Immune-mediated/allergic diseases

11 Immune-mediated/allergic diseases

Inflammatory changes occur in the skin whenever it is injured. These changes are initially related to the specific cause and, secondarily, may relate to autologous changes which develop later. Regardless of the cause, be it heat, cold, infection due to bacterial, fungal, viral or parasitic organisms, radiation, trauma, or allergens, the skin response will be characterized by responses that involve blood vessels, tissue fluids and cells. These changes will be identifiable clinically as the cardinal signs of inflammation, namely heat, pain, redness, swelling and variable loss of function.

Protection of the host is by means of a structured immune response involving antigens, lymphocytes, antibodies, complement, and other mediators and effector cells. Their normal action is to restore natural body function. Tissues themselves have an immune privilege which severely curtails the extent of self-destruction. Under- or over-activity may lead to serious problems for the host. Under-response leads to failure to control infection and poor elimination of toxic by-products. Over-response causes a loss of, or a reduction in, the immune privilege of tissues (which is responsible for preventing the body destroying itself) and therefore an excessive inflammatory response develops which results in the production of autoimmune disease. Both of these responses are common features of skin disease.

The various ways in which the body can respond have been broadly grouped into four types of hypersensitivity (Gell & Coombs 1964) and these have been described in Chapter 1, p. 14). While they are fairly well defined, many reactions are complexes of these and so may show broad variations in clinical features. Types 1, 2 and 3 all rely on antigen–antibody reactions and therefore induce clinical effects following introduction of the antigen to a previously sensitized animal (in the case of type 1 hypersensitivity usually in less than 4 hours and possibly within minutes). Type 4, however, is cell-mediated and has no immediate antibody–antigen component. Therefore, the responses are delayed for a variable period of time (24–72 hours). The clinical situation, however, is frequently complicated by secondary effects such as self-inflicted trauma and the clinician is only able to examine a single moment in the continuing/continuous process. Although crusting and scaling (dry dermatoses) are prominent features of many allergic or autoimmune conditions, other signs, including nodules and moist dermatosis, may be present.

The diagnosis of allergic or autoimmune disease is not simple. Indeed, apart from insect bite hypersensitivity and some forms of urticaria (hives), the immune-mediated diseases are not common and are often very difficult to diagnose. Diagnosis may rely on meticulous clinical and historical findings and the elimination of the other more common causes of crusting and scaling in particular.

A very careful examination of the horse’s history, a carefully considered series of biopsies of recent lesions, and the assistance of a specialist veterinary dermatopathologist are significant aids to reaching a diagnosis.

Knowledge of immune-mediated diseases is being expanded and the similarity to corresponding human disease is evident. However, the horse may present significant or minor variations to the general pattern seen in other species. Similar names are therefore given to some diseases, but it is important to realize that species differences may not entirely justify the name. Extrapolation from the name of the disease to possible diagnostic features and treatment may also therefore not be justified. Further knowledge and research into these diseases may well reclassify them. Table 11.1 demonstrates the major clinical features of the allergic and autoimmune diseases of the horse, dividing these broadly into those associated with hair loss or no hair loss.

Table 11.1A General clinical signs of allergic and autoimmune disorders of the horse in which hair loss does occur

Table 11.1B General clinical signs of allergic/immunological disorders in which hair loss does not (initially) occur

Urticaria and angio-oedema (‘hives’)

Profile

Of all the species of domestic animals, horses probably show the greatest incidence of urticaria. However, urticaria is a symptom or sign of disease rather than a specific disease entity; it is simply one of the cutaneous manifestations of a number of diseases. In the clinical situation it is usually taken as a single entity even though its clinical manifestations vary from a minor transitory cosmetic blemish to a major, systemic and possibly even life-threatening problem. Horses between 1 and 10 years of age appear most liable and there is no gender predisposition. Thoroughbreds and Arabians are possibly predisposed to urticaria from inhaled allergens.

