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The effects of cyclosporin a on eicosanoid excretion in patients with rheumatoid arthritis.

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48 1
BRIEF REPORT
THE EFFECTS OF CYCLOSPORIN A ON EICOSANOID EXCRETION IN
PATIENTS WITH RHEUMATOID ARTHRITIS
M. WEINBLATT, S. HELFGOTT, J. COBLYN, J. SPRAGG, W. M. UEDELHOVEN, S. TUMEH, R. SPERLING,
R. LORENZ, A. MAIER, and P. WEBER
Alterations in renal eicosanoid levels have been
postulated as a factor in cyclosporin A (CSA) nephrotoxicity. The effects of CSA on renal eicosanoid excretion in rheumatoid arthritis were studied over a 24-week
period, during which treatment with nonsteroidal antiinflammatory drugs was discontinued. The initial dosage of CSA was 4 mglkglday; at week 24, the mean
dosage of CSA was 3.9 mglkglday. At week 24, the mean
(2SD) serum creatinine level (1.04 2 0.24 mg/dl) was
32% above the baseline value; renal blood flow had
decreased by 21% (P < 0.03) and the glomerular
filtration rate had decreased by 16%. There was a
significant increase (P < 0.03) in the 2,3-dinor thromboxane B, level at week 2, but there was no significant
change in the levels of the other eicosanoids. This study
demonstrates that after CSA treatment, there is a
selective increase in a thromboxane metabolite that
parallels an increase in renal vascular resistance, even in
the absence of nonsteroidal antiinflammatory drugs,
From the Department of Rheumatology and Immunology
and the Department of Radiology, Brigham and Women’s Hospital,
Harvard Medical School, Boston, Massachusetts, and the Institut
fur Prophylaxe und Epidemiologie der Kreislaufkrankheiten, b.d.
Universitat Munchen, Munich, Germany.
Supported in part by grant HL-35949 from the US Public
Health Service and by grants from Sandoz Pharmaceuticals, Inc.
M. Weinblatt, MD: Harvard Medical School: S. Helfgott,
MD: Harvard Medical School; J. Coblyn, MD: Harvard Medical
School; J. Spragg, PhD: Harvard Medical School; W. M. Uedelhoven, MS: Universitat Munchen; S. Tumeh, MD: Harvard Medical
School: R. Sperling, MD: Harvard Medical School; R. Lorenz, MD:
Universitat Munchen; A. Maier, BA: Harvard Medical School; P.
Weber, MD: Universitat Munchen.
Address reprint requests to M. Weinblatt, MD, Department
of Rheumatology and Immunology, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115.
Submitted for publication June 7, 1990; accepted in revised
form November 6. 1990.
Arthritis and Rheumatism, Vol. 34, No. 4 (April 1991)
and with unimpaired formation of other vasodilator
eicosanoids.
Multiple trials have demonstrated the efficacy
of cyclosporin A (CSA) in the treatment of active
rheumatoid arthritis (RA), but nephrotoxicity frequently occurred (1-4). The mechanism of CSA nephrotoxicity is unknown; an alteration of renal eicosanoid metabolism has been proposed as a factor.
This trial was designed to determine the effects of CSA
on renal eicosanoid excretion in RA patients who were
not receiving concomitant treatment with nonsteroidal
antiinflammatory drugs (NSAIDs).
Patients and methods. Ten patients with active
RA signed informed consent forms and entered the
study (Table 1). The study excluded patients with a
serum creatinine value greater than the range of normal (0.6-1.3 mg/dl) at baseline. Other standard exclusion criteria were also utilized in this study, and are
described elsewhere (1).
This was a 6-month open trial of CSA, in which
NSAIDs and aspirin were discontinued 2 weeks prior
to initiation of CSA therapy. These drugs and all
second-line therapies were not taken during the
6-month trial period. Eight patients continued to take
their stable dosage of prednisone (<15 mg/day). Acetaminophen, propoxyphene, and codeine were allowed for control of pain.
The initial dosage of CSA was 4 mg/kg/day. The
dosage could be increased to 5 mg/kg/day at week 12 if
efficacy was not apparent, or it could be decreased if
toxicity occurred. Bottle counts and serum levels of
CSA demonstrated a high degree of compliance. CSA
was temporarily discontinued if any of the following
occurred: the white blood cell count fell below 3,5001
BRIEF REPORTS
482
Table 1. Characteristics of the rheumatoid arthritis patients studied
-
Age (vears)
_,
Mean
Range
Sex
Female
Male
Disease duration (months)
Mean
Range
Prior therapy
Gold salts
Methotrexate
D-penicillamine
Azathioprine
Sulfasalazine
Functional class
Class I1
Class 111
Rheumatoid factor 2 1: 160
Prednisone dosage 5 15 mgiday
54.2
41-70
7
3
137
42-288
10
10
7
6
3
4
6
9
8
mm3, the platelet count fell below 1.0 X 105/mm3,the
hemoglobin value decreased to below 9.0 gm/dl, serum
creatinine or blood urea nitrogen levels increased to
greater than 30% of the baseline values, liver enzyme
levels increased to twice the upper limits of normal, or
whole blood CSA levels increased above 600 ng/ml.
