Valerie A. Fadok, DVM, PhD, DACVD
We have learned quite a bit about allergic skin disease in dogs in the last decade. Understanding the pathogenesis of allergic disease, particularly atopic dermatitis, has allowed us to develop more effective treatments. We see a number of allergic diseases in mammals, but here we will focus on atopic dermatitis in dogs. Atopy is a condition in which mammals develop hypersensitivity reactions to benign environmental stimuli, which include pollens, molds, dusts, danders, mites, and foods. Diseases include those of the upper respiratory tract and ocular mucous membranes, the lower respiratory tract, the gastrointestinal tract, and the skin. We have learned that atopic dermatitis occurs because there is a skin barrier defect, which contributes to disease by permitting absorption of allergens more deeply into the epidermis, where the immune system can access them.
In addition to the skin barrier defects, there is a skewed immune response, promoting the development of IgE and the types of inflammation we see with allergic disease. The immune response is dominated by Type 2 T helper lymphocytes. Every acquired immune response we have is coordinated by T helper cells. T helper 1 cells help mediate the response to intracellular pathogens like viruses. T helper 17 cells fight extracellular pathogens including bacteria and fungi. The T helper 2 cell response was believed to develop in response to large multicellular parasites such as nematodes. By supporting the production of IgE that binds to the parasites, cells such as eosinophils bind the IgE and spew their toxic contents onto the worm to kill it. It is thought that this pathway, in genetically susceptible mammals, has been co-opted for allergies.
Severity of atopic dermatitis is likely dictated by the number of allergic genes a dog inherits, the severity of the skin barrier defect, and the environment in which the dog lives. We now know that dogs absorb most of their allergens through the skin, and this absorption explains why we see the lesions where we do: in sparsely haired areas such as the feet, the periocular and perioral areas, and the ventrum.
In the past, we believed that dogs absorbed their allergens through their oronasal mucosa, and that somehow these were transported in the blood to the skin, where they bound to IgE. This allergen specific IgE was displayed on the surface of mast cells, and the cross-linking of IgE by allergen triggered release of antihistamines and other proinflammatory mediators. This belief has led to treatment attempts with multiple antihistamines, most of which work poorly for the moderate to severely atopic dog. Lack of response could be mediated by improper dosing, but most likely therapeutic failure relates to what we now know is a disease that is much more complex that we previously thought. We now know that most of the clinical signs we see with atopic dermatitis are related to cytokines produced during the Type 2 response. These allergic cytokines result in IgE production, but also the recruitment of eosinophils and other inflammatory cells into the skin. Some of the cytokines involved in the allergic response come directly from the skin cells themselves. And some of these cytokines bind directly to nerves to stimulate itch.
We have learned in the last decade that the itch associated with atopic dermatitis in mammals is due in large part to a Type 2 cytokine called interleukin 31. This cytokine is released during the allergic immune response and it binds directly to nerves to stimulate itch. A second cytokine that can bind to nerves is TSLP which is produced by the keratinocytes themselves during the allergic reaction.
Here is a sequence of events associated with the response to allergens in atopic dogs:
1. The allergenic proteins are absorbed deeply into the epidermis where antigen-presenting cells can capture them.
2. These antigen-presenting cells (dendritic cells/Langerhans cells) process this allergen and carry it to the lymph nodes where they present it to naïve T lymphocytes.
3. Naïve T lymphocytes get activated and develop into mature T helper 2 lymphocytes. They produce a series of cytokines (IL-4, IL-5, IL-6, IL-13, IL-31) which instruct B lymphocytes to make IgE and which provoke the allergic response.
4. The T helper 2 lymphocytes and IgE make their way back to the skin. The IgE binds to mast cells as well as the dendritic cells/Langerhans cells and lie in wait for the allergens to come along again.
5. When allergens come along, the IgE on the LC and the mast cells captures them. These cells can then present the allergen to the T helper 2 cells right in the skin and activate the allergic process quickly.
6. Interleukin-31 is released to bind directly to nerves to stimulate itch rapidly. Many of the Type 2 cytokines also stimulate keratinocytes to produce TSLP which also binds to nerves to stimulate itch.
