Chronic Sinusitis: Update - TSAAItsaai.org/assets/borish-chronicsinusitis.pdf · Frequent...
Transcript of Chronic Sinusitis: Update - TSAAItsaai.org/assets/borish-chronicsinusitis.pdf · Frequent...
7/2/2019
1
Chronic Sinusitis:Update
Larry Borish, M.D.Professor of Medicine and Microbiology
University of Virginia Health SystemsCharlottesville, VA
Conflicts of Interest
• Grant Support: NIH*, GSK*, Astra Zeneca*
• Consulting: Astra Zeneca, Sanofi-Regeneron
• Clinical Trial: Cumberland*
*All funds go to UVA
7/2/2019
2
Learning Objectives• To appreciate distinct CRS phenotypes
but limitations in their diagnosis
• To appreciate the potential role ofspecific individualized biologics inCRS
Phenotypes of CRS
• Non-eosinophilic• Th1 / Th17 / innate
• ± Neutrophilic
• CF (often)
• Eosinophilic• Idiopathic
• AERD
• AFS
• CF (often)
7/2/2019
3
Non-Eosinophilic CRS
100x200xPayne, SP et al. Laryngoscope 2011;121:2262-7
Clinical Aspects ofNon-Eosinophilic CRS
• Inflammatory sinonasal disease
- e.g., perennial allergic / non-allergic rhinitis
• Frequent episodes of bacterial sinusitis
• Less often associated with nasal polyposis
• No asthma or eosinophilia?
• 1 FESS may be curative?
• Mucus inclusion cysts on CT / CT scores <12?
7/2/2019
4
Pathogenesis of Non-Eosinophilic CRS?
Frequent protracted episodes of acute sinusitis
Remodeling of Sinus Tissue
- Epithelial denudation
- Goblet cell and glandular hypertrophy- Fibrosis ± polyp formation
Bacterial colonization- Formation of biofilm
- Chronic purulent exudate
Eosinophilic CRS
200x 100x
Payne, SP et al. Laryngoscope 2011;121:2262-7
7/2/2019
5
But how useful is this in real life?
• Are these – in fact – distinct phenotypes?
• Can presence or absence of eosinophils (±IL-5 / ± ECP) beused to distinguish type 2/eosinophilic from non-type 2 disease?
• and, can• presence /absence of NPs,• asthma,• absolute eosinophil count,• whatever
• but especially NPs be used as prima facie evidence foreosinophilic disease?
Patterns of Cytokine Expression in CRSsNPsBenelux: Chengdu:
Wang X et al. J Allergy Clin Immunol 2016;138:1344-53
7/2/2019
6
Patterns of Cytokine Expression in CRSwNPsBenelux: Chengdu:
Tomassen P et al. J Allergy Clin Immunol 2016;137:1449-56
Presence of eosinophilia (ECP) / IL-5 in CRSwand CRSs NPs
Tomassen P et al. J Allergy Clin Immunol 2016;137:1449-56
7/2/2019
7
Northwestern’s Experience:
mRNA as % of house keeping gene for CLC and IL-5ECP protein via EIA
ET – ethmoid tissue
Tan BK et al. J Allergy Clin Immunol 2017;139:699
But how useful is this in real life (part 2)?
• Are these – in fact – distinct phenotypes?
• Can presence or absence of eosinophils (±IL-5 / ± ECP) be used todistinguish type 2/eosinophilic from non-type 2 disease?
- is someone with 1189.10 µg/L of ECP in their polyp tissue really“eosinophilic” whereas someone with 1189.09 µg of ECP is non-eosinophilic?
• Can clinical criteria distinguish type 2 high NPs?
7/2/2019
8
Do biomarkers predict tissue eosinophilia?
Tissue Average Eosinophilia Tertile
Ge
om
etr
icM
ea
nA
bso
lute
Eo
sin
op
hil
Co
un
t
1st 2nd 3rd
200
400
600
800
1000
Tissue Average Eosinophilia Tertile
Ge
om
etr
icM
ea
nT
ota
lIg
E
1st 2nd 3rd
0
100
200
300
400
Tissue Average Eosinophilia Tertile
Ge
om
etr
icM
ea
nL
un
dM
acka
yS
co
re
1st 2nd 3rd
10
12
14
16
18
20
A B
C
p = 0.205
p = 0.149
p = 0.311
Steinke J et al. J Allergy Clin Immunol: Practice 2017;5(6):1582-8
and, for the matter, how well does tissueeosinophilia predict “eosinophilia”?
