Canine cutaneous lupus erythematosus with prominent interdigital lesions in two greyhounds.

Canine cutaneous lupus erythematosus (CCLE) is a well-described, yet uncommon, autoimmune disease which can present clinically with different variants. This case report describes the clinical and histopathological presentation, and treatment response, of CCLE affecting a novel location, the interdigital skin, in two unrelated greyhounds.

O lúpus eritematoso cutâneo canino (LECC) é uma doença autoimune bem descrita, porém incomum, que pode se apresentar clinicamente com diferentes variantes. Este relato de caso descreve a apresentação clínica e histopatológica, e a resposta ao tratamento, do LECC afetando uma nova localização, a pele interdigital, em dois galgos não aparentados.

El lupus eritematoso cutáneo canino (CCLE) es una enfermedad autoinmune bien descrita, aunque poco frecuente, que puede presentarse clínicamente con diferentes variantes. Este informe de caso describe la presentación clínica e histopatológica, y la respuesta al tratamiento, de CCLE que afecta a una nueva ubicación, la piel interdigital, en dos galgos no relacionados.

Le lupus érythémateux cutané canin (LECC) est une maladie auto-immune bien documentée, mais peu fréquente, qui peut se présenter cliniquement sous différents variants. Ce rapport clinique décrit la présentation clinique et histopathologique, ainsi que la réponse au traitement, du LECC affectant une nouvelle localisation, la peau interdigitée, de deux lévriers non apparentés.

German Shorthaired Pointer dogs with exfoliative cutaneous lupus erythematosus develop immune-complex membranous glomerulonephropathy.

German Shorthaired Pointer (GSHP) dogs with a UNC93B1 gene mutation develop exfoliative cutaneous lupus erythematosus (ECLE) and kidney disease resembling lupus nephritis in humans. The objective of this study was to characterize the kidney disease by light microscopy, immunofluorescence, and electron microscopy in a population of GSHP dogs with ECLE. Medical records were reviewed, and light microscopy of kidneys from 7 GSHP dogs with a previous histologic diagnosis of ECLE was performed. Immunofluorescence of fresh-frozen kidney from 1 dog and transmission electron microscopy of kidney from that dog and 2 additional dogs were performed. Five of 7 dogs had proteinuria diagnosed by urinalysis or urine protein-to-creatinine ratio. Two of 7 dogs were intermittently hypoalbuminemic, and none were azotemic. Histologic findings included early (2 dogs) to late (5 dogs) membranous glomerulonephropathy characterized by mild-to-severe glomerular capillary loop thickening and tubular proteinosis. In all 7 cases, trichrome staining revealed red granular immune deposits on the subepithelial surface of the glomerular basement membrane. Immunofluorescence revealed strong granular labeling for immunoglobulins and complement protein C3. Electron microscopy demonstrated subepithelial electron-dense immune deposits encircled by the remodeled glomerular basement membrane. These findings are diagnostic of immune-complex membranous glomerulonephropathy and are similar to class V lupus in humans. This cohort of GSHP dogs with ECLE developed immune-complex membranous glomerulonephropathy, which we hypothesize is a manifestation of systemic lupus erythematosus. GSHP dogs with ECLE should undergo clinical evaluation of renal function for early identification and treatment.

Effective treatment of canine chronic cutaneous lupus erythematosus variants with oclacitinib: Seven cases.

BACKGROUND: The treatment of canine chronic cutaneous lupus erythematosus (CCLE) variants generally requires immunosuppression, which often results in potentially severe adverse effects. Janus kinase inhibitors, like oclacitinib, might be a valuable treatment option due to their rapid inhibition of the action of interferons known to be relevant in the pathogenesis of CCLE. OBJECTIVES: To report the efficacy and safety of oral oclacitinib for the treatment of canine CCLE variants. ANIMALS: Seven dogs were diagnosed with CCLE based on clinical signs and compatible histopathological findings. MATERIALS AND METHODS: Oclacitinib was administered at the induction dosage of 0.45 mg/kg twice daily to 1.8 mg/kg once daily. The response to treatment was graded as 'good' when there was ≥50% lesion reduction, or as 'complete remission' if all active lesions had resolved. Complete blood counts were performed at variable intervals. RESULTS: A complete remission of all lesions was obtained in the dog with exfoliative cutaneous lupus erythematosus, both dogs with mucocutaneous lupus erythematosus and three of four dogs with facial discoid lupus erythematosus (FDLE); a good response was seen in the remaining dog with FDLE. The first visible improvement of signs was seen within 2-to-3 weeks, while the time to complete remission was around 2 months. Clinical adverse effects were not seen, and haematological parameters remained within the reference range. CONCLUSIONS AND CLINICAL RELEVANCE: Oclacitinib may be considered an effective treatment option for different variants of canine CCLE.

