close

Вход

Забыли?

вход по аккаунту

?

Peripheral lymphocyte depletion in gold sodium thiomalate В Эtreated rheumatoid arthritis patients.

код для вставкиСкачать
909
BRIEF REPORT
PERIPHERAL LYMPHOCYTE DEPLETION IN GOLD SODIUM
THIOMALATE-TREATED RHEUMATOID ARTHRITIS PATIENTS
MAX S. LUNDBERG, GRANT W. CANNON, AND JOHN R. WARD
It has been reported that gold sodium thiomalate
treatment of rheumatoid arthritis reduces the number of
peripheral blood lymphocytes. In a prospective, doubleblind, randomized trial comparing gold sodium thiomalate, auranofin, and placebo in the treatment of rheumatoid arthritis, we investigated absolute lymphocyte
counts. We found that peripheral lymphocyte counts
decreased, but there was no correlation with clinical
change in disease activity.
P a r e n t e d gold and auranofin have proved beneficial in the treatment of patients with rheumatoid
arthritis (RA) (1). A variety of effects of gold treatment
on inflammation have been described and include
decreased release of lysosomal enzymes, altered activity of phagocytic cells, decreased synthesis of prostaglandin, and altered response of stimulated lymphocytes. Understanding of these and other effects,
however, has not yet produced a unifying explanation
of the mechanism of action of gold or improved its
effect in the treatment of RA.
Lymphocyte depletion by such physical means
as lymphapheresis, thoracic duct drainage, or total
lymphoid irradiation has been reported to be effective
in the treatment of patients with intractable RA (2-4).
From the Division of Rheumatology, University of Utah
Medical Center, Salt Lake City.
Supported in part by grants from the Nora Eccles Treadwell
Foundation, the Valois Egbert Endowment, and the Cooperative
Systematic Studies of Rheumatic Diseases (NIH contract NOI-ARI2204).
Max S. Lundberg, MD; Grant W. Cannon, MD; John R.
Ward, MD.
Address reprint requests to Max S. Lundberg, MD, 50
North Medical Drive, Salt Lake City, UT.
Submitted for publication October 8, 1987; accepted in
revised form December 17, 1987.
Arthritis and Rheumatism, Vol. 31, No. 7 (July 1988)
Recently, Hanly and Bresnihan (5) reported a decrease
in peripheral blood lymphocyte counts in RA patients
treated with parenteral gold. In that study, in which
control subjects were not used, 10 patients were
examined. Those authors reported a significant decrease in peripheral blood lymphocyte counts from
initiation of therapy with parenteral gold salts until a
total dose of 1 gm had been administered. The lymphocyte depletion appeared to correlate with clinical
improvement, as evaluated by multivariate analysis.
The authors suggested that lymphocyte depletion is a
possible mechanism of action of gold in the treatment
of RA. We report here the effects of gold sodium
thiomalate (GST), auranofin, and placebo on peripheral blood lymphocyte counts in RA patients, as
measured prospectively in a randomized, controlled,
multicenter clinical trial.
PATIENTS AND METHODS
Patient selection. Patients were enrolled in a
prospective, multicenter, randomized, double-blind,
controlled clinical trial comparing the effects of auranofin, GST, and placebo in the treatment of RA. A
complete description of the criteria for entry and
exclusion, along with a more detailed description of
the clinical evaluation, has been published previously
(1). Briefly, patients were 18 years of age or older and
had definite or classic RA, according to the American
Rheumatism Association criteria (6), of more than 6
months duration. All patients had active disease that
was not completely controlled with salicylates or other
nonsteroidal antiinflammatory drugs (NSAID). All patients had 6 or more swollenjoints capable of responding to treatment, and at least 2 of the following: 1) 2 9
BRIEF REPORTS
910
joints tender on pressure, 2) 245 minutes of morning
stiffness, and 3) Westergren erythrocyte sedimentation
rate (ESR) 228 mm/hour. No patient had been treated
with gold at any time prior to the study, with Dpenicillamine or antimalarials for 3 months prior to the
study, or with pyrazolones for 1 month prior to the
study.
Drug administration. Every patient received
injections weekly and tablets daily. GST-treated patients took placebo tablets daily and were given
weekly injections of GST (10 mg initially, 25 mg the
second week, and 50 mg weekly for the next 19
weeks). Auranofin-treated patients took 3-mg tablets
of auranofin twice daily and were given weekly placebo injections. Placebo-treated patients received placebo injections and placebo tablets. Patients continued
to take their stable doses of salicylate or NSAID.
Patients were allowed a stable close of prednisone, but
one that did not exceed 10 mgfday.
