What's New In the Pathophysiology of Itch? - Brian S. Kim, MD, MTR, FAAD Assistant Professor of Dermatology, Anesthesiology, and Pathology and ...
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What’s New In the Pathophysiology of
Itch?
Brian S. Kim, MD, MTR, FAAD
Assistant Professor of Dermatology, Anesthesiology, and Pathology and Immunology
Co-Director, Center for the Study of Itch
Itch is a central feature of atopic
dermatitis (AD) or eczema
• Chronic, relapsing
skin disease
• High incidence, costly
• Therapeutic options
limited
• Itch is the central
symptom
The classical paradigm of AD pathogenesis
IgE
IL-4
TH2 cell
IL-13 B cell
The new paradigm of atopic itch
Itch sensation
TH2 cell
IL-31
Dillon et al. Nat Immunol 2004
Cevikbas et al. J Allergy Clin Immunol 2014
The emerging paradigm of AD pathogenesis
TH2 cell
IL-33 and TSLP
Basophil IgE
IL-4
TH2 cell
Kim et al. Sci Transl Med 2013 IL-13
Kim et al. J Immunol 2014 ILC2 B cell
Innate type 2 cells promote AD-like disease
Dupilumab (anti-IL-4/13R mAb) demonstrates
unprecedented efficacy in AD
Itch improves markedly when type 2
cytokines are disrupted
The emerging paradigm of AD pathogenesis
Itch sensation
IL-33 and TSLP
Basophil
IL-4 ?
Kim et al. Sci Transl Med 2013 IL-13
Kim et al. J Immunol 2014 ILC2
Do sensory dorsal root ganglia (DRG)
express type 2 cytokine receptors?
Mouse Human
500 bp
500 bp
Oetjen et al. Cell 2017Do sensory neurons respond to IL-4?
Harvest Load with Fura-2 IL-4
Calcium imaging
sensory ganglia
Before IL-4 After IL-4Sensory neurons respond to type 2 cytokines
IL-4 KCl IL-13 KCl IL-31 KCl
Normalized Fluorescence
Normalized Fluorescence
Normalized Fluorescence
4 4 4
2 2 2
1.5 1.5 1.5
1 1 1
0.5 0.5 0.5
0 60 120 180 1100 1200 0 60 120 180 1100 1200 0 60 120 1801100 1200
Time (s) Time (s) Time (s)
Oetjen et al. Cell 2017Do human sensory neurons respond to IL-4?
Human DRG
IL-4 Capsaicin KCl
1.4
Normalized Fluorescence
1.2
1.0
0.8
0 100 200 300 400 1000 1500 2000
Time (s)
Oetjen et al. Cell 2017An experimental mouse model of AD
Topical vehicle (EtOH) Day 12
WT AD-like disease
or MC903
Oetjen et al. Cell 2017Does neuronal deletion of IL-4Rα abate
chronic itch?
Day 12 Scratching bouts
Topical
Control Ear thickness
MC903
Il4raΔneuron Histopathology
Oetjen et al. Cell 2017How does IL-4 promote itch?
IL le
ic
1
1
h
-3
4
-3
l
KC
Ve
-
IL
IL
Normalized Fluorescence
5
4
IL-31R
3
IL-31 TRPA1 2
TRPV1 1
0
0 500 1000 1500
Time (s)
Oetjen et al. Cell 2017IL-4 promotes neural hypersensitivity
H1R
Histamine
Capsaicin TRPV1
Oetjen et al. Cell 2017Dupilumab (anti-IL-4/13R mAb) may have
direct anti-itch propertiesDupuliumab demonstrates anti-pruritic effects
in refractory AD patients
Immunosuppression:
Azathioprine
Cyclosporine
Mycophenolate mofetil
Mack et al. (In Preparation)How else can we therapeutically approach
chronic itch?Does neuronal deletion of JAK1 limit itch?
Topical Day 7 Scratching bouts
MC903 Control Disease
Jak1Δneuron
Scratching Ear Thickness Littermate JAK1Δneuron
N.S.
300 * 30
Bouts per 30 min
% Change
150 15
0 0
Oetjen et al. Cell 2017Jakinibs may function as neuromodulators
Itch sensation
JAK inhibition
IL-31
TH2 cell
Basophil IL-4
JAK Sensory neuron
inhibition
IL-13 Dillon et al. Nat Immunol 2004
ILC2 Cevikbas et al. J Allergy Clin Immunol 2014Would Jakinibs work in “itch without a rash”?
