Q. Could you review immune-mediated polyarthritis in the dog?

A. Dr. Barbara Kohn at the 28th World Congress of the World Small Animal Veterinary Association in Bangkok, Thailand, gave a lecture on canine immune-mediated polyarthritis. Some relevant points in this lecture are provided below.

Table1. Inflammatory joint diseases

Inflammatory joint disease can be characterized as infectious or immune-mediated disease (see Table 1). The immune-mediated polyarthritides are defined by chronic synovial inflammation, failure to identify a microbial cause on routine culture of the synovial fluid and clinical response to immunosuppressive therapy. These diseases have common immunopathogenic features and may be subdivided based on clinical, radiographic (erosive versus nonerosive types), pathologic features and serological results.

Clinical findingsTypical findings are a stiff gait, reluctance to move, lethargy, fever and often inappetence. Polyarthritis is an important differential diagnosis for "fever of unknown origin". However, some cases can present as chronic lameness without signs of systemic disease. The severity of lameness can vary markedly, and shifting leg lameness often occurs. In the least severe cases, no more than a vague stiffness might be noted, whereas severely effected animals might be unable to stand or walk.

Typical, but not always present, are bilaterally symmetrical thickened or swollen joints with pain on motion. Muscle atrophy may be apparent. Immune-based arthritis is principally a polyarticular disease (six or more joints), although some cases involve fewer joints (oligoarthritis, two to five joints) and occasionally, only a single joint is diseased (monoarthritis). Depending on the form of immune-mediated arthritis, other signs, such as dermatitis, glomerulonephritis, meningitis, myositis, uveitis, lymphadenopathy, cardiac murmur, thrombocytopenia and anemia, will be apparent.

PathogenesisThe basic underlying immunopathologic mechanisms seem to involve the creation of immune complexes. These immune complexes can be generated locally within the joint and/or systemically within the circulation with secondary deposition into the joints (hypersensitivity reaction type III).

The immune complexes may fix complement in the synovial membrane and the synovial fluid. This results in local tissue damage and release of products chemotactic for polymorphonuclear leukocytes. The neutrophils release biologically active products that cause further tissue damage. These events are a normal immunologic response aimed at eliminating a foreign antigen. If the antigen persists or immune dysregulation exists, these events may result in chronic disease. Alternatively, alteration of self antigens may lead to loss of immune tolerance of the individual and to formation of autoantibodies [e.g., rheumatoid factors (circulating auto-antibodies against immunoglobulins G), antinuclear antibodies and anti-heat shock proteins].

Cell responses in chronic inflammatory synovitis of dogs are similar to those in man. A type IV hypersensitivity component of rheumatoid arthritis is suggested by the perivascular infiltration of mononuclear cells into effected synovium. Release of cytokines or matrix metalloproteinases by such cells enhances inflammation and cartilage degeneration. The underlying causative stimuli are unknown; although there is evidence to support the role of microbial infection (e.g., canine distemper virus, infection elsewhere in the body stimulating immune complex formation, and joint infections with persistence of microbial antigens). In addition, genetic factors might be involved in immune-mediated disease.

Idiopathic polyarthritis

Idiopathic polyarthritis (IPA) include all those cases of inflammatory arthropathy that cannot be classified into the other groups. Type I IPA is by far the most common of all the immune-based arthropathies in the dog.

The idiopathic type can be divided into four subcategories:

• Type I IPA: Uncomplicated IPA accounts for about 50 percent of all the idiopathic cases. The rheumatoid arthritic dogs and the IPA dogs have most immunopathologic features in common; therefore, some idiopathic cases might represent an earlier or milder form of rheumatoid disease. In this type of IPA, no underlying disease can be detected.
• Type II IPA: IPA is associated with infectious disease outside the joints (reactive form) and represents about 25 percent of all IPA cases. Infections of the respiratory tract, urogenital tract, teeth, and ears or skin; leishmaniasis; ehrlichiosis; borreliosis; and bacterial endocarditis are associated with immune-mediated arthritis. Borrelia, Ehrlichia and Leishmania species may cause a true infective arthritis and/or immune-mediated arthritis. The infectious process might provide an antigenic source for immune complex formation.
• Type III IPA: IPA associated with gastrointestinal disease (enteropathic form) may show an increased permeability to potential antigens that could stimulate the production of immune complexes. Hepatopathic arthropathies may occur as well.
• Type IV IPA: IPA associated with neoplasia outside the joints (neoplastic form), e.g., squamous cell carcinoma, leiomyoma, mammary carcinoma and lymphoma, can stimulate an immune response by the host and thus the formation of circulating immune complexes.

Vaccination reactions An immune-based polyarthritis can follow vaccinations. It can follow the first injection or booster vaccinations. The arthritis is usually self-limiting and can spontaneously resolve within several days. An accurate vaccination history is therefore important in all dogs presenting with polyarthritis.

Diagnosis CBC, serum chemistry profile, urinalysis and urine culture are helpful in exclusion of other diseases and can point to specific forms of immune-mediated arthritis (e.g., anemia, thrombocytopenia and proteinuria). Due to the same reasons, radiography and ultrasonography of thorax and abdomen are performed.

A radiographic survey of several joints should be carried out in order to differentiate erosive and non-erosive types. In non-erosive forms, joint radiographs either might not show obvious abnormalities or show soft-tissue swelling and synovial effusion. Diagnosis of poly-arthritis is based on arthrocentesis and synovial-fluid analysis of several joints, which is a routine procedure in the investigation of joint disease. Arthrocentesis is performed in anesthetized dogs, and the joint tap site is prepared for surgery. The joint is entered with a 20- or 22-gauge needle attached to a 2-ml syringe, and synovial fluid is aspirated carefully. In normal joints, the yield of synovial fluid is very small. Aspirates might be contaminated with blood because of damage to intra-synovial blood vessels during arthrocentesis. Volume, macroscopic appearance (clarity and color), viscosity, number of nucleated cells with a differential cell count and protein concentration are obtained. In cases of suspected bacterial infective arthritis, synovial fluid should be submitted for aerobic and anaerobic culture. False-negative results can occur because culturing bacteria from synovial fluid is difficult.

