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Effect of low-dose cyclosporin a on systemic lupus erythematosus disease activity.

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ARTHRITIS & RHEUMATISM Volume 37
Number 4, April 1994, pp 551-558
0 1994, American College of Rheumatology
55 1
EFFECT OF LOW-DOSE CYCLOSPORIN A ON
SYSTEMIC LUPUS ERYTHEMATOSUS
DISEASE ACTIVITY
MICHIAKI TOKUDA, NORIYUKI KURATA, AKIHITO MIZOGUCHI, MASAYUKI INOH,
KUNIO SETO, MAKOTO KINASHI, and JIRO TAKAHARA
Objective. To determine the effect of low-dose
cyclosporin A (CSA) treatment on disease activity in
systemic lupus erythematosus (SLE).
Methods. All patients in the study had active
disease as defined by at least the presence of a low CH50
level. Patients were initially given 3 mg/kg/day of CSA.
Dosages were adjusted individually at every visit, according to both clinical and laboratory data.
Results. Eleven women with SLE were enrolled in
the study; 10 were evaluable. After 20 weeks of CSA
treatment, the mean score for disease activity on the
SLE Disease Activity Index decreased significantly,
from 10.6 to 3.8 (P = 0.02). The titer of antinuclear
antibodies decreased in 8 patients and the level of
anti-DNA antibodies decreased in 5. Side effects included hypertension (40%), hypertrichosis (30%), gingival hypertrophy (lo%), and a rise in the blood urea
nitrogen level. Serum creatinine levels remained unchanged.
Concbsion. The favorable responses observed in
our patients strongly suggest that low-dose CSA can
reduce the disease activity of SLE.
the activation of T helperhnducer and cytotoxic cells
(1-3). AIthough CSA therapy has shown promising
results in various diseases associated with disordered
immunoregulation, such as uveitis, type I diabetes,
and psoriasis, therapeutic trials with CSA for human
systemic lupus erythematosus (SLE) have been limited. This may be because the risk of nephrotoxicity
has often been thought to outweigh the potential
benefit of therapy. However, CSA seems to have
several advantages over other immunosuppressive
therapies, because long-term or high-dose corticosteroids clearly increase the risk of osteoporosis and
other metabolic complications, and because the incidence of myelotoxicity with CSA is less than that with
other immunosuppressive drugs, including cyclophosphamide, which has been proven effective in preventing the progression of renal impairment (4).The major
goal of the present study was to determine whether
low-dose CSA could reduce the disease activity
of SLE.
Cyclosporin A (CSA) produces potent immunosuppression, primarily through its inhibitory effect on
Patients. To be eligible for the study, patients were
required to meet the following criteria: 1) definite disease
according to the American College of Rheumatology (formerly, the American Rheumatism Association) 1982 revised
criteria for the diagnosis of SLE (5) and 2) active disease
defined by the presence of low complement hemolytic activity (CH50)(120 units/ml; normal 3CL50) with depressed
levels of complement components (especially C3 and C4).
Exclusion criteria were as follows: 1) seizure or psychosis;
2) altered mental function, including clouding of consciousness, drowsiness, or insomnia; 3) symptoms suggestive of
vasculitis, e.g., polyneuropathy, skin purpura, infarction in
extremities, and severe abdominal pain; 4) pleuritis or pericarditis; 5) hypertension (defined by systolic pressure 2 160
Michiaki Tokuda, MD: Kagawa Medical School, Kagawa,
Japan; Noriyuki Kurata, MD: Kagawa Medical School; Akihito
Mizoguchi, MD: Kagawa Medical School; Masayuki Inoh, MD:
Kagawa Medical School; Kunio Seto, MD: Kagawa Medical
School; Makoto Kinashi, MD: Kinashi Obayashi Hospital, Kagawa,
Japan; Jiro Takahara, MD: Kagawa Medical School.
Address reprint requests to Michiaki Tokuda, MD, First
Department of Internal Medicine, Kagawa Medical School, 1750-1
Ikenobe, Miki-cho, Kita-gun, Kagawa, 761-07, Japan.
