Canine allergic dermatitis is a clinical issue, best treated with integrative therapies that address local and systemic factors as well as key body systems.

Allergic dermatitis is a common and challenging problem in dogs. This article briefly describes canine allergic dermatitis and its local and systemic components, including the influential role of the small intestine, liver, adrenal glands, central nervous system, microbiota and anxiety in allergic inflammation. The importance of a complete patient evaluation will be highlighted, and the rationale for a systemic approach to management using nutritional supplements, herbs, probiotics and homeopathic medicines will be outlined.

More than a local skin issue

Allergic dermatitis has long been viewed as a disease that’s localized in the skin. It is now clear, however, that it is a complex clinical issue with local and systemic inflammatory processes influenced by secondary contributing factors.

The local reactions are an intricate and finely orchestrated interaction between the allergen and resident immune cells. These local reactions are also capable of recruiting non-resident immune cells to reinforce local immune reactions.

Unfortunately, from a clinical management perspective, the local reactions are not the complete story. Beyond the local reaction is an incredible interwoven pattern of interaction between the immune system, nervous system, endocrine system, skin and mucosal barriers with associated immune elements, and the microbiota. Each reacts to and is influenced by the other, meaning that effective integrative management must support multiple body systems simultaneously.

Canine allergic dermatitis – environmental allergens and adverse food reactions

Three main allergy categories have been described: insect bite (i.e. flea) hypersensitivities, adverse cutaneous food reactions, and atopic dermatitis from environmental allergens.¹ Classically, canine atopic dermatitis is defined as a pruritic allergic skin disease commonly associated with IgE to environmental allergens in genetically predisposed individuals.² Interestingly, an atopic-like dermatitis has been described with similar clinical signs as canine atopic dermatitis; however, an IgE response to environmental allergens cannot be demonstrated,³ implying that IgE-mediated reactions are not always the central process in allergic inflammation.It is estimated that 10% to 15% of dogs are affected by dermatitis resulting from reactions to environmental allergens.¹ Cutaneous manifestations of adverse food reactions are recognized as indistinguishable from the classic environmental allergic disease.³ The incidence of adverse food reactions in the dog is not completely clear, but an estimated 9% to 40% of pruritic dogs and 8% to 62% of dogs with allergic skin disease are affected.⁴ Approximately 30% of dogs with allergic dermatitis are affected by reactions to both environmental allergens and food.⁵ Since canine atopic dermatitis is a clinical diagnosis that can result from environmental allergens and adverse food reactions, both will be referred to here as canine allergic dermatitis (CAD), and their intertwined features will be outlined. Clinical signs of CAD generally include pruritus and erythema. Self-induced alopecia and excoriation are common. Secondary infections occur with microbes like Malassezia with epidermal hyperplasia, hyperpigmentation and lichenification; and Staphylococcus with crusts, papules and pustules. Affected areas include the ventral abdomen, distal extremities, axillae, and the inner pinnae, perioral, periocular and perianal regions. Otitis externa is reported in half of dogs with canine atopic dermatitis.² The predominant lesions in atopic dermatitis dogs occur in the skin; however, other organs like the digestive and respiratory tracts can be involved.¹ Breed predisposition and breed-associated cutaneous distribution patterns have been reported. Criteria for diagnosing atopic dermatitis have been developed. Accurate diagnosis and evaluation of secondary factors is essential. Ruling out ectoparasites like fleas is critical. Adverse food reactions can have cutaneous signs that mimic atopic dermatitis in addition to gastrointestinal signs.⁶ CAD related to environmental allergens is generally seasonal at onset; however, it can exhibit a non-seasonal pattern. The majority of dogs with a seasonal pattern have clinical signs in the spring or summer, while those with a non-seasonal pattern are often worse during a specific season. The presence of pruritus is considered an essential component of diagnosis. However, otitis externa was the initial clinical presentation in 43% of canine atopic dermatitis patients.⁶ The variability of presentation underscores the need for a systematic approach to patient evaluation, and consideration of the diagnostic criteria for CAD.

Allergic inflammation: the systemic web

The allergic reaction has been considered an overreaction to harmless allergens. This brings to mind images of immune cells aggressively attacking a harmless invader. The alternative image is of an immune response that is dysregulated because the mechanisms that would normally keep allergic inflammation in balance are not functioning appropriately. The coordination and control of allergic inflammation is a process involving a complex web of interactions, systems and body tissues, which means this control is not strictly a local problem at the site of allergic dermatitis (see Figure 1).

