Introduction

Erythema multiforme (EM) is a cutaneous inflammatory condition that was initially described in 19th century human medicine.¹ In humans, the syndrome is typically associated with previous herpes virus infection with <10% of the cases having a drug-induced etiology.^2,3 The most common etiologies for EM reported in veterinary literature are drug-induced or idiopathic.^4,5 Human EM is typically a self-limiting condition that spontaneously resolves with no treatment required.³ Conversely, in veterinary medicine, EM rarely spontaneously resolves, and treatment is necessary to induce a clinical cure.³ If a drug-induced etiology is suspected in canine or feline EM, drug withdrawal may lead to resolution. If no drug can be withdrawn or clinical disease persists or progresses beyond withdrawal, treatment with immunosuppression is recommended.⁴

The classic clinical presentation in humans with EM is sharply demarcated, round target lesions with three different color zones. The innermost zone is a dark-red disc that is surrounded by a palpable white ring of edema followed by a ring of erythema.⁶ In veterinary medicine, EM will rarely present with the classic raised target lesions described above. Atypical targets, defined as round, irregularly shaped, two-toned lesions are more commonly seen in canine or feline EM. EM can present with a wide variety of skin lesions ranging from erythematous macules to papules, with or without crusts, that can form arciform or annular patterns progressing to include ulcerative, bullous or vesicular lesions.^3,7 Ulceration is typically limited to <10% in cases of EM.² Areas classically involved in dogs include the trunk, groin, and axillae but other possible affected areas include the pinnae, paw pads, and mucocutaneous junctions.^3,7

EM can be clinically divided into EM minor or EM major based on dermatologic examination and supporting histopathology. The severity of mucosal involvement and extensiveness of skin lesions combined with the presence of systemic signs will determine the category. EM minor cases typically have mild skin lesions with one or less mucosal sites involved and no systemic signs.^2,3,7 EM major cases have more severe skin involvement with greater than one mucosal surface involved and systemic signs such as lethargy or pyrexia present.^2,3,7

Human intravenous immunoglobulin (IVIG) is a highly purified suspension of primarily IgG collected from a large pool of human plasma.⁸ IVIG has been used in >50 diseases in human medicine and in over 7 different conditions in veterinary medicine with variable success.⁸ In human medicine, these conditions comprise many different categories including immune-mediate disease, neoplasia, viral disease, sepsis, cutaneous drug eruptions, necrotizing fasciitis, and primary immune deficiency, among many others.⁹ Veterinary medicine has extrapolated from human medicine in trying this therapy but its use has primarily been in immune-mediated conditions.⁸ IVIG therapy has been used successfully to treat one cat with EM.¹⁰ This report is the first to describe EM major in a dog treated with a combination of immunosuppression and IVIG therapy.

Case Report

An ∼12 yr old, 11.0 kg, castrated male mixed-breed dog presented to the Louisiana State University Veterinary Teaching Hospital with a progressive 7 wk history of intermittent hyporexia, lethargy, and erosive dermatitis. Five days prior to presentation, the dog had undergone splenectomy for a splenic mass found on abdominal ultrasound. At the time of the splenectomy, skin biopsies and an aerobic bacterial culture sample had been collected. The histologic diagnoses of the splenic and skin biopsies were a low-grade stromal sarcoma arising in a complex hyperplastic nodule and transepidermal keratinocyte apoptosis with lymphocyte satellitosis and mild lymphocytic and histiocytic infiltration at the dermal–epidermal junction, respectively. The skin culture revealed coinfection with multidrug resistant Escherichia coli and methicillin-resistant Staphylococcus pseudintermedius. The dog was hospitalized following splenectomy and began treatment with enrofloxacin (2.0 mg/kg per os [PO] q 12 hr) but declined rapidly with further spreading of skin lesions and increasing lethargy and anorexia, prompting a referral.

On physical examination at presentation, the dog was lethargic but responsive. Severe bilateral mucopurulent nasal discharge was present. Dermatologic examination revealed multifocal papular lesions coalescing to irregularly shaped macules and serpiginous plaques that were variably eroded and ulcerated covering ∼70% of the ventral abdomen with increased severity of lesions in the inguinal and axillary regions (Figure 1A). Similar lesions also extended down the hind limbs. The affected areas were moist and weeping a clear exudate. Mucous membrane ulcerations were present in two regions on the right maxillary buccal gums and multifocally around the rectum. The dorsal palpebra, ventral palpebrae, and concave aspects of the pinnae displayed moderate to severe erosion and ulceration with moderate crusting. Mild crusting and erosion were also present on the nasal planum. Paw pads were scaling and mildly depigmented but displayed no evidence of erosion or ulceration. Skin adjacent to lesions was negative for a pseudo-Nikolsky sign. The remainder of the physical examination was unremarkable.

