modifying versus symptomatic treatments: The treatments I will focus on in this section are the "disease-modifying
treatments" which are intended to change the course of the disease. These treatments are supposed to affect the
disease process itself and to do things like prevent relapses and stop the accumulation of disability. There are also
a lot of "symptomatic" treatments which are aimed at relieving particular symptoms. These include medicines
to help with fatigue, stiffness, bladder control, or pain. Symptomatic treatments are quite helpful and make many people's
lives better, but they don't change the course of the disease.
Evidence based medicine: Many
physicians today try to practice what is known as "evidence-based medicine". This means that we want
to use treatments which have been rigorously tested and are proven to be effective. And when new evidence becomes available,
we change what we do to take the new information into account. We try to avoid doing something just because that's the
way we have always done it, or because we think it should help. A lot of treatments based on "tradition" or
"expert opinion" have later been demonstrated to be harmful or useless rather than helpful. Evidence-based
medicine is a good ideal or goal at the moment, but only partially practial. There are many situations
where no evidence is available and some situations where the available evidence is inconsistent. But for MS, there are
a large number of studies which guide treatment in many situations.
Testing treatments in MS:
Testing whether a particular treatment works in MS requires a lot of work. The disease varies a lot from person to person,
and a lot even in the same person at different times. Because of this variability, the only way to test new treatments
is to use them in large groups of people over a long time. Part of the group will be on the treatment to be tested,
and the rest of the group will either be on no treatment (placebo) or a comparison treatment. You then look at how the
treated group did compared to the untreated group. Most studies of new treatments in MS require several hundred patients
to be treated for 2 to 3 years. Needless to say, this is very expensive, but it is necessary to know whether a new drug
works for MS.
Quackery in MS: The unpredictable nature of MS makes it a natural target
for quack treatments. Someone is getting worse, tries an ineffective treatment, and gets better. They were
going to get better anyway, but they think that the treatment worked, and they tell all their friends about it. The
word spreads among MS patients unsatisfied with the effectiveness of their current treatment, and soon another treatment fad
has started. The fact that the medical establishment either doesn't know about the treatment or scoffs at it only
adds to the attraction. With time, the fad becomes old news, and a new one replaces it. Be skeptical about any
new treatment which has not been carefully evaluated and compared to either no treatment or an existing treatment. Don't
spend lots of money pursuing things that aren't likely to be helpful.
The influence of money:
The current available disease-modifying treatments for multiple sclerosis are all very expensive ($4000/month).
Once people start on one of these, they typically stay on the same drug for several years. There are several different
companies selling drugs and all of them have a huge financial incentive to get physicians and patients to use their drug first.
The result is a muscular marketing effort directed both at patients and physicians. When you read something about MS
or go to a talk about MS, take into account who is paying for it.
In the interest of full disclosure, no-one is
paying for this website. The opinions here are mine alone, and do not particularly favor any particular company. My
job is taking care of MS patients and doing research on MS, not selling a particular medicine. But like just about everyone
in the field, I have some ties to various companies. I have given talks which were sponsored by Serono (they make Rebif)
and Teva (they make Copaxone). Serono and Teva have sponsored some of my research. I have attended consultant
meetings for Serono, Teva, Biogen (Avonex and Tysabri) and Bayer (Betaseron).
of acute exacerbations
Corticosteroids Corticosteroids in one form or another have been
used for treating acute MS relapses for at least 30 years. Corticosteroids are normally made in the adrenal cortex,
and have several effects in the body. We use them because they suppress inflammation. Corticosteroids are not
the same as the anabolic steroids abused by athletes, nor are they the same as the steroid hormones, testosterone and
How soon do I need to treat and exacerbation? Exacerbations or relapses usually
develop over a few days. Corticosteroids suppress the active inflammation which is there during an exacerbation, and
should be used within the first week or two after the onset of symptoms. If the symptoms have been stable for a while
or are already improving, the inflammation is probably gone already and the steroids won't help much. I advise
people to call when new symptoms have been there for 48 hours, and get the steroids started in the first week.
the dose? Studies have shown that for MS relapses you need to treat with high doses of corticosteroids.
The typical treatment is methylprednisolone 500 or 1000 mg a day for 5 days. Lower doses used for treating other
conditions, such as prednisone 60 mg a day, have not been effective.
How are corticosteroids
given? For the last 20 years or so, we have usually given them intravenously, either in the hospital or
by home iv. But oral corticosteroids are well absorbed, and don't have any worse side effects than iv steroids.
The problem with giving steroids orally is that they are not formulated to give the high doses we need. To get
the same dose with pills, you end up taking 32 tablets a day. To get around this, I have started taking the
1000 mg vials we use for iv dosing and having the patient dilute them in a glass of juice and drinking it once a day.
