26
Approach to the
4 Patient with Arthritis
John B. Imboden, MD
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 evalu-
ation and should never be used as a “screen” for disease.
Musculoskeletal complaints are common in the general pop-
ulation, but the prevalence of inflammatory rheumatic dis-
eases 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 non-
inflammatory 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 syno-
vial 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 labora-
tory 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 symp-
toms 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 sedimenta-
tion 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, intermit-
tent 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 presen-
tation of reactive arthritis, systemic vasculitis, enteropathic
arthritis, and paraneoplastic arthritis but is unusual in rheu-
matoid arthritis of recent onset. Constitutional symptoms
rarely accompany noninflammatory forms of arthritis.
 APPROACH TO THE PATIENT WITH ARTHRITIS 27

Table 4–1. Initial clinical characterization of arthritis. Table 4–3. Rash and arthritis.
• Duration: acute (presenting within hours to days) or chronic
Skin Manifestation Associated Conditions
(persisting for weeks or longer)
• Number of joints involved: monoarticular, oligoarticular (2–4 joints), Erythematous Superimposed drug reaction
or polyarticular (5 joints or more) maculopapular rash Still disease
• If more than one joint is involved: symmetric or asymmetric; additive Viral syndromes
or migratory Kawasaki disease
• Accurate delineation of the involved joints Secondary syphilis
• Inflammatory or noninflammatory Chronic meningococcemia
Urticaria SLE
Hypocomplementemic urticarial vasculitis
 Extra-articular Manifestations Serum sickness
Acute hepatitis B
Extra-articular manifestations, such as glomerulonephritis, Still disease
pulmonary abnormalities, oral ulcerations, ocular inflamma- Schnitzler syndrome
tion, and peripheral neuropathy, may signal that arthritis is a Palpable purpura ANCA-associated vasculitis
manifestation of a systemic rheumatic disease or vasculitis. SLE
The presence of rash can be a very helpful clue to the diag- Hypersensitivity vasculitis
nosis (Table 4–3). Cryoglobulinemia
Henoch-Schonlein purpura
Subacute bacterial endocarditis
 Comorbid Conditions
Papulosquamous Psoriatic arthritis
Certain chronic conditions predispose to the development of lesions Reactive arthritis
particular musculoskeletal problems. For example, patients Discoid lupus
with long-standing, poorly controlled diabetes mellitus are Subacute cutaneous lupus erythematosus
at greatly increased risk for Charcot arthropathy in the feet Secondary syphilis
and limited joint mobility in the hands. Certain medica- Annular lesions Subacute cutaneous lupus erythematosus
tions can trigger drug-induced lupus, which can present as Lyme disease (erythema chronicum migrans)
a polyarthritis, often with serositis. The resurgence in the use Acute rheumatic fever (erythema
of hydralazine for the treatment of hypertension has led to marginatum)
Pustular lesions Disseminated gonococcal infection
Pustular psoriasis
Reactive arthritis (keratoderma
Table 4–2. Fever and arthritis. blenorrhagicum)
Behçet disease
Active infection Acne-associated rheumatic syndromes
Septic arthritis Sweet syndrome (also painful papule/
Disseminated gonococcal infection nodules)
Endocarditis
Acute viral infections Subcutaneous Erythema nodosum
Mycobacterial nodular lesions Sarcoidosis
Fungal Inflammatory bowel disease
Post infection Behçet disease
Reactive arthritis (particularly in its early phases) SLE (lupus profundus)
Acute rheumatic fever and poststreptococcal arthritis Polyarteritis nodosa
Not due to infection Weber-Christian disease
Systemic lupus erythematosus ANCA, antineutrophil cytoplasmic antibodies; SLE, systemic lupus
Drug-induced lupus erythematosus.
Still disease
Gout
Pseudogout
Inflammatory bowel disease an increase in the incidence of hydralazine-induced lupus
Paraneoplastic arthritis as well as the more serious hydralazine-induced, antineu-
Acute sarcoidosis trophil cytoplasmic antibody (ANCA)-associated vasculitis.
