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Synovial fluid analysis for diagnosis of amyloid arthropathy.

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419
SYNOVIAL FLUID ANALYSIS FOR DIAGNOSIS OF
AMYLOID ARTHROPATHY
SHARAD LAKHANPAL, CHIN Y. LI, MORIE A. GERTZ, ROBERT A. KYLE, and GENE G. HUNDER
To detect the presence of amyloid, we studied
synovial fluid samples from 7 patients who had biopsyproven amyloidosis and clinical arthropathy and from
98 patients who had other forms of arthritis. Centrifuged sediments from synovial fluids of all 7 patients
with amyloid and clinical arthropathy were positive on
staining with Congo red, whereas the 98 others were
negative. Under polarized microscopy, the amyloid appeared as an amorphous material with strong Congo red
uptake and typical apple-green birefringence. These
findings indicate that analysis of synovial fluid sediments
with Congo red may represent a simple, yet sensitive,
test for the diagnosis of amyloid arthropathy.
Amyloid arthropathy occasionally occurs in patients who have primary amyloidosis. By its deposition in the synovial membrane and synovial fluid or in
the articular cartilage, amyloid may directly involve
articular structures (1). Amyloid arthropathy may affect any joint in the body and can mimic a number of
rheumatic diseases (2). To establish a diagnosis of
amyloid arthropathy , amyloid must be demonstrated
in the synovium or other joint tissue (3,4). This reFrom the Department of Medicine, Mayo Clinic, Rochester, Minnesota.
Sharad Lakhanpal, MD: Resident in Rheumatology (current address: Division of Rheumatic Diseases, UTHSCD, Southwestern Medical School, Dallas, Texas); Chin Y. Li, MD: Division
of Hematology, Internal Medicine; Morie A. Gertz, MD: Division of
Hematology, Internal Medicine; Robert A. Kyle, MD; Division of
Hematology, Internal Medicine; Gene G . Hunder, MD: Division of
Rheurnatology, Internal Medicine.
Address reprint requests to Gene G . Hunder, MD, Division
of Rheumatology, Mayo Clinic, Rochester, MN 55905.
Submitted for publication July 8, 1986; accepted in revised
form October 31, 1986.
Arthritis and Rheumatism, Vol. 30, No. 4 (April 1987)
quires a biopsy of the synovium or other periarticular
tissues (5).
Diagnosis of amyloid arthropathy by joint aspiration and synovial fluid analysis is preferable to
synovial biopsy because it is simpler and is associated
with less morbidity. The presence of sequestered
fragments of synovial villi containing amyloid in
synovial fluid has been reported in patients with multiple myeloma (5-7). However, in previous reports,
the specificity of amyloid in synovial fluid has not been
established by examination of and comparison with
patients who have other types of arthritis.
To determine how often synovial fluid examination will help in the diagnosis of amyloid arthropathy , we prospectively studied synovial fluids from 7
patients with biopsy-proven primary amyloidosis and
clinical arthropathy, and from 98 other patients with
various rheumatic diseases who served as controls.
PATIENTS AND METHODS
Patients. Seven patients with a biopsy-proven diagnosis of primary systemic amyloidosis and clinical arthropathy, seen at the Mayo Clinic between June 1984 and May
1986, were included in the study. One hundred patients with
primary amyloidosis were seen during this period. All 7 of
our patients had primary systemic amyloidosis. In addition,
3 had multiple myeloma. Synovial fluid was obtained from
the shoulder joints in 2 patients and from the knees in the
other 5 .
Two sets of synovial fluid samples were used as
controls. One set consisted of synovial fluids that had been
frozen in our synovial fluid bank. The other set consisted of
synovial fluids obtained from consecutive patients seen
during the same period in the Rheumatology Division who
did not have amyloidosis and who required synovial fluid
aspiration for other diagnostic or therapeutic reasons,
420
LAKHANPAL ET AL
Examination of synovial fluid for amyloid. Regular,
air-dried cytocentrifuge preparations from 50 pl to 100 pl of
synovial fluid were used for Congo red and crystal violet
staining. Cytocentrifuge preparations were made at 1,000
revolutions per minute for 6 minutes, using a Shandon
cytocentrifuge. Congo red staining was done by the alkaline
Congo red method described by Puchtler et a1 (8), and the
crystal violet staining followed the procedure of Hinds (9).