Methods of assessment. A clinical assessment
was made at study entry and at 4-week intervals
thereafter. This included evaluation of joint tenderness, joint swelling, grip strength, and patient’s and
physician’s global assessment of disease activity. The
weekly laboratory evaluation included urinalysis,
complete blood count, and differential white blood cell
count. A blood chemistry panel and Westergren ESR
were obtained at study entry and at 4-week intervals.
Important clinical improvement was defined as 50%
improvement in either the joint swelling or the joint
pain/tenderness score (1).
In the study reported by Hanly and Bresnihan
(3,the severity of disease was assessed by calculating
an index of disease activity. To compare our findings
with theirs, we calculated an index of disease activity
in all GST-treated patients for whom adequate data
were available. The indices were calculated in a manner similar to that used by Hanly and Bresnihan,
except that joint swelling scores were substituted for
the Ritchie articular indices, and a 4-level patient
assessment of disease activity was substituted for the
visual analog scale. An index of disease activity, based
on 6 clinical and laboratory variables, was determined
at each clinic visit.
A scale of 1-4 was used for each parameter, as
follows. Morning stiffness <lo minutes duration was
graded 1, 10-30 minutes was graded 2,31-120 minutes
was graded 3, and >120 minutes was graded 4. Patient
assessment of disease activity was scored 1 for “very
good,” 2 for “good,” 3 for “fair,” and 4 for “poor” or
“very poor.” Grip strength >200 mm Hg was scored
1, 50-200 mm Hg was scored 2, 21-49 mm Hg was
scored 3, and 520 mm Hg was scored 4. Swelling of
0-10 joints was graded I , 11-30 swollen joints was
graded 2,31-50 swollenjoints was graded 3, and 51-70
swollen joints was graded 4. Westergren ESR was
scored 1 for 0-20 mm/hour, 2 for 21-45 mm/hour, 3 for
46-80 mm/hour, and 4 for >80 mm/hour. A hemoglobin concentration >I4 gm/dl was scored 1 , 13-14
gmidl was scored 2, 10-12.9 gmidl was scored 3, and
<10 gm/dl was scored 4. The index of disease activity
score was calculated as the mean of the scores for the
6 variables.
Statistical analysis. T-tests and paired t-tests
were used to compare lymphocyte counts within and
between treatment groups.
RESULTS
Of the 208 RA patients who entered the study,
157 completed 21 weeks of therapy, with 43 patients
receiving placebo, 62 receiving auranofin, and 52 receiving GST. At study entry, there was no statistical
difference in the mean lymphocyte counts between the
3 treatment groups (t-test). Figure 1 shows the mean
and the standard error of the mean for each clinical
group at study entry and at 4-week intervals throughout the study period. The GST-treated group showed a
significant decline in the mean absolute number of
peripheral blood lymphocytes from study entry to
week 21 of therapy (351 fewer cells/mm3; P < 0,001).
2000 1
Iz
3
8
a
5
A
I5O0l
W
PLACEBO
0AURANOFIN
z
a
W
GST
500
0
4
8
WEEK
12
OF
16
n =43
n.62
n ‘52
21”
THERAPY
Figure 1. Mean lymphocyte counts in 157 rheumatoid arthritis
patients, by treatment group. Only those patients who were treated
with gold sodium thiomalate (GST) experienced a significant decline
in absolute lymphocyte count ( P < 0.001, week 21 versus week 0).
At week 21 (*), P = 0.838, auranofin versus placebo; P = 0.002,
GST versus placebo; P = 0.004, GST versus auranofin.
BRIEF REPORTS
91 1
The mean lymphocyte counts of auranofin- and placebo-treated patients did not change during this same
time period ( P = 0.830 and P = 0.649, respectively).
Figure 2 demonstrates the changes in lymphocyte counts in individual GST-treated patients from
the first visit to the last assessment, after 21 weeks of
therapy. Although there was a wide range of initial and
final lymphocyte counts in the GST-treated patients,
the general trend was toward a decrease in the number
of circulating lymphocytes.
In the clinical trial, there was a significant
difference between the GST-treated group or auranofin-treated group and the placebo-treated group in
“important improvement” (>50% change) in 2 of the
parameters being followed: joint swelling and joint
paidtenderness scores (1). We compared lymphocyte
counts in GST-treated patients who had important
40001
z
3
8
W
+
>
V
0
2
2000
-2000
a 1000
-1000
5
3
W
I-
3
J
0
v)
m
I
0
1
Week 0
I
L
u
I
Y
I
W
I
I
I
0
I
-2000
3
c
2
3
0
0
p -1000
>
x
*
I
I
I
I
I
I
I
I
I
I*
I
I
:
.
