ANIMAL MODEL OF HUMAN DISEASE
Juvenile Rheumatoid Arthritis
Animal Model: Rheumatoid Arthritis in the Dog
Contributed by: Henry L. Allen, VMD, and Charles D. Newton, DVM, University of Pennsylvania School of Veterinary Medicine, 3800 Spruce Street, Philadelphia, Pennsylvania 19174.
Bioogic Features
Rheumatoid arthritis (RA) in the dog is a crippling, spontaneous polyarthritis.1-6 It affects dogs of various ages and breeds. Present data are sufficient to determine that there is a significant preponderance of one breed, the Shetland sheepdog. The disease occurs primarilv in dogs 3 to 8 y-ears old. No sex predeliction has vet been observed; both males and females appear to be afflicted equally. The clinically affected animals show signs which fulfill at least eight of the diagnostic criteria which have been laid down bv the American Rheumatism Association.7 This is considered sufficient to make the diagnosis of RA. .Most of the dogs evidence morning stiffness, pain on motion of one or more joints, and periarticular soft tissue swelling. Joint involvement is typically symmetrical. Radiographic changes are consistently present in the clinicallv affected joints. The earliest radiographic findings are swelling of the soft tissues around a joint or fluid within a joint. These are seen radiographically either as joint capsule distension or minimal widening of the joint space. Later radiographic findings are narrowing of the joint space with varying degrees of irregular, radiolucent, cyst-like areas of destruction involving Publication sponsored by the Registry of Comparatise Patholop- of the Armed Forces Institute of Pathology and supported by Public Health Sernice Grant RR 00:301 from the Disision of Research Resources. L-S Department of Health. Education and W elfare. under the auspices of U niversities Associated for Research and Education in Pathology. Inc Dr. Mlen s current address is 44-1 Merck Sharp and Dohme Research Laboratories. West Point, PX 194S6. 699
700
ALLEN AND NEWTON
American Journal of Pathology
Figure 1-Anteroposterior radiograph of the right tarsus. There is marked joint space narrowing of the tibial-tarsal, fibular-tarsal, and intratarsal joints. Joint capsule distension is present. There are multiple subchondral cysts and erosions of the articular surfaces. _sli
subehondral bone (Figure 1). The radiolucent areas usually are most prominent at the attachment sites of ligaments to the bone. Progressive rarefaction of bone occurs at the ends of bones involving the entire joint surface. Rheumatoid factor, when measured using a procedure designed specificallv for the canine species, is almost always present.' However, it is generally present at low levels (1:8 to 1:236). Antinuclear antibody is usually absent. In addition, the dogs are ill. They are often pyrectic and depressed, and there may be a loss of appetite, particularly during exacerbations of the symptoms. Lymphadenopathv has also been observed in occasional cases. Histologically', there is marked papillarv proliferation of the articular
RHEUMATOID ARTHRITIS
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Vol. 81, No. 3 December 1975
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Figure 2-Photomicrograph of papillary synovium from a dog affected with RA (H&E, x 40).
synovial membranes in the clinicallv affected joints. This is produced by hyperplasia of synovial lining cells and the underlying connective tissue. There is dense infiltrate of lymphocytes and plasma cells (Figures 2 and 3), and hemosiderophages in the synovium are often plentiful. Synovial giant cells and bone production in the sy-novial membranes have not been reported. Granulation tissue "pannus"' frequently invades the subchondral bone and extends over the articular cartilage, destroying it. The svnovial fluid has not vet been adequately studied in canine RA. In the instances where it has been examined, there appears to be only a minor decrease in viscosity and glucose content; mucin precipitation has not been characterized. To complete the clinical picture, aspirin and corticosteroids are palliative, and have been used with success in a number of cases of canine RA. p
Fgure 3-Thickened synovium showing doubling of mesothelial lining and pure mononuclear infiltrate (H&E, x 120).
