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Immune mediated-diseases of the dog and cat. II. Immune-mediated diseases of the haemolymphatic and musculoskeletal system
Br. vel .
7.
(1986) . 142, 403
VETERINARY PROFESSIONAL DEVELOPMENT SERIES
IMMUNE MEDIATED-DISEASES OF THE DOG AND CAT . II. IMMUNE-MEDIATED DISEASES OF THE HAEMOLYMPHATIC AND MUSCULOSKELETAL SYSTEM N . T. GORMAN* and L . L . WERNERt *Department of Clinical Veterinary Medicine, Madingley Road, Cambridge CB3 0ES and tDepartment of Clinical Pathology, School of Veterinary Medicine, University of California, Davis, California
The first article in this series covered the systemic immune-mediated diseases . This paper covers the immune-mediated diseases that involve the haemolymphatic and musculoskeletal systems . The organ-based diseases commonly have systemic clinical manifestations and, in some cases, require intensive systemic treatment .
HAEMOLYMPHATIC SYSTEM Immune-mediated diseases of the haemolymphatic system are relatively common and include autoimmune haemolytic anaemia, immune-mediated thrombocytopenia, and immune-mediated Leukopenia .
Autoimmune haemolytic anaemia (AIHA) Primary AIHA (true autoimmune) is a relatively common immunohaematological disorder in the dog . Cats, on the other hand, have a much higher prevalence of so-called secondary immune-mediated haemolytic anaemia (IHA), in which immune elimination of erythrocytes takes place in conjunction with host responses to infectious (feline leukaemia virus, Haemobartonella felis), or pharmacological (propylthiouracil) agents, and neoplasia (lymphoma, myeloproliferative disease) . The hallmarks of IHA in both species, whether primary autoimmune or secondary, are a progressive, fulminant clinical course characterized by depression, weakness, and pallor . In severe cases, syncope, tachypnoea, tachycardia, icterus, and emesis may be present . Haematological findings usually reflect the haemolytic nature of the anaemia, with a reticulocytosis, spherocytosis, and the presence of nucleated erythrocytes . Leukocytosis with a left shift is also a common finding . When intravascular haemolysis supersedes the less fulminant phagocytic removal of erythrocytes (extravascular haemolysis), icterus, haemoglobinaemia and haemoglobinuria are found . Hepatosplenomegaly is sometimes seen in chronic cases . A
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variant of IHA referred to as cold agglutinin disease causes a distal ischaemic dermatosis in conjuction with a mild to severe anaemia . In dogs and cats, it is more common to see anaemia caused by cold agglutinins without distal extremity lesions . Cold temperatureinduced haemolytic episodes which manifest as haemoglobinuria are generally accompanied by less profound anaemias in warmer climates . The latter clinical presentation is exceedingly rare and is caused by cold-reactive complement-fixing autoantibodies of the non-agglutinating type . A bone marrow aspirate is essential in evaluating all cases of IHA, to exclude occult myeloproliferative and lymphoproliferative disorders can be excluded and erythrophagocytosis, supportive of AIHA can be detected . Increased erythropoiesis, granulopoiesis, and occasionally thrombopoiesis can be found in cases of IHA . There are few documented cases of non-regenerative anaemia associated with IHA in dogs . Erythroid hypoplasia or aplasia in such cases is considered to be the result of immune destruction of red cell precursors, although there is no documented evidence in the dog or cat . Significant biochemical abnormalities in uncomplicated cases of IHA are few . Moderate increases in liver enzyme levels are common, and generally reflect ischaemic hepatocellular damage or corticosteroid therapy . Raised levels of serum urea nitrogen and creatinine are associated with pre-renal causes in most cases . However, haemoglobin nephropathy can be seen in cases with severe intravascular haemolysis . Differential diagnoses for IHA include other causes of regenerative and haemolytic anaemias including internal or external blood loss, toxic drugs or chemicals, and erythroparasitism . The direct Coombs' anti-globulin test is routinely used for diagnosis, and a positive Coombs' test is found in both primary and secondary IHA, reflecting the immune elimination of erythrocytes . A detailed medical history, thorough physical examination, and diagnostic tests to rule out underlying disease are all-important in differentiating primary from secondary IHA . Further examples of underlying disorders associated with IHA in dogs and cats include drug exposure (vaccines, phenothiazines, sulpha-drugs), rickettsial diseases, dirofilariasis, and bacterial infections . Treatment of primary IHA includes the use of short-acting glucocorticoids at immunosuppressive doses . Prednisone, prednisolone, and dexamethasone are all effective in most cases ; the duration of treatment is dictated by response of the individual case . In most cases, clinical remission defined as a return to normal PCV, is achieved during the first two weeks of treatment . At that time, doses are gradually reduced over a period of 6 to 8 weeks . If remission is sustained, low-dose alternate day treatment is maintained for another 2 to 3 months . Treatment should continue until there have been successive normal blood counts and a negative Coombs' test . Relapse is less common, in the authors' experience, in cases treated over a longer period with a more gradual dosage reduction . Failure to achieve a good clinical response within 72 h, i .e . stabilization or increase in PCV, is an indication for treatment with a more potent immunosuppressant such as cyclophosphamide or azathioprine . A blood transfusion may be required in life-threatening anaemia, but should be avoided in clinically stable animals because it may accelerate or, in the case of incompatible blood, induce a haemolytic crisis . Oxygen therapy is helpful in stabilizing cases showing clinical signs of anaemic hypoxia . Splenectomy is indicated only in cases where relapse or drug intolerance are encountered .
