Inflammatory joint diseases can be classified as infectious or immune-mediated. The immune-mediated polyarthritides are defined by (chronic) synovial inflammation, failure to identify a microbial etiology 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 / non-erosive types), pathological and serological parameters. Classification of the arthritides is useful for deciding on treatment and prognosis.

Table 1. Immune-mediated joint diseases.^1,11

 Erosive

 Rheumatoid arthritis

 Periosteal proliferative arthritis

 Polyarthritis of Greyhounds

 Felty's syndrome

 Non-erosive

 "Idiopathic" (type I - "uncomplicated", type II - reactive, type III - entero /hepatopathic, type IV - paraneoplastic)

 Systemic lupus erythematosus

 Vaccination-associated

 Polyarthritis / polymyositis

 Polyarthritis / meningitis

 Polyarteritis nodosa

 Sjögren's syndrome

 Arthritis of Akita Inus

 Shar Pei fever syndrome

 Lymphocytic-plasmacytic gonitis

 Drug-induced

 Juvenile cellulitis and arthritis

Rheumatoid arthritis (RA) is the most common type of erosive polyarthritides. The diagnostic criteria for RA in the dog are adapted from those defined for humans: 1) stiffness, 2) pain on manipulation of at least one joint, 3) signs of arthritis since at least 3 months, 4) periarticular soft tissue swelling, 5) typical radiographic changes: subchondral bone destruction, irregularity of the articular surface/ "punched out" erosions, demineralisation of the epiphysis, calcification of soft tissue around the joint, changes in joint space, finally extensive bone destruction, 6) inflammatory synovial fluid, 7) symmetrical deformations of the distal joints, 8) detection of rheumatoid factors in serum, 9) characteristic histopathological changes of the synovial membrane, 10) extraarticular symptoms (tendovaginitis, lymphadenopathy). The presence of 5 of these criteria suggests RA, with 7 positive criteria the diagnosis is definitive.

The term "idiopathic" polyarthritis (IPA) includes all those cases of inflammatory arthropathies which can not be classified into the other groups. The "idiopathic" type can be divided into 4 subcategories¹:

 Type I ("uncomplicated" IPA) accounts for approx. 50% of all the "idiopathic" cases. No underlying disease or trigger can be identified (diagnosis of exclusion).

 Type II is associated with infectious disease outside the joints (reactive form): Infections of the respiratory tract, urogenital tract, teeth, ears or skin, leishmaniosis, ehrlichiosis, anaplasmosis, borreliosis, bartonellosis, diskospondylitis, bacterial endocarditis.^1,6,8,13

 Type III is associated with gastrointestinal disease (entero-/ hepatopathic form).

 Type IV - paraneoplastic form (e.g., squamous cell carcinoma, leiomyoma, mammary carcinoma, lymphoma).

Etiology and Pathophysiology

The underlying etiological stimuli are unknown; although there is evidence to support the role of microbial infection (e.g., canine distemper virus in RA, extraarticular infections stimulating immune complex formation). Potential antigens may also originate from nonmicrobial sources, such as tumor antigens, drug antigens/haptens, and dietary antigens. Genetic factors might predispose to immune-mediated disease.⁴

The basic underlying immunopathological mechanisms are similar in all types of immune-mediated PA. Immune complexes are deposited into the joints (hypersensitivity reaction type III). This results in local tissue damage and release of products chemotactic for polymorphonuclear leukocytes. A type IV hypersensitivity component is suggested by the perivascular infiltration of T- and B-lymphocytes, plasma cells, and macrophages into the synovial membrane. Alteration of self antigens may lead to loss of immune tolerance of the individual and to formation of autoantibodies (e.g., rheumatoid factors [circulating autoantibodies against IgG/IgM immunoglobulins], antinuclear antibodies). Release of matrix degrading enzymes enhances inflammation and cartilage and bone degeneration and destruction which may result in erosive arthritis.⁴

Clinical Findings

Dogs of all ages and breeds may develop immune-mediated polyarthritis, certain types are described only in certain breeds (Table 1). Typical signs are a stiff gait ("walking on eggs"), shifting leg lameness, reluctance to move, lethargy, fever (major cause of "fever of unknown origin"), and inappetence. Some dogs may present as chronic lameness without signs of systemic disease. In the least severe cases, only vague stiffness may be noted, whereas severely affected dogs may be unable to stand or walk. Typical, but not always present, are bilaterally symmetrical swollen joints with pain on motion. Occasionally, only a single joint is affected (monoarthritis). Opening of the mouth or neck movement can be painful if mandibular articulation or vertebral articular facets are involved.^2,8,12

Depending on the form of the PA other findings such as dermatitis, glomerulonephritis, meningitis, myositis, uveitis, lymphadenopathy, cardiac murmur, thrombocytopenia and anemia will be apparent.

