LaPoliposiNasale: dallagenetica allaterapiae all'esperienzapersonale

Transcription

1 LaPoliposiNasale: dallagenetica allaterapiae all'esperienzapersonale Benedetta Biagioni School of Allergy and Clinical Immunology

2 DEFINIZIONE EPOS DEFINITION OF ACUTE AND CHRONIC RHINOSINUSITISWITH AND WITHOUT NASAL POLYPS La Poliposi Nasale: introduzione

3 EPOS CLASSIFICATION OF NASAL POLYPS La Poliposi Nasale: introduzione CLASSIFICAZIONE DEI POLIPI NASALI

4 La Poliposi Nasale: introduzione EPIDEMIOLOGIA Estimated prevalence of CRSwNP : In Europe 2.1% (France) / 4.4% (Finland) In the USA 4.2% In Asia 1.1% (China) / 2.6% (Korea) Incidence of nasal CRSwNP : higher in men than in women increases after the age of 40 years NP occur more frequently in asthma patients with aspirin sensitivity

5 CRwNP vs CRSsNP La Poliposi Nasale: fenotipi CRSwNP: Eosinophil-rich, Th2-dominated cytokine Downregulation of TGF-β1 protein and its receptors R1 and R2 no collagen deposition CRSsNP: Proinflammatory and neutrophilassociated cytokines : interleukin (IL)- 1β, tumor necrosis factor (TNF)-α, IL-8 increased neutrophil activation Upregulation of TGF-β1 and TGF- β2 and of their receptors TGF-βR1 and TGF-βR3 collagen deposition

6 La Poliposi Nasale: fenotipi CRSwNP E ASMA CRSwNP frequently is found in association with asthma and nonspecific bronchial hyperresponsiveness. In patients with CRSwNP, asthma was found in 20% to 70%. CRSwNP In patients with CRSwNP and bronchial hyperreactivity an eosinophilic bronchial inflammation is observed in the tissue, whereas in patients with CRSwNP without bronchial hyperreactivity, such inflammation is absent. Current or future LOWER AIRWAY INVOLVEMENT NO lower airway involvement

7 Journal of Internal Medicine, 2012, 272; La Poliposi Nasale: endotipi

8 La Poliposi Nasale: endotipi ENDOTIPI INFIAMMATORI IN CRS Multicenter case-control study patients with CRS and control subjects underwent surgery. 173 tissue analyzed for : IL-5, IFN-γ, IL-17A, TNF-α, IL-22, IL-1β, IL-6, IL-8,ECP, MPO, TGF-β1, IgE, Staphylococcus aureus enterotoxin-specific IgE and albumin. J ALLERGY CLIN IMMUNOL nnn 2016

9 La Poliposi Nasale: endotipi ENDOTIPI INFIAMMATORI IN CRS 10 clusters: 6 clusters with high concentrations of IL-5, eosinophilic cationic protein, IgE. 4 clusters with low or undetectable concentrations those markers

10 La Poliposi Nasale: endotipi IL5 negative clusters Predominant CRSsNP phenotype without increased asthma prevalence IL-5 positive clusters were divided into: ENDOTIPI INFIAMMATORI IN CRS 1. Moderate IL-5 levels CRSsNP/CRSwNP and increased asthma phenotype 2. High IL-5 levels almost exclusive nasal polyp phenotype with strongly increased asthma prevalence In clusters with the highest concentrations of IgE and asthma prevalence all samples expressed Staphylococcus aureus enterotoxin specific IgE

11 La Poliposi Nasale: patogenesi RUOLO DIS. AUREUS S. aureus enterotoxins (SAEs) act as superantigens High local polyclonal IgE concentration 1/10 5 1/10 6 T cells 1/5 T cells

12 La Poliposi Nasale: patogenesi RUOLO DIS. AUREUS S. Aureus and its pruduct evoke the release of epithelial cytokines IL-33, TSLP, eotaxin EET Direct contact between eosinophils and S. aureus EET S. Aureus and staphylococcal proteins can directly activate T-cells to release IL-5 EET BARRIER DYSFUNCTION EOSINOPHIL EXTRACELLULAR TRAPS

13 La Poliposi Nasale: endotipi CRSwNP: West vs Est Western world: Th2 signature in 80% of nasal polyps Asian world : Th2 signature between 20% (China and Korea) and 60% (Thailand) Lower asthma comorbidity Low risk of recurrence after surgery Immunological heterogeneity among different regions within the same disease phenotype

