Indication of Anti-IgE treatment in children

Transcription

1 Annual meeting of the Danish Society of Paediatric Allergology and Pulmonology Kolding, 15 th of January 2010 Indication of Anti-IgE treatment in children Matthias Kopp Pediatric Pulmonology and Allergology University of Lübeck

2 Anecdotic Case Report severe asthmatic attack after a ride with a horse-drawn carriage history of allergy to horses one week ago: transfusion of 600 ml blood from a man with a known allergy to horses factor in the blood is able to transfer allergic complaints reagine = immunglobuline IgE Ramirez MA, JAMA 1919 Johansson SG, Lancet 1967

3 effector-phase sensitisation Pathophysiology Allergen IL-5 eosinophils Y F YF F mastcells IL-4 IL-13 IgE basophils Antigen-presenting cells naive T-cell TH2-cells B-cells effector cells Allergic reaction

4 IgE and Anti-IgE IgE allergen Anti-IgE IgE-receptor Omalizumab histamine effector cells leukotriene, IL-4, IL-5

5 IgE and Anti-IgE Corne J, J Clin Invest 1997

6 Leukotriene release [ng/l] Leukotriene release [ng/l] Omalizumab: SIT-Grass + Anti SIT-Grass IgE + Plac Leukotrienes p = p = Grass A Birch A before - after before - after before - SIT + Omalizumab therapy SIT therapy + Placebo ther Kopp MV, JACI 2002

7 IgE and Anti-IgE IgE allergen Anti-IgE IgE-receptor Omalizumab histamine effector cells leukotriene, IL-4, IL-5

8 Anti-IgE: Fc R1 Omalizumab reduce the expression of the high affinity IgE receptor (Fc R1) on basophils and mastcells as well as dendritic cells significantly within 14 days expression of Fc R1 on basophils before (open bar) and after therapy (shaded bar) with omalizumab MacGlashan, J Immunol 1997 Lin H, J Allergy Clin Immunol 2004 Prussin C, J Allergy Clin Immunol 2003

9 Anti-IgE : Eosinophils Omalizumab is able to attenuate the eosinophilic inflammation in patients with allergic rhinokonjunctivitis (AR) during the pollen season eosinophils before and during the pollen season in patients with a birch pollen induced AR treated with omalizumab (right) or placebo (left) Plewako H, J Allergy Clin Immunol 2002 Bez C, Clin Exp Allergy 2004

10 Possibilities and Indication Omalizumab Allergic diseases allergic rhinitis allergic asthma severe allergic asthma food allergy atopic dermatitis bee venom allergy wasp venom allergy urticaria latex allergy drug allergy contact allergy allergic rhinokonjunctivitis allergic rhinitis - allergic asthma drug allergy urticaria - severe allergic asthma food allergy atopic dermatitis bee venom allergy wasp venom allergy urticaria latex allergy drug allergy contact allergy allergic rhinokonjunctivitis allergic rhinitis allergic asthma severe allergic asthma food allergy atopic dermatitis bee venom allergy wasp venom allergy urticaria latex allergy drug allergy contact allergy allergic rhinokonjunctivitis allergic rhinitis allergic asthma severe allergic asthma food allergy atopic dermatitis bee

11 Indication of Anti-IgE Xolair (Omalizumab) is indicated for 1. adults and children (> 6 y) with 2. severe persistent allergic asthma 3. who have a positive skin test or in vitro reactivity to a perennial aeroallergen 4. > 12 y: FEV1 < 80% 5. IgE > ku/l (< 12 y: ) 6. whose symptoms are inadequately controlled despite optimal therapy.

12 Case Report age > 12 optimal therapy IgE ku/l peren. allergen special notes 13-year old boy symptoms since his first year of life budesonide µg 2 x daily salmeterol montelukast IgE 468 ku/l mites (Der p) CAP-class 3; grass pollen 2; birch pollen 3 5 x hospitalisation nesecessary physical fatigue currently

13 Case Report Bronchiolitis obliterans good clinical response to high doses of systemic steroids Omalizumab not indicated Recomendation: The diagnosis of severe asthma must be critically reviewed!

14 Difficult-to-treat asthma COPD, BO CF α1-at- deficiency cardiomyoptahy VCD Systematic assesment 31%: other or additional pulmonary disease! Robinson DS, Eur Respir J 2003

15 Anti-IgE in children 1. sensitization to a perennial aeroallergen? 2. safety and efficacy of anti-ige treatment in young children with sever asthma? 3. use of Anti-IgE in case of other allergic diseases?