Submitted for publication July 29, 1992; accepted in revised
form September 25, 1993.
PATIENTS AND METHODS
552
mm Hg and/or diastolic pressure 2100 mm Hg) that was
refractory to antihypertensive drugs; 6) elevated serum
creatinine levels (22.0 mg/dl; normal 0.3-1.1); 7) previous
therapy with high-dose prednisolone (220 mg/day) or cyclophosphamide within the 3-month period prior to enrollment.
Study design. After informed consent was obtained,
patients were enrolled in a prospective, nonrandomized
study. Initially, each patient underwent clinical, laboratory,
and immunologic assessment. Items relevant to disease
activity were recorded by the same rheumatologist (NK),
according to the SLE Disease Activity Index (SLEDAI) (6).
Definition of each item, with the exception of immunologic
data, was based on the original description in this index.
Low complement was defined as a CH50 level 1 2 0 units/ml,
and increased DNA binding was defined as an anti-DNA
antibody titer 220 units/ml (normal 510). The index was
calculated by assigning predetermined weights to positive
items. The range of possible SLEDAI scores for each patient
was 0-105. At the end of the observation period, the
SLEDAI score for each patient was reassessed in the same
manner.
Clinical and laboratory assessment. Patients were
reviewed every fourth week for 20 weeks. At each visit,
patients were questioned about any side effects (i.e., gingival
hypertrophy, dysesthesia of extremities, ataxia), and resting
blood pressure was recorded. Urine was collected for urinalysis, and levels of N-acetylglucosaminidase (NAG) and
P,-rnicroglobulin (&m) were estimated as markers of renal
damage; these 2 parameters are now considered more sensitive for this purpose than measurement of blood urea
nitrogen (BUN) and creatinine (7,8). Blood was also obtained for standard laboratory tests, including complete
blood cell count, liver function tests (serum bilirubin and
transaminases), BUN, trough level of CSA in whole blood
(determined by radioimmunoassay), and levels of creatinine,
electrolytes, immunoglobulins (determined by nephelometry), CH5O (determined by functional assay), and complement components C3 and C4 (determined by nephelometry).
Other immunologic parameters, i.e., antinuclear antibody
(ANA) titers (determined by indirect immunofluorescence
on HEp-2 cells) and anti-DNA antibody levels (as determined by Farr assay), were assessed both at enrollment and
at the end of the observation period.
Lymphocyte phenotyping. Peripheral blood mononuclear cells were prepared from anticoagulated venous blood
by density centrifugation. Cells were stained with the following fluorescein-conjugated monoclonal antibodies: T3
(mouse anti-CD3; Coulter, Hialeah, FL), NU-TH/I (mouse
anti-CD4; Nichirei, Tokyo, Japan), NU-TS/C (mouse antiCD8; Nichirei), Leu-1 (mouse anti-CD5; Becton-Dickinson,
Mountain View, CA), B1 (mouse anti-CD20; Coulter), and
Leu- 18 (mouse anti-CD45RA; Becton-Dickinson). Single
and dual cell surface flow microfluorometric analysis was
performed with a fluorescence-activated cell sorter (FACS
440; Becton Dickinson), as previously described (9).
Medication regimens. All patients were initially given
3 mg/kg/day of CSA. The CSA was supplied as a solution
containing 100 mg/ml, to be taken orally. Each patient was
given instructions regarding dosage adjustment at the time of
each visit, or was contacted by telephone within 2 days of
the visit. Patients were instructed to increase the amount of
TOKUDA ET AL
CSA by 1 mg/kglday if the level of CH50 did not exceed 25
units/ml and was not more than 110% of the preceding value.
When the level of CH5O remained above 25 units/ml and was
not decreased below 90% of the preceding value, the patient
was instructed to maintain the same dosage until the next
visit. The patient was instructed to reduce the amount of
CSA by 1 mg/kg/day if at least 1 of the following conditions
was observed: 1) the value for any of the following parameters exceeded twice the upper limit of normal: BUN
(normal 3.5-20.0 mg/dl), creatinine (normal <1.4 mg/dl normal), NAG (normal 4 . 7 unitdml), and urinary &m (normal
<380 pglliter); or 2) hypertension developed and resistance
to antihypertensive drugs was shown.