Normal synovial fluid is colorless to slightly yellow, transparent, not clotting on exposure to air, and of high viscosity. Viscosity can be subjectively assessed by allowing a drop of synovia to fall from the end of the needle, the length of the string is normally >2.5 cm. The protein concentration is below 2.5 g/dl and the nucleated cell count below about 1,000 cells per microliter.

The predominating cells are large mononuclear cells and lymphocytes, and neutrophils are <5 percent. Based on evaluation of direct synovial fluid smears, the number of nucleated cells can be roughly estimated (2-3 cells/400X magnification are normally found). In immune-mediated arthritides synovial fluid volume often is increased; it is generally turbid, discolored, of decreased viscosity, may clot, and the protein and nucleated cell content are increased (nucleated cell count often >5000 cells per microliter). The neutrophil counts are increased to 10-95 percent.

Rheumatoid factors may be determined; however, the rheumatoid factor test is not specific for rheumatoid arthritis, and the result may depend on the test and the laboratory.

Further diagnostic testing depends on history, clinical signs and suspected underlying diseases — ANA titer, serology for Borrelia, Ehrlichia and Leishmania, cerebrospinal fluid analysis, muscle biopsy, platelet-bound antibodies, direct antiglobulin test, skin biopsy, cytology of lymph nodes, etc. If endocarditis is suspected, then echocardiography and a blood culture are indicated. In some cases, a definitive diagnosis can be established only by synovial membrane biopsy (histopathology and microbiologic culture).

Therapy In IPA type II-IV, treatment is directed primarily against the underlying disease if possible. In some cases, analgesic/anti-inflammatory drugs or corticosteroids are indicated. In rheumatoid arthritis, IPA type I, and vaccination reactions, analgesics (e.g., meloxicam 0.1 mg/kg SID, carprofen 2-4 mg/kg SID, and other analgesics) and eventually doxycycline (5 mg/kg BID) are given until all test results are available. Spontaneous recovery is possible in vaccination reactions and in some dogs with IPA type I. In most cases, immunosuppressive therapy with prednisolone (2 mg/kg BID) is indicated. Glucocorticoids should not be combined with NSAIDs because gastrointestinal ulceration, liver disease or kidney disease might occur. High prednisone doses are given for two weeks, and then the dose is reduced gradually (about one-fourth reduction every two to three weeks) during the following months. There is generally a marked improvement within a few days, but maintenance therapy is important to prevent relapses. Constant low-dose prednisolone is sometimes necessary to keep the animal in clinical remission. Repetition of the arthrocentesis is helpful to assess response to therapy and is indicated if relapses occur.

A combination of prednisone and cytotoxic drugs can be tried if there is insufficient response, relapse or if severe side effects occur. There are no controlled studies to show that one cytotoxic drug is better than another. Some authors recommend cyclophosphamide — 50 mg/m² administered daily for four days every week. Side effects are sterile hemorrhagic cystitis and bone marrow suppression. If cyto-toxic drugs are given, a complete blood count every one to two weeks is indicated. If the WBC count falls below 6,000 per microliter or the platelet count falls below 125,000 per microliter, then the cyclophosphamide dose should be reduced by one-fourth; if the WBC count falls below 5,000 per microliter (neutrophils <2,500 per microliter) the cyclophosphamide is discontinued for one week and then recommenced at one-half the initial dose. Cyclophosphamide should not be used for more than three to four months because of increasing risk of urinary bladder toxicity. Instead of cyclophosphamide, cyclosporine (initially at 3 mg/kg PO BID) or azathioprine (initially at 2 mg/kg PO for two weeks, maintenance dose 0.5-1 mg/kg every other day alternating with prednisone) can be used. In severe cases of immune-mediated arthritis, gold preparations might be used (aurothiomalate 0.5 mg/kg IM once weekly for six weeks or auranofin 0.05-0.2 mg/kg BID with maximal dose of 9 mg daily). Side effects are bone marrow depression, renal insufficiency, dermatosis, diarrhea and corneal ulcers.

Surgical arthrodesis of diseased joints has been attempted with limited success. Synovectomy might improve signs especially if a single joint is affected predominantly. Cytokine studies in synovial fluid revealed that the cytokine patterns in canine polyarthritis and human rheumatoid arthritis or arthritis mouse models were similar. Immunomodulatory therapies already used in human medicine (e.g., TNF-alpha blocking agents) might be treatment options in canine polyarthritis in the future.

Prognosis IPA type I has a favorable prognosis, and cure is possible. The rate of recurrence is high (up to 50 percent). Some IPA cases might progress to the rheumatoid form. Vaccination reactions and IPA type II-IV carry a good prognosis if the underlying disease can be managed. In systemic lupus erythematosus, the prognosis is guarded, and in cases of renal involvement poor. In rheumatoid arthritis, the prognosis is unfavorable if progressive joint destruction occurs. Dogs with systemic lupus erythematosus and rheumatoid arthritis usually need constant medication.

Dr. Hoskins is owner of DocuTech Services. He is a diplomate of the American College of Veterinary Internal Medicine with specialities in small animal pediatrics. He can be reached at (225) 955-3252, fax: (214) 242-2200, or e-mail: jdhoskins@mindspring.com
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