Intravenous Pulses of Methylprednisolone for Systemic Lupus

Erythematosus
Humeira Badsha and Christopher J. Edwards
Background: Intravenous (IV) pulses of methylprednisolone (MEP) commonly
are used to treat severe manifestations of systemic lupus erythematosus (SLE).
However, despite wide use of this treatment the best dose, timing, and the
situations in which this treatment should be used remain largely anecdotal.
Aim: To review the mechanisms of action and evidence for clinical use of IV
MEP in the treatment of SLE.
Method: The literature on MEP use in SLE from 1966 to 2002, using PubMed
from the National Library of Medicine, was reviewed.
Results: As with other modes of corticosteroid administration, IV MEP has
signicant anti-inammatory and immunosuppressive actions. These actions
have been shown to be effective in treating SLE in clinical trials, for lupus
nephritis. The studies are mainly uncontrolled and retrospective. Long-term
observations from a few double-blind prospective trials suggest that monthly
pulses of MEP, in addition to IV cyclophosphamide, may be useful. Pulse MEP
is benecial for several serious manifestations of SLE, such as neuro-psychi-
atric lupus, pulmonary hemorrhage, severe blood dyscrasias, cardiomyopathy,
and vasculitis. However, signicant side effects may occur, mostly infections,
which are worse in patients with hypoalbuminemia.
Conclusion: IV pulses of MEP rapidly immunosuppress patients with organ
and/or life-threatening manifestations of SLE. However, the gold standard 1
g/day for 3 consecutive days is associated with signicant infectious compli-
cations and lower doses may be just as useful.
Semin Arthritis Rheum 32:370-377. 2003 Elsevier Inc. All rights reserved.
INDEX WORDS: Infection; methylprednisolone; mortality; systemic lupus ery-
thematosus.
I
NTRAVENOUS (IV) pulses of methylpred-
nisolone (MEP) are commonly used to treat the
severe manifestations of systemic lupus erythemato-
sus (SLE). They allow a large dose of corticosteroids
to be delivered rapidly to sick patients who may not
absorb oral medication. However, despite wide use,
the best dose, timing, and circumstances in which this
treatment should be used remain largely anecdotal.
METHODS
We reviewed the literature on MEP use in SLE
from 1966 to 2002 by using PubMed from the
National Library of Medicine with the following
search words: systemic lupus erythematosus, SLE,
lupus, treatment, methylprednisolone, pulse meth-
ylprednisolone, corticosteroids.
RESULTS
Prednisolone and Methylpredisolone
The most commonly used glucocorticoid in the
treatment of patients with SLE is oral pred-
nisolone. Prednisolone at doses of 7 to 15 mg/day
is used frequently to treat symptoms of mild to
From the Department of Rheumatology, Allergy and Immu-
nology, Tan Tock Seng Hospital, Singapore; and Department of
Rheumatology, Southampton University Hospitals, Southamp-
ton, England.
Humeira Badsha, MD: Consultant, Department of Rheuma-
tology, Allergy & Immunology, Tan Tock Seng Hospital,
Singapore; Christopher J. Edwards, MD, MRCP: Consultant,
Department of Rheumatology, Southampton University Hospi-
tals, Southampton, England.
Address reprint requests to Humeira Badsha, MD, Consul-
tant Rheumatologist, Department of Rheumatology, Allergy &
Immunology, Tan Tock Seng Hospital, 11 Jalan Tan Tock Seng,
Singapore 308433.
2003 Elsevier Inc. All rights reserved.
0049-0172/03/3206-0002$30.00/0
doi:10.1053/sarh.2002.50003
370 Seminars in Arthritis and Rheumatism, Vol 32, No 6 (June), 2003: pp 370-377
moderate SLE. At higher doses of 1 to 1.5 mg/kg
body weight oral prednisolone improves survival
of patients with severe SLE (1). Prednisolone is
poorly water-soluble, but the addition of methyl
groups produces MEP that can be used intrave-
nously. The concentration of MEP achieved after
an IV pulse is proportional to the dose used (2,3).
