LaPoliposiNasale: dallagenetica allaterapiae all'esperienzapersonale. B... · CRSwNPE ASMA La Poliposi Nasale: fenotipi CRSwNP frequently is found in association with asthma and nonspecific

La Poliposi Nasale:dalla geneticaalla terapia e

all'esperienza personaleBenedetta Biagioni

School of Allergy and Clinical Immunology

EPOS DEFINITION OF ACUTE AND CHRONIC RHINOSINUSITISWITH AND WITHOUT NASAL POLYPS

DEFINIZIONE

La Poliposi Nasale: introduzione

EPOS CLASSIFICATION OF NASAL POLYPS


CLASSIFICAZIONE DEI POLIPI NASALI

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)


NP occur more frequently in asthma patients with aspirin sensitivity

Incidence of nasal CRSwNP :

• higher in men than in women

• increases after the age of 40 years

La Poliposi Nasale: fenotipi

CRSwNP:

Proinflammatory and neutrophil-

associated 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

CRSsNP:

Eosinophil-rich, Th2-dominated cytokine

Downregulation of TGF-β1 protein and its

receptors R1 and R2 � no collagen

deposition

CRwNP vs CRSsNP

CRSwNP E ASMA

La Poliposi Nasale: fenotipi

CRSwNP frequently is found in association with asthma and nonspecific

bronchial hyperresponsiveness.

In patients with CRSwNP,

asthma was found in 20% to 70%.

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.

CRSwNPCurrent or future LOWER AIRWAY INVOLVEMENT

NO lower airway involvement

Journal of Internal Medicine, 2012, 272; 133–143

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



10 clusters:

• 6 clusters with high concentrations of IL-5, eosinophilic cationic protein, IgE.

• 4 clusters with low or undetectable concentrations those markers


•IL5 negative clusters� Predominant CRSsNP phenotype

without increased asthma prevalence

•IL-5–positive clusters were divided into:

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

La Poliposi Nasale: patogenesi

RUOLO DI S. AUREUS

� S. aureus enterotoxins (SAEs) act as superantigens

� High local

polyclonal IgEconcentration

1/105 –1/106

T cells1/5

T cells

La Poliposi Nasale: patogenesi

RUOLO DI S. AUREUSS. Aureus and its

pruduct evoke

the release of

epithelial

cytokines

IL-33, TSLP,

eotaxin

�EET

S. Aureus and staphylococcal proteins can

directly activate T-cells to release IL-5�EET

Direct contact between eosinophils

and S. aureus

� EET

BARRIER DYSFUNCTION

EOSINOPHIL EXTRACELLULAR TRAPS


CRSwNP: West vs Est

Western world:

Asian world :

Th2 signature in 80% of nasal polyps

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


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


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

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.

La Poliposi Nasale: genetica

POLIPOSI NASALE ED EREDITARIETÀ

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 polyposis in asthmatic adults.

Allergy 2003

•Mfuna et al Association of IL1A, IL1B, and TNF gene polymorphisms with chronic rhinosinusitiswith and without nasal polyposis: A replication study. Archives of otolaryngology--head & neck

surgery 2010

TNF alpha:

•Erbek et al. Proinflammatory cytokine single nucleotide polymorphisms in nasal polyposis. Archives of otolaryngology-- head & neck surgery 2007

•Bernstein et al. Genetic polymorphisms in chronic hyperplastic sinusitis with nasal polyposis.

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

POLIPOSI NASALE E STUDI DI ASSOCIAZIONE


• IL-33

• IL-22 receptor a

• IL-1 receptor a

• IL-1 receptor –like 1

• Matrix metalloproteinase 9

• Matrix metalloproteinase 2

• TSLP

• TGFbeta1

• TLR2

• OSF- 2

• IL-4 promoter

etc etc…..


POLIPOSI NASALE E STUDI DI ASSOCIAZIONE

The other susceptibility genes and loci reported to be associated

could not be replicated:

EPIGENETIC ROLE?