Systemic vasculitis Prior glucocorticoid therapy and alcohol abuse are the lead-
Familial Mediterranean fever and other inherited periodic fever ing risk factors for osteonecrosis, which commonly pres-
syndromes ents as hip pain. Osteonecrosis and bone pain are common
 28 CHAPTER 4
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 fam-
ily histories of rheumatoid arthritis can be inaccurate due to
confusion with osteoarthritis.
ACUTE ARTHRITIS
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.
1. Acute Monoarthritis
E S S E N T I A L F E AT U R E S
 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 impor-
tant 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.
Table 4–4. Common causes of acute monoarthritis.
Cause Example
Bacterial infection Nongonococcal: especially, Staphylococcus
of the joint space aureus, β-hemolytic streptococci,
Streptococcus pneumoniae, gram-
negative organisms
Gonococcal: often preceded by a migratory
tenosynovitis or oligoarthritis associated
with characteristic skin lesions
Crystal-induced arthritis Gout (monosodium urate crystals)
Pseudogout (calcium pyrophosphate
dihydrate crystals)
Trauma Hemarthrosis
A. 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 dis-
ease, 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 sensi-
tive 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 diag-
nosis often depends on identification of Neisseria gonorrhoeae
 APPROACH TO THE PATIENT WITH ARTHRITIS
at other sites by culture or nucleic acid amplification tests. In
some cases, however, the diagnosis of disseminated gonococ-
cal infection rests on the response to appropriate antibiotic
therapy.
B. 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 pseu-
dogout and, when there have been recurrent attacks of gout,
radiographs may reveal erosions characteristic of gout.
Occasionally, imaging studies can be misleading. For exam-
ple, 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
A. 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 cul-
ture. 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.
Septic arthritis indicates the presence of a potentially life-
threatening infection and requires prompt treatment with
appropriate antibiotics. Delay in the treatment of nongono-
coccal septic arthritis also causes substantial morbidity due
to the rapid destruction of articular cartilage. Acute inflam-
matory monoarthritis should be considered septic arthritis
until there is compelling evidence either against bacterial
infection or in favor of an alternative diagnosis.
The differential diagnosis of acute inflammatory mono-
arthritis not due to septic arthritis, gout, or pseudogout is
broad. Many of these entities more commonly present as
subacute or chronic processes (see below). Diseases that are
typically oligoarticular or polyarticular, such as the spon-
dyloarthropathies and rheumatoid arthritis occasionally
begin as an inflammatory monoarthritis (“pseudoseptic”
presentation).
B. Noninflammatory Monoarthritis
Noninflammatory synovial fluid can be seen with internal
derangements (ie, torn meniscus of the knee). Osteoarthritis
of a single joint usually presents with chronic complaints but,
on occasion, can cause the acute onset of pain. Similarly, neu-
ropathic arthropathy, amyloidosis, and osteonecrosis usually
29
cause chronic noninflammatory arthritis of one or several
joints but occasionally present with acute symptoms.
C. Hemarthrosis
Frank blood on arthrocentesis can be indicative of a fracture
or other joint trauma. Hemarthrosis also occurs in patients
who are receiving anticoagulant therapy or have a clotting
factor deficiency, such as hemophilia. Bloody synovial fluid
can be seen in pigmented villonodular synovitis, a rare pro-
liferative disorder of the synovium that presents as a chronic
monoarthritis, typically of the knee, in young adulthood.
2. Acute Oligoarthritis
E S S E N T I A L F E AT U R E S
 Disseminated gonococcal infection, nongonococcal sep-
tic arthritis, and the spondyloarthropathies are leading
causes of acute inflammatory oligoarthritis.
 Arthrocentesis and appropriate cultures are important
diagnostic tests.
 Initial Clinical Evaluation
Acute oligoarthritis is usually due to an inflammatory pro-
cess (Table 4–5). Infectious causes of the arthritis need to
be excluded. Disseminated gonococcal infection is the most
common cause of acute oligoarthritis in sexually active young
people. Nongonococcal septic arthritis is usually monoartic-
ular but involves more than one joint in up to 20% of cases.
Spondyloarthropathies typically cause an asymmetric
oligoarthritis. Of these, reactive arthritis is most likely to
present with acute onset of arthritis and, early in its course,
can be difficult to distinguish from disseminated gonococcal
infection.