There was a I-month washout period following
completion of the 6-month trial. Each patient was
examined biweekly (by the same physiciadinvestigator) for 2 months and then monthly thereafter. Visits
were scheduled for the same time of day. Vital signs
and standard clinical disease variables (1) were determined at each visit.
Laboratory tests were obtained every 2 weeks for
2 months, and monthly thereafter. Tests included a
urinalysis, complete blood cell count, serum chemistry
screen, and a whole blood trough level of CSA (by
radioimmunoassay). Serum rheumatoid factor was
tested at baseline, and a Westergren erythrocyte sedimentation rate was obtained at baseline and at week 24.
A 12-hour collection of urine was obtained for
the baseline visit (prior to discontinuation of NSAIDs)
and at weeks 0, 2, 4, 6 and 8, and monthly thereafter.
Urine was stored at 4°C during the collection period. A
3-ml sample was frozen at -70°C for radioimmunoassay of kallikrein content (5). Creatinine clearance was
calculated directly, by using the data obtained from
the 12-hour urine sample.
Duplicate 50-ml urine samples were stored at
-30°C and analyzed for eicosanoid content. At the
baseline visit (prior to discontinuation of NSAIDs) and
at weeks 0, 2, 6, 12, 24, and 28, prostaglandins (PG) in
the urine were analyzed. PGEz, 6-keto-PGF,,, thromboxane B, (TXB,), and the 2,3-dinor TXB, were
measured by radioimmunoassay using a highly specific
antibody against the respective eicosanoids after extraction and separation of the eicosanoids by high
performance liquid chromatography (6-8). The 2,3dinor 6-keto-PGF1, was measured by gas chromatography-mass spectrometry after extraction and
back-extraction (8).
Renal blood flow and glomerular filtration rates
were measured at week 0 and at week 24. Following an
intravenous injection of 2-5 mCi of y9mTc-DTPA,
blood samples were drawn at 5 , 20, 44, 60, 120, and
180 minutes. As the 180-minute blood sample was
drawn, 0.1 mCi of '3'I-orthoiodohippuran (OIH) was
injected intravenously. Blood samples were obtained
again at 3, 10, 20, 44, and 60 minutes. The glomerular
filtration rate and effective renal plasma flow rate were
calculated from clearance curves of ""Tc-DTPA and
I3'I-OIH by comparing the sample counts with known
amounts of radioactivity (9,lO).
Study parameters were analyzed by the difference in group means between each visit and the entry
visit by Student's t-test, with a log transformation
when appropriate. An endpoint analysis, using the last
visit at which the patient took CSA as the final visit,
was also performed by Student's t-test to account for
premature patient withdrawals.
Results. The dosage of CSA was increased to 5
mglkglday at week 12 in 2 patients because of a lack of
clinical efficacy. At week 12, the mean dosage of CSA
was 3.7 mgikglday (range 1-5), and at week 24, the
mean dosage was 3.9 mg/kg/day (range 1-5). Two
patients withdrew prior to completion of the study
because of adverse reactions: 1 at week 4 (nausea) and
1 at week 16 (thrombophlebitis). A significant improvement was noted in the clinical disease variables
from weeks 12 through 24 (Table 2).
The mean (-CSD) serum creatinine level before
treatment was 0.84 ? 0.13 mgldl. There was a significant increase ( P < 0.01) in serum creatinine levels by
week 2 (Table 3). The mean percent increase in serum
creatinine, however, remained below 30% throughout
the study, except at week 24, when it peaked at 1.04 k
0.24 mg/dl, or 32% above the baseline level. After the
4-week washout period, the mean serum creatinine
level was 0.89 5 0.08 mg/dl, or 13% above the baseline
level. In 4 patients, an increase in the serum creatinine
level of more than 30% necessitated reduction of the
CSA dosage.
BRIEF REPORTS
Table 2.
