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In Vivo LE Cell Formation in Synovial Fluid.

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CLlNlCAL COMMENT
In Vivo LE Cell Formation in Synovial Fluid
Gene G. Hunder and Robert V. Pierre
Smears of synovial fluid specimens from 7 of 10 selected patients were found to
contain lupus erythematosus (LEI cells. In 1 patient, LE cells were found in
smears of synovial fluid but not of blood. Direct smears of synovial fluid immediately after aspiration from 2 patients contained LE cells, thus suggesting that
in vivo these cells form in synovial fluid.
Usually, the formation of lupus erythem- included i n this report because LE cells were found
atosus (LE) cells is considered an in vitro in synovial fluid but not in this patient’s peripheral
blood clot test.
phenomenon (1-3).
Only in rare inRoutinely, the synovial fluid was placed in a
stances has it been demonstrated that LE plastic bottle containing ethylenediaminetetraacecells formed in vivo. I n one patient with tate (EDT.4). ;Zfter gentle mixing to dissolve the
terminal systemic lupus erythematosus, LE EDT.4, the synovial fluid was centrifuged. A smear,
cells were found in direct peripheral blood made of the white cell button on the bottom of the
tube, was stained with Wright’s stain. All smears
smears (4). LE cells also were seen on were made within 1-3 h r after aspiration of the
histologic examination of a cutaneous joint fluid.
lesion of a patient with systemic lupus
RESULTS
erythematosus (5). I n the present study,
Of the 10 patients, synovial fluid smears
LE cells were frequently found in synovial
effusions of patients whose blood LE clot oE 4 women and 3 men contained LE cells
tests (1) showed LE cells. Evidence was (Fig 1 ) . Four of these patients had systemic
obtained showing that in some patients, lupus erythematosus, 2 had rheumatoid arthritis, and in 1 a differential diagnosis
LE cells form in vivo.
between rheumatoid arthritis and systemic
lupus erythematosus could not be made
MATERIALS AND METHODS
(Table 1). T h e volume of synovial fluid
Synovial fluid was obtained from the knees of 4
aspirated
from each patient ranged from
women and 5 men, between the ages of 32 and 69
5
4
0
ml.
T
h e leukocyte counts in fluids
years, whose peripheral blood LE cell clot tests
showed LE cells. A tenth patient, a woman, was showing LE cells ranged from 800 to 24,500/cu mm. There was a predominance of
From the Division of Rheumatology and Internal lymphocytes in the fluids from 3 patients
Medicine, and Department of Clinical Pathology,
and of polymorphonuclear leukocytes in
Mayo Clinic, Rochester, Minn.
GENEG. HUNDER,
MD, MS: Consultant, Division fluids from 5.
of Rheumatology and Internal Medicine, Mayo
I n 3 patients (No. 3, 5 and 6 ) , synovial
Clinic, Rochester, Minn 55901. ROBERTV. PIERRE,
fluid
was obtained from both knees; in 1,
MD: Consultant, Department of Clinical Pathology,
LE cells were seen in the smears of fluid
Mayo Clinic.
Reprint requests should be addressed to Dr. from both knees, and in 2, the synovial
Hunder, Section of Publications.
Submitted for publication March 20, 1970: ac- fluid specimen from only one knee showed
LE cells. I n the patient with bilaterally
cepted April 27, 1970.
44a
Arthritis and Rheumatism, Vol. 13, No. 4 (July-August 1970)
LE CELLS IN SYNOVIAL FLUID
Fig 1. LE cell in synovial fluid from patient No. 4; similar cells were seen in fluids from other patients.
(Wright‘s stain; x 1000)
positive specimens (patient No. 6 ) , abundant LE cells were seen in the fluid from
each knee, whereas the blood LE cell
preparation revealed nucleolysis and rosettes of neutrophils but no classic LE cells.
In the second patient (No. 3), the synovial
fluid from both knees was relatively noninflammatory, but fluid from the “negative
knee” had a lower leukocyte count. I n the
third patient (No. 5 ) , fluid from the “negative knee” had characteristics similar to
those of fluid from the “positive knee.” I n
a fourth patient (No. 4) whose disease
began after therapy with procainamicle and
whose synovial fluid contained LE cells, an
olecranon bursa was also aspirated. Hematoxylin bodies were seen in this fluid, but
LE cells were not.