Atopic Dermatitis (AD) Chronic Idiopathic Pruritus (CIP)
Oetjen et al. Cell 2017Jakinibs demonstrate preliminary efficacy
Figure 6
A B
Tofacitinib Tofacitinib
10
** 10
Cyclosporine Tofacitinib
8
NRS Itch Score
NRS Itch Score
8
6 6
4
4
2
2
0
0
0 10 20 30 40 50 60 70
Day
Oetjen et al. Cell 2017Identification of a novel itch-regulatory
pathwayImplications: Upadacitinib (JAK1-selective
inhibitor) markedly improves pruritus
https://news.abbvie.com/article_print.cfm?article_id=11530Implications: Anti-pruritic effect may outpace
anti-inflammatory effect
- Study shows positive results for upadacitinib and no new safety signals detected[1]
- All doses achieved the primary endpoint ofPRESSROOM
(http://www.abbvie.com/)
greater mean (/) percentage change from
baseline in Eczema Area and Severity Index (EASI) score versus placebo at 16
weeks[1]
- Clear or almost clear skin was achieved by 50 percent of patients receiving 30 mg
SEPTEMBER 7, 2017
once-daily dose of upadacitinib[1]
AbbVie's Upadacitinib (ABT-494) Meets Primary
- Upadacitinib demonstrated reduction in pruritus (itch) within the first week and
Endpoint in Phase 2b Study in Atopic Dermatitis
improvement in skin within the first two weeks for all doses[1] (https://news.abbvie.com/user_pref.cfm) (/article_print.cfm?
- Upadacitinib, an oral agent engineered by AbbVie to selectively inhibit JAK1, is
article_id=11530)
being studied as a once-a-day therapy in atopic dermatitis and across multiple
immune-mediated diseases[2],[3],[4-9]
- Study shows positive results for upadacitinib and no new safety signals detected[1]
- All doses achieved the primary endpoint of greater mean percentage change from
baseline in Eczema Area and Severity Index (EASI) score versus placebo at 16
weeks[1]
- Clear or almost clear skin was achieved by 50 percent of patients receiving 30 mg
once-daily dose of upadacitinib[1]
- Upadacitinib demonstrated reduction in pruritus (itch) within the first week and
improvement in skin within the first two weeks for all doses[1]
- Upadacitinib, an oral agent engineered by AbbVie to selectively inhibit JAK1, is
TH CHICAGO, Ill., Sept. 7, 2017 /PRNewswire/ -- AbbVie (NYSE: ABBV), a global research
being studied as a once-a-day therapy in atopic dermatitis and across multiple
immune-mediated diseases[2],[3],[4-9]
opment based biopharmaceutical company, today announced positive top-line results from
NORTH CHICAGO, Ill., Sept. 7, 2017 /PRNewswire/ -- AbbVie (NYSE: ABBV), a global research andImplications: Topical Jakinibs demonstrate
anti-pruritic effects by Day 1-2Implications: Patients with JAK1 gain-of-
function mutations exhibit severe pruritus
Alanine to aspartate substitution at position 634 (A634D)
Del Bel et al. J Allerg Clin Immunol 2017Implications: JAK1 gain-of-function pruritus
only responsive to JAK inhibitors
Del Bel et al. J Allerg Clin Immunol 2017Conclusions 1. IL-4Rα blockers and JAK1 inhibitors may function as neuromodulators 2. Jakinibs demonstrate efficacy for chronic idiopathic pruritus 3. These pathways are likely conserved across multiple barrier surfaces: asthma, conjunctivitis, eosinophilic GI disorders, IBS, IBD, etc.
Acknowledgements Kim Lab Funding Landon Kyle Oetjen (MSTP Student) K08AR065577-03 Madison Mack (PhD Student) R01AR070116-01 Anna Trier (MSTP Student) Doris Duke Charitable Foundation Fang Wang (Postdoctoral Fellow) American Skin Association Timothy Whelan LEO Pharma Research Grant Nancy Bodet (Research Nurse) Joy Niu (Postdoctoral Fellow) Amy Xu (HHMI Med Fellow) Collaborators Qin Liu Chyi-Song Hsieh Hongzhen Hu Josh Milner (NIH) Zhoufeng Chen Robert Gereau Steve Davidson (U Cinn) Mark Miller
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