Gout is a common cause of acute oligoarthritis.
Oligoarticular gout usually develops after years of antecedent
attacks of acute monoarthritis, but it occasionally can be the
initial manifestation.
The use of four joints as a dividing line between oligo-
arthritis and polyarthritis is somewhat arbitrary, and there
is overlap between disorders that cause oligoarthritis and
polyarthritis. For example, rheumatoid arthritis can be oli-
goarticular in its early stages. Erythrovirus (parvovirus B19)
infection usually causes a true polyarthritis but on occasion
produces an oligoarthritis. Conversely, many of the entities
listed in Table 4–4 sometimes involve more than four joints.
A. Laboratory Evaluation
Complete blood cell count, serum electrolytes and creatinine,
and urinalysis should be obtained. Synovial fluid should
 30 CHAPTER 4
Table 4–5. Differential diagnosis of acute inflammatory
oligoarthritis.
• Infection
Disseminated gonococcal infectiona
Nongonococcal septic arthritis
Bacterial endocarditisb
Viralc
• Post infection
Reactive arthritisb
Rheumatic fever (poststreptococcal arthritis)d
• Spondyloarthropathy
Reactive arthritisb
Ankylosing spondylitisb
Psoriatic arthritisb
Inflammatory bowel diseaseb
• Oligoarticular presentation of rheumatoid arthritis, systemic lupus
erythematosus,a adult-onset Still disease, relapsing polychondritis,a
or other polyarthritis
Gout and pseudogout
a commonly presents as migratory arthralgias.
Often migratory.
b
Can be associated with back pain.
c
Usually causes polyarthritis but occasionally oligoarticular and
sometimes noninflammatory.
d
Migratory in children but usually not in adults.
be sent for culture, cell count, Gram stain, and examina-
tion for crystals. When disseminated gonococcal infection
is suspected, samples from pharynx, urethra, cervix, and
rectum—even when asymptomatic—should be tested for
N gonorrhoeae. Cultures of pharynx, urethra, cervix, and rec-
tum are, in aggregate, positive in 80–90% of cases of dissemi-
nated gonococcal infection. Nucleic acid amplification tests
of samples from these sites and from urine have greater sen-
sitivity than culture for detection of N gonorrhoeae. Urethral
and cervical swabs also should be tested for Chlamydiae. If
bacterial endocarditis is a possibility, at least 3 blood cultures
should be obtained, and a transesophageal echocardiogram
may be indicated. Antibodies to streptococcal antigens (eg,
streptolysin O) should be determined in cases of suspected
acute rheumatic fever or poststreptococcal arthritis. The
presence of antibodies to cyclic citrullinated peptides (CCP)
is a strong predictor of evolution to rheumatoid arthritis.
B. Imaging Studies
Radiographs usually are of little help if the onset of the oligo-
arthritis is truly acute.
 Differential Diagnosis
Disseminated gonococcal infection usually presents as
a migratory tenosynovitis, often with characteristic skin
lesions; meningococcemia can cause a similar syndrome
but is much less common. Bacterial endocarditis can cause
an oligoarthritis with either septic joints (due to hematog-
enous spread) or sterile inflammatory synovial fluid (likely
due to immune complex disease); back pain is common, par-
ticularly in acute bacterial endocarditis (Table 4–5). Reactive
arthritis classically follows within 1 to 4 weeks of enteric
or genitourinary tract infections, but the triggering infec-
tion is sometimes subclinical. In its presenting phase, reac-
tive arthritis has a predilection for the lower extremities and
can be associated with significant constitutional signs and
symptoms including prominent weight loss and fever. Most
patients with the new onset of psoriatic arthritis either have
or have had psoriasis, but, in a minority (15%), the arthritis
precedes the skin disease. Acute rheumatic fever produces a
migratory arthritis in children; in adults, however, poststrep-
tococcal arthritis is usually not migratory and is rarely associ-
ated with the other distinctive manifestations of rheumatic
fever (eg, rash, subcutaneous nodules, carditis, and chorea).
