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RHEUMATOLOGY BOARD REVIEW MANUAL
PUBLISHING STAFF
PRESIDENT, PUBLISHER
Bruce M.White
Synovial Fluid Analysis and
Synovial Biopsy
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Debra Dreger
EDITOR
Bobbie Lewis
ASSOCIATE EDITOR
Robert Litchkofski
Series Editor:
Janet F. Burkholder, MD
Assistant Professor of Medicine
Associate Chief, Section of Rheumatology
Temple University School of Medicine
Philadelphia, PA
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Author:
Sharon L. Kolasinski, MD
Assistant Professor of Medicine, Division of Rheumatology
University of Pennsylvania School of Medicine
Philadelphia, PA
Table of Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
ADVERTISING/PROJECT MANAGER
Patricia Payne Castle
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medical education as they affect residency programs and clinical hospital practice.
Acute Polyarticular Arthritis. . . . . . . . . . . . . . . . 2
Acute Monarticular Arthritis . . . . . . . . . . . . . . . 6
Crystal-Induced Arthritis . . . . . . . . . . . . . . . . . . 9
Chronic Monarthritis . . . . . . . . . . . . . . . . . . . . 10
Pearls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Suggested Readings . . . . . . . . . . . . . . . . . . . . . 12
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Rheumatology Volume 4, Part 3 1
®
RHEUMATOLOGY BOARD REVIEW MANUAL
Synovial Fluid Analysis and Synovial Biopsy
Series Editor:
Janet F. Burkholder, MD
Author:
Sharon L. Kolasinski, MD
Assistant Professor of Medicine
Associate Chief
Section of Rheumatology
Temple University School of Medicine
Philadelphia, PA
Assistant Professor of Medicine
Division of Rheumatology
University of Pennsylvania School of Medicine
Philadelphia, PA
INTRODUCTION
Arthritis results from nearly 100 different diseases,
many of which can be readily distinguished based on the
appearance of the synovial fluid, or synovia, obtained
from affected joints. In certain circumstances, biopsy of
the synovium can provide diagnostic information that
cannot otherwise be ascertained. Frequently, examination of the fluid or tissue from a joint can confirm a clinical suspicion and lead to important management decisions. Learning when to perform synovial fluid or tissue
analysis is critical to appropriate decision making in
patients with arthritis.
ACUTE POLYARTICULAR ARTHRITIS
INITIAL PRESENTATION
A 22-year-old student is referred by her primary care
physician for evaluation of symmetric polyarticular
arthritis.
LABORATORY EVALUATION
The physician had ordered rheumatoid factor (RF)
and antinuclear antibody tests, an erythrocyte sedimentation rate (ESR), hepatitis serologies, and a chest radiograph after documenting joint swelling in both wrists
and in multiple metacarpophalangeal (MCP) joints for
2 Hospital Physician Board Review Manual
more than 6 weeks. The RF was positive at a high titer,
and the ESR was 88 mm/hr. Results of other tests were
within normal limits.
• What are possible diagnoses in a patient with polyarticular symptoms?
• What is the approach to the patient with polyarticular arthritis?
• Should synovial aspiration be performed in this
patient?
DISCUSSION
Differential Diagnosis
The diagnostic possibilities with a polyarticular presentation are numerous. In an acute presentation, the
gamut of possible causes of polyarthritis must be considered (eg, rheumatoid arthritis, systemic lupus erythematosus [SLE], the seronegative inflammatory
arthritides). Although involvement of multiple tendons and/or bursae in the absence of true joint symptoms would be unusual, such involvement could herald
the onset of a seronegative arthritis, an overuse syndrome, or quinolone-associated polytendinitis. Other
disorders that might be considered in the differential
diagnosis are disseminated gonococcal infection, inflammatory myopathies or other muscle disorders, the
vasculitides, peripheral vascular disease (including in
the setting of Raynaud’s phenomenon, atherosclerosis,
or diabetes), fibromyalgia, diseases of bone, and neuropathies. Chronic pain syndromes, particularly in the
Synovial Fluid Analysis and Synovial Biopsy
presence of depression, and malingering also enter the
differential.
Approach to the Patient
The history is critical when deciding if the patient
with a polyarticular complaint requires arthrocentesis.
The initial question is whether the symptoms arise from
the joint or from surrounding structures. A systematic
investigation regarding the type and location of pain
can help answer this question and distinguish the diagnostic possibilities. Questioning should focus on which
joints are involved, the circumstances under which pain
occurs, including precipitating, aggravating, and ameliorating factors, and the course and progression of
symptoms. Past medical history of the patient should
include discussion of prior episodes of joint symptoms
or any illness immediately antedating the current presentation. Social history should include a discussion of
recent sexual activity. Family history of rheumatic diseases should also be obtained.
A complete physical examination with a full joint evaluation is essential. Particular attention should be paid to
the skin, eyes, mucous membranes, cardiovascular system
(including the peripheral pulses), and nervous system.
