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The “Big
Shot” Revisited: 25 Years of
Methylprednisolone Pulses.
John J. Miller,
M.D., Ph.D
Key words: Intravenous corticosteroids,
methylprednisolone, pulse therapy, rheumatic diseases, children
Introduction
The title of this review comes from that of an editorial in Lancet in
1977 [1] which discussed with some surprise the relatively benign nature of the
then new but increasing use of large intravenous boluses of corticosteroids in
transplants, nephritis and systemic lupus erythematosus in adults. It is an extension of a talk at the Park
City IV meeting of Pediatric Rheumatology [2], and, while meant as a review, it
includes editorial opinion and personal unpublished experience. The reason for writing the review is
that, despite 25 years of use, there are still great differences in the way
boluses are given and in what is expected of them in respect to both beneficial
results and complications in different centers. While pediatric rheumatologists and
nephrologists are in general comfortable and experienced with the use of
“pulse” steroid boluses, the general pediatric and medical
community is not always so. This
review will try to cover what is known about “mega-dose”
corticosteroid therapy, and to point out areas about which we are still
ignorant. As with many of our
drugs, not all effects of pulses can be explained by what we know. The situation is complicated by the fact
that the term “pulse” has been used to describe single boluses,
boluses given for 3 days in a row, or in a variety of alternate day programs
for periods of up to 12 days.
History
Very
large intravenous doses of glucocorticosteroids, large by comparison with the
usual daily oral doses, had been used in desperate situations such as acute
transplant rejection [3] or severe renal involvement in systemic lupus
erythematosus since the late 1960's [4, 5]. Pediatric nephrologists started to use
methylprednisoline boluses on alternate days for 2 weeks followed by gradually
less frequent boluses to treat children with resistant nephrotic syndrome in
the early 1970's [6]. The
doses used in adults, 1 to 2 g, were based on a study of young normal adult
male volunteers to determine a safe dose to use in treating traumatic shock
[7], and this was translated into doses of about 30 mg/kg in children. Initially the times of infusion were
also based on the study done in young normal adults, 10 to 20 minutes.
The pharmacokinetics of intravenous methylprednisolone are complex
[8]. There is a rapid peak with a
subsequent serum half life of 3 hr.
A very large proportion of the intravenous bolus rapidly enters the gut,
manifest in part by the appearance of a metallic taste in the mouth, and this
reenters the venous space via the splanchnic circulation causing a secondary
peak in the serum level.
Studies specifically in children have shown similar kinetics, but up to
5 fold variations in serum half-lives between individual children [9]. The drug must be demethylated in the
liver to become pharmacologically active as prednisolone, a fact which led to a
comparative study with similar doses of oral prednisolone [8]. The kinetics of equivalent doses of oral
prednisolone were essentially the same as intravenous methylprednisoline
[8]. Prednisolone is not
available in an oral form which would allow very large doses in the United
States, but parenteral prednisolone powder can be put into gelatin capsules and
be given orally. However, an
attempt to use prednisolone in this manner in a few children at Stanford
resulted in complaints of nausea and malaise for several hours, and the
children definitely preferred the intravenous infusion. This should be looked at again with the
use of ondansitron.
At
the time that we started using mega-dose pulses of corticosteroids at Stanford
in the mid 1970's, there was anticipation that there would be significant
and limiting metabolic side effects.
When these problems were not seen in our first desperately ill patients,
we started to use pulses children who were less severely ill, but had resistant
disease or were unacceptably toxic on their more standard medication [10]. We compared two regimens: single boluses
of methylprednisoline at 30 mg/kg up to 1 g, or 4 repeated doses of 500 mg of
hydrocortisone at 6 hour intervals.
We measured urinary excretion of sodium, potassium and uric acid for 24
hr before and for 2 days after the one or first bolus. As expected there was reduced excretion
of sodium and increased excretion of potassium and uric acid, but only for the
first 24 hr, and the differences were so slight that only the reduction in
excretion of sodium after infusion of hydrocortisone reached statistical
significance. No differences were
noted in total blood cell counts cells.
Although the use of hydrocortisone in this manner has disappeared, two
of our early patients expressed a clear preference for it because they suffered
less malaise than after methylprednisolone, and it might be considered a viable
alternative in some patients.
