upper airways research laboratory department of otorhinolaryngology advanced treatments of nasal...

Upper Airways Research LaboratoryDepartment of Otorhinolaryngology

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


Antibiotics

Anti IL

-5

Anti-IL-5Corticosteroids

IL-5IL-5

ECPECP

EotaxinEotaxin

IgE

Anti IL

-5



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


Nasal corticosteroid DROPS in nasal polyps

double-blind, placebo-controlled study with nasal GCS dropsAfter 12-weeks: nasal blockage, peak nasal inspiratory flow

polyp volume (CT score) need for sinus surgery

Aukema, Mulder, Fokkens; JACI 2005


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

T Van Zele, Gevaert P (in preparation)

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

grade 0 1 2 3 4


Thibaut Van Zele, Philippe Gevaert, Gabriele Holtappels, Achim Beule, Peter John Wormald, Susanne Mayr, Greet Hens, Peter Hellings, Fenna A Ebbens, Paul Van Cauwenberge, Claus Bachert

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)


Methylprednisolone has mild local anti-inflammatory effects

Placebogroup: n=18Methylprednisolone group:

n=14T Van Zele, Gevaert P (in preparation)


Antibiotics

Anti IL

-5Anti-IL-5Corticosteroids

IL-5

ECP

Eotaxin

IgE



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


* *

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, Achim Beule, Peter John Wormald, Susanne Mayr, Greet Hens, Peter Hellings, Fenna A Ebbens, Paul Van Cauwenberge, Claus Bachert


ECP (µg/l)

p=0.035 p=0.033

p=0.009

p=0.18

p=0.8

-1.000

-750

-500

-250

0

250

500

750

1.000

0 7 14 21 28 35 42 49 56 63 70 77 84Days

EC

P (

µg

/l)

in n

asal

secre

tion

Placebo doxy

MPO (ng/ml)

p=0.005

p=0.06

p=0.004

p=0.04

p=0.2

-20.000

-15.000

-10.000

-5.000

0

5.000

10.000

0 7 14 21 28 35 42 49 56 63 70 77 84Axis Title

MP

O (

ng

/ml)

in

nasal

Placebo doxy

MMP-9

p=0.007

p=0,02 p=0,02

p=0,08

p=0.4

-8.000

-6.000

-4.000

-2.000

0

2.000

0 7 14 21 28 35 42 49 56 63 70 77 84Days

MM

P-9

(p

g/m

l) i

n n

asal

secre

tion

s (

Placebo doxy

Placebo group: n=18Methylprednisolone group:

n=14

Oral doxycycline reduces neutrophilic and eosinophilic inflammation

Gevaert P, Van Zele T (in preparation)


First double blind placebo controlled trial with antibiotics in nasal polyps that shows:

a significant effect of doxycycline on nasal polyp sizeDoxycycline reduces local inflammation in terms of ECP and MPO

effect on eosinophilic inflammationeffect on neutrophilic (may be related to the effect on S. aureus)Doxycycline has a sigificant effect on remodeling (MMP-9)

Doxycycline

Gevaert P, Van Zele T (in preparation)


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 1mCombinations?

• Endoscopic sinus surgery: only chance for cure!!in NP: recurrencesin NP: recurrences


Treatment of nasal polyposis following EP³OS


Antibiotics

Anti IL

-5

Anti-IL-5Anti-IL-5Corticosteroids



IL-5 and eosinophils in nasal polyposis

ECP

IL-5

IL-5

IL-5

Migration Homing

Survival

Activation

Maturation

Differentiation

Recruitement

IL5 + Eotaxin


ECP

IL-5

IL-5

IL-5

Migration Homing

Survival

Activation

Maturation

Differentiation

Recruitement

IL5 + Eotaxin

Anti-interleukin 5 in nasal polyposis

Anti IL-5

xx x


Objective and study design

30 SubjectsSevere nasal polyps

20 Subjects

10 Subjects

Weeks 0 1 4 128

*

MEPO 750mg IVPlacebo

Dosing

Follow up

* Primary endpoint

24 36 48


EndpointsPrimary 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

0 1 2 3 4Score

0

1

4

3

2


Endoscopic Nasal polyp score and improvement

**intranasal steroids permitted

10/20

12/20

13/20


Need for surgery - Number of exclusions(= sytemic steroids or AB or surgery)

p=0.03

* *


CT scores improvement from baseline at week 8


8 weeks post 1st Mepo doseBaseline

CT SCAN


Symptoms

intranasal steroids permitted intranasal steroids permitted

intranasal steroids permitted intranasal steroids permitted


Peak nasal inspiratory flow (change from baseline)


Anti IgE in nasal polyposis24 patients: 16 got anti-IgE

8 got placebo

4 (evt 8) Injections over 3 months

IgE

? Local Anti-IgE

Concentration?

Anti IgE

x IgEx

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

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

UPSIT smell test


CT-scans before and after Anti-IgE


CT-scans before and after Anti-IgE

-10

- 5

0

5

10

15

20

25

30

better obsA better obsB

mean percentage improvement

placeboomalizumab


Allergic versus non allergic patients


Anti IgE

Anti-IgE

Antibiotics Vaccination

IL-5

ECP

Eotaxin

IgEAnti

IL-5

Anti-IL-5

Corticosteroids

First DBPC finished in

24 NP patientsIn Ghent

New multicenter trial started with 120 NP patients

Future therapeutic options in nasal polyposis


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


Up

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r A

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ays

Res

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upper airways research laboratory department of otorhinolaryngology advanced treatments of nasal...

Documents

nasal polyps

nasal gcs

nasal douche

nasal blockage

belgium slide

preparation slide

corticosteroids il

immunological memory