The joint examination involves assessment for warmth,
erythema, swelling, tenderness, and active and passive
range of motion of each joint, and a thorough evaluation
of the spine. The absence of inflammation on physical
examination in the patient with a polyarticular presentation should raise additional diagnostic possibilities,
including osteoarthritis of the hands, primary generalized
osteoarthritis, or osteoarthritis related to the presence of
metabolic disorders (eg, hemochromatosis, calcium pyrophosphate deposition, hypothyroidism, ochronosis, acromegaly, and hemophilia).
In this case, the patient meets the criteria for
rheumatoid arthritis, and the 2 entities most likely to be
confused with rheumatoid arthritis have been eliminated by the normal hepatitis serologies and chest radiograph (evaluation for sarcoidosis). Therefore, synovial
fluid aspiration is not needed to make the diagnosis;
however, when large joints are especially symptomatic,
aspiration and injection with a corticosteroid provides
quick relief and restoration of function.
FURTHER CLINICAL COURSE
At diagnosis, the wrists and multiple proximal interphalangeal and MCP joints are involved in both hands.
Shortly thereafter, the patient develops pain and
swelling in the ankles, and over the next 20 years a number of other joints become involved. Approximately
3 years ago, the right knee developed a large effusion
and was treated with an intra-articular steroid injection.
The knee responded promptly but incompletely to the
injection and has been intermittently symptomatic ever
since.
Presently, the patient is being treated with hydroxychloroquine, methotrexate, and low-dose glucocorticoids and has moderately well-controlled disease. However, approximately 3 days ago, she noted the onset of
increased pain and swelling in the right knee. The symptoms gradually worsened and were associated with
warmth of the joint. The left wrist and right ankle became more painful and swollen as well. The patient
found it increasingly difficult to ambulate. She had felt
warm then chilled the previous evening but did not take
her temperature. She presents to her rheumatologist’s
office for urgent evaluation the next morning.
PHYSICAL EXAMINATION
On physical examination, the patient is normotensive with a heart rate of 110 bpm. Her oral temperature
is 99.0° F, and she appears uncomfortable at rest due to
knee pain. Joint examination shows some mild synovial
swelling at multiple MCP joints, moderate swelling and
tenderness at the left wrist and right ankle, and a large,
tense effusion of the right knee. The knee is warm and
mildly erythematous but without evidence of cellulitis,
and there is some restriction in its range of motion.
Multiple chronic deformities are present in the small
joints of the hands.
• What are possible diagnoses at this point?
DISCUSSION
With the diagnosis of rheumatoid arthritis already
established, one possibility is a polyarticular flare of disease. However, the circumstances of the presentation
suggest that a further look should be taken. The relatively abrupt onset of symptoms with a small number of
joints asymmetrically involved out of proportion to the
background chronic synovitis, particularly in the setting
of low-grade fever, suggest septic arthritis as a possibility. Because septic arthritis is a medical emergency, joint
aspiration and synovial fluid analysis should be performed promptly if it is suspected. Most often the disease is monarticular, affecting knees about half the
time; other joints commonly affected include the hip,
shoulder, wrist, ankle, and elbow. Risk factors for infection include young or older age, concurrent systemic
disease (including rheumatoid arthritis, SLE, chronic
liver disease, diabetes mellitus, malignancy, and sickle
cell anemia), presence of prosthetic joints, prior arthrocentesis, and injection drug use.
Rheumatology Volume 4, Part 3 3
Synovial Fluid Analysis and Synovial Biopsy
In this case, synovial fluid analysis is the most reliable
method for differentiating between infection and a polyarticular flare of rheumatoid arthritis. A complete blood
count and ESR may be useful, but they cannot discriminate between infection and inflammation.
• What are the clinical indications for arthrocentesis
and synovial fluid analysis?
• How is arthrocentesis of the knee performed?
Indications for Synovial Analysis
Joint fluid examination can be reasonably performed
as part of the initial diagnostic evaluation of any patient
presenting with joint complaints. It is most appropriate
in patients with a new, acute monarticular presentation
but is also useful in patients with polyarticular presentations or with known joint disease. Synovial fluid directly
reflects the pathology in the joint of interest and therefore is often a valuable adjunct to other diagnostic tests.
The results of laboratory evaluation of blood for RF, antinuclear antibodies, and uric acid levels can be misleading; adding synovial fluid analysis to the diagnostic workup may clarify their interpretation.
In the patient with an acute onset of symptoms, synovial fluid analysis can be used to definitively diagnose a
number of common diseases, such as gout, pseudogout, and septic arthritis. If the acute presentation is
monarticular, synovial fluid analysis will be critical in differentiating the diagnostic possibilities and should always be performed if septic arthritis is a consideration.
Even when the results are not diagnostic, fluid analysis
can be very helpful in distinguishing between inflammatory and noninflammatory causes of new symptoms.
In patients with a less acute presentation, synovial fluid
analysis may definitively identify a variety of more indolent conditions (eg, fungal and mycobacterial infection). In patients with established joint disease, it can
distinguish between flares of known disease and the
occurrence of new or previously undiagnosed conditions. Examples include the presence of calcium pyrophosphate crystals in an osteoarthritic joint or the presence of infection in a joint involved with rheumatoid
arthritis.
