Immune-mediated polyarthritis (Proceedings)

The diagnosis of immune-mediated polyarthritis can be challenging.  The difficulties of establishing a definitive diagnosis of immune-mediated polyarthritis lie in generating a clinical suspicion of the diagnosis, and the absence, with few exceptions, of definitive diagnostic tests for the majority of cases that have the disease.  The diagnosis of immune-mediated polyarthritis is often a diagnosis of exclusion and response to immunosuppressive therapy.

Inflammatory arthropathies

Causes of polyarthritis are usually either infectious or immune-mediated.  Clinical signs, radiographic and laboratory abnormalities may overlap among the diseases that exist in each group.  The identification of infectious agents causing arthritis is not always easy or straightforward and is beyond the scope of this presentation.  However, it is imperative to exclude, to the degree possible given a client's resources, infectious causes of polyarthritis before treating a patient for immune-mediated polyarthritis. 

History and Clinical signs

The history and pattern of clinical signs in patients with polyarthritis of all causes may be surprisingly variable, though some degree of lameness is most common. Other common historical complaints, especially in dogs, include a reluctance to move or get up, lethargy, and loss of appetite.  The classical gait that describes an animal with polyarthritis is that of “walking on eggshells,” but this gait is not pathognomonic for immune-mediated polyarthritis. Some patients exhibit a reluctance to move their head and neck, or refuse to move in a way that demands flexion/extension of the spinal column.  Some patients stand with an arched posture with their nose pointed to the ground.  Again, these features are not pathognomonic for immune-mediated polyarthritis.

Physical examination abnormalities that can be seen include swelling and pain of involved joints, pain on palpation or manipulation of the spinal column, and fever; immune-mediated polyarthritis is a common cause of fever of unknown origin or antibiotic-unresponsive fever. Some patients have no detectable joint pain or effusion, so the absence of these features does not less the suspicion nor exclude the diagnosis of immune-mediated polyarthritis. Animals that are painful in the thoracolumbar spine may appear painful in the abdomen during abdominal palpation, potentially misleading the clinician away from the true source of pain. 

Patients suspicious for polyarthritis should have particular attention paid to the mucous membranes, retinas, and skin for petechial hemorrhages which should alert the clinician to the possibility of an underlying multisystemic disease.  Auscultation of a new heart murmur could suggest the possibility of polyarthritis from bacteremia.  Deep palpation of the large muscle groups should also be performed as some patients with inflammatory myopathies may present with historical and physical examination abnormalities that overlap with polyarthritis.  In juvenile dogs, it is important to palpate the diaphysis and metaphysis of the long bones because panosteitis and hypertrophic osteodystrophy may also mimic the signs of polyarthritis.  A neurological examination is appropriate for patients with clinical signs of spinal column pain and fever as meningeal disease may have a clinical presentation that may be hard to distinguish from that of polyarthritis.

Differential diagnoses

Infectious polyarthritis represents the biggest group of differentials for immune-mediated polyarthritis (Table 1).  Many immune-mediated diseases can have joint involvement (Table 2).

Table 1. Infectious causes of polyarthritis Bacterial Mycoplasma   Rickettsial (Rickettsia rickettsii, Ehrlichia sp.)   E. coli   Streptococcus   Pasteurella   Borrelia burgdorferi   L-form   Bartonella? Protozoal Leishmania Viral Calcivirus (cats)

Table 2. Causes of immune-mediated polyarthritis

Non-erosive Idiopathic Type I: uncomplicated     Type II: reactive associated with infection remote from joints     Type III: enteropathic, associated with GI disease     Type IV: malignant, associated with tumors remote from joints   Systemic lupus erythematosus     Polyarthritis-meningitis syndrome     Polyarthritis-myositis syndrome     Polyarthritis of Akitas     Shar-pei fever   Erosive Rheumatoid arthritis     Polyarthritis of greyhounds     Periosteal proliferative polyarthritis   Miscellaneous Drug-associated (e.g. sulfas)     Post-vaccinal     Lymphocytic plasmacytic synovitis  