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The prognosis for IHA is variable depending upon the severity of the clinical presentation, the response to treatment, and the nature of any underlying disease process . In cats, the high incidence of underlying FeLV infection and haemolymphatic neoplasia associated with IHA dictates a more guarded prognosis for long-term survival . The treatment of secondary IHA requires specific treatment of any underlying disease process and judicious use of corticosteroids, generally for shorter periods of time . Oral Tetracycline, at 20 mg/kg t .i .d . is recommended in addition to corticosteroids for feline IHA in areas where haemobartonellosis is endemic . Immune-mediated thrombocytopenia (IMT) Immune-mediated thrombocytopenia is the single commonest cause of platelet destruction in the absence of consumptive coagulopathies, e .g. DIC . Both primary and secondary IMT occur, as is the case with IHA . Primary idiopathic forms are common in the dog, while in cats IMT is less common . It is generally encountered in conjuction with other haematological abnormalities associated with FeLV infection, haematopoietic neoplasia, or myelodysplasia . Petechial and ecchymotic haemorrhages are the typical clinical findings in most thrombocytopenic disorders . However, bleeding tendencies of any kind can be seen . Additional abnormalities seen in IMT may include fever, hepatosplenomegaly, lymphadenopathy, and anaemia due to either blood loss or accompanying Coombs'positive haemolytic anaemia (Evan's syndrome) . Haematological parameters are quite variable depending on the degree of blood loss and thrombopoietic activity in the bone marrow . Profound anaemias are usually regenerative . Acute forms of IMT can show small, uniformly sized platelets on the blood smear, reflecting lack of accelerated thrombopoietic activity . In more chronic stages, an increase in mean platelet volume (MPV) or size reflects a regenerative bone marrow response . In rare cases, however, platelet regeneration is lacking due to immune destruction of megakaryocytes . Bone marrow aspiration or biopsy is the best diagnostic investigation in a thrombocytopenic disorder since it will help to differentiate between aplastic, hypoplastic, myeloproliferative, dysmyeloplastic, and regenerative haematopoietic defects . Screening tests such as activated clotting time, prothrombin time, partial thromboplastin time, and measurement of fibrin degradation products to detect clotting factor defects are useful in differentiating uncomplicated thrombocytopenic disorders from the multiple clotting defects seen in conjuction with disseminated intravascular coagulopathy . Such test results are normal in cases of IMT . There are no simple, widely available tests to confirm a diagnosis of IMT . The platelet factor-3 test has limited availability and is of dubious sensitivity and specificity . Direct immunofluorescence on bone marrow or peripheral blood smears will sometimes demonstrate antibody or complement on megakaryocytes or platelets . Paucity of these cell types, however, can make diagnosis difficult . The diagnosis of IMT requires a concerted and systematic elimination of differential diagnoses of thrombocytopenia . When myelophthisical, myeloproliferative, and consuptive coagulation disorders are ruled out, a good response to corticosteroid treatment is often the basis for a retrospective diagnosis of IMT . Confirmation by immunological tests is ideal but not always feasible .
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Treatment and prognosis of IMT are essentially the same as outlined for AIHA . In addition, the vinca alkaloids, provide a useful alternative to the more potent cytotoxic immunosuppressive drugs in refractory cases of IMT . Immune-mediated deukopenias Neutropenic or lymphopenic states are less common manifestations of immunohaematological disorders . They are seldom isolated, but can accompany the immunohaematological manifestations of systemic lupus erythematosus and feline leukaemia virus infection . There are no clinically applicable means of documenting immunemediated leukopenias . Ruling out infectious or myeloproliferative causes, and response to immunosuppressive treatment is the usual means of making a presumptive diagnosis . As is the case with AIHA and IMT, phagocytosis of haematopoietic cells observed in bone marrow or lymph node aspirates is also good presumptive evidence for an immunemediated mechanism .
MUSCULOSKELETAL SYSTEM The immune-mediated diseases involving the musculoskeletal system are often varied in their presentation and represent a considerable challenge to the clinician . In all cases a careful and thorough evaluation is required, but good radiographic, immunological and cytological investigations are essential . The major diseases are canine rheumatoid arthritis, non-erosive polyarthritis, myasthenia gravis, feline chronic progressive polyarthritis, and canine familial dermatomyositis . Canine rheumatoid arthritis There is little doubt that a clinical entity exists in the dog that has some similarity to rheumatoid arthritis in man . It is, however, a matter of considerable debate whether or not the equivalent condition in the dog is identical . There is little doubt, however, that an erosive polyarthritis does occur in the dog . The authors' prefer to consider a condition of canine rheumatoid arthritis to distinguish it from the well documented and characterized rheumatoid arthritis in man . Canine rheumatoid arthritis is distinguished among the canine immune-mediated arthropathies by its propensity to cause articular and subchondral bone erosions leading to joint deformity and instability . It is also distinguished by a high association with the finding of serum rheumatoid factor (RF) . Rheumatoid factor is an immunoglobulin that is directed against native IgG, i .e . an autoantibody which can be of either the IgG or IgM isotype . The disease is classified as autoimmune . Typically, canine rheumatoid arthritis is seen in small and toy breeds of dogs and often occurs in youth or middle age . The joints initially involved are the metacarpal, metatarsal, carpal, and tarsal joints, but it may progress to involve large joints as well . Clinical signs, in order of progression, include : 1 . Joint pain, stiff-gaited appearance, periarticular soft tissue swelling . Radiographic evidence of erosive articular disease may not be present early in the disease . 2 . Joint crepitus, laxity and subluxation . Radiographs may show subchondral bone lysis with narrowing of articular spaces indicative of cartilage destruction . 3 . Angular deformities with complete luxation . Highly destructive and proliferative osteophyte formation, with collapse and sclerosis of subchondral bone are seen radiographically .
