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Effect of Medication on Synovial Fluid Leukocyte Differentials in Patients With Rheumatoid Arthritis.

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1173
BRIEF REPORT
EFFECT O F MEDICATION ON SYNOVIAL FLUID LEUKOCYTE
DIFFERENTIALS IN PATIENTS WITH RHEUMATOID ARTHRITIS
MANIJEH BAHREMAND and H. RALPH SCHUMACHER, JR.
We compared leukocyte populations in synovial
fluid samples from 45 rheumatoid arthritis patients,
grouped according to medications taken. Seventeen of
the 22 patients receiving only nonsteroidal antiinflammatory drugs had lymphocytes as the single predominant cell. None of the 23 patients receiving second-line
agents had lymphocyte predominance. These findings
may have important implications for drug mechanisms
and must be considered in future studies of synovial
fluid.
Arthrocentesis and synovial fluid analysis are
techniques of established value in the diagnosis of joint
disease (1). Identification of crystals or infectious
agents can yield prompt diagnoses, and the leukocyte
count can allow the classification of disease in a given
joint, in terms of its inflammatory or relatively noninflammatory nature. In noninfectious inflammatory arthritis, the reaction within the joint space can vary
from mild to severe, and the white cell count will
average 15,000/mm3(2). This total count can exceed
From the University of Pennsylvania School of Medicine,
and the Arthritis and Immunology Center, Veterans Administration
Medical Center, Philadelphia, Pennsylvania.
Supported in part by NIH grant PR-00040 to the Clinical
Research Center.
Manijeh Bahremand, MD: Rheumatology Fellow, University of Pennsylvania School of Medicine, and Veterans Administration Medical Center; H. Ralph Schumacher, Jr., MD: Professor of
Medicine, University of Pennsylvania School of Medicine, and
Director, Arthritis and Immunology Center, Veterans Administration Medical Center.
Address reprint requests to H. Ralph Schumacher, Jr., MD,
Director, Arthritis and Immunology Center (15 IK), Veterans Administration Medical Center, University and Woodland Avenues,
Philadelphia, PA 19104.
Submitted for publication June 13, 1990; accepted in revised form April 17, 1991.
Arthritis and Rheumatism, Vol. 34, No. 9 (September 1991)
50,000/mm3or even 100,000/mm3in an occasional case
of rheumatoid arthritis (RA). Polymorphonuclear neutrophils (PMN) usually constitute more than 50% of
the white cells and not infrequently, as much as 90% of
the total white cell population. Although there are
exceptions, it has been said that there is a rough
correlation between the apparent severity of clinical
symptoms and signs and the elevation of the joint fluid
white cell count, and that severe acute disease is often
associated with higher percentages of PMN (2).
In the present study, we examined synovial
fluids obtained from the knee joints of patients with
RA who were taking only rionsteroidal antiinflammatory drugs (NSAIDs) or NSAIDs plus second-line
drugs (gold, methotrexate [MTX], or hydroxychloroquine [HCQ]). Changes in the percentages and absolute numbers of lymphocytes in synovial fluid, were
correlated with the type of medication and with other
features of the disease.
Patients and methods. All patients had definite
or classic RA according to the American Rheumatism
Association 1958 criteria (l), met the 1987 revised
criteria for RA ( 3 ) , and ha.d at least one knee joint
effusion from which synovial fluid could be collected.
Patients studied represented sequential cases of RA,
with clinical indications for joint aspiration for either
diagnostic assistance or treatment. Patients were included if they were rheumatoid factor positive or, if
seronegative, were also negative for HLA-B27 and
antinuclear antibodies. The clinical findings (duration
of disease, episode duration, pattern of involved
joints, and duration of morning stiffness), treatments
before and at the time of investigation, and laboratory
data were recorded for each patient. These are listed in
Table 1.
BRIEF REPORTS
1174
Table 1. Characteristics of the study patients and synovial fluids, by treatment group*
No. maleslfemales
Disease duration, years (range)
Episode duration, days (range)
Disease activity, 0-10 scale
% with morning stiffness > 1 hour
% with ESR >50 mmlhour
No. seropositive/seronegative, by latex
fixation
Synovial fluid analysis
Total leukocyte count, X 1,000/mm3
% lymphocytes
% PMN
NSAIDs
(n = 22)
MTX
(n = 11)
Gold
(n = 8)
HCQ
(n = 4)
7/15
7.38
(0.5-20)
8.6
(5-14)
6.5 2 1.4
95
76.0
I616
417
11.0
(3-22)
13
(3-20)
5.8 f 1.7
90
80.0
813
513
12.3
(7-20)
8.0
(6-12)
6.4 f 1.0
100
87.5
71 1
31 1
10.4
(3-20)
8.0
(7-1 1 )
6.3 f 1.0
100
66.6
410
18.2 f 20.7
7.8 f 5.6
88.3 10.6
6.0 3.1
22.0 t 9.0
69.0 f 1.0
6.1 f 4.1
56.2 f 27.6
32.1 f 31.4
14.6
6.6
87.1
f
8.5
* 6.8
f 9.6
*
*
* Except as otherwise noted, values are the group mean f SD. NSAIDs = nonsteroidal antiinflammatory drugs; MTX = methotrexate; HCQ = hydroxychloroquine; ESR = erythrocyte sedimentation
rate; PMN = polymorphonuclear neutrophils.
