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21st Century Therapy for
Allergic Dermatitis
Laura Stokking, PhD, DVM, DACVD
Veterinary Specialty Hospital, San Diego
Allergy: Quick Review
• Flea
• Food
• Environment
• Combination
Miller WH, Griffin CE, and Campbell KL. Muller and Kirk’s Small Animal Dermatology, 7th ed, 2013. Elsevier, pp. 184-222.
Flea Allergy
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Flea Allergy
• Prevalence??
• My dog doesn’t have fleas""
• Diagnosis• Pruritus
• Lesion distribution
• Treatment• Flea control
Lots of Treatment Options
Topical
• Vectra/Vectra 3D
• Revolution
• Frontline Gold
• Advantage II
Oral
• Isoxazilones
• Simparica
• Bravecto
• Nexgard
• Comfortis/Trifexis
Food Allergy
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Adverse Reactions to Food
Immunologic
• Food allergy
IgE-mediated
Dermatologic
Gastrointestinal
Respiratory
Combination
Non-immunologic
• Food intolerance
Toxic
Metabolic
Pharmacologic
Food Allergy• Signalment
• Age
Bimodal
• Breed
Not really).
Genetic predisposition to atopic disease?
• Sex
None
• History
• Non-seasonal
clinical signs
• Not steroid-
responsive
• Dermatologic
• Gastrointestinal
Diagnosis
History
• Non-seasonal
• Correlation with diet or
indiscretion
• Can be “flare factor” for
atopic dermatitis
Clinical Signs
• Pruritus!
• Otitis
• Erythema, edema, exudate
• Dermatitis
• Face, feet, axillae, groin,
perianal/perineal
• Urticaria, erythema, alopecia,
scale, papules, pustules,
macules, plaques,
excoriations, lichenification
• Recurrent infections
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Diagnosis
• Diet trial
• Novel or hydrolyzed protein
• Confirm diagnosis by challenge
• Serum tests do not work!
• Presence of IgE does not equal disease
• “Prick” and intradermal tests do not work!
Management• Feed only proteins and carbohydrates that
do not induce HPS
• Other medications
• Dermatologic and gastrointestinal signs
• Manage all contributing factors
• Secondary infections
• Concurrent allergies
Canine Atopic Dermatitis:Environmental Allergens
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Canine Atopic Dermatitis
• Some criteria
• Pruritus w/o lesions at onset
• Onset at <3 years
• Mostly indoor
• Corticosteroid-responsive pruritus
• Malassezia history
• Affected front feet
• Affected ear pinna
• Non-affected ear margins
• Non-affected dorsolumbar
Favrot et al., 2010
Olivry et al., 2011
Canine Atopic Dermatitis
• Prevalence
• Diagnosis
• EXCLUSION!
• NOT IDST or serum tests
• Dermatologic signs
indistinguishable from
food allergy
• Pathophysiology
• Barrier involvement!!!!!
• Genetic predisposition?
• IgE-mediated
• Th2 cytokines!
• IL-31!
• Route of antigen entry
• Percutaneous, not inhalation
IDST is used to identify
allergens for desensitization
AFTER clincal diagnosis has
been made
Serum IgE levels in nonatopic vs atopic West Highland
white terriers
Veterinary Dermatology
Volume 22, Issue 3, pages 257-266, 26 JAN 2011 DOI: 10.1111/j.1365-3164.2010.00939.x
http://onlinelibrary.wiley.com/doi/10.1111/j.1365-3164.2010.00939.x/full#f1
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21st Century Medicine: Targeted Therapy
Apoquel
• Oclacitinib
Cytopoint
• Caninized anti-IL-31
monoclonal antibody
Canine Pathophysiology
Activated receptor
STAT dimer
(phosphorylated)
DNA
Nucleus
Cell membrane
Cytokines
Phosphate
STAT
monomer
JAK
Cytokines convey information
by binding to specific receptors
on the cell membrane that induce
biological responses.
JAK Pathway
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STATs go to the nucleus
and activate gene
transcription
STAT
Nucleus
DNA
PRURITUS
INFLAMMATION
JAK/STAT Signaling
STATs go to the nucleus
and activate gene transcription
STAT
Nucleus
DNA
JAK/STAT Signaling
PRURITUS
INFLAMMATION
X
XAPOQUEL
APOQUEL
• Inhibits Janus kinase (JAK) enzymes,
particularly JAK1 and JAK3
Inhibits the activity of pruritogenic, pro-
inflammatory and pro-allergic cytokines that
use JAK1
• Has minimal impact on cytokines that work
through JAK2
The cytokines responsible for hematopoiesis and
innate immunity
Mechanism of Action
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Apoquel: Target JAK1-dependent Cytokines, Minimize
Effects on JAK2-dependent Cytokines
Data on file, Study Reports 7960Z-60-11-B95, 7960W-60-08-779, 7560W-60-06-626, 1462N-60-08-905,
Zoetis Inc.
