Immune Mediated Polyarthritis

Immune-mediated polyarthritis (IMPA) is a noninfectious form of inflammatory arthropathy in the dog and cat. IMPA is characterized by inflammation of the synovial membranes reflected by inflammatory cell infiltrate in the synovial fluid and accompanied by systemic signs of illness. Classically these include lethargy, arthralgia, and fever. Accompanying signs of systemic illness can be subtle and vague, making the diagnosis elusive. Polyarticular involvement is reportedly more common than monarticular. Distal joints have been suggested to be more frequently affected; however, proximal joint synovitis is more challenging clinically to document, and may be overlooked [1-9].

Categorization of IMPA

IMPA is commonly categorized as nonerosive, which is nondeforming and usually proliferative, and erosive, in which a progressive destructive deformation of joints occurs. Nonerosive IMPA occurs more commonly than erosive disease in both the dog and cat. Nonerosive canine IMPA has been further classified into subtypes based on the identification of associated contributory or causative disorders. These subtypes include type I, or idiopathic (no identifiable associated factors); type II, or reactive (associated with systemic infectious or inflammatory disease, most commonly of the respiratory, urinary, and reproductive systems, as well as of the eye and the skin); type III, or enteropathic (associated with gastrointestinal or hepatic disease); and type IV, or paraneoplastic (associated with neoplasia distant from the joints, or with myeloproliferative disease). Additionally, the nonerosive IMPA category includes arthropathy associated with systemic lupus erythematosis (SLE), the polyarthritis/polymyositis syndrome, the polyarthritis/meningitis syndrome, polyarteritis nodosa, Akita juvenile onset polyarthritis, the Shar-Pei fever syndrome, and that associated temporally with the administration of drugs or vaccination [1-9].

Canine erosive IMPA is characterized by a progressive, refractory, and protracted joint destruction most pronounced in the distal joints. Canine erosive IMPA has been categorized into rheumatoid-like arthritis, idiopathic erosive polyarthritis, and Greyhound polyarthritis [1-9].

Feline IMPA is classified as progressive polyarthritis (PPA) and has a nonerosive proliferative form and an erosive destructive form. Both generally cause serious systemic illness. The disease most commonly affects young (1 to 5 years of age) male cats and can be associated with feline syncytium-forming viral infection and its associated chronic antigenic stimulation [1-9].

Pathogenesis

Primary nonerosive polyarticular arthritis, type I, is the most common form of IMPA reported in the dog. Nonerosive types II, III, and IV IMPA are less common. Identification of concurrent significant medical conditions is important for determining prognosis and in therapeutic decision making. Treatment of type I IMPA is directed at immunosuppression and its associated clinical scenarios (opportunistic infection, myelosuppression, and individual side effects of immunosupressant drugs). Treatment of types II, III, and IV IMPA is specifically directed at the associated systemic disorder in anticipation that joint inflammation will improve once the primary disorder is effectively treated or resolves with time [1-9]. Many type II polyarthridities associated with an infectious disease (i.e., coccidioidomycosis) are actually a granulomatous synovitis ("desert rheumatism") or vasculitis (ehrlichiosis, Rocky Mountain spotted fever (RMSF), Lyme disease) rather than a direct extension of the infectious organism into the synovium [10]. Some forms of nonerosive IMPA have been reported to have an underlying genetic predisposition associated with certain histocompatibilty genotypes [1]. Resolution of synovitis in types II to IV IMPA can be delayed when compared with that in type I and is dependent on the degree to which the contributory disorder is resolved.

The pathogenesis of erosive IMPA is better understood than its etiology. As a consequence of either defective immunoregulation (failure of self tolerance) or production of an immunogenic IgG-antigen molecule, the pathogenic autoantibody rheumatoid factor (RF) is formed. Plasma cells and activated B lymphocytes produce RF which circulates into synovial fluid. The synovium functions as a phagocytic tissue; as a consequence, immune complex ingestion occurs, triggering the activation and proliferation of synoviocytes. Activated synoviocytes release inflammatory mediators and enzymes (interleukin 1, collagenases, peptidases, and prostaglandin E2). Osteoclasts are activated, resorbing subchondral bone. Subchondral bone cysts form as a consequence of this osteolysis. Intraarticular formation of granulation tissue arising from the inflamed synovium forms a pannus. Lymphocytes, plasma cells, neutrophils, and proliferating activated synoviocytes compose the pannus. Fibroblast proliferation promotes fibrosis with scarring and contracture. Joint deformation results [1-4,11].