The aetiopathogenesis of urticaria in horses is complex; a wide variety of factors have been identified as potential causes (Tables 11.2 and 11.3); this can possibly be explained by the fact that the horse seems to be more liable to the condition than many other species and that the clinical signs of ‘urticaria’ are best viewed as a final manifestation common to many related and apparently unrelated conditions (Stannard 1994a).

Table 11.2 The potential causes of urticarial lesions and urticaria-like skin signs

Drugs

• Foods and food additives

• Inhalant or contact allergens

• Transfusion reactions

Physical urticaria

Infections

• Fungal (dermatophytosis)

• Parasitic

• Insect bites/stings

Stress-related urticaria

Ingestion of vasoactive chemicals

Chronic idiopathic urticaria

After Fadok V A (1990) Of horses and men: urticaria. Veterinary Dermatology 1:103–111.

Table 11.3 Urticaria: aetiology and characteristic types

The aetiopathogenesis is not clear and although the condition does resemble that in other species there are significant differences in the horse. However, the basic aspects are likely to be similar. Degranulation of mast cells (and to a lesser extent perhaps, basophils) is presumed to be the basic pathogenesis involving the liberation of chemical mediators which cause increased vascular permeability, inflammation and protein leakage with consequent wheal formation (Fig. 11.1).

• Immunological (type 1 and type 2 hypersensitivity responses) and non-immunological (heat, cold, pressure, exercise, some drugs) causes have been identified but in some cases no aetiology is established – usually termed idiopathic urticaria. The latter does not mean that there is no cause, it simply indicates that we have no real understanding of the possible cause(s).

• Immunological or hypersensitivity reactions in which injected (drugs), ingested (chemical, feeds) or inhaled (pollen, dust, chemicals, moulds) antigens/allergens are delivered to the skin systemically rather than by local contact. Penicillin is the most commonly implicated drug responsible for urticaria.

• Allergic urticaria arises from drugs, food, inhaled allergens (pollens, moulds) (Evans 1987) or more rarely by direct skin or mucous membrane contact. These should be carefully distinguished from allergic contact dermatitis.

• Physical urticaria arises without any immunological component. Dermatographism arises when a wheal develops from a blunt ‘scratch’ on skin (Fig. 11.2). ‘Cold’ or temperature-related urticaria can arise from either cold, heat or even light under some conditions. Exercise-induced urticaria may also be encountered following heavy exercise (particularly in hot or very cold conditions).

Figure 11.1 The suggested role of the mast cell in urticaria. Mast cell degranulation occurs in several different ways. (1) Type 1 hypersensitivity causes massive degranulation and consequent risks of anaphylaxis as a result of the high histamine release into the general circulation. (2) Spontaneous degranulation occurs in recurrent or chronic urticaria and (3) chemically induced degranulation such as follows drug administration (morphine or aspirin for example). (4) Autoimmune or allergic processes are possibly involved in some cases in the horse.

Adapted from Boon N et al, 2006, Davidson’s Principles and Practice of Medicine, 20th edn. Churchill Livingstone, Edinburgh; with permission.

Figure 11.2 Dermatographism arising from light finger scratching over the buttocks.

Note

‘Pitting-on-pressure’ test: When steady and firm digital pressure is applied to an oedematous swelling or wheal for 10–20 seconds, the imprint/indentation of the finger will remain obvious at the site for several minutes (or longer in some cases) (see Fig. 11.43A, B). Inflammatory or solid/tumour-like swellings do not compress in this way, while fluid-filled swellings are compressible but do not retain the shape of the finger.

