"Since being on prednisone, I’ve been
up and down with my weight and up and down with
the milligram dosage,” says Carlie Brinker.
“I’m 19, and I’ve been on prednisone
for 11 years.”
Prednisone is a corticosteroid that’s
commonly prescribed for inflammatory conditions,
such as the dermatomyositis
that Brinker has. Although potent and effective
at quelling an unwanted immune response, particularly
when inflammation is involved, the medication is
well known for its side effects (so much so that
Coping With Prednisone,
by Eugenia Zukerman and Julie Ingelfinger, published
in 1997 by St. Martin’s Press, remains popular
for those taking the drug). In Duchenne
muscular dystrophy, prednisone has been found
to stabilize or improve muscle function, often allowing
people to remain ambulatory for a longer time.
Among the frequent side effects of steroid use
are weight gain, osteoporosis, fat redistribution,
growth slowing, cataracts, and behavioral and mood
changes.
It isn’t easy to know whether you’re
on the right course with corticosteroids. Based
on current knowledge, finding the right balance
between benefits and disadvantages raises questions
about which drug to take, what dosage to use, how
long to take it, and how to deal with side effects.
Researchers and physicians in the field recommend
widely divergent directions, and may even find themselves
lost in the corticosteroid sea.
Steroids
& Autoimmune Diseases
Brinker knows that prednisone has helped her. On
a good day, she can walk the half mile to her sister’s
house; otherwise, a trip to the mailbox and back
to her family’s farmhouse in Millersburg,
Ohio, is about all she can manage.
Without prednisone, she’s not sure she’d
be able to move at all.
“I was off it once before, and I got totally
weak and was in a wheelchair, so they hurried up
and put me back on,” she recalls. “If
I go completely off it, the disease gets really
active, my muscles get weaker, and I’m not
able to do anything for myself.”
Fortunately for Brinker and many others with autoimmune
diseases, in which the body’s immune system
goes haywire and attacks its own tissues, prednisone
isn’t the only solution anymore. (Autoimmune
diseases in MDA’s program are polymyositis,
dermatomyositis,
inclusion-body myositis,
myasthenia gravis
and Lambert-Eaton syndrome.)
She’s now taking only 12.5 milligrams a day
of the drug, down from a high of 60 per day, along
with several other medications to suppress her immune
system and reduce inflammation. She’s also
in a clinical trial to test the immunosuppressant
rituximab (Rituxan).
But weight gain is a troublesome drawback. Although
she’s now on a low dose, Brinker’s weight
remains over 200 pounds, a lot for a 5-foot-1-inch
frame.
It’s also well known for its effects on the
psyche. “On prednisone, I can be happy one
minute and sad and crying the next minute,”
Brinker says, echoing a common theme.
Mimicking Cortisol
Synthetic corticosteroids like prednisone mimic
the actions of the natural hormone cortisol,
which is secreted by the cortex (covering) of the
adrenal glands. (Corticosteroids aren’t the
same as the anabolic steroids some athletes illegally
use. Those are based on sex steroids secreted by
the testes.)
Prednisolone, often prescribed in the United Kingdom,
is the compound to which prednisone is converted
in the body. Deflazacort, a newer synthetic corticosteroid
that isn’t approved by the U.S. Food and Drug
Administration, is available in Canada and some
European countries.
Normally, the adrenal glands secrete cortisol at
a low level each day but in a big burst when the
body is under stress.
Physiologists see adrenaline, with its ability to
increase heart and respiratory rate, as the “first
responder” to extreme stress. Cortisol can
be thought of as maintaining the body’s stress
response over a longer period of time. It raises
blood pressure and pours in blood sugar for extra
energy, breaking down fat, muscles and bones for
use as fuel, if necessary.
If cortisol levels remain high for a long period
of time, these tissues can be seriously affected.
Bone mass can be lost, muscles can be damaged (despite
the apparent benefit in MD), and fat at the periphery
of the body is broken down and redeposited in the
face, abdomen and back. Cataracts can also occur.
