Polyarticular joint pain (i.e., pain in more than four joints) poses a diagnostic challenge because of the extensive differential diagnosis (1) (Table 1). Consequently, family physicians need to keep the diagnosis open in evaluating patients who present with pain in multiple joints. For instance, a 50-year-old woman with symmetric, progressive polyarticular joint swelling and prolonged morning stiffness would seem to have rheumatoid arthritis. However, this patient might develop a malar rash and oral ulcers, which would change the diagnosis to systemic lupus erythematosus. Alternatively, the patient might develop thickening of the skin, which would suggest the diagnosis of scleroderma. Thus, a series of visits over time may be necessary to arrive at a specific diagnosis in many patients with polyarticular joint pain. In some patients, it may not be possible to establish a definitive diagnosis.
Because many rheumatologic laboratory tests lack the desired specificity, results should be interpreted in the clinical context and with caution. Tests with low specificity, such as those in arthritis panels, are frequently positive in the general population. Thus, these tests may be misleading. (2) Furthermore, use of tests with low specificity may increase unnecessary testing and attendant costs, result in inappropriate treatment, and have a negative psychologic impact on patients. (3)
In the absence of definitive rheumatologic laboratory tests, the history and physical examination are key to the early diagnosis and treatment of conditions that cause polyarticular joint pain. Indeed, the differential diagnosis can be narrowed through investigation of six clinical factors: disease chronology, inflammation, distribution, extra-articular manifestations, disease course, and patient demographics (Table 2). More common causes of polyarticular joint pain should be considered first.
Acute polyarticular joint pain (i.e., pain that has been present for less than six weeks) may be the sign of a self-limited disorder or a harbinger of chronic disease. Although chronic polyarticular arthritides more often develop insidiously, they can present abruptly. Thus, chronic conditions such as rheumatoid arthritis and systemic lupus erythematosus should be considered, at least initially, in patients who present with acute polyarticular joint pain (Table 3). (4-7) To avoid treating a self-limited disorder with potentially toxic disease-modifying agents, synovitis should be present for six weeks before rheumatoid arthritis is diagnosed. (4) [Evidence level C, consensus opinion]
Viruses (e.g., human parvovirus B19, hepatitis viruses), crystals, and serum sickness reactions are known causes of acute, self-limited polyarthritis. The specific cause of virus-induced arthritis is not always investigated; thus, the prevalence of viruses as the etiology of arthritis may be underestimated. (8)
Except for Neisseria gonorrhoeae, direct bacterial infections in joints seldom cause polyarthritis. (9) Although typically oligoarticular, extra-articular bacterial infections may induce acute arthritis. Classic reactive arthritis, for example, is associated with enteric infections (Salmonella, Shigella, Campylobacter, or Yersinia species) and urogenital infections (Chlamydia trachomatis).
Early gout usually affects only one joint. However, this disease also should be considered in patients with acute polyarticular arthritis, particularly older women who are taking diuretics and have hypertrophy and degenerative changes of the distal interphalangeal (DIP) joints (Heberden's nodes) and proximal interphalangeal (PIP) joints (Bouchard's nodes). (10)
Arthritis is joint pain with inflammation, whereas arthralgia is joint pain without inflammation. The patient who presents with psoriasis and knee pain in the absence of inflammation may have the dual diagnosis of psoriasis and osteoarthritis. However, the patient who also has inflammation probably has psoriatic arthritis, which may require more aggressive therapy. Inflammatory arthritides include infectious arthritis, gout, rheumatoid arthritis, systemic lupus erythematosus, and reactive arthritis.
Cardinal signs of inflammation include erythema, warmth, pain, and swelling. Patients with severe joint inflammation or systemic disease also may present with fatigue, weight loss, or fever. (8) Morning stiffness lasting longer than one hour suggests underlying inflammation. (1) The duration of morning stiffness provides a useful guide to the extent of inflammation. For instance, morning stiffness associated with rheumatoid arthritis may last for hours. (11, 12)
Palpation of multiple joint capsules is important to look for soft tissue swelling and effusions that result in edema and influx of inflammatory cells into and around the synovium. Soft tissue swelling should be distinguished from noninflammatory bony hypertrophy, such as Heberden's and Bouchard's nodes, which often indicate osteoarthritis (Figure 1). Crepitus indicates the presence of irregularities of the articular cartilage, which most commonly are associated with osteoarthritis, injury, or previous inflammation.
