Ανοσοθεραπεία στο άσθμα ΤΠΕΡ Αικατερίνη υρίγου M.D. Αλλεργιολόγος ςνηονίζηπια Διεςθύνηπια Αλλεπγιολογικού Σμήμαηορ Γενικό Νοσοκομείο Νοζημάηυν Θώπακορ Αθηνών «Η υηηπία»
Ανοσοθεραπεία στο άσθμα ΤΠΕΡ?
Ειδική Ανοζοθεπαπεία Eίναι η επαναλαμβανόμενη χορήγηση ειδικών αλλεργιογονικών εκχυλισμάτων, σε ασθενείς με επιβεβαιωμένη IgE μεσολαβούμενη αντίδραση, με σκοπό την ελάττωση ή αναστολή των IgE μεσολαβούμενων ανοσολογικών αντιδράσεων. Cox L, et al. JACI 127 (1 Sup), S1-S55, 2011
SCIT CLINICAL USE SAFETY Mechanisms Preventive effect SLIT SAFETY EFFICACY Mechanisms Prevention 1910 1960 1985 2010
(-) (-)
Ενδείξειρ ηηρ ανοζοθεπαπείαρ Ενδείκνςηαι για ηο σειπιζμό αζθενών με IgE μεζολαβούμενα νοζημάηα: Αλλεπγία ζηο δηληηήπιο ςμενοπηέπων Αλλεπγική πινοεπιπεθςκίηιδα Αλλεπγικό άζθμα???? Ανηενδείκνςηαι: Μη ελεγσόμενο άζθμα Κύηζη (έναπξη) β-αποκλειζηέρ Ανοζοανεπάπκεια/αςηοάνοζα νοζήμαηα/κακοήθεια Ηλικία <5 έηη Cox L, et al. JACI 127 (1 Sup), S1-S55, 2011
Millions of cases The Asthma Epidemic 18 17 16 14 12 10 8 6 8.5 Asthma related to allergies: 90% in children 50-65% in adults 11 allergic 65% 4 2 0 1980 1998 CDC-NIH Morbidity and Mortality Weekly Report
Asthma Phenotypes Early/childhood onset phenotypes Late/adult onset
ςζσέηιζη μεηαξύ αλλεπγικήρ πινίηιδαρ και άζθμαηορ Αλλεργική ρινίτιδα διαγιγνώσκεται στο 80% των ασθενών με άσθμα Άσθμα διαγιγνώσκεται στο 30% των ασθενών με αλλεργική ρινίτιδα G. Passalacqua Clin. Exper.Allergy, 2011 (41) 1247 1255. A. Cruz et al.allergy 2007: 62 (Suppl. 84): 1 41.
Clinical effects in terms of step-down rate after rush IT in house dust mite-sensitive asthmatics Nagata M, et al Intern Med 1993;32:702-9
Effect of IT in house dust mite-sensitive patients with mild to moderate asthma (DBPC study) changes in a log scale of the PD20FEV1 values Sum of symptom and medication scores Garcıa-Robaina et al.j Allergy Clin Immunol 2006;118:1026-32
Effect of IT in house dust mite-sensitive patients with mild to moderate asthma Garcia-Robaina et al JACI 2006; 118: 1026-32
Randomized controlled trials of SCIT in asthma 5/21 studies published after 1998 Passalacqua G. Clin Exp Allergy,2011, 41, 1247 55
N Engl J Med 1997;336:324-31 121 allergic children with moderate-to-severe, perennial asthma. SCIΣ Υ18 months of a mixture of up to seven aeroallergen extracts or PL The principal outcome was 1. The daily medication score 2. BHR
Scores for Daily Medication Use Adkinson F, et al.n Engl J Med 1997;336:324-31
CHANGES IN OUTCOME MEASURES FROM BASE LINE TO THE LAST FOLLOW-UP VISIT Adkinson F, et al.n Engl J Med 1997;336:324-31
N Engl J Med 1997;336:324-31 121 allergic children with moderate-to-severe, perennial asthma. SCIΣ Υ18 months of a mixture of up to seven aeroallergen extracts or PL The principal outcome was 1. The daily medication score 2. BHR
Allergy 62:317 324, 2007
Meta-Analysis Results Study Effective Ineffective Equivocal Total Adults only 9 Children only 7 All Ages 1 1 2 3 0 0 1 12 10 2 TOTAL 17 71% 4 17% 3 12% 24 (962 patients) Ross RN, et al. Clin Ther 22:329-41, 2000
Effectiveness of Immunotherapy 3 2.5 2 2.76 1.81 2.00 2.87 1.5 1 0.5 0 Reduced Asthma Symptoms Any odds ratio greater than 1.0 shows a positive effect Reduced Bronchial Challenge Reduced Medication Use Improved Pulmonary Function Ross RN, et al. Clin Ther 22:329-41, 2000
