Physicians, researchers discuss myositis treatments. Drug therapy has increased the prospect for a positive outcome for myositis patients far beyond what we could imagine even a decade ago. But understanding the powerful drugs, making informed choices where possible, and managing a meaningful and mutual communication with your doctor about symptoms and side effects is one of the biggest challenges faced by a person with myositis, or any chronic illness. Being an informed patient can add to that challenge. Dr. Paul Plotz of NIH tells us (page 5) that patients with rare diseases often know more than their doctors.
Dr. Plotz wasn't implying that today's doctors are lazy, or uninterested in adding to their professional knowledge. He was acknowledging the truth: That a patient with electronic or literary resources and the motivation born from personal necessity has the incentive to devote every spare minute to educating himself about his disease. On the other hand, very few physicians have ever treated a case of dermatomyositis, polymyositis or inclusion-body myositis.
To help our subscribers make some sense out of the mountain of information available on myositis treatments, we interviewed members of our medical panel and others working in the field. We consulted the medical journal articles reporting on research by our advisors; and those research reports most often cited by them. We've also reviewed some recently published studies, pages 12 and 13. For those of you who are getting the OutLook for the first time, we've referred to treatments recommended by the medical panel at our October, 1999 national conference. Finally, we checked with some researchers in the midst of current drug trials.
What should you do with this information? We suggest that you use it to understand why your doctor may be prescribing certain drugs. You may want to share it with your doctor if you have any questions. It is intended to add to the doctor-patient dialogue, not to replace it. Your doctor will prescribe your treatment after considering both general guidelines like these and the details of your very specific case.
Whatever the drug therapy, reports from our members as well as our medical advisors tell us that most patients with myositis benefit from appropriate physical therapy to prevent contractures (shortening of the muscle) and atrophy of muscle tissue. The best therapy for those in a period of inflammation seems to be gentle, passive stretching and splinting, and more demanding strengthening exercise once the muscle inflammation has improved. For inclusion-body myositis as well as DM and PM, doctors recommend that an exercise program be designed by a professional, and that patients never exercise to the point of exhaustion.
Treatment for calcinosis, a common side effect in dermatomyositis, is extremely difficult, say our advisors. In searching for treatments for calcinosis, we found reports of several drugs that have been shown to benefit a few patients, but none of these drugs are universally effective in the treatment of calcinosis
At the 1999 MAA conference, Dr. Marines Dalakas warned against the surgical removal of calcium deposits because of the subsequent accumulation of scar tissue. An exception to this, said Dr. Jerry Mendell, is when the deposits grow so large they hamper regular movement, as was the case with Kris Branch, page 10. Another member, Charlotte Blom, said she was significantly helped by the removal of several large deposits. In her case, the deposits had stopped forming.
Oral steroids are the initial treatment of choice for dermatomyositis and polymyositis. Steroids target several mechanisms in a kind of "shotgun" approach: the immune complexes; the presence of autoantibodies in many patients; and the association with collagen vascular diseases. Oral prednisone is usually given in a single daily dose of 0.5 to 1.5 mg/kg until the CK test result is normal. Then, prednisone is tapered slowly over a 12-month period.
Another regimen involves oral prednisone in a divided daily dose of 40 to 60 mg/day (1-2 mg/kg in children) until the CK is normal; then consolidation of the prednisone into a single daily dose, which is then reduced by one fourth every three to four weeks, if the CK is still normal. The last step is continuation of the prednisone until a maintenance dose of 5 to 10 mg/day is reached and continued for a year. If there has been long-term steroid use, tapering beyond this is sometimes not possible, said Mendell; but at this small dose, side effects are minimal.
Objective improvement in muscle strength is usually seen by the third month of therapy, but if no progress is noted by this time - something that happens in up to 25% of patients - your doctor may consider other immunosuppressants.
We've learned that early diagnosis is critical. One 1993 study of 113 patients with definite myositis demonstrated that one-third of patients with a short delay in diagnosis responded completely to prednisone, while no patients with a long delay responded. If you see good results in blood tests but still have muscle symptoms, be patient. Sometimes clinical muscle strength improvement lags behind decreasing CK values.