Early disseminated Lyme disease can cause an acute oligo-
arthritis or monoarthritis (especially of the knee) but more
3. Acute Polyarthritis
E S S E N T I A L F E AT U R E S
 Viral infections and rheumatoid arthritis are the leading
causes of acute polyarthritis.
 Observation to distinguish persistent from self-limited
polyarthritis is critical.
 Initial Clinical Evaluation
Viral polyarthritis typically resolves over days to a few weeks.
Thus, the longer polyarthritis persists, the less likely viral
polyarthritis becomes. Rheumatoid arthritis usually has an
insidious onset, and patients seek medical care after weeks
or months of symptoms. Nonetheless, it begins abruptly in
enough patients to warrant consideration as a cause of acute
polyarthritis. Acute polyarthritis can also be the initial mani-
festation of SLE and drug-induced lupus as well as a variety of
uncommon entities, including systemic vasculitis (Table 4–6).
A. Laboratory Evaluation
The clinical setting should guide the decision to send tests for
specific viral infections (eg, erythrovirus [parvovirus B19]
or hepatitis B). If viral polyarthritis is thought unlikely, then
routine laboratory studies (including complete blood cell
count, serum electrolytes and creatinine, liver function tests,
and urinalysis), determinations of the ESR or CRP, and tests
for serum rheumatoid factor, antibodies to CCP, and anti-
nuclear antibodies (ANAs) are indicated.
 APPROACH TO THE PATIENT WITH ARTHRITIS 31

Testing for ANA has sensitivity for SLE but low specificity.
Table 4–6. Differential diagnosis of acute polyarthritis. When ANAs are detected by indirect immunofluorescence
assays using human cell lines (eg, HEp-2 cells), the sensitiv-
• Common
ity for SLE approaches 100%. False-negative results, how-
Acute viral infections
Early disseminated Lyme disease
ever, can occur when ANAs are measured by enzyme-linked
Rheumatoid arthritis immunoabsorbent assays (ELISA) or by high throughput
Systemic lupus erythematosus assays using multiplex beads. In a patient with polyarthritis
• Uncommon or rare or polyarthralgias, a positive assay for ANA should prompt a
Paraneoplastic polyarthritis careful evaluation for other manifestations of SLE and addi-
Remitting seronegative symmetric polyarthritis with pitting edema tional serologic tests (see Chapter 3).
Acute sarcoidosis, usually with erythema nodosum and hilar
adenopathy Aletaha D, Neogi T, Silman AJ, et al. 2010 Rheumatoid Arthritis
Adult-onset Still disease Classification Criteria: an American College of Rheumatology/
Secondary syphilis European League Against Rheumatism Collaborative Initiative.
Systemic autoimmune diseases and vasculitides Arthritis Rheum. 2010;62:2569. [PMID: 20872595]
Whipple disease

CHRONIC ARTHRITIS
B. Imaging Studies
Joint radiographs are rarely of value in acute polyarthritis
1. Chronic Monoarthritis
and may be deferred until it is clear that the polyarthritis is
persistent.
E S S E N T I A L F E AT U R E S

 Differential Diagnosis  Distinguishing between inflammatory and noninflamma-

tory arthritis is a key step toward establishing a diagnosis.
Many acute viral infections cause joint symptoms, with poly-  Arthrocentesis and imaging studies are important diag-
arthralgias being considerably more common than true poly- nostic tests.
arthritis. The prevalence of polyarthritis is high, however, in
adults with acute erythrovirus (parvovirus B19) infection.
The pattern of viral polyarthritis often mimics that of rheu-  Initial Clinical Evaluation
matoid arthritis. Adults with acute erythrovirus (parvovirus
B19) infection, the cause of “slapped cheek fever” in chil- It is important to determine whether the symptoms and
dren, usually have only a faint rash on the trunk or no rash signs point to an inflammatory or noninflammatory process.
at all. IgM antibodies to erythrovirus (parvovirus B19) are Indolent infections are a concern with inflammatory mono-
generally present at the onset of joint symptoms and per- arthritis of weeks to even months in duration. The particular
sist for approximately 2 months. Acute hepatitis B causes an joint involved influences the differential diagnosis.