Within its therapeutic range, MEP has linear pro-
tein binding with approximately 77% bound to
albumin (4). In contrast, oral prednisolone binds in
a nonlinear manner to albumin and exhibits com-
petitive and saturable binding to cortisol binding
globulin (CBG) (5) (Table 1). The duration of
MEP action is 24 to 72 hours after the pulse IV
dose and does not change signicantly even with
higher doses. After 24 hours, approximately 99%
of the IV pulse MEP is eliminated and the main
effects that persist beyond this time are related to
lymphocyte function (3,6).
Inammation and Immunity
Anti-inammatory and immunosuppressive ac-
tions of glucocorticoids. Glucocorticoids act by
binding to glucocorticoid receptors (GR) in the cell
cytoplasm. After binding, steroid-receptor com-
plexes translocate to the nucleus and modulate
gene expression. Glucocorticoids are anti-inam-
matory and immunosuppressive with broad func-
tions on lymphocytes, neutrophils, mononuclear
phagocytes, cytokine production, and cell trafck-
ing (7). In particular, glucocorticoids cause lym-
phopenia, monocytopenia, neutrophilia (8), reduce
the T cell response to interleukin (IL)-1, inhibit B
cell proliferation, reduce total immunoglobulin
production, inhibit monocyte chemotaxis and in-
uence Fc receptor function. In addition, produc-
tion of the cytokines tumor necrosis factor
(TNF)-, interferon (IFN)-, IL-1, IL-2, and IL-3
is inhibited. The effect of glucocorticoids on cyto-
Table 1: Anti-inammatory and Immunosuppressive Effects of Prednisolone Compared
With Pulse MEP
Prednisolone, Oral IV MEP
Equivalent dose 1 0.8
Duration of action 12-36 hours 24-72 hours
Protein binding Binds albumin and cortisol binding
globulin
77% bound to albumin
Anti-inammatory
effects
2Capillary permeability, local blood
ow, endothelial swelling
Similar
Neutrophil effects Increase in peripheral blood neutrophil
numbers,2migration of neutrophils
to inammatory sites
Greater increase in neutrophil numbers
which stay elevated at 72 hours
Lymphocytes 2lymphocyte counts similar for doses
from 15 to 100 mg, occurs at 4-6
hours, and is normal by 24 hours
Lymphopenia more profound at 4-6
hours and reverses by 24-48
hours,2lymphocyte blastogenesis,
and2lymphocyte transformation
Monocytes 2monocytes, migration inhibition
factor, macrophage activating factor,
histamine, and prostaglandin
Similar
Humoral immunity Decreased B lymphocyte
responsiveness and immunoglobulin
synthesis.
Similar, but the decrease could last up
to 3 months
Cellular immunity Redirection of cellular trafc. Fewer
macrophages are presented to
antigen but immune recognition is
normal. Corticosteroids decrease T
cells, especially CD4/Th1 cells.
Similar
Abbreviation: Th, T helper.
371 PULSE METHYLPREDNISOLONE FOR SLE
kines appears to be caused, in part, by effects on
the transcription factors NF-B and activator pro-
tein-1 (9). These transcription factors are pivotal in
the expression of proinammatory cytokines such
as IL-1 , TNF-, and IL-2 (10).
Intravenous MEP is more immunosupressive?
Intravenous MEP produces greater immunosup-
pression and anti-inammatory actions than oral
prednisolone (11-13). Oral prednisolone causes a
similar decrease in lymphocyte counts in doses
ranging from 15 to 100 mg, occurring at 4 to 6
hours, and lasting 24 hours (8). With IV pulse
MEP therapy, the lymphopenia is more marked (a
decrease of 75% of total circulating lymphocytes),
but also occurs at 4 to 6 hours, but may last up to
48 hours (6,14,15). However, IV MEP has addi-
tional effects on lymphocyte development, causing
decreased lymphocyte blastogenesis (16) and sup-
pression of lymphocyte activation (6,17). In vitro
studies have shown that pulse MEP therapy has
immediate effects on lymphocyte activation by
interacting directly with the cell membrane and
decreasing intracellular Ca
2
concentrations (18).
Intravenous MEP also has prolonged effects on
immunoglobulin (Ig)G in healthy individuals, last-
ing up to 3 months (12,19). The decreased IgG
levels with IV pulse MEP in patients with SLE
may selectively affect antidouble-stranded DNA
titres, with a smaller effect on IgG antibodies to
bacterial and viral antigens (20). In addition, en-
hancement of fragment crystallizable receptor
mediated phagocytic function of monocytes in pa-
tients with SLE after IV pulse MEP is associated
with a decrease in circulating immune complexes,
suggesting that some of its therapeutic efcacy
may result from increased clearing of immune
complexes (21).
