5/9/2017. Another Itchy Dog. Skin Diseases are Common. Rule Out Infectious Causes of Itching Prior to Diagnosing Allergy. 2011: VPI Pet Insurance 1

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1 Another Itchy Dog New Understanding of the Pathophysiology of Canine Allergic Disease Dr. Kimberly Greene- DVM, PSV Midwest Skin Diseases are Common 2011: VPI Pet Insurance Ear Infections Skin Allergies Skin Infections 8.2 million dogs with allergic disease Pfizer Animal Health data on file 2 Rule Out Infectious Causes of Itching Prior to Diagnosing Allergy Infectious Diseases Ectoparasites Fleas Sarcoptes Demodex Bacterial Staphylococcal pyoderma Fungal Malassezia Dermatitis Dermatophytosis Allergic Diseases Flea Allergy Dermatitis Food Allergy Dermatitis Atopic Dermatitis 3 3 1

2 Homer: 9 yo MN Mixed Breed Severe itching for 3 months, lives in rural wooded area, no prior Scabies history of skin disease, owner found dead fox on property 4 4 Gertrude: 2 yo FS English Bulldog Moderate pruritus, hair loss, rash over face, neck, chest, paws x 6 Generalized Demodicosis w/ Secondary Pyoderma months. No response to prednisolone, flea control. 5 5 Louise: 5 yo FS Pit Bull 4 month history of moderate Superficial pruritus, pyoderma skin rash and hair loss 6 6 2

3 Corky: 3 yo MN W Highland White Terrier 2 year history of increasingly severe non-seasonal itching non-responsive to Malassezia prednisolone, dermatitis antibiotics, or ivermectin, no other dogs or people affected 7 7 We are Focusing on Allergic Disease Infectious Diseases Ectoparasites Fleas Sarcoptes Demodex Bacterial Staphylococcal pyoderma Fungal Malassezia Dermatitis Dermatophytosis Allergic Diseases Flea Allergy Dermatitis Food Allergy Dermatitis Atopic Dermatitis 8 8 Buttons: 8 yo FS Poodle Mix Severe itching over Flea back Allergy end since Dermatitis camping trip in late fall, stopped (with flea secondary preventative pyoderma) 2 months ago 9 9 3

4 Misty: 6 yo FS Cocker Spaniel mix 2 year history of non-seasonal Food itching Allergyof ears and rear end area, no (with improvement secondary with Malassezia prednisolone, dermatitis, antibiotics otitis) Reuben: 2 yo MN Shepherd-Collie mix 1 year history of rubbing face, chewing/licking paws, scratching axilla, groin; Atopic worse Dermatitis in summer/fall but all year long, good (with response secondary to prednisolone Malassezia but pododermatitis) still chews paws Chronic Itch Takes a Toll On: Pet s quality of life Human-animal bond Pet owner s trust of veterinarian 8.2 million dogs with allergic disease

5 The Emotional Rollercoaster of Atopic Dermatitis is as Big a Problem as the Dermatitis Itself Owner Notices Itching Initial Concern & Sympathy Frustration Guilt Optimism and Frustration with Info Search If Find Effective Solution No Effective Solution Alternating Hope and Disappointment While Trying Solutions 13 Why should we care about the new pathophysiology of allergic disease? Understanding how disease works provides basis for optimal therapy Hope for a targeted therapy: more effective, less side-effects What We Were Taught: Allergic Inhalant Dermatitis Marsella R, et al. Current understanding of the pathophysiologic mechanisms of canine atopic dermatitis. JAVMA 241: , 2012 Inhaled Route of Allergen Exposure 15 5

6 And that Itch came from Mast cells, IgE and Histamine Cross linking of Allergen- specific IgE bound to the surface of Mast cell: degranulates, releases inflammatory mediators Marsella R, et al. Current understanding of the pathophysiologic mechanisms of canine atopic dermatitis. JAVMA 241: , Recent Research: Atopic Dermatitis Allergen exposure through skin, may be epidermal barrier defect Dust mite releasing allergens Marsella R, et al. Current understanding of the pathophysiologic mechanisms of canine atopic dermatitis. JAVMA 241: , 2012 Allergen is absorbed through epidermis with decreased barrier function Inhaled Route of allergen exposure 17 Langerhans Cell Marsella R, et al. Current understanding of the pathophysiologic mechanisms of canine atopic dermatitis. JAVMA 241: , 2012 Allergen Is Engulfed By Langerhans Cell 18 6

7 Langerhans cell enters into the lymph node Marsella R, et al. Current understanding of the pathophysiologic mechanisms of canine atopic dermatitis. JAVMA 241: , 2012 Lymph node 19 Langerhans cell within the lymph node makes contact with the naïve T-cell Naïve T-cell Marsella R, et al. Current understanding of the pathophysiologic mechanisms of canine atopic dermatitis. JAVMA 241: , Naïve T-cell changes to T helper 2 cell Marsella R, et al. Current understanding of the pathophysiologic mechanisms of canine atopic dermatitis. JAVMA 241: , 2012 T helper 2 cell 21 7

8 T helper 2 cell releases cytokines IL-4 and IL-13 Marsella R, et al. Current understanding of the pathophysiologic mechanisms of canine atopic dermatitis. JAVMA 241: , Cytokines are key to allergic itch cycle JAVMA, Vol 241, No.2, July 15, 2012 T helper 2 cell releases allergic cytokines 23 What are Cytokines? Protein messages sent from one cell to another, stimulating receiving cell to action Think of them like text messages between neighbors Many types of cytokines million Interleukins dogs (IL) with are allergic important disease type of cytokine in allergic disease 2 Commins SP, Borish L, Steinke JW. Immunologic messenger molecules: Cytokines, interferons, and chemokines. J Allergy Clin Immunol 125:S53-72,