14 La Poliposi Nasale: endotipi CRSwNP: West vs Est IL-5-POSITIVE NASAL POLYPS mediators of eosinophilic inflammation associated with greater Gram-positive bacterial colonization. KEY CYTOKINE-NEGATIVE NASAL POLYPS mediators of neutrophilic inflammation associated with Gram-negative bacterial load

15 La Poliposi Nasale: endotipi CRSwNP: West vs Est Journal of Allergy and Clinical Immunology (2017) These differences in type-2 signatures all over the world would stay over time or would be matter to change? several publications show a dramatic change in the expression of eosinophilic disease within the CRSwNP population in Thailand and Korea EOSINOPHILIC SHIFT accompanied by higher S. aureus carriage

16 La Poliposi Nasale: genetica POLIPOSI NASALE ED EREDITARIETÀ Chronic rhinosinusitis (CRS) is a complex disease, with a pathophysiology that is likely to be affected by multiple genetic and environmental factors Family and twin studies: 100 patients with NP and 102 controls from the general population, 13.3% of the patients and none of the controls had a history of polyps in the family, 224 CRSwNP patients 52% had a positive family history of NP Studies of monozygotic twins have NOT shown that both siblings always develop polyps, environmental factors are likely to influence the occurrence of CRSwNP.

17 La Poliposi Nasale: genetica POLIPOSI NASALE E STUDI DI ASSOCIAZIONE A variety of cytokines, cytokine receptors, immunity and mucosal airway remodeling related molecules have been associated with CRS. Among them only three polymorphisms have been replicated : IL1 alpha: Karjalainen et al. The IL1A genotype is associated with nasal polyposisin asthmatic adults. Allergy 2003 Mfuna et al Association of IL1A, IL1B, and TNF gene polymorphisms with chronic rhinosinusitis with and without nasal polyposis: A replication study. Archives of otolaryngology--head & neck surgery 2010 TNF alpha: Erbek et al. Proinflammatorycytokinesingle nucleotide polymorphismsin nasalpolyposis. Archivesofotolaryngology-- head & necksurgery2007 Bernstein et al. Geneticpolymorphismsin chronichyperplasticsinusitiswithnasalpolyposis. The Laryngoscope 2009 AOAH: Mfuna-Endam et al. Genetics of rhinosinusitis. Current allergy and asthma reports 2011 Zhang et al. Polymorphisms in RYBP and AOAH genes are associated with chronic rhinosinusitis in a Chinese population: a replication study. PloS one 2012

18 La Poliposi Nasale: genetica POLIPOSI NASALE E STUDI DI ASSOCIAZIONE The other susceptibility genes and loci reported to be associated could not be replicated: IL-33 IL-22 receptor a IL-1 receptor a?? IL-1 receptor like 1 Matrix metalloproteinase 9? Matrix metalloproteinase 2 EPIGENETIC ROLE?? TSLP TGFbeta1?? TLR2? OSF- 2 IL-4 promoter etc etc.. heterogeneity and poor repeatability of the genetic findings The differentiation of CRS into endotypes rather than phenotypes will offer further opportunities to discover genetic and epigenetic patterns

19 La Poliposi Nasale: genetica GENETICA DELLA AERD Aspirin-exacerbated respiratorydisease (AERD) > 50% NP associated Widal-Samter s Triad LTC4S promoter SNP

20 La Poliposi Nasale: terapia TRATTAMENTO DELLE FORME LIEVI-MODERATE EPOS2012

21 La Poliposi Nasale: terapia CORTICOSTEROIDI TOPICI Laryngoscope, 122: , 2012 Forest plot of randomized controlled trials evaluating topical steroids in patients with nasal polyposis. CI ¼ confidence interval; RR ¼ risk ratio. Methods: randomized, placebo controlled trials, nasal polyposis, and topical steroid therapy. Results: A total of 12 studies were combined for quantitative analysis and demonstrated a pooled risk ratio of 1.72 (95% confidence interval, ), indicating a significant improvement in nasal symptoms. All three topical steroid preparations (fluticasone, mometasone, and budesonide) resulted in symptom improvement. Conclusions: Topical nasal steroid therapy improves nasal symptoms in CRS patients with nasal polyposis. Level of Evidence: 1a