Regulation involves a series of interactive adjustments that influence each component of allergic inflammation. Some events are rapid-acting; others are delayed. When IgE with bound allergen contacts the mast cell membrane receptor FcεRI, the mast cell degranulates, releasing substances like histamine followed by synthesis and release of cytokines and chemokines. Histamine’s rapid reactions include vasodilation and increased vascular permeability. Cytokine and chemokine reactions, which occur later, include recruitment and activation of inflammatory cells at the local site as a result of increased local concentrations, and from systemic circulation. In the naïve individual, the process takes longer because the allergen has to be initially processed. Antigen processing cells like the dendritic cell (DC) take up the allergen and transport it to the regional lymph or local tissue site. When the DC presents the processed allergen peptides to naïve T cells, they become T helper 2 cells (TH2). The TH2 influence later allergic reactions by producing interleukin-4 (IL-4) and IL-13 that combine with other co-stimulatory molecules to induce B cells to produce IgE. The IgE diffuses locally and in the lymphatics for eventual systemic distribution in the bloodstream.⁷This simplified presentation of the local allergic inflammatory reaction, and the implication of a modest systemic effect, is inadequate for describing the sophisticated systemic influence. This complex regulation is why allergic inflammation and CAD are so difficult to manage clinically. Stated in another way, allergic dermatitis is a whole body problem (see Figure 1).The skin and mucous membranes form the first barrier against allergens. Allergens enter tissues in multiple ways — for example, through a damaged or altered surface barrier, penetration facilitated by allergen proteolytic properties, and allergen epithelial binding. Mucosal barrier damage in the intestine can result from inflammation, inadequate levels of certain nutritional factors, and dysbiosis of intestinal microbiota. This inflammation provides opportunity for allergen penetration beyond the mucosal surface, which can elicit local and systemic reactions. Note that “intestinal microbiota” refers to the living microorganisms inhabiting the gastrointestinal tract, including bacteria, viruses, fungi and protozoa,⁸ as opposed to the term “microbiome”, which includes microbe genomes.

In addition to local and systemic signaling with cytokines and chemokines, an intimate interaction between the immune and nervous systems plays an important role in regulating the inflammatory response. Communication between these systems involves neurotransmitters, endocrine hormones and cytokines. The autonomic nervous system and hypothalamic-pituitary-adrenal (HPA) axis play central roles.⁹ There is evidence that a hyporeactive HPA axis significantly increases the susceptibility to developing chronic inflammation. The sympathetic adrenomedullary system also has significant effects on immune regulation and stress responses.¹⁰ Lymphoid tissues, including mucosal-associated lymphoid tissue, lymph nodes, spleen, liver and bone marrow are innervated by the parasympathetic nervous system through the neurotransmitter acetylcholine and the sympathetic nervous system (SNS) through norepinephrine. Neurotransmitter receptors for acetylcholine and norepinephrine are present on lymphocytes as well as serotonin, substance P and histamine. Receptors for neuroendocrine mediators like corticotropin-releasing hormone (CRH) and leptin are present in lymphoid tissue.¹¹ Glucocorticoids are the key effector molecules of the HPA axis. Adrenocorticotropic hormone (ACTH) appears to increase pro-inflammatory cytokines that are modulated by the glucocorticoid production they stimulate. Interestingly, chronic allergic disease has been associated with higher levels of TH2 and reduced glucocorticoid levels.¹² A peripheral HPA axis, distinct from the central HPA axis, has been described in the skin.

The peripheral HPA axis has similar components and a regulatory hierarchy that exists for the central HPA axis. Keratinocytes are able to produce CRH, ACTH, cortisol, neurotransmitters, neurotrophins, neuropeptides and their respective receptors. This peripheral HPA axis appears to be an important part of maintaining the epidermal barrier and modulating inflammation.¹²

The liver contains a large population of resident immune cells and is responsible for the production of substances involved in immune reactions, such as cytokines, chemokines and acute phase proteins. This is in addition to its metabolic, nutrient storage and detoxification functions. The hepatic immune system is exposed to a wide range of dietary, microbial and environmental molecules derived from the gut. Resident macrophages (Kupffer cells), which constitute almost a third of the non-parenchymal cells of the liver, and hepatocytes are able to recognize and remove immunogenic substances without producing inflammatory mediators. This is important because it prevents these immunogenic substances from entering the systemic circulation to elicit a wider immune reaction. Other immune cells in the liver include DC, T cells, B cells and natural killer cells. Even though the hepatic immune system has evolved to have some level of immune tolerance, there is some level of ongoing regulated inflammation that is thought to be beneficial for the liver.¹³