In children, initial pulsed intravenous methylprednisolone - another form of steroid treatment - has been used with good results (30 mg/kg per dose for 3 days, then as needed for 4-5 weeks), followed by oral prednisone.
Patients with IBM generally do not significantly improve with prednisone. Dr. Richard Barohn analyzed some of the studies done by him and others in his talk at the 1999 MAA conference. Because a small number of patients respond in a limited way or stabilize on steroids, he allows his patients to choose a three- to six- month trial of oral prednisone if they are fully knowledgeable about the side effects and accept them. Barohn has tried a course of 100 mg/day for two to four weeks; then 100 mg every other day for two to three months. There are many possible side effects to prednisone, including weight gain, cataracts, diabetes, stomach symptoms, osteoporosis, and insomnia.
Methotrexate
If you do not respond to prednisone, if the side effects are significant, if steroids cannot be reduced without a relapse, or if your disease is progressing rapidly despite the steroids, methotrexate is usually considered as the next step. Dr. Lisa Rider of the FDA said in a recent interview that rheumatologists usually choose this drug as a "steroid-sparing agent," while neurologists are more likely to choose azathioprine. In DM, methotrexate also is likely to reduce the rash, says Dr. Chester Oddis (see page 6).
Methotrexate is usually begun at 7.5 to 10 mg per week, increasing by 2.5 mg increments to a total dosage of 25 mg per week. When the methotrexate dosage is increased, prednisone should be tapered. Side effects of methotrexate use are liver problems, nausea, abdominal pain, changes in the blood, itching, fever, lung inflammation, and gastrointestinal symptoms. Doctors often prescribe folic acid to reduce the side effects.
IBM patients exhibit much the same lack of response to methotrexate as they do to prednisone, but Dr. Barohn has used it as an adjunct to prednisone for his IBM patients choosing that path, if there is no improvement on the prednisone after three months. Barohn recommends discontinuing all drug treatment in IBM if there is no response in a year. Dr. Dalakas also believes trial courses of drugs are useful for people with IBM, beginning with IVIG (next page) and moving to trials of prednisone, adding methotrexate or azathioprine if that doesn't work, and also trying cyclosporine or cyclophosphamide. Drs. Valerie Askanas and W. King Engel, MAA Medical Advisors, also recommend trying a variety of different therapies on IBM patients starting with L-carnitine and coenzyme Q10 (page 8), since some treatments work on some patients.
Azathioprine
Azathioprine is commonly known by its brand name, Imuran. In one of the few prospective, double-blind trials of drug therapy for myositis, azathioprine plus prednisolone provided some long- but not short- term (less than three months) benefit to patients with polymyositis compared to those patients treated with steroids alone. The usual dosage of azathioprine is 100 to 200 mg/day. Monthly reductions in dosage are usually done in 25-mg intervals, aimed at maintaining the patient on a regimen of 50 mg/day. Side effects include increased risk of Iymphoma, nausea and vomiting, liver problems, bone marrow suppression, and oral ulcers. Screening patients for certain enzymes can reduce the chance of toxicity.
Cyclophasphamide
Cyclophosphamide, known also as Cytoxan or Neosar, its brand names, is usually used only in cases that don't respond to the above medications. Cyclophosphamide has been added to prednisone with much improvement in patients with myositis and pulmonary disease. Prednisone in combination with methotrexate and cyclophosphamide or chlorambucil can be used in severe disease not responding to the usual medications. Oral cyclophosphamide is often used at 1 to 3 mg/kg per day or intravenous administration at 2 to 4 mg/kg per day, along with prednisone. Possible side effects: increased risk of malignancy, cystitis, anorexia, nausea, vomiting, hair loss, and stomach symptoms.
