άσθ α σ ι ι ούς θ σ ούς: οβα ό άσθ α αι σύ ο ο Churg-Strauss ού α Π α ία, MD, PhD ι ή ια ο ο ο ι ή Κ ι ι ή ΑΠΘ Κ ι ι ά ι ά ια σ ο ο ο ία Ο Η Α ΑΑ Α Ω Ω 27-28/5/2017, Olympian Bay Hotel - Κα ί
ERS/ATS: Ο ισ ός ο σοβα ού άσθ α ος Άσθ α ο ο οίο α αι ί θ α αί έ α ο ι οσ «ύ ο ι ή ώσ ό ο ο φά ό ώ α ο ία έ ο ή/ αι σ σ α ί αι ο» α ά ςά ο άσθ α ο α ο όσ ICS ή ές όσ ις ICS ό θ α θ ί OCS ή ά οή ο αι ά α α έ ι ία αι α ά ί σ βιο ο ι ώ α α ό ATS/ERS Guidelines on Severe Asthma, KF Chung Eur Respir J 2014; 43: 343 373
οβα ό θ ί αι ο άσθ α ο α αι ί ι ά σ θ α ίας ια ί Severe asthma Disease severity When the diagnosis of asthma is confirmed and comorbidities addressed έ ισ έ ο Moderate asthma Mild asthma PREFERRED CONTROLLER CHOICE reslizumab Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, 2017
α ά ο ς ο ο ού α σ φαι ό ο ο ασθ ούς βά ο σ ο ι ό σοβα ό άσθ α ATS/ERS Guidelines on Severe Asthma, KF Chung Eur Respir J 2014; 43: 343 373
ιο- ι ι οί φαι ό οι ο σοβα ού άσθ α ος
Α α ό οι ό οι σ ο σοβα ό άσθ α: Th high Th lo άσθ α Woodruff, AJRCCM 2009; 180: 388-395
Markers of allergy, eosinophilic inflammation and airway remodelling are increased in Th2-high asthma Woodruff, AJRCCM 2009; 180: 388-395
Η σι οφι ι ό άσθ α: αθοφ σιο ο ία Brusselle GG, Nat Med 2013; 19: 977-9
Ο σχ ί αι σοβα ό ο άσθ α, ιω έ α α σ ι ή ι ο ία, α ό έ χο αι α έ ο ί ο σοβα ώ α ο ύ σ ω Α αφέ α α σι οφι ι ός φαι ό αι σ ούς ος ο άσθ α ος α σι όφι α ο αί α ος φαί αι ό ι σ ί ο αι ο Th- high ό ο αι σοβα ό α ο άσθ α ος σι οφι ία σ ο ς ά χ ι ο οφω ία ως ος ο ο ισ ό -> 3% Η σ α ο ά ύ α? Haldar, JACI 2007 Haldar, AJRCCM 2008, Berry, Thorax 2007, de Groot, ERJ Open Res. 2015, Nixon J, Pharmacol Ther 2016 Woodruff, AJRCCM 2009; 180: 388-395
Severe asthma cohort The diagnostic accuracy described as ROC AUC was 85% (p<0.001, 95% CI 0.81-0.96) Wagener, Thorax 2015; 70: 115-120
Bl-eos >400 σχ ί ο αι σοβα ούς α ο σ ούς αι ωχό έ χο ο άσθ α ος Price DB, Lancet Respir Med. 2015; 3: 849-58
Anti-IgE therapy: Omalizumab Busse W, J Allergy Clin Immunol. 2001; 108:184-190
Hanania. AJRCCM 2013;187:804 811.
