Erosive and ulcerative stomatitis in dogs and cats: which immune-mediated diseases to consider?

Immune-mediated and autoimmune diseases of the skin often present with oral cavity involvement. Autoimmune subepidermal blistering diseases and pemphigus vulgaris are classic examples. While the primary lesions (vesicles and bullae) are relatively specific, these fragile lesions evolve rapidly into erosions and ulcers, which are lesion types that overlap with many diseases. Furthermore, some immune-mediated diseases such as severe adverse drug reactions, lupus diseases, canine uveodermatological syndrome, and vasculitis, may or may not involve the oral cavity, and often nonoral clinical manifestations are more diagnostic. In these situations, disease knowledge combined with signalment, lesion distribution, and history help to narrow the differentials. Surgical biopsy is required for confirmation in most diseases, while immunosuppressive treatments most typically involve glucocorticoids with or without nonsteroidal immunosuppressants.

Comorbidity of ectopic thymoma-associated exfoliative dermatitis and pemphigus foliaceus in a cat.

An 8-year-old cat was presented with pruritus, purulent paronychia, scaling, crusting, and spontaneous alopecia. Histopathology revealed intraepidermal neutrophilic pustular acantholytic dermatitis and hyperkeratotic cytotoxic interface dermatitis. No thoracic mass was seen on a lateral radiograph. Ectopic thymoma was discovered on necropsy. This case highlights the necessity for thorough investigation of any case of feline exfoliative dermatitis and pemphigus foliaceus for the presence of thymoma. Key clinical message: Comorbidity of exfoliative dermatitis and pemphigus foliaceus in a cat should prompt a thorough investigation for presence of a thymoma, possibly with advanced imaging techniques.

Comorbidité de dermatite exfoliative et de pemphigus foliacé associés à un thymome ectopique chez un chat. Un chat de 8 ans a été présenté avec prurit, panaris purulent, desquamation, croûtes et alopécie spontanée. L'histopathologie a révélé une dermatite acantholytique neutrophilique intra-épidermique et une dermatite d'interface cytotoxique hyperkératosique. Aucune masse thoracique n'a été observée sur une radiographie latérale. Un thymome ectopique a été découvert à l'autopsie. Ce cas met en évidence la nécessité d'une investigation approfondie de tout cas de dermatite exfoliative féline et de pemphigus foliacé pour la présence d'un thymome.Message clinique clé :La comorbidité d'une dermatite exfoliative et de pemphigus foliacé chez un chat devrait inciter à une enquête approfondie pour la présence d'un thymome, éventuellement avec des techniques d'imagerie avancées.(Traduit par Dr Serge Messier).

Bullous amyloidosis in a horse: first description in veterinary medicine.

BACKGROUND: Bullous amyloidosis is a rare disease in humans that has not been described in a veterinary species in the peer-reviewed literature. The human disease is characterised by haemorrhagic vesicles and bullae on the skin and mucosae, which form due to amyloid deposition. HYPOTHESIS/OBJECTIVES: To describe the clinical features, laboratory analysis and histopathological features of an unique presentation of bullous disease in a horse. ANIMALS: A 17-year-old thoroughbred mare presented for weight loss and severe oral cavity ulcers. METHODS AND MATERIALS: Investigations involved haematological evaluation, chemistry profiles, gastroscopy and serum protein electrophoresis, and, postmortem, histopathological evaluation, Congo-red staining and transmission electron microscopy (TEM). RESULTS: Haemorrhagic vesicles and bullae occurred on the mucosa of the oral cavity, lips, oesophagus and stomach, and much less the muzzle, face and mucocutaneous areas of the perineum, where scarring was evident. Histopathological evaluation and Congo-red staining confirmed the presence of amyloid deposits in dermis and submucosa, in association with vesicle and bulla formation, consistent with bullous amyloidosis. TEM confirmed amyloid fibril deposition in the dermis and along the basement membrane zone. Clefts occurred in the superficial dermis and submucosa, which explained haemorrhage and scarring. The presence of a polyclonal gammopathy and the rapid abolishment of Congo-red staining with performate pretreatment supported serum amyloid A and secondary amyloidosis. CONCLUSION AND CLINICAL IMPORTANCE: Bullous amyloidosis is a novel disease of the horse and a newly recognised differential for bullous disease, for which the haemorrhagic nature of bullae, scarring and deep secondary ulcers are considered clinical clues to the condition.

Rapid response of hyperkeratotic erythema multiforme to oclacitinib in two dogs.