Differential Diagnoses

Infectious arthritides (e.g., due to Borrelia, rickettsia, Anaplasma, Mycoplasma, Leishmania, fungal infection). Septic arthritis, degenerative, traumatic, hemophilic and neoplastic arthropathies (manifest usually in only one joint).

Diagnosis

Hematology, clinical chemistry, urinalysis and urine culture, radiography and ultrasonography of thorax and abdomen are helpful in exclusion of other diseases and may point to specific forms of immune-mediated PA (e.g., thrombocytopenia and proteinuria in SLE). Radiographs of several joints should be performed in order to differentiate erosive and non-erosive types.

Diagnosis of inflammatory PA is based on arthrocentesis and synovial fluid analysis of several joints. Contraindications for arthrocentesis such as periarticular infections or hemostatic disorders are rare. The following synovial fluid parameters are routinely examined: volume, macroscopic appearance (clarity and color), viscosity, number of nucleated cells, differential cell count, protein concentration. In cases of suspected septic arthritis, synovial fluid should be submitted for aerobic and anaerobic culture. Normal synovial fluid is colorless to slightly yellow, transparent, and of high viscosity. The protein concentration is below 2.5 g/dl and the nucleated cell count below approx. 1000/µl. The predominating cells are large mononuclear cells and lymphocytes, the percentage of neutrophils is < 5%. Based on evaluation of direct synovial fluid smears the number of nucleated cells can be roughly estimated (2–3 cells/400X magnification are considered normal). In immune-mediated PA synovial fluid volume is often 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/µl). The neutrophil counts are increased to 10–95%.^7,8,10

Rheumatoid factors may be determined, however, the test is not specific for RA. Positive results may occur in different chronic inflammatory diseases, e.g., leishmaniasis, pyometra.² Further diagnostic testing depends on the history, clinical signs and suspected underlying diseases: antinuclear antibody titer, serology/ PCR testing for infectious diseases, cerebrospinal fluid analysis, muscle biopsy, platelet bound antibodies, Coombs test, skin biopsy, cytology of lymph nodes, synovial membrane biopsy (histopathology, microbial culture), etc. If endocarditis is suspected echocardiography and a blood culture are indicated.^1,11

Therapy

In IPA type II–IV treatment is primarily directed against the underlying disease. If possible drugs as potential triggers should be withdrawn or replaced. Analgesic/anti-inflammatory drugs or in some cases corticosteroids are indicated.

If RA, IPA type I or a vaccination reaction is suspected analgesics (e.g., metamizole 20 mg/kg BID–TID, meloxicam 0.1 mg/kg SID, carprofen 3–4 mg/kg SID,) and often doxycycline (5 mg/kg BID) are given till all test results are available. Spontaneous recovery is possible in vaccination reactions and in some dogs with IPA type I. In most cases of IPA type I immunosuppressive therapy with prednisolone (initial dose 1–1.5 mg/kg BID) is necessary. Glucocorticoids should not be combined with NSAIDs because of the risk of life-threatening gastrointestinal ulcer formation. After 2 weeks the prednisolone dose is gradually reduced (approx. 1/4–1/5 every 2–3 weeks) and changed to an alternate-day-therapy over the next months. Because of the potential of gastrointestinal ulceration with high-dose glucocorticoid therapy, gastrointestinal protectants (sucralfate, proton pump inhibitors) are administered. There is generally a marked improvement within a few days, but maintenance therapy is important to prevent relapses. Serum C-reactive protein might represent a useful parameter for monitoring response to therapy.⁹ Repetition of the arthrocentesis is helpful to assess response to therapy and is indicated if relapses occur. Patients receiving immunosuppressive therapy should be checked regularly for secondary infections (e.g., of the urinary tract). The owner has to be informed of the potential side effects of high glucocorticoid doses.