[FIGURE 1 OMITTED]
Because findings can be subtle, it is important to palpate each hand joint. Although palpation often can identify synovitis, it may not detect inflammation of more proximal joints in, for example, elderly patients with polymyalgia rheumatica. (13)
Morning stiffness and a history of swelling suggest an inflammatory process but also are characteristic of fibromyalgia, a noninflammatory condition (Table 3). (4-7) Typically, patients with fibromyalgia have a subjective sense of swelling but no objective signs of synovitis. Fibromyalgia is suggested by the presence of polyarticular joint pain without synovitis, along with myalgias and tender points. (14)
The pattern of joint involvement provides diagnostic clues. For instance, osteoarthritis of the hand usually involves the DIP and PIP joints, but not the metacarpophalangeal (MCP) joints. (15) Alternatively, rheumatoid arthritis of the hand most often involves the PIP and MCP joints, but not the DIP joints. (4, 15) Psoriatic arthritis, crystal-induced arthritis, and sarcoidosis may affect all of these joints. Hand synovitis is distinctly unusual in chronic Lyme disease. (16)
Spondyloarthropathies typically involve the larger joints of the lower extremities. Osteoarthritis tends to spare wrists, elbows, and ankles, unless there is a history of trauma, inflammation, or a metabolic disorder such as hemochromatosis.
Depending on the underlying cause, the pattern of arthritis may change over time. For example, the acute stage of Lyme disease may include polyarticular arthralgias, whereas the chronic phase may include oligoarthritis, primarily in the knees. (17)
Joint involvement tends to be symmetric in systemic diseases such as rheumatoid arthritis, systemic lupus erythematosus, polymyalgia rheumatica, viral arthritides, and serum sickness reactions. Of eight variables examined in one study, (18) symmetric pain was the most potent discriminating feature for rheumatoid arthritis. Psoriatic arthritis, reactive arthritis, and gout are more likely to present with asymmetric peripheral involvement. (1, 19, 20)
Axial pain may be a helpful indicator in the evaluation of peripheral joint pain. In addition to peripheral joints, osteoarthritis may involve the lower back, the neck, or both. In contrast, rheumatoid arthritis is seldom an explanation for low back pain.
A young adult who presents with peripheral arthritis accompanied by the insidious onset of chronic low back pain and prolonged morning stiffness that improves with exercise probably has one of the spondyloarthropathies, such as ankylosing spondylitis, psoriatic arthritis, inflammatory bowel disease-associated arthropathy, or reactive arthritis. (21) Another common manifestation of spondyloarthropathies is enthesitis (inflammation of the muscular or tendinous insertions), (22) such as Achilles tendonitis or plantar fasciitis. (23) Dactylitis (inflammation of the finger or toe) is another classic sign of spondyloarthropathies; this condition, often referred to as "sausage digits," is caused by a combination of synovitis and enthesitis (22) (Figure 2).
[FIGURE 2 OMITTED]
Extra-articular manifestations may provide clues to the presence of some rheumatologic diseases but, of themselves, are not diagnostic (Table 4). For instance, extra-articular signs and symptoms can point to the likely reason for swollen PIP joints: a malar rash and oral ulcers indicate probable systemic lupus erythematosus (Figure 3); proximal muscle weakness suggests polymyositis; and psoriatic skin and nail lesions raise the possibility of psoriatic arthritis. (24, 25)
Similarly, in a patient with knee arthritis, the presence of conjunctivitis, oral ulcers, vesicopustules on the soles, or recent diarrhea may indicate reactive arthritis. (21, 26) A history of erythema chronicum migrans and Bell's palsy points to the diagnosis of Lyme disease. (27) As a final example, a health care worker who presents with fever, a lacy rash, and symmetric joint pain (especially in the hands) may have erythema infectiosum caused by human parvovirus B19 infection. (28-30)
When symptoms are present for a limited period (usually a few days to a month) and resolve completely before presenting again, crystal-induced arthritis (e.g., gout, pseudogout) is the likely diagnosis. Arthrocentesis should be considered during a symptomatic flare. (10, 19, 27, 31) If synovial fluid analysis fails to identify crystals, palindromic rheumatism should be considered; this condition may progress to rheumatoid arthritis.
