Barbara Kohn, Prof. Dr. med. vet., DECVIM
Inflammatory joint diseases can be classified as infectious or immune-mediated (table 1, modified according to Bennett, 1997). 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, radiographical (erosive / non-erosive types), pathological and serological parameters. Classification of the arthritides is useful for deciding on treatment and prognosis.
Table 1. Inflammatory joint diseases
Bacterial (discospondylitis, etc.) Borreliosis Mycoplasmal Ehrlichiosis Fungal Protozoal (Leishmaniasis)
Rheumatoid arthritis (RA) Polyarthritis of Greyhounds Felty's syndrome (rheumatoid arthritis, splenomegaly, neutropenia)
"Idiopathic" (IPA) (type I-no associations, II-reactive, III enteropathic, IV-neoplasia related) Systemic lupus erythematosus (SLE) Vaccination-associated Polyarthritis / polymyositis (e.g., spaniel breeds) Polyarthritis / meningitis (e.g., Weimaraner, Boxer, Bernese Mountain Dog) Polyarteritis nodosa Sjogren's syndrome Arthritis of Akita Inus Amyloidosis (Shar Peis) Lymphocytic-plasmacytic gonitis Drug-induced (e.g., trimethoprim-sulfonamide)
Rheumatoid Arthritis (RA)
The diagnostic criteria for RA in the dog are adapted from those defined for humans.
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 or "punched out" erosions), loss of mineralization of the epiphysis, calcification of the soft tissue around the joint, changes in joint space (increase or decrease), extensive bone destruction with gross joint deformity.
6. Inflammatory synovial fluid
7. Characteristic, symmetrical deformations of the distal joints
8. Detection of rheumatoid factors in serum
9. Characteristic histopathological change in synovial membrane
10. Extraarticular symptoms (tendovaginitis, lymphadenopathy)The presence of 5 of these criteria suggests RA with 7 positive criteria the diagnosis is definitive.
"Idiopathic" Polyarthritis (IPA)
Includes all those cases of inflammatory arthropathy which can not be classified into the other groups, e.g., RA or SLE (see table 1). Type I is by far the most common of all the immune-based arthropathies in the dog. The "idiopathic" type can be divided into 4 subcategories:
Type I: - Uncomplicated IPA - This type accounts for approx. 50% of all the "idiopathic" cases. The RA dogs and the IPA dogs have most immunopathological features in common, therefore, some idiopathic cases might represent an earlier or milder form of rheumatoid disease. In this type, no underlying disease can be detected.
Type II: - IPA associated with infectious disease outside the joints (reactive form) (approx. 25% of all IPA cases) Infections of the respiratory tract (incl. tonsillitis), urogenital tract, teeth, ears or skin, leishmaniasis, ehrlichiosis, borreliosis, and bacterial endocarditis have been reported in association with immune-mediated arthritis. (Borrelia, Ehrlichia and Leishmania 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 associated with gastrointestinal disease (enteropathic form). The diseased gut may show an increased permeability to potential antigens which could stimulate the production of immune complexes. Hepatopathic arthropathies have been described as well.
Type IV: - IPA associated with neoplasia outside the joints (neoplastic form): e.g., squamous cell carcinoma, leiomyoma, mammary carcinoma, lymphoma. Neoplasia can stimulate an immune response by the host and thus the formation of circulating immune complexes.
An immune-based polyarthritis can follow vaccinations. It can follow after the first injection or after booster vaccinations. The arthritis is usually self-limiting and can spontaneously resolve within several days. More severe forms have been described in Weimaraner and Akita Inu puppies. An accurate vaccination history is therefore important on all dogs presenting with PA.
Incidence of the different immune-mediated arthritides - During a 4-year period, 35 cases of immune-mediated polyarthritis were diagnosed at the Small Animal Clinic: 3 dogs with RA, 16 IPA type I, 4 IPA type II, 2 IPA type III, one dog with IPA type IV, 3 SLE, 5 vaccination-associated and one dog with polyarthritis/meningitis.
Etiology and pathophysiology
The basic underlying immunopathological mechanisms seem to involve the creation of immune complexes. These immune complexes may 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 which cause further tissue damage. These events are a normal immunological 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 autoantibodies against immunoglobulins G), antinuclear antibodies, and anti-heat shock proteins). Studies from human medicine have implicated the major importance of cell mediated immune responses; cell responses in chronic inflammatory synovitis of dogs are similar to those in man. A type IV hypersensitivity component of RA is suggested by the perivascular infiltration of mononuclear cells into affected synovium. Release of cytokines or matrix metalloproteinases by such cells enhances inflammation and cartilage degeneration. The underlying etiological 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.
Typical findings are a synovitis, generally affecting several joints simultaneously, with a thickened and discoloured synovial membrane. The chief inflammatory cells in the synovial membrane are lymphocytes and plasma cells, in the synovial fluid polymorphonuclear leukocytes predominate. Inflammatory fibrovascular proliferations of the synovial membrane develop when this granulation tissue covers and adheres to the articular surface, a condition referred to as pannus. Depending on the stage of the disease irreversible cartilage and subchondral bone destruction with deformity and irregularity of the joint surfaces may develop.