The intestinal tract provides a selective barrier for nutrient absorption and the exclusion of harmful substances and microbes. This process requires a properly-functioning mucosa and mucosal immune system. Intestinal microbiota have significant impacts on health based on their composition and interaction with the mucosal immune system. Interaction between intestinal microbes and the mucosal immune system allows for immune tolerance to microbes and harmless substances while allowing the immune system to react to pathogens. Epigenetic modifications of intestinal epithelial cells following exposure to microbial products facilitate tolerance. Intestinal DC sample intestinal microbiota and transport the bacterial-derived antigens to the mesenteric lymph nodes. This allows the immune system to be rapidly responsive if there is damage to the mucosa and leakage of microbes or microbial metabolites that overwhelm the liver immune system.¹⁴ Mucosal barrier health is essential for preventing the absorption of microbes, microbial metabolites and other immunogenic substances. By extension, a healthy mucosal barrier significantly reduces the level of inflammation.

Alterations in the composition of the skin and intestinal microbiota have been linked to allergic dermatitis.¹⁵Interaction between intestinal microbes, dietary nutrients, the gut microenvironment, mucosal immune system and neuroendocrine substances have direct and indirect effects on the composition of the skin and intestinal microbiota. This can significantly influence the quality of the mucosal and dermal barriers, exposure to allergens, relative levels of allergic inflammation, development of allergic dermatitis, and response to therapy. For example, beneficial microbes directly and indirectly impact the growth and colonization of pathogens.⁸ This impacts inflammation, mucosal barrier function, and tolerance.¹⁶

Studies in humans demonstrate that stress is associated with increased allergic inflammation.⁹ Stress activates the HPA axis, SNS and sympathetic adrenomedullary system, which lead to increased CRH, ACTH and glucocorticoids. A chronically-activated HPA axis results in a dysregulatory effect on inflammation that may be due to low glucocorticoid levels from adrenal exhaustion or tissue receptor resistance. In addition, chronic elevations in ACTH may result in increases in pro-inflammatory cytokines.^11,12 Chronic stress and inflammation result in changes to the dermal barrier that predispose the skin to secondary infections and increased response to allergens.

Managment of canine allergic dermatitis

Current conventional therapy for CAD involves managing acute flares and chronic skin lesions, and attempts to prevent relapses.¹⁷ Avoiding trigger allergens, controlling secondary skin infections, and reducing pruritus form the foundation of therapy. This often involves topical and oral therapies, including antimicrobials, antihistamines, shampoos and immune-suppressive drugs. Food elimination trials and hydrolyzed diets are frequently used for adverse food reactions.¹ Each option has variable degrees and quality of research support for efficacy. The selection and implementation of each management component depends on careful patient assessment, severity of clinical signs, and prior history. Clinician experience plays a role in selection of the therapeutic plan.

From an integrative perspective, once a clear diagnosis has been achieved, it is critical to evaluate the patient as a whole so clear therapeutic goals and a management plan can be defined. Particular attention should be paid to historical factors like prior antimicrobial and immune-suppressive therapy, vaccination history, personality and level of anxiety, and gastrointestinal sensitivities. Identify the presence of secondary infections and ectoparasites. Observe the severity of the pruritus and the allergic dermatitis.

Realistic goals for CAD management include reducing pruritus to a tolerable level and decreasing the severity of acute flares and relapses. It is not always possible to completely resolve all pruritus and prevent acute flares. Immune-suppressive therapies and systemic antimicrobials may be necessary to initially control allergic inflammation and address secondary infections, thereby providing patient comfort or preventing self-mutilation.

Based on a broader view of allergic inflammation and the role of systemic factors, as briefly discussed here, key areas of focus for supportive therapy include the adrenal glands, liver, intestine, autonomic nervous system, immune system, intestinal microbiota, skin and mucosa (see Figure 1). All these areas should be supported at the same time instead of sequentially. Focusing on these areas will provide support for reducing the inflammatory process, improving barriers, and decreasing allergen exposure. Additional areas of support should include managing the anxiety that is not addressed through support of the adrenal glands (see Table 1).

Specific Therapies

The systemic approach to managing CAD patients described here relies on published research related to the physiological mechanisms of allergic inflammation and responses to therapy, the author’s decades of clinical experience with allergy patients and whole food nutritional supplements, and his clinical exploration of the organ and gland imbalances that influence allergic inflammation. This perspective led to his development of Canine Dermal Support™ for Standard Process Inc®.

Consistent clinical response was a critical component in product development and patient management. No controlled studies are currently available to validate this approach in its entirety.

The foundational product for this approach is Canine Dermal Support™, which is a whole food concentrate product. A discussion of the use of whole food concentrates as compared to isolated nutrients is beyond the scope of this article; however, whole food concentrates are an essential component of the systemic approach described here.