Changes in clinical variables during cyclosporin A therapy*
Variable
No. of
patients
Value at
study entry
Change
from baseline
P
9
8
10
42.4 f 11.2
43.0 t 11.8
39.4 f 14.3
13.3 f 14.2
8.5 t 11.8
6.8 ir 9.3
0.02
0.08
0.04
9
8
10
35.2 f 11.6
36.4 t 11.9
33.3 2 12.5
10.8 f 15.4
17.0 2 13.8
10.9 ? 32.0
0.07
0.01
0.06
8
7
9
84.1
86.3
76.3
f 31.4
f 33.3
f 37.6
32.4 ir 48.2
36.1 ir 40.5
23.4 f 32.0
0.10
0.05
0.06
9
8
9
46.2 t 17.7
48.6 t 17.3
46.2 t 17.7
17.1 t 24.0
27.4 t 20.0
17.7 t 18.9
0.06
0.006
0.023
9
8
10
4.3 f 0.7
4.4 ir 0.7
4.1 2 0.9
1.0 t 0.87
0.75 f 0.71
0.4 f 0.7
0.008
0.02
0.10
9
8
10
4.3 f 0.7
4.4 f 0.7
4.1 f 0.9
1.0 t 0.87
0.88 t 0.83
0.40 t 0.7
0.008
0.02
0.10
9
8
10
154 f 112
160 f 118
141 t 113
35 f 130
79 t 96
-6 t 88
0.4
0.05
0.8
No. painful joints
12 weeks
24 weeks
Endpoint
No. swollen joints
12 weeks
24 weeks
Endpoint
Joint tenderness/
pain index
12 weeks
24 weeks
Endpoint
Joint swelling
index
12 weeks
24 weeks
Endpoint
Physician global
assessment
12 weeks
24 weeks
Endpoint
Patient global
assessment
12 weeks
24 weeks
Endpoint
Duration of
morning
stiffness
12 weeks
24 weeks
Endpoint
~~
* Values are the mean
SD. Two patients withdrew prior to study
completion because of adverse reactions: 1 at week 4 and 1 at week
16. For explanation of scoring systems, see reference 1.
2
The calculated creatinine clearance changed
significantly ( P < 0.02) only at week 2, when it
decreased from a mean 2 SD value of 93.2 ? 35.8
mllminute to 73.9 t 23.8 ml/minute. A corresponding
increase (P < 0.004) in the blood urea nitrogen levels
was noted by week 6. Blood urea nitrogen levels
decreased when the drug was discontinued or the
dosage was decreased. There were no significant
changes in the serum potassium or serum magnesium
levels during the study. The mean total kallikrein
excretion decreased from a baseline level of 126.1 2
51.8 pg/24 hours, but statistical significance ( P < 0.03)
was reached only at week 2, when the value decreased
by 42% to 52.6 2 55.4 pgl24 hours.
There was a significant reduction ( P < 0.03) in
the renal plasma flow at week 24, with a reduction of
91.5 +- 72.0 ml/minute (mean t SD) from a baseline
level of 431.8 t 126.7 ml/minute (21% decrease). The
glomerular filtration rate decreased by 16% at week 24,
with a reduction of 16.6 +- 27.3 ml/minute, but this was
not a significant reduction from the baseline value of
101.2 ? 23.9 ml/minute.
There was no significant change in the urinary
excretion of PGE,, 6-keto-PGF1,, or the 2,3-dinor
6-keto-PGF1, (Figure 1). All of these values remained
in the low normal range (Table 4). Because of the short
half-life of thromboxane A,, its metabolites (TXB, and
the 2,3-dinor TXB,) were measured; these metabolites
serve as excellent markers of in vivo thromboxane A,
formation. TXB, levels did not change significantly,
but there were large variations in individual patients,
with a trend toward an increase, particularly at weeks
2-6. The 2,3-dinor TXB, level increased and reached
statistical significance at week 2 ( P = 0.028). This
increase did not correlate with the serum creatinine
levels, the creatinine clearance rate, or with increases
in blood pressure.