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The clinical findings which often accompany the above articular changes include fever unresponsive to antibiotics, leukocytosis, raised fibrinogen and gamma globulin levels, non-regenerative anaemia, and synovial fluid findings characteristic of sterile inflammation (reduced viscosity, raised protein content, and increased numbers of neutrophils and small and large mononuclear cells) . The major differential diagnoses for erosive inflammatory joint disease are septic polyarthritis and rheumatoid arthritis . Culture of synovial fluid and biopsy are important in distinguishing between them . Serum rheumatoid factor tests are positive in 40 to 75% of canine rheumatoid arthritis cases, and although a useful screening test, a negative result does not preclude the use of further diagnostic tests for rheumatoid arthritis . The best indicators are the radiogaphic and synovial biopsy appearances . The latter is particularly indicated in predisoposed breeds showing sterile-synovitis, but no radiographic evidence of destructive articular disease . In such early cases of rheumatoid arthritis, a diagnosis by synovial biopsy will allow early therapeutic intervention to delay the progression of the disease . Characteristic histopathological findings include villous hyperplasia and hypertrophy, and an inflammatory infiltrate marked by proliferating plasma cells, lymphocytes, and, to a lesser extent, neutrophils . Canine rheumatoid arthritis is not a curable disease, although there are examples of apparent spontaneous remission, or sustained remission after immunosuppressive treatment . Aspirin is not particularly effective, but may help to control fever and pain . Corticosteroids are useful in the acute stages, but prolonged use at high dosage is thought to contribute to the articular and soft tissue breakdown that may occur . The most common treatment regimen is cyclophosphamide alone or in combination with azathioprine to induce and sustain remission . Gold therapy has also had limited success in the treatment of canine rheumatoid arthritis . All of these medications will be discussed in detail in part IV . Surgical arthrodesis is effective in restoring mobility in advanced cases .
Non-erosive polyarthritis Sterile synovitis affecting a few joints, or multiple joints in a symmetrical pattern is a very common sequella to a number of infectious diseases . Less commonly, neoplasia, drugs (trimethoprim, sulfadiazine), and parasites (dirofilariasis) have been incriminated . Circulating immune complexes are thought to be involved in the synovitis, but many cases are classified as idiopathic when no underlying disease process can be identified . The polyarthritis seen in some cases of canine SLE has many features in common with non-erosive polyarthritis . In fact, the term `lupus-like' has been used to describe the synovial inflammatory changes seen in all non-rheumatoid arthritis (non-erosive) polyarthropathies caused by circulating immune complexes . There is a mild synovial hyperplasia and a predominance of neutrophils migrating from synovial vessels . LE cells are seen only rarely in synovial fluid smears . Thus, the serum ANA test and LE preparation are the best methods to distinguish lupus polyarthritis from the other types of non-erosive polyarthritis . As is the case in canine rheumatoid arthritis and systemic lupus erythematosus, systemic signs often accompany the remainder of the non-erosive polyarthropathies . These include fever, leukocytosis, low grade anaemias, raised fibrinogen and gamma globulin levels, lymphadenopathy, and occasionally hepatosplenomegaly . Joint fluid analysis allows rapid diagnosis of immune-mediated joint disease in cases of unexplained lameness or walking difficulties . Polyarthritis is often
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misdiagnosed as a neurological problem when terms such as `can't walk', `down in the rear quarters', or `paralyzed' are used to describe the presenting complaint . Radiographs of affected joints are almost uniformly normal, with the possible exception of soft tissue swelling or joint capsule distension . Joint fluid culture is recommended to rule out an infectious cause of the synovitis . Elimination of suspect drugs, parasites, or infectious agents is of prime importance in treatment . Judicious use of corticosteroids and cytotoxic immunosuppressant drugs is often necessary to suppress the inflammation and restore mobility . Many cases do not recur after treatment, but some are prone to relapse .
Myasthenia gravis Acquired myasthenia gravis has been identified as an autoimmune disorder in both dogs and cats . Periods of weakness, often profound, exacerbated by activity, but responsive to rest and cholinesterase inhibitors are among the most important clinical findings . Autoantibodies to acetylcholine receptors at the myoneural junction can be detected by both direct and indirect immunofluorescence . Corticosteroid treatment has been successful both alone and in conjunction with long-acting cholinesterase inhibitors . The long-term prognosis is guarded, particularly in cases with pharyngeal, oesophageal, or respiratory muscle involvement . Dysphagia, aspiration pneumonia, and respiratory failure are the most life-threatening consequences of this disease .
Feline chronic progressive polyarthritis Feline chronic progressive polyarthritis is a destructive, debilitating inflammatory disorder that predominantly affects male cats . The clinical signs include fever, lethargy, and lameness, or a stiff, stilted gait . Inappetence and emaciation usually ensue . Although any of the synovial joints, including those of the vertebral articulations, can be involved, favoured sites include the interphalangeal, metacarpal, metatarsal, carpal, tarsal, radiohumeral, and stifle joints, in order of decreasing severity with a symmetrical distribution . The common physical findings include fever, lymphadenopathy, muscle wasting, and swollen, tender joints . Two slightly different forms are distinguishable clinically, radiographically, and histologically . The fibrous ankylosing form is most common and causes rigidity with decreased range of movement in affected joints . Juxtaarticular osteopenia, periosteal new bone formation, marginal periarticular erosions of subchrondral bone, and collapse of joint spaces are typical radiographic findings in advanced stages of the ankylosing or non-deforming type . The second form is more common in older cats and distinguished by severe crepitus of the affected joints, less periosteal new bone formation, and severe subchondral bone erosions with collapse and subluxation leading to an unstable or deformed joint . Synovial fluid abnormalities include decreased viscosity and a sterile fibrinous exudate rich in segmented polymorphonuclear cells . Inflammatory changes in the synovium are characterized histologically by intimal hyperplasia and subintimal perivasculitis rich in neutrophils and mononuclear cells . In chronic cases, plasma cells and lymphocytes dominate the infiltrates, often in a nodular pattern, and fibroplasia is advanced . Granulation tissue originating from the inflamed synovium extends in a pannus formation across articular surfaces and erodes subchondral bone at the margins of synovial attachment . Similar destructive lesions extend to the bony insertions of tendons, causing a pronounced tenosynovitis . Synovial fluid and tissue are uniformly negative for
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bacterial or mycoplasmal pathogens . Consistent findings are the isolation of feline syncytium-forming virus (FeSFV) from blood or synovium of affected cats and the detection of concomitant viral infection with FeLV . Thus, dual virus infection is thought to be important in the pathogenesis of the disease . Immune-mediated mechanisms in feline chronic progressive polyarthritis are thought to include immune-complex injury and T lymphocyte cytoxicity . Although clinical and histological similarities exist between the destructive form of this disease and human rheumatoid arthritis (RA), the lack of rheumatoid factor activity in affected cats' sera is in striking contrast with human rheumatoid arthritis . Affected cats are also negative for ANA . Interestingly, some of these cats also have mild to severe glomerulonephritis . Treatment of feline progressive polyarthritis is difficult because of the relentless progression of destructive articular lesions . Anti-inflammatory doses of corticosteroids are most beneficial in the early stages of the disease, but with prolonged use may contribute to the severity of osteopenia and articular destruction . Cytotoxic immunosuppressant drugs such as azathioprine or cyclophosphamide may prove beneficial in achieving temporary periods of remission . The prognosis for this disease is guarded at best, although some do well for long periods .