Average Tissue Eosinophil Count Interval
Fre
qu
en
cy
(n)
0
5
10
15
20
25
30
Fre
qu
en
cy
(n)
0
5
10
15
20
25
30
[0-3)[3-5)
[5-7)[7-9)
[9-11)[11-13)
[13-15)
[15-17)
[17-19)
[19-21)
[21-23)
[23-25)
[25, + )
Peak Tissue Eosinophil Count Interval
A
B
[0-3)[3-5)
[5-7)[7-9)
[9-11)[11-13)
[13-15)
[15-17)
[17-19)
[19-21)
[21-23)
[23-25)
[25, + )
and, does it make adifference if theeosinophils arediffusely expressedor just present infoci?
Steinke J et al. J Allergy Clin Immunol: Practice 2017;5(6):1582-8
7/2/2019
9
So if these are (primarily) eosinophilic diseasesshouldn’t eosinophil depletion cure them?
e.g.,- IL-5 antagonists- dexpramipexole
Biological Activities of IL-5
• IL-5 is the most important eosinophil hematopoietin• TSLP and IL-33 may also have a role in the induction of inducible
eosinophilia
• also, eosinophils are constitutively made
• IL-5 is an important survival factor for eosinophils• although in the airway autocrine production of GM-CSF may take on a more
important role
• IL-5 is chemotactic for mature eosinophils and a priming factor forenhanced functional activities
7/2/2019
10
Anti-IL-5 / Anti-IL-5R
• Anti-IL-5 will deplete bone marrow and circulating eosinophils- although less effective in depleting tissue eosinophils (~50%)
- Anti-IL-5R will block IL-5 engagement on IL-5R on eosinophils- but via ADCC may opsonize and deplete eosinophils in the absence of IL-5
- and may target other IL-5R+ cells (e.g., basophils)
Anti-IL-5 in CRS
Gevaert, P et al. J Allergy Clin Immunol 2011;128:989-995
7/2/2019
11
Bachert C. et al. J Allergy Clin Immunol 2017;140:1024-31
Mepolizumab reduces need for surgery
Who might respond best to eosinophiltargeting therapies?
• Presumably those with an eosinophil-mediated disease
- IL-5high
- other specific phenotypes? e.g.,• AERD• EGPA
7/2/2019
12
Nasal IL-5 levels determine the responseto anti-IL-5 in nasal polyposis:
• DBPC randomized trial ofreslizumab in NPs
• Reslizumab reduced AECand serum ECP for up to8 weeks
• NP response lasted for 4weeks
Gevaert, P et al. J Allergy Clin Immunol 2006;118:1133-41
Problems with eosinophil targeting therapies
• We have no meaningful markers as to who has eosinophilic disease- AEC, NPs, FeNO, and perhaps even tissue biopsies are all inadequate
• Current therapies may not adequately eliminate tissue eosinophils
• Even if tissue eosinophils were all eradicated, CRSs or wNPs mayvariably be driven by numerous other inflammatory cells:
- Basophils
- Mast cells
- PMNs
- others
7/2/2019
13
So, is eosinophil elimination sufficient toeradicate CRSwNPs?
Eosinophil Reduction in NPs: Dexpramipexole
Laidlaw, TM et al. Laryngoscope doi.org/10.1002/lary.27564
Tissue histology:
7/2/2019
14
and how does that translate in terms ofclinical benefit?
Laidlaw, TM et al. Laryngoscope doi.org/10.1002/lary.27564
So if this isn’t (just) an eosinophilic diseasewhat else might it be?• What is the role of mast cells in refractory CRSwNPs?
7/2/2019
15
CHLOROACETATEANTIBODY
Payne, SP et al. Laryngoscope 2011;121:2262-7
and, a fun bonus observation in thedexpramipexole study:
Laidlaw, TM et al. Laryngoscope doi.org/10.1002/lary.27564
7/2/2019
16
How might mast cells be activated in CRS?
• IgE- aeroallergen (perhaps)
- staph (intriguing)
- something local?
• Non-IgE- cytokines: IL-4/IL-13, TSLP/IL-25/IL-33, numerous chemokines/cytokines
- LTE4
- TNTC alarmins / PAMPs
Can Allergen Even Access the Sinuses?
• Radiolabeled allergen can not access the sinus cavityAdkins, T.N. et al. Ann Allergy Asthma Immunol. 1998;81:181-4
• Radioisotope placed on nasal mucosa can access the healthy sinuscavity with nose blowing but not with nasal breathing, sneezing, orcoughing
Gwaltney JM Jr., et al. Clin Infect Dis 2000;30:387-9
7/2/2019
17
CRS exacerbations occur in a seasonal pattern
Rank MA, J Allergy Clin Immunol 126:168, 2010but that seasonal pattern is the season of respiratory viral infections!