The choice of which joint to aspirate in monarticular disease is obvious. If the presentation is polyarticular,
the most symptomatic joint should be aspirated. If
more than one joint appears to be involved in the acute
process and if their degree of involvement seems equivalent, the size of the joint can be taken into consideration. Larger joints are more accessible and thus more
likely to yield a diagnostic result. In general, arthrocentesis should be performed on any joint that seems to be
4 Hospital Physician Board Review Manual
involved out of proportion to other joints on physical
examination.
Arthrocentesis of the Knee
The physician performing an arthrocentesis should
be thoroughly familiar with the anatomy of the joint to
be aspirated. The knee is the easiest joint to aspirate and
is the most frequently aspirated joint. Synovial effusion
of the knee joint can be detected by a number of methods. Gross inspection may readily reveal large effusions,
since the usual medial concavity may not be present.
However, special maneuvers may be required to detect
smaller effusions. The bulge sign may be elicited as follows: with the patient supine, fully extend the knee;
press the soft tissue over the medial aspect of the knee to
push any fluid laterally; then, press the lateral aspect of
the knee with the thumbs and observe the medial side
for the presence of a fluid wave or bulge. Alternatively,
ballottement may be attempted. This maneuver is particularly helpful when effusions are too large to permit a
bulge sign. In this technique, the fingers of one hand are
placed along the medial and lateral aspects of the patella and the patella is firmly compressed posteriorly
against the tibiofemoral joint with the other hand. The
fingers alongside the patella may be pushed outward as
fluid is displaced medially and laterally, and the patella
may produce a click as it strikes the underlying bone.
Once the knee is identified as an appropriate joint
for aspiration, the needle may be inserted medially or
laterally. The medial approach may more reliably yield
fluid when the effusion is small. The midpoint of the
patella should be identified and the needle inserted parallel to the floor and under the patella. In the lateral
approach, the needle is inserted at the cephalad border
of the patella, again parallel to the floor. Once the
appropriate landmarks are identified, make an indentation in the skin with the retracted tip of a ballpoint pen
to mark the location at which the needle will be inserted. The indentation will remain, and the skin can then
be sterilely prepared and the needle inserted. As with all
procedures involving bodily fluids, gloves should always
be worn during the aspiration of synovia.
• What tests should be performed as part of synovial
fluid analysis?
• How is synovial fluid classified?
DISCUSSION
Synovial Fluid Analysis
Gloves should be worn at all times while examining
synovial fluid. Gross examination of normal synovial
fluid shows that it is clear and transparent and has a high
Synovial Fluid Analysis and Synovial Biopsy
viscosity (synovia literally means “like egg [white]”).
Viscosity can be assessed by the “string test.” In this
manipulation, the synovial fluid is slowly expressed from
the syringe or a few drops are manipulated between the
gloved thumb and forefinger. Fluid of normal viscosity
will stretch intact to a length of 1 to 2 inches. Although
viscosity is among the characteristics upon which we
judge synovial fluid as normal, it is not a completely reliable predictor. Similarly, the utility of the mucin clot test
is limited, given the wide availability of rapid and reliable
cell counts. The mucin clot test involves adding a few
drops of synovial fluid to 20 mL of 5% acetic acid. The
mixture is observed for the formation of a firm mass that
does not fragment on shaking. This reflects the normal
integrity of hyaluronic acid.
Microscopic examination of the fluid for inflammatory cells is the most important test for classifying synovial
fluid; the most useful test for diagnosing inflammation is
the cell count. Microscopic examination requires making a wet preparation of joint fluid by placing 1 or 2 drops
on a clean glass slide and covering it with a glass cover
slip. Cleaning slides with lens paper should be avoided
because it can introduce confusing birefringent fibrils
onto the slide. Similarly, allowing the fluid to dry can create birefringent artifacts. The fluid should first be examined using the low-power lens of a regular light microscope. This should be followed by an examination using
a compensated polarized light microscope, since even
joint fluid without an abnormal number of white blood
cells (WBCs) may reveal birefringent crystals. In normal
joint fluid, red blood cells should be absent and there
should be no more than 200 WBCs/mm3. Cell count is
critical to the initial diagnosis and subsequent management of infectious arthritis. Fluid should always be sent
for routine bacterial culture if infection is within the differential; normal synovial fluid will be sterile.
A variety of special stains may be used to detect the
presence of less commonly identified crystals as well as
infectious agents (Table 1).
Classification
The classification of synovial fluid into 4 groups is
outlined in Table 2. This classification system was first
proposed in the 1950s and distinguished between noninflammatory and inflammatory fluid; it has subsequently been modified to include a separate category
for fluid characteristic of septic arthritis (Group III).
Normal joint fluid is an ultrafiltrate of plasma with relatively few large macromolecules to which the synovial
lining cells have added hyaluronic acid. It is sufficient
in volume to coat the normal folds of the synovial
Table 1. Special Stains for Joint Fluid
Stain
Finding
Alizarin red S
Hydroxyapatite crystals and other
calcium- and phosphate-containing
crystals
Sudan black III
Lipid droplets
Congo red
Amyloid
Prussian blue
Iron deposits in phagocytic cells in
hemochromatosis, pigmented villonodular synovitis, recurrent hemarthrosis
Gram stain
Gram-positive and gram-negative bacteria
Acridine orange
Fluorescent bacteria, including Borrelia
Ziehl-Neelsen
Acid-fast bacteria
Adapted with permission from Gatter RA, Schumacher HR: A Practical
Handbook of Joint Fluid Analysis, 2nd ed. Philadelphia: Lea & Febiger, 1991.
membrane but in the normal joint does not distend
the joint. Therefore, aspiration of normal joints should
yield only a small volume of fluid. Even a large joint
like the knee is expected to have less than 3.5 mL of
synovia.