ti2L -_~
I
i
I
702
ALLEN AND NEWTON
Cornpanson
American Journal of Pathology
hthe Human Disease
Canine RA has many features in common with juvenile RA of man.8 Constitutional signs, such as fever and malaise are more pronounced in children with RA than in adults. The low titers of rheumatoid factor found in many dogs would not be significant in adults, but are acceptable for diagnosis of the disease in children. The rheumatoid nodule (of the subcutis) which is so diagnostic of the disease in adults has been reported in 1 dog.3 The nodules are rare in children affected with RA. In its other aspects, the canine disease closely mimics rheumatoid disease of man. Because of the nature of the disease, many of the diagnostic criteria are based on clinical observation. However, the canine RA cases fulfill not only the clinical but also the radiographic, histopathologic, and clinical laboratory criteria as well. Potential Usefuless of the Model and Availabiut
The dog appears to be an excellent model for the study of RA. Dogs are plentiful, and they live under conditions similar to those of their human masters. Although the condition does not appear to be common, it occurs sufficientlv often to warrant increased awareness on the part of veterinar clinicians and their medical counterparts to recognize the disease when the animal is presented. An additional advantage in using the dog is that there are large quantities of synovial fluid, synovium, etc., available for biopsy. Likewise, the radiographic and laboratory parameters for the dog are widely known. References Halliwell RE%, Lavelle RB, Butt KM: Canine rheumatoid arthritis: A review and a case report. J Small Anim Pract 13:239-248, 1972 2. Lewis RM, Borel Y: Canine rheumatoid arthritis: A case report. Arthritis Rheum 1.
3. 4.
5. 6. 7.
8.
14:67-74, 1971 Lewis RMI, Hathawav JE: Canine systemic lupus erythematosus presenting with symmetrical polyarthritis. J Small Anim Pract 8:273-284, 196-7 Liu SK, Suter PF, Fischer CA, Dorfman HD: Rheumatoid arthritis in a dog. J Am V'et Med Assoc 154:495-02 1969 Rudy RL, Hohn RB, Harrison JW: Rheumatoid and osteoarthritis in the dog. Gaines Veterinary Svmposium, 1972, New York, Gaines Dog Research Center Newton CD, Allen HL, Halliwell REW, Schumacher HR Jr: Juvenile rheumatoid-like arthritis in a dog: Clinicopathologic conference. J Am Vet Med Assoc 165:459, 1974 McEwen C: The diagnosis and differential diagnosis of rheumatoid arthritis. Arthritis and Allied Conditions, Eighth edition. Lea and Febiger, 1972 Philadelphia, Pennsvlvania 8th Ed. Robinson WD: Juvenile rheumatoid arthritis. Cecil-Loeb Textbook of Medicine, Edited by PB Beeson, W McDermott, Philadelphia, W. B. Saunders Companv, 1971, p 1898
Juvenile Rheumatoid Arthritis
Animal Model: Rheumatoid Arthritis in the Dog
Contributed by: Henry L. Allen, VMD, and Charles D. Newton, DVM, University of Pennsylvania School of Veterinary Medicine, 3800 Spruce Street, Philadelphia, Pennsylvania 19174.
Bioogic Features
Rheumatoid arthritis (RA) in the dog is a crippling, spontaneous polyarthritis.1-6 It affects dogs of various ages and breeds. Present data are sufficient to determine that there is a significant preponderance of one breed, the Shetland sheepdog. The disease occurs primarilv in dogs 3 to 8 y-ears old. No sex predeliction has vet been observed; both males and females appear to be afflicted equally. The clinically affected animals show signs which fulfill at least eight of the diagnostic criteria which have been laid down bv the American Rheumatism Association.7 This is considered sufficient to make the diagnosis of RA. .Most of the dogs evidence morning stiffness, pain on motion of one or more joints, and periarticular soft tissue swelling. Joint involvement is typically symmetrical. Radiographic changes are consistently present in the clinicallv affected joints. The earliest radiographic findings are swelling of the soft tissues around a joint or fluid within a joint. These are seen radiographically either as joint capsule distension or minimal widening of the joint space. Later radiographic findings are narrowing of the joint space with varying degrees of irregular, radiolucent, cyst-like areas of destruction involving Publication sponsored by the Registry of Comparatise Patholop- of the Armed Forces Institute of Pathology and supported by Public Health Sernice Grant RR 00:301 from the Disision of Research Resources. L-S Department of Health. Education and W elfare. under the auspices of U niversities Associated for Research and Education in Pathology. Inc Dr. Mlen s current address is 44-1 Merck Sharp and Dohme Research Laboratories. West Point, PX 194S6. 699
700
ALLEN AND NEWTON
American Journal of Pathology
Figure 1-Anteroposterior radiograph of the right tarsus. There is marked joint space narrowing of the tibial-tarsal, fibular-tarsal, and intratarsal joints. Joint capsule distension is present. There are multiple subchondral cysts and erosions of the articular surfaces. _sli
subehondral bone (Figure 1). The radiolucent areas usually are most prominent at the attachment sites of ligaments to the bone. Progressive rarefaction of bone occurs at the ends of bones involving the entire joint surface. Rheumatoid factor, when measured using a procedure designed specificallv for the canine species, is almost always present.' However, it is generally present at low levels (1:8 to 1:236). Antinuclear antibody is usually absent. In addition, the dogs are ill. They are often pyrectic and depressed, and there may be a loss of appetite, particularly during exacerbations of the symptoms. Lymphadenopathv has also been observed in occasional cases. Histologically', there is marked papillarv proliferation of the articular
RHEUMATOID ARTHRITIS
-
Vol. 81, No. 3 December 1975
.-.