Long-term successful treatment of a donkey with cutaneous lupus erythematous with methotrexate.

Cutaneous lupus erythematosus (CLE) is a rare immune-mediated dermatitis. To the best of the authors' knowledge it has not been described in donkeys. A 5-year-old male neutered donkey, living in south-east France, was diagnosed with CLE. Clinical signs included generalized symmetrical areas of alopecia, erythema, crusting and scales. Diagnostic tests included examination of skin biopsy samples by histopathological and immunohistochemical analysis which demonstrated an interface dermatitis with CD8+ T cells. The skin condition was successfully treated initially with glucocorticoids and methotrexate; successful long-term maintenance was associated with administration of methotrexate.

Le lupus cutané érythémateux (CLE) est une dermatite à médiation immune rare. A la connaissance des auteurs, il n'a pas été décrit chez le singe. Un singe mâle castré de 5 ans, vivant dans le sud-est de la France a été diagnostiqué avec CLE. Les signes cliniques incluaient des zones symétriques généralisées d'alopécie, d'érythème, de croûtes et de pellicules. Les tests diagnostics comprenaient un examen histopathologique et immunohistochimique de biopsies cutanées qui ont révélé une dermatite d'interface avec cellules T CD8+. La dermatose a été traitée avec succès initialement avec des corticoïdes et du méthotrexate; un traitement efficace au long cours a été associé avec l'administration de méthotrexate.

El lupus eritematoso cutáneo (CLE) es una rara dermatitis inmunomediada. A entender de los autores, esta enfermedad no se ha descrito en burros. Un burro castrado macho de 5 años de edad, que vive en el sureste de Francia fue diagnosticado con CLE. Los signos clínicos incluyeron áreas simétricas generalizadas de alopecia, eritema, costras y escamas. Las pruebas de diagnóstico incluyeron el examen de muestras de biopsia de piel mediante análisis histopatológico e inmunohistoquímico que demostró una dermatitis de interfase con células T CD8+. La condición de la piel se trató con éxito inicialmente con glucocorticoides y metotrexato; el control exitoso a largo plazo de la enfermedad se obtuvo con la administración de metotrexato.

O lúpus eritematoso cutâneo (LEC) é uma dermatite imunomediada rara. De acordo com os conhecimentos do autor, a doença ainda não foi descrita em jumentos. Um jumento macho castrado de cinco anos de idade, habitante do sul da França, foi diagnosticado com LEC. Os sinais clínicos incluíram alopecia, eritema, crostas e descamação generalizadas e simétricas. Os testes diagnósticos utilizados foram avaliação de amostras de biópsia por análise histopatológica e imunohistoquímica, que demonstraram dermatite de interface com células T CD8+. A dermatopatia foi tratada satisfatoriamente inicialmente com glicocorticoide e metotrexato; a manutenção satisfatória a longo prazo foi associada à administração de metotrexato.

A Missense Variant Affecting the C-Terminal Tail of UNC93B1 in Dogs with Exfoliative Cutaneous Lupus Erythematosus (ECLE).