Migratory arthritis is characterized by rapid onset of swelling in one or two joints, with resolution over a few days. As the symptoms resolve, similar symptoms emerge in another joint, usually in an asymmetric location. (20, 28) This symptom pattern can occur in gonococcal arthritis, rheumatic fever, sarcoidosis, systemic lupus erythematosus, Lyme disease, bacterial endocarditis, and Whipple's disease. (32)
Before menopause, women are nine times more likely to develop systemic lupus erythematosus and three to four times more likely to develop rheumatoid arthritis. (20) After men and women reach 50 years of age, the gender difference for systemic lupus erythematosus and rheumatoid arthritis becomes less significant. (1)
Compared with men, women are nine times more likely to develop fibromyalgia. An estimated 60 percent of women with symptomatic human parvovirus B19 infection manifest arthropathy, whereas men with this infection appear to develop arthropathy much less often. (33, 34) The gender ratio is more balanced for spondyloarthropathies and vasculitic conditions such as polyarteritis nodosa.
Gout usually presents about 20 years after puberty in men and about 20 years after menopause in women. This disease is rare in premenopausal woman, unless renal insufficiency is present. (10)
Certain diagnoses are more common in specific age groups. Rheumatic fever, systemic lupus erythematosus, rheumatoid arthritis, reactive arthritis, and spondyloarthropathies occur more often in younger persons. Osteoarthritis, polymyalgia rheumatica, and giant cell arteritis are more common in older persons. (13)
Polymyalgia rheumatica and Wegener's granulomatosis are more likely to affect whites. (13) In contrast, sarcoidosis and systemic lupus erythematosus are more common in blacks.
Familial aggregation occurs in some arthritic diseases, such as spondyloarthropathies, rheumatoid arthritis, and Heberden's nodes of osteoarthritis. (1) There is a particularly strong association between ankylosing spondylitis and the HLA-B27 allele.
As previously noted, many rheumatologic laboratory tests must be interpreted in the context of the individual patient. For example, antinuclear antibody (ANA) tests are positive in 5 to 10 percent of the general population, a rate that increases with age. Thus, given a one in 20 frequency for ANAs and a one in 2,000 frequency for systemic lupus erythematosus, only one in 100 persons with a positive ANA test will have the disease. Consequently, positive ANA test results must be interpreted with caution (Table 3). (4-7) Given the high sensitivity of the currently used substrate for testing, a negative ANA test essentially rules out systemic lupus erythematosus. (1, 5) Spondyloarthropathies affect fewer than 1 percent of the general population. Indeed, patients who are HLA-B27 positive and do not have a family history of ankylosing spondylitis have only a 2 percent risk of developing this disorder. (35)
Spondyloarthropathies can be overdiagnosed by relying only on a positive HLA-B27 test, because this test is positive in 8 percent of white persons. (35)
Rheumatoid factor testing lacks both sensitivity and specificity: the test is positive in 5 to 10 percent of the general population and negative in approximately 20 percent of persons with rheumatoid arthritis. (36) Therefore, both positive and negative rheumatoid factor test results must be interpreted cautiously. Indeed, rheumatoid factor testing is not useful when a patient lacks other diagnostic criteria for rheumatoid arthritis, especially synovitis. (36) The American Rheumatology Association's revised diagnostic criteria for rheumatoid arthritis use findings from the history, physical examination, and laboratory tests. (4) These criteria, which have been shown to be 91 to 94 percent sensitive and 89 percent specific, are useful for establishing a diagnosis of rheumatoid arthritis. (4, 12, 15)
A complete blood count, urinalysis, and a metabolic panel may provide more useful diagnostic clues than classic rheumatologic laboratory tests (Table 5). For instance, hematuria, proteinuria, a low white blood cell (WBC) count, and thrombocytopenia may indicate the presence of systemic lupus erythematosus. Anemia with a low mean corpuscular volume may be a sign of underlying inflammatory bowel disease that is causing chronic gastrointestinal blood loss. Human parvovirus B19 infection can induce a decrease in the reticulocyte count, followed by anemia and, occasionally, leukopenia and thrombocytopenia. (30, 34)
Synovial fluid analysis is performed primarily to diagnose infection or a crystal-induced arthritis. A synovial fluid WBC count of at least 2,000 per [mm.sup.3] (2 3 [10.sup.9] per L) suggests inflammation, whereas a count higher than 50,000 per [mm.sup.3] (50 3 [10.sup.9] per L) typically indicates synovial infection (Table 6). (37) Fluid with a highly elevated WBC count or a predominance of neutrophils should be cultured to exclude infection.