9 Janus Kinase Enzymes (JAKs) Family of intracellular cell signaling enzymes Named after Janus, two-faced Roman god of doorways, due to enzyme containing 2 nearly identical binding sites 3. Important for cell communication, regulation of activity 8.2 million JAK enzyme dogs signaling with allergic pathway disease used by 2 4. many allergic cytokines to trigger itch, inflammation in skin 25 Sigal LH. Basic Science for the Clinician 41: Tails of Cytokine Receptor Activation and Control: JAKs, STATs, PIASs, and SOCSs J Clin Rheumatol 12: , Allergic cytokines use JAK enzyme signaling pathway to initiate itch cycle, regardless of cause of itch Cytokine Receptor JAK Gonzales AJ, et al Interleukin-31: its role in canine pruritus and naturally occurring canine atopic dermatitis. Vet Dermatol. 24:48-e12, IL-2 IL-4 IL-5 IL-9 IL-13 IL-31 TSLP 26 How Do Cytokines and JAKs Signal the Cell to Respond? Th2 cell releases allergic cytokines Cytokines bind to receptors on cell membrane Activation of JAK enzyme on intracellular portion of cytokine receptor Proteins (STATs) sent to cell nucleus to convey signal, cause the cell to respond Triggers itch, inflammation in skin Receptor Cytokine JAK Sigal LH. Basic Science for the Clinician 41 Tails of Cytokine Receptor Activation and Control: JAKs, STATs, PIASs, and SOCSs J Clin Rheumatol 12: , 2006 Cell membrane 27 9

10 JAK Signaling in Action Cytokine Cell membrane Cytokine Receptor JAK (Janus kinase STAT STAT phosphorylation Phosphate Dimerized STAT Cytoplasm 28 DNA Gene transcription Nucleus Target gene transcription Itch 28 Neuronal stimulation through JAK: Key component in itch cycle in allergic dogs IL-31 binds to cutaneous neurons Activating JAK Sends neuronal signal to brain IL-31 Receptor JAK JAK Gonzales AJ, et al Interleukin-31: its role in canine pruritus and naturally occurring canine atopic dermatitis. Vet Dermatol. 24:48- e12, Itch Cycle Video

11 Itch Cycle Video (Part 1) Itch Cycle Video (Part 2) Itch Cycle Video (Part 3)

12 Itch Cycle Video (Part 4) Itch Cycle Video (Part 5) Current Therapies Have Limitations Efficacy Efficacy, speed Side-effects Efficacy, speed Speed, side-effects Olivry T et al. Treatment of canine atopic dermatitis: clinical practice guidelines from the International Task Force on canine atopic dermatitis. Vet Dermatology 21: ,

13 Could a More Targeted Approach For Treatment of Atopic Dermatitis Work? Corticosteroids bind corticosteroid receptors present in all cells Effects on: immune system, CNS, metabolism, homeostasis Atopica binds cyclophilin and inhibits calcineurin function Effects on: NFAT signaling and antigen presentation APOQUEL inhibits JAK1 and JAK3 enzyme function Effects on: JAK1 and JAK3 dependent cytokines driving clinical signs Anti-IL-31 monoclonal antibody Effects on: IL-31, a key JAK1-dependent cytokine driving clinical signs Atopica is registered trademark of Eli Lilly and Company, its subsidiaries and affiliates. 37 Management of Atopic Dermatitis Acute Flares Mild shampoos Topical/oral GCs Oclacitinib Chronic Atopic Dermatitis Improve skin and coat hygiene Topical/oral GCs Oclacitinib Cyclosporine Allergen-specific immunotherapy (prevent flares/recurrence) Olivry et al. BMC Vet Res 2015: 11; Summary 1. Cytokines orchestrate the cycle of itch and inflammation in allergic skin disease 2. Allergic cytokine signaling requires Janus Kinase (JAK) enzyme system 3. The JAK system could be targeted for itch control

14 ExcellenceinDermatology.com Questions? 41 References Commins SP, Borish L, Steinke JW. Immunologic messenger molecules: cytokines, interferons, and chemokines. J Allergy Clin Immunol Feb;125(2 Suppl 2):S Gonzales AJ, Humphrey WR, Messamore JE, Fleck TJ, Fici GJ, Shelly JA, Teel JF, Bammert GF, Dunham SA, Fuller TE, McCall RB. Interleukin-31: its role in canine pruritus and naturally occurring canine atopic dermatitis. Vet Dermatol Feb;24(1):48-e12. Marsella R, Sousa CA, Gonzales AJ, Fadok VA. Current understanding of the pathophysiologic mechanisms of canine atopic dermatitis. J Am Vet Med Assoc Jul 15;241(2): Olivry T, Foster AP, Mueller RS, McEwan NA, Chesney C, Williams HC. Interventions for atopic dermatitis in dogs: a systematic review of randomized controlled trials. Vet Dermatol Feb;21(1) Sigal LH. Basic Science for the clinician 41: tales of cytokine receptor activation and control: JAKs, STATs, PIASs, and SOCSs. J Clin Rheumatol Dec;12(6):

15 All trademarks are the property of Zoetis Inc., its affiliates and/or its licensors. All other trademarks are the property of their respective owners. APQ (c) 2013 Zoetis Inc. All rights reserved. March Supporting Slides 44 Antihistamines

16 Fatty Acids Glucocorticoids Cyclosporine

17 Allergenspecific Immunotherapy