..
.
. --.-
.
--.
Pf%4
7U1
~~~-
I I
Figure 2-Photomicrograph of papillary synovium from a dog affected with RA (H&E, x 40).
synovial membranes in the clinicallv affected joints. This is produced by hyperplasia of synovial lining cells and the underlying connective tissue. There is dense infiltrate of lymphocytes and plasma cells (Figures 2 and 3), and hemosiderophages in the synovium are often plentiful. Synovial giant cells and bone production in the sy-novial membranes have not been reported. Granulation tissue "pannus"' frequently invades the subchondral bone and extends over the articular cartilage, destroying it. The svnovial fluid has not vet been adequately studied in canine RA. In the instances where it has been examined, there appears to be only a minor decrease in viscosity and glucose content; mucin precipitation has not been characterized. To complete the clinical picture, aspirin and corticosteroids are palliative, and have been used with success in a number of cases of canine RA. p
Fgure 3-Thickened synovium showing doubling of mesothelial lining and pure mononuclear infiltrate (H&E, x 120).
ti2L -_~
I
i
I
702
ALLEN AND NEWTON
Cornpanson
American Journal of Pathology
hthe Human Disease
Canine RA has many features in common with juvenile RA of man.8 Constitutional signs, such as fever and malaise are more pronounced in children with RA than in adults. The low titers of rheumatoid factor found in many dogs would not be significant in adults, but are acceptable for diagnosis of the disease in children. The rheumatoid nodule (of the subcutis) which is so diagnostic of the disease in adults has been reported in 1 dog.3 The nodules are rare in children affected with RA. In its other aspects, the canine disease closely mimics rheumatoid disease of man. Because of the nature of the disease, many of the diagnostic criteria are based on clinical observation. However, the canine RA cases fulfill not only the clinical but also the radiographic, histopathologic, and clinical laboratory criteria as well. Potential Usefuless of the Model and Availabiut
The dog appears to be an excellent model for the study of RA. Dogs are plentiful, and they live under conditions similar to those of their human masters. Although the condition does not appear to be common, it occurs sufficientlv often to warrant increased awareness on the part of veterinar clinicians and their medical counterparts to recognize the disease when the animal is presented. An additional advantage in using the dog is that there are large quantities of synovial fluid, synovium, etc., available for biopsy. Likewise, the radiographic and laboratory parameters for the dog are widely known. References Halliwell RE%, Lavelle RB, Butt KM: Canine rheumatoid arthritis: A review and a case report. J Small Anim Pract 13:239-248, 1972 2. Lewis RM, Borel Y: Canine rheumatoid arthritis: A case report. Arthritis Rheum 1.
3. 4.
5. 6. 7.
8.
14:67-74, 1971 Lewis RMI, Hathawav JE: Canine systemic lupus erythematosus presenting with symmetrical polyarthritis. J Small Anim Pract 8:273-284, 196-7 Liu SK, Suter PF, Fischer CA, Dorfman HD: Rheumatoid arthritis in a dog. J Am V'et Med Assoc 154:495-02 1969 Rudy RL, Hohn RB, Harrison JW: Rheumatoid and osteoarthritis in the dog. Gaines Veterinary Svmposium, 1972, New York, Gaines Dog Research Center Newton CD, Allen HL, Halliwell REW, Schumacher HR Jr: Juvenile rheumatoid-like arthritis in a dog: Clinicopathologic conference. J Am Vet Med Assoc 165:459, 1974 McEwen C: The diagnosis and differential diagnosis of rheumatoid arthritis. Arthritis and Allied Conditions, Eighth edition. Lea and Febiger, 1972 Philadelphia, Pennsvlvania 8th Ed. Robinson WD: Juvenile rheumatoid arthritis. Cecil-Loeb Textbook of Medicine, Edited by PB Beeson, W McDermott, Philadelphia, W. B. Saunders Companv, 1971, p 1898
