Frane Banovic

Mucocutaneous lupus erythematosus in dogs (21 cases).

BACKGROUND The diagnosis of dogs with chronic juxtamucosal erosive lesions and histopathology typical of cutaneous lupus erythematosus (CLE) is unclear. HYPOTHESIS/OBJECTIVES We report herein 21 dogs with mucocutaneous erosive lesions and lupus-specific histopathology that we propose to be affected with mucocutaneous lupus erythematosus (MCLE), another variant of chronic CLE. METHODS Inclusion criteria were the presence of the following: (i) a >2 month history of chronic or recurrent skin lesions; (ii) erosions or ulcers predominating at mucosae or mucocutaneous junctions; (iii) microscopic lesions of CLE (i.e. a lymphocyte-rich interface dermatitis with basal keratinocyte damage); and (iv) a lack of complete remission following antimicrobials. Clinical questionnaires and skin biopsies were reviewed. Direct immunofluorescence and antinuclear antibody serology were performed whenever possible. RESULTS More than half of the 21 dogs were German shepherds or their crosses. The disease affected mostly dogs in their mid-adulthood and there was an over-representation of females. Erosions and ulcers predominated at genital/perigenital and anal/perianal areas, with a lower frequency of involvement of periocular, perioral and perinasal regions. In these dogs, there were no clinical signs suggestive of an associated systemic lupus erythematosus. Microscopic lesions were specific for CLE, but they were patchy and often infected with bacteria. The most common immunological finding was focal IgG deposition at the basement membrane zone. Lesions responded to varying interventions, but oral glucocorticoids led to a shorter time to complete remission. Relapses were common upon treatment tapering. CONCLUSIONS AND CLINICAL IMPORTANCE These observations support MCLE being another variant of canine CLE.

Clinical and Microscopic Characteristics of Canine Toxic Epidermal Necrolysis

Canine toxic epidermal necrosis (TEN), a rare and life-threatening cutaneous drug reaction, traditionally has been described as full-thickness devitalization of the epidermis with minimal dermal inflammation; however, few reports detail the histologic findings. We characterize the clinical features and histologic variations of 3 canine TEN patients. Clinically, irregular erythematous and purpuric macules evolved into widespread and severely painful erosions. The number of eroded mucosae varied; however, periocular and perilabial mucocutaneous junctions frequently were affected. Thirteen of 17 biopsies were evaluated. Apoptosis at multiple epidermal levels was the most common pattern of epidermal necrosis (12/13 biopsies, 92%). In contrast, full-thickness coagulation necrosis was present less often (7/13 biopsies, 52%). Lymphocytic interface dermatitis was the predominant inflammatory pattern, and intraepidermal lymphocytes, along with fewer histiocytes, were present to some degree in all samples along with lymphocytic satellitosis of apoptotic keratinocytes. The sequence of changes points to lymphocyte-mediated keratinocyte apoptosis as an early step in lesion development with subsequent variation in progression to coagulation necrosis among patients. Histopathologic changes overlapped with those reported for erythema multiforme, in contrast to traditional histologic descriptions of canine TEN. A specific algorithm for assessment of drug causality in epidermal necrolysis (ALDEN) was applied for each patient; carprofen was associated with a probable score for causality in 1 dog. Clinicians should be encouraged to take multiple biopsies in TEN suspect cases as nearly 25% of all biopsies lacked epithelium and were not diagnostic.

Ciclosporin therapy for canine generalized discoid lupus erythematosus refractory to doxycycline and niacinamide

BACKGROUND Generalized discoid lupus erythematosus (DLE) is an autoimmune skin disease variant rarely reported in dogs. The antimalarial immunomodulator hydroxychloroquine has been suggested as maintenance therapy for generalized DLE in one dog, but several recurrences were noted in the 1 year follow-up of that patient. HYPOTHESIS/OBJECTIVE To describe the effective treatment of generalized DLE with ciclosporin in one dog. ANIMAL A 6-year-old, castrated male crossbred dog was presented with pruritic, well-demarcated annular to polycyclic, hyperpigmented plaques with marginal erythema on the dorsal head, neck, trunk and medial extremities; these had been nonresponsive to treatment with doxycycline and niacinamide. METHODS Investigation included complete blood count, serum chemistry profile, urinalysis, serum antinuclear antibody test, histopathological examination and direct immunofluorescence testing of skin biopsies. RESULTS The presence of lymphocyte-rich interface dermatitis on histology, together with generalized chronic recurrent hyperpigmented plaques, was consistent with the diagnosis of a generalized variant of DLE. The absence of systemic signs and unremarkable laboratory tests excluded concurrent systemic lupus erythematosus. Treatment was initiated with oral dexamethasone and ciclosporin. After 1 month, dexamethasone was discontinued and oral ketoconazole was added to the therapeutic regimen. Four months later, pruritus and erythema resolved, with most skin lesions becoming impalpable. Over the last 6 months, the patients DLE was maintained in remission with oral ciclosporin and ketoconazole in combination every 3 days. CONCLUSIONS AND CLINICAL IMPORTANCE The combination of ciclosporin and ketoconazole appeared effective to induce and maintain lesion remission in this dog with generalized DLE.