Choosing the best dose of IV MEP. Pulse IV
MEP in severe SLE generally has been given as
10 mg/kg (frequently, a dose of 1 g is used)
repeated daily for 3 days, which is equivalent to an
oral prednisolone dose of 1250 mg. This dose was
chosen after experience in treating graft rejection
in renal transplant recipients (22). Subsequently,
laboratory and animal experiments showed anti-
inammatory and immunosuppressive effects at
these doses. As the dosage of corticosteroids in-
creases there is an increase in several effects in-
cluding the inhibition of inducible cyclooxygen-
ase-2 (COX-2) (18). The dosage of corticosteroid
needed to achieve this is in the range of 200 to 300
mg of prednisolone equivalent per day. Adminis-
tration of this dose has been calculated to result in
nearly complete occupation of all GRs (7.5 mg and
15 mg of prednisolone result in 42% and 63%
binding of the receptors, respectively). A further
increase in dosage may result in receptor off-
loading, reoccupancy, and increased receptor syn-
thesis and expression, increasing the effects of
corticosteroids.
When 80, 250, 500, and 1000 mg of MEP were
compared in healthy volunteers and patients, neu-
trophil counts were maximally increased in the
1000-mg group. This effect lasted for 72 hours in
the 1000-mg group compared with 24 to 48 hours
in the others. The decrease in lymphocyte count
and suppression of lymphocyte transformation also
were more prolonged in the 1000-mg group (6).
Higher doses also may have additional therapeutic
benets because of nongenomic effects mediated
by membrane-bound receptors and initiated by
physicochemical interactions of corticosteroids
with cellular membranes (Table 2). MEP at high
doses (1000 mg) in vitro inhibits calcium and
sodium movement across plasma membranes, in-
creases proton permeability, and partially uncou-
ples oxidative phosphorylation, which may inhibit
lymphocyte activation.
Patients with SLE usually require higher doses
of glucocorticoids to control disease activity than
those with rheumatoid arthritis. This may be attrib-
uted to increased cortisol catabolism in lympho-
Table 2: Dose Effect Relationships of Corticosteroids
Prednisolone Doses Mechanisms Onset of Action
Low doses Genomic After 30 min
High dose up to 300 mg/day Genomic effects increase with higher doses
300-1000 mg/day Nongenomic receptor-mediated effects 1-2 min
1000 mg/day or greater Physicochemical membrane interactions seconds
372 BADSHA AND EDWARDS
cytes from patients with SLE (23). In addition,
some patients with SLE are relatively steroid re-
sistant, perhaps because of a reduced rate of glu-
cocorticoid-induced apoptosis among lymphocytes
(24). The mechanism underlying this is unclear but
may be a function of decreased numbers or poly-
morphisms of GR on peripheral blood mononu-
clear cells (25).
Recent clinical data suggest that lower doses of
MEP also may be efcacious. A group from Johns
Hopkins University showed that there was no in-
creased efcacy in treating patients with rheuma-
toid arthritis with 1000 mg MEP as compared with
100-mg doses (26). Recently, our group reported
that doses of pulse MEP at 500 mg daily for 3 days
are equally effective as conventional high-dose
therapy (27).
Clinical Uses of MEP
Methylprednisolone for lupus nephritis. Most
publications on IV MEP in SLE describe its use in
treating lupus nephritis; most are uncontrolled and
retrospective (Table 3). The use of MEP to treat
SLE was rst described in 1976 when it was given
to 7 patients with diffuse proliferative lupus ne-
phritis, and renal function improved in more than
half within 3 days (28). These patients had reduced
urine protein excretion attributable to increased
creatinine clearance. However, improvement in lu-
pus nephritis was not documented clearly. Subse-
quently, daily doses of IV pulse MEP as the initial
treatment for 43 patients with diffuse proliferative
lupus nephritis appeared efcacious (29). At 10
years, the renal survival rate was 91%, with only 4
patients failing to respond to treatment and pro-
ceeding to end-stage renal failure (30). Kimberly et
al (31) treated 34 patients with lupus nephritis with
pulse MEP in combination with cyclophosphamide
or azathioprine; renal improvement was noted in
35% of patients and 5 patients developed serious
infections and 4 died (32).