The systemic approach (see sidebar above) becomes more effective if the adrenal glands, small intestine, liver, nervous system and intestinal microbiota are supported together as the initial step. Canine Dermal Support contains a combination of whole food concentrates and herbs like Silybum marianum, Emblica officinalisand Taraxacum officinale that provide nutrients and bioactive substances for the adrenal glands, liver, small intestine, nervous and immune systems. If support from this product for targeted tissues is inadequate based on patient evaluation and clinical response, Canine Adrenal Support™, Canine Hepatic Support™ or Canine Enteric Support™ can provide additional help. Herbs like Silybum marianum, beneficial for its liver and bile support, as well as Rehmannia glutinosa for its adrenal and immune benefits, can be employed as needed.

Concern has been expressed regarding the use of supplements containing bovine origin ingredients in patients with a known or suspected adverse reaction to beef. In the author’s experience, this has not been a clinical problem when using the supplements discussed here. A number of likely reasons contribute to this observation, including the relatively small quantity of bovine origin ingredients in the recommended supplements; also, these supplements support improvement in the intestinal mucosal barrier while reducing dysregulation of the immune reactions contributing to allergic inflammation. A high quality probiotic containing a prebiotic will complement this regimen. Selecting a probiotic product should be based on clinically-demonstrated effects. Determination of probiotic efficacy can be challenging and may require changing probiotics or initiating therapies that change the microenvironment of the gut. This would include using products or herbs that increase the flow of bile, adding soluble fiber to the diet, or facilitating the reduction of high SNS tone if present.

The role that vaccination plays in promoting allergic inflammation is unclear, but clinical observations and reports of dogs with pre-existing allergies have shown increases in IgE following prophylactic vaccination. This increase was present at one and three weeks, but not eight weeks, post-vaccination.¹⁸ While the implications are not clear, it shows how allergic dogs could worsen following vaccination, and why there has been a casual observation that allergies are exacerbated four to six weeks post-vaccination. In addition, since the IgG was also shown to increase, it is possible to speculate that a low grade chronic inflammatory process could be established in susceptible individuals. The author has found consistent improvements in allergy patients by using the homeopathic rubric related to vaccinations. Commonly-used homeopathic medicines include Silicea and Thuja occidentalis; however, selection should be based on the individual patient. The selected homeopathic medicine, potency and dosing plan can be initiated at the beginning of therapy.

Anxiety and other psychological stresses should be addressed early in the management of allergies since stress can play a significant role in immune dysregulation and the stimulation of pruritus. A variety of approaches is available and should be selected for the individual patient, especially if adrenal support alone does not appreciably change the stress response pattern. These include Bach flower remedies, supplements like Min-Chex®, nutraceutical products such as Composure™, herbs or combinations selected for the individual patient, and/or medications. It is also important to consider working with a behaviorist or qualified trainer to find ways to manage stress or reduce sensitivity to stimuli. Manual therapies can be used to reduce pain and activation of SNS responses.

For patients with otitis externa problems, the approach described above is useful in addition to topical management of the ear canals. It is important to treat the infections and reduce inflammation. Anti-inflammatory ear products and washes can be helpful. Since otitis externa can be a long-term problem with occasional flares, it may require ongoing therapy.

Patients with secondary infections often benefit from antimicrobial shampoos while the systemic management plan is being instituted. Multiple shampoo treatments may be required until control is established and barrier health has improved. Ectoparasites like fleas and lice should be treated and the environment managed as appropriate.

For patients that are excessively pruritic and self-mutilating, a course of diphenhydramine, prednisone or oclacitinib may be indicated. While there is concern that the use of immune-suppressive drugs like prednisone can make later management more difficult, the patient has need for more immediate relief than can be provided with nutritional supplements alone. If immune-suppressive therapy has been ongoing and the liver and adrenal glands have been impacted, consider additional Canine Hepatic Support™ and Canine Adrenal Support™.

Clinical response to Canine Dermal Support™ and probiotics takes four to six weeks depending on the severity of the clinical condition, presence of complicating factors, and history of previous suppressive therapies. Adjustments to the support plan are made at monthly rechecks, unless needed sooner based on patient condition. Keep in mind that regardless of how the patient is managed (conventionally or integratively), pruritus is not always completely controlled and acute flares can occur. It is also interesting to note that in addition to the initial benefits of this approach, patients will continue to improve clinically over the course of a four- to five-year period when this approach is continuously used

Disclosure: The author of this publication formulated and clinically evaluated the original 16 Standard Process Veterinary Formulas™ during product development as a paid consultant for Standard Process Inc.® He is not employed by Standard Process Inc.®, derives no financial benefit and has no equity interest in either Standard Process Inc.® or Standard Process Veterinary Formulas™.