Diagnostic approach

The diagnosis of immune-mediated polyarthritis for the majority of patients requires exclusion of infectious disease as the cause of polyarthritis.  It is appropriate in most cases to perform a complete blood count, biochemical profile, and urinalysis to assess the presence of systemic disease. If the physical examination suggests the possibility of muscle disease, evaluation of serum creatine kinase (CK) activity can be useful.  Radiographs of affected joints may detect changes suggesting alternative causes (neoplasia, hypertrophic osteopathy) of lameness or joint pain.  Radiographs are important in the differentiation of non-erosive from erosive arthropathies.  The key diagnostic test in the evaluation of the animal with inflammatory arthritis is arthrocentesis and joint fluid analysis/examination.

Arthrocentesis is easily accomplished but requires adequate restraint of the patient, syringes and needles (22 gauge needles are the author's preference for most dogs and cats), glass microscope slides and stain, and tubes for submission of samples to specialized laboratories.  Small clot tubes are suitable for submission of samples for culture and general analysis if performed quickly.  EDTA tubes preserve cell morphology and may inhibit bacterial growth, but may be necessary if the aspirate is hemorrhagic.  While some patients tolerate joint aspirates without pharmacologic restraint, the author prefers some sedation (e.g. 4-5 ug/kg dexmedetomidine plus 0.1 mg/kg butorphanol) or brief anesthesia. 

Multiple joints are aspirated even if there is no obvious evidence of joint pain or effusion; aspiration of at least 3 different joints representing at least 2 different joint types (e.g. metacarpal and tibiotarsal) is suggested.  Avoid strong negative pressure on the syringe to reduce iatrogenic hemorrhage.  Normal joint fluid is colorless or occasionally pale yellow, viscous, and should form a string if a drop is touched by a fingertip; poor joint fluid viscosity is consistent with inflammation, joint effusion, or dilution if the sample was submitted in an EDTA tube.  An orange tint to the fluid (xanthochromia) suggests old hemorrhage.

The yield of fluid from some joints can be very small, and the author considers the most important and informative aspect of joint fluid analysis to be the cytological examination. Thus, a drop of joint fluid for smear on a glass slide is the first allocation of joint fluid.  Normal joint fluid contains predominantly lymphocytes and macrophages; neutrophils constitute fewer than 10% of cells.  Joint fluid from patients with polyarthritis has an increase in neutrophils which are often the predominant cell type.  Regardless of the etiology, inflamed joints commonly have a “non-degenerate” appearance to neutrophils, which thus cannot be relied upon to distinguish infectious from non-infectious etiologies.  The predominance of neutrophils also tends to distinguish inflammatory arthropathies from degenerative arthropathies, which tend to preserve the normal proportion of cell types (lymphocytes, macrophages).  Other abnormalities that may be seen on the slide include erythrophagocytosis, which suggests true intra-articular hemorrhage, or rarely, the formation of LE cells, which if observed, are nearly pathognomonic for systemic lupus erythematosus.  It is imperative that joint fluid should be examined microscopically as even grossly normal appearing joint fluid may be cytologically abnormal.

If a sufficient volume of joint fluid is obtained, other tests that can be done include a mucin clot test, nucleated cell counts, total protein and glucose concentrations, and microbial culture and sensitivity testing.  Normal joint fluid should have a good mucin clot (results are commonly reported as good, fair, poor and very poor), and a small total cell count.  Total protein concentrations should be less than 2.5 g/dl.  Glucose concentrations can be variable and interpretation is aided by analysis shortly after collection.  Glucose concentrations may be reduced in infected joints, or in fluid with hemorrhage, because of consumption by erythrocytes.

Microbial culture and sensitivity testing is often considered in the diagnostic approach to patients with inflammatory joint disease.  Negative results, however, do not exclude an infectious arthritis.  Some have suggested that the best material for culture is a synovial biopsy, which adds expense and morbidity to the diagnostic process.  Questionable reliability of joint fluid cultures in the diagnosis of bacterial arthritis makes empiric treatment with antibiotics appropriate for some patients.  Selection of appropriate antibiotics can be guided by history, physical examination and laboratory data as these may point the clinician toward bacterial or rickettsial causes of arthritis.  Tetracycline or its relatives makes an excellent empirical choice of antibiotic due to its broad bacterial spectrum of activity, including activity against L-form bacteria and Mycoplasma.  Response to antibiotic therapy should be prompt, with some clinical improvement expected within 48-72 hours.  An absence of clinical response in this time period suggests either an inappropriate antibiotic, or an incorrect diagnosis.