Most of the randomized, controlled trials for
treatment of lupus nephritis have come from the
National Institutes of Health. This includes 1 of the
largest groups of patients with SLE (n 82) with
proliferative lupus nephritis to receive pulse MEP
(33). Patients were randomized into 3 groups re-
ceiving either monthly doses of pulse MEP alone,
monthly doses of MEP in combination with IV
cyclophosphamide, or monthly cyclophosphamide
Table 3: Selected Clinical Trials Using Pulse MEP for SLE
Author (Reference) Year Study Design n Disease Manifestation Response to Therapy
Cathcart (28) 1976 Open label 7 Nephritis Improved
Dosa (64) 1978 Open label 4 Nephritis Improved
Eyanson (44) 1980 Open label 2 Coma, idiopathic
thrombocytopenia
purpura, anemia
Improved
Leibling (65) 1982 DB, PC 9 Nephritis Monthly IV; MEP improved
Isenberg (37) 1982 Open label 20 Various Improved
Ballou (66) 1985 Open label 11 Various No sustained improvement
Edwards (39) 1987 DB 21 Various No difference 100 or 1000 mg
Mackworth-Young (40) 1988 DB, PC 25 Various Response not sustained
Howe (49) 1990 Retrospective 39 Various Increased infection
Rose (67) 1991 Open label 35 Pediatric nephritis 30 mg/kg
Honma (35) 1994 DB 91 Nephritis MEP 400 mg/day better than
high-dose oral prednisolone
Bertoni (68) 1994 Open label 12 Nephritis Improved
Gourley (33) 1996 DB, PC 82 Nephritis IV cyclophosphamide MEP
more effective than MEP or
cyclophosphamide alone
Badsha (27) 2001 Retrospective 55 Various 500 mg/day effective, fewer
infections
Abbreviations: DB, double blind; MEP, methylprednisolone; PC, placebo controlled.
373 PULSE METHYLPREDNISOLONE FOR SLE
alone. The combination and cyclophosphamide-
alone groups achieved remission of nephritis more
frequently than the MEP group. However, it is
uncertain whether monthly IV MEP produced ad-
ditional benet over high-dose prednisone (1
mg/kg daily) in the combination group. Long-term
observations from this trial reported that the MEP
and cyclophosphamide combination groups had
higher rates of renal response and lower doubling
of serum creatinine than the cyclophosphamide-
alone group. In addition, Boumpas et al (34) found
that patients administered only pulses of MEP
monthly had a signicant risk of renal failure
compared with those who received monthly cyclo-
phosphamide infusions.
A study of 102 patients with lupus nephritis
administered either pulse MEP at doses of 400 mg
daily or high-dose oral prednisolone suggested
there were more favorable outcomes with regard to
laboratory values and physicians global assess-
ment in the MEP group (35). A 21-month prospec-
tive open label study of a single course of 3 doses
of MEP (20 mg/kg body weight) followed by
low-dose prednisolone showed control in 11 of 12
patients with lupus nephritis, and was equally ef-
fective as oral prednisolone (36). Impaired absorp-
tion of the oral prednisolone because of bowel
edema in nephrotic states also has encouraged the
use of the IV route for pulse therapy in life- or
organ-threatening disease.
Methylprednisolone for other manifestations of
SLE. Results of pulse MEP therapy for nonrenal
SLE are less clear. Several small open studies have
reported benecial effects of MEP pulses for var-
ious disease manifestations such as arthralgias,
pleurisy, vasculitis and fever (37), and dermatitis
refractory to high-dose oral prednisolone (38).
However, other studies have been less favorable or
suggest that pulse MEP at lower doses of 100 mg
may be equally effective (39,40). In addition, there
are reports of the successful use of IV pulse MEP
for bone marrow aplasia (41); thrombocytopenia
(42); gastrointestinal disease (43); central nervous
system lupus, including seizures (44), cerebrovas-
cular accidents (27), lupus cerebritis, aseptic men-
ingitis (45), transverse myelitis (46); and pulmo-
nary hemorrhage (47). A study of 22 patients with
central nervous system lupus showed equivalent
benet from pulse MEP at doses of 400 and 800
mg daily (45).