Carbohydrate metabolism changes, and weight increases.
Nonessential functions, such as growth and reproduction,
cease. And over the long term, the alert, attentive
brain required in an emergency can become anxious
and distressed.
The effect that’s desired from a corticosteroid
medication is dampening of the immune response,
particularly inflammation, probably to keep the
body from being damaged by excessive inflammatory
reactions from injury or infection. To achieve and
sustain a dampened immune response usually requires
high corticosteroid doses for prolonged periods
of time.
Dosage and Duration
Charting a successful corticosteroid course to treat
an autoimmune disease generally means taking the
lowest possible dose for the shortest possible time.
Timothy Miller, who directs the MDA clinic at Children’s
Clinics for Rehabilitative Services in Tucson, Ariz.,
has been on the horns of this dilemma many times.
“My goal with my patients on prednisone with
myasthenia gravis or polymyositis is to get them
on a dose that allows us to suppress their immune
system, to stop the disease process as much as we
can,” he says, “and then to slowly back
off that and get them on the lowest possible dose
that keeps them from relapsing.”
Another strategy is adding a second immune system
suppressant, which allows the patient to take a
lower corticosteroid dose.
“In myasthenia gravis, many people add a short-acting
drug, such as prednisone, and a longer-acting drug,
such as Imuran [azathioprine] or CellCept [mycophenolate
mofetil],” Miller notes.
Steroids
& Muscular Dystrophy
Duchenne muscular dystrophy
(DMD) is a relative newcomer to the list of
diseases treated by corticoster-oids. In fact, it
isn’t certain how these medications help in
this genetic disease, but reducing inflammation
associated with degenerating muscle tissue is a
leading hypothesis.
Taylor Fetrow’s DMD was diagnosed when he
was 3, but for four years, he held his own most
of the time with boys his age.
That began to change when he was 7. His energy flagged,
and he started having difficulty walking long distances.
His parents bought a wheelchair, which he used at
school in McKinney, Texas, to get between his classroom,
the cafeteria and the playground.
Stephanie and Chris Fetrow were hesitant about corticosteroids,
having heard a lot about side effects. But when
their doctor proposed an experimental dosing schedule
for their son — prednisone on Friday, Saturday
and Sunday only — they decided to take a chance.
The change in Taylor amazed his parents and even
his doctor, Susan Iannaccone, now director of the
MDA clinic at Children’s Medical Center of
Dallas.
“Immediately, we saw an increase in his energy,”
Stephanie Fetrow says. “Then, about six months
into the steroids, we realized that we had seen
a big increase in his ability and strength and stamina.
“He got to the point where he didn’t
want the chair around.” Taylor, now 13, hasn’t
used it since.
Walking Longer, Breathing
Better
Corticosteroid treatment trials in Duchenne MD go
back to the 1970s, but they didn’t become
widespread until the 90s. Since then, more than
a dozen clinical trials have demonstrated that a
corticosteroid, such as prednisone, prednisolone
or deflazacort, stabilized or improved muscle function
in boys with DMD. The most common side effects were
weight gain, fat redistribution, growth slowing,
cataracts and behavioral problems.
See “History of Corticosteroids in DMD” for details.
In 2004, a report from the European Neuromuscular
Centre said, “Children treated with daily
steroids are likely to walk for longer, have improved
respiratory function, may avoid the need for spinal
surgery and might have better heart function than
untreated children. Benefits of starting steroids
in children who have already lost ambulation are
not yet established. The two main types of steroid
used (prednisone/prednisolone and deflazacort) appear
to be equally effective.”
The report advocated a low-fat, low-calorie diet
to help minimize weight gain, and adequate intake
of calcium and vitamin D, with exposure to sunshine,
to promote bone health.
It also noted that side effects might be reduced
by giving steroids at a low dose or on a less than
daily schedule, but that neither alternative had
been tested against daily steroids.