Forty-five patients were studied and were divided into 2 groups. Group 1 consisted of 22 patients
who were currently being treated with only NSAIDs.
The NSAIDs and dosages used were naproxen 500 mg
2-3 times daily in 5 patients, sulindac 15CL200 mg
twice daily in 3 patients, indomethacin 25 mg 3-4 times
daily in 3 patients, aspirin 3,6004,800 mg daily in 7
patients, salsalate 1,500 mg twice daily in 2 patients,
ibuprofen 800 mg 3 times daily in 1 patient, and
ketoprofen in unknown doses in 1 patient. None of
them had previously taken systemic corticosteroids.
Six of them had never received an intraarticular injection of corticosteroids into the knee joint; none of
them had received an injection during the previous 2
months. Group 2 consisted of 23 patients who had
been receiving a second-line drug for at least 6 months.
Only 1 patient was taking prednisone (2.5 mg/day).
Eleven of them were currently being treated with
MTX, 8 with intramuscular injections of gold, and 4
with HCQ. All patients in group 2 had previously
undergone joint aspiration and intraarticular injection
of depot corticosteroids, but none had received an
intraarticular injection into the study joint during the
previous 2 months.
Total clinical disease activity was scored on a
scale of &lo (10 = most severe), according to a rough
estimate by one of us (HRS) along with each patient’s
physician. Each synovial fluid sample was analyzed
within 2 hours of aspiration, by staff in the Arthritis
Research Laboratory. Leukocytes were manually
counted, smears were treated with Wright’s stain, and
the absence of crystals was confirmed using compen-
sated polarized light microscopy. Statistical analysis
was done by Student’s t-test for unpaired data.
Results. Total leukocyte counts and differential
counts in synovial fluid from the 45 RA patients are
given in Table 1 . Lymphocyte predominance was
found in 17 of the 22 group 1 patients, who were
receiving only NSAIDs. Patients in group 2, who were
receiving NSAIDs plus a second-line drug, showed
significantly lower ( P < 0.001) percentages and absolute numbers of lymphocytes. The patients taking
MTX or gold had significantly higher ( P < 0.001) total
leukocyte counts than did those taking HCQ plus
NSAIDs. Synovial fluid was available from 5 group 2
patients both during treatment with NSAIDs alone and
during treatment with NSAIDs plus a second-line drug
(patients 1-5, Table 2). All these had PMN predominance during treatment with the second-line drug, but
lymphocytes predominated during treatment with
NSAIDs alone.
Although there were some between-group differences in sex distribution and seropositivity, none of
the other variables examined, including sex, disease
duration, estimated disease activity, episode duration,
joints affected, duration of morning stiffness, peripheral blood leukocyte and differential counts, rheumatoid factor, and erythrocyte sedimentation rate,
showed statistically significant correlations with the
synovial fluid leukocyte counts or differential counts.
Discussion. The fact that some joint effusions
from patients with RA have a predominance of lymphocytes was noted by Ropes and Bauer (4),but this
has rarely been commented on by others and has not
BRIEF REPORTS
1175
Table 2. Changes in WBC counts and lymphocyte percentages in synovial fluid samples from
patients assessed while taking only an NSAID and while taking an NSAID plus a second-!ine agent*
First synovial fluid
Patient
1
2
3
4
5
6
7
* WBC
Medication
NSAID
NSAID
NSAID
NSAID
NSAID
NSAID
NSAID
+ HCQ
+ MTX
+ MTX
Second synovial fluid
%
WBC/mm3 lymphocytes
3,650
7,550
3,750
1,250
5,250
13,050
19,100
= white blood cells; see Table 1
14
76
79
12
88
13
8
Medication
NSAID
NSAID
NSAID
NSAID
NSAID
NSAID
NSAID
+ gold
+ gold
+ gold
+ gold
+ gold
+ gold
WBC/mm3
%
lymphocytes
3,700
6,600
5,800
6,600
6,100
17,600
21,100
45
5
13
5
3
10
7
for other definitions.
been systematically investigated. Gatter and Richmond (9,in their studies of RA synovial fluid, reported that lymphocytosis was present in early stages
of the disease in some RA patients. Neither report
mentioned any effect of, or correlation with, medications the patients were taking, although one might
suspect that few of the patients in these studies would
have been taking current second-line agents. Indeed,
Ropes and Bauer’s patients were assessed prior to
1953. A previous report from our laboratory showed
that only 2 of the 6 patients with early RA had
predominantly lymphocytes in their synovial fluid, and
stated only that most patients were not taking any
medication at the time of the study (6).