Improvement of symptoms and reduction in medication and BHR after ΙΣ in 20 randomized placebo-controlled trials (1954-1990) Outcome measure Dust mite OR, (95% CI) Other allergens OR, (95% CI) All Allergens OR, (95% CI) Symptom Improvement Reduction in medication 2.7 (1.7 4.4) 4.2 (2.2-7.9) Decreased BHR 13.7 (3.8-50) CI: confidence Interval; ND: not done; OR: odds ratio 4.8 (2.3-10.1) ND 5.5 (2.8-10.7) 3.2 (2.2-4.9) ND 6.8 (3.8-120) Abramson MJ, et al. Am J Respir Crit Care Med 1995; 151: 969-974
Meta-analysis SCIT and asthma Investigations: allergen immunotherapy versus placebo 75 randomised, controlled trials (33 HDM, 3 HD, 20 pollen, 10 animal dander, 2 cladosp., 1 latex, 6 multiple allergen) 1954 2002 3459 patients Abramson MJ, et al. Cochrane sys Rev 2003 CD001186 Ia
Significant reduction of symptoms and medication use and BHR after ΙΣ in 75 randomized placebo-controlled trials (1954-2002) Asthma Symptoms Scores SMD (95% CI) Asthma Medication Scores SMD (95% CI) Allergen-Specific BHR SMD (95% CI) -0.72, (-0.99, -0.33) -0.90 (-1.13,-0.40-0.66 (-0.87, -0.45) Abramson MJ, et al. Cochrane sys Rev 2003 CD001186 Ia
Meta-analysis SCIT and asthma Investigations: allergen immunotherapy versus placebo house dust mite versus placebo pollen versus placebo 88 randomised, controlled trials (42 HDM, 26 pollen, 10 animal dander, 2 cladosp., 2 latex, 6 multiple allergen) 1954 2005, 3792 patients NNT: 1 3 symptoms, 4 medication (%responders active - %responders placebo ) Abramson MJ, et al. Cochrane sys Rev 2010, CD001186 Ia
Meta-analysis SCIT and asthma Parameter No. studies n patients active n patients placebo SMD [95%-confidence interval] Symptom score HDM 12 247 161-0.48 [-0.96; 0.0] Medication score HDM 12 242 182-0.61 [-1.04; -0.18] Symptom score pollen 18 374 289-0.61 [-0.87; -0.35] Medication score pollen 8 182 142-0.52 [-0.91; -0.13] Unspecific BHR metacholin 12 248 205-0.25 [-0.51; 0.00] Unspecific BHR histamin 4 41 35-0.55 [-1.37; 0.28] Lung function: PEF 11 282 242 0.14 [-0.33; 0.61] Lung function: FEV1 7 110 89-0.32 [-0.96; 0.31] Lung function: TGV 2 45 36 0.0 [0.0; 0.0] Specific BHR HDM 6 98 50-0.98 [-1.39;-0.58] Specific BHR pollen 5 104 98-0.55 [-0.84;-0.27] Abramson MJ, et al. Cochrane sys Rev 2010, CD001186 Ia
Ann Allergy Asthma Immunol. 2009;102:69 75 5 years SYMPTOMS (3 yrs) 5 yrs) (3 yrs) 5 yrs)
Ann Allergy Asthma Immunol. 2009;102:69 75 5 years SYMPTOMS (3 yrs) 5 yrs) (3 yrs) 5 yrs)
Meta-analysis: SLIT and asthma Investigations: asthmatic symptoms asthmatic medication requirements 25 randomized-controlled trials 1706 patients (adults and children) Calamita et al.allergy. 2006 Oct;61(10):1162-72
Meta-analysis: SLIT and asthma Parameter No. studies n patients active n patients placebo SMD [95%-confidence interval] Asthma Symptoms only Allergic symptoms group Reduction of medication use to asthma Reduction of medication use to allergies general 9 150 153-0.38 [-0.79; 0.03] 10 188 172-1.18 [-1.93; -0.43] 6 132 122-0.91 [-1.94, 0.12] 10 250 238-0.82 [-1.25; -0.39] Calamita et al.allergy. 2006 Oct;61(10):1162-72