immune complex–mediated arthritis, often with urticaria or
maculopapular rash, during the preicteric phase of infection; A. Laboratory Evaluation
tests for hepatitis B surface antigen are positive. Effective vac-
A critical step is to determine whether the monoarthritis is
cination programs in the United States have substantially
inflammatory or noninflammatory, preferably by analysis of
reduced the incidence of acute hepatitis B and have elimi-
synovial fluid. Synovial fluid should be sent for culture (for
nated acute rubella infection, which is also associated with
bacteria, mycobacteria, and fungus), cell count, and Gram
acute polyarthritis.
stain and should be examined for crystals by polarized light
Acute-onset rheumatoid arthritis can be difficult to dis-
microscopy.
tinguish from virally induced acute polyarthritis, and many
Routine laboratory studies (eg, complete blood cell count,
rheumatologists are hesitant to make a diagnosis of rheu-
serum electrolytes and creatinine, and urinalysis) and deter-
matoid arthritis in the acute setting. The joint American
minations of the ESR or CRP can provide helpful ancillary
College of Rheumatology (ACR) and European League
information. Patients with inflammatory monoarthritis and
Against Rheumatism (EULAR) 2010 Rheumatoid Arthritis
negative bacterial cultures should be tested for Lyme disease
Classification Criteria are weighted toward polyarthritis, the
and for reactivity to purified protein derivative (PPD).
involvement of “small joints” (metacarpophalangeal [MCP]
joints, proximal interphalangeal [PIP] joints, second through
B. Imaging Studies
fifth metatarsophalangeal [MTP] joints, thumb interphalan-
geal joints, and wrists), the presence of either anti-CCP anti- In contrast to acute monoarthritis, radiographs can be helpful
bodies or rheumatoid factor, particularly in high titer. in the evaluation of processes present for weeks or more and
 32 CHAPTER 4

Table 4–7. Differential diagnosis of chronic inflammatory
monoarthritis.
• Infection
Nongonococcal septic arthritis
Gonococcal
Lyme disease and other spirochetal infections
Mycobacterial
Fungal
Virala
• Crystal-induced arthritis
Gout
Pseudogout
Calcium apatite crystalsb
• Monoarticular presentation of an oligoarthritis or polyarthritis
Spondyloarthropathy
Rheumatoid arthritis
Lupus and other systemic autoimmune diseases
• Sarcoidosisa
• Familial Mediterranean fever and other inherited periodic fever
syndromesc
• Amyloidosisa,c
• Foreign-body synovitis due to plant thorns, sea urchin spikes, wood
fragments, etc.c
• Pigmented villonodular synovitisc,d
a
Also can cause noninflammatory synovial fluid.
b
Not detected by polarized light microscopy.
c
Uncommon or rare.
d
Commonly associated with bloody, or blood-tinged brown, synovial
fluid.
can point to the correct diagnosis in cases of infection, osteo-
arthritis, osteonecrosis, neuropathic joints, and other entities.
 Differential Diagnosis
A. Inflammatory
A wide range of disease processes can cause inflamma-
tory arthritis in a single joint for several weeks or longer
(Table 4–7). Most patients with septic arthritis and gonococ-
cal arthritis experience significant pain in the infected joint
and seek medical attention within hours to days of the onset
of symptoms. However, patients occasionally seek medical
care after a delay of several weeks, particularly if symptoms
have been partially masked by the use of nonsteroidal anti-
inflammatory drugs, antibiotics, or glucocorticoids (systemic
or intra-articular).
Untreated indolent infections, on the other hand,
commonly present after weeks or more of symptoms.
These are associated with negative synovial fluid cul-
tures for bacteria and require additional diagnostic tests
and cultures to establish the correct diagnosis. Chronic
Lyme disease can cause an inflammatory monoarthritis,
often of the knee, with synovial fluid WBC typically in
Table 4–8. Differential diagnosis of chronic
noninflammatory monoarthritis.
