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Find information on animal health topics, written for the veterinary professional.

Excessive Innate Responses

By Ian Tizard, BVMS, PhD, DACVM, University Distinguished Professor of Immunology; Director, Richard M. Schubot Exotic Bird Health Center, Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University

While acute inflammation is a defensive process and central to innate immunity, it may occur without appropriate provocation and in locations where it causes discomfort, tissue damage, or systemic disease. This results in significant morbidity and resulting disability.

Canine Rheumatoid Arthritis:

This disease results from excessive, uncontrolled inflammation around joints. It manifests initially as a shifting lameness with soft-tissue swelling around involved joints. Within weeks or months, the disease localizes in individual joints, and characteristic radiographic changes develop. The earliest radiographic changes consist of soft-tissue swelling and a loss of trabecular bone density in the area of the joint. Lucent cyst-like areas frequently are seen in the subchondral bone. The most prominent lesion is a progressive erosion of cartilage and subchondral bone in the area of synovial attachments, resulting in loss of articular cartilage and collapse of the joint space. Angular deformities often occur, and luxation of the joint is a frequent sequela. Deformities are most frequent in the carpal, tarsal, and phalangeal joints and less frequent in the elbow and stifle. Synovial fluid examination shows a sterile, inflammatory synovitis, with increased cell count and a high proportion of neutrophils in the synovial fluid cell population. The excessive inflammation is believed to be due to the deposition of immune complexes in the synovia with subsequent complement activation.

An erosive arthritis has also been recognized in cats. It tends to occur in older male cats and frequently is associated with feline syncytia-forming virus infection. The development of disease in cats is much more insidious than in dogs.

Canine rheumatoid arthritis responds poorly to systemic glucocorticoids alone. Immunosuppressive agents with anti-inflammatory activity such as cyclophosphamide and azathioprine are used with glucocorticoids to treat these disorders; NSAIDs (eg, aspirin, carprofen, etodolac, meloxicam) may bring relief.

Plasmacytic-Lymphocytic Synovitis:

Possibly a variant of rheumatoid arthritis, this synovitis occurs in medium-sized and large breeds of dogs. Although multiple joints often are involved, the disease has a predisposition for the stifle. The most common clinical sign is hindlimb lameness and anterior drawer motion of the stifles. Lymphocytes, plasma cells, and neutrophils predominate in the synovial fluid, although in some cases the fluid is essentially normal. Gross inspection of the joint shows proliferation of the synovial membrane and stretching or rupture of the cruciate ligaments. Treatment is as for canine rheumatoid arthritis, above.

Idiopathic Polyarthritis:

Arthritis of unknown etiology is most common in large dogs, particularly German Shepherds, Doberman Pinschers, retrievers, spaniels, and pointers. In toy breeds, it is most frequent in Toy Poodles, Yorkshire Terriers, and Chihuahuas, or mixes of these breeds. There is no evidence of a primary chronic infectious disease process or of systemic lupus erythematosus. Arthritis is often the sole manifestation.

Diagnosis is based on the history of cyclic antibiotic-unresponsive fever, malaise, and anorexia, with stiffness or lameness. Bony changes are not seen on radiographs until the disease is well established. Even then, radiographic changes are mild and can mimic degenerative joint disease. Synovial fluid contains leukocytes but is sterile.

The disease may be controlled with daily high-dose glucocorticoids followed by low-dose, alternate-day therapy. Treatment usually can be discontinued after 3–5 mo. Dogs with poor response to such therapy (>50%) may be treated with more potent immunosuppressive drugs such as azathioprine or cyclophosphamide in addition to glucocorticoids. Gold salts help augment glucocorticoid therapy in some animals.

Immune-mediated Meningitis:

This disease occurs in adolescent or young adult Beagles, Boxers, German Shorthaired Pointers, and Akitas but is very rare in other pure and mixed breeds. The clinical signs consist of cyclic episodes of fever, severe neck pain and rigidity, reluctance to move, and depression. Each attack lasts 5–10 days, with intervening periods of complete or partial normality lasting approximately a week. During attacks, protein and neutrophils in the CSF are increased. The lesion is an arteritis, primarily of the meningeal vessels, but occasionally of other organs as well. The disease is often self-limiting over several months; attacks become milder and less frequent. Glucocorticoid therapy reduces the severity of attacks. In some animals, the disease becomes chronic and only partially amenable to therapy.

A more severe form of this meningitis has been reported in young Bernese Mountain Dogs. The disease in this breed is somewhat cyclical, but the resolution in intervening periods is less than in other species. CSF abnormalities resemble those seen in other breeds. The condition requires longterm, high-dose glucocorticoid therapy.

A syndrome of meningitis, often associated with polyarthritis, is seen in young Akitas. The dogs show severe episodes of fever, depression, cervical pain and rigidity, and generalized stiffness. Affected dogs grow slowly and often appear unthrifty. The condition responds poorly to glucocorticoid and combination immunosuppressive therapy, and most affected dogs are euthanized as young adults. In older Akitas, a milder and more drug-responsive form of the disease is seen, which may be associated with pemphigus foliaceus, uveitis, and plasmacytic-lymphocytic thyroiditis.

Systemic Inflammatory Response Syndrome

In severe infections or after massive tissue damage, large amounts of cytokines and reactive oxygen and radicals enter the bloodstream and cause a form of shock known as systemic inflammatory response syndrome.

Septic shock is the name given to the systemic inflammatory response syndrome specifically caused by severe infections and associated with trauma, ischemia, and tissue injury. Animals with severe infections may generate vastly excessive cytokine production, most notably IL-1, TNF-α, IL-8, and IL-6. This massive cytokine release has been called “a cytokine storm.” High doses of cytokines are toxic and induce severe acidosis, fever, lactate release in tissues, an uncontrollable drop in blood pressure, increased plasma catecholamines, and eventually renal, hepatic, and lung injury and death. The procoagulant-anticoagulant balance is upset so that endothelial procoagulant activity is enhanced, while many anticoagulant pathways are inhibited, leading to disseminated intravascular coagulation and capillary thrombosis.

All these effects are initiated by excessive triggering of toll-like receptors leading to a massive and uncontrolled release of cytokines. The cytokines damage vascular endothelial cells, activating them so that procoagulant activity is enhanced, which leads to blood clotting. The nitric oxide causes vasodilation and a drop in blood pressure. The widespread damage to vascular endothelium eventually causes organ failure. Multiple organ dysfunction syndrome is the end stage of severe septic shock. It is characterized by hypotension, insufficient tissue perfusion, uncontrollable bleeding, and organ failure caused by hypoxia, tissue acidosis, tissue necrosis, and severe local metabolic disturbances. The severe bleeding is due to disseminated intravascular coagulation. The sensitivity of mammals to septic shock varies greatly. Species with pulmonary intravascular macrophages (cat, horse, sheep, and pig) tend to be more susceptible than dogs.