The dosage of prednisolone was kept stable for at
least 4 weeks before study entry. Patients were instructed
not to change the dosage during the observation period.
Withdrawals from the study. Patients were permanently withdrawn from the study if their clinical condition
worsened to such an extent that they needed other therapy.
Patients were also withdrawn if they failed to take the trial
medication or to keep scheduled clinic appointments.
Statistical analysis. Student’s 2-tailed t-test for paired
samples was used for comparisons. The Wilcoxon matched
pairs signed rank test was substituted if the distribution of
the differences between paired data deviated substantially
from normal. For both statistical methods, P values less than
0.05 were considered significant.
RESULTS
Patient characteristics. Eleven women were enrolled in the trial, which lasted from August 1990
through September 1991. Ten patients were evaluable;
I patient was excluded from the study because she
dissolved CSA in hot milk. The mean -+ SD age of the
10 patients was 39.6 2 13.2 years. Renal biopsies had
been performed in all patients at the time of the first
manifestations of SLE. Histologic changes were classified according to the WHO morphologic classification of lupus nephritis (Table 1). All patients had
experienced more than 2 recurrences of active disease
and had been treated with high-dose corticosteroids or
other immunosuppressive agents on each occasion.
Two patients (patients 1 and 2) had developed avascular necrosis of the femoral head, and 1 (patient 3) had
a history of steroid-induced psychosis. Marked atherosclerosis was diagnosed in another patient (patient 9),
based on extensive calcification of the aortic arch
observed on plain chest radiography.
Clinical manifestations and laboratory data at
the time of study entry are shown in Table 1. None of
the patients had central nervous system (CNS) symptoms, vascular manifestations, serositis, or constitutional symptoms of SLE. All of the patients had
553
LOW-DOSE CSA IN ACTIVE SLE
Table 1. Patient characteristics
Patient
1
2
3
4
5
6
7
8
9
10
Ageisex
51iF
42lF
50/F
47lF
40lF
32lF
27lF
37/F
40lF
24/F
Disease
duration
(years)
5
5
14
14
8
9
2
2
15
11
Renal
histology*
Previous
treatmentt
Complications
at enrollment
IIa
IIa
IV
IV
V
IV
IIb
IV
IV
IV
PRED
Pulse + PRED, DFPP
Pulse + PRED, DFPP
Pulse + PRED, DFPP
Pulse + PRED, DFPP
Pulse + PRED, DFPP
PRED
PRED
Pulse + PRED, DFPP, AZA
Pulse + PRED, DFPP
Avascular necrosis (femoral head)
Avascular necrosis (femoral head)
Steroid psychosis
Atherosclerosis$
~
~
~~~~~~~~~
* Pathologic glomerular changes observed on antecedent renal biopsy, scored according to the WHO morphologic classification of lupus
nephritis.
t Pulse + PSL = steroid pulse therapy for active disease, and then low-dose prednisolone (PRED) after remission was achieved. DFPP =
double-filtration plasmapheresis; AZA = azathioprine.
$ Extensive calcification at the aortic arch was visible on plain chest radiography.
hypocomplementemia, and 5 (patients 4, 6, 7, 8, and
10) had elevated anti-DNA antibody titers. Four patients (patients l , 4 , 6 , and 8) had both musculoskeletal
and skin manifestations. Four patients (patients 6 , 8 , 9 ,
and 10) had urinary abnormalities, and 2 (patients 3
and 5) showed no symptoms other than hypocomplementemia.
During the observation period, the CSA dosage
had to be increased in 4 patients (patients 1 , 4, 9, and
10). Although 2 of these 4 patients (patients 1 and 4)
showed satisfactory responses to 4 mg/kg/day of CSA,
the remaining 2 (patients 9 and 10) did not respond
even at a dosage of 5 mg/kg/day, which later had to be
reduced to 1 mg/kg/day until the urinary excretion of
NAG decreased to below twice the normal limit. Six
patients continued to take 3 mg/kg/day of CSA
throughout the observation period. All of the patients
continued to take stable dosages of prednisolone
(mean ? SD 10.5 -+ 3.2 mg/day) throughout the study.