Noninflammatory joint fluid is seen in a variety of
arthritides, including osteoarthritis. It is generally increased in volume and has a modestly increased WBC
count (200 to 2000/mm3) compared with normal joint
fluid. The color of noninflammatory fluid ranges from
straw-colored to yellow, but it remains transparent
enough to read newsprint through. Culture should be
negative.
Inflammatory joint fluid is characteristic of numerous
systemic rheumatologic disorders and other medical disorders, including some infections (Table 3). Typically, inflammatory joint fluid is increased in volume. Its viscosity
is usually reduced due to the rapidity of the increase in
volume and a reduction in the quantity of hyaluronate.
Inflammatory fluid is straw-colored to yellow and is not
transparent enough to read through. However, microscopy is required to ensure that the opacity of the fluid is
due to the accumulation of WBCs. Synovial fluid may
appear opaque due to the presence of large amounts of
crystals, lipids, fibrin, or amyloid. Inflammatory synovia
results in a friable mucin clot, reflecting the dilution and
destruction of hyaluronate. The number of WBCs present may be moderately elevated but may rival the cell
counts of septic fluid, with up to 100,000/mm3. Often,
more than half of the WBCs present are neutrophils.
Culture should again be negative.
Rheumatology Volume 4, Part 3 5
Synovial Fluid Analysis and Synovial Biopsy
Table 2. Classification of Synovial Effusions
Characteristics
Normal
Noninflammatory
(Group I)
Inflammatory
(Group II)
Septic
(Group III)
Volume (knee), mL
< 3.5
Often > 3.5
Often > 3.5
Often > 3.5
Viscosity
High
High
Low
Variable
Color
Clear
Straw to yellow
Yellow
Opaque
Mucin clot
Firm
Firm
Friable
Friable
Cells per mm3
< 200
200 to 2000
2000 to 100,000
Often > 100,000
< 25
< 25
Often > 50
> 75
Negative
Negative
Negative
Often positive
Neutrophils, %
Culture
Adapted with permission from Gatter RA, Schumacher HR: A Practical Handbook of Joint Fluid Analysis, 2nd ed. Philadelphia: Lea & Febiger, 1991.
Septic synovial fluid is similar to inflammatory fluid,
but the culture is usually positive. The presence of a
negative culture does not completely rule out septic
arthritis, and if septic arthritis remains the most likely
diagnosis based on clinical features the patient should
be treated presumptively with antibiotics. Infected
joints will have an increased volume of synovial fluid,
but the fluid’s viscosity will vary. The viscosity may be
reduced due to the increase in volume and the reduction in hyaluronate content or may be increased due to
the large number of WBCs. Color will vary from yellow
to purulent white or gray and will be opaque. The
mucin clot will be friable, and the WBC count will be
high (often > 100,000/mm3) and composed mostly of
neutrophils (> 75%).
DIAGNOSIS AND PATIENT COURSE
Arthrocentesis of the right knee is performed after
sterile preparation of the skin. Aspiration yields 50 mL
of cloudy, yellowish-white synovia. Numerous WBCs per
high-power field are observed on microscopic examination. Cell count reveals 70,000 WBCs/mm3, 80% of
which are neutrophils. No crystals are seen. On Gram
stain, numerous gram-positive cocci are identified, and
routine bacterial culture grows out Staphylococcus aureus.
Subsequent synovial specimens aspirated from the left
wrist and right ankle also grow S. aureus. The patient is
admitted to the hospital for intravenous antibiotics and
serial joint drainage. By the third hospital day, the WBC
count from the knee aspirate has declined dramatically,
and there is no fluid to be obtained from the wrist. The
patient is discharged to home with arrangements for
6 weeks of antibiotic therapy.
6 Hospital Physician Board Review Manual
ACUTE MONARTICULAR ARTHRITIS
INITIAL PRESENTATION
A 21-year-old college athlete presents with a subacute
onset of discomfort in his right knee.
HISTORY
The patient has been active in track-and-field events
since high school but has concentrated on longdistance running since entering the university. He has
recently been training to enter the New York City
Marathon but has had no clear episode of trauma. He was
participating in his usual schedule of strength-training
and running when he noted intermittent discomfort in
his right knee. On further questioning, it becomes
apparent that he is experiencing pain in a variety of
joints on a migratory basis. The right ankle will be achy
one day, and then the left shoulder will be bothersome
several days later. However, the right knee seems to have
been more consistently involved over the past 10 days,
and the increasing pain is associated with some warmth
and a sensation of swelling. The patient is concerned
that he might be developing shin splints because he has
been experiencing bone pain in the lower extremities.
Ibuprofen has been helpful in relieving his symptoms,
but he is worried about his ability to perform in the
upcoming marathon.