Meta-analysis of the efficacy of sublingual immunotherapy in allergic asthma in pediatric patients, 3 to 18 years of age (9 trials, 441 patients) M Penagos, G Passalacqua, E Compalati, C Baena-Cagnani, S Orozco, A Pedroza, GW Canonica 2008, 133:599-609 SYMPTOMS MEDICATIONS
ASTHMA: Summary of meta-analyses for SCIT and SLIT Viswanathan R, Busse W. CHEST 2012; 141(5):1303 1314
Ππόλητη άζθμαηορ ΡΑΣ Study (Preventive Allergy Treatment ) : 6 σώπερ 208 παιδιά (6-14) με αλλεπγική πινοεπιπεθςκίηιδα ζημύδα ή/και γπαζίδι 43 124 41 Οθθαλμική ππόκληζη (+), SPT(+) Σςσαιοποιημένη: SCIT - θαπμακοθεπαπεία Μöller C, et al. JACI 2002; 109: 251
PAT Study period 1 2 3 Jacobsen L, et al. Allergy, 2007; 62: 943
PAT Study period 1 Jacobsen L, et al. Allergy, 2007; 62: 943
Ππόλητη άζθμαηορ (24%) (44%) Μöller C, et al. JACI,2002; 109: 251
PAT Study period 2 Jacobsen L, et al. Allergy, 2007; 62: 943
The percentage of children with and without asthma 2 years after termination of immunotherapy 20% 43% Niggemann B, et al. Allergy, 2006; 61: 855
PAT Study period 3 Jacobsen L, et al. Allergy, 2007; 62: 943
The percentage of children with and without asthma 7 years after termination (10-year follow-up) of specific immunotherapy 25% 45% Jacobsen L, et al. Allergy, 2007; 62: 943
SLIT reduces the development of asthma in children with allergic rhinitis. Novembre E. et al, JACI 2004 37 NO ASTHMA ASTHMA 18% 8 40% 18 26 113 children (5-14y) Allergic rhinitis only (grasses) SLIT X 3y Follow-up: 3 yrs SLIT+med:45 Med (No SLIT):44
Preventive effect of immunotherapy on the development of new allergen sensitizations in monosensitized patients Study Age (yr; mean) Immunotherapy Method and Number of Patients in Each Treatment Group Immunotherapy (% of Patients with New Allergen Sensitizations) Control (% of Patients with New Allergen Sensitizations) p Value Des Roches 1997 4 6 (5) 3 5 (4) SCIT, 22 Control, 22 54 100 0.001 Purello- D Ambrosio 2001 Adults and pediatric SCIT, 7182 Control,1214 23 68 <0.00001 Pajno 2001 6 8 (7.14) 5 7 (6.38) SCIT, 75 Control, 63 24.6 66.7 <0.0002 Marogna 2004 5 60 (22.8) 5 58 (21.5) SLIT, 319 Control,192 5.9 38 0.01 Cox L. Allergy Asthma Proc 2008 29:1
Ππόλητη άζθμαηορ και νέυν 28 παιδιά (6-14 εηών): εςαιζθηζιών αλλ. πινίηιδα: αγπυζηώδη (14) 3εηή SCIT (14) θάπμακα 6 έηη μεηά ηη διακοπή (13 10) Άζθμα: 23% ηυν SCIT - 70% ηυν άνες SCIT Νέερ εςαιζθηζίερ: 61% SCIT - 100% άνες SCIT 12 έηη μεηά ηη διακοπή (12 10) Άζθμα: 30% ηυν SCIT - 70% ηυν άνες SCIT Νέερ εςαιζθηζίερ: 61% SCIT - 100% άνες SCIT Eng PA, et al. Allergy, 2002; 57: 306 Eng PA, et al. Allergy, 2006; 61: 198
12 έηη μεηά [12-10] 6 έηη 12 έηη
Why immunotherapy fails? wrong patient wrong allergen(s) wrong dose wrong duration
Selection of patients for immunotherapy Symptoms induced by allergen IgE to relevant allergen (SPT/CAP-FEIA) No contra-indications (severe asthma, beta/blockers, inability to comply with IT)
Selection of allergens for immunotherapy rphlp7 :πολκαλσίνη rphlp12:προφιλίνη J Investig Allergol Clin Immunol 2007; Vol. 17, Supplement 1: 88-92
Selection of allergens for immunotherapy g6: g2:
Παν-αλλεργιογόνα g6: g2
g6: g2:
Selection of dose Standardisation - units of biologic potency - major allergen content SCIT: 5-20 mcg major Ag/dose, SLIT: 15-25 mcg major Ag/dose.