Immune-mediated arthritis

Given the types of predisposing causes, simply making a diagnosis of idiopathic polyarthritis is not doing justice to patients, and more diagnostic testing should be recommended for any patient with an apparent idiopathic polyarthropathy.  In the author's practice, it is routine to advise abdominal ultrasound or abdominal radiographs, and thoracic radiographs when evaluating a patient with a diagnosis of idiopathic polyarthritis.  The author also considers it important if performing thoracic radiographs that three views be obtained (right and left lateral, and either a ventrodorsal or dorsoventral projection).  Cases of neoplasia and localized infection have been discovered because the third view (typically the opposite lateral) was obtained.  Abdominal imaging may reveal organomegaly or lymphadenomegaly that escaped abdominal palpation and may suggest an occult site of neoplasia or inflammation.  Should masses or enlarged organs be discovered, aspiration cytology or needle biopsy, with ultrasound guidance as needed, can be safely accomplished in the majority of patients.

Treatment

Treatment of many syndromes of immune-mediated polyarthritis requires immunosuppressive therapy (Table 3); administration of analgesics may benefit some patients.  Cases of idiopathic polyarthritis (types II-IV) that develop secondary to a precipitating cause should have treatment directed whenever possible at the underlying disease.  Should the underlying disease not be amenable to therapy, immunosuppressive therapy may be needed to provide relief from the discomfort of the joint inflammation.  For such patients, the goal of treatment is control of clinical signs with the least amount of drugs necessary. The author often begins treatment with prednisone and azathioprine. Leflunomide has been described as an alternative to prednisone as successful primary therapy in dogs with immune-mediated polyarthritis.

Table 3. Immune suppressive therapy used in treatment of immune-mediated polyarthritis

• Prednisone:  1-2 mg/kg PO q12h

• Azathioprine1: 1-2 mg/kg PO q24h for 10-14 days, then q48h

• Cyclosporine: 3-5 mg/kg PO q12h

• Leflunomide 3-4 mg/kg PO q24h

• Cyclophosphamide 50 mg/m2 PO q24h for 4 days weekly; monitor neutrophil count

• Gold salts

1 Monitor for cytopenias, increases in liver enzymes (ALT>AP), hyperbilirubinemia; not recommended in cats

Important principles in the treatment of immune-mediated joint disease (or many other immune-mediated diseases) are 1) use proper dosages, and 2) do not taper too quickly.  Clinical relapses are more likely to occur if prednisone is tapered too quickly. 

Cases refractory to treatment with prednisone and azathioprine are candidates for other therapy with cyclosporine or another immunosuppressive drug.  If one drug has not worked in combination with prednisone, it is considered worthwhile to try one of the others before conceding to treatment failure. Using more than one drug, each representing a different mechanism of immunosuppressive activity (e.g. prednisone, azathioprine, cyclosporine), can be considered for some refractory patients.

In addition to resolution of clinical signs, efficacy of treatment may be monitored if needed by periodic evaluation of joint fluid cytology.  Effective treatment will be reflected in decreased numbers of neutrophils in the joint fluid.

Summary

Immune-mediated polyarthritis should be considered in patients with unexplained fever.  It can look like many other inflammatory diseases, and physical examinations may be misleading.  Arthrocentesis and joint fluid analysis easily excludes or supports polyarthritis as the cause of the clinical signs.

Selected references (additional references available on request)

Battersby IA, et al.  Retrospective study of fever in dogs: laboratory testing, diagnoses and influence of prior treatment. J Small Anim Pract 2006;47:370-376.

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

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

Dunn KJ, Dunn JK. Diagnostic investigations in 101 dogs with pyrexia of unknown origin. J Small Anim Pract 1998;39:574-580.