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Complete blood count revealed mild normocytic normochromic regenerative anemia (hematocrit –34.5%; reference range, 35–54%; reticulocytes 92,000) and mild thrombocytosis (634,000 thrombocytes/µL; reference range, 220,000–600,000 thrombocytes/µL). Serum biochemical analysis revealed hypoalbuminemia (2.0 g/dL; reference range 2.6–4.2 g/dL) and hypocalcemia (8.9 mg/dL; reference range 9.4–11.4 mg/dL) as the only significant findings. Repeat complete blood count 24 hr later revealed rare spherocytosis and further decrease in hematocrit (30%; reference range 35–45%). Thoracic and abdominal radiographs were interpreted as normal. Swabs for aerobic bacterial culture were submitted. Combining the chronicity of clinical signs with the extensiveness of the dermatologic disease and histopathology results, a diagnosis of EM major was determined. The dog was hospitalized and treatment initiated with dexamethasone sodium phosphate^a (0.3 mg/kg IV q 24 hr), enrofloxacin^b (20.0 mg/kg IV q 24 hr), pentoxifylline^c (36.3 mg/kg PO q 8 hr), mycophenolate mofetil^d (10.9 mg/kg PO q 12 hr), a continuous rate infusion of fentanyl^e (3.0mcg/kg/hr), intravenous fluids^f (90.0 mL/kg/day), and every-other-day hydrotherapy. After 36 hr of hospitalization and treatment, the dog showed no improvement in clinical status with decreased mentation, appetite, and attitude. At that time it was elected to administer 5 g of human IVIG^g (0.45 mg/kg IV) as a continuous rate infusion over 4.5 hr.⁸ Approximately 2 hr after initiating the IVIG infusion, the dog’s attitude and appetite improved. Forty-eight hours post-IVIG infusion, remarkable improvement was noted in the dog’s appetite, attitude, and dermatologic lesions with a prominent decrease in erythema and exudation. (Figure 1B). Skin culture results revealed methicillin-resistant S pseudintermedius with resistance to enrofloxacin. Therapy with enrofloxacin^b was discontinued and replaced with chloramphenicol^h (28.4 mg/kg PO q 8 hr) based on culture results. Chloramphenicol therapy was initiated after 44 hr of hospitalization, 8 hr following the start of IVIG infusion.

The patient was discharged 5 days after presentation with the following medications: prednisoneⁱ to replace IV dexamethasone (1.9 mg/kg PO q 24 hr), pentoxifylline^c (33.3 mg/kg PO q 8 hr), mycophenolate^d (10.0 mg/kg PO q 12 hr), chloramphenicol^h (28.4 mg/kg PO q 8 hr), omeprazole^j (0.9 mg/kg PO q 24 hr), Vitamin A (10,000 IU PO q 12 hr), mirtazapine^k (1.25 mg/kg PO q 12 hr), maropitant^l (2.0 mg/kg PO q 24 hr), a fentanyl patch^m (25.0 μg/hr), and a 2% miconazole with 2% chlorhexidine gluconate sprayⁿ to be applied every-other-day to skin lesions. Vitamin A was included in the treatment regimen to help counter the negative effects steroids can have on wound healing as there was concern for dehiscence of the abdominal incision.¹¹

Following discharge, the patient remained bright and alert with increased strength, appetite and skin lesion improvement noted daily by the owners (Figures 1C–D). To promote healing of the dog’s abdominal surgical site, 8 days postdischarge the prednisone dose was decreased (0.7 mg/kg PO q 24 hr). Three days later, hematologic analysis was repeated as a result of the previous presence of spherocytosis and recent steroid taper and revealed a regenerative normocytic hyperchromic anemia (hematocrit 17.18%; reference range, 37–54%; mean corpuscular hemoglobin concentration 43.1 g/dL, reference range 31.0–34.0; absolute reticulocyte count 163,900 reticulocytes/µL), with moderate polychromasia on blood smear. Strong agglutination was appreciated on saline agglutination test. The acute severe drop in hematocrit with strong auto-agglutination combined with regeneration and previous rare spherocytosis on analysis prior to discharge supported the diagnosis of concurrent immune-mediated hemolytic anemia (IMHA). Prednisoneⁱ was increased back to the original dose (1.9 mg/kg PO q 24 hr) and slowly tapered over a 3 mo period with multiple recurrent hematologic analyses revealing stable hematocrits within the reference range. The adjunctive immunosuppressive therapy, mycophenolate, remained at the initial dose until 4 mo postdischarge when it was slowly tapered over a month and then discontinued. The dog remained stable and bright with no recurrence of skin lesions or hematologic abnormalities for 7 mo postdischarge. Following this period, the dog slowly became lethargic and hyporexic and liver masses were diagnosed on abdominal ultrasound. The dog was euthanized 1 yr postdischarge and was confirmed to have mesenteric lymph node and liver metastasis from the splenic sarcoma on necropsy.