The patient has not noted fever, rash, eye symptoms,
back pain, diarrhea, urethral discharge, dysuria, prior
infection, or Lyme disease exposure. He has no family
history of rheumatic disease.
Synovial Fluid Analysis and Synovial Biopsy
PHYSICAL EXAMINATION
On physical examination, the patient has normal vital
signs, including a temperature of 98.6°F. Examination of
the skin is unremarkable, with no erythema over the
joints. The joint examination is within normal limits
except for the presence of a positive bulge sign at the
right knee and a minimal increase in warmth. However,
the patient is quite apprehensive about having his knee
examined and appears to have pain out of proportion to
the physical findings of the joint examination.
Table 3. Disorders Resulting in Inflammatory Joint
Fluid
Rheumatic diseases
Rheumatoid arthritis
Sjögren’s syndrome
Palindromic rheumatism
Juvenile chronic arthritis
Rheumatic fever
Systemic lupus erythematosus
• What is the approach to the patient with monarticular arthritis?
• What diagnoses should be considered?
Scleroderma
Polymyositis
Polychondritis
DISCUSSION
Approach to the Patient
The differential diagnosis of acute monarticular
arthritis is broad and encompasses numerous causes of
inflammatory arthritis and infectious diseases (Table 4).
The approach to the patient should include a complete
history and physical examination; however, in a previously healthy individual the list of potential diagnoses
can be considerably shortened by the use of joint aspiration and synovial fluid examination. Synovial fluid
analysis distinguishes between inflammatory and noninflammatory causes of monarticular arthritis, which
could lead to substantially different diagnostic evaluations. The initial decision regarding whether to aspirate
the joint will take into account whether there is joint
involvement or periarticular disease. The physician will
need to localize the anatomic site of the abnormality in
the patient presenting with pain in a specific region.
History. During the history, the physician should ascertain as precisely as possible what kind of discomfort the
patient is experiencing, for how long, and under what circumstances. Distinguishing between joint and periarticular involvement may be aided by a history of morning stiffness or gelling more likely to accompany joint pathology.
Attention should be paid to a history of occupational or
recreational overuse. History-taking should include careful review of symptoms in other joints to establish that the
current presentation is truly monarticular. Constitutional
signs and symptoms should be sought as well. In particular, a history of fever, chills, or rigors or risk factors for
infections should be elicited.
If symptoms are abrupt in onset (hours to 1 week)
and if there is no history of trauma, infection and crystal-induced arthritis should be considered. In addition,
the possibility of a compartment syndrome needs to be
eliminated; such syndromes can occur in the setting of
trauma, infection, or hemorrhage. Immediate diagnosis
Polymyalgia rheumatica
Vasculitis
Behçet’s syndrome
Seronegative spondyloarthropathies
Crystal-induced disease
Multisystem diseases
Goodpasture’s syndrome
Familial Mediterranean fever
Sarcoidosis
Multicentric reticulohistiocytosis
Infectious diseases
Whipple’s disease
Parasitic infections
Viral infections (eg, hepatitis, mumps, rubella)
Fungal infections
Mycoplasma infections
Bacterial infections (eg, Staphylococcus, gonococcus)
Mycobacterial infections
Spirochetal infections with Treponema, Borrelia
Acute bacterial endocarditis
Other conditions
Erythema nodosum
Erythema multiforme (Stevens-Johnson syndrome)
Carcinoid
Hyperlipidemias
Serum sickness
Agammaglobulinemia
Leukemia
Adapted with permission from Schumacher HR: Synovial fluid analysis
and synovial biopsy. In Textbook of Rheumatology, 5th ed. Kelley WN,
Harris ED, Ruddy D, Sledge CB, eds. Philadelphia:WB Saunders, 1997.
Rheumatology Volume 4, Part 3 7
Synovial Fluid Analysis and Synovial Biopsy
Table 4. Causes of Monarticular Arthritis
Inflammatory
Crystal-induced arthritis
Monosodium urate (gout)
Calcium pyrophosphate (pseudogout)
Hydroxyapatite
Calcium oxalate
Cholesterol
Infectious arthritis
Bacteria (Staphylococcus, gonococcus)
Mycobacteria
Fungi
Spirochete (ehrlichiosis, Lyme disease)
Virus (hepatitis B, HIV, parvovirus)
Monarticular presentation of systemic disease
Enteropathic arthritis (bypass arthritis, inflammatory
bowel disease)
Henoch-Schönlein purpura
Juvenile chronic arthritis
Psoriatic arthritis
Reactive arthritis
Relapsing polychondritis
Rheumatic fever
Rheumatoid arthritis
Sarcoidosis
Still’s disease
Systemic lupus erythematosus
Noninflammatory
Amyloidosis
Avascular necrosis of bone
Benign neoplasm
Osteochondroma
Osteoid osteoma
Pigmented villonodular synovitis
Foreign body
Fracture
Hemarthrosis (trauma, coagulopathy, anticoagulation
therapy)
Intermittent hydrarthrosis
Internal derangement, loose body
Malignant neoplasm (primary, metastatic)
Neuropathic
Osteoarthritis
Osteochondritis desiccans
Paraneoplastic syndromes
Pulmonary hypertrophic osteoarthropathy
Reflex sympathetic dystrophy
8 Hospital Physician Board Review Manual
is essential because surgical intervention may be
required. An additional consideration when symptom
onset is abrupt is avascular necrosis. When the history
includes the presence of long-standing joint disease, it is
important to distinguish an exacerbation of preexisting
disease from a new condition.