In spite of the frequency with which this condition occurs in clinical practice, little is understood about its aetiology/pathogenesis. Certain ‘allergens’ are ‘known’ circumstantially at least to be involved including some drugs such as penicillin and some sedative compounds including romifidine and morphine, for example, but other cases are induced by stress, exercise, cold exposure, and very commonly when certain diets are fed. There remains much controversy over the existence of ‘food allergy’ in horses. Many dermatologists consider the urticaria that occurs in racehorses and others on a high cereal diet to be an ‘inappropriate food response’ or a food idiosyncrasy or food intolerance, but it is hard to see what this is other than a hypersensitivity condition, given that withdrawal of the feed resolves the issue and reintroduction restores the problem! It is also true, however, that in some cases simple reduction in the volume of cereal may help to reduce the signs and so a true hypersensitivity may be less convincing in these circumstances. Food hypersensitivity seems, however, a logical possibility given the similar conditions in other species and the fact that removal of a causative food material will often result in disappearance of the condition. Plant sugars may be more involved given the high correlation between cereal feeding and recurrent episodes in racehorses in particular. It also seems that endogenous allergens can be produced possibly within the gut so that recurrent episodes may persist for some time after the primary causative agent has been withdrawn. Exogenous or endogenously produced vasoactive chemicals may be involved in some of these cases but if they were present then all horses should react in the same way to them.

Key points: Urticaria and angio-oedema

1. Very common complex of conditions that are poorly under-stood in spite of the high incidence. Immunological and non-immunological causes have been identified.

2. Clinical signs include abrupt appearance of wheals of vary-ing sizes and sometimes linear, circular and serpiginous oedematous skin changes. Angio-oedema, in which there is massive intracellular protein loss and plasma exudation, is very rare in horses.

3. Biopsy is remarkably disappointing compared to the clinical lesions. Diagnosis can be suggested by feed/withdrawal trials in which suspected causative feeds are withheld for 2 weeks before being reintroduced to the diet. Radioallergosorbent and ELISA tests and intrademal allergy tests can be used to help identify putative allergens. In many cases a careful history will help considerably. Known exposure to drugs, pos-sible contact allergens and some infections can be helpful.

4. Treatment is usually simple in simple cases – intravenous dexamethasone even at lower doses usually quickly resolves the early cases – even some severe cases respond rapidly. Repeated episodes often become more refractory to treat-ment. Removal of the causative agent is curative.

5. Recurrent episodes become more difficult to treat effectively and may require long-term management and repeated corti-costeroid drugs by injection or by mouth.

Urticaria is often reported to occur under stress, cold, warmth, exercise, etc. and the diversity of suggested causes makes the condition difficult to investigate without an exhaustive history and careful clinical examination.

Contact with irritant plants such as nettles will also induce an urticarial reaction – this, however, is recognizably different by the systemic signs of pruritus and severe discomfort that they cause. Affected horses are often thought to have colic.

Insect bites cause a localized ‘wheal’ but this is a quite different circumstance to true urticaria (see p. 207).

Recurrent episodes at random intervals are relatively common (especially when these are due to inhaled or ingested allergens).

Individual horses may have regional urticaria, i.e. the lesions remain localized and recurrences often seem to be similarly restricted to the ‘susceptible areas’. Persistent episodes may be a result of repeated exposure to the causative agent or to the failure of the body to rid itself of the causative process. However, some persistent cases are more a reflection of serious underlying disease and so whilst the large majority of cases are benign and have few serious implications, a few cases are very serious. In these the urticaria-like plaques may be the only and certainly the most obvious clinical indicator of pathology. Inflammation-related oedema due to local vasculitis produces a very similar plaque but of course carries a very different implication.

Clinical signs

The onset can be acute or peracute with signs developing within minutes up to a few hours following exposure to the instigating factor. In some cases the onset is far slower and these often are more chronic in nature. Often a careful historical investigation can identify an associated substance such as a feed or a drug.

Characteristically the signs are oedematous lesions of the skin and/or mucous membranes called ‘wheals’ which are flat-topped, papules/nodules with steep-walled sides (Fig. 11.3).

Figure 11.3 Urticaria. Wheals showing the steep-sided, sharply demarcated nature of the typical lesions.

The typical urticarial lesions develop quickly and often fade away equally quickly. Typically the individual lesion is a steep-sided papular dermal swelling – usually there are many and some are confined to specific locations. Single lesions can vary in size from 0.5 cm to 15 cm or more and these can coalesce to produce much larger areas in which individual urticarial plaques are not obvious. Usually, however, under the circumstances the skin takes on a ‘bumpy’ appearance. Anular, arciform and serpiginate urticarial eruptions are common in horses (see p. 258).