Discussion

In the present case, a diagnosis of EM major was made as a result of the presence of systemic signs, anorexia and lethargy, and the degree of mucosal involvement. Mucosal surface involvement was noted at two sites, the rectum and oral cavity, and suspected in a third site, the nasal passage, as there was severe bilateral mucopurulent nasal discharge and erosion on the nasal planum noted at presentation.

Although the pathogenesis of EM has been described in human medicine, it remains unknown in veterinary medicine. A study by Affolter et al. used immunohistochemistry to demonstrate a similar inflammatory cell population when comparing samples of dogs with EM to dogs with graft-versus-host disease.¹² This has led to the theory that EM represents a host-specific cell-mediated hypersensitivity reaction, but ultimately, the trigger for the hypersensitivity reaction has not been elucidated.⁷

In veterinary medicine, EM had historically become incorrectly synonymous with an adverse drug reaction, placing it in a spectrum with Steven-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). SJS and TEN are severe, life-threatening, ulcerative cutaneous reactions predominately associated with drug triggers in both human and veterinary medicine. ^2,6,7,13,14 An animal is classified with SJS, SJS-TEN overlap, or TEN when there is an acute onset of severe systemic signs such as lethargy, depression, and anorexia with concurrent acute widespread epidermal ulceration with supporting histopathology. Animals suffering from SJS and TEN also display severe mucosal ulceration with frequent footpad lesions and a positive pseudo-Nikolsky sign. The similarity between EM, SJS, and TEN comes from a similar basic pathogenesis where a misdirected immune system targets keratinocytes leading to apoptosis in all three conditions.^3,15 Because of this similar pathogenesis, these syndromes overlap histologically, making it difficult for pathologists to differentiate between them.^3,5 The classic histopathology finding in cases of EM, SJS, and TEN is interface dermatitis with keratinocyte apoptosis and lymphocyte satellitosis.¹⁶ Recently, Banovic et al. described no difference in the number of apoptotic cells when comparing samples of canine EM with TEN further supporting the fact that the diagnosis of EM, SJS, or TEN is based on the clinical presentation of the animal combined with histology.¹⁴ Clinical presentation or histology alone cannot be used to diagnose a patient with one of these conditions.

In the present case, transepidermal keratinocyte apoptosis with lymphocyte satellitosis and lymphocytic and histiocytic interface infiltrate with multifocal ulceration were present (Figure 2). As mentioned above, these histologic alterations can also be observed in SJS/TEN cases. The extensive skin lesions in this case make it easy to misdiagnose the patient with SJS, as may have happened in previous cases in the literature.¹⁷ Justification for the diagnosis of EM versus SJS stands on the history of this case as well as the dermatologic examination. Cases of SJS/TEN typically have sudden disease onset with severe systemic signs such as anorexia and lethargy. Systemic signs were present in this case; however, both the systemic signs and dermatologic disease developed gradually over the course of 7 wk. On dermatologic examination, the dog had severe erosion and ulceration with a negative pseudo-Nikolsky sign and absent footpad lesions.³ Cases of SJS often have footpad involvement and a positive-pseudo-Nikolsky sign, neither of which were noted in this case.

