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Effect of high-dose methylprednisolone infusion on polymorphonuclear leukocyte function in patients with systemic lupus erythematosus.

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ARTHRITIS
64 1
&
RHEUMATISM
0F F I C I A L J 0 U K N A L 0F T H E A ME R I C A N R H E U M ;I\-1-1SM ASS 0C I A T I 0N
SECTION O F T H E A R T H R I T I S F O U N D A T I O N
EFFECT OF HIGH-DOSE
METHYLPREDNISOLONE INFUSION ON
POLYMORPHONUCLEAR LEUKOCYTE FUNCTION
IN PATIENTS WITH
SYSTEMIC LUPUS ERYTHEMATOSUS
H. DANIEL PEREZ, ROBERT P. KIMBERLEY, HOWARD B. KAPLAN, HENRY EDELSON,
ROBERT D. INMAN, and IRA M. GOLDSTEIN
We have studied the effect of high-dose (1 gm)
methylprednisolone infusion on polymorphonuclear leukocyte (PMN) function in 11 patients with active systemic lupus erythematosus (SLE). The only alteration
of polymorphonuclear leukocyte function produced consistently by methylprednisolone was decreased adherence to plastic surfaces when tested 2 hours after infusion. This steroid-induced abnormality, however, was
transient. Cells obtained from patients 24 hours after a
single dose of drug exhibited normal adhesiveness.
These results indicate that single, large doses of methylprednisolone do not produce long-lasting abnormalities
of PMN function in patients with lupus.
From the Department of Medicine, Division of Rheumatology, New York University Medical Center, New York, NY 10016 and
the Department of Medicine, The Hospital for Special Surgery and
The New York Hospital, Cornell University Medical College, New
York, NY 10021.
Supported by grants from the National Institutes of Health
(AM-18531, AM-25374, and EY-03179) and the Kroc Foundation.
H. Daniel Perez, MD: Assistant Professor of Medicine, recipient of NIAMDD Clinical Investigator Award (AM-00463); Robert P.
Kimberley, MD: Assistant Professor of Medicine; Andrew W. Mellon:
Teacher-Scientist; Howard B. Kaplan, MS; Henry Edelson, BA; Robert D. Inman, MD: Assistant Professor of Medicine; Ira M. Goldstein,
MD, FACP: Associate Professor of Medicine, recipient of a Career
Scientist Award from the Irma T. Hirschl Trust.
Address reprint requests to H. Daniel Perez, MD, The Medical Service, 5-H-22, San Francisco General Hospital, San Francisco
CA 941 10.
Submitted for publication July 8, 1980; accepted in revised
form December 4, 1980.
Arthritis and Rheumatism, Vol. 24, No. 5 (May 1981)
Continuous administration of large doses of adrenal corticosteroids has been advocated for the treatment of active nephritis in some patients with systemic
lupus erythematosus (SLE) (42). Such therapy, however, results in a variety of adverse effects (3). For example, prolonged administration of steroids has been
implicated as an important contributing factor to the
unusually high incidence of infections observed among
patients with SLE (4-6).
The deleterious effect of steroids on host defenses
against infection has been attributed, at least in part, to
drug-induced depression of polymorphonuclear leukocyte (PMN) function. High concentrations of steroids in
vitro have been demonstrated previously to reduce the
ability of normal PMN to migrate in response to chemotactic stimuli (7,8), to generate superoxide anion radicals (9), and to degranulate in response to surface stimulation (9,lO). Furthermore, studies in human volunteers
have demonstrated that continuous administration of
prednisone (50 to 60 mg daily) diminishes the ability of
PMN to adhere to artificial surfaces in vitro (1 1,12) and
to migrate extravascularly in vivo (13).
Recently, large doses of intravenous methylprednisolone (1 gram daily for 3 days) have been advocated for the treatment of active nephritis in lupus patients (14). Indeed, we have found this so-called pulse
therapy capable of improving creatinine clearance in a
group of patients with active systemic lupus who were
suffering from the recent onset of glomerulonephritis
( 15,16).
PEREZ ET AL
642
Table 1. Clinical and laboratory findings in patients with SLE
Patient no.
1
2
3
4
5
6
7
8
9
10
II
* ESR
=
Age
(years)
Disease
duration
(months)
29
26
14
22
22
25
28
23
42
17
36
84
24
9
37
27
3
6
3
24
28
29
Prednisone
(mg/day)
ESR*
(mm/hour)
CH50
(units)t
25
None
None
15
70
20
59
50
52
90
58
23
93
54
31
<50
82
t50
t50
67
73
1I9
4 0
150
<50
93
10
None
None
None
5
2.5
5
Raji cell
bindingt
AntiDNA
(% binding)?