7. Scratching and continued inflammation causes the epidermis to thicken, the number of nerve fibers to increase, and the development of secondary infections. Even more TSLP is produced, and we have a continued amplification cycle of itch and inflammation.
8. Secondary infections promote this abnormal immune response and make the allergic lymphocytes less sensitive to glucocorticoids and normal immune regulatory mechanisms. Ultimately dogs can become allergic to their staphylococci and their Malassezia. Staphylococcal proteins can drive the Th2 response, making allergies worse.
9. Chronic atopic dermatitis appears to be less T helper 2 focused and T helper 1/T helper 17 cytokines also participate in the inflammatory response.
Without intervention, these dogs develop worsening disease and perhaps, like people, they develop autoallergic dermatitis, in which IgE is produced against self-antigens released from cells following the trauma of scratching. IgE against keratinocyte-derived self-antigens have been described in human atopics, and their presence is associated with a more severe disease manifestation. That this might occur in dogs and cats is suggested by the anecdotal reports of dogs and cats showing skin test reactivity to dog and cat dander respectively. Interestingly the auto-reactivity to self-antigens is associated with production of IFN gamma and other Th1 cytokines, explaining the presence of these cytokines in chronic atopic dermatitis. Exposure to self-antigens can drive the dermatologic signs even in the absence of exposure to exogenous allergens.
One of the most fascinating findings in atopic dermatitis is the close interplay between the immune system and the nervous system. The skin is considered a neuroimmunoendocrine organ. Skin immune cells and nerves produce neuromediators that function bidirectionally. Immune cells secrete neuromediators that can stimulate nerves to induce vasodilation and plasma exudation. Nerves produce mediators such as substance P, vasoactive intestinal peptide (VIP), and calcitonin gene related peptide (CGRP) affect the function of macrophages, mast cells, and T lymphocytes. Some of the observations in atopic dermatitis include increased density of cutaneous nerve fibers, increased numbers of nerve/mast cell interaction, and a reduced threshold to initiate itch. Furthermore, once stimulated the itch lasts longer than it would in a nonatopic dog!
Understanding the pathogenesis of atopic dermatitis in dogs, particularly its great similarity to human disease, has resulted in a change in our approach, and the development of new innovative treatments.
Veterinary dermatologists advocate for a multimodal approach based on each dog's individual presentation.
1. Avoidance. Practically speaking, the allergens most easily avoided are foods and ectoparasites (fleas, other insects). Additional approaches can be taken to minimize allergen exposure to pollens or dust mites. For dogs with pollen allergies, reducing their time outside when pollen counts are high is helpful, as is wiping face, feet, and belly when dogs come back inside. Measures to control house dust mites, for dogs with mite allergies, can reduce itch as well.
2. Immunotherapy. Allergen-specific immunotherapy is the only treatment that actually changes the abnormal immune response. We recommend allergy testing and immunotherapy early in life to help induce tolerance and prevent progression of the disease. In my opinion, immunotherapy works for most dogs, as defined by reduction of itch and inflammation, and reduced need for anti- itch medications. Reduction in staphylococcal and yeast infections also occur. Sublingual immunotherapy has provided us with an alternative to injection therapy, and allergy drops are embraced by many clients. Daily exposure of the immune system to the allergens, as well as improved compliance, may lead to a more rapid and improved response (observed in my practice).
3. Infection control. Many dogs with atopic dermatitis have recurrent staphylococcal and yeast infections, and they can develop allergic reactions to these organisms, which we can determine by intradermal testing and/or serum testing. It can be helpful to include staphylococcal antigen and Malassezia allergen in the immunotherapy (subcutaneous or sublingual) when microbial allergy is found. Bathing is a critical part of infection control and has the added benefit of removing allergens from the surface of the skin. When indicated, systemic antibiotics and antifungal drugs should be used.