Relationship of low-dose CSA treatment to
SLEDAI score. During the observation period, the
mean 4 SD SLEDAI score decreased significantly,
from 10.6 k 7.1 to 3.8 ? 7.0 (P = 0.02) (Figure 1).
Disease activity was completely suppressed in 7 patients (patients 1-7) and was markedly reduced in l
(patient 8, whose SLEDAI score decreased from 21 to
4) (Tables 2 and 3). These 8 patients were defined as
responders. In 4 of the responders who had demonstrable symptoms at study entry, both musculoskeletal
and skin manifestations completely disappeared. Urinary abnormalities also disappeared in 1 responder
(patient 6) and improved in another (patient 8). The
improvements in both musculoskeletal and skin man-
ifestations were observed at least 8 weeks after the rise
in CH50 was noted.
The SLEDAI score did not change in 1 patient
SLEDAI
(n=lO)
I
,,i
P =0.02
.0f 30
Q
W
20 -
0
0
20
Weeks
Figure 1. Changes in Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores after treatment with cyclosporin A.
Closed circles denote responders; open circles denote poor responders (see text). Bars show the mean f SD.
TOKUDA ET AL
Table 2. Systemic Lupus Erythematosus Disease Activity Index
(SLEDAI) scores at study entry*
c3
CH50
C4
(W10)
("=lo)
("=lo)
Patient
SLEDAIcomponent
Renal
Casts
Hematuria
Proteinuria
Pyuria
Musculoskeletal
Arthritis
Myositis
Skin
Malar rash
Alopecia
Mucous membrane
Immunologic
Low complementt
Increased anti-DNA
Hematologic
Thrombocytopenia
Leukopenia
Total SLEDAI score
1
2
3
4
5
6
7
8
9
10
0
0
0
0
0
0
0
1
1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1
0
0
0
0
0
1
0
1
1
0
0
1
1
0
1
0
0
0
0
0
1
0
0
0
1
0
0
0
1
0
0
0
1
0
1
1
1
0
0
0
0
0
0
1
0
0
0
0
0
1
0
1
0
0
0
1
1
0
1
1
0
1
0
1
0
1
0
1
0
1
1
1
0
1
1
1
1
1
1
1
0
1
0
0
1
0
0
0
0
0
0
0
0
0
0 1 0
0 1 1
12
3
2 10
0
2 16
4
21 18
I
0
0
18
Table 3. Systemic Lupus Erythematosus Disease Activity Index
(SLEDAI) scores at the end of the observation period*
Patient
Renal
Casts
Hematuria
Proteinuria
Pyuria
Musculoskeletal
Arthritis
Myositis
Skin
Malar rash
Alopecia
Mucous membrane
Immunologic
Low complement
Increased anti-DNA
Hematologic
Thrombocytopenia
Leukopenia
Total SLEDAI score
10
0
* Four components (central nervous system, vascular system, serositis, and constitutional) included in the original description of the
SLEDAI were omitted here because none of the patients had the
relevant symptoms. Items were scored 1 (positive) or 0 (negative).
The total SLEDAI score was calculated by assigning a predetermined weight to the scores for positive items. See Patients and
Methods for definitions.
SLEDAIcomponent
0--
1
2
3
4
5
6
7
8
9
10
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1
0
1
1
1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1
1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1
0
1
1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1
0
0
0
0
0
0
0
0
0
4
18
16
* See Table 2 for explanations.
1
1
0
0
4
1 2
W&.
2
0
0
4 1 2
WWk.
2
0
0
4
1 2
WWk.
2
0
Figure 2. Serial measurements of serum complement hemolytic
activity (CH50) levels and C3 and C4 values after treatment with
cyclosporin A. Closed circles denote responders; open circles
denote poor responders. Bars show the mean 2 SD; shaded bars
along the y-axis represent the range of normal values in healthy
controls. = P < 0.01.
(patient 9) and was reduced by only 11% in another
(patient lo), in whom only skin manifestations improved. These 2 patients were considered to be poor
responders.