There
are relatively few reports of the metabolic effects of large boluses of
methylprednisolone. Cortisol levels
do drop initially but return to normal levels within 24-48 hr after infusions
[11]. The 5 patients studied at
Stanford after long courses [10] had normal morning and evening cortisol
variation and ACTH responses after 3 months to 5 years of weekly boluses. Bijlsma et al. [12, 13] studied bone
metabolism in adults with rheumatoid arthritis, finding decreased calcium gut
absorption and renal excretion, increased parathyroid hormone and 1,25
dihydroxycholecalciferol, and decreased bone resorption and formation
immediately after single boluses [12], but no net change except for a slight
decrease in hydroxyproline excretion after 3 boluses given on alternate
days [13]. This was confirmed by a study of
deoxypyridinoline excretion as a measure of bone collagen degradation [14].
There
are reasons to believe that the very high levels of steroid obtained by pulse
methylprednisolone therapy have qualitatively different pharmacologic effects
which are not just a result of more drug molecules exaggerating the same
mechanisms. Boumpas [15] found that
high doses of glucocorticoids increased NF-kappaB
binding proteins in the cytosol thus reducing the amount of the
pro-inflammatory transcription factors that could reach the nucleus and
activate the genes for IL-1, IL-6, and TNF-alpha,
but this only occurred at concentrations within the cell obtainable by the
highest oral or intravenous doses.
Buttgereit et al. [16] have postulated 3 “modules” of
glucocorticoid effect on cells resulting from different concentrations: 1) low
concentrations bind to cytosol receptors which move to the nucleus to become
direct transcription factors for genomic events; 2) medium concentrations bind
as well to cell surface receptors which activate cross membrane signal
transmission for genomic and non-genomic intracellular events; and 3) at very
large concentrations steroids dissolve in the cell membrane resulting in
greater membrane stability and reduced non-genomic cell function
generally. Both groups propose that
the effects they describe or postulate may be related to increased
immunosuppression, although this is an effect which has not in fact been
demonstrated (vide infra).
Immunology and Anti-inflammatory Activity
Silverman and Myones [17] showed that there was an acute drop in
circulating T and B cells 5 hr after infusion of methylprednisoline, but that
pre-infusion levels had returned within 24 hr, except for the population
stained by Leu-3a monoclonal antibodies, presumed helper T cells, which reached
normal levels by 48 hr. This data,
using different labeling methods for CD 4 and CD 8 cells has been confirmed by
others [18]. These findings, along with the lack of significant rise in uric
acid excretion, indicate that these doses do not, as expected, kill a
measurable number of cells, but probably caused transient redistribution
between the circulation and lymphoid organs.
Normal
immune responses do not appear to be affected by large pulses of
methylprednisolone. Fan et
al. [19] found no change in circulating immunoglobulins, primary or secondary
antibody responses, or delayed hypersensitivity skin reactions after single
boluses of 1 g or pulses of 1 g per day for three consecutive days in
adults. We studied 5 children who
had received single boluses once per week for periods of from 3 months to 3 years
but no oral steroid or immunosuppressant drugs, and found normal immunoglobulin
levels in 4 of 6, abnormally low levels in one, and abnormally high levels in
one [10]. Primary responses to
pneumococcal vaccine were normal as were delayed hypersensitivity reactions to
antigens to which the children had been exposed before the treatment. However, Smith et al. [20] found that in
adults with rheumatoid arthritis a three day pulse resulted in lowered
immunoglobulins and a drop in the titer of rheumatoid factor and levels of
circulating immune complexes, but, again, delayed hypersensitivity remained
intact. Other presumed
auto-antibodies have been reported to decrease after pulse steroid therapy
alone [4,21]. However,
immunological effects of pulse steroids have been studied in the absence of
immunosuppressive drugs in only a few instances, and do not allow us to be sure
that the change in autoantibody levels are not just secondary to the
anti-inflammatory effect.
Most
of the work on the mechanisms of anti-inflammatory action of steroid pulses has
been done by Smith's group in Australia in adults with rheumatoid
arthritis [22-26]. They labeled
peripheral blood and synovial fluid neutrophils from patients with radioactive
technetium, and re-injected them intravenously or back into the synovial cavity
before and after single steroid boluses [22]. Before pulsing, the neutrophils injected
intravenously localized in the inflamed joints while the synovial fluid cells appeared
to migrate to draining lymph nodes, although it is not clear whether they were
following intact cells or cell debris draining from the joints. After the pulse, circulating neutrophils
no longer entered the joints while the synovial cells still migrated to lymph
nodes as before. They subsequently
demonstrated a decrease in the cell surface adhesion molecules CD 11b, CD 18
and L-selectin on neutrophils in peripheral blood after a 1g intravenous bolus
of methylprednisolone [23].