Plasma concentration oclacitinib 0.6 mg/kg BID
Plasma concentration oclacitinib 0.6 mg/kg SID
JAK1 dependent cytokines IC50s
JAK2 dependent cytokines IC50s
IL-6
IL-13
0 6 12 18 24
1
10
100
1000
10000
IL-31
IL-2
IL-4
EPO, GM-CSF
IL-12, IL-23
Time (Hours)
Co
nce
ntr
ati
on
(n
g/m
L)
APOQUEL® Works Fast
Reference: Cosgrove SB, Wren JA, Cleaver DM, et al. Efficacy and safety of oclacitinib for the
control
of pruritus and associated skin lesions in dogs with canine allergic dermatitis. Vet Dermatol. 2013;24(5):479-e114.
Mean APOQUEL® Scores Were Significantly Better Than Placebo Scores on Each Assessment Day
APOQUEL® for Short-Term and Long-Term
Pruritus Control
References: Cosgrove SB, Wren JA, Cleaver DM, et al. Efficacy and safety of oclacitinib for the control of
pruritus and associated skin lesions in dogs with canine allergic dermatitis. Vet Dermatol. 2013;24(5):479-e114.
Data on file. Study report 1962C-60-11-A75, 2013, Zoetis Inc. Cosgrove SB, Wren JA, Cleaver DM, et al. A
blinded, randomized, placebo-controlled trial of the efficacy and safety of the Janus kinase inhibitor oclacitinib (APOQUEL®) in client-owned dogs with atopic dermatitis. Vet Dermatol. 2013;24(6):587-e142.
doi:10.1111/vde.12088. Aleo MM, Galvan EA, Fleck JT, et al. Effects of oclacitinib and prednisolone on skin
test sensitivity [abstract]. Vet Dermatol. 2013;24(3):297.
Minimal Side Effects
Safe for Long-Term
Use
Can Be Used Concomitantly with
Many Other Medications
Allows You to Diagnose the
Underlying Cause
Side effects of
APOQUEL® were similar
to placebo without
many of the side effects
associated with the use
of steroids
Owners reported
minimal side effects in
dogs who were given
APOQUEL® for more
than 2 years in a pre-
approval, observational
continuation study
APOQUEL® can be used
in combination with
many common therapies
including vaccines,
NSAIDs, antibiotics and
allergen immunotherapy
APOQUEL® does not
compromise diagnostic
testing, allowing
veterinarians to
diagnose the underlying
cause of the itch and
improve the quality of
life for dog and its
owner
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Apoquel:
Not just for atopy
Flea Allergy Food Allergy Contact Allergy Atopic Dermatitis
APOQUEL works on all of them!
References: Cosgrove SB, Wren JA, Cleaver DM, et al. Efficacy and safety of oclacitinib for the control of pruritus and associated skin
lesions in dogs with canine allergic dermatitis. Vet Dermatol. 2013;24(5):479-e114. Cosgrove SB, Wren JA, Cleaver DM, et al. A blinded,
randomized, placebo-controlled trial of the efficacy and safety of the Janus kinase inhibitor oclacitinib (Apoquel®) in client-owned dogs
with atopic dermatitis. Vet Dermatol. 2013;24(6):587-e142. doi:10.1111/vde.12088.
Apoquel and Adverse Effects
• CBC
• Lymphopenia?
• Rare
• Chemistry
• No effect on liver or
kidneys
• Thyroid
• No effect
• Urinalysis• Common with
glucocorticoids, cyclosporine
• Subclinical UTIs in trials?
• CSU Prospective Study• Dogs with no history or
predisposition to UTIs
• Quantitative urine culture negative at Day 0
• 58 to 280 days Apoquel: no UTIs
Apoquel and Adverse Effects
• CBC
• Lymphopenia?
• Chemistry
• No effect on liver or
kidneys
• Urinalysis
• Subclinical UTIs?
• UTIs?
• Thyroid
• No effect
• Neoplasia??