All specimens were examined for the typical green birefringence which, when viewed under polarized light, is considered to be diagnostic of amyloid deposits. The synovial fluids
from patients and controls were read “blindly,” i.e., without
knowledge of the diagnosis, by one of us (CYL).
RESULTS
Amyloid arthropathy. Six patients were men
and 1 was a woman. The age range was from 45 to 66
years (mean 58). Shoulders were the joints most
frequently affected with arthropathy and were in-
Table 1. Clinical features of 7 patients with primary systemic
am yloidosis*
Immunoelectrophoresis
Sex/age
Urine
Serum
Affected joints
M/65
AK
K
M/66
Free L
L
M/52
F/65
Free L
Free L
L
ND
M/62t
Free L
L
M/45t
M/51t
Free K
Free K
K
K
Both shoulders, wrists,
MCPs, PIPS, and knees
Both shoulders, It wrist,
and rt knee
Both wrists and ankles
Both shoulders, wrists,
and knees
Both shoulders, wrists,
knees, ankles, and rt
elbow
Both shoulders and knees
Both shoulders and knees
Duration
2 years
I year
1 year
4 months
3 months
4 years
7 months
* A = Immunoglobulin heavy chain A; K = K immunoglobulin light
chain; MCP = metacarpophalangeal; PIP = proximal interphalangeal; L = Aimmunoglobulin light chain; ND = notdetected; It = left;
rt = right.
t Multiple myeloma associated with amyloidosis. All patients had
carpal tunnel syndrome.
Table 2. Diagnoses of patients whose stored and fresh synovial
fluid samples were used as controls
Diagnosis
Rheumatoid arthritis
Osteoarthritis
Psoriatic arthritis
Pseudogout
Ankylosing spondylitis
Reiter’s syndrome
Systemic lupus
erythematosus
Primary Sjogren’s
syndrome
Gout
Temporal arteritis
Crohn’s associated arthritis
BehCet’s disease
Adult-onset Still’s disease
Total
Stored synovial
fluid
Fresh synovial
fluid
20
20
5
5
5
5
4
3
0
0
1
0
0
0
68
2
0
1
1
1
30
control samples, 68 were previously frozen and stored,
and 30 were fresh.
Amyloid staining. Synovial fluids from all 7
patients with amyloid arthropathy stained positively
for amyloid with Congo red stain. The amyloid appeared as an amorphous material and showed typical
apple-green birefringence under polarized light (Figures 1 A and B). The amorphous amyloid material also
stained metachromatically with crystal violet.
All 98 control synovial fluid samples were negative for amyloid when stained by both Congo red and
crystal violet. Some synovial fluid samples from control subjects, primarily from rheumatoid and osteoarthritic joints, contained fragmented crystalline-like
material that stained with Congo red, but was distinguished from amyloid by sharp, angulated edges and
was negative for apple-green birefringence on polarization microscopy (Figures 2A and B). Furthermore,
these materials did not show metachromatic staining
with crystal violet.
Freezing and storing the synovial fluid samples
SF IN AMYLOID ARTHROPATHY DIAGNOSIS
A
42 1
B
Figure 1. Synovial fluid sample (under polarized light) from the shoulderjoint of a patient with amyloid arthropathy. A, Amyloid with positive
Congo red stain. B, Apple-green birefringence.
for several months did not influence the results of
Congo red stain in either patients or controls. However, smudged nuclear material, caused by freezing
and storing fluid samples, may show metachromatic
staining with crystal violet that simulates the staining
pattern of amyloid, thus making Congo red the preferred stain.
DISCUSSION
Articular involvement has been described most
often in patients with primary systemic amyloidosis
(1). It is not usually a feature of secondary amyloidosis
or familial amyloidosis. This selectivity may be based
on differences in the chemical structure of various
amyloid fibrils which may determine their predilection
for different tissues. Secondary amyloidosis amyloid
fibrils are deposited in glomerular subendothelium,
whereas prealbumin amyloid fibrils have a propensity
for deposition in the heart and peripheral nerves.