House dust mite IT in children with asthma: 3 years duration induces tolerance Des Roches A et al, Allergy 1996; 51 :430-3
Why immunotherapy succeeds? right patient right allergen(s) right dose right duration
According to the update AIPP (Allergen Immunotherapy Practice Parameters) In asthmatic patients, immunotherapy is indicated in individuals who experience symptoms of asthma after natural exposure to aeroallergens AND one of the following: Poor response to pharmacotherapy, allergen avoidance, or both; Unacceptable adverse effects of medication; Wish to reduce or avoid long-term pharmacotherapy; Co-existing allergic rhinitis and allergic asthma. Cox L, et al. JACI 127 (1 Sup), S1-S55, 2011
Indications for specific immunotherapy (SLIT) 1) Patients with rhinitis, conjunctivitis, and/or asthma caused by allergy to pollens or house dust mites 2) Patients who are inadequately controlled with conventional pharmacotherapy 3) Patients who have had systemic reactions during specific immunotherapy by injection 4) Patients who have compliance problems with or refuse immunotherapy by injection Cox L, et al. JACI 127 (1 Sup), S1-S55, 2011
ΤΜΠΕΡΑΜΑΣΑ Η ανοζοθεπαπεία ζηο άζθμα ςπεπέσει ηηρ θαπμακοθεπαπείαρ διόηι 1. Έσει αποηελεζμαηικόηηηα πος διαπκεί και μεηά ηη διακοπή ηηρ 2. Προλαμβάνει τη κλινική συμπτωματολογία από άλλα όργανα 3. Ππολαμβάνει νέερ εςαιζθηηοποιήζειρ Passalacqua G, et al. JACI, 2007; 119: 881.
RHINITIS When to Consider Immunotherapy Mild Moderate ± conjunctivitis Severe ± conjunctivitis Allergen avoidance when possible Pharmacotherapy Consider immunotherapy Intermittent Mild persistent Moderate persistent Severe persistent Pharmacotherapy Consider immunotherapy
Ενδείξειρ ηηρ ανοζοθεπαπείαρ Ενδείκνςηαι για ηο σειπιζμό αζθενών με IgE μεζολαβούμενα νοζημάηα: Αλλεπγία ζηο δηληηήπιο ςμενοπηέπων Αλλεπγική πινοεπιπεθςκίηιδα Αλλεπγικό άζθμα (ήπιο/μέτριο) Ανηενδείκνςηαι: Μη ελεγσόμενο άζθμα Κύηζη (έναπξη) β-αποκλειζηέρ Ανοζοανεπάπκεια/αςηοάνοζα νοζήμαηα/κακοήθεια Ηλικία <5 έηη Cox L, et al. JACI 127 (1 Sup), S1-S55, 2011
Ανοσοθεραπεία στο άσθμα ΤΠΕΡ
Αποηελέζμαηα ανοζοθεπαπείαρ Ανηιζυμαηική απάνηηζη: - IgG1, IgA - Blocking IgG4 (Ανταγωνισμός IgE) Σ-κςηηαπική απάνηηζη: PBMCs: ΙL-4 mrna IL-10 ηοςρ ιζηούρ: IL-12 mrna, IFNγ mrna IL-4 mrna, IL-5 mrna Απόπηυζη Σh2-κςηηάπυν (activation-induced cell death) Akdis M, et al. JACI, 2007; 119: 780
SPECIFIC IMMUNOTHERAPY IN ASTHMA AND RHINITIS
Prevalence of rhinitis among asthmatics A. Cruz et al.allergy 2007: 62 (Suppl. 84): 1 41
Effect of specific immunotherapy added to pharmacologic treatment and allergen avoidance in asthmatic patients allergic to house dust mite 3 years SCIT 3 years SCIT Maestelli et al.j Allergy Clin Immunol 2004;113:643-9
Stelmach et al. Ann Allergy Asthma Immunol 109 (2012) 274 278
Minimal daily inhaled corticosteroids controlling dose in all study groups. Stelmach et al. Ann Allergy Asthma Immunol 109 (2012) 274 278