Synovial fluid neutrophils had decreased cell surface CD 11b and CD 18,
but increased L-selectin.
Histological studies of synovial biopsies after similar boluses showed
reduction of expression of the adhesion molecules E-selectin and ICAM 1 in
endothelial cells, and of ICAM 1 in synovial lining cells [24]. These adhesion molecules are
up-regulated by proinflammatory cytokines, particularly TNF-alpha [27], and Youssef et al. [25] have
shown that expression of TNF-alpha is
decreased in peripheral blood, synovial fluid, and synovial tissue after single
boluses of methylprednisolone. In
addition, macrophages in the synovial lining layer, but not deeper in synovial
tissue, had reduced cell surface marker proteins associated with activation and
cytokine production after pulses [26].
Thus it appears that the methylprednisolone pulses down regulate
macrophage activation and proinflammatory cytokine production leading to
reduced expression of adhesion molecules and reduced movement of neutrophils
into inflamed joints. Interestingly,
these effects are qualitatively similar to those seen with anti-TNF-alpha
therapy [28].
While
there is no reason to doubt that these anti-inflammatory effects also occur in
children, they do not explain all of the clinical phenomenon seen after
pulses. Down regulation of the
state of activation of, and cytokine production by, phagocytes in
systemic-onset juvenile idiopathic arthritis would explain the sometimes
dramatic, transient effect on fever spikes. However, it is hard to relate these
findings to the more reliably obtained dramatic drops in muscle-derived enzymes
after boluses of methylprednisolone seen in juvenile dermatomyositis, in which
acute inflammation with macrophages or neutrophils is not ordinarily seen. It is tempting to speculate that methylprednisolone
also depresses TNF-alpha expression
by muscle fibers directly since TNF-alpha
is over expressed in muscle fibers in some untreated children with
dermatomyositis [29]. Alternatively
one could postulate a direct effect on endothelial cells, where the primary
pathology occurs in this disease, or perhaps an effect on myocyte membrane
stability as proposed by Buttgereit et al. [16].
There
is an extensive cardiovascular surgery literature on the use of large
methylprednisolone boluses which has recently been reviewed by Chaney
[30]. Thirty m/kg boluses are
routinely given before or before and during cardiac bypass surgery to
ameliorate the “systemic inflammatory response syndrome” which is
thought to be the result of mechanical activation of the complement system by
bubble oxygenating pumps. Chaney
[30] has a strong bias that this use of bolus methylprednisolone has not been
shown in fact to have clinical efficacy, but he quotes extensive literature
that shows that patients with this syndrome who receive bolus steroids have
lower circulating levels of complement activation fragments and the
pro-inflammatory cytokines IL-1, IL-6, IL-8 and TNF-alpha and have higher levels of anti-inflammatory IL-4 and IL-10.
Adverse
side effects of high dose methylprednisolone boluses in adults are quite
diverse in adults [31,32] and in children [33]. In spite of the early expectations,
serious side effects in children are rare, although mild ones are common. In my experience most patients
complained of a metallic taste in the mouth, malaise for several hours after
the infusion, and a manic or euphoric state on the day after. Mild hypotension occurred in otherwise
normotensive children during the relatively rapid infusions that were used
early in our experience.
Klein-Gitelman's detailed study of adverse effects in children [33] noted
more and varied significant behavioral complaints, but only in 10% [33]. The most significant serious effects in
children are increased blood pressure in already hypertensive children during
and in the hours after the infusion, seizures particularly in systemic lupus
erythematosus [32], which may be related to the flux in electrolytes in
patients with clinical or sub-clinical central nervous system disease, and
anaphylactic shock after even only one prior infusion. This last is due to the
methylprednisolone itself [34, 35].
