Many diseases can cause arthritis. Obtaining a history and performing a physical examination are the first steps in allowing the clinician to accurately characterize the arthritis and approach the differential diagnosis in a focused, logical fashion based on the duration of symptoms, the presence or absence of joint inflammation, the number of joints affected, and the pattern of joint involvement (Table 4–1).

When evaluating a patient with joint symptoms, it is important to determine whether the symptoms are due to an articular process and not to bursitis, tendinitis, or other soft tissue conditions. The physical examination should also establish whether there are objective findings of arthritis, such as swelling, in the symptomatic joints. Arthralgias in the absence of objective arthritis commonly occur in systemic lupus erythematosus (SLE) and acute viral illnesses but have less diagnostic significance than true arthritis.

Laboratory tests cannot substitute for clinical evaluation and should never be used as a “screen” for disease. Musculoskeletal complaints are common in the general population, but the prevalence of inflammatory rheumatic diseases is relatively low. Hence, the positive predictive value of many rheumatologic tests is low when tests these are ordered indiscriminately. In general, radiographs add little to the evaluation of acute presentations of arthritis (except in cases of suspected trauma) but often are critical for the assessment of chronic arthritis.

Inflammatory versus Noninflammatory Arthritis

The distinction between inflammatory arthritis and noninflammatory arthritis is a critical bifurcation point in the differential diagnosis of arthritis. The most reliable means for making this distinction is analysis of the white blood cell (WBC) count in the synovial fluid. The synovial fluid WBC count is >2000/mcL in inflammatory arthritis and is <2000/mcL in noninflammatory arthritis (see Chapter 2). Arthrocentesis should be performed whenever feasible because although clinical features and other laboratory investigations also help distinguish inflammatory and noninflammatory arthritis, no single finding is definitive.

Patients with an inflammatory arthritis usually complain of pain and stiffness in involved joints; typically these symptoms are worse in the morning or after periods of inactivity (the so-called “gel phenomenon”) and improve with mild to moderate activity. On examination, the larger joints can be warm and, when severely inflamed as in acute gout or septic arthritis, can have erythema of the overlying skin. Laboratory investigations often reveal an elevated erythrocyte sedimentation rate (ESR) and a high C-reactive protein (CRP) level. In contrast, patients with noninflammatory arthritis have pain that worsens with activity and improves with rest. Stiffness is generally mild, lasts <30 minutes in the morning, and is not a prominent symptom. The ESR and CRP are usually normal.

Constitutional Symptoms

The presence of fever raises the possibility of infection. Most patients with septic arthritis or disseminated gonococcal infection are febrile. Fever can also accompany arthritis that is not due to active infection (Table 4–2). Indeed, intermittent high-grade fever ≥39°C is characteristic of Still disease. SLE can also cause fever ≥39°C. However, fever more often occurs when serositis, rather than polyarthritis, is the major manifestation of SLE. On the other hand, fever ≥38.3°C is unusual in rheumatoid arthritis, occurring in <1% of patients.

Significant weight loss is common at the initial presentation of reactive arthritis, systemic vasculitis, enteropathic arthritis, and paraneoplastic arthritis but is unusual in rheumatoid arthritis of recent onset. Constitutional symptoms rarely accompany noninflammatory forms of arthritis.

Extra-Articular Manifestations

Extra-articular manifestations, such as glomerulonephritis, pulmonary abnormalities, oral ulcerations, ocular inflammation, and peripheral neuropathy, may signal that arthritis is a manifestation of a systemic rheumatic disease or vasculitis. The presence of rash can be a very helpful clue to the diagnosis (Table 4–3).

Comorbid Conditions

Certain chronic conditions predispose to the development of particular musculoskeletal problems. For example, patients with long-standing, poorly controlled diabetes mellitus are at greatly increased risk for Charcot arthropathy in the feet and limited joint mobility in the hands. Certain medications can trigger drug-induced lupus, which can present as a polyarthritis, often with serositis. The resurgence in the use of hydralazine for the treatment of hypertension has led to an increase in the incidence of hydralazine-induced lupus as well as the more serious hydralazine-induced, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Prior glucocorticoid therapy and alcohol abuse are the leading risk factors for osteonecrosis, which commonly presents as hip pain. Osteonecrosis and bone pain are common manifestations of Gaucher disease. Injection drug use carries the risk of septic arthritis; endocarditis; and infection with hepatitis B, hepatitis C, and HIV—each of which is associated with rheumatic conditions.