If symptoms are intermittent rather than constant,
consideration should be given to internal derangement
of the joint or the presence of a loose body. Under these
circumstances, there may be a history of clicking, locking,
or giving way of the joint. It is important to remember
that internal derangement can occur in a setting of
degenerative or inflammatory arthritis as well as result
from trauma. Intermittency of symptoms unrelated to
patterns of use, especially with a history of fluctuations in
pain and swelling, prolonged morning stiffness, and
gelling suggest an inflammatory disorder. Symptoms
exacerbated by use, improved by rest, and involving
weight-bearing joints suggest a mechanical disorder.
If pain is radiating, poorly localized, or described in
the distribution of a peripheral nerve, consideration
should be given to compression or irritation of peripheral nerves, including radiculopathy. The presence of
bone pain should alert the physician to the possibility of
a periosteal or marrow involvement by a disease process.
Malignancy must be ruled out, including hematologic
malignancies, primary bone tumors, and metastases.
Other conditions in the differential diagnosis include
fractures, osteomyelitis, hemoglobinopathies, and infiltrative diseases such as Paget’s disease of bone.
Physical examination. During the physical examination, a search should be made for the presence of periarticular involvement. The possibility of bursitis, tendinitis, strains, sprains, or soft tissue infection should be
considered. Findings localized to one side of the joint as
well as local tenderness and more pain on active rather
than passive range of motion can indicate the presence
of bursitis or tendinitis. Abnormalities in the joint should
be detectable during both active and passive range of
motion. Particularly, when considering olecranon or
prepatellar bursitis, the assessment of range of motion is
imperative. The range of motion will tend to be greater
in the presence of soft tissue inflammation than in septic
arthritis or a similar degree of soft tissue swelling. It is
important to note the contralateral joint and surrounding structures to help establish the baseline for the individual patient. If tendinitis is found, it is important to
remember that in addition to trauma, disseminated
gonococcal infection can cause isolated tendinitis.
The presence of an effusion will almost always indicate the presence of intra-articular pathology, but an
effusion may not always be obvious until arthrocentesis
Synovial Fluid Analysis and Synovial Biopsy
is performed. Uncommonly, a noninflammatory effusion may be the result of a periarticular syndrome with
a sympathetic effusion.
JOINT ASPIRATION AND SYNOVIAL FLUID EXAMINATION
Arthrocentesis of the right knee is performed after
sterile preparation of the skin. Twenty mL of strawcolored, slightly turbid fluid is obtained. On gross examination, the viscosity is high. Microscopic examination
reveals 10,000 WBCs/mm3; most are neutrophils, but
some appear to be morphologically unusual. Subsequent evaluation of the fluid by the hematology laboratory reveals the presence of leukemic cells. A diagnosis of acute leukemia is confirmed upon review of the
peripheral blood smear.
joint problems. His medical history includes a diagnosis
of hypertension for the preceding 12 years. Medications
include furosemide. On a routine executive health
screening a decade ago, the patient had been told by
his physician that he had a high uric acid level. There is
a family history of gout in the patient’s father and an
older brother. The patient’s usual alcohol intake is less
than 1 drink per week.
• How often do musculoskeletal symptoms occur with
leukemia?
PHYSICAL EXAMINATION
The patient is normotensive but has a heart rate of
120 bpm and a temperature of 99.9°F. He is experiencing chills. Physical examination is unremarkable except
for the presence of localized erythema, warmth, and
swelling over the right first MTP joint. The joint is
exquisitely tender to the touch, and the patient withdraws his foot when the physician attempts to move the
joint through a range of motion.
DISCUSSION
Musculoskeletal symptoms are associated with
leukemias most often in children with acute or chronic
lymphocytic leukemia but also occur in up to 13.5% of
adults with the disease. Involvement is most often characterized by an asymmetric polyarthritis that can be
additive or migratory, but a rheumatoid-like picture
with polyarthritis of numerous small joints can be seen
about one-third of the time. Knees, ankles, and shoulders are most frequently involved.
JOINT ASPIRATION
Arthrocentesis of the right first MTP joint is performed under sterile conditions. Two drops of cloudy
synovial fluid are obtained. The procedure causes the
patient considerable discomfort. Microscopic examination of the joint fluid reveals numerous WBCs and
intracellular and extracellular rod-shaped, negatively
birefringent crystals, some piercing through the many
neutrophils present (Figure 1). One drop of fluid is
sent for bacterial culture and sensitivity.
• What is the diagnosis?
CRYSTAL-INDUCED ARTHRITIS
INITIAL PRESENTATION
A 51-year-old executive on a business trip is brought
to the local infirmary with a complaint of severe pain in
the right great toe.