. ..
I
.
‘I
I
z
I
W
I
..
:.
.
I
.4000
- 3000
+ 3000
- -3000
-0
Week 21
Figure 2. Individual lymphocyte counts, week 0 to week 21 of
treatment, in rheumatoid arthritis patients receiving gold sodium
thiomalate therapy.
improvement in joint swelling or joint pain/tenderness
scores with those in GST-treated patients who did not
experience important improvement. Of the 52 patients
who completed treatment with GST, 25 showed important improvement in joint painkenderness scores,
and had a mean decrease in the lymphocyte count of
441 cells/mm3. In the 27 patients who did not show
important improvement in joint paidtenderness, the
mean decrease in the lymphocyte count was 267
cells/mm3. This difference between the 2 groups was
not statistically significant ( P = 0.194).
Nineteen patients who had important improvement in joint swelling scores had a mean decrease in
lymphocyte counts of 370 cells/mm3. Thirty-three patients who did not show important improvement in
joint swelling had a mean decrease in lymphocyte
counts of 339 cells/mm3. Again, this difference between groups was not statistically significant ( P =
0.382). Figure 3 shows changes in lymphocyte counts
plotted against the percentage of improvement in joint
swelling scores in GST-treated patients. Although
many patients showed some improvement in joint
swelling score with a decrease in the number of
circulating lymphocytes, many also showed either
worsening of the joint swelling score with a decrease in
the lymphocyte count or improvement in the joint
BRIEF REPORTS
912
swelling score with an increase in the lymphocyte
count (r = 0.18).
For 24 patients, data were available to calculate
the scores for the index of disease activity at study
entry and after 21 weeks of GST therapy. The index of
disease activity scale ranges from 1 to 4, with the
lower values indicating low levels of disease activity.
The mean score at study entry was 2.5, and at 21
weeks, it was 2.0. The difference was not statistically
significant by paired t-test (P = 0.075).
DISCUSSION
The presence of extensive lymphocyte infiltration into rheumatoid synovium suggests the importance of these cells in the pathogenesis and perpetuation of RA. Treatments have been designed with the
aim of decreasing lymphocyte number and function in
an attempt to reduce synovial inflammation. Thoracic
duct drainage, lymphapheresis, and total lymphoid
irradiation have achieved lymphocyte depletion with
improvement in the clinical features of RA (2-4). A
number of drugs with “disease-modifying” potential
are known to decrease synovial inflammation. Glucocorticoids and azathioprine produce a general depression in the number of circulating lymphocytes (7,8).
Various in vitro assays have demonstrated that Dpenicillamine and gold interfere with lymphocyte function (9-ll), and GST treatment has been correlated
with a decline in spontaneous lymphocyte activity
(12). With this background, one might hypothesize
that lymphocyte depletion could explain, in part, the
mechanism of action of gold salts, and, if proven, this
might provide a functional assay to predict which
patients will show a clinical response to this therapy.
Our data and the earlier work by Hanly and
Bresnihan (5) identify a quantitative decrease in peripheral lymphocyte counts in RA patients receiving
parenteral gold salts. One question is whether this
lymphocyte depletion correlates with clinical improvement. In the analysis of their data, Hanly and Bresnihan inferred a correlation between the decrease in
peripheral blood lymphocyte counts and the improvement in clinical parameters because of a parallel
decline in mean peripheral blood lymphocyte counts
and mean disease activity scores. Clinical improvement in their study was quantitated by a method of
multivariate analysis, where a mean disease activity
score was generated by assigning numerical severity
scores to 6 clinical and laboratory parameters (5,13).
When we calculated index of disease activity scores
for the GST-treated patients, we saw a trend toward
improvement in disease activity, but this trend did not
reach statistical significance.
There are two problems with the use of index of
disease activity scores to measure treatment response.
The index of disease activity scores are based on
information collected on multiple dependent variables.
It is possible that changes that are not clinically
significant could be magnified when several dependent
variables are assessed together, giving the impression
that there is a degree of clinical improvement that is
greater than the improvement that actually exists. The
other problem arises when means are correlated. In
this case, there appears to be some correlation between the mean change in peripheral lymphocyte
count and improvement in disease activity. However,
when the values for the change in lymphocyte count
and the percentage of change in the joint swelling
score for individual patients were evaluated together,
as shown in Figure 3, no correlation was seen.
It is also important to consider whether lymphocytes in the peripheral circulation reflect the type
of lymphocytes present in synovium or synovial fluid.
A number of investigations have shown differences in
the types of lymphocyte in these populations (14-16).
