Not Always Smooth Sailing

Charting a corticosteroid course

"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 and 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 and muscular dystrophy

Duchenne muscular dystrophy (DMD) is a relative newcomer to the list of diseases treated by corticosteroids. 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.

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” section below). “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 (Imuran), 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.

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.”

War on weight gain

Of all the side effects that corticosteroids can cause, excessive weight gain probably concerns patients and families the most. In MD, it can also have a serious adverse effect on motor function.

Nancy Hunter, a registered dietician and nutrition support counselor at Children’s Clinics for Rehabilitative Services in Tucson, Ariz., works with MDA clinic director Tim Miller and routinely sees children taking prednisone.

Weight gain caused by prednisone must be fought the same way all other weight gain is combated — by a healthier diet.

“The primary dietary intervention for kids is the parental focus,” Hunter says. “If the parents make environmental changes and healthy lifestyle changes, managing the amount of and the types of foods they give and rearranging what they used to do, the child will more likely follow healthy dietary recommendations.”

Hunter doesn’t recommend that parents weigh and measure food or count calories. Not only is that a burden to parents, she says, but “it really feels stressful to the child that the parent is measuring every little piece they eat.”

Instead, she focuses on making the right foods available and controlling portions.

“We use the plate method. Half of a standard 7-inch plate should be vegetables; one-fourth is carbs and one-fourth is protein. So you get the bulk of your plate from things that are not as calorically dense. The plate method works better than counting calories.”

Hunter teaches parents strategies for managing “hunger episodes” with small, frequent servings of fibrous foods that are low in calories, like fruits and vegetables.

“You can also do low-calorie or no-calorie drinks, or any kind of sugar-free dessert item, like diet gelatins, diet puddings, in certain portions; chewing gum; anything that will keep them kind of on the full side but not give them a significant amount of calories.”