A number of radiographic findings are characteristic of specific rheumatic disorders. For instance, sacroiliitis is indicative of ankylosing spondylitis, erosions with periarticular osteopenia are typical of rheumatoid arthritis, and "pencil-in-cup" deformities are a sign of psoriatic arthritis. However, these radiographic findings take months to develop; early in the process, radiographs may be normal or show only nonspecific changes.
In early rheumatoid arthritis, magnetic resonance imaging demonstrates cartilage damage that is not evident on plain-film radiographs. (38) This damage highlights the importance of diagnosing rheumatoid arthritis early on the basis of the history and physical examination so that disease-modifying treatment can be initiated.
The authors thank Robert M. Wesley, M.A., project director for this series and director of research and program development for the Department of Family and Community Medicine at Southern Illinois University (SIU) School of Medicine, Springfield, for editing and commentary throughout development of the paper. The authors also acknowledge valuable suggestions from Rob Ewart, M.D., associate professor in the Department of Family and Community Medicine at SIU School of Medicine.
Members of various family practice departments develop articles for "Problem-Oriented Diagnosis." This is one in a series from the Department of Family and Community Medicine at Southern Illinois University School of Medicine, Springfield. Guest editor of the series is Robert M. Wesley, M.A.
The authors indicate that they do not have any conflicts of interests. Sources of funding: none reported.
Differential Diagnosis of Polyarticular Joint Pain
Viral infection: human parvovirus (especially B19), enterovirus, adenovirus, Epstein-Barr, coxsackievirus (A9, B2, B3,
B4, B6), cytomegalovirus, rubella, mumps, hepatitis B, varicella-zoster virus (human herpes virus 3), human
Indirect bacterial infection (reactive arthritis): Neisseria gonorrhoeae (gonorrhea), bacterial endocarditis,
Campylobacter species, Chlamydia species, Salmonella species, Shigella species, Yersinia species, Tropheryma whippelii
(Whipple's disease), group A streptococci (rheumatic fever)
Direct bacterial infection: N. gonorrhoeae, Staphylococcus aureus, gram-negative bacilli, bacterial endocarditis
Other infections: Borrelia burgdorferi (Lyme disease), Mycobacterium tuberculosis (tuberculosis), fungi
Crystal-induced synovitis: gout, pseudogout (calcium pyrophosphate deposition disease), hydroxyapatite
Systemic rheumatic disease: rheumatoid arthritis, systemic lupus erythematosus, polymyositis/dermatomyositis, juvenile
rheumatoid arthritis, scleroderma, Sjogren's syndrome, Behcet's syndrome, polymyalgia rheumatica
Systemic vasculitis disease: Schonlein-Henoch purpura, hypersensitivity vasculitis, polyarteritis nodosa, Wegener's
granulomatosis, giant cell arteritis
Spondyloarthropathies: ankylosing spondylitis, psoriatic arthritis, inflammatory bowel disease, reactive arthritis
Endocrine disorders: hyperparathyroidism, hyperthyroidism, hypothyroidism
Malignancy: metastatic cancer, multiple myeloma
Others: osteoarthritis, hypermobility syndromes, sarcoidosis, fibromyalgia, osteomalacia, Sweet's syndrome, serum
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ANNA MIES RICHIE, M.D., is assistant professor in the Department of Family and Community Medicine at Southern Illinois University School of Medicine, Springfield, where she earned her medical degree and completed a family practice residency and fellowship.
MARK L. FRANCIS, M.D., is associate professor and chief of the Division of Rheumatology at Southern Illinois University School of Medicine. Dr. Francis received his medical degree from Saint Louis University School of Medicine, St. Louis, and completed an internal medicine residency at William Beaumont Army Medical Center, El Paso, where he was chief resident. He also completed three years of a rheumatology fellowship at Walter Reed Army Medical Center, Washington, D.C.
Address correspondence to Anna Mies Richie, M.D., Department of Family and Community Medicine, Southern Illinois University School of Medicine, P.O. Box 19671, Springfield, IL 62794-9671 (e-mail amiesrichie@ siumed.edu). Reprints are not available from the authors.
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