JPC SYSTEMIC PATHOLOGY
Signalment (JPC 2602974): Dog.
HISTORY: Tissue from the nose of a dog with proteinuria.
HISTOPATHOLOGIC DESCRIPTION: Planum nasale: Diffusely within the superficial dermis, surrounding blood vessels and adnexa, multifocally obscuring the dermal-epidermal junction (interface dermatitis) and forming a lichenoid band, there is a dense infiltrate of predominantly plasma cells, lymphocytes, fewer macrophages, and rare neutrophils. Inflammatory cells often transmigrate the epidermis frequently forming variably sized intracorneal pustules, with rare intraepidermal pustules. Multifocally, there are several erosions and ulcers characterized by partial to complete loss of the epithelium with replacement by a serocellular crust composed of serum and necrotic cellular debris. Diffusely the epidermis and superficial follicular epithelium are spongiotic and hyperplastic with acanthosis, anastomosing rete ridges, and moderate parakeratotic hyperkeratosis. There is occasional hydropic degeneration and apoptosis (Civatte bodies) within the stratum basale, and basal keratinocytes are often disorganized or jumbled. Within the superficial dermis, scattered macrophages contain melanin (pigmentary incontinence). There is mild, diffuse apocrine gland ectasia and lymphatics are ectatic (edema).
Lymph node: Diffusely the medullary sinuses are expanded by increased numbers of histiocytes that often contain phagocytized erythrocytes and hemosiderin, and extravasated erythrocytes (draining hemorrhage). There are moderate numbers of plasma cells within the medullary cords.
MORPHOLOGIC DIAGNOSIS: 1. Planum nasale: Dermatitis, interface, lymphoplasmacytic, diffuse, severe, with scattered basal cell apoptosis, moderate epidermal and follicular hyperplasia and parakeratotic hyperkeratosis, breed not specified, canine.
2. Lymph node: Draining hemorrhage, diffuse, mild.
ETIOLOGIC DIAGNOSIS: Immune-mediated dermatosis
CONDITION: Systemic lupus erythematosus (SLE)
- Lupus erythematosus (LE) refers to a spectrum of inflammatory disorders that varies from mild skin-limited conditions to life-threatening systemic disease (Systemic lupus erythematosus - SLE)
- SLE is a rare, multisystemic immune-mediated disease that affects dogs, cats, horses, humans, nonhuman primates, mice, snakes, and iguanas that is characterized by high levels of circulating antigen-antibody complexes; the main tissue damage is caused by antigen-antibody complexes that deposit at various sites throughout the body and incite a type III hypersensitivity reaction; type II and type IV hypersensitivities play a lesser role
- SLE is historically thought to include dermatitis as a common lesion; true cutaneous manifestations of SLE are probably rare
- Cutaneous lupus erythematosus (CLE) refers to the skin-specific effects of LE, regardless of whether or not there is systemic involvement
- Historically, LE restricted to skin was termed discoid lupus erythematosus (DLE); however, DLE in domestic animals is not comparable to that in humans, and the term CLE is now preferred
- Most frequently diagnosed autoimmune skin disease in the dog
- CLE in domestic animals generally does not precede the onset of SLE
- Well-described CLE disorders in dogs are often breed specific and presumed hereditary
- Disseminated discoid lupus erythematosus – Chinese crested, spitz
- Exfoliative cutaneous lupus erythematosus – German shorthaired pointer
- Vesicular cutaneous lupus erythematosus – rough-coated collies, Shetland sheepdogs, border collies
- Mucocutaneous lupus erythematosus – GSD overrepresented
- No age or sex predilection for SLE; collies, Shetland sheepdogs, poodles, German shepherd dogs, and Siamese, Himalayan and Persian cats appear to be predisposed
- Genetic, environmental, and transmissible factors have been implicated; the definitive cause of SLE remains unknown
- Polyarthritis, glomerulonephritis, mucocutaneous lesions, fever of unknown origin, anemia, thrombocytopenia, and dermatitis are the most common manifestations; dermatologic signs occur in approximately 1/3 of the cases
- Failure of mechanisms that maintain B- and T-cell self-tolerance
- Production of autoantibodies against a range of nuclear and cytoplasmic components of the cell (histones, double-stranded DNA, nonhistone proteins bound to RNA, and nucleolar antigens)
- Regulatory T-cell response is reduced or absent, essentially allowing a positive feedback loop of immunoreactivity to autoantibody-antigen complexes
