Proceeding of the SEVC Southern European Veterinary Conference

Transcription

1 Proceeding of the SEVC Southern European Veterinary Conference Oct , 2008 Barcelona, Spain Reprinted in the IVIS website with the permission of the SEVC

2 Equine Understanding Allergic Skin Disease Dr. D. Knottenbelt Although the skin acts as a physical barrier to viruses, bacteria, funguses, toxins, insects and allergens of various sorts, it is also an active component of the immune system and can react to external challenges and to internal hypersensitivity states. It can provide an effective and clinically significant window to systemic and local responses. Allergic skin disease in horses offers significant clinical challenges for the practicing veterinarian. Set against the perception that allergies are common in horses it is important to realise that there are only a few common allergic diseases and these are relatively well recognised others are singularly rare but remain significant from a clinical perspective because they offer significant differentials for the more common ones.

3 Figure 1: Urticarial wheals of various types that developed within minutes of eating barley. The horse had a persistent and repeated problem with this and although food allergies are viewed by many dermatologists as extremely rare, they are in fact relatively commonly recognised by both practitioners and owners. The diagnosis depends on repeatability of response following exposure and resolution on withdrawal. Hypersensitivity responses have been classified into 4 basic types. Most dermatological manifestations of allergic / hypersensitivity fall into Type 1 and / or the Type 3 hypersensitivity responses but there are some circumstances when other reactions are present either on their own of as complex responses involving mixtures or other classical response patterns. The breadth of the pathophysiology of the responses means that glucocorticoids are the most rational therapy for most of them. A crude reaction requires a crude therapy is a useful maxim. Antihistamines are generally not helpful in horses. TYPE 1 Hypersensitivity: (anaphylactic / immediate) reactions are mediated by IgE antibodies, that deond on Th-2 cytokines (IL-4, IL-5, IL13) which activate B-cells and induce the production of IgE and IgA. These act predominately on mast cells (and to a lesser extent on basophils) causing degranulation when exposed to the allergen. This releases mediators including histamine, prostaglandins and leukotrienes resulting in the immediate symptoms typical of the allergic response i.e. increased vascular permeability, smooth muscle contraction and the recruitment of eosinophils from the circulation. The site of mast cell degranulation is either in tissue or the circulation, and this determines the type of response; the former inducing localised reactions while the latter causes systemic anaphylaxis. TYPE 2 Hypersensitivity: This is an antibody-mediated cytotoxic response. In these responses specific antibodies bind to cell surfaces or extracellular matrix molecules: Cell lysis results from complement activation of Fc or C3b receptor-mediated opsonisation leading to phagocytosis of the damaged cell by macrophages and to ea lesser extent by neutrophils. Cells with a lower capacity for complement regulation are more susceptible (e.g. red cells, and platelets). TYPE 3 Hypersensitivity: This results from the deposition of immune complexes on (predominately) vascular endothelial cells and thereby cause direct inflammatory responses. In this reaction circulating soluble antigens react with specific antibodies to create immune complexes.. Additionally, antigen

4 antibody complexes resulting from repeated exposure to antigen in the presence of pre-existing anti-igg antibodies may activate C3a and C5 and so increase vascular permeability and cause recruitment of polymorphs (this is the so called Arthus Reaction). Type 4 Hypersensitivity: This delayed response hypersensitivity reaction s mediated by antigen specific T cells. The local inflammatory responses typically develop hours after the antigen challenge. Th1 cells migrate into the site (this can be and insect bite or other deposition), where they recognise MHC class II complexes on antigen presenting cells and release cytokines including IL2, IFN-γ, TNF and other chemo-attractants. These in combination induce an increased local vascular permeability and recruitment and activation of macrophages and CD*+ cytotoxic T cells. By far the commonest cutaneous allergic disorders are urticaria and Insect Bite Hypersensitivity (IBHs, Sweet Itch ). The latter is s is by far the commonest seasonal (summer) cause of pruritus in horses. In addition there is a significant group of systemic autoimmune hypersensitivity responses that affect the skin either as a part of the syndrome or specifically and solely affect the skin. There are definite genetic aspects to IBHs. The Icelandic pony is particularly liable to the disease and whilst an individual remains in Iceland it shows no clinical signs simply because there are no Culicoides midges in Iceland. When a susceptible horse moves to another location the disease erupts in a dramatic fashion. However, when a pure Icelandic foal is born in another country, the severity of the disease is far less. This implies that the condition is modified by early exposure to the bites of Culicoides. This probably suggests that there are components of IgE and IgG responses. Icelandic ponies bitten for the first time as an adult get a much more severe disease than those that are bitten for the first time as very young foals. This has led to the suggestion that fly repellents should not be applied to foals! However, this still does not explain fully why other breeds native to UK for example such as the Shire and the Welsh pony are often severely affected because they would surely have been bitten as young foals. Many individuals of all breeds are affected by the condition so there is genuine hypersensitivity aspect to it even in breeds that may not be known to be susceptible. IBHs is extremely common in Australia with up to 20% of all horses showing some sign of the condition. The diseased usually manifests first at around 5-8 years and in each succeeding year the signs become more severe. The signs are typical but the location of the inflammation / pruritus depends to some extent on the species of Culicoides responsible for the allergy. Some bite ventrally while others bite dorsally on the sides of the neck and base of the tail (Figure 3) Others bite around the head only./ The legs are almost never involved at all in any species possibly simply because the midges do not feed there! The management of IBHs is universally problematic. There is naturally reliance on avoidance strategies and corticosteroids administered parenterally or by mouth. Topical steroids and local anaesthetic sprays and creams can be helpful but are logistically difficult.