Other forms of corticosteroids may also cause anaphylaxis [35], but it
is not clear whether all are contraindicated after a reaction to one, since
skin test reactivity varies from one to another steroid in individual patients
[34] but never seem very reliable from patient to patient [35]. As with oral steroids, prolonged use of
pulses may be associated with cataract formation, but most other effects, such
as Cushingoid facial appearance are not as severe as with daily steroid
therapy. Bradycardia and
cardiovascular collapse have been reported in the pediatric oncology literature
[36]
Rational
use of single or of three repeated methylprednisolone boluses should be based
on the premise outlined above: i.e. that profound but transient
anti-inflammatory effects are to be expected, but not immunosuppression. In theory pulse methylprednisolone
should be adequate and less toxic than daily oral steroids in inflammatory
diseases in which natural remissions are expected, as in systemic-onset
juvenile idiopathic arthritis, a disease known to be associated with
over-expression of pro-inflammatory cytokines [37]. Indeed, Adebajo and Hall [38] have
reported treating 18 patients with this disease by using single pulses of
methylprednisolone and non-steroidal drugs without oral steroids or to decrease
oral steroids, using return of fever or systemic features as an indication to
repeat the bolus, but never more frequently than every 4 days. This usually resulted in frequent
boluses at the initiation of therapy but gradual reduction in frequency. All parameters of inflammation showed
improvement in greater than 50% of the patients. In my experience at Stanford using
exactly the same method, most children treated in this manner reached remission
of systemic features in several months without becoming Cushingoid or
hypertensive. Relapses occurred in
some but not all children. The
course of the arthritis per se in
these children, as opposed to the systemic manifestations, is not clear,
particularly in respect to the longer term outcome. Three day pulses followed by a bolus of
cyclophosphamide and weekly methotrexate have been reported to be effective for
months in this disease [39].
Empirically
steroid boluses are known to be useful in juvenile dermatomyositis, but, as
pointed out above, the reason for the effectiveness is not clear. When pulse therapy first came into
vogue, attempts were made to treat juvenile dermatomyositis by pulses alone because
the effect on muscle enzyme concentration in blood is so rapid and usually
dramatic, but this is potentially a devastating disease, and this treatment
should not be primary but as an adjunct to aggressive oral therapy. In the leucocytoclastic vasculitides
characterized by polymorphonuclear cell infiltration of the vessel wall, pulse
methylprednisolone pulses should reduce acute inflammation but not remove the
immune complexes presumably triggering the inflammatory cascade, nor affect the
causative agent. In my
experience pulmonary hemorrhage and hemolytic anemia in systemic lupus
erythematosus rapidly and reliably respond to steroid pulses, but boluses in
lupus carry a risk of hypertension and seizures, must be used cautiously, and
mainly are indicated as an adjunct to cyclophosphamide pulse therapy for lupus
nephritis [40]. I do not consider
as “pulses” the high doses of methylprednisolone given at 6 hour
intervals for several days in lupus crises or in CNS lupus. There is, of course, a large body of
experience reported in the pediatric nephrology literature regarding use of
intravenous pulse steroid therapy, particularly in the nephrotic syndrome
[6]. Newer uses have been reported
in
Although
less used by internist rheumatologists than by pediatricians, pulse
methylprednisolone therapy is being used in rheumatoid arthritis
[11-14,18,20-26,31,32]. Particular
interest has been its role as “bridge” therapy while waiting the
effects of slower-acting disease modifying drugs [45,46]. It has been compared equivalently for
efficacy and toxicity with the effects of infliximab in theory [28] and in
practice [47]. As with children,
there are many individual case reports of successful use in a variety of
inflammatory diseases.
Although pulse methylprednisolone may provide symptomatic relief in
inflammatory diseases, it may not change the long term course of any specific
disease. The girl with ankylosing
spondylitis described in detail previously [10] had had to drop out of high
school due to pain uncontrolled by any modality then available, but was able to
finish a Master's degree while receiving weekly pulses. However, her spine fused completely
during that period in spite of her relative comfort. Similarly, eye disease progressed to
blindness in a child with early onset sarcoidosis whose anterior chamber cell
count, arthritis, and skin disease were controlled by boluses every other week.
Pulses
of high doses of methylprednisolone, either singly or repeated over a period of
three days, have a significant but transient anti-inflammatory effect, probably
due to down regulation of phagocyte activation. They must also have other effects not
yet understood, and probably have unique pharmacologic properties not just
related to exaggerating mechanisms obtained with lower doses. In the absence of other therapy, they
have not by themselves been shown to suppress normal immune responses. When used in appropriate diseases and
circumstances, large intravenous pulses of corticosteroid are cumulatively less
toxic than sustained steroid treatment at lower quantitative dosage, but no
evidence exists that by themselves they can cure or alter long term outcomes in
diseases which are not by themselves self-limited.
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