• No evidence of increased risk
• No difference in type or
prevalence of neoplasia
compared with general
population
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Apoquel and Neoplasia?
• Oclacitinib does not damage DNA, not genotoxic
• Immunosuppression and cancer
Viral infections
• No increase in malignancy in humans treated with
JAK inhibitors
• IL-6 drives tumor development and metastasis
Inhibited by JAK-1 inhibitors
• Clinical trial data
No evidence of increased risk
No difference in type or prevalence of neoplasia
compared with general population
Cytopoint
• Anti-IL-31 monoclonal antibody
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What Are Antibodies and Antigens?Antibody (Immunoglobulin) structure
modeled on structural protein data
Antibody represented schematically
Constant
regions
Variable
regionsHeavy
chains
Light chains
LOCK-AND-KEY(CDR-Complementarity
Determining Region
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How Do Antibodies Work?
The body naturally produces antibodies in response to ‘foreign’
protein (antigen) as part of its normal response to disease.
Plasma cells
Antibodies
Antigen(i.e., rabies virus)
Not shown to scale
Using the same principles, antibodies can now be administered
by injection and used therapeutically.
Therapeutic
medicine
A. Murine antibody
Murine
(green)
B. Canine-murine chimeric antibody
Murine
portion
(green)
Canine
portion
(blue)
C. 90% Caninized antibody
Canine
portion
Murine
portion
Caninization of Monoclonal Antibodies
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Cytokines Involved in Canine Allergic
Skin Disease
Langerhans
cell
T-lymphocyte
IL-2
IL-4
IL-6
IL-13IL-31
IL-5
Activate Other Immune Cells Involved in Allergy
and Inflammation
Induce NeuronalItch Stimulation
McCandless et al. Production of IL-31 by canine Th2 cells and identification of inflammatory and neuronal
target cells. Vet Dermatol 2012; 23(Suppl. 1): FC-64, p52
• Associated with AD
• Th2 lymphocytes and CLA+ skin homing T cells (mice, humans)
• Serum levels correlate with disease severity in atopic humans
• Pathways activated:• JAK-STAT
• MAPK
Interleukin-31
Gonzales, A. J., Humphrey, W. R., Messamore, J. E., Fleck, T. J., Fici, G. J., Shelly, J. A., Teel, J. F., Bammert, G. F., Dunham, S. A., Fuller, T. E. and McCall, R. B. (2013), Interleukin-31: its role in canine pruritus and naturally occurring canine atopic dermatitis. Veterinary Dermatology, 24: 48–e12.
• Keratinocytes
• T lymphocytes
• Macrophages
• Eosinophils
• Dorsal root ganglia
Interleukin-31 Receptors
Gonzales, A. J., Humphrey, W. R., Messamore, J. E., Fleck, T. J., Fici, G. J., Shelly, J. A., Teel, J. F., Bammert, G. F., Dunham, S. A., Fuller, T. E. and McCall, R. B. (2013), Interleukin-31: its role in canine pruritus and naturally occurring canine atopic dermatitis. Veterinary Dermatology, 24: 48–e12.
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Cytopoint
• IL-31• Th2 lymphocytes,
• Keratinocytes
• Pruritus and inflammation
• Anti-IL-31 mAb• Binds to IL-31
• PREVENTS
RECEPTOR
ACTIVATION!!!
1. Gonzales AJ et al., 2013. Interleukin-31: its role in canine pruritus and naturally
occurring canine atopic dermatitis. Vet Dermatol 2013; 24: 48–e12
2. Protocol C863R-US-12-018
Canine Pathophysiology
Cytopoint Results
• Decreases pruritus
• Duration of control 3 to 6 weeks
• Increased benefit after 2 to 3
injections
• To date, no injection site or
other adverse reactions
• Other therapies?
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• Need for complementary treatments varied
• Cytopoint alone
• Cytopoint with Apoquel or Temeril P
Decrease dose of complementary therapy
Improved quality of life vs. either alone
Results
• Block itch
• Decrease inflammation
• Monthly biologic vs. daily pill
• Opportunity to re-evaluate patient
• Not every treatment works for every
patient—we need everything we can get!
Role in Multimodal Therapy
Summary: 21st Century Dermatology
• The more we understand about pathways, the more targets we can identify• Skin barrier
• Pro-inflammatory cytokines
• Microbiologic control/microbiomes
• The more specific the target, the more effective the therapy.• Pro-allergic cytokines
Inhibit
Block
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