Canine familial dermatomyositis This condition has only recently been described . The disorder occurs in collies and collie cross-breds . The clinical findings include a variably severe dermatitis with onset between 7 to 12 weeks of age . Skin lesions include erythema, vesicles on the lips and pinnae, ulceration, crusting, scaling, alopecia, facial or limb swelling, and pigmentary alterations . Head and facial involvement often resembles the `butterfly' or `wolf-like' lesions of SLE . Pressure points including the elbows, sternum, stifles, and tail tips frequently show severe ulceration . Nail beds and foot pads may also be involved . Acute, chronic-active, and chronic stages can occur, with spontaneous resolution anywhere from 9 to 24 weeks after onset. Some dogs recover completely without evidence of permanent scarring alopecia or pigmentary changes . Severely affected animals often die or are destroyed owing to severe secondary pyoderma, acute moist dermatitis, or the debilitating effects of the concomitant myopathy . The initial sign of myopathy is bilateral temporalis muscle atrophy beginning as early as 13 weeks of age . This may or may not progress to severe generalized muscle atrophy . Facial palsy (jaw drop) and trismus are sometimes seen in severely affected cases . A stiff gaited appearance, megaoesophagus, retarded growth due to difficulty in eating, peripheral lymphadenopathy, and severe conjunctivitis/keratitis due to loss of palpebral reflex are also sometimes seen . Skin lesions are characterized histologically by intra- and,subepidermal vesicles and pustules filled with neutrophils . Epidermal ulceration may be marked . Dermal capillaries contain a mixed population of inflammatory cells within the lumen or perivascularly . Dermal fibrosis is seen in advanced cases . Muscle lesions show myofibre degeneration, regeneration, and atrophy, with variable interstitial accumulations of lymphocytes, plasma cells, macrophages, and neutrophils in a perivascular pattern . The haematological picture shows inflammatory changes with mild anaemia, but plasma muscle enzyme activities are normal even in the presence of active myositis . There is some evidence that circulating immune complexes are involved . Infectious agents, particularly enteric viruses, are under investigation, as is the familial nature of the
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disease. To date, a multifactorial aetiology involving viral, immune-mediated, and genetic components is postulated . There is no effective treatment . Immunosuppressant drugs may cause more harm than good, since pyoderma and sepsis are common causes of death . Antibiotics and local debriding therapy are recommended for severe cutaneous involvement .
REFERENCES 1984) . Autoimmune disease in the dog . In practice 6, (3), 74. BENNETT, D . (1985) . Two cases of pemphigus erythematosus in the dog . Journal of Small Animal Practice 26, 219. COOK, A ., LYDYARD, P . M ., RoiTT, I . M . (1983) . Mechanisms of autoimmunity : a role for cross reactive idiotypes . Immunology Today 4, 170 . DODDS, J . (1984) . Immune mediated diseases of blood . Advances in Veterinary Science and Comparative Medicine 27, 103 . FAUCi, A . S . (1983). Vasculitis . Journal of Allergy and Clinical Immunology 72, 211 . BENNETT, D . (
GORMAN, N . T . & WERNER, L. L . (1986) . Diagnosis of immune mediated diseases and interpretation of immunological tests . In Current Veterinary Therapy IX, ed . R. Kirk. Philadelphia : Saunders . GOSSLEIN, S. J ., CAPEN, C . C ., MARTINI, S . L ., et al (1982) . Autoimmune lymphocytic thyroiditis in dogs . Veterinary Immunology and Immunopathology 3, 185 . HALLIWELL, R . E. W . (1978) . Autoimmune disease in the dog . Advances in Veterinary Science and Comparative Medicine 22, 221 . JAIN, N . C . & SWITZER, J . W . (1981) . Autoimmune thrombocytopenia in dogs and cats . Veterinary Clinics of North America (Small Animal) 2, 421 . KOLLER, L. D . (1982) . Chemical induced immunodalation . Journal of the American Veterinary Medicine Association 181, 1102 . LENNON, V . A ., PALMER, A . C ., PFLUFELDER, C . & INDIERI, R . J . (1978) . Myasthenia gravis in dogs :
acetylcholine receptor with and without antireceptor autoantibodies ., In Genetic Control of Autoimmune Disease, ed . N. R . Rose, P . E . Bigazzi and N. L . Warner . Amsterdam : Elsevier. PEDERSEN, N . C ., POOL, R . R . & MORGAN, J . P . (1983) . Joint diseases of dogs and cats . In Textbook of Veterinary Internal Medicine Diseases of the Dog and Cat, ed . S . J . Ettinger. . p. 2187 . Philadelphia : Saunders. PETERSON, M . E ., HURVITZ, A. I ., LEIB, M . B ., et al. (1984) . Propylthiouracil associated haemolytic anaemia and thrombocytopaenia in cats with hyperthyroidism . Journal of the American Veterinary Medicine Association 184, 804 . ScoTT, D. W ., WALTON, D . K., MANNING, T. O ., et al. (1983) . Canine lupus erythematosus I : Systemic lupus erythematosus . Journal of the American Animal Hospital Association 19, 461 . SCHULTZ, R. D . & ADAMS, L . S . (1978) . Methods for detecting humoral and cellular immunity . Veterinary Clinics of North America (Small Animal) 14, 1039 . SISKIND, G . W . (1984) . Immunological Tolerance . In Fundamental Immunology, ed . W . E . Paul. p . 537 . New York: Raven Press . TAN, E . M ., COHEN, A. S ., FRIES, J . F., et al. (1982) . Revised criteria for the classification of systemic lupus erythematosus . Arthritis and Rheumatism 25, 1271 . TAN, E . W . (1982). Autoantibodies to nuclear antigens : their biology and medicine. Advances in Immunology 33, 167 . WERNER, L . L . & GORMAN, N . T. (1984) . Immune mediated disorders of cats . Veterinary Clinics of North America (Small Animal) 14, 1039 . WERNER, L . L . & HALLIWELL, R . E . W . (1984). Diseases associated with autoimmunity . In Canine Medicine and Therapeutics, ed . E . A . Chandler, J . B . Sutton, and D . J . Thompson, p . 270 . Oxford : Blackwell .