Typically the lesions themselves will ‘pit on pressure’, but the surrounding skin will usually be normal and will not pit on pressure. This test may be difficult to apply effectively to small urticarial lesions but they will compress away only to return a few minutes later – testing after clipping gives the best information. Some lesions have slightly depressed centres, but in true urticaria there is no central focus of inflammation (in contrast to insect bites; see p. 207).

In contrast to inflammation-related oedematous plaques there is seldom any pain on palpation or any palpable heat in the lesions. Pruritus may or may not be present. Some severely affected cases show no pruritus while mild cases with a few lesions sometimes show severe pruritus with extensive self-inflicted trauma suggestive of insect bite hypersensitivity.

Hair loss is not usually present unless individual lesions are exudative (angio-oedema) and long-standing.

Individual urticarial lesions vary in size and shape and, quite arbitrarily, may be divided into:

• Conventional wheals: 2–5 mm in diameter (Fig. 11.4).

• Papular wheals: multiple, small, uniform 3–6 mm diameter wheals (similar to the appearance of insect bites but without a central focus). Insect bites can induce a very similar localized wheal at the site (Fig. 11.5).

• Giant wheals: either single or coalesced, multiple wheals 20–30 cm in diameter or more (Fig. 11.6).

• Linear wheals: usually multiple ‘lines’ of urticarial oedema most often occurring along the sides of the body (Fig. 11.7). This form tends to be more obvious in warmer weather and may be pruritic.

• Anular wheals: ‘doughnut’-like lesions with a regular or irregular ring of oedema surrounding a depressed, non-oedematous or less oedematous centre (Fig. 11.8).

• Gyrate/serpiginate urticaria: the urticarial lesions take on a variety of shapes with some straighter linear, some curvilinear lesions and some serpiginous lesions (Fig. 11.9). This has been referred to as the dermal form of ‘erythema multiforme’ but it should be stressed that this syndrome is not related to ‘true’ erythema multiforme, which is a primary epidermal disease (see Fig. 11.37). Drug reactions appear to be the most common cause of this form of urticaria.

• Exudative urticaria: poorly defined or diffuse exudative oedema of the skin over localized areas or regions (Fig. 11.10). Possibly best regarded as angio-oedema.

Figure 11.4 Urticaria. Conventional wheals. Lesions are 2–3 mm up to 3–5 mm in diameter.

Figure 11.5 Urticaria. Papular wheals: multiple, small, uniform 3–6 mm diameter wheals. These lesions developed following intravenous sedation with an alpha-2 agonist.

Figure 11.6 (A, B) Urticaria. Giant wheals. Single and coalesced, multiple wheals up to 20–30 cm diameter. Note the variety of sizes on this case.

Figure 11.7 Linear urticaria that occurred repeatedly when the animal was exposed to cereal foods even in small amounts and this response was markedly exacerbated by warm weather and rugging. Note the biopsy sites. Biopsies showed very little significant pathology.

Figure 11.8 Anular urticarial wheals. ‘Doughnut’-like lesions with a regular or irregular ring of oedema surrounding a depressed, non- (or less) oedematous centre.

Figure 11.9 Urticaria. Gyrate and serpiginous wheals. Note the open linear nature of these lesions. In this case the lesions were persistent and required high doses of corticosteroids to resolve the problem No recurrences were encountered thereafter.

Figure 11.10 Exudative urticaria. Note the ill-defined lesions and the marked exudation indicative of protein leakage from blood vessels. This may be best termed angio-oedema.

The clinical appearance of the lesions may also present in several different ways depending on the precise location of the response in the skin. The classification is a convention but there is little merit in it simply because the type of urticaria is seldom pathognomonic for any potential aetiology and the treatment will probably not vary a great deal.