Osteoarthritis
Internal derangements (eg, torn meniscus)a
Chondromalacia patellaea
Osteonecrosisa
Neuropathic (Charcot) arthropathyc
Sarcoidosisa–c
Amyloidosisa–c
a
Radiograph of the affected joint often normal at presentation.
b
Can also cause inflammatory synovial fluid.
c
Uncommon or rare.
the 10,000–25,000/mcL range. Tuberculous infection of
a joint can present after days, weeks, or months of symp-
toms. Smears for acid-fast bacilli are positive in only 20%
of cases; cultures for mycobacteria are positive in 80% but
take weeks. Synovial biopsy can greatly expedite the diag-
nosis of tuberculous arthritis and is also indicated in sus-
pected cases of fungal arthritis.
B. Noninflammatory
Osteoarthritis is the leading cause of chronic noninflam-
matory monoarthritis, particularly when the hip, knee,
first carpometacarpal joint, or acromioclavicular joint is
involved (Table 4–8). Internal derangements, such as a torn
meniscus in the knee, often produce mechanical symptoms
and characteristic findings on physical examination. Pain
is frequently a prominent feature of osteonecrosis, which
can produce large knee effusions when the distal femur is
involved. Radiographs are often normal early in the course
of osteonecrosis, and diagnosis may require MRI. Hip pain
with a normal radiograph should raise the possibility of
early osteonecrosis, particularly if the patient is relatively
young and has a risk factor for osteonecrosis. Diabetes mel-
litus is the most common underlying cause of neuropathic
arthropathy, which should be considered in a diabetic
patient with foot, ankle, or knee arthritis. The involved joint
may be warm and painful, but the joint fluid is typically
noninflammatory. Radiographs usually show characteristic
neuropathic changes.
2. Chronic Oligoarthritis
E S S E N T I A L F E AT U R E S
 Careful delineation of the arthritis and detection of
extra-articular disease facilitate accurate diagnosis.
 Radiographs are often of diagnostic value.
 APPROACH TO THE PATIENT WITH ARTHRITIS 33

 Differential Diagnosis
Table 4–9. Differential diagnosis of chronic oligoarthritis.
Although spondyloarthropathies typically cause an asym-
Inflammatory Causes Noninflammatory Causes metric oligoarthritis and rheumatoid arthritis is usually a
Common symmetric polyarthritis, it can be difficult to differentiate
these entities in patients with early disease. Several features
Spondyloarthropathy Osteoarthritis are helpful in making this distinction. Ankylosing spondy-
Reactive arthritisa
litis always, and the other spondyloarthropathies often, pro-
Ankylosing spondylitisa
Psoriatic arthritisa duce inflammatory axial skeleton disease with sacroiliitis that
Inflammatory bowel diseasea causes pain and stiffness in the low back, particularly in the
Atypical presentation of morning. Sacroiliitis is not a feature of rheumatoid arthri-
rheumatoid arthritis tis, which involves the cervical spine but no other part of the
Gout axial skeleton. The prominent tenosynovitis of the spondylo-
Uncommon or rare arthropathies can produce dactylitis (“sausage digits”) of the
toes or fingers. Dactylitis is not seen in rheumatoid arthritis.
Subacute bacterial endocarditis Hypothyroidism (Dactylitis is not specific for the spondyloarthropathies; it
Sarcoidosisb Amyloidosis also occurs in sarcoidosis and gout). Reactive arthritis and
Behçet disease the arthritis of inflammatory bowel disease have a predilec-
Relapsing polychondritis tion for the lower extremities. Rheumatoid arthritis invari-
Celiac diseasea ably involves the hands, and >90% of cases eventually have
a
Can be associated with involvement of the axial skeleton. wrist arthritis.
b
Can be a migratory arthritis and have either inflammatory or non- Many of the entities that cause chronic oligoarthritis have
inflammatory synovial fluid. extra-articular manifestations that point to the correct diag-
nosis but that are easily overlooked. For example, psoriasis
may be subtle, and the patient may be unaware of psoriatic
lesions, particularly in the umbilicus, the external auditory
 Initial Clinical Evaluation canal, the scalp, and the anal cleft. The oral ulcers of reac-
tive arthritis are painless and usually not detected unless
Spondyloarthropathies are the most common cause of specifically sought by the examining physician. Patients with
chronic inflammatory oligoarthritis (Table 4–9). For months inflammatory bowel disease may not volunteer that they have
or longer, however, it may be difficult to distinguish spon- chronic diarrhea, particularly if bowel symptoms are inter-
dyloarthropathies from early-onset rheumatoid arthritis. mittent. Antecedent anterior uveitis can be an important
Osteoarthritis commonly presents as a noninflammatory oli- clue to the presence of a spondyloarthropathy, but patients
goarthritis of the hips or knees and usually does not present generally do not associate ocular inflammation with arthritis
diagnostic difficulties. and may not mention a past episode of anterior uveitis unless
asked directly.