Direct smears of synovial fluid from 2
patients (No. 3 and 6 ) , made immediately
Arthritis and Rheumatism, Vol. 13, No. 4 (July-August 1911
after aspiration-ie, less than 1 min after
the fluid was taken from the knee joict,
showed I,E cells. An aliquot of positive
fluid (No. Z ) , which was placed in tubes
containing sodium fluoride and cooled
in ice immediately after aspiration, also
showed LE cells. Aliquots of synovial fluid
drawn at the same time and handled in the
routine manner contained many more LE
cells than did fresh or cooled samples.
Synovial fluid smears from 3 patients were
verified as to the morphologic appearance
of the cells described as being typical LE
cells.*
DISCUSSION
LE cells have been reported to occur in
synovial fluid (6), pericardial fluid (7),
*Dr. M. M. Hargraves, Department of Internal
Medicine, Mavo Clinic.
449
HUNDER 8. PIERRE
Table 1. Patients With Lupus Dythematosus Cells in Synovial Fluid
Patient
No.
Diagnosis
Leukocyte
count/cu m m
1
Systemic lupus
erythematosus
1,400
2
Systemic lupus
erythematosus
5,600
3
Systemic lupus
erythematosus
800*
73 lymphocytes
14 monocytes
13 neutrophils
83 lymphocytes
8 rnonocytes
7 neutrophils
2 histiocytes
80 lymphocytes
3 monocytes
16 neutrophils
1histiocyte
78 lymphocytes
2 monocytes
16 neutrophils
4 h istiocytes
8 lymphocytes
5 monocytes
85 neutrophils
2 histiocytes
11lymphocytes
5 monocytes
83 neutrophils
1h istiocyte
10 lymphocytes
10 monocytes
77 neutrophils
3 histiocytes
7 lymphocytes
5 rnonocytes
85 neutrophils
1eosinophil
2 h istiocytes
5 lymphocytes
3 monocytes
87 neutrophils
5 histiocytes
24 lymphocytes
8 monocytes
63 neutrophils
5 h istiocytes
300t
4
Systemic lupus
erythematosus
8,600
5
R heumatoid
arthritis
8,600*
10,500t
6
Rheumatoid
arthritis
20,500*
24,Oat
7
Rheumatoid
arthritis or
systemic lupus
erythematosus
Differential
count (%)
8,300
M u c h clot
LE cells
Good
Present
Poor
Present
Good
Present
Good
Not present
Poor
Present
Poor
Present
Poor
Not present
Poor
Present
Poor
Present
Poor
Present
* Right knee.
iLeft knee.
pleural fluid (8) and peritoneal exudates
(1) , but detailed observations and evidence
that they form in vivo have not been given.
LE cells also have been reported to de450
velop in vivo under experimental condi:Ions in patients (9, 10) with lupus erythematosiis arid in normal persons (11). DNA
particles that resemble amorphous ex-
Arthritis and Rheumatism, Vol. 13, No. 4 (July-August 1970)
LE CELLS IN SYNOVIAL FLUID
tracellular material (hematoxylin bodies)
were found in synovial fluids from patients
with rheumatoid arthritis, but these particles were not observed in synovial fluid
from 4 patients with systemic lupus erythematosus (12) ; nor were LE cells found in
these fluids.
T h e results of the present study suggest
that LE cells are probably a frequent,
natural in vivo phenomenon in synovial
fluid of patients with systemic lupus erythematosus as well as in some patients with
rheumatoid arthritis. A search for LE cells
in synovial fluid may be a more sensitive
method for detecting LE cells, a t times,
than are tests on peripheral blood. I n addition to the patient (No. 6) whose synovial
fluid (but not blood) showed LE cells,
another patient (No. 7) had only a few
LE cells on his peripheral blood preparation, whereas many were seen in his synovia1 fluid smear.
T h e reasons for the presence of LE cells
in synovial fluid in vivo and not in circulating peripheral blood remain to be elucidated. A high concentration of antinuclear antibody in synovial fluid could be
important, but in patient No. 6 the titer of
antinuclear antibody, as determined by the
immunofluorescent method
(13) , was
greater in serum than in synovial fluid.
Perhaps damaged or dead leukocytes are
not cleared as efficiently from synovial fluid
as from the bloodstream, thus affording
more opportunity for the LE cell to form in
synovial fluid from degenerating leukocyte
nuclei.
ACKNOWLEDGMENT
We thank Drs. Hollander and Kitridou for
their informative and thoughtfui comments
which help point out the value of careful examination of synovial fluid and other parenteral
Huids in patients suspected of having systemic
lupus erythematosus.