Cutaneous lupus erythematosus (CLE) in humans encompasses multiple subtypes that exhibit a wide array of skin lesions and, in some cases, are associated with the development of systemic lupus erythematosus (SLE). We investigated dogs with exfoliative cutaneous lupus erythematosus (ECLE), a dog-specific form of chronic CLE that is inherited as a monogenic autosomal recessive trait. A genome-wide association study (GWAS) with 14 cases and 29 controls confirmed a previously published result that the causative variant maps to chromosome 18. Autozygosity mapping refined the ECLE locus to a 493 kb critical interval. Filtering of whole genome sequence data from two cases against 654 controls revealed a single private protein-changing variant in this critical interval, UNC93B1:c.1438C>A or p.Pro480Thr. The homozygous mutant genotype was exclusively observed in 23 ECLE affected German Shorthaired Pointers and an ECLE affected Vizsla, but absent from 845 controls. UNC93B1 is a transmembrane protein located in the endoplasmic reticulum and endolysosomes, which is required for correct trafficking of several Toll-like receptors (TLRs). The p.Pro480Thr variant is predicted to affect the C-terminal tail of the UNC93B1 that has recently been shown to restrict TLR7 mediated autoimmunity via an interaction with syndecan binding protein (SDCBP). The functional knowledge on UNC93B1 strongly suggests that p.Pro480Thr is causing ECLE in dogs. These dogs therefore represent an interesting spontaneous model for human lupus erythematosus. Our results warrant further investigations of whether genetic variants affecting the C-terminus of UNC93B1 might be involved in specific subsets of CLE or SLE cases in humans and other species.

Treatment of exfoliative cutaneous lupus erythematosus in a German shorthaired pointer dog with mycophenolate mofetil.

BACKGROUND: Immune-modulating drugs show limited therapeutic efficacy in canine exfoliative cutaneous lupus erythematosus (ECLE); over half of ECLE dogs are eventually euthanized for their lack of response to therapy. OBJECTIVE: To describe a case of generalized ECLE in a dog in which mycophenolate mofetil (MMF) treatment achieved complete remission. ANIMAL: A 3-year-old, male castrated German shorthaired pointer was presented with a three months history of generalized scaling, erythematous macules and plaques, follicular casts and hypotrichosis affecting the head, trunk, ventrum and medial aspects of all limbs. The dog exhibited lameness and stiff gait. METHODS AND MATERIALS: Complete blood count, serum chemistry profile, urinalysis, serum antinuclear antibody test, histopathological examination and RT-qPCR of skin biopsies. RESULTS: Histologically, skin biopsy specimens revealed lymphocyte-rich interface dermatitis, infundibular interface mural folliculitis and periglandular lymphocytic infiltrate. The absence of systemic signs and unremarkable laboratory tests excluded concurrent systemic lupus erythematosus. Treatment of ECLE was initiated with oral MMF (22 mg/kg, twice daily). Within three weeks of starting MMF therapy, a marked improvement in lameness and a moderate decrease in erythema and scaling was observed. After four months, erythema, scaling and follicular casts had completely resolved, and at the time of writing the dog's ECLE remains in complete remission with twice daily MMF (10 mg/kg). The lesional skin transcriptome revealed predominant T helper 1 (Th1) lymphocytic inflammatory response with strong upregulation of interferon pathway. CONCLUSIONS AND CLINICAL IMPORTANCE: To the best of the authors' knowledge, this is the first reported case of successful treatment of ECLE with MMF as a single-agent therapy.

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.

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.

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.

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.

A case of vesicular cutaneous lupus erythematosus in a Border collie successfully treated with topical tacrolimus and nicotinamide-tetracycline.

BACKGROUND: Canine vesicular cutaneous lupus erythematosus (VCLE) is an autoimmune skin disease of the Shetland sheepdog and rough collie, which manifests as an erosive dermatitis of sparsely haired skin of the ventrum and concave pinnae. Reported treatment consists of immunosuppression with glucocorticoids alone or in combination with azathioprine, but successful treatment is unpredictable. OBJECTIVES: To report on the treatment of VCLE in a Border collie dog with topical 0.1% tacrolimus and nicotinamide in combination with tetracycline. CASE REPORT: An 8-year-old male neutered Border collie was presented with multiple coalescing erosions on the ventral abdomen, groin and axillae and ulceration on the oral commissures. Clinical presentation, routine diagnostics, histology and immunohistochemistry were consistent with VCLE. Remission was achieved with topical 0.1% tacrolimus and combination therapy of nicotinamide and tetracycline. CONCLUSION AND CLINICAL IMPORTANCE: This dog responded well to treatment with topical 0.1% tacrolimus, nicotinamide-tetracycline and sun avoidance. Complete remission was achieved after 2.5 months, and the dog was lesion free during a 1 year follow-up period.

