Patients with relapsing-remitting multiple sclerosis (MS) who have not responded well to one of the standard treatments for the disease can take heart: A new study has shown that supplementing beta interferons with the high-dose steroid methylprednisolone reduces the rate of relapse.
Approximately 85 percent of people with MS are initially diagnosed with relapsing-remitting MS. These patients experience attacks (called relapses) of worsening neurologic function, followed by either partial or complete recovery periods (called remissions). Typical MS symptoms include tremor, pain, fatigue, and dizziness. Symptoms occur because MS damages the insulating material (“myelin”) around nerve cells in the central nervous system.
COMBINED TREATMENT STUDY
The standard medications for treating relapsing-remitting MS are the beta interferons—interferon beta-1a (Rebif, Avonex) or interferon beta-1b (Betaseron)—and glatiramer acetate (Copaxone), says Gary Birnbaum, M.D., director of the Multiple Sclerosis Treatment and Research Center at the Minneapolis Clinic of Neurology, Ltd. While success rates vary from almost complete disease remission to no response at all, Dr. Birnbaum says, “Most people will have a reasonable response to one or the other drug, with a change in the pattern of their disease.”
Both classes of drugs—the beta-interferons and glatiramer acetate—work by modulating the immune system, says Dr. Birnbaum. The exact mechanisms of action are not completely known. But the end results are twofold: less infiltration of the central nervous system by immune cells capable of destroying myelin; and a change in the pattern of immune response to myelin, from a destructive to a protective one.
Steroids, in contrast, are general immune suppressants. They reduce inflammation throughout the body. Short-term use of steroids in people with MS reduces the duration of acute attacks and may promote healing, while their long-term use supplements the immune-modulating effects of the disease-modifying drugs. In some individuals, this results in better control of their MS.
“The usual approach for someone who doesn't respond to a drug is to change to a different one,” Dr. Birnbaum says. For example, someone might be switched from one of the interferons to glatiramer acetate. If the person still doesn't respond well, the neurologist might supplement the first disease-modifying medication with another drug. High-dose methylprednisolone, administered in single monthly pulses, is frequently used for this purpose, he says.
Hence the three-year study by Mads Ravnborg, M.D., of the Danish Multiple Sclerosis Research Center at Copenhagen University Hospital in Denmark and supported by Biogen Idec., which makes interferon beta-1a. The study examined the combined effect of methylprednisolone and interferon beta-1a on 341 people with relapsing-remitting MS. Half of the participants received 500 mg of oral methylprednisolone in monthly “pulses,” which means three doses over three days, in addition to regular weekly injections of the drug interferon beta-1a. The other half received only interferon beta-1a and a placebo.
Prior to the study, participants had not received a disease-modifying drug like beta interferon. The average duration of disease among participants was three years.
LOWER RELAPSE RATE
The research team concluded that taking both methylprednisolone and interferon beta-1a reduced the rate of relapses—times when the disease is active—by 38 percent compared to standard treatment of the interferon drug alone. Patients on both drugs also improved on several tests that assessed leg functions, walking, arm-and-hand function, and cognitive function, while those on only interferon beta-1a saw their scores slightly decrease. The lesions in the brain that are a sign of disease activity were measured at the beginning and end of the study. For patients receiving both drugs, the lesions stayed the same size or shrunk, but for those taking only interferon beta-1a, the lesions grew.
“These results indicate that these two drugs may have a synergy when taken together and provide a more beneficial effect on disease activity,” says lead author Dr. Ravenborg. “This is a promising finding, as the benefit from interferon is only moderate and not everyone responds fully to the treatment. Anything we can do to boost those results is positive.”
“The concept of supplementing standard therapy with another immune-modulating therapy is not novel. What is important is that this study provides support for the efficacy of this approach,” Dr. Birnbaum notes.
Both steroids and beta interferons can cause significant adverse effects. Long-term use of steroids can cause cataracts, high blood pressure, weight gain, diabetes mellitus, and aseptic necrosis (in which parts of bone fail to get blood and die). Side effects of beta interferons can include flu-like symptoms, fatigue, and liver and thyroid changes.
Adding more drugs to a patient's regimen typically increases the risks of side effects. But, says Dr. Birnbaum, “To the best of my knowledge, addition of monthly pulses of steroids does not alter the side-effect profile of the beta interferons and vice versa.” In the study, complications such as thinning bones, hair loss, and increased infections from the monthly steroid treatment were rare. Side effects in the study included heartburn, increased heart rate, and difficulty sleeping, but these symptoms were well controlled with medication, Dr. Ravnborg says.
Currently, the Food and Drug Administration does not approve the use of steroids as long-term therapy for MS. And experts warn that long-term, monthly courses of steroids could lead to serious complications. According to Dr. Birnbaum, single monthly pulses of high dose steroids can be continued for the long term with careful monitoring. But because of the potential for side effects, he adds, the combination treatment “should be reserved for those individuals who have not responded sufficiently to either one of the beta interferons or to glatiramer acetate, or were unable to tolerate these drugs.”