Clinical Presentation

IMPA should be part of the differential list for any dog or cat with fever of unknown origin or inexplicable lethargy. Arthralgia can be subtle or obvious, ranging from a simple reluctance to move to a peculiar, stilted, and crouching gait indicative of pain in numerous joints. Fever is common, generally in the range of 103.5 to 104.5°F. Palpation of joints can elicit pain, and the joints can feel effusive and warm, especially later in the course of the disease. With chronicity, the joint capsule may become thickened. Arthralgia can be misinterpreted clinically as myalgia, neuralgia, abdominal discomfort, or even neuropathic or myopathic disorders. Anorexia is variably present, and has been reported to be a poor prognostic sign [3]. Atypical house soiling can occur if the animal is reluctant to move outdoors or to a litter box for defecation or urination. Altered disposition, even aggression, can occur as a result of marked pain. The arthropathic signs of types II to IV IMPA can be completely masked by those of the primary, associated disorder. Incomplete response to therapy for the primary disorders associated with types II to IV IMPA should prompt evaluation of the joints for inflammatory changes. Alternatively, a poor response to immunosuppression for suspected type I IMPA should prompt consideration that the condition could be type II to IV, and clinical evaluation for associated disorders should be pursued.

Some generalizations exist. Type I IMPA is most commonly but not exclusively diagnosed in dogs less than 6 years of age, of either gender. A breed predilection may exist in German shepherds, Doberman pinschers, collies, spaniels, retrievers, terriers, and poodles. Polyarthritis associated with SLE is reported more commonly in German shepherds, collies, Shetland sheepdogs, beagles, and poodles, of any age. Females are more commonly affected [12,13]. Atypical cases of cranial cruciate ligament rupture (young, otherwise fit individuals of large breeds) can belong to a subclass of dogs with plasmacytic-lymphocytic synovitis/tendonitis [7]. Young (less than 3 years), large-breed dogs are more commonly affected with plasmacytic-lymphocyticsynovitis/tendonitis, most frequently diagnosed in the stifle and associated with damage (often bilateral) to the cranial cruciate ligament (ACL). Acute lameness associated with rupture of the ACL occurs and presents as a sudden worsening of lameness and reluctance to ambulate in an individual otherwise successfully under therapy for IMPA. Drug-associated polyarthritis, a vasculitide, has been reported to be associated with Doberman pinschers and Labrador retrievers [14,15]. Vaccine-associated IMPA is suspected clinically if the syndrome occurs within 3 to 4 weeks of vaccination [7].

Erosive IMPA in the dog typically affects young to middle-aged members of toy and small breeds. A semierosive polyarthritis of greyhounds has been reported, generally in dogs between 3 and 30 months of age. Feline chronic progressive polyarthritis typically affects male cats from 1 to 5 years of age [1-4].

Diagnostics

Evaluation of veterinary patients with unexplained lethargy, arthralgia, or fever should include arthrocentesis for cytologic evaluation of synovial fluid. Arthrocentesis can be performed in most medium to large dogs with minimal sedation/analgesia. Small dogs and cats usually require sedation or anesthesia to obtain synovial fluid samples without iatrogenic hemorrhage secondary to inadvertent trauma to the synovium during collection. Synovial fluid contaminated with hemorrhage markedly limits conclusive cytology [8].

Arthrocentesis should be performed on a minimum of four joints. Usually the carpi, stifles, tarsi, and elbows are preferred sites for synovial fluid collection. The site of centesis should be clipped and prepared with aseptic technique. Carpal arthrocentesis is generally performed with a 25-gauge needle and 3-ml syringe. Fluid is aspirated from the joint space between the distal medial radius and the radial carpal bone joint, approached medially (Fig. 117-1). Tarsal arthrocentesis is usually performed with a 22-gauge needle and 3-ml syringe, aspirating fluid from the joint space between the fibula and the calcaneus bone of the tarsus, approached laterally (Fig. 117-2). Stifle arthrocentesis usually requires a longer needle to penetrate the patellar fat pad; a 20-gauge needle and a 3-ml syringe are typically used, aspirating the joint space between the lateral femoral epicondyle and the lateral tibial intercondylar area (Fig. 117-3). Elbow arthrocentesis is technically more difficult. A 22-gauge needle and a 3-ml syringe are used to aspirate the joint space between the radial articular fovea and the ulnar lateral coronoid process (Fig. 117-4). Synovial fluid should be immediately evaluated for color and clarity, as well as viscosity. Normal synovial fluid is clear, with viscosity producing a strand when dabbed with a gloved finger or needle. Abnormal synovial fluid is opaque to hemorrhagic with watery consistency [8,11].

Figure 117-1. Arthrocentesis of the medial proximal radiocarpal joint. (Courtesy of Alexander J. Frederick, University of California School of Veterinary Medicine, Class of 2009).

Figure 117-2. Arthrocentesis of the lateral tarsal joint (fibula-calcaneous). (Courtesy of Alexander J. Frederick, University of California School of Veterinary Medicine, Class of 2009).