Other immunosuppressive therapy (often in addition to glucocorticoids) is warranted when prednisolone fails, only controls the disease at persistently high doses, causes unacceptable side effects or if a relapse occurs. There are no controlled studies to show that one cytotoxic drug is better than another. The following drugs have been used: leflunomide (3–4 mg/kg SID for 6 weeks, then dose reduction), cyclosporine (initially 5 mg/kg BID), cyclophosphamide (50 mg/m² SID 4 days/week), azathioprine (2 mg/kg SID for 2 weeks, maintenance dose 0.5 mg/kg every other day). Side effects are bone marrow suppression, gastrointestinal signs, hepatopathy/pancreatitis (azathioprine), sterile hemorrhagic cystitis (cyclophosphamide). If cytotoxic drugs are given a complete blood count every 1–2 weeks is indicated. Levamisole as an immunomodulatory drug has also been described (5–7 mg/kg every other day, maximum 150 mg daily).^1,3,6 Further drugs which are used in human medicine are mycophenolate mofetil (20–40 mg/kg SID) and methotrexate. Dietary supplements such as omega-3-fatty acids, green-lipped mussels, glycosaminoglycans and physiotherapy can be useful supportive therapies. In severe cases of RA gold preparations might be used (aurothiomalate 0.5 mg/kg IM once weekly for 6 weeks, auranofin 0.05–2 mg/kg BID). Synovectomy or arthrodesis might be attempted especially if a single joint is predominantly affected.

Prognosis

IPA type I has a favourable prognosis and cure is possible. However, the rate of recurrence is high (up to 44%).^2,8 Some IPA cases may progress to the rheumatoid form. Vaccination reactions and IPA type II–IV with treatable underlying disease have a good prognosis. Dogs with SLE and RA have a guarded to poor prognosis.

References

1.  Bennett D. Immune-mediated and infective arthritis. In: Ettinger SJ, Feldman EC, eds. Textbook of Veterinary Internal Medicine. St Louis: Saunders Elsevier, 2010:743–749.

2.  Clements DN, Gear RNA, Tattersall J, et al. Type I immune-mediated polyarthritis in dogs: 39 cases (1997–2002). J Am Vet Med Assoc 2004;224:1323–1327.

3.  Colopy SA, Baker TA, Muir P. Efficacy of leflunomide for treatment of immune-mediated polyarthritis in dogs: 14 cases (2006–2008). J Am Vet Med Assoc 2010;236:312–318.

4.  Day MJ, Bennett D. Immune-mediated musculoskeletal and neurological disease. In: Day MJ, ed. Clinical Immunology of the Dog and Cat. London: Manson Publishing/The Veterinary Press; 2008:172–200.

5.  Kohn B, Garner M, Lübke S, et al. Polyarthritis following vaccination in four dogs. Vet Comp Orthop Traumatol 2003;16:6–10.

6.  Kohn B. Immunbedingte (Poly-)arthritiden, immuninduzierte Arthritiden, immunreaktive Arthropathien. In: Suter P, Kohn B, Schwarz G, eds. Praktikum der Hundeklinik. Stuttgart: MSV Medizinverlage, in press. 2011.

7.  Kohn B. Canine immune-mediated polyarthritis. Eur J Comp Anim Pract 2007;17:119–124.

8.  Kohn B, Lübke S, Schmidt MFG, et al. Idiopathische immunbedingte Polyarthritis Typ I beim Hund: Inzidenz, Klinik, Laborbefunde, Therapie und Verlauf von 16 Fällen (1996–2000). Kleintierprax 2008;50:415–426.

9.  Ohno K, Yokojama Y, Nakashima K, et al. C-reactive protein concentration in canine idiopathic polyarthritis. J Vet Med Sci 2006;68:1275–1279.

10. Parry BW. 1999. Synovial fluid. In: Cowell RL, Tyler RD, Meinkoth JH, eds. Diagnostic Cytology of the Dog and Cat. St Louis: Mosby Inc; 104–115.

11. Pedersen NC, Morgan JP, Vasseur PB. Joint diseases of dogs and cats. In: Ettinger SJ, Feldman EC, eds. Textbook of Veterinary Internal Medicine. Philadelphia: WB Saunders; 2000:1875–1886.

12. Webb AA, Taylor SM, Muir GD. Steroid-responsive meningitis-arteritis in dogs with noninfectious, nonerosive, idiopathic, immune-mediated polyarthritis. J Vet Intern Med 2002;16:269–273.

13. Stull JW, Evason M, Carr AP, et al. Canine immune-mediated polyarthritis: clinical and laboratory findings in 83 cases in western Canada (1991–2001). Can Vet J 2008;49:1195–203.