Typical findings are a stiff gait ("walking on eggs"), reluctance to move, lethargy, and fever (polyarthritis is an important differential diagnosis for "fever of unknown origin"), and often inappetence. However, some cases may present as chronic lameness without signs of systemic disease. The severity of lameness can vary markedly, and a shifting leg lameness often occurs. In the least severe cases, no more than a vague stiffness may be noted, whereas severely affected animals may 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, 2-5 joints) and, occasionally, only a single joint is diseased (monoarthritis). Depending on the form of immune-mediated arthritis other symptoms such as dermatitis, glomerulonephritis, meningitis, myositis, uveitis, lymphadenopathy, cardiac murmur, thrombocytopenia and anemia will be apparent.
Hematology, clinical chemistry, urinalysis and urine culture are helpful in exclusion of other diseases and may point to specific forms of immune-mediated arthritis (e.g., anemia, thrombocytopenia and proteinuria in SLE). 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 may either not show obvious abnormalities or show soft tissue swelling and synovial effusion. Diagnosis of polyarthritis 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 anaesthetised animals, the joint tap site is prepared as for surgery. The joint is entered with a 20 or 22-gauge needle attached to a 2 ml syringe and synovial fluid is carefully aspirated. In normal joints the yield of synovial fluid is very small. Aspirates may be contaminated with blood because of damage to intra-synovial blood vessels during arthrocentesis. The following synovial fluid parameters are routinely examined: Volume, macroscopic appearance (clarity and colour), viscosity, number of nucleated cells with a differential cell count, and protein concentration. In cases of suspected bacterial infective arthritis, synovial fluid should be submitted for aerobic and anaerobic culture. False negative results can occur, however, since 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 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 normally found). In immune-mediated arthritides 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%.
Rheumatoid factors may be determined, however, the 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 echocardiography and a blood culture are indicated. In some cases a definitive diagnosis can only be established by synovial membrane biopsy (histopathology, microbiologic culture).
Infectious (e.g., due to borrelia, ehrlichia or mycoplasmal infection) and immune-mediated arthritides may be difficult to differentiate by clinical examination, radiology or synovial fluid analysis. Moreover, infectious diseases may give rise to immune-mediated disease. Septic arthritis manifests usually in only one joint. Other differentials include degenerative, traumatic, hemophilic and neoplastic arthropathies, which are usually monoarticular. Together with primary bone marrow disease (e.g., leukemia, multiple myeloma) immune-based arthritides are a major cause of "fever of unknown origin". Other causes are infectious diseases (e.g., discospondylitis, bacterial endocarditis, urinary tract infection, pyothorax, leishmaniasis, toxoplasmosis, viral disease), neoplasia (e.g., lymphoma), splenic torsion, and others.
In IPA type II-IV treatment is primarily directed against the underlying disease if possible. In some cases analgesic/anti-inflammatory drugs or corticosteroids are indicated. In RA, IPA type I and vaccination reactions analgesics (e.g., meloxicam 0.1 mg/kg SID, carprofen 2-4 mg/kg SID, metamizole 20 mg/kg BID-TID) and eventually doxycyclin (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 immunosuppressive therapy with prednisolone (1 mg/kg BID) is indicated. Glucocorticoids should not be combined with NSAIDs because gastrointestinal ulceration might occur. High prednisolone doses are given for 2 weeks and then the dose is gradually reduced (approx. ¼ every 2-3 weeks) over the next 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 prednisolone 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 4 days/week). Side effects are sterile hemorrhagic cystitis and bone marrow suppression. If cytotoxic drugs are given a complete blood count every 1-2 weeks is indicated. If the WBC count falls below 6000/µl or the platelet count below 125,000/µl the dose should be reduced by ¼; if the WBC count falls below 5000/µl (neutrophils < 2500/µl) the drug is discontinued for 1 week and then recommenced at ½ the initial dose. Cyclophosphamide should not be used for more than 3-4 months because of increasing risk of bladder toxicity. Instead of cyclophosphamide cyclosporine (initially approx. 3 mg/kg PO BID) or azathioprine (initially approx. 2 mg/kg PO for 2 weeks, maintenance dose 0.5-1 mg/kg every other day alternating with prednisolone) can be used. Levamisole as an immunomodulatory drug has been described for canine polyarthritis (2-5 mg/kg every third day). In severe cases of RA gold preparations might be used (aurothiomalate 0.5 mg/kg IM once weekly for 6 weeks; auranofin 0.05-0.2 mg/kg BID, maximal dose 9 mg/day). Side effects are bone marrow depression, renal insufficiency, dermatosis, diarrhea and corneal ulcers.
Surgical arthrodesis of diseases joints has been attempted with limited success. Synovectomy might improve symptoms especially if a single joint is predominantly affected. Cytokine studies in synovial fluid revealed that the cytokine patterns in canine PA 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.
IPA type I has a favourable prognosis and cure is possible. The rate of recurrence is high, however (up to 50%). Some IPA cases may progress to the rheumatoid form. Vaccination reactions and IPA type II-IV carry a good prognosis if the underlying disease can be treated. In SLE the prognosis is guarded, and in cases of renal involvement poor. In RA the prognosis is unfavorable if progressive joint destruction occurs. Dogs with SLE and RA usually need constant medication.