- Autoantigen-antibody complexes deposit throughout the body, inciting a type III hypersensitivity reaction, resulting in inflammation of joints, skin, and kidney (i.e. arthritis [nonerosive], dermatitis, glomerulonephritis)
- To a lesser extent, tissue damage is induced by antibodies directed toward self-antigen on erythrocytes, leukocytes and thrombocytes initiating a type II hypersensitivity reaction, or cell-mediated immunity (type IV hypersensitivity)
- Proposed triggers:
- Endogenous (genetic, hormonal, metabolic)
- Exogenous (UV light, drugs, infectious agents)
- Ultraviolet-exacerbated cutaneous lesion (humans): Induces the translocation of antigens normally expressed only intracellularly to the keratinocyte cell membrane; damaged cells then release IL-1, IL-2, IL-6, and TNF-beta that increase damage; UV light also induces ICAM-1 expression, which is the major ligand for LFA-1, an adhesion molecule found on all leukocytes
- Abnormality in cellular immunity includes a lymphopenia that is characterized by a high CD4+:CD8+ ratio (as high as 6 in dogs with SLE versus <2 in normal dogs)
TYPICAL CLINICAL FINDINGS:
- Variable; may mimic numerous diseases
- Chronic illness characterized by periods of progression and remission
- Associated syndromes: Dermatitis, shifting leg lameness with swollen and painful joints (nonerosive polyarthritis), glomerulonephritis, stomatitis, pericarditis, myocarditis, generalized muscle wasting (polymyositis), pneumonitis, pleuritis, meningitis, myelitis, polyneuropathy, and lymphedema
- Lethargy, anorexia, fever of unknown origin
- Clinical pathology: Proteinuria, hemolytic anemia, thrombocytopenia, bone marrow necrosis
TYPICAL GROSS FINDINGS:
- Gross skin lesions are extremely variable. The more classic lesions consist of non-specific distribution of erythematous, alopecic, crusting, oozing, ulcerative skin lesions affecting sparsely haired areas of the face (especially the nose, lips, pinnae), limbs (especially the cranial aspect of the thoracic limbs), axilla, groin, and ventral abdomen
TYPICAL LIGHT MICROSCOPIC FINDINGS:
- Lichenoid (interface) dermatitis (mononuclear cell infiltrate at
- dermoepidermal junction, lymphocytes predominate)
- Basal cell hydropic degeneration that may involve follicles and pigmentary incontinence
- Civatte bodies (basal cell apoptosis)
- Cleft and bulla formation between epidermis and dermis with severe subepidermal vacuolization
- Vasculitis (leukocytoclastic) may occur
- Basement membrane thickening
ADDITIONAL DIAGNOSTIC TESTS:
- Clinical signs and laboratory data of systemic disease
- Antinuclear antibody (ANA): Identifies serum antibodies to nuclear material
- High sensitivity for SLE, less specificity
- By itself is not diagnostic; may be positive in animals with leishmaniasis, bartonellosis, ehrlichiosis, or malignancies
- CLE is usually ANA negative
- PAS: To demonstrate thickened basement membranes in the kidney or skin
For histologic lesions:
- Epidermolysis bullosa acquisita: May be histologically identical and requires identification of criteria compatible with SLE for differentiation; IHC staining of collagen IV is ABOVE the subepidermal vesicles, whereas in all other autoimmune blistering diseases the staining is below the vesicle
- Lupoid drug reactions: May be essentially identical; history of treatment
- Erythema multiforme: Individual keratinocyte apoptosis in all layers of epidermis in addition to interface dermatitis and basal cell degeneration
- Canine dermatomyositis (of Shetland sheepdogs and collies): Marked basal cell necrosis (colloid bodies), dermal-epidermal vesiculation, and rarefaction of dermal collagen
- Mouse model of SLE: NZB/W/F1
- Cats: Lesions similar to those in dogs; primarily fever, glomerulonephritis, and hemolytic anemia; rare; intraepidermal acantholytic pustular dermatitis; true SLE dermatitis is more often present than in dogs or horses
- Horses: The most common presenting sign in horses with SLE is a sharply demarcated zone of depigmentation of the skin around the eyes, lips, nostrils, genitalia, and skin of the perianal and perineal regions
- Humans: Similar presentation to dogs; more common in females
- Banovic F, Olivry R, Linder KE. Ciclosporin therapy for canine generalized discoid lupus erythematosus refractory to doxycycline and niacinamide. Vet Dermatol. 2014;25(5):483-e79.
