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Advanced medical treatments in recurrent nasal polyposis

Advanced treatments of nasal polyposis: Anti-IL-5 and Anti-IgE Which for whom?  Prof. Dr. Philippe Gevaert Department of Otorhinolaryngology Ghent University Hospital, Belgium. Advanced medical treatments in recurrent nasal polyposis. Surgery = removing immunological memory. Eotaxin. IgE.

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Advanced medical treatments in recurrent nasal polyposis

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  1. Advanced treatments of nasal polyposis: Anti-IL-5 and Anti-IgE Which for whom? Prof. Dr. Philippe GevaertDepartment of OtorhinolaryngologyGhent University Hospital, Belgium

  2. Advanced medical treatments in recurrent nasal polyposis Surgery = removing immunological memory Eotaxin IgE IL-5 ECP

  3. Advanced medical treatments in recurrent nasal polyposis Eotaxin IgE Anti IL-5 Corticosteroids Anti IL-5 Anti-IL-5 IL-5 ECP Antibiotics

  4. J Allergy Clin Immunol 2005;116:1275-81 N=354

  5. Nasal corticosteroid DROPS in nasal polyps double-blind, placebo-controlled study with nasal GCS drops After 12-weeks:  nasal blockage,  peak nasal inspiratory flow  polyp volume (CT score)  need for sinus surgery Aukema, Mulder, Fokkens; JACI 2005

  6. Oral steroids in nasal polyps: a 3-month double blind, randomized, placebo-controlled trialDBPC in 32 patient with nasal polyps, 20days methylprednisolon(Day 1-5 32 mg, day 6-10 16 mg, day 11-20 8 mg) • Primary endpoint: endoscopic scoring with a five grade system • Secoundary endpoints • symptoms • evaluation of local and systemical biological activity and efficacy • measurement of IgE, IL-5 and ECP on nasal secretions (merocell) • measurement of blood eosinophilia • daily measurement of nasal peak inspiratory flow Participating centers: ENT Dept: University Hospital Ghent, Belgium, University Hospital St. Rafael Leuven Belgium; University Hospital Erlangen, Germany, Adelaide University Hospital, Australia, Academic Medical Center, Amsterdam, the Netherlands 2 grade 0 1 3 4 T Van Zele, Gevaert P (in preparation)

  7. Oral steroids in nasal polyps: a 3-month double blind, randomized, placebo-controlled trialDBPC in 32 patient with nasal polyps, 20days methylprednisolon(Day 1-5 32 mg, day 6-10 16 mg, day 11-20 8 mg) Thibaut Van Zele, Philippe Gevaert, Gabriele Holtappels, AchimBeule, Peter John Wormald, Susanne Mayr, Greet Hens, Peter Hellings, Fenna A Ebbens, Paul Van Cauwenberge, Claus Bachert

  8. Methylprednisolone has mild local anti-inflammatory effects Placebogroup: n=18 Methylprednisolone group: n=14 T Van Zele, Gevaert P (in preparation)

  9. Advanced medical treatments in recurrent nasal polyposis Eotaxin Anti IL-5 Anti-IL-5 IgE Corticosteroids IL-5 ECP Antibiotics

  10. Long term antibiotic treatment in NP • DBPC study in 90 patients: • 3m low-dose erythromycin, nasal douche, nasal GCS vs. sinus surgery • 50% Improvement of symptoms • no difference vs sinus surgery

  11. Doxycycline reduces MMP9, ECP, MPO and nasal polyp size, in a double-blind, randomized, placebo controlled, multicenter trial.20 days doxycycline (100mg/d) reduces PND * * Philippe Gevaert, Thibaut Van Zele, Gabriele Holtappels, AchimBeule, Peter John Wormald, Susanne Mayr, Greet Hens, Peter Hellings, Fenna A Ebbens, Paul Van Cauwenberge, Claus Bachert

  12. Oral doxycycline reduces neutrophilic and eosinophilic inflammation Placebo group: n=18 Methylprednisolone group: n=14 Gevaert P, Van Zele T (in preparation)

  13. Doxycycline • First double blind placebo controlled trial with antibiotics in nasal polyps that shows: • a significant effect of doxycycline on nasal polyp size • Doxycycline reduces local inflammation in terms of ECP and MPO • effect on eosinophilic inflammation • effect on neutrophilic (may be related to the effect on S. aureus) • Doxycycline has a sigificant effect on remodeling (MMP-9) Gevaert P, Van Zele T (in preparation)