REFERENCES
1. Hargraves MM: T h e L.E. cell phenomenon.
Advances Intern Med 6:133-160, 1954
2. Zinkham WH, Conley CL: Some factors influencing the formation of L.E. cells: .4
method for enhancing L.E. cell production.
Bull Hopkins Hosp 98:102-119, 1956
3. Sundberg RD, Lick NB: “L.E.” cells in the
blood in acute disseminated lupus erythematosus. J Invest Derm 12:83-84, 1949
4. Chomet B, Kirshen MM, Schaefer G et al:
T h e finding of the L.E. (lupus erythematosus) cells in smears of untreated, freslily
drawn peripheral blood. Blood 8: 11071109, 1953
5. Wilson RM, Abbott RR, Miller DK: The
occurrence of L.E. cells and hematoxylin
bodies in the naturally occurring cutaneous
lesions of systemic lupus erythematosus.
Amer J Med Sci 241:31-43, 1961
6. Hollander JL, Reginato A, Torralba TP:
Examination of synovial fluid as a diagnostic aid in arthritis. Med Clin N Amer 50:
1281-1293, 1966
7. Seaman AJ, Christerson JW: Demonstration of L.E. cells in pericardial Huid: Report of a case. JAMA 149:145-147, 1952
8. Grondahl R: (7)
9. Sickley JF, Friedman IA, Feldhake C, et al:
I n vivo demonstration of the lupus erythematosus phenomenon. J Lab Clin Med
46:624-627, 1955
10. WatEon JB, O’Leary PA, Hargraves MM:
Neutrophils resembling L.E. cells in artificial blisters. Arch Derm (Chicago) 63:328333, 1951
11. Rebuck JW, Berman L: Experimental production of the L.E. phenomenon in the
skin of man. Proc SOCExp Biol Med 75:
259-264, 1950
12. Pekin TJ Jr, Malinin T I , Zvaifler NJ: The
clinical significance of deoxyribonucleic
acid particles in synovial fluid. Ann Intern
Med 65:1229-1236, 1966
13. Beck JS: Variations in the morphological
patterns of “autoimmune” nuclear fluorescence. Lancet 1:1203-1205, 1961
Arthritis and Rheumatism, Vol. 13, No. 4 (July-August 1970)
451
HUNDER & PIERRE
DISCUSSION
J o x p h L. Hollander, AJD, Philadelphia, Pa: Dis.
Hunder and Pierre are to be congratulated on
presenting concisely a fine piece of definitive
clinical research which should be of help in any
situation i n which the differential diagnosis of
arthritis in suspected systemic lupus could not be
made by the clinical or serologic findings alone.
Similarly, in the “overlap syndrome” presenting
findings of both rheumatoid arthritis and systemic
lupus erythematosus, the demonstration of LE cells
in the synovial fluid of an effused joint suggests that
lupus pathogenetic mechanisms may he responsible
for at least some of the observed signs and symp.
toms.
Not only can we completely confirm the findings
prescnted, but our experience began in 1961 out of
dcsperation. A 31-year-old woman had been admitted with a high fever and acute pericard;al
effusion, but without previous history to suggest
systemic lupus erythematosus. Aside from the fever
and pericarditis, there were no diagnostic physical
signs of the disease. LE preparations from the
clotted blood take hours to prepare, Not knowing
at that time of the previous findings of Seaman
and Christerson, quoted hy the authors, we simply
centrifuged some of the pericardial fluid, smeared
the sediment, stained it with Wright’s stain, and
found hrindreds of LE cells. T h e diagnosis was
established within 15 minutes after pericardiocentcsis had been completed. Corticosteroids were
prescribed and she responded dramatically.
This finding suggested to us that joint effusions
f l o m patients with systcniic lupus erythematosus
might also contain such LE cells in vivo. Although
joint symptoms are extremely common in systemic
lupus, effnsion is not quite as common. Thereafter
our laboratory has routinely examined Wright’sstained smears of joint fluid from every patient
with known or suspected lupus, as well as from any
patient with known or suspected “overlap syndrome.” El ery fellow in rhcumatology who trained
with us has been inqtrncted in the simple technic
for demonstrating LE cells in joint pleural, or
peiicardial fluid. T h e total number of such examinations is not available from our records, but all
positive slides have hcen kept. There were 11 lupus
joint fluids that showed LE cells, 3 pleural fluids,
and 2 pericardial fluids. We can only remember 2
instances in which fluids from patients with known
or subsequently proven SLE did not show LE cells
on such smears, but d o remember that a mud:
452
larger nnmher of rheumatoid joint fluids did not
show LE cells on joint fluid smear even though the
patient had a positive serum LE preparation. We
have heen derelict in not keeping more complete
records on this portion of our routine spnovianalysis.