Four patients developed hypertension (defined
as a diastolic blood pressure >90 mm/Hg), which
required therapy with calcium channel blockers or
Table 3. Serum creatinine levels before, during, and after cyclosporin A therapy*
Study
week
No. of
patients
Baseline
value
Visit
value
Difference
P
2
4
6
8
12
16
20
24
28
9
10
10
9
9
8
8
8
7
0.86 ? 0.13
0.84 ir 0.13
0.84 f 0.13
0.82 f 0.13
0.82 t 0.13
0.80 f 0.12
0.80 t 0.12
0.80 t 0.12
0.80 f 0.12
0.96 f 0.18
0.95 f 0.22
0.90 f 0.27
0.91 t 0.22
1.00 2 0.29
0.94 f 0.15
0.94 f 0.15
1.04 t 0.24
0.89 f 0.08
0.11 f 0.08 (13)
0.13 f 0.13 (15)
0.08 f 0.20 (8)
0.10 ir 0.14 (11)
0.20 t 0.24 (24)
0.14 f 0.08 (18)
0.14 t 0.13 (18)
0.26 t 0.21 (32)
0.10 ? 0.06 (13)
0.007
0.02
0.27
0.08
0.05
0.02
0.02
0.02
0.03
* Cyclosporin was discontinued after week 24. Values are the mean 2 SD rngidl or the mean t SD
change from baseline. Numbers in parentheses are the percentage of change from baseline.
BRIEF REPORTS
484
-
Y
OA.
4
'
' i z ' i 6 ' 2 0 ' 2 4 ' i 8
tj
Weeks
CYCLOSPOWN
Figure 1. Mean urinary excretion of eicosanoids, over time, during
a 6-month trial of cyclosporin A in patients with rheumatoid
arthritis. Cyclosporin A was administered from weeks 0-24 and was
discontinued during weeks 24-28. TXB, = thromboxane B,; 6 keto
PGF,, = 6-keto-prostaglandin F,a.
angiotensin-converting enzyme inhibitors. Two of
these patients had a history of mild hypertension that
was previously well controlled but required higher
doses of antihypertensive agents during the study.
Other side effects included nausea in 5 patients, headaches in 4, hypertrichosis in 3 , abdominal discomfort
in 3 , gingival hyperplasia in 2, flushing in 1, paresthesias in 1, and fatigue in 1 patient.
Discussion. The efficacy of cyclosporin A in
active rheumatoid arthritis has been noted, but varying
degrees of renal dysfunction have been observed (14). Nonsteroidal antiinflammatory drugs have been
implicated as a possible risk factor for this toxicity. It
has also been proposed that CSA alters the balance of
the vasodilator prostacyclin and the vasoconstrictor
thromboxane in renal cortical tissue (1 1-1 3 ) , leading to
renal toxicity. An increase in urinary TXB, produced
by renal cells and an increase in the 2,3-dinor TXB,
produced, for example, by macrophages and platelets
have been noted in rats treated with CSA (14). The
purpose of this study was to determine the effects of
Table 4.
Study
week
Baseline
2
6
12
24
28
CSA on renal prostaglandin excretion and to determine whether CSA, when admi'nistered without
NSAIDs, would produce nephrotoxicity .
In this study, CSA did not induce a general
activation of the eicosanoid system. The selective
increase in a thromboxane metabolite 2,3-dinor TXB,
suggests activation of the thromboxane pathway in
cells that possess this pathway, including platelets,
monocyte/macrophages, and mesangial cells. These
data suggest that in some patients, CSA can increase
thromboxane levels in vivo; this finding confirms the
findings of experimental studies in rats (14). Whether
this increase in thromboxane levels is causative in the
nephrotoxicity of cyclosporin A remains to be determined.
Serum creatinine elevations were less marked
in patients in this study; however, serum creatinine
levels and creatinine clearance rates are not sensitive
indices of glomerular injury, and they underestimate
changes in the physiologic glomerular filtration rate.
Progressive glomerular disease may be concealed by
tubular hypersecretion of creatinine; it has been estimated that a 50% reduction in the glomerular filtration
rate is necessary before there is an increase in the
serum creatinine level (15). Determinations of the
glomerular filtration rate and the renal blood flow rate
are required to provide a more accurate measurement
of renal function during CSA therapy. With lower
doses of CSA and discontinuation of NSAIDs, there
was still a 21% reduction in the renal plasma flow rate
and a 16% reduction in the glomerular filtration rate
after 24 weeks of therapy.
We have demonstrated that mild renal dysfunction and hypertension occurs with cyclosporin A therapy, independently of the coadministration of nonsteroidal antiinflammatory drugs. A global effect on the
renal eicosanoid excretion was not seen with CSA
therapy; however, a selective increase in a thromboxane metabolite was observed. Whether the increase in
Urinary levels of eicosanoids before, during, and after cvclosporin A therapy*
No. of
patients
PGE,
6-keto-PGF1,
2,3-dinor
6-keto-PGF1,
TXB,
2,3-dinor
TXB,
130 ? 73
112 ? 91
116 t 88
192 2 187
163 f 79
172 2 106
203 t 117
225 f 144
137 t 72
125 t 81
343 2 286
145 f 98
128 t 133
97 t 64
125 2 71
116 87
196 t 322
101 f 51
211 t 206
313 t 328
242 2 239
145 2 151
138 t 124
124 f 81
690 2 1,000
1,629 f 1,419
2,348 t 3,800
1,312 t 1,280
1,089 t 742
617 4 561
*
* Values are the mean 2 SD ngi24 hours (see Patients and Methods for details). P > 0.05 for all comparisons with baseline, except for the level
of the 2,3-dinor TXB, at week 2, for which P = 0.028 (versus baseline). PGE, = prostaglandin E,; TXB, = thromboxane B,.