HISTORY
The patient awoke in the middle of the night with
abrupt onset of severe pain in the right first metatarsophalangeal (MTP) joint. Over the next few hours, the
pain became increasingly severe to the point that the
patient could not tolerate the weight of the sheet on his
foot. The base of the toe became visibly red and
swollen. It was difficult for him to walk to the phone to
call the concierge for assistance. That evening before
retiring to bed, he had enjoyed a 6-course meal accompanied by 3 different wines at a local restaurant.
There is no prior history of trauma. He has not had
any recent sexual contacts. He has no prior history of
DISCUSSION
Gout
Crystal-induced arthritis is one of the most common
reasons for an acute monarticular presentation. Usually
it is easily identified on microscopic synovial fluid analysis. In gout, the crystals are rod-shaped and negatively
birefringent (yellow when parallel to the axis of the
compensator and viewed under a polarizing microscope) (Figure 2). In pseudogout, the crystals tend to
be more difficult to identify, thicker, more irregularly
shaped, and positively birefringent (blue when parallel
to the axis and viewed under polarizing conditions)
(Figure 3).
Making a distinction between crystal-induced arthritis and infection is one of the most important uses of
arthrocentesis. Historical information that suggests
that gout is likely in this case includes the antecedent history of asymptomatic hyperuricemia, which
may be present for many years, the family history,
recent alcohol consumption, and dietary indiscretion.
Rheumatology Volume 4, Part 3 9
Synovial Fluid Analysis and Synovial Biopsy
A
B
C
D
A
B
Figure 1. (A) Monosodium urate crystals viewed under polarized light. The needle-shaped crystal is brightly birefringent and
yellow when parallel to the axis of the polarizer. (B) Under ordinary light, the large crystal is more difficult to see and the smaller crystal is not visualized.
Figure 3. Chondrocalcinosis. (A) Calcium pyrophosphate dihydrate (CPPD) crystal viewed with polarizer and (B) under ordinary light. (C) CPPD crystal under polarized light and positioned
parallel to the axis of the polarizer. (D) CPPD crystal positioned
perpendicular to the axis.The crystal is only weakly birefringent.
Consumption of high purine foods (organ meats,
sweetbreads, sardines, herring, mussels, smelts, yeast)
may precipitate a gout attack, but consumption of alcohol is much more frequently a part of the pre-attack
history.
CHRONIC MONARTHRITIS
INITIAL PRESENTATION
A 33-year-old office worker with a 6-month history of
left knee pain that has progressively worsened over
recent weeks is referred to a rheumatologist by his primary care physician.
A
B
C
Figure 2. Three views of a urate crystal demonstrating the
change in color when the crystal is rotated 90°. (A) When perpendicular to the axis of the polarizer, the crystal is bright blue.
(B) Extinction of birefringence. (C) When parallel to the axis, the
crystal is yellow.
10 Hospital Physician Board Review Manual
HISTORY
The patient was born in Korea and immigrated to the
United States at age 15 years. He has had normal childhood development and has no prior history of illness.
There is a history of tuberculosis in his father that had
been treated when the patient was a child. The patient
Synovial Fluid Analysis and Synovial Biopsy
has no history of prior trauma and does not participate
in regular physical exercise. He noted a gradual onset of
discomfort in the left knee, without associated warmth
or erythema. The knee has seemed a bit stiff lately, and
prolonged standing is increasingly uncomfortable. No
other joints are symptomatic, and the patient feels well
otherwise.
PHYSICAL EXAMINATION
The patient has normal vital signs. The skin is unremarkable, the lungs are clear, and cardiac examination
reveals no murmur. Joint examination reveals the presence of mild diffuse synovial swelling around the left
knee with a positive bulge sign but without warmth or
erythema.
SYNOVIAL FLUID ANALYSIS AND FURTHER COURSE
Initial evaluation of the patient involves joint aspiration and synovial fluid analysis. Aspiration yields 30 mL
of cloudy yellow fluid with rice bodies evident on gross
inspection. WBC count is 15,000/mm3. Gram stain, initial microscopic evaluation for fungi, and smear for
acid-fast bacilli are negative. Despite the prompt initiation of broad-spectrum antibiotic therapy, daily needle
aspirations of the joint show no diminution in cell
count.
• What are the clinical indications for synovial biopsy?
DISCUSSION
Synovial Biopsy
Synovial biopsy is used to obtain synovial tissue to aid
in the differential diagnosis. It is also used as a research
tool to learn more about the pathophysiology of joint
disease. In clinical practice, synovial biopsy is generally
reserved for those patients in whom synovial fluid analysis and other less invasive investigations have failed to
reveal a diagnosis. This may be the case for several causes of unexplained monarticular inflammatory arthritis,
including a number of infectious arthritides in which
the microorganism responsible is difficult to culture
from synovial fluid. Examples are acute monarticular or
oligoarticular infections with Neisseria and Chlamydia or
chronic monarticular infections with mycobacteria or
fungi. In addition, crystal-induced arthritis will occasionally be identified on examination of synovial tissue
when it has not been obvious on previous examination
of synovial fluid.
