Autoimmune diseases (Proceedings)

The immune system is responsible for protection against invasion and is a beneficial (and necessary) part of animals' existence. Regulation of immunity is finely tuned, so that in most cases when the immune system is activated there is an adequate but controlled response. If the immune system overreacts or responds inappropriately, harmful effects may occur. Allergies (also called Type I hypersensitivities) are relatively common in humans and dogs, and less so in cats. Manifestations usually involve skin disease, but other systems may be involved (e.g. respiratory, gastrointestinal). The following discussion is an overview of the basis for allergies, common diseases, and current treatments.

Pathophysiology

Allergic responses are due to acute inflammation of tissues, either local or systemic. The inciting cause is called an allergen, which is usually defined as a normally harmless antigen that provokes an IgE-mediated hypersensitivity. Allergens are often (but not exclusively) proteins found in the environment or in food. Non-allergic animals respond normally to these innocuous molecules by mounting a mild IgG response that does not cause inflammation or other problems. Allergic animals on the other hand have excessive IgE production which may lead to an overreaction to the antigen.

At the cellular level, animals have mast cells throughout the body that serve a major role in the innate (nonspecific) immune system. They originate from bone marrow stem cells and travel to tissues where they live for several weeks to months. Mast cells act as sentinels, ready to respond to invasion by a microbe or foreign substance. Their main defense is to release contents of granules contained in cytoplasm, which include enzymes, cytokines, and vasoactive or chemotactic molecules. These products may be released preformed from the granules or synthesized in a few hours and then released. The various molecules then lead to local tissue inflammation and can act both as lethal weapons against the invaders and as recruiters for other parts of the immune response. Mast cells, unlike neutrophils, do not die when stimulated to release contents – instead, they can continue to synthesize more granules for an ongoing or future response.

The stimulus that makes mast cells release their contents is an antigen (allergen) that becomes bound to IgE molecules which are in turn bound to the mast cell surface. IgE is unique among immunoglobulins in that it is mostly found already attached to mast cells instead of freely circulating in the bloodstream. In nonallergic animals, there is less IgE produced and therefore less binding occurs on mast cells. The reason why some animals overproduce IgE is not well understood, but genetics play a role (allergic parents often produce allergic offspring and certain breeds are predisposed to allergic diseases) as well as early environmental influences such as the presence of parasites, infections, and exposure to various antigens.

Multiple effects are seen whenever mast cells degranulate. The most important molecule released is histamine, which causes vasodilation, increased vascular permeability, pruritus, and pain. Tumor necrosis factor- combined with interleukin-1 causes the cardinal signs of inflammation (heat, swelling, pain, and redness) locally and systemically causes decreased cardiac output, microvascular thrombosis, and capillary leakage. Interleukin-6 mediates the acute-phase reaction and septic shock. Vasoactive and chemotactic products from mast cells are useful for enhancing and prolonging the immune response but in large quantities can be harmful.

Individuals who are prone to allergies are also called "atopic", or said to have "atopy" (from Greek "apotos" meaning out of place). Atopy itself is not an illness, but it means that the animal is predisposed to allergic responses to normally harmless substances. Clinicians commonly say that itchy dogs have atopy, but the more accurate term is "atopic dermatitis". Discussing the genetic basis for allergies with concerned owners sometimes helps with the frustration of dealing with allergic pets. There are no cures for allergy in humans or animals, and the problem is more widespread in people, as a recent survey found that 54.6% of US citizens test positive to one or more allergens. The healthcare cost is estimated at $18 billion, not including days lost from school or work. The common allergic diseases in people include atopic dermatitis (eczema), allergic rhinitis (hay fever), asthma, latex allergy, contact dermatitis, sinusitis, food allergy, allergic drug reactions, acute urticaria, and allergy to insect stings. Most of these conditions also occur in companion animals, and several are discussed below.

Anaphylaxis

Exposure to certain allergens in predisposed individuals may lead to the most severe allergic reaction possible, anaphylaxis. In dogs the main "shock organ" is the liver, or more specifically the hepatic veins. A sudden degranulation of many mast cells, with the release of large quantities of vasoactive molecules, causes hepatic vein occlusion due to smooth muscle contraction and hepatic swelling. This leads to portal hypertension, visceral pooling, and decreased venous return which in turns causes decreased cardiac output and arterial blood pressure. Signs of shock are evident, and death may occur within an hour if not treated with epinephrine and supportive care such as IV fluids. In cats the shock organ is the lungs, where anaphylaxis leads to bronchoconstriction, emphysema, pulmonary hemorrhage, and edema of the glottis. Treatment is also epinephrine along with support such as oxygen and fluid therapy.