BRIEF REPORTS
this vasoconstrictor eicosanoid has a direct effect in
inducing nephrotoxicity is not known. Therapeutic
strategies designed to attenuate thromboxane production as a possible method for reducing nephrotoxicity
should be explored in patients receiving cyclosporin A.
REFERENCES
1. Weinblatt ME, Coblyn JS, Fraser PA, Anderson RJ,
Spragg J, Trentham DE, Austen KF: Cyclosporin A
treatment of refractory rheumatoid arthritis. Arthritis
Rheum 30: 11-17, 1987
2. Dougados M, Awada H , Amor B: Cyclosporin in rheumatoid arthritis: a double blind, placebo controlled
study in 52 patients. Ann Rheum Dis 47:127-133, 1988
3. Yocum DE, Klippel JH, Wilder RL, Gerber NL, Austin
HA, Wahl SM, Lesko L , Minor JR, Preuss HG, Yarboro
C, Berkebile C, Dougherty S: Cyclosporin A in severe,
treatment-refractory rheumatoid arthritis: a randomized
study. Ann Intern Med 109:863-869, 1988
4. Tugwell P, Bombardier C, Gent M, Bennett KJ, Bensen
WG, Carette S, Chalmers A, Esdaile JM, Klinkhoff AV,
Kraag GR, Ludwin D, Roberts RS: Low-dose cyclosporin versus placebo in patients with rheumatoid arthritis. Lancet 335:1051-1055, 1990
Spragg J, Weinblatt ME, Coblyn J, Fraser P, Austen
KF: Effect of cyclosporine on urinary kallikrein excretion in patients with rheumatoid arthritis. J Lab Clin
Med 112:324-332, 1988
Scherer B, Schnermann J, Sofroniev M, Weber PC:
Prostaglandin (PG) analysis in urine of humans and rats
by different radioimmunoassays: effect on PG-excretion
by PG-synthetase inhibitors, laparotomy and furosemide. Prostaglandins 15:255-266, 1978
485
7. Scherer B, Fischer S, Siess W, Weber PC: Analysis of
6-keto-prostaglandin F1a in human urine: age-specific
differences. Prostaglandins 23:41-52, 1982
8. Fischer S, Bernutz C, Meier H, Weber PC: Formation of
prostacyclin and thromboxane in man as measured by
the main urinary metabolites. Biochim Biophys Acta
876:194199, 1986
9. Hilson AJW, Mistry RD, Maisey MN: 99mTc DTPA for
the measurement of glomerular filtration rate. Br J
Radio1 49:794-796, 1976
10. Taux WN, Dubovsky EV, Kidd T, Diaz F, Smith LR:
New formulas for the calculation of effective renal
plasma flow. Eur J Nucl Med 751-54, 1982
11. Coffman TM, Carr DR, Yarger WE, Klotman PE: Evidence that renal prostaglandin and thromboxane production is stimulated in chronic cyclosporine nephrotoxicity. Transplantation 43:282-285, 1987
12. Neild GH, Rocchi G, Imberti L, Fumagalli F, Brown Z,
Remuzzi G, Williams DG: Effect of cyclosporine on
prostacyclin synthesis by vascular tissue in rabbits.
Transplant Proc I5 (Suppl 1):2398-2400, 1983
13. Neild GH, Rocchi G, Imberti L, Fumagalli F, Brown Z,
Remuzzi G, Williams DG: Effect of cyclosporin A on
prostacyclin synthesis by vascular tissue. Thrombosis
Res 32:373-379, 1983
14. Kawaguchi A, Goldman MH, Shapiro R, Foegh ML,
Ramwell PW, Lower RR: Increase in urinary thromboxane B2 in rats caused by cyclosporine. Transplantation
40:214-216, 1985
15. Ross EA, Wilkinson A, Hawkins RA, Danovitch GM:
The plasma creatinine concentration is not an accurate
reflection of the glomerular filtration rate in stable renal
transplant patients receiving cyclosporine. Am J Kidney
Dis 10: 113-1 17, 1987
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