This works pretty well, but the only pharmacy in the area that routinely stocks the iv vials is the one downstairs in
our clinic building. So I usually give corticosteroids orally, but sometimes still use the intravenous route.
What is the benefit of corticosteroids? MS relapses get better more quickly with corticosteroids.
Often, there will be noticeable improvement by the end of the 5 day course. Sometimes improvement starts after
a week or so. Most relapses improve spontaneously with time, but recovery is faster with corticosteroids. Steroids don't
seem to affect how much recovery occurs, or how long it is until the next relapse, so the benefit is mainly
short-term with a quicker recovery. If you have symptoms which are keeping you from your usual activities, treatment
Should all relapses be treated with corticosteroids? I recommend treatment
only if the symptoms are affecting your usual activities.
What are the side effects of corticosteroids?
The usual side effects are insomnia, mood changes, fluid retention, a metallic taste in the mouth, and increased appetite.
Corticosteroids are activating, which makes some people feel energetic and happy, while others feel restless and jittery.
Rare side effects include more severe psychiatric problems and bone problems. These symptoms typically go away
in a week or two after treatment is finished. Longer treatment with corticosteroids has a lot more associated
problems, including bone thinning, weight gain, and suppression of the immune system, but these are not usually an issue with
the brief courses we use for MS.
Disease-modifying treatments for relapsing remitting
These are listed
and discussed in the order they appeared on the market
Interferons (Betaseron, Rebif, and Avonex)
Interferons were the first medicine shown to affect the course of MS. They decrease the relapse rate by about 30%, decrease
the disease activity on MRI scans by about 90%, and may reduce the accumulation of disability over the long term. Interferon
is a protein your body makes naturally in response to infections, and it has a lot of effects on the immune system.
Side effects from interferon include flu-like symptoms, injection site reactions, and effects on liver function and blood
counts. The flu-like symptoms are typically worst at the start of treatment and get more tolerable with time.
There are three interferons currently on the market. Betaseron is given by subcutaneous injection (under the skin)
every other day, Avonex is given by injection into the muscle once a week, and Rebif is given by subcutaneous injection three
times a week. Betaseron and Rebif are a higher weekly dose than Avonex. Two different studies directly comparing
Avonex to high dose interferon showed that the higher dose was more effective. Extavia is essentially the same as Betaseron,
but marketed by a different company.
Glatiramer acetate (Copaxone) Glatiramer is a
mixture of synthetic protein molecules which was originally intended to mimic one of the major proteins in myelin. The
idea was that regularly injecting this protein would desensitize the immune system. It is not clear how it works, but
treatment with glatiramer decreases the relapse rate by about 30%, and may also have a benefit on accumulation of disability.
It is given by daily subcutaneous injection. Side effects are usually limited to minor injection site reactions.
There is also a rare post-injection reaction consisting of various combinations of chest tightness or pain, rapid
or strong heart beats, shortness of breath, sweating, feeling faint, etc. This resolves on its own after about 5 minutes.
Natalizumab (Tysabri) Natalizumab is a treatment which interferes with the
movement of white blood cells around the body. Normally your immune cells patrol the body, circulating in the blood,
crossing the blood vessel wall into the tissues, including the brain, moving from tissues to lymph nodes, and then back into
the blood. Natalizumab blocks the movement of white blood cells from the blood into the brain. In the clinical
studies, natalizumab decreased the relapse rate by about 65%, which was very exciting. Unfortunately, it also causes
a rare brain infection called PML. The risk of PML varies with duration of treatment, and whether you
are already infected with the JC virus that causes PML. There is now a fairly good test to determine
whether someone is infected with JC virus, which is very useful for deciding when to use natalizumab.
Natalizumab is given by intravenous infusion every 4 weeks.
fingolimod (Gilenya) Fingolimod is a second
treatment that interferes with the movement of white blood cells around the body. With fingolimod, the white blood cells
can't get out of the lymph nodes and spleen, and thus can't get in to the brain and cause new MS lesions. Fingolimod
is an oral medicine given once a day, and it decreases the number of relapses by about 50 to 55%. It has a number of
side effects that need to be considered, including effects on the heart, the retina, and a small increase in infections
which can be severe.
teriflunomide (Aubagio) This
is an oral treatment, given once daily, that affects dividing cells, particularly white blood cells. It decreases the
number of relapses by about 30%. It has some side effects, particularly altered liver function, and has potential bad
effects on pregnancy. It has been available since fall of 2012.
dimethyl fumarate (Tecfidera)
This is a twice a day oral treatment which affects the immune system. It was approved for use in the US in March, 2013.
