PEMPHIGUS VULGARIS (PV)

PV is an erosive and ulcerative autoimmune disease affecting skin and oral mucosa of animals. Oral lesions are found in 90% of affected dogs and 10% of cats. In 50% of cases oral lesions occur first.(1) Clinical signs may include anorexia, halitosis, pyrexia, and dysphagia in the most severe form. The disease manifests as discrete non-healing ulcers on lips, tongue, palatine mucosa, and mucocutaneous junctions. There can be widespread cheilitis, glossitis, and gingivitis.

Diagnosis is based primarily on histology and direct immunofluorescence. Biopsy samples are ideally placed in Michel’s solution. In PV, there are clefts and bullae within the epidermis. There is a separation between the stratum spinosum and stratum germinativum.(2) There is intercellular fluorescence in the epidermis.

Suggested treatment regimes include:

 Prednisolone 4–12 mg/kg daily in divided doses.

 Cyclosporine 1.5 mg/kg daily for four days each week. May be synergistic with prednisolone.

 Azathioprine 1.5 mg/kg daily.

 Aurothioglucose 1 mg/kg once weekly until remission (six to nine weeks).(2)

 Chlorambucil and tetracycline/niacinamide combinations are also used.

BULLOUS PEMPHIGOID (BP)

Lesions of BP are similar to those of PV. Oral lesions concurrent with skin lesions occur in about 80% of cases.(1) There is a high incidence in the Collie. The course of the disease is more acute (2) with lesions having a higher predilection for lip commissures, oral mucosa, hairless concave aspects of the pinna, axillae, inguinal areas, and foot pads.(3)

Diagnosis is made by biopsy of ulcerative lesions with examination by direct immunofluorescence. An attempt to biopsy an intact bulla is often very difficult. Samples from the leading edge of the lesion are acceptable. Histologically bullae occur between the epidermis and dermis with separation at the basement membrane. Fluorescence is seen in a linear pattern at the basement membrane.(3)

It has been established in a recent study that canine BP is a homologue of human BP by demonstration of antiBP180 (a hemidesmosomal protein).(4) The basement membrane autoantibodies are IgG class. There is a feline counterpart. Eosiniphils within the vesicles are a reliable marker for BP that is not seen in other autoimmune basement membrane disease.(3) Treatment is similar to PV.

SYSTEMIC LUPUS ERYTHEMATOSIS (SLE)

In humans, this is considered the disease of 1000 faces. It is often elusive to diagnose due to its multisystem involvement and waxing and waning signs. Antibodies are directed against nuclear and tissue proteins.(5) Circulating immune complexes create a Type III immune injury—a necrotizing fibrinoid vasculitis. The composition and size of the immune complex relative to vessel size dictates the distribution of the lesions.(6) Oral lesions are considered minor signs and may occur infrequently.(7) Clinical signs include shifting leg lameness; Coombs positive anemia; idiopathic thrombocytopenia; glomerulonephritis; depigmentation; leukoderma; ulceration and crusting of the lips, nose and oral cavity; shallow oral ulcers; and gingivitis.

Serology refers to ANA titres and LE prep tests. ANA titres are not specific but have higher sensitivity. Transient low titres in cats occur with feline leukemia, lymphocytic cholangiohepatitis, and in 10% of normal cats (titres of 1:2 or 1:10). (8). LE preparations are specific for SLE, but have low sensitivity with false negatives.(1) Immunofluorescence of biopsies display patchy granular or linear deposits at the dermoepithelial junction. Treatment is similar to other autoimmune disease.

Discoid lupus is the mild benign variant of SLE involving skin and oral cavity only. It presents as loss of normal pigmentation of planum nasale, lips, and gingiva with occasional ulceration of the tongue. Seborrhea, alopecia, scaling, and crusting of the nose is a common clinical picture. Diagnosis is based on biopsy, with immunofluorescence seen at the dermoepidermal junction. Basal cell degeneration is common.(9) Treatment often includes prednisone and vitamin E (400 IU q12h).(1)

Drug eruptions are acute hypersensitivity reactions with recent association to drug ingestion, e.g., sulfonamides, penicillin, tetracycline, and chloramphenicol. It creates ulceration of the oral mucosa with hemorrhage and edema.(1) Diagnosis is based on history and biopsy.