16 Perennial allergens n age duration symptoms allergen Casale TB, JAMA mo ragweed Ädelroth E, JACI mo. birch Kuehr J, JACI mo birch and grass Casale TB, JACI we ragweed Okubo K, Allergol Int we cedar Kopp MV, 2008 sub we grass

17 Trials: Anti-IgE & asthma + placebo Inhalant steroids (ICS) + omalizumab stepwise reduction of ICS lowest tolerated ICS dose 4 w 16 w 8 w 4 w 28 weeks primary outcome: number of asthma exacerbations

18 Adolescents > 12 y Clinical Trials in children 6-12 years: children without ICS (%) p< asthma exacerbation (%) p< Omalizumab Placebo 0 Omalizumab Placebo Milgrom H, Pediatrics 2001

19 Number of clinical relevant exacerbations Number of clinical relevant exacerbations Asthma exazerbations 24 weeks: stable ICS dose 28 weeks: ICS reduction phase % p= % p< Omalizumab (n=159) Placebo (n=76) 0 Omalizumab (n=159) Placebo (n=76) ERS, Vienna 2009 (Poster)

20 Number needed to treat to prevent asthma exacerbation IA05 high dose ICS + LABA (n=235) IA05 total (n=576) INNOVATE (n=419) Clinical relevant exacerbations 1,4 1,7 2,7 ERS, Vienna 2009 (Poster)

21 Evidence from clinical trials It is a mammoth! Es ist ein Mammut!

22 Safety (n > 5200 patients) number of adverse events severe adverse events causal relationship: Urtikaria anaphylactic reaction? Anti-IgE-AK Komplementaktivierung Immunkomplexablagerung local reaction: mild- moderat

23 Risk of anaphylaxis June 2003 December 2006; patients 124 cases of anaphylaxis (1:625) mean age 43 y (9 78); 82% females pulmonary involvement 89%; hypotension or syncope 17% 39% first-dose; 19% second-dose; 33% > third dose reaction time to onset < 30 min 35%; < 60 min 26%; < 120 min 8%; > 24 h up to 4 days 5% Delayed onset and protracted progression of symptoms! Limb SL, JACI 2007

24 Indication and Perspectives Atopic Dermatitis Urticaria food-allergy ABPA Anti-IgE + SIT Allergic Rhinitis effective safety

25 IgE [ku/l] Vigo PG, J Am Acad Dermatol 2006 Atopic Dermatitis & Anti-IgE Some case reports show that Anti-IgE might be effective in AD Lane Krathen Vigo recommendation effects: only case reports! Lane JE, J Am Acad Dermatol 2006 Krathen RA, J Am Acad Dermatol 2005

26 Atopic Dermatitis & Anti-IgE 150 mg omalizumab every second week over 10 weeks 11 patients worse IgE levels: IU/ml Results: good satisfying +/- 0 6/11 satisfying good => effect in selected patients Belloni B, JACI 2007

27 Atopic Dermatitis & Anti-IgE No data from randomized controlled trials available No recommendation for standard use based on case series.

28 ABPA Allergic bronchopulmonary aspergillosis: pulmonary complication in CF patients CF: ~ 50% colonized with Aspergillus fumigatus CF: prevalence of ABPA in Europe ~7.8% Aspergillus fumigatus: fungi inhalation of fungi => TH2- driven inflammation Therapy: systemic steroids & antimycotic drugs mastcells IgE complement Mastella G, Eur Respir J 2000 Thia LP, Pediatric Respir Rev 2009

29 ABPA + Anti-IgE are there additive therapeutic effects of omalizumab in CF patients with ABPA treated with steroids? is omalizumab a steroid-saving therapeutic option?