No patient experienced a paradoxical rise in the
SLEDAI score from the baseline value during the
observation period.
Laboratory data. The mean 2 SD CH5O value
increased significantly, from 17.0 2 1.9 units/ml to
21.4 2 5.1 unitdm1 at the fourth week (P < 0.01)
(Figure 2). At the end of the observation period, this
value exceeded 25 unitdm1 in the 8 responders and
remained below 20 unitdm1 in the 2 poor responders.
Levels of both C3 and C4 had increased by the fourth
week (P = 0.02 and P = 0.03, respectively). The
degree of the rise in C4 at the end of the observation
period was comparable with that for C3 (42.8% and
46.7%, respectively).
Immunoglobulin levels did not change significantly (IgG 1,574 5 515.2 mg/dl to 1,406 2 495.1
170.2 mg/dl to 345 & 207.7 mg/dl,
mg/dl, IgA 357
IgM, 151 f 117.4 mg/dl to 148 2 11.3 mg/dl; mean 2
SD). It was of considerable interest that, independently of the amount of immunoglobulin, the ANA
titer decreased only in the 8 responders. Anti-DNA
antibody levels decreased in 5 patients with demonstrable titers at study entry (P = 0.01) (Figure 3).
The absolute white blood cell count increased,
from 5.8 ? 1.89 x 106/liter to 7.3
2.73 X 106/liter
*
*
555
LOW-DOSE CSA IN ACTIVE SLE
Anti-DNA
antibody
Antinuclear
antibody
CD3c cell
(n=6)
CM+cell
CD&Cell
CD4+ 45RA+
cell
In=6)
lW61
b7)
CDZW cell
("4
(n=5)
@=lo)
P =0.01
m
1:640
/
1320
El
L
.-2 1:160
*
c
::
E
c
a
1:80
CI
Figure 5. Changes in percentages of lymphocyte subsets after treatment with cyclosporin A. Closed circles denote responders; open
circles denote poor responders. Bars show the mean -+ SD: shaded
bars along the y-axis represent the range of normal values in healthy
controls. NS = not significant.
1:40
1:20
0
20
0
20
Weeks
wedts
Figure 3. Changes in titers of antinuclear and anti-DNA antibodies
after treatment with cyclosporin A. Closed circles denote responders; open circles denote poor responders. Bars show the mean ?
SD; shaded bars along the y-axis represents the range of normal
values in healthy controls.
(P = 0.01) (Figure 4). The platelet count also increased, from 2.1 ? 1.01 x lO"/liter to 2.4 k 0.99 x
lO"/liter (P = 0.04). In contrast to the increase in
neutrophils, from 4.6 1.97 X 106fliterto 5.9 ? 2.67 x
106/liter(P= 0.02), the number of circulating lymphocytes remained unchanged. Moreover, there were no
significant alterations in the percentages of the following fractions in the patients examined (Figure 5): T
cells (defined as CD3+ cells; normal range, 63-85%),
CD4+ cells (normal 27-50%), CD8+ cells (normal
19-42%), T suppressorhnducer cells (defined as
*
WBC
Neulrophils
Lymphocyles
1"=101
(Il=10)
ln.101
CD4+, 45RA+ cells; normal &35%), or B cells (defined as CD20+ cells; normal 5-14%).
Side effects. Hypertrichosis was observed in 4
patients (40%) (patients 2, 3, 6, and 7). Three patients
(patients 1, 2, and 4) developed hypertension which
responded to the usual antihypertensive drugs. Mild
gingival hypertrophy was noted in 1 patient (patient 2).
No liver damage or neurologic deterioration was noted
during the observation period.
Changes in the values of the 4 parameters that
suggest the presence of renal damage are shown in
Figure 6. At the end of the observation period, there
was a significant rise in BUN levels, from a mean k
SD of 14.3 5.7 mg/dl to 19.5 k 7.1 mgldl (P = 0.03),
but there were no significant changes in the values for
the other 3 parameters. As noted above, however, a
*
BUN
Creatinine
NAG
("=101
("=lo1
("=10l
1n=101
2
W&.