Toxic epidermal necrolysis (TEN) is the most severe form of drug eruption. Clinical signs include depression, anorexia and pyrexia with large painful oral and mucocutaneous ulcers.(10) Diagnosis is based on biopsy and history. Treatment involves drug withdrawal, supportive care, glucocorticoids, and antibiotics.

Paraneoplastic Syndromes can cause unusual clinical signs that mimic autoimmune disease. There is a report of bullous stomatitis in a horse associated with hemangiosarcoma.(11) In this case, antiepithelial autoantibodies were identified.

Antiepithelial autoantibodies have been associated with feline eosinophilic granuloma complex (EGC).(12) Ulcerative and proliferative lesions occur in the oral cavity. Histology identifies inflammatory cell infiltrate of the dermis or submucosa containing eosinophils, mast cells, plasma cells, histiocytes, collagen lysis, and giant cells. There is a question as to whether the autoantibodies are a consequence of tissue damage from EGC or whether autoimmune disease produces EGC.

Sjogren’s syndrome presents as a combination of xerophthalmia, xerostomia, and plasmacytic infiltrates of the salivary glands in man. Xerostomia secondarily produces stomatitis. There has been a recent report of suspected Sjogren’s syndrome in the cat. The presenting signs were dysphagia, weight loss, and crusty ocular discharge. The cat demonstrated stomatitis, had Schirmer tear tests of 0mm in each eye, had enlarged salivary glands, and produced no saliva from atropine drops placed in the eyes. Histology of the salivary glands showed plasmacytic infiltration of the gland.(13) This study suggests that stomatitis cats should be examined for xerophthalmia on a regular basis as perhaps this syndrome does exist in cats. There is a suggestion of viral etiology in humans where Epstein Barr virus genome and the gag protein of HIV1 have been found.(14)

Polyarteritis nodosa (PAN) is a rare polysystemic necrotizing vasculopathy of unknown etiology.(8) In man, it is an immune mediated collagen disorder. One case has been reported with ulcerative gingivitis, glossitis, and infarction of the distal tongue.(8)

IMMUNE MEDIATED MUSCLE DISEASES

Canine polymyositis is usually seen in large breed dogs (incidence in females is greater than males). It is an acute disease causing progressive weakness of the head, trunk, and limbs. The clinical signs include pain, undulating fever, dysphagia, and megaesophagus. Diagnosis is by eosinophilia on the CBC, leukocytosis, increases in ALT, LDH, and CPK. Fifty percent of cases will have immunofluorescence for ANA or antisarcolemmal antibodies.(15) Biopsies demonstrate Type I and II fibres with multifocal necrosis with vacuolization and hyalinization. Treatment is with corticosteroid at 0.5 mg–1 mg/kg q12h. If a response is noted after one week, the prognosis is good.(15)

Masticatory myositis involves antibodies directed at the type 2M fibres unique to the muscles of mastication: the temporalis, masseter and pterygoid. Embryologically these muscles are derived from mesoderm.(16) By two weeks postpartum, these muscles have developed the unique 2M fibres.

There are two distinct disorders in masticatory myositis: 1) acute eosinophilic myositis; and 2) chronic atrophic myositis.