Omalizumab attenuates airways and systemic eosinophilia Induced sputum Eosinophils in peripheral blood Airway submucosa Massanari, Respir Med 2010; 104: 188-96 Djukanovic, AJRCCM 2004;170:583-593
Basophils p=0.001 pdc2 p=0.001 Improvements in FEV1, reduction in exacerbation frequency and better asthma control FcεRI expression Garcia. CHEST 2013;144(2):411 419
Anti-IL5/IL5-R Therapy: Mepolizumab, Reslizumab, Benralizumab (IL5-Rα) Legrand, J Allergy Clin Immunol Pract 2015
Pavord Lancet 2012;380:651-59
(SIRUS investigation) Blood eosi ophil le el of ells/ L during the 12-month period before screening or ells/ L during the optimization phase Bel, N Engl J Med 2014.371:1189-97
patie ts ith re urre t asth a e a er atio s a d > ells/ L at baseline or >300 cells/ L during the 12-month period before screening, despite high doses of ICS plus additional controller medication(s) Lung function QoL Symptoms Chupp GL, Lancet Respir Med. 2017;5:390-400
The nasal polyp endotype ACQ Castro, Am J Respir Crit Care Med 2011;148:1125-32
Patients with asth a e a er atio s during the previous year and >400/ LB-Eos at baseline Patients receiving RES had a significant reduction in the frequency of asthma exacerbations compared with PBO (Study 1: RR 0.50 [95% CI 0.37 0.67]; Study 2: 0.41 [0.28 0.59]; both p<0.0001). The grater benefit was seen in the OCS-treated subset of patients Castro, Lancet Respir Med. 2015; 3:355-66
315 patients, inadequately controlled (ACQ. at least a ediu dose of ICS a d at least one Bl-Eos ou t of Reslizumab 0.3 mg/kg i.v., 3.0mg/Kg i.v. or PBO, once every 4 wks for 16 wks Change in baseline FEV1 ells/ L during the screening period Change in baseline symptoms ACQ *P Change in rescue inhaler use. ASUI Bjermer L, CHEST. 2016; 150: 789-798
1205 patients ith e a er atio s during the previous year, while on high doses ICS + LABA were randomized to receive Benralizumab 30mg s.c. Q4W, Benralizumab Q8W or placebo (1:1:1) for 48 wks as add on to their standard Tx 1306 patients ith e a er atio s during the previous year, while on high doses ICS + LABA were randomized to receive Benralizumab 30mg s.c. Q4W, Benralizumab Q8W or placebo (1:1:1) for 56 wks as add on to their standard Tx Annual asthma exacerbation rates according to baseline Bl-Eos concentrations Benralizumab significantly improved pre-bronchodilator FEV1 (Q4W and Q8W) and total asthma symptom score (Q8W only) compared with PBO Bleecker ER, Lancet. 2016; doi: 10.1016/S0140-6736(16)31324-1 FitzGerald JM, Lancet. 2016; doi: 10.1016/S0140-6736(16)31322-8
Patients with high periostin levels have a reduced rate of exacerbations Hanania, Thorax 2015; 70: 748-755
Patients with high Periostin have improved Lung function with Tralokinumab Brightling, Lancet Respir Med 2015; 3: 692-701
Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial 769 patients were randomly assigned (1:1:1:1:1) to receive subcutaneous dupilumab 200 mg or 300 mg every 2 weeks or every 4 weeks, or placebo, over a 24-week period The every 2-week regimens showed a significant decrease in severe asthma exacerbations i patie ts with Eos cells/ L, Eos < 300 cells/ L and in the overall population Wenzel S, Lancet. 2016;388:31-44
Th-2 low άσθ α: αθοφ σιο ο ία αι ιθα οί θ α ι οί σ ό οι Barnes PJ, J Allergy Clin Immunol. 2015; 136: 531-545
AZ: 250mg/OD, 3 times a week vs placebo for 24 wks PEP: rate of severe exacerbations and LRTI requiring Tx with antibiotics SEP: lung function and scores on the ACQ and AQLQ ασθ ίς σοβα ό NEA: ί σ ς σ ό ας α ού σ αά % (p=0.013) Brusselle G, Thorax 2013;68:322 329.