2
W d S
0
0
2
W d .
0
0
2
W&S
(".l)
Plateleta
0
0
U-BMG
0
0
2
0
W d S
Figure 4. Changes in white blood cell (WBC), neutrophil, lymphocyte, and platelet counts after treatment with cyclosporin A. Closed
circles denote responders: open circles denote poor responders.
Bars show the mean f SD. NS = not significant.
0
0
2 0
Wd.
0
2
Wd.
0
0
2
0
W&S
Figure 6. Changes in 4 parameters of renal damage (blood urea
nitrogen [BUN], creatinine, N-acetylglucosaminidase [NAG], and
urinary P,-microglobulin [U-BMG]) after treatment with cyclosporin A. Closed circles denote responders; open circles denote poor
responders. Bars show the mean t SD; shaded bars along the y-axis
represent the range of normal values in healthy controls. NS = not
significant.
TOKUDA ET AL
556
transient rise in the urinary excretion of NAG (higher
than twice the normal limit) was seen during the
observation period in the 2 poor responders. These
levels returned to normal after the dosage of CSA was
reduced.
The side effects observed in these patients were
tolerable and did not warrant the discontinuation
of CSA.
Blood trough level of CSA. The mean ? SD
trough level of CSA at the fourth week was 46.4 k 13.9
ng/ml. The trough level seemed to reach a plateau by
the eighth week after the dosage was adjusted (data
not shown). In the 6 patients who continued to take 3
mg/kg/day throughout the study, the mean & SD
trough level at the eighth week was 94.6 64.1 ng/ml.
The maximal level of CSA in the 2 poor responders
was comparable with that in the responders. For
example, in patient 10, a poor responder, the level
reached 128 ng/ml at the fourth week, after the dosage
had been increased to 5 mglkglday.
*
DISCUSSION
Therapeutic trials of CSA in patients with SLE
have been limited. Miescher and Miescher (10) treated
20 SLE patients with 5 mg/kg/day of CSA combined
with low-to-moderate doses of corticosteroids. They
found that, among 16 patients with favorable responses, there was a marked drop in antibody activity
against double-stranded DNA (dsDNA) in 8 patients
who had demonstrable antibody titers before the CSA
treatment. Levels of C3d, which reflect activation of
the complement system, were also reduced in 10
patients. Those authors observed no serious complications that would warrant the discontinuation of
CSA. Feutren et a1 (11) also noted a steroid-sparing
effect of CSA in 8 of 13 patients with steroid-resistant
SLE, some of whom had several critical clinical manifestations such as cerebral vasculitis, pulmonary hypertension, and pleuropericarditis. However, they reported that titers of both ANA and anti-dsDNA
antibodies remained unchanged after 6 months of CSA
therapy. In addition, C4 continued to be depressed at
the end of CSA treatment.
Although the reason for the discrepancy between the results of these studies is not clear, it should
be emphasized that the dosage of corticosteroids used
in the 2 studies was not constant and was occasionally
higher than that used in our study. Specifically, Miescher and Miescher used 1,000 mg/day of methylprednisolone in 1 patient, and the majority,of Feutren et
al’s patients took >0.5 mg/kg/day of prednisolone.
Regarding the interaction between CSA and corticosteroids, Bloemena et a1 (12) found that prednisolone
enhanced the effectiveness of CSA to a considerable
extent. Thus, taking into account the fact that the
dosage of prednisolone used in the present study was
low (515 mg/day) and that it remained constant
throughout the study period, we believe that our study
reflects the effect of CSA more clearly than do previous investigations.
We included hypocomplementemia as a required criterion at study entry so that we could use
CH5O level as an objective marker for determining the
need for CSA dosage adjustment. We excluded patients with CNS symptoms, vasculitis, pleuritis, and
pericarditis from our study so that high-dose corticosteroid treatment could be established as promptly as
possible for these critical clinical manifestations.