22 La Poliposi Nasale: terapia CORTICOSTEROIDI TOPICI Congestion score Sense of smell JACI 2005; 116: 1275

23 La Poliposi Nasale: terapia CORTICOSTEROIDI TOPICI

24 La Poliposi Nasale: terapia TRATTAMENTO DELLE FORME SEVERE EPOS2012

25 La Poliposi Nasale: terapia CORTICOSTEROIDI ORALI

26 La Poliposi Nasale: terapia INIEZIONE LOCALE DI CORTICOSTEROIDI Group A: oral prednisolone 1 mg/kg/day tapering by 5 mg/day, for 2 weeks Group B: endoscopic intrapolyp steroid injection weekly (40 mg/ml triamcinolone, 1 ml) for up to five times In both groups the treatment was followed by fluticasone propionate nasal drops 40 mg twice a day for 12 weeks. decrease in symptom score and polyp score with no significant difference between groups. decrease in Lund-Mackaystaging and no significant difference was found between two groups. Plasma cortisol and ACTH levels of the injected patients were normal before treatment, 1 week after the first injection, and 1 week after the last injection.

27 La Poliposi Nasale: terapia MACROLIDI Anti-inflammatory effects of macrolide antibiotics. Efficacy in CR patients with neutrophilic inflammation, not elevated IgE Low CT score Cervin& Wallwork Curr Allergy Asthma Rep (2014)

28 La Poliposi Nasale: terapia DOXICICLINA Doxycycline J ALLERGY CLIN IMMUNOL MAY 2010 Doxycycline causes a long-term reduction in nasal polyp size, methylprednisolone causes an initial reduction in polyp size but complete recurrence after 2 months 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)

29 La Poliposi Nasale: terapia POLIPOSI NASALE NON CONTROLLATA 389 CRS patients who had undergone bilateral 3 5 years prior to the study. Postal questionnaire asking for control items according to EPOS control criteria, visual analogue scale (VAS) scores for total and individual sinonasal symptoms, sinonasal outcome test (SNOT)-22 and Short Form (SF)- 36 questionnaires.

30 La Poliposi Nasale: terapia POLIPOSI NASALE NON CONTROLLATA Subgroup analysis revealed that female gender, aspirin intolerance and revision ESS were associated with higher prevalence of uncontrolled CRS, whereas allergy, asthma and smoking status d id not alter the percentage of patients in each category of control

31 La Poliposi Nasale: terapia FARMACI BIOLOGICI J ALLERGY CLIN IMMUNOL MAY 2017

32 La Poliposi Nasale: terapia OMALIZUMAB Int Arch Allergy Immunol 2009; 148:87 98 Improvement in total nasal polyp score: Omalizumab (n=15) versus placebo (n=8) , , ,5 placebo omalizumab placebo omalizumab , BL W2 W4 W6 W8 W10W12W14W16W18 0 W2 W4 W6 W8 W10 W12 W14 W16 W18

33 La Poliposi Nasale: terapia OMALIZUMAB JACI 2013; 131:110-6

34 La Poliposi Nasale: terapia ANTI IL-5: RESLIZUMAB J Allergy Clin Immunol 2006

35 La Poliposi Nasale: terapia ANTI IL-5: MEPOLIZUMAB J Allergy Clin Immunol 2011 Clin Immunol 2017

36 La Poliposi Nasale: terapia DUPILUMAB

37 La Poliposi Nasale: terapia

38 La Poliposi Nasale: terapia For many patients with severe disease, uncontrolled with the current surgical and pharmacological possibilities, biotherapeutics soon will offer a new and significant treatment option,,

39 Subject Disease CRS onset FESS Revision FESS La Poliposi Nasale: esperienza Mepolizumab in CRSwNP patients Treatment start Outcome SM (m) EGPA 1995 yes > Qol DR (m) EGPA 2013 no no 2017 Stationary QM (f) EGPA 2010 no no 2011 Stationary DF (m) EGPA 2009 no no 2015 Stationary MS (f) EGPA > 10 years yes > Recurrence PS (f) EGPA 1995 yes > TC improvement TS (f) EGPA 2009 yes Stationary Omalizumab in CRSwNP patients Subject Disease CRS onset FESS Revision FESS Treatment start Outcome RR (m) EGPA 2016 no no 2017 Recurrence GS (f) asthma 2007 yes > Stationary PA (f) asthma 2006 yes no 2010 Stationary NR (m) asthma 2006 yes no 2014 Recurrence

40 Grazie ai professori, agli strutturati, ai miei giovani colleghi..e a tutti voi per l attenzione