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(1986) . 142, 403
VETERINARY PROFESSIONAL DEVELOPMENT SERIES
IMMUNE MEDIATED-DISEASES OF THE DOG AND CAT . II. IMMUNE-MEDIATED DISEASES OF THE HAEMOLYMPHATIC AND MUSCULOSKELETAL SYSTEM N . T. GORMAN* and L . L . WERNERt *Department of Clinical Veterinary Medicine, Madingley Road, Cambridge CB3 0ES and tDepartment of Clinical Pathology, School of Veterinary Medicine, University of California, Davis, California
The first article in this series covered the systemic immune-mediated diseases . This paper covers the immune-mediated diseases that involve the haemolymphatic and musculoskeletal systems . The organ-based diseases commonly have systemic clinical manifestations and, in some cases, require intensive systemic treatment .
HAEMOLYMPHATIC SYSTEM Immune-mediated diseases of the haemolymphatic system are relatively common and include autoimmune haemolytic anaemia, immune-mediated thrombocytopenia, and immune-mediated Leukopenia .
Autoimmune haemolytic anaemia (AIHA) Primary AIHA (true autoimmune) is a relatively common immunohaematological disorder in the dog . Cats, on the other hand, have a much higher prevalence of so-called secondary immune-mediated haemolytic anaemia (IHA), in which immune elimination of erythrocytes takes place in conjunction with host responses to infectious (feline leukaemia virus, Haemobartonella felis), or pharmacological (propylthiouracil) agents, and neoplasia (lymphoma, myeloproliferative disease) . The hallmarks of IHA in both species, whether primary autoimmune or secondary, are a progressive, fulminant clinical course characterized by depression, weakness, and pallor . In severe cases, syncope, tachypnoea, tachycardia, icterus, and emesis may be present . Haematological findings usually reflect the haemolytic nature of the anaemia, with a reticulocytosis, spherocytosis, and the presence of nucleated erythrocytes . Leukocytosis with a left shift is also a common finding . When intravascular haemolysis supersedes the less fulminant phagocytic removal of erythrocytes (extravascular haemolysis), icterus, haemoglobinaemia and haemoglobinuria are found . Hepatosplenomegaly is sometimes seen in chronic cases . A
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variant of IHA referred to as cold agglutinin disease causes a distal ischaemic dermatosis in conjuction with a mild to severe anaemia . In dogs and cats, it is more common to see anaemia caused by cold agglutinins without distal extremity lesions . Cold temperatureinduced haemolytic episodes which manifest as haemoglobinuria are generally accompanied by less profound anaemias in warmer climates . The latter clinical presentation is exceedingly rare and is caused by cold-reactive complement-fixing autoantibodies of the non-agglutinating type . A bone marrow aspirate is essential in evaluating all cases of IHA, to exclude occult myeloproliferative and lymphoproliferative disorders can be excluded and erythrophagocytosis, supportive of AIHA can be detected . Increased erythropoiesis, granulopoiesis, and occasionally thrombopoiesis can be found in cases of IHA . There are few documented cases of non-regenerative anaemia associated with IHA in dogs . Erythroid hypoplasia or aplasia in such cases is considered to be the result of immune destruction of red cell precursors, although there is no documented evidence in the dog or cat . Significant biochemical abnormalities in uncomplicated cases of IHA are few . Moderate increases in liver enzyme levels are common, and generally reflect ischaemic hepatocellular damage or corticosteroid therapy . Raised levels of serum urea nitrogen and creatinine are associated with pre-renal causes in most cases . However, haemoglobin nephropathy can be seen in cases with severe intravascular haemolysis . Differential diagnoses for IHA include other causes of regenerative and haemolytic anaemias including internal or external blood loss, toxic drugs or chemicals, and erythroparasitism . The direct Coombs' anti-globulin test is routinely used for diagnosis, and a positive Coombs' test is found in both primary and secondary IHA, reflecting the immune elimination of erythrocytes . A detailed medical history, thorough physical examination, and diagnostic tests to rule out underlying disease are all-important in differentiating primary from secondary IHA . Further examples of underlying disorders associated with IHA in dogs and cats include drug exposure (vaccines, phenothiazines, sulpha-drugs), rickettsial diseases, dirofilariasis, and bacterial infections . Treatment of primary IHA includes the use of short-acting glucocorticoids at immunosuppressive doses . Prednisone, prednisolone, and dexamethasone are all effective in most cases ; the duration of treatment is dictated by response of the individual case . In most cases, clinical remission defined as a return to normal PCV, is achieved during the first two weeks of treatment . At that time, doses are gradually reduced over a period of 6 to 8 weeks . If remission is sustained, low-dose alternate day treatment is maintained for another 2 to 3 months . Treatment should continue until there have been successive normal blood counts and a negative Coombs' test . Relapse is less common, in the authors' experience, in cases treated over a longer period with a more gradual dosage reduction . Failure to achieve a good clinical response within 72 h, i .e . stabilization or increase in PCV, is an indication for treatment with a more potent immunosuppressant such as cyclophosphamide or azathioprine . A blood transfusion may be required in life-threatening anaemia, but should be avoided in clinically stable animals because it may accelerate or, in the case of incompatible blood, induce a haemolytic crisis . Oxygen therapy is helpful in stabilizing cases showing clinical signs of anaemic hypoxia . Splenectomy is indicated only in cases where relapse or drug intolerance are encountered .