Side Effects
Side effects associated with use of high-dose IV
MEP infection. Infections are the most frequently
reported adverse effects of pulse MEP, occurring
more often in patients with SLE than in other
patients receiving MEP (32,48,49,50). Those who
received monthly infusions of high-dose pulse
MEP when receiving concomitant cyclophospha-
mide are particularly at risk of infection. In our
retrospective study of MEP administered to pa-
tients with SLE, a high rate of infections (23 of 55
patients) was reported (27). Similar infection rates
have been described in other studies from South-
east Asia (49,50). However, the higher incidence
of infections with pulse MEP therapy in these
patients may have been caused, in part, by the
severity of the disease are rather than just a higher
endemic rate of infection. Patients with SLE who
are administered pulse MEP may be at an even
higher risk for infections than those administered
conventional high-dose steroids because pulse
therapy considerably delays the secretion of lacto-
ferrin, the adherence of neutrophils, and impairs
bacterial killing and digestion (51,52). This is in
addition to the pan lymphopenia and decrease in
IgG and IgM levels.
Other Complications of MEP
A variety of neuropsychiatric complications such
as seizures, mania, psychoses, and hemiplegia have
been reported in patients with SLE receiving pulse
MEP therapy (53,54). Intractable hiccups (55), severe
arthralgia, and myalgia are among other adverse ef-
fects. In 1 study (56), arthralgias were the most
frequent adverse effect reported. It has been ob-
served, although not reported, that pulse MEP can
worsen pain at preexisting osteonecrosis sites.
Deaths Associated With MEP and Its Use in
Patients With Low Albumin Levels, Liver, and
Kidney Disease
In our retrospective study, patients with a low
albumin level who received MEP had more infec-
tious complications and increased mortality (27).
In patients with liver disease and hypoalbumine-
mia, a reduced steroid dose has been advocated; it
may be prudent to follow this policy when using
pulse MEP in hypoalbuminemic patients with SLE
(57). Most of the reported fatalities attributed to
pulse MEP have been caused by infectious com-
374 BADSHA AND EDWARDS
plications. Other causes of death include those
caused by arrhythmias, myocardial infarction
(56,58) usually attributed to sudden uxes of po-
tassium, or other electrolytes and uid-volume
changes. These cardiac toxicities are more com-
mon in renal transplant recipients. However, there
are no recommendations to use reduced doses with
renal impairment, because pulse MEP can reverse
signicant renal impairment in lupus nephritis and
renal allograft rejection (59).
Reduced Side Effects With Methylprednisolone?
There is little data concerning the long-term safety
of pulse MEP. The use of pulse MEP increases the
risk of osteoporotic fractures and avascular necrosis
(60,61). However, IV MEP therapy may have less
effect on the hypothalamic-pituitary-adrenal axis
(HPA) and cause less steroid-related side effects than
oral prednisolone. After IV MEP, endogenous corti-
sol production is reduced for 24 hours and the sup-
pression of the HPA lasts 2 to 3 days (62,63). This is
in contrast to prednisolone, in which doses of 20 mg
daily for as fewas 5 days cause more prolonged HPA
suppression that may last for months (13). There also
may be a reduction of total steroid dose after IV MEP
because this may allow a more rapid tapering of
subsequent oral prednisolone.
DISCUSSION
IV pulses of MEP is a way of rapidly immuno-
suppressing patients with organ- and/or life-threat-
ening manifestations of SLE. The efcacy of this
approach is well established especially in the con-
text of lupus nephritis in combination with cyclo-
phosphamide. Several smaller trials and anecdotal
reports attest to its usefulness in other serious
lupus manifestations such as pulmonary hemor-
rhage and neuropsychiatric lupus. However, the
gold standard of 1 g/day for 3 consecutive days can
be associated with signicant infectious complica-
tions and may be unnecessary. Recent work sug-
gests that doses of 500 mg/day may be equally
effective. This lower dosage regimen may be par-
ticularly important in individuals with a decreased
MEP binding capacity because of hypoalbumine-
mia.
The authors use pulse MEP in severe organ- or
life-threatening SLE, which appears particularly
useful in rapidly progressive glomerular disease.
However, we use 500 mg IV on 3 successive days
and reduce the dose further in patients with re-
duced albumin levels. Prospective studies are un-
derway to establish the efcacy of lower doses in
selective patients.
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