5 Table 1: Table showing the basis of each of the Coombs Hypersensitivity responses with examples of the clinically significant cutaneous conditions in horses. Other significant cutaneous conditions that have an immunological (though not necessarily a hypersensitivity) origin. These include atopy, drug-related skin allergy and the highly controversial food allergy syndromes. Inappropriate inflammatory responses also occur to some other cutaneous challenges such as bacterial and fungal infections where the cutaneous local or generalised response is disproportionate to the challenge. Swarm attacks by stinging insects can be fatal if an allergic component is superimposed on the direct response to the venom. Deaths have also resulted from severe anaphylactic responses to the bites of Simulium spp. flies. Local contact allergies are rare but can be significant in horses these include contact hypersensitivity to plant allergens and to applied chemicals and drugs; it is not the response that is seen to contact with nettles and other plants containing histamine and its derivatives. Adverse drug reactions (drug hypersensitivities) also present with skin eruptions of various types including urticarial plaques (such as commonly follow penicillin, other antibiotics, and in some cases other drugs). Cutaneous signs may also reflect deeper allergic / hypersensitivity responses, for example in headshaking horses. There is a suggestion that an allergic rhinitis results in facial and nasal rubbing - there is however, little evidence to suggest that this is the primary aspect of the condition; it is far more probable that this is a trigger factor rather than a primary pathology.

6

7 Figure 1: The typical signs of Insect Bite Hypersensitivity (Sweet Itch) are a result of self-inflicted trauma which follows a Type 1 / IV hypersensitivity reaction to antigens in the saliva of Culicoides spp. midges. The location of the predominate signs relate to the preferred feeding region of the insects. Similar signs may be caused by other flies also where they have common antigens. The range of autoimmune conditions are also hypersensitivity disorders but the pathogenesis of these is significantly different and they are not usually classified as allergic disorders. Additionally few of them are characterised by pruritus. The diagnosis of allergic skin disease remains a clinical one in most cases. Even with advances in our understanding of the aetiopathogenesis, the available diagnostic tests remain unconvincing. Skin testing and specific IgE blood testing (using RAST and ELISA) methods have become widely available commercially but given the relatively narrow choice of allergens included in both (based largely on the dog!) and given the variations between clinical and histological responses (Sloet et al., 2004) there remain many problems. A positive skin test or IgE blood test may be detected in animals that have no exposure at that time to the allergen the condition being caused by some untested allergen. Similarly it is clear that skin and blood tests are only as good as the panel of potential allergens they use and the interpretation of the results by the clinician. By far the majority of allergic skin diseases can be diagnosed with a reasonable degree of clinical certainty through an exhaustive history and clinical investigation (usually based on elimination of alternative diagnoses). Remarkably it seems that allergic skin disease does not always equate with pruritus and the differentiation of the various pruritic diseases does not necessarily cover all the allergic diseases of the horse. Nevertheless, pruritus is a common sign in the major allergic (hypersensitivity) diseases including insect hypersensitivity, food hypersensitivity and drug eruptions Therapy for allergic skin disease in the horse is best based on the fundamental premise that removal of the allergen results in a cure Avoidance however, requires that the antigen is known or can be reasonably deduced and then avoided. The avoidance approach is a major aspect of the therapy for Insect Hypersensitivity syndromes but there are still problems with this in that there are common antigens in many insects and so defining the cause and then being able to avoid all related antigens is always likely to be problematical. Avoidance is seldom of value in the management of atopic skin disease, being either ineffective (often because the causative agent cannot be identified) or impractical