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The prognosis for IHA is variable depending upon the severity of the clinical presentation, the response to treatment, and the nature of any underlying disease process . In cats, the high incidence of underlying FeLV infection and haemolymphatic neoplasia associated with IHA dictates a more guarded prognosis for long-term survival . The treatment of secondary IHA requires specific treatment of any underlying disease process and judicious use of corticosteroids, generally for shorter periods of time . Oral Tetracycline, at 20 mg/kg t .i .d . is recommended in addition to corticosteroids for feline IHA in areas where haemobartonellosis is endemic . Immune-mediated thrombocytopenia (IMT) Immune-mediated thrombocytopenia is the single commonest cause of platelet destruction in the absence of consumptive coagulopathies, e .g. DIC . Both primary and secondary IMT occur, as is the case with IHA . Primary idiopathic forms are common in the dog, while in cats IMT is less common . It is generally encountered in conjuction with other haematological abnormalities associated with FeLV infection, haematopoietic neoplasia, or myelodysplasia . Petechial and ecchymotic haemorrhages are the typical clinical findings in most thrombocytopenic disorders . However, bleeding tendencies of any kind can be seen . Additional abnormalities seen in IMT may include fever, hepatosplenomegaly, lymphadenopathy, and anaemia due to either blood loss or accompanying Coombs'positive haemolytic anaemia (Evan's syndrome) . Haematological parameters are quite variable depending on the degree of blood loss and thrombopoietic activity in the bone marrow . Profound anaemias are usually regenerative . Acute forms of IMT can show small, uniformly sized platelets on the blood smear, reflecting lack of accelerated thrombopoietic activity . In more chronic stages, an increase in mean platelet volume (MPV) or size reflects a regenerative bone marrow response . In rare cases, however, platelet regeneration is lacking due to immune destruction of megakaryocytes . Bone marrow aspiration or biopsy is the best diagnostic investigation in a thrombocytopenic disorder since it will help to differentiate between aplastic, hypoplastic, myeloproliferative, dysmyeloplastic, and regenerative haematopoietic defects . Screening tests such as activated clotting time, prothrombin time, partial thromboplastin time, and measurement of fibrin degradation products to detect clotting factor defects are useful in differentiating uncomplicated thrombocytopenic disorders from the multiple clotting defects seen in conjuction with disseminated intravascular coagulopathy . Such test results are normal in cases of IMT . There are no simple, widely available tests to confirm a diagnosis of IMT . The platelet factor-3 test has limited availability and is of dubious sensitivity and specificity . Direct immunofluorescence on bone marrow or peripheral blood smears will sometimes demonstrate antibody or complement on megakaryocytes or platelets . Paucity of these cell types, however, can make diagnosis difficult . The diagnosis of IMT requires a concerted and systematic elimination of differential diagnoses of thrombocytopenia . When myelophthisical, myeloproliferative, and consuptive coagulation disorders are ruled out, a good response to corticosteroid treatment is often the basis for a retrospective diagnosis of IMT . Confirmation by immunological tests is ideal but not always feasible .
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Treatment and prognosis of IMT are essentially the same as outlined for AIHA . In addition, the vinca alkaloids, provide a useful alternative to the more potent cytotoxic immunosuppressive drugs in refractory cases of IMT . Immune-mediated deukopenias Neutropenic or lymphopenic states are less common manifestations of immunohaematological disorders . They are seldom isolated, but can accompany the immunohaematological manifestations of systemic lupus erythematosus and feline leukaemia virus infection . There are no clinically applicable means of documenting immunemediated leukopenias . Ruling out infectious or myeloproliferative causes, and response to immunosuppressive treatment is the usual means of making a presumptive diagnosis . As is the case with AIHA and IMT, phagocytosis of haematopoietic cells observed in bone marrow or lymph node aspirates is also good presumptive evidence for an immunemediated mechanism .
MUSCULOSKELETAL SYSTEM The immune-mediated diseases involving the musculoskeletal system are often varied in their presentation and represent a considerable challenge to the clinician . In all cases a careful and thorough evaluation is required, but good radiographic, immunological and cytological investigations are essential . The major diseases are canine rheumatoid arthritis, non-erosive polyarthritis, myasthenia gravis, feline chronic progressive polyarthritis, and canine familial dermatomyositis . Canine rheumatoid arthritis There is little doubt that a clinical entity exists in the dog that has some similarity to rheumatoid arthritis in man . It is, however, a matter of considerable debate whether or not the equivalent condition in the dog is identical . There is little doubt, however, that an erosive polyarthritis does occur in the dog . The authors' prefer to consider a condition of canine rheumatoid arthritis to distinguish it from the well documented and characterized rheumatoid arthritis in man . Canine rheumatoid arthritis is distinguished among the canine immune-mediated arthropathies by its propensity to cause articular and subchondral bone erosions leading to joint deformity and instability . It is also distinguished by a high association with the finding of serum rheumatoid factor (RF) . Rheumatoid factor is an immunoglobulin that is directed against native IgG, i .e . an autoantibody which can be of either the IgG or IgM isotype . The disease is classified as autoimmune . Typically, canine rheumatoid arthritis is seen in small and toy breeds of dogs and often occurs in youth or middle age . The joints initially involved are the metacarpal, metatarsal, carpal, and tarsal joints, but it may progress to involve large joints as well . Clinical signs, in order of progression, include : 1 . Joint pain, stiff-gaited appearance, periarticular soft tissue swelling . Radiographic evidence of erosive articular disease may not be present early in the disease . 2 . Joint crepitus, laxity and subluxation . Radiographs may show subchondral bone lysis with narrowing of articular spaces indicative of cartilage destruction . 3 . Angular deformities with complete luxation . Highly destructive and proliferative osteophyte formation, with collapse and sclerosis of subchondral bone are seen radiographically .