Which argues against CRS being an “allergic”disease
7/2/2019
18
Does efficacy of omalizumab support an“allergic” mechanism for CRS?
Efficacy of omalizumab in non-atopic asthma* andchronic urticaria
*deLlano, LP et al. J. Asthma 2013;50(3):296-301
and, in the CRS study (pending)…
improvements occurred irrespective of thepresence of allergy
IgE in Chronic Sinusitis:Mucosal tissue polyclonal IgE is functional but not particularlyresponsive to allergen
Zhang N et al Allergy 2011;66:141-8
7/2/2019
19
IgE in Chronic Sinusitis:Mucosal tissue polyclonal IgE is functional but not particularlyresponsive to allergen
Zhang N et al Allergy 2011;66:141-8
Non-IgE Mechanisms?
7/2/2019
20
Implications for Treatment
• IgE targeting therapies• Omalizumab
• Mast cell stabilizers / mast cell targeting therapeutics• Omalizumab
• Dupilumab
• Imatinib?
• Anti-SigLEC8?
Omalizumab in CS
• Improvements occurred irrespective of presence of allergy• Omalizumab may be particularly effective in AERD
Gevaert P et al. 2013 J Allergy Clin Immunol 131:110-6Bergmann KC et al. 2015 J Allergy Clin Immunol Pract 3:459-60)
• 16 week DBPC study of omalizumab in 24 (16:8) subjectswith asthma and NPs
7/2/2019
21
Dupilumab in CRS: IL-4 and IL-13Receptors
Unique patterns of distribution of type I (IL-4)and type II (IL-4 and IL-13) receptors
IL-4 (g chainexpression)
Hematopoieticcells
T lymphocytesmast cells
IL-13 (type IIreceptors)
Hematopoieticand non-hematopoieticcells
Epithelial cells,smooth muscle,endothelialcells
IL-4 and “Leaky” Mast Cells: IL-4 InducesExpression of FcRI on Mast Cells
Pawankar R, et al. J Clin Invest 1997;99:1492
IL-4 but not IL-13 inducesFceRI on human mast cells
IL-4-stimulated mast cells (lane 1)demonstrate enhanced expressionof FceRIa chain
7/2/2019
22
IL-4 Regulates IgE-dependent CysLT production by MastCells: Profound Induction of LTC4 Synthase expression byIL-4:
Hsieh FH et al. J. Exp Med. 2001;193:123.
Effect of IL-4 priming of human MCs onIgE mediated CysLT release
Effect of IL-4 priming on5-LO/LTC4S pathwayprotein expression byhMCs
Distal actions of IL-13 inallergic inflammation
• Endothelial cells: Eosinophil adhesion;chemokine expression
• Airway smooth muscle hyperplasia: Bronchialhyperreactivity
• Epithelial cell metaplasia
7/2/2019
23
IL-13 and Goblet Cell Metaplasia
• IL-13 induces reversible trans-differentiation ofepithelial cells into goblet cells
• This occurs via expression of foxa3 (master regulatorof goblet cells)– which drive expression of mucin genes (Muc5ac)
Effect of IL-13 on Mucus Production
AB/PAS(mucus stain
MUC5AC geneexpression
Control
IL-13(250 ng i.n.,single dose)
Dabbagh K, et al. J Immunol 1999; 162:6233-7.
7/2/2019
24
Dupilumab for CRS
Bachert C et al. JAMA 2016;315:469-479
Nasal polyp score:
Dupilumab for CRSSNOT22 Score
Bachert C et al. JAMA 2016;315:469-479
7/2/2019
25
Dupilumab in AERD
• Clearly can be beneficial…. But in whom?• AERD
Nasal polyp Scores:
Where biologics may be most useful• IL-5/IL-5R antagonists:
• CRS with or without NPs where pathological exam demonstrates robusteosinophilia
• AERD• EGPA (mepolizumab 300 mg/month)
• Omalizumab• atopic rhinosinusitis• ? AFS (no data)
• Dupilumab• ? excessive mucus metaplasia• AERD
7/2/2019
26
Summary
• Eosinophils alone cannot explain the severity of CRSwNPs- eosinophil depletion is useful but no panacea
• Mast cells are an inviting and underappreciated target in CRS- they are present in high numbers
- they are activated
- and, even if not IgE-mediated, you don’t need IgE to activate a mast cell
• IgE / mast cell targeting therapies show promise