The tolerability issues include flushing and sometimes nausea or diarrhea. These are reported to be most bothersome at the
start of treatment. Other side effects can include a decrease in the white blood cell count. The effect on relapse
rate was variable in different studies, but relapses decreased about 45 to 50% in the phase III trials. Although recently
approved, similar compounds have been used for treatment of psoriasis in Germany for the last 10 years, so we have a little
more safety data than usual for a newly approved treatment. There have been 4 reported cases of PML (the same brain
infection seen with natalizumab) in psoriasis patients. This complication may be avoidable, but long term safety remains
an open issue.
alemtuzumab (Lemtrada) This treatment is not approved yet, but is under review by the
FDA and may be available in late 2013. It is an infusion given yearly which depletes most types of white blood cells.
It has been very effective in clinical studies in early MS, with a decrease in relapse rate of about 70% and a dramatic reduction
in MRI activity. It can have infusion related reactions at the time of infusion, and can cause autoimmune disease affecting
the thyroid or platelets. There is a concern for infection, and I am not sure how many years you could use it.
If approved, I expect I would use it for people with early MS that looks really bad.
mitoxantrone (Novantrone) Mitoxantrone is a chemotherapy drug which is used
to suppress the immune system in people with really active MS. It is given intravenously, sometimes every three months
and sometimes once a month. It can stabilize symptoms in active disease. Short term side effects are mild nausea,
hair thinning, and immune suppression. Potentially severe, but infrequent, long-term side effects are weakening of the
heart muscle and leukemia. Treatment is limited to two years to avoid most of the heart problems. I am not using
this much any more, preferring natalizumab or fingolimod.
Which medicine is best?
Based on effectiveness, there is not a clear first choice. I think that there is good evidence that the high dose
interferons are more effective than low dose, so I rarely use Avonex. Direct comparisons of high dose interferon and
glatiramer demonstrate similar effectiveness and tolerability. Other direct comparisons suggest that fingolimod is better
than interferon and that dimethyl fumarate is more effective than glatiramer.
None of them combines outstanding
effectiveness with convenience, tolerability, and safety. I use all these medicines to some degree. In choosing
a treatment for the patient, I consider how severe I expect their MS to be, how likely they are to take each treatment, and
whether future pregnancy is a potential issue.
When should I start treatment? These
treatments can prevent some relapses, but they do nothing for problems that are already there. They are better used
early rather than late. My approach is to start treatment as soon as I am sure someone has relapsing-remitting multiple
sclerosis and that they will likely benefit from the treatment. Usually, this is when they have had a single episode
of symptoms and evidence of disease activity on MRI.
When should I think about switching treatments?
There are no clear guidelines on when to consider a change in treatment. These treatments are only partially effective;
they decrease relapses, but do not completely prevent them. You will have new symptoms whether you are treated or not.
I consider changing treatments if someone has more than one relapse per year.
How long should I be on
treatment? There is no definite stopping point. We now have patients who have been on interferon or glatiramer
for more than 10 years. The medicines don't lose their effectiveness over time.
How about combining treatments? Since the treatments are only
partially effective, there has been a lot of interest in combining two different treatments to get a better effect.
The problem with doing this is that we don't know for sure how any of the effective treatments work. One of the combined
treatments might block the effect of the other, or even worse, the combination might interact in a way that is dangerous.
This worst-case scenario, where each treatment alone is beneficial but the combination is dangerous, has been reported
at least twice. In 2012, we concluded a study that demonstrated the combination of interferon and glatiramer was
no more effective than glatiramer alone.
practice is to start with a single treatment which I know is effective and safe, usually interferon or glatiramer. If
that doesn't work, I will move on to more effective, but less safe medicines, such as natalizumab or fingolimod. I am
not combining treatments, and use chemotherapy drugs to suppress the immune system pretty infrequently.
Other options There are numerous other treatments which are used at times in MS, but the evidence
that any of them are effective is limited. These include azathioprine, methotrexate, cyclophosphamide, cladribine, IVIg,
plasmapheresis, etc. These are sometimes useful when the primary treatments are ineffective.
for secondary and primary progressive multiple sclerosis
This is a lamentably short section, and we desperately
need an effective treatment for progressive MS. Mitoxantrone may have some usefulness in early secondary progressive
disease. I often keep my secondary progressive patients on the treatment they were getting while they were relapsing-remitting
in the hope that it is still helping. For someone who is progressing rapidly, I will try immunosuppressive
treatments, usually without good results. Most of my progressive patients are on no disease modifying treatment.