Atopic dermatitis

This condition is more common in dogs than cats but should be on the ruleout list of any animal presented for pruritus (itching, scratching, rubbing), diffuse erythema (reddened skin or ears), otitis externa, recurrent skin infections, or rarely rhinitis or bronchitis. Atopic dermatitis is not a simple allergy or Type I hypersensitivity, as other immune system reactions and changes in the skin occur after a period of time. Newly recognized Th17 cells produce IL-17, a mediator of tissue inflammation, and human patients with atopy have higher concentrations. Environmental allergen exposure in predisposed individuals is the cause, but other concepts such as "pruritus threshold" and interaction with other conditions play a role. In the past, animals were thought to inhale allergens and be exposed via the respiratory tract. Now, the percutaneous route appears to be the most significant. IgE blood levels are not always elevated in atopic dermatitis, as mast-cell bound IgE predominates.

Diagnosis is based on history, clinical findings, and ruling out other disorders. There is no test specifically for atopic dermatitis, and even dermatohistopathology is nonspecific. The age of onset is usually 1-3 years (range 6 months to 6 years). Clinical signs include skin erythema and pruritus involving the feet, flanks, groin, axillae, face, and ears. Secondary skin infections and lesions are common. Allergy testing (intradermal and serologic) is available to identify specific allergens but should not be used to rule in or rule out atopy. There is little correlation between serology (blood testing for allergens) and skin testing (IDST), and most dermatologists report greater success with immunotherapy based on IDST.

A complete discussion of therapy is beyond the scope of this discussion. The author prefers to work up suspected cases by looking carefully for skin and ear infections (e.g. Staph, Malassezia) with a thorough physical exam and cytology, and performing skin scrapings, flea combing, and other routine diagnostics. If other conditions are identified, they should be specifically treated. In otherwise healthy animals, glucocorticoids are the most effective first-line medications. These drugs work by blocking production of prostaglandins and leukotrienes, which are inflammatory mediators. Prednisone at 0.5-1.0 mg/kg PO once a day for 3-10 days is often successful in decreasing or resolving the pruritus. Methylprednisolone tablets (Medrol) may be substituted in small dogs and cats. If ongoing treatment is needed, every other day therapy may be given for 1-2 more weeks, then the lowest possible dose at the greatest interval (every 3 or 4 days) reduces the risk of side effects. If there is no or limited response to prednisone, consider other diagnoses such as food allergy, secondary infections (especially yeast dermatitis), or ectoparasites. In most cases, injectable steroids are avoided for treatment of atopic dermatitis as the dose and duration are difficult to control. Adverse effects are more common with injectables, but may be considered in animals (specifically cats) that will not tolerate oral medications.

Safer but somewhat less effective medications include antihistamines, essential fatty acids (omega-3 supplements), and topical shampoos, conditioners, and sprays. Cyclosporine (Atopica, Novartis) reduces pruritus in most but not all atopic animals, and has a slower onset (4-6 weeks). It is useful when animals cannot tolerate or don't respond to steroids or other medications. A recent case report found 4 humans whose allergic symptoms became worse after prolonged treatment with cyclosporine due to a shift to a Th2 immune response and increased levels of IgE. Immunotherapy may be formulated after allergy testing, and is approximately 75% effective in reducing pruritus (a delay in onset of several months leads to other treatments in the meantime). The overall prognosis is good, but most animals need lifelong therapy. Breeding atopic individuals should be discouraged.

Flea allergy dermatitis

Hypersensitivity reactions to fleabites are thought to occur when components of flea saliva act as haptens, which are molecules that are too small to stimulate an immune response unless bound to something else. In the skin, dermal collagen combines with the haptens leading to a Type IV (delayed hypersensitivity) response, which over time results in acute Type I, reactions. Early exposure to fleas is one of the causes of flea allergy dermatitis (FAD), but the condition occurs in many dogs and cats in different environments.

The diagnosis may be straightforward (presence of fleas or flea dirt, skin lesions in and around the caudal dorsum and tail base) but the absence of fleas does not rule it out. Cats in particular are fastidious groomers and often remove all evidence of fleas and flea dirt yet still have pruritus and clinical signs. Allergy testing specifically for fleas is not commonly performed but is usually a part of IDST and serologic testing. False negatives are possible, and even dermatohistopathology is nondiagnostic.