Familial cutaneous lupus erythematosus (CLE) in the German shorthaired pointer maps to CFA18, a canine orthologue to human CLE.

A familial form of lupus, termed exfoliative cutaneous lupus erythematosus (ECLE) has been recognized for decades in German shorthaired pointer dogs (GSP). Previous studies were suggestive of autosomal recessive inheritance. The disease presents as a severe dermatitis with age of onset between 16 and 40 weeks, and mirrors cutaneous lupus erythematosus (CLE) in humans. Lameness and, in advanced cases, renal disease may be present. Most affected dogs are euthanized before reaching the age of 4 years. The diagnosis is made by clinical observations and microscopic examination of skin biopsies. In humans, many different forms of CLE exist and various genes and chromosomal locations have been implicated. The large number of potential candidate loci combined with often weak association prevented in depth screening of the dog population thus far. During the course of our studies, we developed a colony of dogs with ECLE as a model for human CLE and the genetic analysis of these dogs confirmed the autosomal recessive mode of inheritance of CLE in GSPs. Using canine patient material, we performed a genome-wide association study (GWAS) to identify the genomic region harboring the gene involved in the development of the disease in GSPs. We identified a SNP allele on canine chromosome 18 that segregated with the disease in the 267 dogs tested. The data generated should allow identification of the mutant gene responsible for this form of cutaneous lupus erythematosus in dogs and assist in the understanding of the development of similar disease in humans.

Exfoliative cutaneous lupus erythematosus in German shorthaired pointer dogs: disease development, progression and evaluation of three immunomodulatory drugs (ciclosporin, hydroxychloroquine, and adalimumab) in a controlled environment.

Six German shorthaired pointer dogs (two females, four males) with exfoliative cutaneous lupus erythematosus (ECLE) were studied in a controlled setting until disease progression necessitated euthanasia. During investigations into the heredity of disease, five dogs received immunomodulatory drugs to alleviate clinical signs (lameness, erythema, scaling, erosions/ulcers). One dog served as a control and received only baths and oral fatty acids. Four dogs received ciclosporin (5-10 mg/kg once daily) for 4.5 months to 2 years. Ciclosporin decreased erythema and arthralgia, but did not halt worsening of lesions. Three dogs received hydroxychloroquine (5-10 mg/kg once daily) for 8 weeks, 7 months, and 9 months, respectively, with no side effects. Hydroxychloroquine appeared to slow clinical progression in two dogs on extended treatment and normalized globulin levels in all three dogs while receiving the drug. Four dogs, including the control dog, were euthanized between 1 and 4.5 years of age. Two remaining male dogs received a tumour necrosis factor (TNF)-α antagonist, adalimumab, at 0.5 mg/kg every 2 weeks for 8 weeks then weekly for 8 weeks. Serum TNF-α levels were not significantly altered nor were quantifiable changes seen in skin lesions or lameness. Subsequently, the dogs were maintained on hydroxychloroquine for another year. This is the first study to evaluate the use of a TNF-α inhibitor for canine lupus and the first to address the safety of long-term administration of hydroxychloroquine, albeit in a small number of dogs. The study documents the progression of ECLE and generally poor response to therapy.

Porcine ulcerative dermatitis syndrome in sows: a form of vesicular cutaneous lupus erythematosus?

Severe ulcerative lesions were observed in the skin of two sows in a herd of 540 hybrid sows. Annular to polycyclic, severe crusting dermal ulcerations were found on the abdomen and flanks; moderate lesions were also found at the base of the tail and on the perineum. The lesions were histologically characterised as cell-poor interface dermatitis and folliculitis, basal cell vacuolisation, vesicle formation at the dermal-epidermal junction and serocellular crusts. A subepidermal mild to moderate band, characterised as a mixed inflammatory infiltrate, was present. A test for antinuclear antibodies was negative; however, immunofluorescence testing revealed a linear pattern of IgG precipitation in the skin. Staphylococcus hyicus was demonstrated in the serocellular crusts of one sow. Treatment with antibiotics, topical antiseptics and corticosteroids did not improve the sows' condition. Porcine circovirus and porcine respiratory and reproductive syndrome virus were not isolated from samples taken at postmortem examination. The observed gross lesions, the absence of response to treatment and the exclusion of other skin diseases suggested that the sows were affected with porcine ulcerative dermatitis syndrome.