Figure 117-3. Arthrocentesis of the lateral stifle joint (femoral-tibial). (Courtesy of Alexander J. Frederick, University of California School of Veterinary Medicine, Class of 2009).

Figure 117-4. Arthrocentesis of the lateral elbow joint (radial-ulnar). (Courtesy of Alexander J. Frederick, University of California School of Veterinary Medicine, Class of 2009).

Cytology of synovial fluid can be performed in the clinical setting or submitted to a commercial or academic laboratory for evaluation. Normal synovial fluid is poorly cellular (< 2500 nucleated cells/ml). The majority (> 90%) of cells in normal synovial fluid are large and small mononuclears. Synovitis associated with IMPA is characterized by suppurative cytology, with more than 5000 cells/ml, and with neutrophils accounting for more than 10 to 25% of the total cell count. The white blood cell count of synovial fluid can be estimated by counting the number of cells per high dry field and multiplying by 1000. Synovial fluid contaminated iatrogenically with hemorrhage from a traumatic arthrocentesis will have a white blood cell differential similar to peripheral blood, and synovial neutrophilia cannot be readily determined [8,16].

Careful history-taking and a thorough review of physical examination findings can assist in the characterization of IMPA. Once inflammatory synovitis has been identified, collection of the minimum data base (complete hemogram, serum chemistries, urinalysis with culture) should be accompanied by specific, appropriate diagnostics to identify contributory and concurrent significant disease. Because immunosuppression is the goal of therapy for type I IMPA, prior evaluation for concurrent infectious disorders is important. Hyperglobulinemia and an inflammatory leukogram can be the only clinicopathologic abnormalities with type I nonerosive IMPA, other than suppurative, sterile synovial fluid [9].

Survey thoracic and abdominal radiographs, serum titers for tick-borne diseases (ehrlichia, RMSF, and Lyme), abdominal and cardiac ultrasonography, and radiography of the thorax and affected joints can be performed. Culture of synovial fluid is performed if sepsis is suspected, but blood and urine cultures are usually more rewarding [5,8].

Heartworm infection, pyometra, periodontal disease, chronic bacterial endocarditis, discospondylitis, chronic Actinomyces infections, juvenile cellulitis, chronic salmonellosis, and occult urinary tract infection have all been associated with nonerosive type II arthritis, and should be considered [5,7,8]. Idiopathic arteritis causing meningitis can be accompanied by distal joint inflammation. Enteropathic type III arthritis can be associated with inflammatory bowel disease, and hepatopathic arthropathy can be associated with chronic active hepatitis [5,8].

Differentiation of nonerosive from erosive forms of IMPA can be made with radiography, and should always be pursued if response to therapy for presumed nonerosive IMPA is less than anticipated. Viral serology for feline leukemia can be positive in 66% of cats with progressive polyarthritis associated with feline syncytium-forming virus, and may exacerbate the disease [4,8].

Review of the physical examination findings and clinical pathology results should identify criteria of SLE if it is present: cytopenia (hemolytic anemia and/or thrombocytopenia), dermatologic lesions, protein losing nephropathy (urine protein: creatinine ratio), myositis, myocarditis/pericarditis, pleuritis, or glossitis. The presence of antinuclear antibodies and LE cells can help confirm the diagnosis of SLE, but are not specific for it. Similarly, a positive Coomb’s test can support the diagnosis of SLE [12,13].

Rheumatoid factor testing is neither sensitive nor specific for erosive polyarthritis in the dog. Serologic testing for the presence of rheumatoid factor is reported to be positive in 25% to 75% of dogs with erosive polyarthritis when performed using the Rose-Waaler test. Additionally, the mucin clot test may support the diagnosis of erosive arthritis. Mucin levels in synovial fluid are typically lowered in patients with erosive arthritis owing to the action of inflammatory substances. Synovial biopsy can support the diagnosis if histopathologic changes typical of erosive arthritis are found: periarticular fibrosis, synovial hyperplasia and villous hypertrophy, and the formation of pannus [4,11].

Therapeutics

Type I IMPA and SLE-associated polyarthritis are successfully treated in most cases with immunosuppressive levels of corticosteroids alone. One to 2 weeks after initiation of therapy, repeat arthrocentesis and synovial fluid cytologic evaluation should be performed. Effective control of IMPA is reflected by normalization of gross characteristics of synovial fluid and cell counts with return to a predominance of mononuclear cells, in addition to clinical improvement. Gradual tapering of corticosteroid doses should occur in concert with continued improvement of clinical signs and normalization of synovial fluid. Serial arthrocentesis for cytologic evaluation of synovial fluid is important in assessing response to therapy and maintenance of remission. The typical course of immunosuppression in type I idiopathic IMPA is 6 to 12 weeks. Combination therapy as described for erosive IMPA (see below) can be necessary if the initial response (within 2 weeks) to corticosteroids is incomplete, if tapering results in relapse, or if unacceptable side effects are associated with prednisone administration.