If the itching and clinical signs resolve with appropriate flea control, then the diagnosis is established (although some flea products eliminate other parasites such as Sarcoptes). Fipronil spray (Frontline) at the highest label dose as a good initial treatment, unless the skin has significant lesions or ulcerations. A short course of nitenpyram (Capstar, every 24-48 hours for 1-2 weeks) is very effective in removing adult fleas and may be done concurrently with other topicals or systemics such as lufenuron (Program, Sentinel). Other flea control products such as imidacloprid (Advantage, Advantage Multi, or K-9 Advantix) and selamectin (Revolution) also have proven efficacy for FAD. Newer flea control products are available (Promeris, Vectra, Comfortis). Retreatments are based on label recommendations, and environmental control may be necessary in heavy infestations.

Glucocorticoids are useful for treating the pruritus, and the doses are similar to those used for atopic dermatitis. If steroids are not tolerated, antihistamines along with fatty acids or topical antipruritic products can be used. Secondary infections are common and should be treated with appropriate antibiotics or antifungals (for Malassezia dermatitis).

Food allergy

Also called food hypersensitivity or cutaneous adverse food reaction, this condition is less common than atopic dermatitis and FAD but does occur alone or along with other allergies. A significant number of itchy dogs have both atopy and food allergy. An accurate diagnosis can be difficult, as nonimmunologic food intolerances (abnormal reactions to foods, ingredients, irritants, etc.) commonly occur.

As all foods are foreign antigens in the body, the immune system uses barriers (GI mucosa), local IgA responses, and clearance by the liver to prevent allergens from entering systemic circulation. Immune tolerance (specific IgG response) will occur even if food antigens are absorbed. In true food allergy, one or more types of antigen binds to IgE resulting in a Type I hypersensitivity. Previous exposure to the food is necessary for the allergic response.

Clinical signs include dermatologic problems (pruritus, erythema, otitis externa, secondary infections) and gastrointestinal disorders (vomiting, soft stools, diarrhea, increased frequency of defecation). There is no defined age range of onset, as both young and old dogs and cats may be affected. The signs are nonseasonal and may occur even if the animal is eating the same food. There is no diagnostic test, although increased blood levels of histamine have been reported. Serologic testing for food allergens, performed by some diagnostic labs, is not valid and should not be ordered by itself or in combination with testing for environmental allergens (or ignored even if results are offered). The only accurate method is to feed the animal a hypoallergenic or novel diet for 8-12 weeks and see if the clinical signs resolve. Three types of diets are available: home-cooked, commercial novel protein, and commercial hydrolyzed protein. Owner compliance can be very difficult, as all other foods, treats, flavored medications, and chew toys must be stopped during the trial.

Homemade diets are unbalanced unless formulated by a nutritionist, but usually do not result in deficiencies or problems in a short-term trial. Many commercial novel protein diets are marketed, and owners should be carefully questioned as to what foods the animal has had previously to avoid duplication. Diets containing proteins such as lamb or fish are widely sold so may not be "novel". A good first choice for dogs is kangaroo/oatmeal (Eukanuba Response KO). There are several new choices from Hill's (Prescription Diet d/d, various formulas) and Royal Canin (Limited Ingredient Diets) for both dogs and cats. This list is incomplete and other quality diets are available. Hydrolyzed protein diets are also available (e.g. Hill's Prescription Diet z/d, Purina Veterinary Diets HA, Royal Canin Hypoallergenic HP 19). Some dermatologists prefer novel protein diets rather than hydrolyzed although cost, availability, palatability, and client acceptance are important considerations.

If the clinical signs improve within 8-12 weeks, then the animal should be challenged with the suspect ingredient (such as beef or chicken) by adding a small amount to the diet for 2 weeks. If the signs reoccur, then the diagnosis of food allergy is established. At that point, the special diet can be continued long-term or different balanced diets that avoid the allergen can be offered. It is important to consider food allergy as a ruleout not only for itchy dogs and cats, but also for animals with chronic or recurrent ear infections, GI problems (including inflammatory bowel disease), and any chronic skin condition.

Allergic rhinitis and bronchitis

Clinical signs in dogs such as reverse sneezing or chronic cough may be due to inhaled allergens. Diagnosis is by ruling out other causes, identifying increased eosinophils in samples, and good response to glucocorticoids. If avoidance is possible (e.g. cigarette smoke), the prognosis is excellent. Otherwise, supportive care and medications may be needed lifelong.

Feline asthma

Reversible airway obstruction due to eosinophilic inflammation and excessive mucus production lead to clinical signs such as coughing, wheezing, and open-mouth breathing in cats. Radiographs may show a bronchial lung pattern with hyperinflation (air trapping), and cytology of material obtained through tracheal wash or bronchial lavage demonstrates eosinophils. Traditional treatments include glucocorticoids and bronchodilators. Newer therapies such as inhaled medications and cytokine modulators are available. Some dermatologists will perform IDST to identify allergens and formulate immunotherapy.