In 2005, the American Academy of Neurology (AAN)
published guidelines suggesting that prednisone
given at 0.75 milligrams per kilogram of body weight
per day or deflazacort at 0.9 mg/kg/day is optimal
for prolonging muscle function in DMD. Side effects,
the guidelines say, must be monitored; if they become
too burdensome, the steroid dose should be reduced
to 0.5 mg/kg/day and then to as low as 0.3 mg/kg/day,
as necessary. The guidelines noted that there wasn’t
enough information to determine whether deflazacort
has fewer side effects than prednisone.
Staring Down Side
Effects
Miller, like many neuromuscular disease specialists,
is a firm believer in corticosteroids for DMD, along
with management of side effects.
“I always feel like it’s my failure
if I can’t communicate that well enough to
the patients’ families to make them understand
that side effects are deterrable and fixable, and
that if we follow patients appropriately, then we
can manage any complications that come up,”
he says.
Miller says it’s been known for years that
steroids are beneficial in regard to skeletal muscle
function and that “there’s evidence
now that respiratory function is preserved and that
cardiac function is improved in patients who have
been on steroids. I would say that nearly all of
my [DMD] patients are on steroids at some point
in the course of their illness.”
He acknowledges that side effects can be a problem,
but says that “all steroid side effects are
potentially treatable, although you may have to
change the dosage or the regimen.”
Miller follows patients’ weights at least
every four months and refers them to a nutritionist
in the clinic for specific guidance (see “War
on Weight Gain” ). “If you focus
on the problem of weight gain, I think you can reduce
it,” he says. “We try to intervene from
a nutritional standpoint.”
Miller orders a bone density scan when patients
start on prednisone and follows up with another
one yearly to every two years. He also prescribes
calcium and vitamin D to help offset bone loss from
corticosteroids.
He puts adults who take corticosteroids on medications
called bisphosphonates (such as Fosamax), which
interfere with bone breakdown, but he doesn’t
usually do that with children. “I think the
data on the use of bisphosphonates is limited in
children,” Miller says, “but certainly
in older kids and adults, I would not hesitate to
use a bisphosphonate if they were developing osteoporosis.”
Medications can also help with some of the psychological
effects of these drugs. Carlie Brinker takes imipramine
(Tofranil) for depression and lorazepam (Ativan)
for anxiety. A therapist has been an additional
source of support.
Miller offers families the option of either daily
prednisone at 0.75 mg/kg/day or high-dose, weekends-only
prednisone at 2.5 mg/kg day.
“We don’t know exactly if the weekend
dosing is as good as other dosing, but several centers
continue to collect data that’s positive,”
he says.
Not all doctors share Miller’s unbridled enthusiasm
for corticosteroids to treat DMD, but many MDA clinic
directors endorse their use.
John Kissel, co-director of the MDA clinic at Ohio
State University Hospital in Columbus, says about
70 percent to 90 percent of his Duchenne patients
start on corticosteroids, usually at the time when
a boy is falling more often and having trouble with
steps. About 50 percent stay on them for more than
five years. He tells parents they can expect to
see a mild to moderate improvement in strength with
steroids and that there may be other benefits.
“It seems to me that it’s relatively
uncommon to see a boy on steroids with this very
severe cardiomyopathy [heart muscle deterioration]
that we’re seeing in some of the other boys,”
Kissel says. “If we’ve got a boy in
his teens and we get an echocardiogram and it comes
back normal, it’s almost invariably a boy
on steroids.”
The Deflazacort Debate
Is deflazacort a better choice than prednisone in
DMD? Again, doctors disagree.
“On average, there was more of a weight problem
with the prednisone than there is with deflazacort,”
says Douglas Biggar, a professor of pediatrics at
the University of Toronto and staff pediatrician
at Bloorview Kids Rehab (Toronto), who has a special
interest in Duchenne MD. (Deflazacort is available
by prescription in Canada, but doctors have to get
special permission from a regulatory agency on a
case-by-case basis.)