ο ι ήθ ο ασ ι ή σ α ι ή β ίωσ σ PEFR, BHR, ώ α α, α ο ύ σ ις αι QoL Cox, N Engl J Med 2007;356:1327 37 Castro, Am J Respir Crit Care Med 2010;181:116 24 Pavord. AJRCCM. 2007:176:1185-91 έθο ος ασφα ής, χω ίς σοβα ές α οχ ό ι ς ι ο ές, ια ή σ ο FEV1 σ ία Thomson, BMC Pulm Med 2011;11:8 Wechsler, JACI 2013;132:1295-302 Α αι ί αι ι ύ σ ω φαι ο ύ ω ω ασθ ώ ο α α ο ί ο αι αι ς α ο σ α ι ό ας σ σοβα ή α όφ α FEV1< 60%) ERS/ATS Guidelines Severe Asthma Eur Respir J. 2014
αο ι έ θ α β ί σ ο θ α ι ή οσέ ισ σό ο ι ού α ο έσ α ος TAILORED THERAPY Dunn RM, Clin Pharmacol Ther. 2015;97:55-65
ί αι ό ως ά α «άσθ α»;
οσή α α ο ο ί α ο οιά ο σοβα ό άσθ α Eosinophilic Granulomatosis with Polyangiitis (EGPA) ATS/ERS Guidelines on Severe Asthma, KF Chung Eur Respir J 2014; 43: 343 373
Η σι οφι ι ή ο ι ά σ ο α ιί ι α Πο σ σ α ι ή όσος ο οία α ή ι σ ις ι ού έως σαίο έθο ς α ιί ι ς ο σχ ί ο αι α ο σία ANCA α ισω ά ω. ι ο ασ ός: 0.7ι ώσ ις α ά α ο ύ ιο ί ωσ :. -. έ ς ι ώσ ις α έ ος α ά α ο ύ ιο θ σ ού Π οσβά ι ά ο α ώ έσ ι ία φά ισ ς α έ χω ίς α α ού ς ιαφο ές ως ος ο φύ ο, φ ή ή οι ο ίς ο φές ια σ ι ά ι ή ια Vaglio A, Allergy 2013; 68: 261 273
αθο έ ια Gioffredi A, Front Immunol. 2014;5:549
Κ ι ι ά σ ά ια Η όσος α α ύσσ αι σ σ ω άω : ς όσο ια οχι ά σ ά ια, 1ο σ ά ιο ό ο οήα ι ό - Άσθ α, α ι ή ι ί ι α αι α α 2-3 α ία ς ωής ι ή ι ο ο όο ο ω ί ι α σ ήθως σ 2ο σ ά ιο σι οφι ι ό) - Π ιφ ι ή ωσι οφι ία αι ωσι οφι ι ές ι θήσ ις ο ά ω σ χ ό α ύ ο ς, α ιά αι ασ ι ός σω ή ας 3ο σ ά ιο α ιι ι ι ό) - Πο φύ α, ιφ ι ή ο άθ ια αι ός, α ο χία αι α ώ ια βά ο ς ι άσ ώ α α ό ως Pagnoux C, Curr Opin Reumatol. 2007; 19:25-32
Κ ι ι ές ώσ ις ς όσο Vaglio A, Allergy 2013; 68: 261 273
Α ι ο ισ ι ά ή αα Vaglio A, Allergy 2013; 68: 261 273
ασ ια ά ή αα Π ιφ ι ή ωσι οφι ία: 5000-9000 ύ α α/ L ο άχισ ο > ύ α α/ L ή > % CRP αι Κ ί α ο ι ής IgE σ ο ο ό ί α IgG4 σ ο ο ό (σ ο % ANCA (p-anca σ ο % ί α eotaxin-3 σ ο ο ό (at a cut-off level of 80 pg/ml: sensitivity 87.5% and specificity 98.6%) Vaglio A, Ann Rheum Dis. 2012;71:390-3, Sinico RA, Arthritis Rheum. 2005;52:2926-35, Zwerina J, Rheumatology. 2011;50: 1823-27
Παθο ο οα α ο ι ά The key histological features of EGPA are tissue eosinophilia, necrotizing vasculitis, and extravascular eosinophilic granulomas. Vaglio A, Allergy 2013; 68: 261 273 Vasculitis is characterized by fibrinoid necrosis and eosinophilic vessel wall infiltration. ή αα Granulomas may involve the arteries, but the more EGPAspecific lesion is the extravascular granuloma, which consists of a core of necrotic eosinophilic material surrounded by palisading lymphocytes and epithelioid and multinucleated giant cells