Following the 20-week low-dose CSA treatment, disease activity, as measured by SLEDAI
scores, was reduced to a great extent in 80% of our
patients. Of particular note, both musculoskeletal and
skin manifestations completely disappeared in 4 responders who had had demonstrable symptoms at the
time of study entry. Urinary abnormalities also disappeared in 1 responder (patient 6) and improved in
another (patient 8). These clinical responses appear to
support our choice of CH50 level as a marker for
adjusting the dose of CSA.
There was no apparent difference in age, disease duration, or previous treatment between responders and poor responders. Peak trough levels of CSA in
both groups were comparable, as stated above. Differences in the severity of disease activity did not appear
to affect treatment response, as shown by the finding
that 2 responders (patients 6 and 8) had activity indices
as high as those in poor responders.
With regard to the changes in immunologic
parameters, our results were quite similar to those
reported by Miescher (10) and appear to be in sharp
contrast to those reported by Feutren and coworkers
(11). Specifically, ANA titers dropped in the 8 responders and anti-DNA antibody levels decreased in 5
patients who had demonstrable titers at study enrollment. Further, we noted at the end of the study that
CH5O levels exceeded 25 units/ml in the 8 responders
and that the values for both C3 and C4 increased as
well. Our finding that the percentage of T cells did not
change contrasted sharply with Feutren’s observation
that the percentage of CD3+ cells progressively increased during CSA therapy. These discrepancies
557
LOW-DOSE CSA IN ACTIVE SLE
between Feutren’s immunologic findings and ours
might be explained, to some extent, by differences
both in the severity of disease activity in the patients
studied and in the dosage of the combined corticosteroids.
Regarding the effect of CSA on the number of
circulating mononuclear cells, we found no significant
changes in the numbers of T cells, CD4+ cells, CD8+
cells, CD4+, 45RA+ cells, or B cells. Other methods
that could reflect changes in the quantity of “autoreactive lymphocytes,” including CD4-, CD8- y/6T cells
(13), might elucidate the effects of CSA on autoantibody production. There is a wealth of detailed information on the effects of CSA on interleukin-2 (IL-2)
synthesis by T cells (1-3), and we are therefore now
investigating whether low-dose CSA can reduce IL-2
synthesis by CD4-t T cells to the same extent as does
high-dose CSA. This approach may also illuminate the
effects of this drug on autoantibody production.
Little is known about the effects of CSA on B
cells. Mayus et a1 (14) have recently shown that
anti-DNA antibody production by isolated B cells of
MRL-lprllpr mice was much more sensitive to CSA
than was total immunoglobulin production in vitro.
This finding correlates with our finding that titers of
both ANA and anti-DNA antibodies decreased independently of the amount of total IgG. However, even
in experimental mice, conflicting findings have been
presented regarding whether CSA actually reduces
titers of anti-DNA antibodies in vivo (15-22). As is the
case with the effects of CSA on B cells, there is little
information available about the effects of the drug on
the complement system. More data are needed to
determine whether and how CSA influences the consumption of complement and the production of autoantibodies by B cells.
The reasons for the increase in neutrophil and
platelet counts after CSA therapy are obscure. It is
possible that CSA might inactivate T cells, which
secrete potent myelosuppressive substances, including interferon-? (23). It is also possible that titers of
both antineutrophil and antiplatelet antibodies decreased. These assumptions must be tested in future
experiments.
All side effects observed in our patients were
tolerable and none necessitated the discontinuation of
CSA. Although Feutren et a1 (11) reported a high
incidence of hypertension and nephrotoxicity, the
dosage of CSA used in their study was higher than that
used in ours: the mean k SD trough level of CSA in
their patients was 346 f 84 ng/ml at the sixth month,
compared with 77.4 t 38.2 ng/ml in our patients at the
twentieth week. Furthermore, we used NAG and
urinary p,m as markers of renal damage; these 2
parameters are now considered more sensitive than
BUN and creatinine for assessing this (7,8). Hence,
these factors might explain the lower incidence of side
effects in our study compared with previous reports.
In conclusion, although the small number of
patients in this study precludes the formulation of
definite conclusions, our findings strongly suggest that
low-dose CSA can reduce the activity of SLE. It will
be necessary to carry out randomized trials to establish the role of CSA in the treatment of this disease.
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