Our data reported here are consistent with the
concept that the differential cell counts of synovial
fluids from patients with RA may be greatly influenced
by medications. Seventeen of the 22 RA patients being
treated with NSAIDs alone had lymphocytes as the
predominant cell in the synovial fluid. None of the 23
patients taking NSAIDs plus a second-line agent had
predominantly lymphocytes. Overall, the patients taking NSAIDs alone had significantly higher (P< 0.001)
percentages of lymphocytes than did those taking
NSAIDs plus second-line drugs. Since not all of the
patients taking NSAIDs alone had lymphocyte predominance in synovial fluid, other factors will need to
be studied. Subtherapeutic levels of these drugs in the
joint could account for some of the variation (7).
There may be a variety of mechanisms involved
in these suspected drug-related changes in synovial
fluid cell populations. Although it would be of great
interest, there is little published information about
joint fluids of RA patients taking no medications. We
have been able to study only 2 patients with RA who
were not taking medications. Both had predominantly
PMN; leukocyte counts were 7,700/mm3 and 8,2501
mm3, with 64% and 88% PMN, respectively. The first
patient was subsequently studied while on a regimen
of NSAID therapy and had 54% lymphocytes with
39% PMN in the synovial fluid. To ascertain whether
the use of NSAIDs influences leukocyte counts or
differential counts, as these 2 cases would suggest,
more untreated patients must be studied.
Aspirin and other NSAIDs may influence the
migration of neutrophils and monocytes and can directly affect the surface of granulocytes, which might
alter their ability to enter the extravascular space (8).
An interesting report of studies in experimental arthritis suggested that indomethacin increased the number
of lymphocytes in synovium; synovial fluid lymphocyte counts were not performed (9). Haynes et a1 (10)
also recently reported that one NSAID, piroxicam,
can enhance cytokine-induced lymphocyte proliferation both in vitro and in vivo. Our studies suggest that
indomethacin and other NSAIDs also increase the
percentage of synovial fluid lymphocytes. Prostaglandin E, as well as prostaglandin E, can inhibit lymphocyte proliferation, presumably through their effects on
CAMP and phosphodiesterase (1 1). Thus, NSAID inhibition of prostaglandin production could be one
factor involved in increasing the numbers of exudate
lymphocytes.
In our study, all patients taking second-line
drugs showed PMN as the single predominant cell in
the synovial fluid, even though the estimated clinical
disease severity in these patients was the same as or
less than that in patients receiving only NSAIDs. The
fact that we were studying patients with detectable
joint effusions necessarily excluded patients who had
the most complete responses to a second-line drug.
We plan in future studies to aspirate some joints of
excellent responders who have no clinical need for an
arthrocentesis to see if better therapeutic response is
BRIEF REPORTS
1176
reflected by any differences in the cell population.
Disease severity overall and in the involved joint can
also be quantified more precisely in future studies.
Although the disease activity was similar in both
groups of patients described here, it had been more
severe in those prescribed second-line therapy.
Low-dose MTX is clearly efficacious in the
treatment of RA; however, the mechanisms of its
activity remain unclear. We know of no observations
that would fully explain increases in synovial fluid
PMN or decreases in synovial fluid lymphocytes in
patients treated with MTX. MTX has been shown to
decrease the number of synovial high endothelial
vessels, which might be expected to decrease migration of lymphocytes into synovium and synovial fluid
(12). We have some evidence to suggest that after
MTX treatment, the PMN might be less phlogistic,
since in vitro, MTX seems to be able to depress
neutrophil degradation (13).
Gold compounds may also suppress rheumatoid
synovitis, in part, by reducing the number of high
endothelial small blood vessels, available for emigration of lymphocytes. Both oral and injectable gold
compounds added in vitro have some effect on lymphocytes, as shown by their ability to suppress lymphocyte responses to mitogens (14). Antimalarials can
also act on lymphocytes, as has been shown by
decreased lymphocyte responsiveness to both nonspecific mitogens and specific mitogens in RA patients
taking chloroquine (15). The mechanism underlying
these effects remains unclear.
We were somewhat surprised that joints with
higher leukocyte counts and percentages of PMN were
not clinically worse than those with more lymphocytes. Further sequential correlative studies with a
careful measurement of local and general disease
activity would be of interest.
Acknowledgments. We thank Susan Rothfuss, Gilda
Clayburne, and Marie Sieck for technical assistance, Dr.
Mahboob U. Rahman for performing the statistical analyses,
and Sharon Johnson for secretarial assistance.
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