** This article is peer reviewed

References

1 Gedon NKY, Mueller RS. “Atopic dermatitis in cats and dogs: a difficult disease for animals and owners,” Clin Transl Allergy, 2018;8:41.

² Hensel P, Santoro D, Favrot C, et al. “Canine atopic dermatitis: detailed guidelines for diagnosis and allergen identification,” BMC Vet Res, 2015;11:196.

³ Marsell R, Benedetto AD. “Atopic dermatitis in animals and people: an update and comparative review,” Vet Sci, 2017;4:37.

⁴ Olivry T, Mueller RS. “Critically appraised topic on adverse food reactions of companion animals (3): prevalence of cutaneous adverse food reactions in dogs and cats,” BMC Vet Res, 2017;13:51.

⁵ Jackson HA, Murphy KM, Tater, KC et al. “The pattern of allergen hypersensitivity (dietary or environmental) of dogs with non-seasonal atopic dermatitis cannot be differentiated on the basis of historical or clinical information: a prospective evaluation 2003-2004,” 1Vet Dermatol, 2005;16:200.

⁶ Favrot C. “Clinical signs and diagnosis of canine atopic dermatitis,” EJCAP, 2009;19(3):219-222.

⁷ Galli SJ, Tsai M, Piliponsky AM . “The development of allergic inflammation,” Nature, 2008;454(7203):445-54.

⁸ Kim D, Zeng MY, Nunez G. “The interplay between host immune cells and gut microbiota in chronic inflammatory diseases,” Exp Mol Med, 2017;49:e339.

⁹ Dave ND, Xiang L, Rehm KE, et al. “Stress and allergic diseases,” Immunol Allergy Clin North Am, 2011;31(1):55-68.

¹⁰ Buske-Kirschbaum A, Geiben A, Hollig H, et al. “Altered responsiveness of the hypothalamic-pituitary-adrenal axis and the sympathetic adrenomedullary system to stress in patients with atopic dermatitis,” J Clin Endocr Metab, 2002; 87(9):4245-51.

¹¹ Steinman L. “Elaborate interactions between the immune and nervous systems,” Nature Immunology, 2004;5(6):575-81.

¹² Lin T-K, Zhong L, Santiago JL. “Association between stress and the HPA axis in the atopic dermatitis,” Int J Mol Sci, 2017;18:2131.

¹³ Robinson MW, Harmon C, O’Farrelly C. “Liver immunology and its role in inflammation and homeostasis,” Cell Mol Immunol, 2016;13:267-76.

¹⁴ Steiner A, Radulovic K, Niess JH. “Gastrointestinal tract: the leading role of mucosal immunity,” Swiss Med Wkly, 2016;146:w14293.

¹⁵ Lee S-Y, Lee E, Park MY, et al. “Microbiome in the gut-skin axis in atopic dermatitis,” Allergy Asthma Immunol Res, 2018;10(4):354-62.

¹⁶ Pickard JM, Zeng MY, Caruso R, et al. “Gut microbiota: role in pathogen colonization, immune responses, and inflammatory disease,” Immunol Rev, 2017;279:70-89.

¹⁷ Olivry T, DeBoer DJ, Favrot C, et al. “Treatment of canine atopic dermatitis: 2015 updated guidelines from the International Committee on Allergic Diseases of Animals (ICADA),”BMC Vet Res, 2015;11:210.

¹⁸ Tater KC, Jackson HA, Paps J, et al. “Effects of routine prophylactic vaccination or administration of aluminum adjuvants alone on allergen-specific serum IgE and IgG responses in allergic dogs,” Am J Vet Res, 2005; 66 (9):1572-7. (abstract)

AUTHOR PROFILE

Ron Carsten, DVM, PhD, CVA, CCRT

Dr. Ron Carsten was one of the first practicing veterinarians in Colorado to advocate an integrative approach to patient management. He has lectured on the integrative approach and use of nutritional supplements, published on a range of topics in peer-reviewed journals, taught in a number of college and university programs, was faculty for the NIH National Cancer Institute Molecular Prevention Course, has been involved in research, and is a past NIH National Research Service Award Fellow. As a consultant, he developed the original Standard Process Veterinary Formulas™. Dr. Carsten has an AAS in animal health technology, BS in microbiology, MS in anatomy and neurobiology, and PhD in cell and molecular biology. He is a certified veterinary acupuncturist and canine rehabilitation therapist, and practices integrative veterinary medicine in Glenwood Springs, Colorado.