IMPA associated with significant concurrent systemic disease warrants treatment of the primary disorder first and synovitis second. Antimicrobial, antiparasitic, antineoplastic, immunomodulatory, and nutritional therapies should prevail Fig. 117-5. Analgesic and anti-inflammatory therapy can accompany treatment of the primary disorder if dictated by the level of discomfort associated with arthritis. The use of nonsteroidal anti-inflammatory drugs in combination with corticosteroids is not advised owing to the risk of gastric ulceration. Combination antimicrobial and immunosuppressive therapy can be cautiously instituted if clinically indicated, while awaiting serologic and microbiologic results, but this demands close patient monitoring.

Figure 117-5. Flow chart for clinical evaluation of arthralgia and IMPA.

Current recommendations for therapy of erosive IMPA dictate combination corticosteroid and cytotoxic drug administration. Immunosuppressive doses of prednisone (2.2 mg/kg/day) are combined with cyclophosphamide (Cytoxan, 50 mg/M2 PO every 24 hours x 4 days each week, or MWF), azathioprine (Imuran, 50 mg/M2 every 24 hours for 7-14 days, then every 48 hours), or cyclosporine (10 mg/kg). Generally, cyclophosphamide is not used for longer that 4 months in dogs owing to its association with sterile hemorrhagic cystitis. Cats are much more susceptible to azathioprine toxicity, and its use is generally not recommended. Chlorambucil (1-2 mg/cat every 24-72 hours) is used as an alternative. Both cyclophosphamide and azathioprine require close monitoring for myelosuppression. Hepatic enzyme elevation can occur with azathioprine. Chlorambucil (Leukeran, 2-6 mg/M2 every 48 hours canine) can be substituted for cyclophosphamide once remission has been attained, if necessary, in the dog. Side effects of cyclosporine include gastrointestinal upset, anorexia, and gingival hyperplasia. Cyclosporine reversibly inhibits immunocompetent lymphocytes in the G0 - or G1 – phase, affecting T-helper cells, T-suppressor cells, and reducing lymphokine production and release. Cyclosporine has variable bioavailability, and the various formulations do not have equal efficacy or dosing. Microemulsified products have improved oral absorption (Neoral, Novartis, Greensboro NC, 5-10 mg/kg/day divided bid). Ketoconazole (10 mg/kg/day divided tid PO with food) can be used concurrently to decrease cytochrome P-450 clearance of cyclosporine, permitting a lower dosage to be effective and saving client expenses. Serum levels should be monitored starting 2 to 3 days after the initiation of therapy; trough levels of 200 to 500 ng/ml are advised [17]. Leflunomide (4 mg/kg every 24 hours, with dosage adjustment based on trough plasma levels of 20 µg/ml) is a new immunosuppressive agent showing promise in the treatment of refractory immunologic disease in dogs and cats. Leflunomide can be considered for IMPA unresponsive to conventional therapy. Other than repair of ruptured cranial crucial ligaments, surgical intervention (synovectomy, arthrodesis) for IMPA is unrewarding and uncommon. As with type I IMPA, immunosuppressive drug withdrawal should be performed in concert with clinical signs of remission coupled with synovial fluid evaluation, as improvement in gait does not always correlate with normalization of synovial fluid.

Prognosis

The prognosis for dogs and cats with IMPA varies. The prognosis for nonerosive forms of IMPA is better than that for erosive forms. Early appropriate immunosuppressive therapy, tapered carefully based on clinical and clinicopathologic evaluations, can result in resolution and discontinuation of medication in 1.5 to 3 months [5,7,8].

The prognosis for polyarthritis associated with concurrent disease (types II-IV) depends on the potential for resolution of the primary, contributory disorder. IMPA associated with infectious/inflammatory diseases responsive to therapy (rickettsial infections, enteropathies) carries a better prognosis than that associated with more refractory disorders (mycoses, viruses, neoplasia) [7].

Erosive forms rarely resolve, but remission with continued medical therapy is possible. Feline erosive progressive polyarthritis carries a poor prognosis. Canine erosive polyarthritis has a fair prognosis if diagnosed and treated early in its course, but is generally considered to be a more aggressive condition than the similar disease in humans (rheumatoid arthritis). Semierosive polyarthritis of greyhounds is reported to have a poor prognosis. Aggressive combination immunosuppressive therapy is indicated to slow progression of erosive IMPA, and postpone joint subluxation, luxation, ankylosis, and collapse, and to minimize periarticular osteophyte production. These changes are irreversible. Caution must be taken that therapy does not result in serious complications such as refractory sterile hemorrhagic cystitis, viral relapse, myelosuppression, or opportunistic bacterial sepsis. Therapy can be expected to continue at high doses for 3 to 6 months, and at maintenance levels for months to years [4,7].