30 ABPA + Anti-IgE Patient age Genotyp ABPA Therapy: Itraconazol + Outcome afetr Xolair 300 mg sc every other week: 13-y boy F508/ A141D 7 y Prednison 4 weeks 1 mg/kg KG Weaning impossible 0.5 mg/kg every other day Prednison-Weaning Stop of steroids after 9 m FEV1 77% => 87% 13-y Boy F508/ F508 6 y Prednison 20 mg/ Tag Weaning impossible 1 mg/kg every other day Prednison-Weaning Stop of steroids after 18 months 17-y boy F508/ F508 6 y Prednison 20 mg/ every other day Prednison-Weaning Stop of steroids after 4 m FEV1 83% => 102% Summary: effective Steroid-saving Zirbes JM, Pediatric Pulmonology 2008

31 Case report: Maria, 12 years CF, F-508/ F-508; FEV1 pred. 92% cough exercise tolerance Serratia marescens => i.v. antibiotics, no improvement tentative diagnosis: ABPA - 27% eosinophils; absolut 3180/µl - IgE increased 133 ku/l => 524 ku/l - rasp. f. 4: 3,27 ku/l; IgG-AK - Sputum: Asp. fumigatus - SPT positive - expirium, rhonchi - shortness of breath => ABPA confirmed

32 Case report: Maria, 12 years 2,80 2,60 2,40 2,20 2,00 1,80 1,60 1,40 1,20 1,00 FVC FEV1 May October January predicted predicted therapy: steroids Itraconazol - Xolair rapid improvement symptom free: 10 days after start of Xolair normal exercise tolerance after 4 weeks, LuFu

33 ABPA & Omalizumab only published case reports open issues: - How effective is omalizumab? - Responder and non responder? - Steroid-saving effect? - Therapy without steroids possible? - Early or late therapy with omalizumab?

34 Anti-IgE & SIT

35 Anti-IgE & SIT 1. Are additional clinical benefits of omalizumab + SIT? 2. Is the number of adverse events of SIT reduced by pretreatment of omalizumab? 3. SIT + omalizumab: enhanced longlasting effects?

36 Anti-IgE & SIT Allergic Rhinitis Grass- and birch pollen Kühr 2002 ragweed Casale 2006 Saisonal asthma grasspollen Kopp 2009

37 Anti-IgE & SIT 6-17 years sensitization: birch + grass SIT + placebo + Anti-IgE + placebo + Anti-IgE 0,5 0,4 0,3 0,2 0,1 0 symptom load - score (median) P=0.01* 35% 0.46 n=54 SIT birch + placebo 0.30 n=55 SIT birch + omalizumab 0.38 n=53 SIT grass + placebo P=0.011* 45% 0.21 n=59 SIT grass + omalizumab *=Wilcoxon Test Kühr J, JACI 2002

38 Anti-IgE & SIT Visit 0 Omalizumab start of the ragweed season Rush-SIT > 3 weeks 9 weeks 4 weeks 12 weeks 8 weeks Rush-IT: 6 injections in 3 h Build-up µg Amb a µg 12 µg Maintenance

39 Anti-IgE prior to SIT 120 ragweed-sensitized patients (18 50 y) with allergic rhinitis Omalizumab + Placebo all adverse events n= 11 (29.7%) anaphylaxis n= 1 (2.7%) Omalizumab + SIT n= 12 (33%) n= 2 (5.6%) Placebo + SIT n= 22 (56%) * n= 10 (25.6%) * Placebo n= 7 (18.9%) n= 1 (2.7%) Placebo + SIT: 20.5% received epinephrine Casale, JACI 2006

40 Anti-IgE & SIT: DUAL - Population: n= 132 (2006) and n= 119 (2007; 92% ) years; allergic rhinitis + seasonal asthma - endpoint: symptom load (symptoms + medication) + Rush-SIT SIT Placebo 2 w 8 w pre 8 w season 1 s 2 s 3 Omalizumab + Rush-SIT w 0 w 2 w 10 w SIT

41 Symptom severity score (median) Allergic Rhinitis and Asthma 0,5 p = , , ,2 0,1 0,0 SIT + Placebo SIT + Omalizumab Kopp MV, Clin Exp Allergy 2009

42 LS means LS means Quality of life improved Asthma Control Questionnaire Asthma Quality of Life Questionnaire 2,2 p = ,6 p = , ,5 6, ,8 6,3 1, ,2 6, ,4 6,0 1,2 5,9 5,8 1,0 SIT + Placebo SIT + Omalizumab 5,7 SIT + Placebo SIT + Omalizumab SIT + Omalizumab: asthma control significantly improved Kopp MV, Clin Exp Allergy 2009

43 Kissing decreases IgE production Patients with atopic dermatitis or allergic rhinitis spent 30 minutes with their partner without kissing (control study) or with kissing while listening to music (kissing study) Control study Kissing study before after before after IgE [ng/ml] * IL-4 [pg/ml] * IFN-γ [pg/ml] * Kimata H, J Psychosom Res 2006

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