A. Laboratory Evaluation
Synovial fluid should be analyzed for crystals and cultured. 3. Chronic Polyarthritis
The distinction between inflammatory and noninflamma-
tory chronic oligoarthritis often can be made on clinical
grounds but is confirmed by the synovial fluid WBC count. E S S E N T I A L F E AT U R E S
Antibodies to CCP and rheumatoid factor have similar
sensitivity in identifying rheumatoid arthritis, but the anti-  Rheumatoid arthritis and osteoarthritis are the leading
bodies to CCP have greater specificity and can help establish causes of chronic polyarthritis.
the diagnosis in the proper clinical context. Testing for HLA-  Careful delineation of the joints involved, particularly in
B27 has usefulness in certain circumstances.
the hands, can help point to the correct diagnosis.

B. Imaging Studies
Radiographs can be of considerable value. An experienced
radiologist or rheumatologist often can distinguish among
the erosions of the spondyloarthropathies, rheumatoid
arthritis, and gout. Radiographic demonstration of sacroili-
itis points to a spondyloarthropathy and narrows the differ-
ential diagnosis considerably.
 Initial Clinical Evaluation
Rheumatoid arthritis is the leading cause of chronic inflam-
matory polyarthritis, and osteoarthritis is the most com-
mon cause of chronic noninflammatory polyarthritis.
Nonetheless, polyarthritis that persists for weeks or more
has many possible etiologies and warrants careful diagnostic
 34 CHAPTER 4

SLE, drug-induced lupus, and chronic hepatitis C is usually

Table 4–10. Differential diagnosis of chronic polyarthritis. nonerosive and does not produce characteristic radiographic
findings.
Inflammatory Polyarthritis Noninflammatory Polyarthritis
Common
Rheumatoid arthritis Primary generalized  Differential Diagnosis
osteoarthritis
Osteoarthritis and rheumatoid arthritis have different pat-
Systemic lupus erythematosus Hemochromatosisa terns of joint involvement in the hand. Osteoarthritis involves
Spondyloarthropathies Calcium pyrophosphate the distal interphalangeal (DIP) and PIP joints and the first
(especially psoriatic arthritis) deposition diseasea carpometacarpal joint. Rheumatoid arthritis, in contrast,
Chronic hepatitis C infection involves the PIP and MCP joints and the wrists.
Gout Osteoarthritis and rheumatoid arthritis typically spare
Drug-induced lupus syndrome certain joints. Osteoarthritis usually does not involve the
Uncommon or rare MCP joints, wrists, elbows, glenohumeral joints, and ankles;
degenerative arthritis of these joints raises the possibility of
Paraneoplastic polyarthritis
antecedent trauma, calcium pyrophosphate deposition dis-
Remitting seronegative symmetric
polyarthritis with pitting edema
ease, underlying osteonecrosis, or neuropathic arthropathy.
Adult-onset Still disease Rheumatoid arthritis usually spares DIP joints, the thoracic
Systemic autoimmune diseases and and lumbosacral spine, and sacroiliac joints.
vasculitides In generalized osteoarthritis, interphalangeal joints, par-
Sjögren syndrome ticularly the DIPs, may appear to be inflamed (“inflammatory
Viral infections other than hepatitis C osteoarthritis”) and thus cause some diagnostic uncertainty.