4. Skin barrier repair. Optimal nutrition, oral fatty acids, and topical lipid therapy are used to improve the skin barrier. We don't have hard clinical evidence for any specific products, but preliminary evidence is promising. Reduction in the rate of pyoderma as a result of skin barrier repair is what I have valued, but owners appreciate the improved coat quality and reduction in dry skin and scaling.
5. Itch control. It is critical to control itch in atopic patients, so that owners can tolerate the time it takes for immunotherapy to work well. The most effective agents include glucocorticoids, cyclosporine, and oclacitinib.
The newest innovation in the treatment of atopic dermatitis is the JAK1 inhibitor oclacitinib (APOQUEL, Zoetis). Ten years of development and testing has led to a novel targeted treatment for allergic itch control, which many clients call amazing. For most dogs, dramatic reduction in itch is seen within a matter of hours, with few side effects. When used according to directions, this drug has provided substantial itch control for chronic atopic dogs for over 2–4 years. JAK1/3 pathways are utilized by the cytokines in the allergic pathways, so the treatment is quite targeted, and spares the cytokines that mediate innate immunity and bone marrow function (JAK2). This is the first JAK inhibitor in veterinary medicine and is the most targeted JAK1/3 inhibitor, as the JAK inhibitors for humans are considered pan-JAK inhibitors. Oclacitinib can be used for acute allergic eruptions as well, and is very well tolerated. Its discovery and development is a direct result of our new understanding about the pathogenesis of atopic dermatitis.
1. Altrichter S, Kriehuber E, Moser J, Valenta R, Kopp T, Stingl G. Serum IgE autoantibodies target keratinocytes in patients with atopic dermatitis. J Invest Dermatol. 2008;128(9):2232–2239.
2. Bexley J, Nuttall TJ, Hammerberg B, Fitzgerald JR, Halliwell RE. Serum anti-Staphylococcus pseudintermedius IgE and IgG antibodies in dogs with atopic dermatitis and nonatopic dogs. Vet Dermatol. 2013;24(1):19–24, e5–e6.
3. Bieber T, Novak N. Pathogenesis of atopic dermatitis: New developments. Curr Allergy Asthma Rep. 2009;9(4):291–294.
4. Bieber T. Atopic dermatitis 2.0: from the clinical phenotype to the molecular taxonomy and stratified medicine. Allergy. 2012;67(12):1475–1482.
5. Cosgrove SB, Wren JA, Cleaver DM, Walsh KF, Follis SI, King VI, 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):587–597, e141–e142.
6. Eyerich K, Novak N. Immunology of atopic eczema: overcoming the th1/th2 paradigm. Allergy. 2013;68(8):974–982.
7. Farver K, Morris DO, Shofer F, Esch B. Humoral measurement of type-1 hypersensitivity reactions to a commercial Malassezia allergen. Vet Dermatol. 2005;16(4):261–268.
8. Forsythe P, Paterson S. Ciclosporin 10 years on: indications and efficacy. Vet Rec. 2014;174(Suppl 2):13–21.
9. Gonzales AJ, Humphrey WR, Messamore JE, Fleck TJ, Fici GJ, Shelly JA, et al. Interleukin-31: its role in canine pruritus and naturally occurring canine atopic dermatitis. Vet Dermatol. 2013;24(1):48–53, e11–e12.
10. Hau CS, Kanda N, Watanabe S. Suppressive effects of antimycotics on thymic stromal lymphopoietin production in human keratinocytes. J Dermatol Sci. 2013;71(3):174–183.
11. Jung JY, Nam EH, Park SH, Han SH, Hwang CY. Clinical use of a ceramide-based moisturizer for treating dogs with atopic dermatitis. J Vet Sci. 2013;14(2):199–205.
12. Klukowska-Rötzler J, Chervet L, Müller EJ, Roosje P, Marti E, Janda J. Expression of thymic stromal lymphopoietin in canine atopic dermatitis. Vet Dermatol. 2013;24(1):54–59, e13–e14.
13. Leung DY. New insights into atopic dermatitis: role of skin barrier and immune dysregulation. Allergol Int. 2013;62(2):151–161.