Cyclosporine
Cyclosporine, also known as Neoral, Sandimmune and SagCya, impairs the reproduction of inflammatory cells called T-cells, a preliminary 1993 study on children found. It is an immunosuppressant derived from a fungus and was originally developed to prevent organ transplant rejection. In the early 1980s, Cyclosporine was first used for dermatomyositis unresponsive to conventional therapy. In an earlier study on children, published in the Lancet, 14 patients with long-standing disease were able to drastically reduce or stop their prednisone, with an increase in muscle strength. Cyclosporine has also been used as a single agent for initial treatment of myositis with excellent results, again in children. Response to the medication can be as rapid as one week. Dosage in the Lancet study was 2.5 to 10 mg/kg, although some studies suggest starting at or below 5 mg/kg. Cyclosporine's many risks may limit the use of the drug in myositis, and these include liver problems, Iymphomas, hypertension, unusual hair growth, swollen gums, numbness, sensitive skin, fatigue, and depression.
Tacrolimus
Tacrolimus, also known as Prograf, was also originally developed to prevent transplant rejection. It is an immunosuppressant derived from bacteria and has been used as an adjunct in treating myositis. It is toxic to the kidneys and other organs. Like all the immunosuppressants, the dosage will be set at a level that is most effective for treatment, with the least harm for the patient.
Hydroxychloroquine
Hydroxychloroquine (Plaquenil) can be used as an additional treatment, and has been reported in several studies to reduce the rash of dermatomyositis not responding to other treatments. However, studies differ on the efficacy of Hydroxychloroquine as a steroid-sparing agent. MAA Advisory Board member Dr. Chester Oddis said that his experience has found little effect on the muscle symptoms. Hydroxychloroquine is an anti-malarial drug that's been used for that disease for many years. No one knows exactly how it works, Oddis said. Common dosage is 200 mg twice a day for adults and 2 to 5 mg/kg per day in children. Oddis cited a 1991 study in Muscle, Nerve that reported Hydroxychloroquine can actually cause a myopathy almost indistinguishable from an inflammatory myopathy.
Intravenous lmmunoglobulins (IVIG)
IVIG is made up of millions of different antibodies taken from the blood of thousands of donors. Through donor screening and extensive processing, the therapeutic antibodies are cleansed of possible infectious agents or toxins. IVIG is diluted and then administered very slowly through a needle into the patient's vein over a period of several hours. This is often repeated over several days. No one is quite sure how IVIG works. It has been described as an immune system modulator: it works to put the immune system back in balance. Perhaps the greatest advantage of IVIG is that it does not suppress the immune system as do most other inflammatory myopathy treatments. The side effects tend to be less severe than many of the other treatments. Some of the more common side effects are headache, muscle pain, vomiting or troubled breathing. In a double-blind, placebo-controlled trial in patients with therapy-resistant dermatomyositis, led by MAA advisor Dr. Marines Dalakas, intravenous immunoglobulin administered at 2 gm/kg in a divided dose, once per month for three months, offered significant improvement in more than 70% of patients. Studies with juvenile myositis, at a dose of I to 2 gm/kg per day twice monthly for nine months, have also proved the efficacy of intravenous immunoglobulin in children. Experts disagree on the use of IVIG for IBM. Dr. Barohn notes that its expense and limited effect make it impractical as a treatment. Dr. Dalakas believes that IBM patients should be given high-dose IVIG for three months, adding the other immunosuppressants listed above if there is no response. Studies noted by Patrick Cherin (see Research Review, p. 12 and 13) on IVIG for IBM patients showed promise. Several doctors cited the need for larger studies on IVIG. This therapy is expensive, but insurers have covered it for some of our members. Please call us if you need information on IVIG and insurance.
Plasmapheresis
A 1981 study reported some good results from plasmapheresis (the removal of blood cells, cleansing by centrifuge, and reinfusion). This uncontrolled study was contradicted by a later, double-blind randomized trial in 39 different patients with PM or DM, which found no significant differences in outcome in the three treatment groups. In a paper recently published on the Internet by a group of Australian researchers, the authors pointed out that the improvement found in the earlier trial probably resulted from the continuation of cytotoxic therapy. Paul Plotz, head of the Arthritis and Rheumatism Borsch of NIH, said in an April interview that he never recommends this expensive and apparently ineffective therapy. Total Body Irradiation A 1981 study led by MAA Medical Advisor W. King Engel, M.D., and a later one led by S.H. Morgan, indicated that whole body, low-dose irradiation over a five-week period caused remission in some patients with severe refractory PM. These studies reported effects using 150 reds in fractionated doses. Total Iymphoid irradiation, usually with 2,OOO reds delivered to the Iymphoid areas over a 5-6 week period, was effective in some cases, as reported by a 1988 study led by N.L. Rosenberg. Adverse reactions were mild with the low-dose, whole-body irradiation; quite common with the Iymphoid irradiation. One study reported fatal bone marrow suppression in one patient following this treatment. Most physicians consider this therapy as a last resort, in patients who either can't tolerate or fail to respond to all other available forms of treatment.