64
46
100
90
70
360
950
200
175
435
450
125
155
71
100
98
36
11
98
100
100
34
erythrocyte sedimentation rate.
t Normal values: total complement hemolytic activity (CH50),
150-250; antiDNA binding activity, <25%; Raji cell binding, 3.8
&
3.4 pg equiva-
lents of heat-aggregated human IgG/ml.
It has been suggested that short-term therapy
with even very large doses of corticosteroids would not
affect host defenses adversely and, in particular, would
not influence PMN function as severely as continuous
administration of these compounds. There have been no
reports, however, concerning the effects on P M N function of either short- or long-term administration of high
doses of corticosteroids in lupus patients. Therefore, we
have examined in a small group of patients with active
SLE the effects of large doses of intravenous methylprednisolone on several PMN functions.
MATERIALS AND METHODS
Patient population. The study population was composed of 11 patients with well-documented systemic lupus
erythematosus who were followed by the Rheumatology Division at the Hospital for Special Surgery and the New York
Hospital-Come11 University Medical Center. Controls included healthy, volunteer blood donors who were matched to
the patients with respect to age and sex. The criteria for diagnosis of SLE were those of the American Rheumatism Association (17). Patients ranged in age from 14 to 42 (mean 26
years). There were 10 females and 1 male.
None of the patients had very severe impairment of
renal function (blood urea nitrogen greater than 35 mg/dl or
serum creatinine greater than 2.0 mg/dl). All patients, however, had a diminished creatinine clearance. Eight patients
had diffuse proliferative lupus glomerulonephritis, 1 patient
had focal proliferative glomerulonephritis, and the remaining
2 patients had membranous lupus glomerulonephritis. All
diagnoses were confirmed by percutaneous renal biopsy. All
patients received 1 gram of methylprednisolone sodium succinate intravenously over 30 minutes on 3 successive days for
treatment of active lupus nephritis.
Routine chemical analyses were performed by the
Clinical Pathology Laboratories of the Hospital for Special
Surgery and the New York Hospital. Serum antiDNA antibodies were determined by a modified Farr technique (18).
Total hemolytic complement was measured by the method of
Kent and Fife (19). Circulating immune complexes were measured by the Raji cell assay (20). All serologic determinations
were performed on serum samples stored at -70°C within 4
hours of venipuncture. Determinations of serum levels of
methylprednisolone (measured as methylprednisolone and
methylprednisolone hemisuccinate) were kindly performed by
the Upjohn Co, Kalamazoo, Michigan.
Studies of PMN function. Adherence of PMN to plastic surfaces was measured by using a minor modification of a
method described previously (21). Briefly, 1.0 ml aliquots of
purified leukocytes (1 X lo6 PMN) (22) suspended in phosphate (10 mM) buffered 140 mM NaCl, pH 7.4, supplemented
with 0.6 mM CaCl, and 1.0 mM MgCl, (PCM), were incubated in plastic Petri dishes (35 mm diameter) (Falcon Plastics Division of BioQuest, Oxnard, California) for 30 minutes
at 37OC. After washing 3 times with 140 mM NaC1, the betaglucuronidase content of adherent cells was extracted with 1.0
ml of 0.2% (v/v) Triton X-100 (Calbiochem, San Diego, California). The beta-glucuronidase activity in both these extracts
and those of the original cell suspension (1 X lo6 PMN) was
measured as described previously (9). Percentage of adherence was calculated as: enzyme activity extracted from adherent cells/total enzyme activity (1 X lo6 PMN) x 100.
PMN chemotaxis was assessed as described previously
(23). Leukocyte suspensions containing approximately 85%
PMN were prepared from venous blood by dextran sedimentation (9,23). Cells were suspended in PCM containing 2.W0
(w/v) bovine serum albumin (Grand Island Biological Co,
Grand Island, New York). As a chemoattractant, we used human serum in which the alternative complement pathway had
been activated with zymosan (1.0 mg/ml) (Nutritional Biochemicals Div, International Chemical and Nuclear Corp,
Cleveland, Ohio) (23).
PMN random motility and directed migration
(chemotaxis) were assessed by using the “leading front”
method of Zigmond and Hirsch (24). The responses of PMN
to either buffer alone (random motility) or zymosan-treated
serum (ZTS) are reported as the distance that the leading
front of cells migrated into 3.0 pm pore-diameter cellulose nitrate micropore filters separating the upper, or cell, com-
METHYLPREDNISOLONE FOR SLE
partments from the lower, or stimulus, compartments of modified Boyden chambers @/35 minutes). Triplicate chambers
were used in each experiment and 10 fields were examined in
each filter.
Generation by PMN of superoxide anion radicals (i.e.,
superoxide dismutase-inhibitable cytochrome C reduction)
and degranulation (i.e., extracellular release of the lysosomal
marker enzyme, beta-glucuronidase) were measured as described previously (9,23) in reaction mixtures containing 3 x
lo6 PMN, cytochalasin B (5.0pg/ml) (Aldrich Chemical Co.,
Milwaukee, Wisconsin), and opsonized zymosan (2.0 mg/ml).