Family History

A positive family history, particularly among first-degree relatives, increases the likelihood of certain forms of arthritis. Most notably, the risk of ankylosing spondylitis for children or siblings of a patient with ankylosing spondylitis is as much as 75-fold that of the general population. The relative risk for SLE among first-degree relatives ranges from 20 to 30. A positive family history of rheumatoid arthritis is less helpful. The relative risk for siblings may be as low as 3, and family histories of rheumatoid arthritis can be inaccurate due to confusion with osteoarthritis.

Except in cases of trauma, arthritis that is acute in onset is usually inflammatory. Septic arthritis and crystal-induced arthritis typically have an acute onset, and patients often seek medical attention within hours to days after the onset of symptoms. These disease processes, therefore, always warrant serious consideration in cases of acute arthritis. Nonetheless, the differential diagnosis of acute arthritis is broad and includes such entities as rheumatoid arthritis and the spondyloarthropathies; however, these entities more commonly present as chronic conditions.

Acute Monoarthritis

Essential Features

• Septic arthritis is the major diagnostic concern.
  
• Arthrocentesis is the most important diagnostic test.

Initial Clinical Evaluation

The history and physical examination should determine whether the process is acute (onset over hours to days), involves the joint rather than surrounding tissues or bone, and is truly monoarticular. The most common causes of acute monoarthritis are infection, crystal-induced arthritis, and trauma (Table 4–4). In cases of suspected trauma, it is important to ascertain whether the reported trauma was sufficiently severe to account for the joint findings. (Patients with new-onset joint effusions often attribute the joint abnormality to incidental bumps, turns, or other minor trauma.) Joint space infection is the foremost concern in patients with acute pain and swelling in a single joint not clearly due to trauma.

Laboratory Evaluation

Arthrocentesis is indicated for all cases of unexplained acute monoarthritis. Synovial fluid should be sent for culture (for bacteria, mycobacteria, and fungus), cell count, Gram stain, and examination for crystals by polarized light microscopy. Routine laboratory determinations (eg, complete blood cell count, serum electrolytes and creatinine, and urinalysis) can provide helpful ancillary information. Blood cultures should be obtained if septic arthritis is suspected.

The characteristics of the synovial fluid guide the initial differential diagnosis. Nongonococcal septic arthritis usually causes synovial fluid WBC counts >50,000/mcL and often generates very high counts (>100,000/mcL). The synovial fluid WBC count in gonococcal arthritis is generally lower than in nongonococcal septic arthritis (mean synovial fluid WBC as low as 34,000/mcL in some series). Crystal-induced arthritis is also very inflammatory, with synovial fluid WBC counts often >50,000/mcL; WBC counts >100,000/mcL, however, are uncommon.

Gram staining for bacteria in synovial fluid is relatively insensitive (false-negative rates range from 25% to 50% for nongonococcal septic arthritis and are substantially higher for gonococcal infections). On the other hand, examination of synovial fluid by polarized light microscopy is a sensitive test for urate crystals. Calcium pyrophosphate dihydrate crystals are somewhat more difficult to visualize due to their weaker birefringence, but their detection should not present difficulties for the experienced observer. Thus, the absence of crystals is a strong argument against microcrystalline disease, but a negative Gram stain does not exclude infection. Occasionally, infection and microcrystalline disease coexist; therefore, the finding of crystals in the synovial fluid does not exclude the possibility of infection.

Properly performed cultures of synovial fluid are a sensitive test for nongonococcal septic arthritis (positive in up to 90% of cases). In contrast, synovial fluid cultures are positive in only 20–50% of cases of gonococcal arthritis, and the diagnosis often depends on identification of Neisseria gonorrhoeae at other sites by culture or nucleic acid amplification tests. In some cases, however, the diagnosis of disseminated gonococcal infection rests on the response to appropriate antibiotic therapy.

Imaging Studies

Radiographs can demonstrate fractures in cases of trauma but usually contribute little to the diagnosis of nontraumatic monoarthritis if the process is truly acute. Radiographic evidence of chondrocalcinosis can be seen in cases of pseudogout and, when there have been recurrent attacks of gout, radiographs may reveal erosions characteristic of gout. Occasionally, imaging studies can be misleading. For example, radiographs may demonstrate osteoarthritis or other chronic conditions that predispose to the development of septic arthritis but are not the proximal cause of the acute joint inflammation.

Differential Diagnosis

Inflammatory Monoarthritis

The leading causes of acute inflammatory monoarthritis—infection and crystal-induced arthritis—are difficult to differentiate in the absence of synovial fluid analysis and culture. Patients with septic arthritis may be afebrile and may not manifest a peripheral leukocytosis. Conversely, patients with crystal-induced arthritis can have fever and an elevated peripheral blood WBC count. An elevated serum uric acid level does not establish a diagnosis of gout, and patients with gout can have a normal serum uric acid level at the time of an acute attack.