Deep pyoderma caused by Burkholderia cepacia complex associated with ciclosporin administration in dogs: a case series.

BACKGROUND Bacteria of the Burkholderia cepacia complex (Bcc) are ubiquitous Gram-negative bacilli associated with fatal nosocomial infections in humans; multi-antibiotic resistance makes this organism a serious threat in hospital settings. OBJECTIVE To describe the historical, clinicopathological and treatment characteristics of Bcc-associated deep skin infections in dogs. ANIMALS Six dogs with skin infections in which skin bacterial cultures resulted in pure growth of Bcc. METHODS Retrospective study with review of medical records and skin biopsies. RESULTS All dogs were receiving oral ciclosporin at the time of skin infection development. All dogs were castrated males and four of six were West Highland white terriers. Cutaneous lesions consistent with deep pyoderma were confined mainly to the trunk. In all dogs skin cytology revealed a strong inflammatory response, with moderate to abundant numbers of intracellular (neutrophils and macrophages) and extracellular bacilli. In three dogs histopathology showed a multifocal, nodular to coalescing pyogranulomatous dermatitis associated with multifocal folliculitis and furunculosis. Tissue Giemsa and Gram stains identified numerous Gram-negative rods within macrophages. Antimicrobial susceptibility testing revealed multidrug-resistant Bcc strains with sensitivity to trimethoprim/sulfonamides in all dogs and to marbofloxacin, piperacillin and ceftazidime in three dogs. Successful treatment was achieved in all dogs using trimethoprim/sulfonamides or quinolones (marbofloxacin, ciprofloxacin) or doxycycline in conjunction with ciclosporin withdrawal. CONCLUSIONS AND CLINICAL IMPORTANCE Clinicians should be aware of the rare potential for Bcc-associated deep skin infections in dogs receiving oral ciclosporin. Owners should be made conscious of the potential transmission risk to humans or other animals.

Cutaneous lupus erythematosus in dogs: a comprehensive review

Since the first description of discoid lupus erythematosus (LE) in two dogs in 1979, the spectrum of canine cutaneous lupus erythematosus (CLE) variants has expanded markedly.In this review, we first propose an adaptation of the Gilliam-Sontheimer classification of CLE for dogs. We then review the signalment, clinical signs, laboratory and histopathology and treatment outcome of the currently recognized variants of canine CLE, which are vesicular CLE, exfoliative CLE, mucocutaneous LE and facial or generalized discoid LE. We end with a short description of the rare cutaneous manifestations of systemic LE in dogs.Canine CLE variants are heterogeneous, some of them mirror their human counterparts while others appear—thus far—unique to the dog. As most CLE subtypes seem to have a good prognosis after diagnosis, veterinarians are encouraged to become familiar with the spectrum of often-characteristic and unique clinical signs that would permit an early diagnosis and the rapid implementation of an effective treatment.

Apoptosis as a Mechanism for Keratinocyte Death in Canine Toxic Epidermal Necrolysis.

In humans and dogs, toxic epidermal necrolysis (TEN) is a life-threatening dermatosis characterized by sudden epidermal death resulting in extensive skin detachment. There is little information on the pathogenesis of keratinocyte cell death in canine TEN. We studied the occurrence of apoptosis in skin lesions of dogs with TEN to determine if apoptosis contributes to the pathogenesis of this disease. Immunostaining with antibodies to activated caspase-3 and the terminal deoxynucleotidyl-transferase (TdT)–mediated deoxyuridine triphosphate (dUTP) nick-end labeling technique revealed positive apoptotic keratinocytes in basal and suprabasal epidermal compartments in 17 biopsy specimens collected from 3 dogs with TEN and 16 from 3 dogs with erythema multiforme (EM). There was no significant difference in the number of positively stained epidermal cells between TEN and EM. These results suggest that apoptosis of epidermal keratinocytes and lymphocytic satellitosis represent one of the early steps in the pathogenesis of canine TEN, as in the human disease counterpart.

Therapeutic effectiveness of calcineurin inhibitors in canine vesicular cutaneous lupus erythematosus

BACKGROUND Oral and topical calcineurin inhibitors (CIs) have been reported to lead to complete lesion remission in several dogs with vesicular cutaneous lupus erythematosus (VCLE). OBJECTIVES To report retrospectively on the effectiveness and adverse effects of systemic (ciclosporin) and/or topical (tacrolimus/pimecrolimus) CIs in 11 dogs with VCLE. METHODS Inclusion criteria were: (i) presence of characteristic annular, polycyclic or serpiginous ulcerations distributed over the groin, axillae and/or ventral abdomen; (ii) a histopathological diagnosis of VCLE (i.e. a lymphocyte-rich interface dermatitis with vesiculation); (iii) treatment that included CIs for at least eight weeks; and (iv) follow-up until death/euthanasia or for a minimum of 12 months post-diagnosis. RESULTS Initial therapy included the avoidance of excessive sun exposure, oral glucocorticoids [six of 11 dogs (55%); progressively tapered over a month] and once daily ciclosporin [11 dogs (100%); median 5.8 mg/kg]. A complete remission (CR) of signs occurred between days 35 and 70 after starting CIs in eight dogs (73%); increasing ciclosporin dosage and adding topical tacrolimus induced a CR in two additional dogs (18%). Relapses were common when doses were tapered or discontinued. With the exception of three dogs that were euthanized, clinical signs were maintained in CR with oral ciclosporin (eight of eight dogs treated, 100%) or topical tacrolimus/pimecrolimus (four of eight dogs; 50%) with a median follow-up of 2.9 years. CONCLUSIONS AND CLINICAL IMPORTANCE These observations support CIs as the preferable therapeutic alternatives to long-term immunosuppression with oral glucocorticoids in dogs with VCLE.