  14. Practical management of Nasal Polyposis • Nasal douche with saline • Nasal corticosteroids • GCS sprays: 2x/d, symptoms↓, no resolution of NP • GCS drops: symptoms↓, surgery↓↓ • Oral corticoids: effective but fast recurrence • Antibiotics: • Antibiotic ointment • Long-term antibiotics: macrolides 500mg/d ged 3m doxycycline 100 mg/d ged 1m Combinations? • Endoscopic sinus surgery: only chance for cure!! in NP: recurrences

  15. Treatment of nasal polyposis following EP³OS

  16. Advanced medical treatments in recurrent nasal polyposis Eotaxin Anti IL-5 IgE Corticosteroids Anti-IL-5 IL-5 ECP Antibiotics

  17.       IL-5 and eosinophils in nasal polyposis Migration Homing IL5 + Eotaxin  IL-5   IL-5  IL-5 Maturation Differentiation Recruitement Survival Activation  ECP

  18.       Anti IL-5 Anti-interleukin 5 in nasal polyposis Migration Homing IL5 + Eotaxin x x x  IL-5   IL-5  IL-5 Maturation Differentiation Recruitement Survival Activation  ECP

  19. MEPO 750mg IV Placebo * Primaryendpoint Dosing Follow up Objective and study design • To asses the therapeutic potential of • two injections of 750 mg IV mepolizumab (28days) • endoscopic score • symptom scores • CT scan • Two-arm, randomized, double blind, placebo controlled, trial 20 Subjects 30 Subjects Severe nasal polyps 10 Subjects Weeks 1 8 12 0 4 24 36 48 *

  20. Endpoints Primary endpoint • Endoscopic Nasal polyp score 8 weeks post 1st dosing Secondary endpoints • CT scan assessment (blinded) • Difference <10% or 10-30% or 30-50% or >50% • Symptom score • Peak nasal inspiratory flow • nasal (merocel) and systemic Inflammatory mediators 1 0 3 2 4 Score 0 1 2 3 4

  21. EndoscopicNasalpolypscore and improvement 13/20 12/20 10/20 intranasalsteroidspermitted * *

  22. Need for surgery - Number of exclusions (= sytemic steroids or AB or surgery) p=0.03 * *

  23. CT scores improvement from baseline at week 8

  24. CT SCAN 8 weeks post 1stMepo dose Baseline

  25. Symptoms intranasalsteroidspermitted intranasalsteroidspermitted intranasalsteroidspermitted intranasalsteroidspermitted

  26. Peak nasal inspiratory flow (change from baseline)

  27. Anti IgE Anti IgE in nasalpolyposis24 patients: 16 got anti-IgE 8 got placebo4 (evt 8) Injections over 3 months ? Local Anti-IgE Concentration? x  IgE x  IgE

  28. Improvement in total nasal polyp scoreOmalizumab (n=15) versus placebo (n=8)

  29. Improvement in symptomsOmalizumab (n=15) versus placebo (n=8)

  30. UPSIT smell test

  31. CT-scans before and after Anti-IgE

  32. CT-scans before and after Anti-IgE

  33. mean percentage improvement 30 25 20 15 placebo 10 omalizumab 5 0 better obsA better obsB - 5 - 10 CT-scans before and after Anti-IgE

  34. Allergic versus non allergic patients

  35. Anti IgE Anti IL-5 Future therapeutic options in nasal polyposis Anti-IgE Eotaxin First DBPC finished in 24 NP patients In Ghent IgE Anti-IL-5 New multicenter trial started with 120 NP patients IL-5 Corticosteroids ECP Antibiotics Vaccination

  36. Practical management of Nasal Polyposis • Nasal douche with saline • Nasal corticosteroids • GCS sprays: 2x/d, symptoms↓, no resolution of NP • GCS drops: symptoms↓, surgery↓↓ • Oral corticoids: effective but fast recurrence • Antibiotics: • Antibiotic ointment • Long-term antibiotics: macrolides 500mg/d ged 3m doxycycline 100 mg/d ged 1m • Future: • Omalizumab (antiIgE) allergic 85% vs non allergic NP 55% • Mepolizumab (anti-IL5): 2 injections in 65% better

  37. Upper Airways Research Laboratory 2009

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