Eosinophilic myositis is prevalent in German Shepherds and Dobermans of a young age (less than four years). The acute phase lasts two to three weeks followed by remission and recurrent attacks. Peripheral eosinophilia is noted. Histology reveals large numbers of eosinophils, plasma cells infiltrating the muscles, hemorrhage, and necrosis. Chronic lesions demonstrate scar tissue. Treatment involves use of corticosteroids at 0.5–1 mg/kg.(17)

Atrophic myositis has no breed, sex, or age predilection. There is usually a single less dramatic attack followed by progressive atrophy and fibrosis. Peripheral eosinophilia is not a feature. Eosinophils are less predominant in histology. Treatment is less effective and the prognosis is guarded.(17)

Masticatory myositis has been described as a result of infection with the protozoa Leishmania infantum.(18) Leishmania is transmitted by the sandfly and is zoonotic. The disease is endemic in the Mediterranean and Portugal with sporadic reports in Europe and the United Kingdom. Muscle fibre necrosis, atrophy, mononuclear infiltrates, vasculitis, and amastigotes within macrophages are histological features. IgG immune complexes have been detected.(18)

REFERENCES

1.  Harvey, Colin Oral Disease in the dog and cat. In Veterinary Dentistry. 1985 pp 42-47.

2.  Bennett D, Laudeer IM, Kickham D, M^cQueen A; Bullous autoimmune skin disease in the dog (1) clinical and pathological assessment. Vet Record 1980;106:497-503.

3.  Olivry T, Chan LS, Xu L, Chace P, Dunston SM et al Novel feline autoimmune blistering disease resembling bullous pemphigoid in humans. IgG autantibodies target the NC16A ectodomain of type XVII collagen. Vet Pathol 1999; 36: 328-335.

4.  Iwasaki T, Olivry T, Lapiere JC et al Canine bullous pemphigoid(BP) identification of the 180kd canine BP antigen by circulating autoantibodies. Vet Pathol 1995; 32:387-393.

5.  Halliwell R, Skin diseases associated with autoimmunity PartII The non bullous autoimmune skin diseases. Comp Contin Educ Pract Vet 1981;3(2): 156-162.

6.  Gorman NT, Werner LL, Immune mediated diseases of the dog and cat. PartI Basic concepts and the systemic immune mediated diseases. Br Vet J 1986;142(5): 395-402

7.  Anderson JG Approach to diagnosis of canine oral lesions. Compend Contin Educ Poract Vet 1991; 13(8):1215-1335.

8.  Werner ll, Gorman NT Immune mediated disorders of cats. VCNA Sm An Pract 1984 14(5): 1039-64.

9.  Parker WM Autoimmune skin diseases in the dog CVJ 1981;22(10) 302-304.

10. Scott D, Halliwell R, Goldschmidt M et al Toxic epidermal necrolysis in two dogs and a cat JAAHA 1979;15:271-279.

11. Williams MA, Dowling PM et al Paraneoplastic bullous stomatitis in a horse. JAVMA 1995; 207(3):331-4

12. Gelberg HB, Lewis RM, Felsburg PJ, Smith CA Antiepithelial autoantibodies associated with the feline eosinophilic granuloma complex. Am J Vet Res1985;46(1)263-5.

13. Canapp SQ, Cohen LA, Maggs DJ et al xerostomia, xerophthalmia and plasmacytic infiltrates of the salivary glands (Sjogren’s like syndrome) in a cat. JAVMA 2001; 218(1):59-65.

14. Jonsson R, Mountz, J, Koopman W. Elucidating the pathogenesis of autoimmune disease. Recent advances at the molecular level and relevance to oral mucosal diseases. J Oral Path Med 1990;19(8):341-50.

15. Lewis RM Immune mediated muscle disease. VCNA Sm An Prac 1994;24(4): 703-10.

16. Shelton GD, Cardinet GH, Bandman E. Expression of fiber type specific proteins during ontogeny of canine temporalis muscle. Muscle and Nerve 1988; 11:124-32.

17. Roberts ZE, Hanson P, Zaslow IM Masticator myopathy in the dog VMSAC 1975; 70(7):840-3.

18. Vamvakidis CD, Koutinas AF, et al. Masticatory and skeletal muscle myositis in canine leishmaniasis (Leishmania infantum) Vet Rec 2000; 146(24): 698-703.