“Why that is, I don’t know. Parents
also tell us that there’s less of a weight
problem with deflazacort,” Biggar says. “On
balance, it seems we have better luck using deflazacort
daily because we don’t have the weight problem
and some of the other side effects.”
On the other hand, Biggar says, he has seen cataracts
that result from deflazacort and bone loss (osteoporosis)
that might be related to it.
“Our data show that after you’re on
it for 10 or 12 years, there’s a 70 percent
chance that you’re going to have cataracts.
In my experience, with four exceptions out of 175,
they have not interfered with visual function.”
If visual difficulties arise because of the cataracts,
they can be surgically removed.
As for bone health, Biggar is less certain. “One
of the things that’s been reported for deflazacort
is more bone sparing [than with prednisone]. I don’t
know if it is or isn’t true.”
About 25 percent to 30 percent of Biggar’s
DMD patients sustain a long bone fracture at some
point.
“If the fracture rate goes up to 35, 40 percent,
which I suspect it might, people are going to say
it’s the deflazacort,” he says. “But
I’d say it’s because they’re walking
longer. The only way you break a leg when you’re
in a chair is when someone drops you or falls on
top of you.”
Not everyone believes side effects would be less
severe with deflazacort over the long term.
“I’m not convinced,” says John
Day, MDA clinic director at Fairview University
Medical Center in Minneapolis. “I believe
that there are individual and idiosyncratic differences
between drugs and between boys, so I’m open
to using whatever works best with minimal side effects
in any boy.”
Help Is on the Way
Help with the details of corticosteroid treatment
of DMD is on the way. A multicenter trial involving
about 300 boys in some 11 countries is slated to
launch in 2008, with funding from the National Institutes
of Health.
The investigators will compare boys randomly assigned
to 0.75 milligrams per kilogram per day of prednisone;
0.75 mg/kg of prednisone for 10 days alternating
with 10 days off the drug; and boys on 0.9 mg/kg/day
of deflazacort. Benefits and side effects will be
tracked for at least three years.
Exploring
Other Waters
To treat autoimmune disease, in contrast to treating
DMD, physicians now have a broad range of choices
that can supplement corticosteroids, allowing a
lowering of the steroid dosage, or even replace
them.
Older immunosuppressants include azathioprine (Imu-ran),
methotrexate (Rheumatrex), cyclosporine (Sandimmune)
and cyclophosphamide (Cytoxan). Newer medications
include rituximab (Rituxan), infliximab (Remicade),
etanercept (Enbrel) and tacrolimus (Prograf).
Unfortunately, in DMD, the options are far more
limited. A 1993 study showed that azathioprine alone
or added to 0.3 mg/kg of prednisone didn’t
result in any benefit for boys with the disease.
However, there’s some evidence that cyclosporine
may be effective; and studies in DMD-affected mice
have shown promise with etanercept and infliximab.
Losartan (Cozaar) and pirfenidone, which take aim
at scar formation associated with an inflammatory
response, are also being tested in these mice. (
See “Two
Anti-Fibrosis Drugs.” )
Course Corrections
Douglas Biggar has been treating boys with DMD at
a starting dose of 0.9 mg/kg/day for some 15 years
and has accumulated a lot of evidence.
“We start at 0.9, usually when the boys are
between 4 and 6 years old,” he says. “Most
start on prednisone at 0.75. What no one can agree
on is how much do you give to a 12-year-old, or
how much do you give to a 15-year-old? Nobody knows.
“We don’t know the best age to start,
and we don’t know the best dose over time.
All I know is we do what we do, and I’m sure
we could do it better. It’s just that I don’t
know how to do it better, yet.”
In Miller’s view, “The data continue
to reveal that we can give our patients the clear
and proven benefits of steroid therapy without causing
significant disability from side effects. If you’re
seeing changes in their bones, or if you’re
seeing other things, you can correct your course.
“More research is needed to maximize the safety
and efficacy of steroid use and to limit the known
side effects, but I think the benefits far outweigh
the risks.” |