Oozing urticaria

Dermal oedema is severe, resulting in oozing of serum from the skin surface and possibly cracking and superficial sloughing of the hair and skin (Fig. 11.10). In the early stages the oedematous lesions will still ‘pit on pressure’ in spite of their apparent severity. Care should be taken to distinguish this from a bullous condition, or an erosive/ulcerative process or a pyoderma or vasculitis.

Angio-oedema (angioneurotic oedema)

This is a subcutaneous form of urticaria which tends to be more diffuse owing to lack of restraint of the spread of the fluid through the subcutis (Fig. 11.11). In some cases the condition is more reflective of vasculitis (see p. 27). It usually involves the head and extremities and is more indicative of systemic and/or serious disease than ‘simple’ urticaria. Pruritus may or may not be present. It can easily be mistaken for vasculitis and the skin manifestations of the two conditions may in some cases be indistinguishable. Fortunately in horses angio-oedema is rare.

Figure 11.11 (A) Focal angio-oedema with severe exudation occurring at each affected lesion. (B) Diffuse angio-oedema with serum exudation. Note that the oedema is diffuse and ill-defined but it will still pit on pressure.

Individual affected horses showing any of the forms of urticaria may have associated systemic signs also. Dullness, diarrhoea, congested mucous membranes and an ocular/nasal discharge may occur concurrently in some cases and in every case the clinician should establish whether the urticaria is part of the primary condition or secondary as a result of other primary conditions.

It is a particularly common event in horses being fed high cereal rations. Many higher performance horses perform less effectively during acute episodes and often also during periods of remission, and so the condition can have serious implications. Often recurrences coincide with stress or changes in management, for example when the horse is expected to perform well at race meetings. The occasional systemic effects suggest that the condition can affect more body systems than is appreciated. The skin signs may, however, be all that is seen.

3. Persistence: if the condition persists after 4–6 weeks, it is important to reassess the whole case again and possibly evaluate by intradermal (injection or patch) testing (Chapter 3, p. 81) for atopic disease (IgE) or specific ELISA or RAST tests for IgE. It may be possible in this way to identify possible/probable causes from the panel of positive results and attempt to avoid them. However, the results from these tests are very unreliable and repeated samples from the same horse can give very different results over very short intervals.

Hyposensitization and neutralization may be attempted but this is not generally available and carries risks. It may hold some promise for inhaled allergic urticaria and atopy (see p. 262). The specific dose of the allergen used and the required frequency of challenge are variable according to the individual response but usually the injections have to be maintained throughout life. Recent reports have questioned the relevance and therapeutic benefits of these methods but opinions are divided. Many practitioners feel that they are an effective approach whilst others have less faith in them.

Long-term management

Corticosteroid

Where single doses of dexamethasone fail to resolve the issue for long enough or where the lesions persist, it is possibly unwise to continue with increasing doses of dexamethasone. Daily oral doses of prednisolone (0.2–0.4 mg/kg q 24 h) or dexamethasone (0.01–0.06 mg/kg q 24–48 h) administered in feed in the morning should be manipulated so as to obtain an acceptable effect.

Note

Prednisone has no material value in horses and should not be used.

The dose of corticosteroid should then be reduced to reach a minimal effective (therapeutic) single daily dose (MESDD). Double this daily dose should then be administered using twice the interval (48 hours for prednisolone and 48–96 hours for dexamethasone) in the mornings only (see p. 96). Provided that this dose is effective it is then gradually reduced to establish a minimum effective alternate-day dose (MEADD). The objective is to use the least possible drug consistent with a complete absence of clinical signs. Concurrently every effort should be made to remove any possible causative agent.

Antihistamines

Antihistamines including oral hydroxyzine hydrochloride, chlorphenhydramine and promethazine are largely disappointing in the horse. If effective, a remission in 3–4 days will be achieved and the drug can then be reduced to a minimum effective daily dose. Side-effects include sedation and/or hyperactivity. The antihistamines may be more effective in preventing episodes than treating them – they will seldom stop episodes from developing, however, but may reduce the amount of corticosteroid required to bring an episode under control. The drugs should probably not be used in pregnant mares as there is a suggestion of teratogenicity.

