Erythema multiforme: is it a cutaneous reaction pattern or a diagnosis?

Erythema multiforme (EM) in dogs is an uncommon multifactorial condition, usually of acute onset. In humans the condition is characterised clinically by classical “target lesions” whereas in animals it is recog­nised on histological findings of epidermal apoptosis and lymphocytic satellitosis, making it a histological diagnosis. This is a reaction pattern which can be triggered by an immune response targeting the antigenically altered kerat­inocytes. Depending on the extent of the body involved and the severity of lesions it is classified as erythema multiforme minor (EM minor), or erythema multiforme major (EM major). EM minor in dogs has a wide range of lesions with truncal, axillary and inguinal, mucocutaneous, head and/or general­ised distribution, with only one or no mucosal site involve­ment. The affected animals have no systemic signs. Dogs with EM major have similar lesions and distribution; however, more than one mucosal site will be involved and they may have systemic signs (Yager, 2014).

Pathogenesis

Although the exact pathogenesis of EM is not understood, it is thought to be a T cell-mediated hypersensitivity response in which the cytotoxic T-lymphocytes target the antigenical­ly altered keratinocytes leading to cell death by apoptosis.

The antigens implicated include drugs, viruses and bacteria, vaccines, neoplasia, food (Itoh et al., 2006) and nutraceuticals, but are often not proven in individual cases, except if re-challenged accidently. In one case, immuno­histochemical staining with CPV-2-specific monoclonal antibodies confirmed parvovirus-associated EM major in a dog (Favrot et al., 2000). In another case, EM was directly associated with a thymoma, when the clinical signs re­solved following thymectomy (Tepper et al., 2011).

In humans, the condition is associated with herpesvirus infections, even though the viral particles are not found in the damaged skin. Herpesvirus-associated erythema mul­tiforme is reported in cats, but, unlike in humans, viral DNA has been demonstrated in lesioned skin.

Clinical signs and diagnosis

The distribution of the lesions is generally symmetrical and tends to involve the trunk (mainly axillae and groin), head and mucocutaneous areas. The lesions tend to be on the concave aspects of the pinnae, foot pads, mucocutaneous junctions and oral cavity. The lesions typically described as “target lesions” are erythematous macules, papules or plaques (Figure 1), vesicles and bullae which when ruptured cause ulcers. Unlike the typical target lesions seen in EM in humans, these generally lack the indurated borders and central purpuric area. The lesions tend to have arciform or annular configurations. Thick adherent crusted plaques which are a particular entity of idiopathic chronic EM is seen in older dogs. These plaques tend to wax and wane.

The clinical signs and histological findings should be cor­related to reach, or support, the diagnosis of the reaction pattern. The other differentials such as dermatophytosis, demodicosis, pemphigus complex, bacterial folliculitis and superficial spreading pyoderma (when target lesions seen) should be ruled out. If there is marked scaling and crusting, superficial necrolytic dermatitis, ichthyosis and zinc respon­sive dermatosis must also be ruled out.

To make the histological diagnosis, it is crucial that the biopsy sites are areas of erythema, without crusting or ulceration, because otherwise the secondary changes are likely to mask the changes due to EM. The findings include interface dermatitis, where the dermo-epidermal junction is targeted by mononuclear cells. Apoptotic keratinocytes and lymphocytic satellitosis are seen in both the basal and spinous layers. The follicular epithelium can also be involved.

Hyperkeratosis and parakeratosis are seen in canine EM, which is sometimes then referred to as hyperkeratotic EM.

Identification of suspected triggers requires meticulous history taking and correlation with onset of the condition. The time between the trigger and onset varies from days to weeks and, in some cases, months.

Prognosis and treatment

The prognosis varies depending on the severity of the con­dition, ranging from poor to guarded, and the condition also tends to wax and wane. There is no single universal drug for each condition, but there are a range of drugs with immuno­modulating properties that can be employed (Table 1).

For suspected drug-induced cases of EM, drug withdrawal is essential. Idiopathic forms may require long-term sympto­matic treatment. Generally, ciclosporin, azathioprine, gluco­corticoids, pentoxifylline and mycophenolate mofetil (Figures 2 and 3) can be considered for EM. None of these drugs have evidence-based information to validate their use in any case. This is probably because they are rare conditions.

The choice of treatment should depend on an individual assessment and if there is a poor response, or adverse effects, alternatives to the chosen treatment should be considered. Regular monitoring of haematological and biochemical parameters is required, and the frequency will depend on the drug of choice.

Topical shampoo treatment is useful to remove crusts and scale and prevent secondary microbial infections.

Summary

Erythema multiforme is a reaction pattern with typical histological changes, with variable clinical signs depending on individual response. It usually has an acute onset and can involve mucocutaneous areas. It can be triggered by drugs, infections and neoplasia; meticulous history taking and assessment is needed to identify the trigger. The condition has a variable prognosis depending on the severity of the disease.