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The clinical findings which often accompany the above articular changes include fever unresponsive to antibiotics, leukocytosis, raised fibrinogen and gamma globulin levels, non-regenerative anaemia, and synovial fluid findings characteristic of sterile inflammation (reduced viscosity, raised protein content, and increased numbers of neutrophils and small and large mononuclear cells) . The major differential diagnoses for erosive inflammatory joint disease are septic polyarthritis and rheumatoid arthritis . Culture of synovial fluid and biopsy are important in distinguishing between them . Serum rheumatoid factor tests are positive in 40 to 75% of canine rheumatoid arthritis cases, and although a useful screening test, a negative result does not preclude the use of further diagnostic tests for rheumatoid arthritis . The best indicators are the radiogaphic and synovial biopsy appearances . The latter is particularly indicated in predisoposed breeds showing sterile-synovitis, but no radiographic evidence of destructive articular disease . In such early cases of rheumatoid arthritis, a diagnosis by synovial biopsy will allow early therapeutic intervention to delay the progression of the disease . Characteristic histopathological findings include villous hyperplasia and hypertrophy, and an inflammatory infiltrate marked by proliferating plasma cells, lymphocytes, and, to a lesser extent, neutrophils . Canine rheumatoid arthritis is not a curable disease, although there are examples of apparent spontaneous remission, or sustained remission after immunosuppressive treatment . Aspirin is not particularly effective, but may help to control fever and pain . Corticosteroids are useful in the acute stages, but prolonged use at high dosage is thought to contribute to the articular and soft tissue breakdown that may occur . The most common treatment regimen is cyclophosphamide alone or in combination with azathioprine to induce and sustain remission . Gold therapy has also had limited success in the treatment of canine rheumatoid arthritis . All of these medications will be discussed in detail in part IV . Surgical arthrodesis is effective in restoring mobility in advanced cases .
Non-erosive polyarthritis Sterile synovitis affecting a few joints, or multiple joints in a symmetrical pattern is a very common sequella to a number of infectious diseases . Less commonly, neoplasia, drugs (trimethoprim, sulfadiazine), and parasites (dirofilariasis) have been incriminated . Circulating immune complexes are thought to be involved in the synovitis, but many cases are classified as idiopathic when no underlying disease process can be identified . The polyarthritis seen in some cases of canine SLE has many features in common with non-erosive polyarthritis . In fact, the term `lupus-like' has been used to describe the synovial inflammatory changes seen in all non-rheumatoid arthritis (non-erosive) polyarthropathies caused by circulating immune complexes . There is a mild synovial hyperplasia and a predominance of neutrophils migrating from synovial vessels . LE cells are seen only rarely in synovial fluid smears . Thus, the serum ANA test and LE preparation are the best methods to distinguish lupus polyarthritis from the other types of non-erosive polyarthritis . As is the case in canine rheumatoid arthritis and systemic lupus erythematosus, systemic signs often accompany the remainder of the non-erosive polyarthropathies . These include fever, leukocytosis, low grade anaemias, raised fibrinogen and gamma globulin levels, lymphadenopathy, and occasionally hepatosplenomegaly . Joint fluid analysis allows rapid diagnosis of immune-mediated joint disease in cases of unexplained lameness or walking difficulties . Polyarthritis is often
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misdiagnosed as a neurological problem when terms such as `can't walk', `down in the rear quarters', or `paralyzed' are used to describe the presenting complaint . Radiographs of affected joints are almost uniformly normal, with the possible exception of soft tissue swelling or joint capsule distension . Joint fluid culture is recommended to rule out an infectious cause of the synovitis . Elimination of suspect drugs, parasites, or infectious agents is of prime importance in treatment . Judicious use of corticosteroids and cytotoxic immunosuppressant drugs is often necessary to suppress the inflammation and restore mobility . Many cases do not recur after treatment, but some are prone to relapse .
Myasthenia gravis Acquired myasthenia gravis has been identified as an autoimmune disorder in both dogs and cats . Periods of weakness, often profound, exacerbated by activity, but responsive to rest and cholinesterase inhibitors are among the most important clinical findings . Autoantibodies to acetylcholine receptors at the myoneural junction can be detected by both direct and indirect immunofluorescence . Corticosteroid treatment has been successful both alone and in conjunction with long-acting cholinesterase inhibitors . The long-term prognosis is guarded, particularly in cases with pharyngeal, oesophageal, or respiratory muscle involvement . Dysphagia, aspiration pneumonia, and respiratory failure are the most life-threatening consequences of this disease .