Clinical, histopathological and immunological characteristics of exfoliative cutaneous lupus erythematosus in 25 German short-haired pointers.

Clinical, histopathological and immunological features of exfoliative cutaneous lupus erythematosus, an uncommon generalized exfoliative dermatitis occurring exclusively in German short-haired pointers, were characterized in 25 dogs. The disease affects young adult dogs and its familial incidence strongly suggests a hereditary origin. Lesions were characterized by scaling and alopecia affecting 100 (25/25) and 76% (19/25) of dogs, respectively. Follicular casts were present in 28% (7/25) of dogs. The muzzle, pinnae and dorsum were typically affected. Generalized skin lesions were described in 52% (13/25) of dogs. Systemic signs of pain and lameness affected several dogs. Anaemia and thrombocytopenia were detected in several dogs with a more severe clinical phenotype. The most common histopathological features were hyperkeratosis and a lymphocytic interface dermatitis. Direct immunostaining revealed IgG deposition in the epidermal and follicular basement membrane of 100 (19/19) and 41% (7/17) of dogs, respectively. Circulating antifollicular and antisebaceous gland IgG antibodies were demonstrated by indirect immunostaining in 57% (4/7) of dogs. This disease usually responds poorly to immunosuppressive therapy and it has a guarded prognosis. Where outcome was recorded, 85% (10/12) of dogs were euthanased due to either a failure to respond to, or complications associated with, immunomodulatory therapy. Two affected dogs are in remission and maintained on immunomodulatory dosages of prednisolone. This study demonstrates the existence of a cellular and humoral immune response directed against the epidermal basement membrane of dogs with exfoliative cutaneous lupus erythematosus. Additional studies are required to further characterize the immunological pathogenesis of this disease.

Immunopathology of vesicular cutaneous lupus erythematosus in the rough collie and Shetland sheepdog: a canine homologue of subacute cutaneous lupus erythematosus in humans.

Clinical and histological features of an erosive disease in the rough collie and Shetland sheepdog are most consistent with a vesicular variant of cutaneous lupus erythematosus (VCLE). This paper reports the immunopathological findings of canine VCLE using samples from 17 affected dogs. Lesional skin sections were stained with monoclonal antibodies specific for CD3 (11 dogs) or a panel of monoclonal antibodies specific for leukocyte antigens (two dogs). Apoptotic cells were detected using the TUNEL method in 12 cases. Direct (14 dogs) and indirect immunofluorescence tests (five dogs) were also performed. Circulating antibodies to extractable nuclear antigens (ENA) were surveyed in 11 dogs by immunoblotting and ELISA. The predominant cells at the dermal-epidermal interface were identified as CD3(+) T lymphocytes expressing CD4 or CD8 and CD1(+) dendritic antigen presenting cells. In 7/12 dogs (58%), apoptosis of basal keratinocyte nuclei was present. Up-regulation of MHCII and ICAM-1 was observed on basal keratinocytes from the two dogs examined. Direct immunofluorescence revealed deposition of immunoglobulins bound to the cytoplasm of keratinocytes (6/14 dogs; 43%), to the dermal-epidermal junction (7/14 dogs; 50%), or to superficial dermal venules (13/14 dogs; 93%). Circulating IgG auto-antibodies targeting one or more ENA were detected in nine (82%) and eight (73%) of 11 dogs by immunoblotting and ELISA, respectively. These auto-antibodies recognized Ro/SSA and/or La/SSB in four (36%) and six (55%) of 11 dogs respectively by these two methods. Altogether, results of these studies provide evidence supporting the hypothesis that canine VCLE is an immunological homologue of subacute cutaneous lupus erythematosus in humans.