T h e technic and implications of the in vivo
formation of LE cells have been discussed in an
article on synovial fluid analysis in 1966 ( I ) , and
color slides of the appearance of such preparations
have been shown in all of our presentations on
synovial fluid examination over the years (2), but
we have never documented the phenomenon as well
as the present authors have done. Probably the first
description of LE cells in synovial fluid was a footnote in the classic monograph by Ropes and
Rauer (3).
T o quote from our previous report, “The formation of LE cells has been described previously as a
‘post-vital’ phenomenon, but some have argued that
such inflamed cavities are actually not part of the
hody proper. Whether or not they are, fluid from
joints or seroiis cavities provide a quick source for
LE cells when the rapid diagnosis of such an acute
inflammatory process may be lifesaving by suggesting immediate corticosteroitl therapy.”
REFERENCES
I . Hollander JL, Reginato A, Torralba TP: Examination of synovial fluid as a diagnostic aid in
arthritis. Med Clin N .lmcr 50:1281-1293, 1966
2. Hollander JL: Intrasynovial corticosteroid therapy in arthritis. Maryland Med J 19:1-5, 1970
3. Ropes MW, Bauer W: Synovial Fluid Changes
in Joint Disease. Cambridge, Mass, Harvard
University Press, 1953, p 91
Kodntrilri C. Kittidou, dfD, Pliiladelphia, Pa: I
read with interest Drs. Hunder and Pierre’s papcr.
kip owti experience with sjnoiial fluids from
patients with systemic lupus erythematosus (SLE)
concurs with that of the authors.
There were hematoxylin bodies and LE cells in
fluids from 3 patients with SLE and from 1 patient
with rheumatoid arthritis (RA) (Table 1). Direct
smears of two fluid samples showed 3 and 11% LE
cells. T h e RA fluid contained only rare LE cells and
Arthritis and Rheumatism, Vol. 13, No. 4 (July-August 1970)
LE CELLS IN SYNOVIAL FLUID
hematoxylin bodies. The percentage in both fluid
samples increased somewhat after treatment with
hyaluronidase, centrifugation and staining of the
sedinient (1able 1, Fig 1 ) . In addition, many cell
nuclei appeared homogeneous and “glassy.”
Antinuclear antibody (ANA) titers were similar
Table 1. LE Cells in Synovial Fluid of 4 Patients
Patient
with RA
Patients with S1.E
No. 1
No. 2
No. 4
No. 3
-
~
Cell types
Direct
smear
Sediment
Direct
smear
Sediment
Direct
smear
Sediment
Direct
smear
~
WBC/cu rnrn
Polymorphonuclears
Lymphocytes
Mononuclear, large
Hernatoxyl in bodies
LE cells
An tin uclear antibodies*
Serum
Synovial fluid
425
35
53
4
8
0
25
44
11
15
5
160
160
450
31
40
7
11
11
160
160
-
41
24
1
18
16
2750
50
35
8
4
3
50
29
2
12
7
9250
60
39
0
0.5
0.5
80
80
’ Reciprocal of titer.
t Granulocyte-specific ANA.
Fig 1. LE cells (large arrows) and hematoxylin bodies (small arrows) in the synovial fluid sediment of
patient No. 2.
Arthritis and Rheumatism, Vol. 13, NO. 4 (July-August 1970)
453
HUNDER & PIERRE
in serum and synovial fluid of patients with SLE
(Table I ) , while RA synovial fluid contained
granulocyte-specific ANA. Synovial fluids from 2
more patients with R A and granulocyte-specific
ANi\ in their sera did not contain LE cells.
I agree with the authors that the presence of LE
cells and/or hematoxylin bodies in direct smears of
451
synovial fluid suggests that they can and do form in
vivo. Apparently, AN,A may bind to nuclear constituents in vivo. T h e motion of joints, lungs and
heart might provide the “trauma” factor for the in
vivo formation of LE cells in synovial, pleural and
pericardial fluids, in a manner analogous to the in
vitro action of glass beads.
Arthritis and Rheumatism, Vol. 13, No. 4 (July-August 1970)
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