- Gerhauser I, Strothmann-Luerssen A, Baumgartner W. A case of interface perianal dermatitis in a dog: Is this an unusual manifestation of lupus erythematosus? Vet Pathol. 2006;43:761-764.
- Gross TL, Ihrke PJ, Walder EJ, Affolter VK. Diseases of the epidermis. In: Skin Diseases of the Dog and Cat. 2nd ed. Ames, IA: Blackwell Publishing Company; 2005:505.
- Hargis AM, Ginn PE. The integument. In: Zachery JF, McGavin MD, eds. Pathologic Basis of Veterinary Disease. 5th Philadelphia, PA: Elsevier Saunders Company; 2012: 1055-1056.
- Marks SL, Henry CJ. CVT update: Diagnosis and treatment of systemic lupus erythematosus. In: Kirk’s Current Veterinary Therapy XIII. Philadelphia, PA: WB Saunders Co; 2000: 514-516.
- Mauldin EA, Peters-Kennedy J. Integumentary system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed. Philadelphia, PA: Elsevier; 2015: 604-607.
- Olivry T, Dunston SM. Usefulness of collagen IV immunostaining for diagnosis of canine epidermolysis bullosa acquisita. Vet Pathol. 2010;47(3):565-568.
- Olivry T, Linder KE. Bilaterally symmetrical alopecia with reticulated hyperpigmentation: A manifestation of cutaneous lupus erythematosus in a dog with systemic lupus erythematosus. Vet Pathol 2013;50(4);682-685.
- Olivry T, Rossi MA, Banovic F, Linder KE. Mucocutaneous lupus erythematosus in dogs (21 cases). Vet Dermatol.2015;26(4):256-e55.
- Rottman JB, Willis CR. Mouse models of systemic lupus erythematosus reveal a complex pathogenesis. Vet Pathol. 2010;47:664-676.
- Salas EN, Kotschwar JL. Pathology in practice: Exfoliative cutaneous lupus erythematosus in a German shorthair pointer. J Am Vet Med Assoc. 2014;245(3):291-293.
- Smee NM, Harkin KR, Wilkerson MJ. Measurement of serum antinuclear antibody titer in dogs with and without systemic lupus erythematous: 120 cases (1997-2005). J Am Vet Med Assoc. 2007;224:1180-1183.
- Smith BE, Tompkins MB, Breitschwerdt EB. Antinuclear antibodies can be detected in dog sera reactive to Bartonella vinsonni berkhoffii, Ehrlichia canis, or Leishmania infantum antigens. J Vet Intern Med. 2004;18:47-51.
- Snyder PW. Diseases of immunity. In: McGavin MD, Zachary JF, eds. Pathologic Basis of Veterinary Disease. 5th ed. St. Louis, MO: Mosby Elsevier; 2012: 275-278.
- Weiss DJ. Bone marrow necrosis in dogs: 34 cases (1996-2004). J Am Vet Med Assoc. 2005;227:263-267.