BACKGROUND: Hyperkeratotic erythema multiforme (HKEM) is a clinically distinct dermatosis and poorly characterized syndrome, comprised of hyperkeratotic plaques with variable symmetry and apoptosis similar to "classic" erosive canine EM. Hyperkeratotic EM has a protracted clinical course and, although treatments with glucocorticoids, azathioprine and/or ciclosporin have been tried, rates of remission are low. OBJECTIVES: To describe successful treatment of HKEM in two dogs using oclacitinib. ANIMALS: A 7-year-old, spayed Havanese dog (Case 1) and a 1-year-old, intact cryptorchid Dachshund dog (Case 2). METHODS: Case characterization and clinical diagnoses were based on lesion character, surgical biopsy, cytological evaluation, culture, direct immunofluorescence (DIF) and expected responses to treatments. RESULTS: Both cases exhibited multifocal, often symmetrical hyperkeratotic plaques with adherent scale. Histological findings revealed prominent epidermal hyperplasia, parakeratotic hyperkeratosis, lymphocytic dermatitis and transepidermal apoptosis with lymphocytic satellitosis. DIF revealed fine, patchy IgG, IgM and IgA basement membrane deposits (Case 2). Both dogs exhibited rapid improvement with oral oclacitinib (0.6-0.9 mg/kg twice daily) with a complete remission of clinical signs observed in 12 and seven weeks in cases 1 and 2, respectively. CONCLUSION AND CLINICAL IMPORTANCE: Oclacitinib could be considered as a fast-acting and effective treatment option for HKEM in dogs.

Efficacy of a Bruton's Tyrosine Kinase Inhibitor (PRN-473) in the treatment of canine pemphigus foliaceus.

BACKGROUND: Bruton's tyrosine kinase (BTK) is important in B-cell signalling. Efficacy has been reported for BTK inhibitors (BTKi) in human autoimmune diseases. Canine pemphigus foliaceus (cPF) is the most common canine autoimmune skin disease. OBJECTIVES: To determine the safety and efficacy of a BTKi in cPF treatment. ANIMALS: Nine privately owned dogs. METHODS AND MATERIALS: Nine dogs diagnosed with PF were administered BTKi PRN473. Initial dosages were ≈15 mg/kg once daily, increased to twice daily if inadequate response was seen. Treatment continued for a maximum of 20 weeks, attempting decrease to every other day. Dogs were monitored with complete blood counts, serum biochemistry panels, urinalyses and evaluated with a modified version of a validated human Pemphigus Disease Activity Index (cPDAI). Anti-desmocollin-1 (DSC-1) and desmoglein-1 (DSG-1) immunoglobulin G (IgG) titres were performed before and after the treatment period. Drug bound to target was measured in peripheral blood mononuclear cells. RESULTS: All nine dogs showed reduction in lesions and cPDAI score during the first two weeks of treatment. At the end of the study, four responses were considered "good", two "fair", two "poor" and one dog withdrawn due to recurrence of a previously excised mast cell tumour. Four dogs continued to improve by Week 4; three sustained near complete remission by study's end. The anti-DSC-1 IgG titre decreased in three dogs, increased in two, was undetected in three and was not performed in the withdrawn dog. No dogs had detectable IgG to DSG1. Possible adverse effects occurred in three dogs. CONCLUSIONS AND CLINICAL IMPORTANCE: Bruton's tyrosine kinase inhibitor monotherapy may have beneficial effects in some cases of cPF.

Endothelial alterations in a canine model of immune thrombocytopenia.

Bleeding heterogeneity amongst patients with immune thrombocytopenia (ITP) is poorly understood. Platelets play a role in maintaining endothelial integrity, and variable thrombocytopenia-induced endothelial changes may influence bleeding severity. Platelet-derived endothelial stabilizers and markers of endothelial integrity in ITP are largely underexplored. We hypothesized that, in a canine ITP model, thrombocytopenia would lead to alterations in the endothelial ultrastructure and that the Von Willebrand factor (vWF) would serve as a marker of endothelial injury associated with thrombocytopenia. Thrombocytopenia was induced in healthy dogs with an antiplatelet antibody infusion; control dogs received an isotype control antibody. Cutaneous biopsies were obtained prior to thrombocytopenia induction, at platelet nadir, 24 hours after nadir, and on platelet recovery. Cutaneous capillaries were assessed by electron microscopy for vessel thickness, the number of pinocytotic vesicles, the number of large vacuoles, and the number of gaps between cells. Pinocytotic vesicles are thought to represent an endothelial membrane reserve that can be used for repair of damaged endothelial cells. Plasma samples were assessed for vWF. ITP dogs had significantly decreased pinocytotic vesicle numbers compared to control dogs (P = 0.0357) and the increase in plasma vWF from baseline to 24 hours correlated directly with the endothelial large vacuole score (R = 0.99103; P < 0.0001). This direct correlation between plasma vWF and the number of large vacuoles, representing the vesiculo-vacuolar organelle (VVO), a permeability structure, suggests that circulating vWF could serve as a biomarker for endothelial alterations and potentially a predictor of thrombocytopenic bleeding. Overall, our results indicate that endothelial damage occurs in the canine ITP model and variability in the degree of endothelial damage may account for differences in the bleeding phenotype among patients with ITP.