Feline chronic progressive polyarthritis Feline chronic progressive polyarthritis is a destructive, debilitating inflammatory disorder that predominantly affects male cats . The clinical signs include fever, lethargy, and lameness, or a stiff, stilted gait . Inappetence and emaciation usually ensue . Although any of the synovial joints, including those of the vertebral articulations, can be involved, favoured sites include the interphalangeal, metacarpal, metatarsal, carpal, tarsal, radiohumeral, and stifle joints, in order of decreasing severity with a symmetrical distribution . The common physical findings include fever, lymphadenopathy, muscle wasting, and swollen, tender joints . Two slightly different forms are distinguishable clinically, radiographically, and histologically . The fibrous ankylosing form is most common and causes rigidity with decreased range of movement in affected joints . Juxtaarticular osteopenia, periosteal new bone formation, marginal periarticular erosions of subchrondral bone, and collapse of joint spaces are typical radiographic findings in advanced stages of the ankylosing or non-deforming type . The second form is more common in older cats and distinguished by severe crepitus of the affected joints, less periosteal new bone formation, and severe subchondral bone erosions with collapse and subluxation leading to an unstable or deformed joint . Synovial fluid abnormalities include decreased viscosity and a sterile fibrinous exudate rich in segmented polymorphonuclear cells . Inflammatory changes in the synovium are characterized histologically by intimal hyperplasia and subintimal perivasculitis rich in neutrophils and mononuclear cells . In chronic cases, plasma cells and lymphocytes dominate the infiltrates, often in a nodular pattern, and fibroplasia is advanced . Granulation tissue originating from the inflamed synovium extends in a pannus formation across articular surfaces and erodes subchondral bone at the margins of synovial attachment . Similar destructive lesions extend to the bony insertions of tendons, causing a pronounced tenosynovitis . Synovial fluid and tissue are uniformly negative for
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bacterial or mycoplasmal pathogens . Consistent findings are the isolation of feline syncytium-forming virus (FeSFV) from blood or synovium of affected cats and the detection of concomitant viral infection with FeLV . Thus, dual virus infection is thought to be important in the pathogenesis of the disease . Immune-mediated mechanisms in feline chronic progressive polyarthritis are thought to include immune-complex injury and T lymphocyte cytoxicity . Although clinical and histological similarities exist between the destructive form of this disease and human rheumatoid arthritis (RA), the lack of rheumatoid factor activity in affected cats' sera is in striking contrast with human rheumatoid arthritis . Affected cats are also negative for ANA . Interestingly, some of these cats also have mild to severe glomerulonephritis . Treatment of feline progressive polyarthritis is difficult because of the relentless progression of destructive articular lesions . Anti-inflammatory doses of corticosteroids are most beneficial in the early stages of the disease, but with prolonged use may contribute to the severity of osteopenia and articular destruction . Cytotoxic immunosuppressant drugs such as azathioprine or cyclophosphamide may prove beneficial in achieving temporary periods of remission . The prognosis for this disease is guarded at best, although some do well for long periods .
Canine familial dermatomyositis This condition has only recently been described . The disorder occurs in collies and collie cross-breds . The clinical findings include a variably severe dermatitis with onset between 7 to 12 weeks of age . Skin lesions include erythema, vesicles on the lips and pinnae, ulceration, crusting, scaling, alopecia, facial or limb swelling, and pigmentary alterations . Head and facial involvement often resembles the `butterfly' or `wolf-like' lesions of SLE . Pressure points including the elbows, sternum, stifles, and tail tips frequently show severe ulceration . Nail beds and foot pads may also be involved . Acute, chronic-active, and chronic stages can occur, with spontaneous resolution anywhere from 9 to 24 weeks after onset. Some dogs recover completely without evidence of permanent scarring alopecia or pigmentary changes . Severely affected animals often die or are destroyed owing to severe secondary pyoderma, acute moist dermatitis, or the debilitating effects of the concomitant myopathy . The initial sign of myopathy is bilateral temporalis muscle atrophy beginning as early as 13 weeks of age . This may or may not progress to severe generalized muscle atrophy . Facial palsy (jaw drop) and trismus are sometimes seen in severely affected cases . A stiff gaited appearance, megaoesophagus, retarded growth due to difficulty in eating, peripheral lymphadenopathy, and severe conjunctivitis/keratitis due to loss of palpebral reflex are also sometimes seen . Skin lesions are characterized histologically by intra- and,subepidermal vesicles and pustules filled with neutrophils . Epidermal ulceration may be marked . Dermal capillaries contain a mixed population of inflammatory cells within the lumen or perivascularly . Dermal fibrosis is seen in advanced cases . Muscle lesions show myofibre degeneration, regeneration, and atrophy, with variable interstitial accumulations of lymphocytes, plasma cells, macrophages, and neutrophils in a perivascular pattern . The haematological picture shows inflammatory changes with mild anaemia, but plasma muscle enzyme activities are normal even in the presence of active myositis . There is some evidence that circulating immune complexes are involved . Infectious agents, particularly enteric viruses, are under investigation, as is the familial nature of the
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disease. To date, a multifactorial aetiology involving viral, immune-mediated, and genetic components is postulated . There is no effective treatment . Immunosuppressant drugs may cause more harm than good, since pyoderma and sepsis are common causes of death . Antibiotics and local debriding therapy are recommended for severe cutaneous involvement .
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GORMAN, N . T . & WERNER, L. L . (1986) . Diagnosis of immune mediated diseases and interpretation of immunological tests . In Current Veterinary Therapy IX, ed . R. Kirk. Philadelphia : Saunders . GOSSLEIN, S. J ., CAPEN, C . C ., MARTINI, S . L ., et al (1982) . Autoimmune lymphocytic thyroiditis in dogs . Veterinary Immunology and Immunopathology 3, 185 . HALLIWELL, R . E. W . (1978) . Autoimmune disease in the dog . Advances in Veterinary Science and Comparative Medicine 22, 221 . JAIN, N . C . & SWITZER, J . W . (1981) . Autoimmune thrombocytopenia in dogs and cats . Veterinary Clinics of North America (Small Animal) 2, 421 . KOLLER, L. D . (1982) . Chemical induced immunodalation . Journal of the American Veterinary Medicine Association 181, 1102 . LENNON, V . A ., PALMER, A . C ., PFLUFELDER, C . & INDIERI, R . J . (1978) . Myasthenia gravis in dogs :
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