ιαφο ι ή ιά σ Πα ασι ι ές οι ώ ις Α ι άσ ις αισθ σίας - ωσι οφι ι ό σύ ο ο (HES) Α ι ή β ο χο ο ι ή ασ ί ωσ Ο ία ωσι οφι ι ή ο ία ό ια ωσι οφι ι ή ο ία Ά ς α ιί ι ς (GPA, MPA) IgG4-RD
The five factors score (FFS) Gastrointestinal involvement CNS involvement Cardiac involvement Proteinuria >1 g/24h Serum creatinine >141mmol/L FFS=1: GCS (1mg/kg/day, max 75mg/day, for 1 month, then tapered) + CYC (2mg/kg/day), FFS=0 : only GCS Remission maintenance (according to BVAS score): AZA or MTX Rapidly progressive glomerulonephritis, peripheral neuropathy or alveolar hemorrhage: Plasmapheresis ANCA (+) with renal involvement or refractory disease: RTX 2nd or 3rd line Tx (selected patients): IVIg or INF-α
136 patients with relapsing or refractory EGPA on stable prednisolone or prednisone dose Mepolizumab 300 mg or PBO sbc every 4 weeks, plus standard care, for 52 weeks. PEPs: accrued weeks of remission over a 52-week period and the proportion of participants in remission at both weeks 36 and 48 SEPs: time to first relapse and the average daily GCS dose during weeks 48 through 52 Mepolizumab led to significantly more weeks of remission than PBO (28% vs. 3%, P<0.001) and a higher % of participants in remission at both weeks 36 and 48 (32% vs. 3%, P<0.001) Wechsler ME, NEJM. 2017; 376: 1921-32
ό ω ίς θ α ία, ής ό θ α ία, α οσοσ ά % α ίσ οιχα σ ιβίωσ ά ο ιβίωσ ς σ αι έ % φθά ο ο % αι Π ο ωσ ι ούς α ά ο ς ο ο ής α ο ού α θ ι ά ANCA αι οι οσβο ή ο ά ω ό ως α ιά αι α ιφ ι ά ύ α, ώ θ α ία α οσο α ασ α ι ά σ βά ι σ θ ό α α ό όσο οι ώ ις, α οήθ ι ς χ ό ς αι ί ς θα ά ο : - Κα ια ή α ά ια, έ φ α α ο φ ι ή α ά ια φα ι ή αι ο α ία - Αι ο α ία α ό ο - Status asthmaticus ο α ίο ή αι α ύο Greco A, Autoimmun Rev. 2015 ; 14:341-8
Mepolizumab efficacy was only associated with baseline Bl-Eos and exacerbation frequency in the previous year Pavord Lancet 2012;380:651-59
ο σοβα ό άσθ α α α ί αι α ό ά ο έ ια
COSMOS: 52-wk, open-label extension study in patients who received mepolizumab or PBO in MENSA or SIRIUS studies Exacerbation rate during MENSA and COSMOS periods Median OCS doses during SIRIUS and COSMOS periods Mepolizumab exerted a durable and stable effect over time Lugogo N, Clin Ther. 2016; 38: 2058-2070
. Sputum neutrophilis Blood neutrophilis p=0.03 Reduction of mild exacerbations (1.3 vs. 2.25, p=0.05) Improvement in ACQ (-0.42 points, p = 0.053) Increased time to first exacerbation (8.5 vs 4.5 days, p = 0.153) Nair. Clin Exp Allergy. 2012; 42:1097-103