Although the histologic findings in unexplained
polyarticular inflammatory arthritis are usually nonspecific, a number of inflammatory conditions may
yield specific enough histopathology to be diagnostic
on synovial biopsy. These include leukemia, Crohn’s
disease, sarcoidosis, multicentric reticulohistiocytosis,
and Whipple’s disease. If these entities are of particular consideration, synovial biopsy is an appropriate
diagnostic choice. Rheumatoid arthritis cannot be
definitively diagnosed by biopsy, but the nonspecific
histologic findings of villous proliferation, superficial
fibrin, a marked increase in synovial lining cells, focal
necrosis, plasma cells, and lymphoid follicles strongly
suggest it. A picture of chronic synovitis can also sometimes be seen in the presence of foreign bodies, such
as plant and animal spines.
The systemic disorders hemochromatosis, amyloidosis, and ochronosis also may yield a characteristic noninflammatory histologic picture. Causes of hemarthrosis can be distinguished, including the presence of
neoplasms (eg, pigmented villonodular synovitis or
osteochondromas), metastatic tumors, and scurvy.
A synovial tissue specimen can be obtained by closedneedle biopsy using a 14-gauge Parker-Pearson needle.
Information that affects clinical management is
obtained about 35% of the time using needle biopsy.
Synovial biopsy is performed most frequently on the
knee, and the route of entry is the same as that for
arthrocentesis. An arthroscopic approach may be taken
and has the advantage of visualizing focally involved tissue. An open surgical approach might be considered if
focal lesions (eg, tumors) or deeper lesions (eg, vasculitis) are being diagnostically entertained.
BIOPSY RESULTS
Synovial biopsy is undertaken in this patient because
there is no improvement in his status despite appropriate conservative management of inflammatory monarticular arthritis. Closed-needle biopsy is performed at
bedside, and histologic examination of tissue obtained
reveals granulomata with caseating necrosis. Cultures of
synovial fluid and synovial tissue eventually grow Mycobacterium tuberculosis.
DISCUSSION
Tuberculosis affects the vertebrae in about half of
the cases of skeletal involvement, especially the thoracolumbar spine. Appendicular tuberculosis is most likely to be found in the weight-bearing joints, particularly
the hip, knee, and ankle; it is usually monarticular. In
the past 2 decades, increases in osteoarticular tuberculosis have paralleled the rise in cases of HIV infections
but are also seen in increased numbers among immigrant populations. Diagnosis can be made by acid-fast
staining of synovial fluid in only about 20% of cases.
Although synovial fluid culture grows M. tuberculosis from
Rheumatology Volume 4, Part 3 11
Synovial Fluid Analysis and Synovial Biopsy
infected specimens about 80% of the time, synovial
biopsy is diagnostic in 90% of cases. Long-term therapy
with a multidrug regimen is required.
SUGGESTED READINGS
Gatter RA, Schumacher HR: A Practical Handbook of Joint Fluid
Analysis, 2nd ed. Philadelphia: Lea & Febiger, 1991.
PEARLS
• If a joint swells immediately following trauma and
arthrocentesis reveals synovial fluid with a hematocrit level approaching that of blood, the joint must
be evaluated for fracture.
• Moderate and large effusions can be seen in congestive heart failure, anasarca, myxedema, and other
processes that cause tissue edema.
• Synovial fluid monocytosis can be found in patients
with acute arthritis associated with viral disease.
• The yellow color of synovial fluid results from diapedesis of red blood cells that occurs even with very
mild inflammation. As the red blood cells break
down, the heme is metabolized to the yellow-hued
bilirubin.
• Amyloidosis can be diagnosed if the synovial fluid is
stained with congo red.
• Cells that can suggest a specific diagnosis when
observed in synovial fluid include sickled erythrocytes and Gaucher’s and tumor cells.
Mahowald ML: Septic arthritis. In Primer on the Rheumatic
Diseases, 11th ed. Klippel JH, ed. Atlanta, GA: Arthritis
Foundation, 1997:196–200.
McCune WJ: Monarticular arthritis. In Textbook of Rheumatology, 5th ed. Kelley WN, Harris ED, Ruddy D, Sledge CB,
eds. Philadelphia: WB Saunders, 1997.
Meier JL, Hoffman GS: Mycobacterial and fungal infections.
In Textbook of Rheumatology, 5th ed. Kelley WN, Harris ED,
Ruddy D, Sledge CB, eds. Philadelphia: WB Saunders, 1997.
Saaibi DL, Schumacher HR Jr: Percutaneous needle biopsy
and synovial histology. Baillieres Clin Rheumatol 1996;10:
535–554.
Schumacher HR: Synovial fluid analysis and synovial biopsy.
In Textbook of Rheumatology, 5th ed. Kelley WN, Harris ED,
Ruddy D, Sledge CB, eds. Philadelphia: WB Saunders, 1997.
Sergent JS: Polyarticular arthritis. In Textbook of Rheumatology,
5th ed. Kelley WN, Harris ED, Ruddy D, Sledge CB, eds.
Philadelphia: WB Saunders, 1997.
Simms RW: Arthropathies associated with hematologic and
malignant disorders. In Primer on the Rheumatic Diseases, 11th ed.
Klippel JH, ed. Atlanta, GA: Arthritis Foundation, 1997:335–338.
Copyright 2000 by Turner White Communications Inc., Wayne, PA. All rights reserved.
12 Hospital Physician Board Review Manual