The fact that peripheral blood lymphocytes were depleted in GST-treated patients, without a corresponding improvement in disease activity, may reflect a
more significant antilymphocyte activity at the synovial level. There may also be specific suppression of
specific T cell populations encompassed in the more
general depletion, which might correlate better with
disease activity. Further studies of T cell subsets could
answer this question.
While it appears that GST treatment results in a
decrease in peripheral blood lymphocyte counts in
patients with RA, this decrease cannot be correlated
with clinical changes in disease activity. The specific
effects on T cell subsets or specific lymphocyte populations, such as those in synovial fluid, need further
study.
Acknowledgments. We appreciate the assistance of
Miki Karg with the data retrieval and statistical analyses,
and Marta Gomez for help in the statistical analyses.
REFERENCES
1. Ward JR, Williams HJ, Egger MJ, Reading JC, Boyce E,
Altz-Smith M, Samuelson CO Jr, Willkens RF, Solsky
MA, Hayes SP, Blocka KL, Weinstein A, Meenan RF,
Guttadauria M, Kaplan SB, Klippel J: Comparison of
auranofin, gold sodium thiornalate, and placebo in the
BRIEF REPORTS
2.
3.
4.
5.
6.
7.
8.
9.
treatment of rheumatoid arthritis: a controlled clinical
trial. Arthritis Rheum 26: 1303-1315, 1983
Karsh J, Klippel JH, Plotz PH, Decker JL, Wright DG,
Flye MW: Lymphapheresis in rheumatoid arthritis: a
randomized trial. Arthritis Rheum 24:867-873, 1981
Paulus HE, Machleder HI, Levine S, Yu DTY, MacDonald NS: Lymphocyte involvement in rheumatoid
arthritis: studies during thoracic duct drainage. Arthritis
Rheum 20:1249-1262, 1977
Kotzin BL, Strober S, Engleman EG, Calin A, Hoppe
RT, Kansas GS, Terrell CP, Kaplan HS: Treatment of
intractable rheumatoid arthritis with total lymphoid irradiation. N Engl J Med 305:969-975, 1981
Hanly JG, Bresnihan B: Reduction of peripheral blood
lymphocytes in patients receiving gold therapy for rheumatoid arthritis. Ann Rheum Dis 44:299-301, 1985
Ropes MW, Bennett GA, Cobb S, Jacox R, Jessar RA:
1958 revision of diagnostic criteria for rheumatoid arthritis. Bull Rheum Dis 9:175-176, 1958
Fauci AS, Dale DC: The effect of in vivo hydrocortisone
on subpopulations of human lymphocytes. J Clin Invest
53:240-246, 1974
Yu DT, elements PJ, Peter JB, Levy J, Paulus HE,
Barnett EV: Lymphocyte characteristics in rheumatic
patients and the effect of azathioprine therapy. Arthritis
Rheum 17:37-45, 1974
Merryman P, Jaffe IA: Effect of penicillamine on the
913
10.
11.
12.
13.
14.
15.
16.
proliferative response of human lymphocytes. Proc SOC
Exp Biol Med 157:155-158, 1978
Lipsky PE, Ziff M: Inhibition of antigen and mitogen
induced human lymphocyte proliferation by gold compounds. J Clin Invest 59:455-466, 1977
Lies RB, Cardin C, Paulus HE: Inhibition by gold of
human lymphocyte stimulation. Ann Rheum Dis 36:216218, 1977
Duke 0, Panayi GS, Janossy G, Poulter LW, Tidman N:
Analysis of T cell subsets in the peripheral blood and
synovial fluid of patients with rheumatoid arthritis by
means of monoclonal antibodies. Ann Rheum Dis 42:
357-361, 1983
Mallya RK, Mace BEW: The assessment of disease
activity in rheumatoid arthritis using a multivariate
analysis. Rheumatol Rehabil 20:14-17, 1981
Fox RI, Fong S, Sabharwal N, Carstens SA, Kung PC,
Vaughan JH: Synovial fluid lymphocytes differ from
peripheral blood lymphocytes in patients with rheumatoid arthritis. J Immunol 128:351-354, 1982
Warrington RJ, Wilkins JA: Synovial T lymphocytes in
rheumatoid arthritis. J Rheumatol 10 (suppl 11):93-96,
1983
Carter SD, Bacon PA, Hall ND: Characterisation of
activated lymphocytes in the peripheral blood of patients with rheumatoid arthritis. Ann Rheum Dis 40:293298, 1981
Документ
Категория
Без категории
Просмотров
0
Размер файла
436 Кб
Теги
periphery, patients, эtreated, sodium, gold, arthritis, depletion, lymphocytes, thiomalate, rheumatoid
1/--страниц
Пожаловаться на содержимое документа