Generalized papillomatosis in three horses associated with a novel equine papillomavirus (EcPV8).

BACKGROUND: Currently, seven equine papillomaviruses (PV) are known and are associated with one of three different and distinct clinical presentations. HYPOTHESIS/OBJECTIVES: To report the clinical, histopathological and immunohistochemical findings in horses with generalized papillomatosis associated with a novel equine PV, Equus caballus papillomavirus 8 (EcPV8). ANIMALS: Three client-owned quarter horses. METHODS: Case report, retrospective. RESULTS: Dozens to thousands of papillomas involved the axilla, inguinal area and proximal limbs as well as the ventral and lateral neck, thorax and abdomen. Lesions were sometimes confluent in ventral areas. Fewer lesions were on the face, ears, distal limbs and genitalia. Plaque-type papillomas were small, 0.5 to 1.5 cm in diameter and hyperkeratotic. Histologically, plaque-type papillomas prominently involved follicular infundibula. Immunohistochemical findings demonstrated PV antigen in superficial keratinocyte nuclei. PCR using degenerate primers for the PV L1 gene and sequencing of amplicons revealed PV DNA sequences that were 98% identical for all three cases, but shared <70% identity to other PVs. Horses were otherwise healthy; serum immunoglobulin levels and peripheral blood lymphocyte phenotyping did not identify a known immunodeficiency syndrome. Lesions nearly completely resolved after 1.5 years in one horse and persisted for two years in another, despite intralesional human IFN-alpha treatment. The oldest horse was lost to follow-up. CONCLUSION AND CLINICAL IMPORTANCE: A novel equine papillomavirus (EcPV8) is associated with a distinct, plaque-type, generalized papillomatosis. Papillomas persisted for months to years, with or without treatment.

Localized demodicosis due to Demodex cati on the muzzle of two cats treated with inhalant glucocorticoids.

BACKGROUND: Feline demodicosis due to Demodex cati is a rare skin disease often associated with concurrent disease and generalized immunosuppression. Local immunosuppression due to the application of topical immunomodulatory drugs, such as glucocorticoids and tacrolimus, or by tumour cells has been suggested as a potential trigger for development of localized demodicosis in humans and animals. OBJECTIVES: The goal was to describe two cats with asthma that developed localized demodicosis on the muzzle as a result of chronic therapy with a glucocorticoid administered via dispensing inhaler mask. RESULTS: In both cats, the muzzle area exposed to the fluticasone-dispensing chamber exhibited patchy alopecia, mild erythema, crusting and scaling. Deep skin scraping revealed D. cati. Discontinuation or reduction of fluticasone and administration of milbemycin resulted in resolution of clinical signs within 2 months in both cats. A negative skin scrape was obtained after 7 months of milbemycin in one of the cats. CONCLUSIONS AND CLINICAL IMPORTANCE: Demodicosis should be considered as a possible differential diagnosis in cats with primary alopecia or other skin lesions on the face exposed to inhalant glucocorticoids. Minimization of contact between the inhalant glucocorticoid and the skin can be achieved by wiping residual powder from the face and by keeping the mask tightly pressed to the skin to avoid contact with the surrounding area.

Deficient plakophilin-1 expression due to a mutation in PKP1 causes ectodermal dysplasia-skin fragility syndrome in Chesapeake Bay retriever dogs.