14. Marsella R, Olivry T, Carlotti DN. International Task Force on Canine Atopic Dermatitis. Current evidence of skin barrier dysfunction in human and canine atopic dermatitis. Vet Dermatol. 2011;22(3):239–248.
15. Marsella R, Sousa CA, Gonzales AJ, Fadok VA. Current understanding of the pathophysiologic mechanisms of canine atopic dermatitis. J Am Vet Med Assoc. 2012;241(2):194–207.
16. Marsella R. Fixing the skin barrier: past, present and future - man and dog compared. Vet Dermatol. 2013;24(1):73–76, e17–e18.
17. McCandless EE, Rugg CA, Fici GJ, Messamore JE, Aleo MM, Gonzales AJ. Allergen-induced production of IL-31 by canine th2 cells and identification of immune, skin, and neuronal target cells. Vet Immunol Immunopathol. 2014;157(1–2):42–48.
18. Mittermann I, Aichberger KJ, Bünder R, Mothes N, Renz H, Valenta R. Autoimmunity and atopic dermatitis. Curr Opin Allergy Clin Immunol. 2004;4(5):367–371.
19. Novak N, Bieber T, Allam JP. Immunological mechanisms of sublingual allergen-specific immunotherapy. Allergy. 2011;66(6):733–739.
20. Novak N, Leung DY. Advances in atopic dermatitis. Curr Opin Immunol. 2011;23(6):778–783.
21. Nuttall TJ, Halliwell RE. Serum antibodies to Malassezia yeasts in canine atopic dermatitis. Vet Dermatol. 2001;12(6):327–332.
22. Nuttall T, Uri M, Halliwell R. Canine atopic dermatitis - what have we learned? Vet Rec. 2013;172(8):201–207.
23. Nuttall T, Reece D, Roberts E. Life-long diseases need life-long treatment: long-term safety of ciclosporin in canine atopic dermatitis. Vet Rec. 2014;174(Suppl 2):3–12.
24. Olivry T, Mueller RS. International Task Force on Canine Atopic Dermatitis. Evidence-based veterinary dermatology: a systematic review of the pharmacotherapy of canine atopic dermatitis. Vet Dermatol. 2003;14(3):121–146.
25. 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. 2010;21(1):4–22.
26. Olivry T, DeBoer DJ, Favrot C, Jackson HA, Mueller RS, Nuttall T, et al. Treatment of canine atopic dermatitis: 2010 clinical practice guidelines from the international task force on canine atopic dermatitis. Vet Dermatol. 2010;21(3):233–248.
27. Olivry T. What can dogs bring to atopic dermatitis research? Chem Immunol Allergy. 2012;96:61–72.
28. Olivry T, Bizikova P. A systematic review of randomized controlled trials for prevention or treatment of atopic dermatitis in dogs: 2008–2011 update. Vet Dermatol. 2013;24(1):97–117, e25–26.
29. Raap U, Ständer S, Metz M. Pathophysiology of itch and new treatments. Curr Opin Allergy Clin Immunol. 2011;11(5):420–427.
30. Roosterman D, Goerge T, Schneider SW, Bunnett NW, Steinhoff M. Neuronal control of skin function: the skin as a neuroimmunoendocrine organ. Physiol Rev. 2006;86(4):1309–1379.
31. Schlotter YM, Rutten VP, Riemers FM, Knol EF, Willemse T. Lesional skin in atopic dogs shows a mixed type-1 and type-2 immune responsiveness. Vet Immunol Immunopathol. 2011;143(1–2):20–26.
32. Turner MJ, Zhou B. A new itch to scratch for TSLP. Trends Immunol. 2014;35(2):49–50.
33. Valenta R, Mittermann I, Werfel T, Garn H, Renz H. Linking allergy to autoimmune disease. Trends Immunol. 2009;30(3):109–116.
34. Wilson SR, Thé L, Batia LM, Beattie K, Katibah GE, McClain SP, et al. The epithelial cell-derived atopic dermatitis cytokine TSLP activates neurons to induce itch. Cell. 2013;155(2):285–295.