Superoxide anion generation is expressed as nmol cytochrome
C reduced/l5 minutes/l X lo6 PMN. The extent of degranulaton is expressed as percentage of total enzyme activity
released by Triton X-100 (0.276, v/v) from simultaneously
run, duplicate reaction mixtures. All values were corrected for
background activity in medium blanks.
RESULTS
Clinical and laboratory findings in patients with
SLE. All 11 patients with systemic lupus erythematosus
had active disease associated with elevated erythrocyte
sedimentation rates, low levels of total hemolytic complement, high titers of antiDNA antibodies, and evidence of circulating immune complexes (Table l). Six
patients were receiving oral therapy with corticosteroids
at the time they were initially studied. One patient was
receiving 25 mg of prednisone daily, two were being
treated with 10 and 15 mg daily, two were receiving 5.0
mg daily, and one was being treated with only 2.5 mg
daily. Patients 1, 9, and 10 also were receiving therapy
with azathioprine (50 to 100 mg daily).
None of the remaining 5 patients were receiving
therapy with either corticosteroids or immunosuppressive agents at the time the study was performed.
None of the patients had a history of bacterial infections
and no episodes of infections were documented either
Table 2. Absolute numbers of circulating PMN in patients with
SLE before and after infusion of methylprednisolone
PMN/pl
Patient no.
I
2
3
4
5
6
7
8
9
10
I1
Before
methylprednisolone
24 hours after
mcthylprednisolone
8,750
5,500
3,060
6,216
2,952
2,176
2,709
4,290
1,400
2,856
2,268
10,800
ND
15,318
15,960
4,752
ND
5,890
8,580
2,904
4,828
6,160
643
80
7c
8
-
0
0
0
0
60 - :
W
V
b
c
50
-0
a
c
0
a
0
0
0
g
r
c
0
0
4c
-..
0
0
W
:
a 3c
2c
0
8
L
1c
0
0
~~
Norma I
Subjects
SLE
SLE
SLE
Before 2 hours 24 hours
Infusion
After Infusion
a
Figure 1. Adherence of normal and SLE PMN to plastic surfaces
during or after pulse therapy with methylprednisolone.
In almost all cases, administration of intravenous
methylprednisolone resulted in an increase in circulating PMN. This increase was apparent after 2 hours and
persisted for 24 hours (Table 2).
P M N functions. PMN from all 1 1 patients with
active SLE were studied before the intravenous administration of 1 gram of methylprednisolone sodium succinate. PMN were obtained from 8 patients 2 hours after,
and from 5 patients 24 hours after methylprednisolone
infusion. In addition, PMN from 2 of these patients
were studied at 2 and 24 hours after steroid administration.
When examined before the administration of
methylprednisolone, PMN from the lupus patients were
found to be comparable to normal PMN with respect to
their ability to adhere to plastic surfaces (Figure l), to
migrate randomly and in a directed fashion (Figure 2),
to generate superoxide anion radicals (Figure 3), and to
degranulate in response to surface stimulation (Figure
4). Values for superoxide anion generation and degranulation by SLE PMN were not significantly different from the values obtained when normal PMN were
PEREZ ET AL
644
unchanged in the other 4 patients (Figure 3). PMN
degranulation was diminished in one and unaltered or
increased in the remaining 4 patients (Figure 4). Similar
results were observed when PMN from patients 2 and 4
were studied before, as well as 2 and 24 hours after, a
5-cond intravenous infusion of methylprednisolone (results not shown).
a
P
130
a
E
i
-
120
DISCUSSION
C
0
5
5
a
A
Normal
Subjects
9 *
A
SLE
Before
Infusion
A
A
Before pulse therapy with methylprednisolone,
polymorphonuclear leukocytes from 11 patients with
active SLE behaved comparably to normal cells with respect to their ability to adhere to plastic surfaces, to migrate randomly and chemotactically, to generate superoxide anion radicals, and to degranulate in response to
surface stimulation. It should be emphasized that these
studies were performed either in the complete absence
of serum or in the presence of serum from normal donors. Furthermore, superoxide anion generation and
degranulation were measured in an experimental system (i.e., with cytochalasin B-treated PMN) that excludes particle ingestion as a variable (9).
Consequently, these studies would not have revealed either defects in phagocytosis (25) or other abnormalities of PMN function that could be mediated by
SLE
2 hours
SLE
24 hours
After Infusion
Figure 2. Migration of normal and SLE PMN toward buffer (A = random motility) and toward zymosan-treated serum (2.070, v/v) (0 =
chemotaxis).
used in the assays. Furthermore, the ability of SLE
PMN to generate superoxide anion and to degranulate
was similar to that of normal PMN even when suboptimal concentrations of opsonized zymosan particles
were used. Neither the presence of active disease nor the
high levels of circulating “immune complexes” in sera
from these patients (Table 1) appeared to have any effect on the PMN functions studied.
