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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