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Although some cases of EM have been confirmed as triggered by a drug, there are cases in which no cause could be identified.⁵ Reported drugs and conditions potentially associated with EM in veterinary medicine include antibiotics, levamisole, sulfonamides, a beef/soy diet, a commercial dog food, a neutraceutical product, infectious processes and neoplasia.^3,4,18–20 As true causality can be difficult to prove, the association between each trigger is typically anecdotal. In this dog, a sudden worsening in his condition was noted following splenectomy, which coincided with the administration of enrofloxacin. While it is possible that enrofloxacin acted as a trigger to perpetuate clinical disease in this case, the patient was already systemically ill prior to starting the medication. The authors suspect that patients, postoperative decline was more likely a result of the stress of surgery and a preoperative negative energy balance from chronic systemic disease. Ultimately, the authors have no way of knowing if enrofloxacin acted in any way as a drug trigger in this case; however, the dog received a course of enrofloxacin (6.8mg PO q 24h) 6 mo postdischarge for an impacted anal sac, and no recurrence of skin lesions was noted.

The various etiologies of EM combined with the unknown pathogenesis make standardization of treatment difficult. If a drug-induced etiology is suspected, then drug withdrawal may provide clinical resolution and cure.⁷ If no drugs can be identified and clinical signs persist, cases may respond to immunosuppression with corticosteroids and adjunctive agents.^3,4 When therapy is tapered, recurrence is possible.⁴ Human IVIG has been used successfully to treat one cat with EM,¹⁰ one dog with SJS,¹³ and two dogs with severe cutaneous drug reactions suspected to be SJS and SJS-TEN overlap.²¹ IVIG is thought to interact with each disease process in a variety of mechanisms including, but not limited to, mediating Fas-Fas ligand interactions, blocking Fragment crystallizable and neonatal Fragment crystallizable receptors, directly binding auto-antibodies, modulating cytokine synthesis, and inhibiting complement.⁸ The limiting factors regarding IVIG therapy in veterinary medicine are typically associated with the high cost of therapy and concern for a hypersensitivity reaction as a result of the xenoprotein nature of the therapy. Uncommon side effects reported in human medicine that could potentially occur in veterinary cases receiving therapy include hypotension, renal failure, hypercoagulation, hypersensitivity, and anaphylaxis.^8,9 In the present case, immunosuppressive therapy was initiated at presentation. Despite 36 hr of therapy, the patient continued to decline clinically with worsening of his attitude and continued anorexia, which prompted the use of IVIG administration. Despite complete anorexia for 7 days, the dog’s appetite returned within 2 hr of initiating IVIG administration, and his attitude showed remarkable improvement during this timeframe as well. The temporal association between IVIG administration and the patient’s rapid clinical response led the authors to suspect that IVIG treatment was responsible for the improvement; however, this cannot definitively be determined as there were other concurrent therapies including prednisone, pentoxifylline, and mycophenolate. It is also unknown if the dog’s improvement was related to the IVIG alone or if the IVIG worked in a synergistic manner with the other immunosuppressive medications to create the response seen. This is the first successful case report of EM major in a dog treated with a combination of IVIG and immunosuppressive therapy.

IMHA occurs when there is phagocytosis or lysis of red blood cells as a consequence of autoantibodies coating or complement fragments opsonizing red blood cells.¹⁷ The final diagnosis of IMHA is made when there is accelerated red blood cell destruction causing anemia with concurrent evidence of hemolysis and an underlying immune-mediated pathogenesis.^17,22 The diagnosis of IMHA in this dog was supported by the presence of spherocytes, strong auto-agglutination, and regeneration evident by reticulocytosis. The association between EM and IMHA in this case is unclear. The IMHA could be originating from the same presumed idiopathic primary immune dysfunction that caused the EM or the IMHA could have been secondary to the numerous drugs administered in this case to treat the EM. Unfortunately, there is no clear way to determine the cause of the IMHA or EM in this case; however, to the authors’ knowledge, this is the first report to describe EM major with concurrent IMHA.

The dog in this case was also diagnosed with a low-grade splenic stromal sarcoma that was removed while the patient was debilitated with severe skin disease. Although IMHA has been reported secondary to numerous neoplastic conditions, EM has only been suspected as secondary to neoplastic conditions in dogs.^3,17 It was considered that both the IMHA and EM in the present case were paraneoplastic syndromes; however, the presence of confirmed metastases at necropsy makes this unlikely as the EM and IMHA should have recurred upon discontinuation of immunosuppressive therapy. Overall, the connection between EM, IMHA and the splenic stromal sarcoma in this case is unclear.

Conclusion

This is the first report of a dog with EM major that was successfully treated with a combination of IVIG and immunosuppressive therapy. This is also the first case report to describe a dog who developed EM major with concurrent IMHA. Further studies are needed to investigate the pathogenesis of EM in veterinary medicine so that standardized treatments can be developed.