1 Severe Chronic Upper Respiratory Disease: Phenotyping Inflammation Claus BachertDGAKI GermanyGA2LEN GhentUpper Airways Research LaboratoryDepartment of Otorhinolaryngology
2 Prevalence of SCURD in the EU Total population (2007): 490 millionsDisease%CURD SCURDAllergic rhinitis15-25113 millions mNon-allergic rhinitis10-1568 millions mChronic rhinosinusitis6-1870 millions mMore than surgeries/yearIn Europe, 1M in the worldAspirin sensitivity0.5-312 millions mConsider socio-economic impact of SCURD !
5 Lack of T-regulatory cells in nasal polypsThe expression of the transcription factors FOXP3, T-bet, GATA-3, the suppressive cytokines TGF-β1, IL-10 and major TH1/ TH2 cytokines (IFN-γ , IL-4, IL-5, IL13) were analyzed by means of RT-PCR in 13 CRSsNP, 16 CRSwNP and 10 control samples. Additional protein measurements were performed for TGF-β1 and IFN-γ by means of ELISA, and immunohistochemistry was performed for FOXP3N. Van Bruaene et al, JACI 2008.
6 TGF-beta receptors (mRNA) ***Van Bruaene et al, submitted
7 Different types of T effector cells orchestrate mucosal inflammationin chronic sinus diseaseNan Zhang ; T Van Zele; C Perez-Novo; N Van Bruaene; G Holtappels;N Deruyck; C Bachert. JACI 2008
8 Different types of T effector cells orchestrate mucosal inflammation South Chinese controlsSouth Chinese nasal polypsBelgian controlsBelgian nasal polypsANOVA* Fisher’s Exact testN292126Age, yr (range)38·6 (33·2-43·5)36·4 (28·6-46·5)30·3 (21·3-37·9)46·2 (38·4-55·5)Female / Male10/199/209/1211/150.767Asthma0/292/292/2114/26<0.0001*Phadiotop positive11/299/298/2111/260.845Aspirin intolerance0/217/26CT score (Lund & Mackay)16 (11-20)1 (0-2)13 (11-20)<0.0001Polyp score (Davos)0 (0-0)5 (4-6)4 (4-6)Total symptom score5 (3-6)10 (7-11)5 (3-7)9 (7-11)Nasal congestion2 (2-3)3 (2-3)2 (1-3)0.033Rhinorrhea0 (0-1)0 (0-2)0.008Sneezing0.093Loss of smellHeadache2 (1-2)0.006Different types of T effector cellsorchestrate mucosal inflammationin chronic sinus diseaseNan Zhang ; T Van Zele; ClaudinaPerez-Novo; N Van Bruaene;Gabriele Holtappels; NatalieDeRuyck; C Bachert. JACI 2008
9 Objective and study design To asses the therapeutic potential oftwo injections of 750 mg IV mepolizumab (28days)endoscopic scoresymptom scoresCT scanTwo-arm, randomized, double blind, placebo controlled, trial20 Subjects30 SubjectsSevere nasal polypsMEPO 750mg IVPlaceboDosingFollow up*Primary endpoint10 SubjectsThe design of this study was a two-arm, randomized, double-blind, placebo-controlled study.30 patients with severe nasal polyposis were randomized in a double blinded way. 20 patients received 2 single IV injections with mepolizumab with a 4 week interval, and 10 patients received placebo injections.Follow up visits are scheduled 1 week after first dosing and 1, 3, 6, 9 months post last dose.Weeks14812243648*
10 Endoscopic Nasal polyp score and improvement 13/2012/2010/20intranasal steroids permittedWhen we look at our primary endpoint, the endoscopic NP score, we see that after two injections of mepolizumab, wet get a strong significant decrease in NP score at week 8, which was maintained until 6 months after treatment . Of importance, After w8 rescue medication was permitted. In the placebo group, none of the patients had a change in the NP score. When we then look at the number of patients that had an improvement in NP scoreEventually, we could even speculate that if we could give even more than 2 injections, we could expect an even further decrease of the nasal polyp score.When we look then at the number of patients that showed an improvement on the endoscopic score, we found 10/20 patients that were better, which was significantly higher compared to placebo with 1/10 better. a significant higher number of better patients that were better in the treated group compared to placebo 1 month after the first dosing. This number increased after the second dosingThe percentage of patients that showed an improvement in endoscopic score was significantly better after treatment compared to placebo after week 4, week 8 till week 12.**
11 S. aureus superantigens as disease modifiers Massive polyclonal lymphocyte activationEpithelial damage (barrier dysfunction)BTHyper IgE Cytokines colonisationMulticlonal IgESuperantigensEosinophils ( apoptosis)ChemokinesBachert C et al. JACI 2001Review: Bachert C et al. Clin Allergy Immunol. 2007
13 SCURD - Phenotyping Inflammation Unmet needs:Create valid nomenclatureImprove clinical diagnostics and markersDefine and validate targets per subgroupUnderstand link to lower airwaysAdvantages:Easy access, SCURD may serve as „model“Animal and human ex-vivo models availableClinical and epidemiologic studies achievable
14 Sinusitis cohort study GA2LEN 8 centres in Europe (2 co-operative centres in Asia)Inclusion started in March 2007Clinical phenotyping completed by end of 2008800 patients and 250 controls includedBiobank1050 blood samples and nasal secretions450 tissue samples