Mean change in ACQ Overall population High reversibility group Busse, Am J Respir Crit Care Med. 2013; 188: 1294 1302
TH2 / Non-TH2 grouping Wenzel SE, Nat Med. 2012; 18: 716-25
αθοφ σιο ο ία ο σοβα ού άσθ α ος αι ιθα οί θ α ι οί σ ό οι Targeting Eosinophilic Inflammation Targeting Neutrophilic Inflammation Barnes PJ, J Allergy Clin Immunol. 2015; 136: 531-545
Ο ό ος ς IL-5 σ σι οφι ι ή φ ο ή Catley MC, Pharmacol Ther. 2011;132:333-51
MENSA STUDY 576 patients with re urre t asth a e a er atio s and >150 cells/ L at baseline or >300 cells/ L during the 12-month period before screening, despite high doses of ICS Ortega, N Engl J Med 2014;371:1198-207
Η ILιο ί αι σ ί ς άσ IL- έσ έ αι ασ ί α ό οι ς ο οί σ ς ο IL-4αR
Ο ε ε απε ε α π πε α ο ο α όα ε ό α χου όχο ο α ε απε α οα ε α Charriot, Eur Respir Rev 2016; 25: 77-92
Ann Am Thorac Soc 2014; 11: 1011 1017
Η ιά σ ο σοβα ού άσθ α ος θα α ί αι α ό ι ι ό ια ό έ ι Prospective study: 701 adult participants reporting a history of physician-diagnosed asthma in the last 5 years Evaluated FEV1 reversal or metacholine hyperresponsiveness Specialist evaluation of non-pulmonary evidence of asthma Aaron SD, JAMA. 2017;317: 269-179
33% of these individuals treated by physicians did not have asthma The main contributor to o asth a: patients did not have lung function testing at time of diagnosis Aaron SD, JAMA. 2017;317: 269-179
οσ ό ς αι ιβα ι οί α ά ο σ ο σοβα ό άσθ α ς ATS/ERS Guidelines on Severe Asthma, KF Chung Eur Respir J 2014; 43: 343 373
Χ ι ισ ός σοβα ού άσθ α ος-gina 2016 Θ α ί ς αθο ού ς α ό φαι ό Θ α ία αθο ού α ό ο α ιωθού οι α ο ύ σ ις αι/ή ο ι ο ι ώ οβα ό α ά όσ ο ύ α ια ι ό άσθ α: Οmalizumab (anti-ige) οβα ό σι οφι ι ό άσθ α: Mepolizumab (antiil5 mab) (>12 ώ GINA 2016, Box 3-14 (2/2)
Symptoms/airway hyperresponsieness (A) Discordant Symptoms Measuring inflammation allows down -titration of corticosteroids EARLY SYMPTOM PREDOMINANT Non-eosinophilic Normal BMI High symptom expression Concordant disease Symptom based approach to therapy titration maybe appropriate OBESE FEMALE NON EOSINOPHILIC High symptom expression Neutrophilic airway inflammation Primary Care Asthma Refractory Asthma Measuring inflammation allows targeted corticosteroids to lower exacerbation frequency BENIGN ASTHMA Mixed middle aged cohort Few symptoms No airway inflammation Little airway dysfunction Discordant Inflammation INFLAMMATION PREDOMINANT Late onset Greater proportion of males Few daily symptoms Rhinitis and nasal polyps Aspirin sensitivity Eosinophilic Inflammation/exacerbations(B) Haldar, AJRCCM 2008;178:218-24