Whipple disease Radiographs, however, usually show typical degenerative
a
Degenerative changes are seen on radiographs; can cause flares changes (irregular joint-space narrowing, sclerosis, and
with inflammatory synovial fluid. osteophytes). Psoriatic arthritis also commonly involves the
DIP joints, usually with radiographic changes distinct from
those of osteoarthritis. Psoriatic changes of the fingernail
evaluation (Table 4–10). As is the case with other forms of on the same digit often occur concomitantly with psoriatic
arthritis, the distinction between inflammatory and nonin- involvement of a DIP joint.
flammatory processes is critical.

A. Laboratory Evaluation
Table 4–11. Clinical findings and their associated
If arthrocentesis is feasible, synovial fluid should be obtained
diagnoses that can mimic chronic rheumatoid arthritis.
and sent for cell count and analysis for crystals. Routine labo-
ratory investigations (complete blood cell count, serum elec- Clinical Finding Examples of Associated Diagnoses
trolytes and creatinine, and urinalysis) should be done. If the Arthritis with Spondyloarthropathies, especially
process appears inflammatory, studies also should include radiographic erosions psoriatic arthritis
determinations of the ESR or CRP and tests for serum rheu- Gout
matoid factor, anti-CCP antibodies, ANA, and hepatitis B
Arthritis with positive Chronic hepatitis C infection
and C infection.
rheumatoid factor Systemic lupus erythematosus
Sarcoidosis
B. Imaging Studies Systemic vasculitides
Radiographs are indicated in most cases of chronic polyar- Polymyositis/dermatomyositis
Subacute bacterial endocarditis
thritis of the hand. Radiographs of the hand usually show
characteristic changes at the time of presentation of primary Arthritis with nodules Chronic tophaceous gout
generalized osteoarthritis, hemochromatosis, calcium pyro- Granulomatosis with polyangiitis (formerly
phosphate deposition disease, and chronic tophaceous gout. Wegener granulomatosis)
In cases of rheumatoid arthritis and the spondyloarthropa- Eosinophilic granulomatosis with polyangiitis
(Churg-Strauss syndrome)
thies, however, the likelihood of radiographic joint erosions
Hyperlipoproteinemia (rare)
and other characteristic findings increases with the duration Multicentric reticulohistiocytosis (rare)
of the polyarthritis; hand radiographs may be normal or
demonstrate nonspecific changes only, for months or lon- Arthritis of Hemochromatosis
ger. Radiographs of the feet can reveal rheumatoid erosions metacarpophalangeal Calcium pyrophosphate
joints and/or wrists deposition disease
even when hand films are unrevealing. The polyarthritis of
 APPROACH TO THE PATIENT WITH ARTHRITIS
Many diseases can mimic rheumatoid arthritis, but sev-
eral warrant particular emphasis (Table 4–11). Features that
distinguish rheumatoid arthritis and the spondyloarthropa-
thies are discussed above. Chronic infection with hepatitis C
can produce a symmetric polyarthritis and a positive test for
rheumatoid factor (but not for anti-CCP antibodies). The
polyarthritis of SLE is nonerosive but can lead to reducible
“swan neck” deformities of the fingers. On occasion, chronic
tophaceous gout is a remarkable mimic of rheumatoid arthri-
tis, with tophi mistaken for rheumatoid nodules. Gout is not
associated with rheumatoid factor (virtually all cases of nod-
ular rheumatoid arthritis are seropositive), and the erosions
of gout and rheumatoid arthritis have different radiographic
characteristics. Analysis of synovial fluid for urate crystals is
the definitive diagnostic test. Hemochromatosis and other
35
causes of calcium pyrophosphate deposition disease lead to
arthritis of the MCPs (especially the second and third) and
wrists; radiographs often reveal “hook-like” osteophytes of
the MCPs and degenerative changes, usually with chondro-
calcinosis, of the wrist.
Although rheumatoid arthritis is the leading cause of
chronic inflammatory polyarthritis, physicians must be cer-
tain that rheumatoid arthritis accounts for the full clinical
picture. Rheumatoid arthritis is not a plausible explanation
for the following: fever >38.3°C, substantial weight loss,
significant adenopathy, rashes (apart from subcutaneous
nodules), hematuria, and proteinuria. Failure to account for
these additional clinical findings can lead to a failure to diag-
nose SLE, Still disease, subacute bacterial endocarditis, para-
neoplastic syndromes, vasculitides, and the like.