Coenzyme Q10
Coenyme Q10 is produced by mitochondria in cells. It was discovered in cow hearts in 1956 by Frederick Crane, a biochemist studying the way heart cells use energy converted from sugar to keep beating. Crane mistakenly thought he had found a vitamin. Later, the research team realized it was a coenzyme, the ignition for a chemical reaction. Since Crane's discovery, the coenzyme has been found in every cell in humans that contains mitochondria. It's an antioxidant, a substance thought to protect people from cancer, heart disease, and other effects of aging. Coenzyme Q10 supplements come in chewable wafers and pills, containing between 30 and several hundred milligrams each and recommended for one to three doses a day. Since it is fat-soluble, it should be taken with a small amount of fat, like peanut butter or a meal with some fat. The enzyme occurs naturally in meat and poultry, with some smaller amounts in trout, salmon, oranges and broccoli, according to the American Dietetic Association.
In an article in The Washington Post, Sally Squires quoted Rebecca Costello of NIH as saying the supplement looks promising enough to launch a $2 million multi-center pilot study for 80 people with early-stage Parkinson's disease. A second federally-funded study, a $6.5 million, four-year trial, will follow 347 people with Huntington's disease, Squires reported. In both trials, no-one expects a cure, but researchers hope it will slow progression of these degenerative disorders. Other claims made by the supplement's fans: that it boosts athletic performance and prevents gum disease. Side effects appear to be minimal.
L-carnitine with coenzyme Q10
There is no approved drug therapy for IBM, but some of our members report good results with L-carnitine with coenzyme Q10, substances that can be bought over the counter and appear to have no significant side effects. Drs. Askanas and Engel recommend these supplements as a first resort: one gram of L-carnitine should be taken 4 or 5 times daily, with 100-150 mg of coenyme Q- 10 four times daily, both to be taken with food. We have anecdotal information on these supplements indicating they are helpful for some people, not helpful for others.
Women who are pregnant or nursing have additional concerns about the drugs they take. An article on drugs and pregnancy was published in the September 1999 OutLook, reporting that every drug crosses the placenta to some degree. The first trimester is when organs form and is the most sensitive time for drug adverse effects, said Dr. Chester Oddis. The third trimester, particularly close to the time of delivery, also carries risks for the mother and baby.
Over-the-counter anti-inflammatory drugs appear to be safe but should be avoided in the third trimester as they may prolong labor, Oddis said.
Steroids are safe throughout pregnancy, but are associated with premature delivery.
Azathioprine (Imuran) and cyclosporine have been widely used in pregnancy with little adverse effects, although caution is advised. Cyclophosphamide (cytoxan) should NOT be used and is associated with birth defects.
Methotrexate also should be avoided during pregnancy.
Plaquenil is more controversial, and some physicians stop it several months before conception.
If you breastfeed, it is important to remember that all drugs are excreted in breast milk to some extent. Be careful with all over-the-counter drugs.
Doctors studying ibuprofen found that when this drug was taken by the mother at a dose of 400 mg every six hours, traces were almost undetectable in breast milk.
In nursing mothers taking Plaquenil for DM rash, researchers found small amounts in breast milk, with the infant ingesting approximately two percent of the maternal dose daily.
Prednisone is of no consequence to the baby when the maternal dose is 20 mg daily or less (and probably when doses are under 40 mg daily). Larger doses are a cause for concern.
Cytoxan and cyclosporine are toxic to the infant and should be avoided. On the other hand, Methotrexate is only excreted to a minor extent in breast milk and is considered non-toxic at doses of less than 20 mg, but nursing should be avoided for at least 10-12 hours after dosing.
This information is provided for educational purposes only and should not be interpreted as medical advice. June 2000