8 (because the aetiological material is impossible to avoid) or both. Non specific treatment includes general improvement in coat quality through feeding of a good quality diet and possibly the addition of fatty acids have yet to be critically evaluated but they are at least benign. Sometimes sedation is required to control the self-trauma. Topical local anaesthetics and corticosteroids (and to a lesser extent antihistamine creams) can be used for small localised areas but are clearly impractical for wide areas. Non-steroidal anti-inflammatory drugs have a rather disappointing effect but may reduce the severity of the pain associated with the pruritic areas. Pentoxyfylline is probably the most logical of these. (1) Sloet von Oldruitenborgh-Oosterbaan M. (2004) Proceedings de the International Workshop on Equine Allergic Skin Disease. European College de Veterinary Dermatology Annual Congress, Vienna, Table 2: table showing the dose rates and intervals of the common corticosteroids for horses affected with acute allergic skin disease. [* MESDD = Minimum effective single daily dose / MEADD = Minimum effective alternate daily dose] In the majority of cases corticosteroids are the pillar of management this is largely because they are usually effective and in spite of the common (slightly) misconceived perceptions that the drugs are very dangerous in horses, they are well tolerated. It is certainly the treatment of choice for the acute case most acute allergic reactions respond to a single or a few doses of parenteral dexamethasone or oral prednisolone (note that oral prednisone is virtually useless in horses). Doses for the various steroids are shown in table 2.

9 Table 3: Table showing summary of the available treatment modalities for allergic skin disease in horses. The value of various desensitisation methods, including hyposensitisation using graded doses of the defined allergen or mixture of allergens) and allergen neutralisation, are still being explored in horses. As yet the correct titrations of test doses and the implications of IgE concentrations in particular cases are not yet established. Understandably, there are very variable reports of its value ranging from the optimistic (Rosencrantz, 2004) to the pessimistic (Knottenbelt, 2004, Sloet 2004). This probably reflects that the panel of antigens that are used are not necessarily appropriate in all cases and that false positives and false negatives occur. Desensitisation methods for Culicoides hypersensitivity are understandably more focussed than most other putative allergens the diagnosis is relatively easy to confirm and so the desensitisation could be expected to have some benefit. By contrast the value of the treatment in cases of atopy are far more variable this may simply reflect the fact that definition of the true (causative) allergen may be very difficult to make there may be as many false positives and false negatives and in any case the treatment method relies on managemental avoidance of the allergens as well and so it is hard to necessarily ascribe any perceived improvements solely to the hyposensitisation process. All hyposensitisation programmes at present available take at least 2 3 years to achieve the desired result and during this time clinical signs may recur at variable intervals and severity. A successful treatment is taken to be when no drugs are required to control the clinical signs avoidance of the allergen is a concurrent requirement. Up to 50% of cases are reported to be cured by the combination of avoidance and hyposensitisation but many of these have periods of remission (probably these are associated with exposure to the allergen or to another allergen!). There are simply too many variables in the process to be sure what is being achieved but it is nevertheless important that the processes are followed to establish a better process of both diagnosis and treatment.

10

11 Figure 2: If a horse is allergic to something, the only sensible management is avoidance of contact! Easier to say than to do but sometimes it is possible to help considerably and thereby avoid excessive medication. SUMMARY: The management of allergic diseases in the horse is critically hampered by a lack of understanding of the pathogenesis of the various conditions. Extrapolated data from other species are not helpful apart from the broad principles. The horse has special requirements for treatments and there are significant difficulties with the various medications. There are no really effective antihistamine drugs for equidae and corticosteroids have a generally bad reputation for inducing laminitis, although this is probably largely unjustified and not supported by evidence. Ultimately allergies are best prevented by avoidance of the allergen but strategies for this depend on knowing what that is and then being able to avoid it / them in a practical fashion. REFERENCES AND FURTHER READING Scott DW & Miller WH (2003) Equine Dermatology WB Saunders, Philadelphia Pascoe RR and Knottenbelt DC (1997) Manual of Equine Dermatology, Saunders, London Rosencrantz WE, (2004) Proceedings of the International Workshop on Equine Allergic Skin Disease. European College of Veterinary Dermatology Annual Congress, Vienna, 2004 Knottenbelt, DC (2004) Proceedings of the International Workshop on Equine Allergic Skin Disease. European College of Veterinary Dermatology Annual Congress, Vienna, 2004 Sloet von Oldruitenborgh Oosterbaan, M (2004) Proceedings of the International Workshop on Equine Allergic Skin Disease. European College of Veterinary Dermatology Annual Congress, Vienna, 2004 Pilsworth R and Knottenbelt DC (2006) Syndromes in Equine Dermatology BEVA Publications, Newmarket