Two hours after administration of methylprednisolone, at a time when the mean serum drug concentration was 10.8 pg/ml (2.2 X 10-5M), the ability of
SLE PMN to migrate randomly and in a directed fashion was unaffected (Figure 2). Superoxide anion generation was diminished in l patient (Figure 3), and degranulation was reduced by approximately 30% in 3
patients (Figure 4). PMN adherence, however, was decreased by at least 50% in 7 of 8 patients tested (Figure
1). Intravenous administration of normal saline in
amounts comparable to those used during the infusion
of methylprednisolone had no effect on PMN adherence.
Twenty-four hours after steroid infusion, at a
time when the mean serum concentration of methylprednisolone was 0.2 pg/ml (4 x lO-’M), PMN adherence had returned to normal (Figure 1). PMN random
motility and chemotaxis remained unaltered. Superoxide anion generation was depressed in 1 patient and
E
U
a,
20
V
3
!A
15
01
-
Ec
I
I
Before
Infusion
I
I
, 2 hours
24 hours
,
I
After Infusion
Figure 3. Generation of superoxide anion radicals by stimulated SLE
PMN before and after infusion of methylprednisolone. Mean values
(+ SEM): SLE PMN before infusion, 18.2 f 1.7; normal (control)
PMN, 18.6 + 1.7 (n = 11).
METHYLPREDNISOLONE FOR SLE
factors in SLE serum (26-29). Such factors in SLE
serum have been demonstrated previously as being capable of influencing PMN adhesiveness (26), chemotaxis (23,27,28), particle ingestion (29), and degranulation (29).
Washed PMN from patients with SLE have been
reported previously to behave like normal cells in vitro
with respect to their ability to adhere to artificial surfaces (26) and to migrate randomly and in a directed
fashion (30,31). Furthermore, low doses of prednisone
(less than 40 mg daily) have been demonstrated to have
no effect on several functions in vitro of PMN from either patients with SLE (30) or patients undergoing renal
transplantation (32). Consequently, it is not surprising
that we found that PMN from SLE patients receiving
low doses of corticosteroids were capable of functioning
normally in vitro.
Administration of single, large doses of methylprednisolone sodium succinate intravenously to patients
with active SLE had no effect on the ability of their
PMN to migrate in vitro, either randomly or in a directed fashion. Similar results were obtained in studies
of PMN from normal volunteers who received large
doses (60 mg) of prednisone orally (12). Despite the
ability of PMN from steroid-treated individuals to respond to chemotactic stimuli in vitro, it has been reported that these cells do not migrate normally in vivo
from the vascular compartment into dermal abrasions
(i.e., Rebuck skin windows) (13).
It is unclear, however, whether this is a reflection
of abnormal PMN chemotactic responsiveness in vivo
or simply a consequence of decreased PMN adherence
to vascular endothelium (33). It should be noted that although incubation of normal PMN with methylprednisolone in vitro has been shown to diminish chemotactic responsiveness (7, 8), the concentrations of drug
required to produce this effect were 50-100 times
greater than the concentrations observed in serum from
our patients.
Single large doses of methylprednisolone produced only minor and inconsistent effects on the ability
of SLE PMN to generate superoxide anion radicals and
to degranulate in response to surface stimulation. These
PMN functions, which are essential for normal microbicidal activity (34), apparently can be inhibited by
methylprednisolone in vitro but only after cells are incubated with very high concentrations of drug (9). Corticosteroid-induced depression of these PMN functions
in vivo has not been reported.
The only alteration of SLE PMN function produced consistently by infusion of methylprednisolone
645
Q)
v)
0
Q)
-
&!
Q)
u)
0
16-
\
PEREZ ET AL
646
nism accounted for these results. It has been demonstrated previously that administration of even small
doses of adrenal corticosteroids to human volunteers alters the distribution of PMN in the intravascular compartment (36). Samples of peripheral venous blood from
steroid-treated individuals contain PMN that previously
were sequestered within the bone marrow and in the
marginating pool (i.e., cells that were weakly adherent
to vascular endothelium) (36,37). Consequently, it is
quite possible that the inhibition of PMN adhesiveness
observed after infusion of large doses of methylprednisolone reflected only these changes in the population of circulating PMN.
Whatever the explanation may be for our findings, it is apparent that single, large doses of methylprednisolone do not produce long-lasting abnormalities
of PMN function in patients with systemic lupus erythematosus. It is possible, therefore, that intravenous
pulse therapy with methylprednisolone might be less
likely to affect host defenses against infection adversely
than continuous oral administration of high doses of
corticosteroids.
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