?

??

?

??

?

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


GENETICA DELLA AERD

Aspirin-exacerbatedrespiratory disease (AERD)

> 50% NP associated

Widal-Samter’sTriad

LTC4S promoter SNP

EPOS2012

La Poliposi Nasale: terapia

TRATTAMENTO DELLE FORME LIEVI-MODERATE

Forest plot of randomized controlled trials evaluating

topical steroids in patients with nasal polyposis. CI ¼

confidence interval; RR ¼ risk ratio.

Laryngoscope, 122:1431–1437, 2012Methods: 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, 1.41–2.09), 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

CORTICOSTEROIDI TOPICI


Congestion score

Sense of smell

JACI 2005; 116: 1275





EPOS2012


TRATTAMENTO DELLE FORME SEVERE


CORTICOSTEROIDI ORALI

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.


INIEZIONE LOCALE DI CORTICOSTEROIDI

decrease in Lund-Mackay staging and

no significant difference was found between two groups.

Plasma cortisol and ACTH levels of the injected patients were normalbefore treatment,

1 week after the first injection,

and 1 week after the last injection.


MACROLIDI

Cervin & Wallwork

Curr Allergy Asthma Rep (2014)

Anti-inflammatory effects of

macrolide antibiotics.

Efficacy in CR patients with

•neutrophilic inflammation,

•not elevated IgE

•Low CT score

Doxycycline

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)


DOXICICLINA

J ALLERGY CLIN IMMUNOL

MAY 2010

J ALLERGY CLIN IMMUNOL

MAY 2010

Doxycycline causes a

long-term reductionin nasal polyp size,

methylprednisolone

causes an initial

reduction in polyp

size but complete

recurrence after 2

months

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.


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


POLIPOSI NASALE NON CONTROLLATA


FARMACI BIOLOGICI

J ALLERGY CLIN IMMUNOL MAY 2017


Improvement in total nasal polyp score: Omalizumab (n=15) versus placebo (n=8)

OMALIZUMAB

Int Arch Allergy Immunol 2009; 148:87–98

0

10

20

30

40

50

60

70

80

W2 W4 W6 W8 W10 W12 W14 W16 W18

placebo

omalizumab

-3

-2,5

-2

-1,5

-1

-0,5

0

0,5

1

BL W2 W4 W6 W8 W10W12W14W16W18

placebo

omalizumab

JACI 2013; 131:110-6


OMALIZUMAB


ANTI IL-5: RESLIZUMAB

J Allergy Clin

Immunol 2006


ANTI IL-5: MEPOLIZUMAB

J Allergy Clin Immunol 2011

Clin Immunol 2017


DUPILUMAB



“ For many patients with

severe disease,

uncontrolled with the

current surgical and

pharmacological

possibilities,

biotherapeutics soon will

offer a new and significant

treatment option,,

La Poliposi Nasale: esperienza

Subject Disease CRS onset FESS RevisionFESS

Treatmentstart

Outcome

SM (m) EGPA 1995 yes > 1 2017 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 > 1 2013 Recurrence

PS (f) EGPA 1995 yes > 1 2016 TC

improvement

TS (f) EGPA 2009 yes 1 2014 Stationary

Subject Disease CRS onset FESS RevisionFESS

Treatmentstart

Outcome

RR (m) EGPA 2016 no no 2017 Recurrence

GS (f) asthma 2007 yes >2 2013 Stationary

PA (f) asthma 2006 yes no 2010 Stationary

NR (m) asthma 2006 yes no 2014 Recurrence

Mepolizumab in CRSwNP patients

Omalizumab in CRSwNP patients

Grazie ai professori, agli strutturati, ai miei giovani colleghi

..e a tutti voi per l’attenzione

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LaPoliposiNasale: dallagenetica allaterapiae all'esperienzapersonale. B... · CRSwNPE ASMA La Poliposi Nasale: fenotipi CRSwNP frequently is found in association with asthma and nonspecific