α ά ο σ ασθ ς ο ίς ο άο ι ο ή ς θ α ίας ί αι ο ήφιοι αι ια ις θ α ί ς Papathanassiou E et al. Eur Clin Resp J. 2016;3:31813 Magnan A et al. Allergy. 2016;71:1335-1344
Sputum eosinophils are higher in asthmatics than in controls and their amount in sputum increases with the severity of the disease Louis R, AJRCCM. 2000; 161:9-16
ιο ί ς: ς αο ι ήσι α «α ία» σ α αίσια έ ςθ α ι ής οσέ ισ ς Biomarkers: diagnostic (mechanism) Predictive Prognostic
CS: clinical strategy, based on symptoms and spirometry SS: sputum strategy, sputum cell counts guiding CS to keep Eos 2% Very mild-mild Eosinophilic Moderate -Severe Non-eosinophilic CS CS RR:0.28 SS CS CS SS SS p<0.01 RR:0.63 p=0.07 SS Significant reductions in the number of eosinophilic exacerbations and in the severity of exacerbations Jayaram, Eur Respir J 2006; 27: 483-494
αο ι έ θ α σό ο β ί σ ι ή οσέ ισ σ ο σοβα ό άσθ α, ο θ α ι ού α ο έσ α ος Barnes PJ, J Allergy Clin Immunol. 2015; 136: 531-545
ύ ο ς αι α α ό ςθ α ί ς ια ο σοβα ό Th2-high άσθ α αι ιαθέσι οι βιο ί Approved by the FDA Periostin, DPP-4 ς
Άσθ α: Α ασ ό σ Η ί ωσ ο άσθ α ος α οσ ίως ο ο ί αι σ α 300 α ο ύ ια ι ώσ ις αι α α έ αι α α θ ί α ά 100 α ο ύ ια έχ ι ο 2025 250.000 θά α οι σίως α ο ί ο αι σ ο άσθ α, θ ό α α ί αι α έ σ ις α α σσό ς χώ ς ι οί αι ιβα ο ι οί α ά ο ς αί ο σ α ι ό ό οσ έ φ ασ ς όσο α ι ό οσοσ ό ω ασθ ώ άσθ α α α έ ο οθ α ό οι, ο ός ο σ βά ι σ αύ σ ς οσ ό ας 5-10% ω ασθ ώ άσθ α φα ί ο σοβα ή όσο, ο οία σ χ ά α α ο ί αι σ ις σ βα ι ές θ α ί ς Bousquet J, Bulletin WHO. 2005;83: 548-554
Blood eosinophils are associated with asthma phenotypes and disease severity Woodruff, AJRCCM 2009; 180: 388-395
g BD or equivalent/day +LABA + tiotropium g or placebo p<0.001 p=0.03 154±32ml -21% Kerstjens. N Engl J Med 2012;367:1198-207
PDE4/ PDE3 inhibitors Roflumilast Επ α η η α απ υ Α πα απ ου ο ΓΕΣ αα ο η α ICS Bousquet, Allergy 2006 Ε ε α ο PDE4ηα φ πα α ε π εό ε ο PDE3/PDE4 α α ο η α ο χο α α ο ε η Leaker, BMC Pulm Med. 2014 Franciosi, Lancet Respir Med 2013
1306 patients ith e a er atio s during the previous year, while on high doses ICS + LABA were randomized to receive Benralizumab 30mg s.c. Q4W, Benralizumab Q8W or placebo (1:1:1) for 56 wks as add on to their standard Tx Annual exacerbation rate Total asthma symptom scores Change in baseline prebronchodilator FEV1 FitzGerald JM, Lancet. 2016; doi: 10.1016/S0140-6736(16)31322-8
Η IL-13 έ ι ι ό ό οσ ς σι οφι ι ής φ ο ής αθο έ ια α α ώ.. Arron, Clin Immunol 2015; 161: 11-22
When the diagnosis of asthma is confirmed and comorbidities addressed ATS/ERS Guidelines on Severe Asthma, KF Chung Eur Respir J 2014; 43: 343 373