The anti-inflammatory effect of topical tofacitinib on immediate and late-phase cutaneous allergic reactions in dogs: a placebo-controlled pilot study

BACKGROUND Topical Janus kinase (JAK) inhibition is a promising therapeutic target for several inflammatory skin diseases of humans. OBJECTIVES To evaluate the anti-inflammatory effect of tofacitinib, a JAK 1/3 inhibitor, on immediate and late-phase skin reactions in dogs. ANIMALS Five healthy laboratory beagle dogs. METHODS Topical tofacitinib (total daily dosage: 0.5 mg/cm2 ) or its gel vehicle were applied on either the left or right lateral thorax of each dog for eight days. Three days before application and after eight days of topical treatment, intradermal injections of histamine and anticanine-IgE antibodies were performed on both sides; they were evaluated by an investigator blinded to the interventions. RESULTS The tofacitinib gel was well-tolerated; one dog developed mild erythema at Day 5 that resolved by the next application. Treatment with tofacitinib reduced histamine and anticanine-IgE global wheal scores (one-way ANOVA, P ≤ 0.005 for both) compared to baseline; there was no significant difference for the vehicle placebo (histamine; P = 0.163; IgE, P = 0.223). Late-phase reactions (LPRs) were markedly, but not significantly reduced after tofacitinib treatment (P = 0.071). A blinded histological evaluation of 6 h-anti-IgE-associated LPRs revealed a significant reduction in the total leucocyte superficial dermal cellularity (P = 0.022), as well as eosinophil (P = 0.022) and mast cell (P = 0.022) counts at tofacitinib-treated sides compared with pretreatment values. Post-treatment complete blood counts and serum chemistry profiles did not show relevant tofacitinib-induced changes. CONCLUSIONS Our observations suggest that topical tofacitinib exerts an inhibitory effect on activated canine skin-emigrating immune cells; this drug should be investigated further as a topical immunosuppressive drug in dogs.

Diluted sodium hypochlorite (bleach) in dogs: antiseptic efficacy, local tolerability and in vitro effect on skin barrier function and inflammation

BACKGROUND Diluted sodium hypochlorite represents an inexpensive and widely available topical antiseptic, but there are no tolerability and efficacy data in veterinary dermatology. OBJECTIVES To determine the in vivo antibacterial effect and tolerability of topical diluted bleach application and to assess its in vitro effect on skin barrier lipids and anti-inflammatory properties on keratinocytes. METHODS Topical hypochlorite at 0.05% and tap water were applied to both sides of the thorax of four healthy dogs. The anti-inflammatory effect on canine keratinocytes was determined by real-time polymerase chain reaction; skin barrier integrity was assessed by evaluating stratum corneum lipid changes in canine stratified epidermal constructs. RESULTS The cell viability of primary keratinocytes treated with water and diluted hypochlorite at 0.005 and 0.01%, reduced the percentage of viable cells by 10%. The exposure of primary keratinocytes to 0.005% diluted hypochlorite significantly reduced the induction of inflammatory genes chemokine ligand-2 (CCL2; P = 0.015) and thymus and activation-regulated chemokine (TARC/CCL17, P = 0.032). There were no changes in skin lipid ceramide and nonceramide fractions in stratified epidermal constructs cultured for 17 days with 0.05% hypochlorite. Topical hypochlorite at 0.05% and tap water were well-tolerated without signs of skin irritation. Although a marked reduction in bacterial counts was seen within 20 min of diluted bleach application compared to the tap water control, this was only marginally significant (P = 0.06). CONCLUSIONS AND CLINICAL IMPORTANCE The results indicate that a topical diluted bleach solution, at either 0.05 or 0.005% hypochlorite concentrations, is a well-tolerated antiseptic that also exhibits anti-inflammatory properties.

Canine Cutaneous Lupus Erythematosus: Newly Discovered Variants

As the spectrum of canine cutaneous lupus erythematosus (CLE) variants has expanded markedly in the recent 2 decades, veterinarians are encouraged to become familiar with the characteristic clinical features of CLE variants to permit early diagnosis and appropriate treatment. This article describes the signalment, clinical signs, treatment outcome, and laboratory and histopathology findings of 2 new canine CLE variants, generalized discoid lupus erythematosus and mucocutaneous lupus erythematosus.