In humans, congenital and hereditary skin diseases associated with epidermal cell-cell separation (acantholysis) are very rare, and spontaneous animal models of these diseases are exceptional. Our objectives are to report a novel congenital acantholytic dermatosis that developed in Chesapeake Bay retriever dogs. Nine affected puppies in four different litters were born to eight closely related clinically normal dogs. The disease transmission was consistent with an autosomal recessive mode of inheritance. Clinical signs occurred immediately after birth with superficial epidermal layers sloughing upon pressure. At three month of age, dogs exhibited recurrent superficial skin sloughing and erosions at areas of friction and mucocutaneous junctions; their coat was also finer than normal and there were patches of partial hair loss. At birth, histopathology revealed severe suprabasal acantholysis, which became less severe with ageing. Electron microscopy demonstrated a reduced number of partially formed desmosomes with detached and aggregated keratin intermediate filaments. Immunostaining for desmosomal adhesion molecules revealed a complete lack of staining for plakophilin-1 and anomalies in the distribution of desmoplakin and keratins 10 and 14. Sequencing revealed a homozygous splice donor site mutation within the first intron of PKP1 resulting in a premature stop codon, thereby explaining the inability to detect plakophilin-1 in the skin. Altogether, the clinical and pathological findings, along with the PKP1 mutation, were consistent with the diagnosis of ectodermal dysplasia-skin fragility syndrome with plakophilin-1 deficiency. This is the first occurrence of ectodermal dysplasia-skin fragility syndrome in an animal species. Controlled mating of carrier dogs would yield puppies that could, in theory, be tested for gene therapy of this rare but severe skin disease of children.

Clinical and immunological heterogeneity of canine subepidermal blistering dermatoses with anti-laminin-332 (laminin-5) auto-antibodies.

Laminin-332 (laminin-5) is a basement membrane heterotrimeric protein composed of alpha-3, beta-3 and gamma-2 laminin chains. Laminin-332 polypeptides are targeted by auto-antibodies in human patients with mucous membrane (cicatricial) pemphigoid or, more rarely, subepidermal vesicular diseases that resemble epidermolysis bullosa acquisita (EBA) or bullous pemphigoid (BP). The objectives of this report were to characterize the clinical, histopathological and immunological characteristics of nine dogs with auto-antibodies targeting laminin-332. Immunological investigations consisted of direct immunofluorescence (IF), indirect IF with intact and salt-split canine gingival, and salt-split normal or laminin-332-deficient human skin, immunoblotting with purified human laminin-332 and immunoblotting with recombinant NC1 domain of human collagen VII. All dogs exhibited varying degrees of skin blistering and ulceration associated with microscopic subepidermal vesiculation with or without inflammatory cells. Indirect IF established that circulating IgG auto-antibodies bound the dermal side of salt-split canine lip and human skin. In five dogs, IgG variably recognized the basement membrane of laminin-332-deficient human skin (three dogs negative, two dogs positive). In all nine dogs, IgG auto-antibodies detected purified human laminin-332 by immunoblotting. In two dogs, additional targeting of collagen VII-NC1 was present. These observations establish laminin-332 as a novel basement membrane antigen in dogs with autoimmune blistering diseases with variable clinical phenotypes. The names 'acquired junctional epidermolysis bullosa', 'anti-laminin-332 mucous membrane pemphigoid (MMP)' and 'mixed auto-immune subepidermal blistering dermatosis' are proposed for dogs with clinical signs reminiscent of EBA, MMP or BP respectively.

Canine cutaneous epitheliotropic T-cell lymphoma with vesiculobullous lesions resembling human bullous mycosis fungoides.

The broad spectrum of clinical signs in canine cutaneous epitheliotropic T-cell lymphoma mimics many inflammatory skin diseases and is a diagnostic challenge. A 13-year-old-male castrated golden retriever crossbred dog presented with multifocal flaccid bullae evolving into deep erosions. A shearing force applied to the skin at the periphery of the erosions caused the epidermis to further slide off the dermis suggesting intraepidermal or subepidermal separation. Systemic signs consisted of profound weight loss and marked respiratory distress. Histologically, the superficial and deep dermis were infiltrated by large, CD3-positive neoplastic lymphocytes and mild epitheliotropism involved the deep epidermis, hair follicle walls and epitrichial sweat glands. There was partial loss of the stratum basale. Bullous lesions consisted of large dermoepidermal and intraepidermal clefts that contained loose accumulations of neutrophils mixed with fewer neoplastic cells in proteinaceous fluid. The lifted epidermis was often devitalized and bordered by hydropic degeneration and partial epidermal collapse. Similar neoplastic lymphocytes formed small masses in the lungs associated with broncho-invasion. Clonal rearrangement analysis of antigen receptor genes in samples from skin and lung lesions using primers specific for canine T-cell receptor gamma (TCRgamma) produced a single-sized amplicon of identical sequence, indicating that both lesions resulted from the expansion of the same neoplastic T-cell population. Macroscopic vesiculobullous lesions with devitalization of the lesional epidermis should be included in the broad spectrum of clinical signs presented by canine cutaneous epitheliotropic T-cell lymphoma.