Prognosis/prevention

Provided that the cause can be eliminated the outlook is excellent because most animals are little affected by it. However, from an owner’s and veterinarian’s perspective the condition can be extremely frustrating. Some cases are clinically affected and in any case the animals are unsightly. In some cases no explanation can be found for a single or few episodes and then many such cases are not materially affected. Some may show one or two episodes and then remain free of the condition for life. There is little that is predictable about the condition.

It is the recurrent and deteriorating cases that create the long-term problem. Some badly affected horses are never free of the condition or the threat of it. Animals that have concurrent signs such as diarrhoea or respiratory tract obstructions are clearly much more difficult to manage.

Cereal foods are commonly implicated and it is difficult to maintain a high performance horse on a hypoallergenic diet free of all cereal products.

Atopy

Profile

Atopy is a rare, multifactorial, (probably) genetically determined predisposition to allergic responses to environmental antigens that results in formation of excessive IgE, which leads to a generalized and prolonged (Coombs type 1, immediate and late phase) hypersensitivity to common environmental antigens including pollens, grasses, weeds and trees, moulds, dust, feathers, cotton, wool and other fibres. These antigens usually cause no difficulties in non-atopic animals. A type 4 hypersensitivity is also involved in some cases. The skin is the major target organ for the changes.

Little is known about the condition in horses but it is widely recognized as a definitive clinical entity (Scott & Miller 2003a). It is not known whether it is heritable but Arabians and Thoroughbreds in early adulthood appear to be predisposed to the condition (Degler 1997).

The condition is classically attributed to IgE responses to the allergens (often inhaled or contacted but sometimes ingested) but it is likely that the condition is a complicated immune disorder involving IgG, eosinophils, Langerhans cells and other components of the immune system. It is usually characterized by pruritus associated with exposure to specific allergens that provoke allergen-specific IgE production. Repeated exposures result in increasing amounts of allergen-specific IgE that may bind to Langerhans and possibly less significantly cutaneous mast cells, and so lead to increasing disease. Once the exposure is re-established, the clinical signs (moderate to severe pruritus) are triggered locally.

There is debate whether the classical disease exists in the horse. Although it is considered to be a rare disease, it may in fact be under-diagnosed.

Clinical signs

The clinical signs are dependent upon exposure to the allergen and so may be seasonal or non-seasonal; seasonal cases may become non-seasonal over the years, especially if exposure to the allergen is not restricted or measures are not taken to treat the disease (see below).

Key points: Atopy

1. Rare, genetically predisposed inflammatory and allergic skin disease that manifests, initially at least, in younger horses

2. The predominate sign is pruritus. Seborrhoea and occasion-ally concurrent respiratory tract and other evidence of allergic disease including urticaria may be present.

3. Diagnosis is based on exclusion of other causes of pruritus, serum ELISA and intradermal or patch skin testing.

4. Treatment is limited in horses to corticosteroids and avoidance strategies of proven or putative trigger factors. Hyposensitiza-tion procedures involving injection of ‘specific’ antigen con-centrations have been reported to be effective in a few cases.

5. The prognosis is guarded – if the allergens can be avoided then the signs will be minimal but will seldom clear completely.

The primary sign is pruritus developing at a young age (Table 11.4). Some cases have urticaria and some are less pruritic than others. There is recurrent pruritus unrelated to season without obvious or histological primary lesions other than self-mutilation. The affected horse may bite aggressively at a localized site until it is significantly damaged and then turn its attention to another site. Horses often bite unrelated regions in subsequent attacks (Fig. 11.13). Some have more general signs but most seem to have body pruritus as opposed to limb or head pruritus but no site is exempt. Rubbing of the skin (even at sites that are not apparently affected at the time of examination) often induces a ‘pleasure response’ at the lips and muzzle.

Table 11.4 Criteria for diagnosis of atopic dermatitis in horses

(a) Pruritus without other defined cause at unpredictable and variable sites

(b) Dry seborrhoeic skin

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