Amyloid protein purified from material taken from a
patient with amyloid arthropathy has recently been
sequenced as immunoglobulin light chain fragment
(lo), which is associated with more diverse clinical
manifestations.
Amyloid arthropathy may mimic a number of
rheumatic diseases and can affect any joint in the
body. Often it resembles rheumatoid arthritis in its
distribution of affected joints, the presence of subcutaneous nodules, and in radiologic features (1-3,
11,12). The diagnosis of amyloid arthritis may be
difficult to establish until autopsy (13,14). Small and
large joints are involved with almost equal frequency.
The initial symptoms generally are pain, stiffness, and
422
LAKHANPAL ET AL
A
B
Figure 2. Synovial fluid sample (under polarized light) from the knee of a patient with osteoarthritis. A, Crystalline debris with sharp, angulated
edges that stained orange-red with Congo red. B, Negative apple-green birefringence of the same.
swelling of the affected joints; however, morning stiffness and fatigue may also be present. The joints have
fewer features of inflammation than are found in
rheumatoid arthritis, and there is often a firmness or a
sense of induration on palpation of the joints. Infiltration of the glenohumeral articulation produces the
characteristic “shoulder-pad sign.” Subcutaneous
nodular deposits of amyloid may be seen in association
with this arthropathy, often near the olecranon bursa,
and may mimic rheumatoid nodules. Synovial fluid
usually is noninflammatory, with a low white blood
cell count, a fair-to-good rnucin clot, a predominance
of mononuclear cells, and no crystals. Occasionally,
the fluid has characteristics of inflammation similar to
those of rheumatoid arthritis. Synovial fluid may be
xanthochromic. Rheumatoid factor is absent. Roentgenograms may show osteoporosis, lytic lesions, or
soft tissue swelling. Bony erosions are seen in 5% of
patients.
Amyloid arthropathy should be considered in
patients with seronegative polyarthritis. The presence
of subcutaneous nodules in the absence of rheumatoid
factor should alert one to the possibility of amyloid
arthropathy . Approximately 5% of patients who have
multiple myeloma develop amyloid arthropathy . Some
may respond to treatment (3,6,7). An unusual erosive
arthritis, possibly due to amyloid, has also been reported in 2 distinct kindreds with familial amyloidosis
(15). Therefore, it is important that the correct diagnosis be established because of differences in treatment and prognosis.
The presence of amyloid deposits in articular
cartilage and subsynovial tissue may, at times, be a
localized phenomenon related to age or trauma, rather
SF IN AMYLOID ARTHROPATHY DIAGNOSIS
than a manifestation of systemic amyloidosis. In one
study, at surgery, amyloid material was found in the
subsynovial connective tissue in 6 hips and 8 knees of
patients with pyrophosphate arthritis (16). Amyloid
material was also identified in hip joint tissues from
patients undergoing arthroplasty for osteoarthritis
(17-20), and in the routine examination of knee joints
from unselected subjects at autopsy (19). Amyloid
arthropathy has been reported in a patient with psoriasis (21), but their presence together may have been
coincidental. Thus, amyloid localized in some tissue
may not indicate systemic disease; demonstration of
amyloid elsewhere by biopsy of other clinically involved organs, or of bone marrow, rectum, or abdominal fat aspirate would help substantiate amyloid
arthropathy.
The facts that all 7 patients with amyloidosis
had positive staining of synovial fluid, and all 98
control fluids were negative on staining, suggest that
analysis of synovial fluid sediments with Congo red
represents a simple, yet sensitive and possibly specific, test for the diagnosis of amyloid arthropathy.
The technique of staining centrifuged smears for
amyloid is easier, simpler, and requires a much smaller
sample (0.1 ml) than does the preparation of paraffin
sections as described in earlier reports (3,5,6). Congo
red staining of synovial fluid is advised in cases of
seronegative polyarthropathies when the diagnosis is
uncertain, particularly if the patient has, or has had,
carpal tunnel syndrome. Synovial fluid examination
for amyloid material may also be an equally effective,
but easier, means of confirming the diagnosis of
amyloidosis.
ACKNOWLEDGMENTS
We thank M. A. Moms for technical assistance and
Lisa Petersen for help with preparation of the manuscript.
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423
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