Immune Therapy

Your Immune System

The immune system is a highly evolved way for your body to fight infections and to heal injuries. The development of immunity begins in the womb and continues throughout your life. For example, when you come into contact with a bacterium or virus, your body can learn how to recognize that invader and become better able to fight it.

Many different bodily components are involved in this immune response. White blood cells (WBC) are made in the bone marrow and engulf bacteria. One type of WBC is called a lymphocyte, which includes T cells and B cells. T cells are made in the thymus gland (found in your chest) and are involved in killing infected cells and fine-tuning the immune response. They work in concert with T helper (Th) cells, which release various chemicals as part of the immune response. B cells are made in bone marrow and release antibodies (also called immunoglobulins, or Ig), which react to different proteins (called antigens) and learn to "recognize" them. This enables the immune system to react more quickly if it encounters the same infecting agent again.

The accurate recognition of foreign invaders, such as a bacterium or virus, is the key to an effective immune system. Your body has to know how to tell the difference between what belongs in your body ("self") and what doesn’t belong ("not-self"). To do this, it produces MHC molecules (Major Histocompatibility Complex), which serve as the "police force" that patrols your body looking for foreign invaders. When MHC finds something foreign, it puts the offender in a line-up: it "presents" proteins for inspection by other cells in your body. If a protein passes this inspection, it is free to go. But if it isn’t known, it is "arrested". Your Th cells flag the protein as foreign and trigger an immune reaction. The different cells of the immune system then rally round and attack the foreigner.

When people talk about organ transplants, they often refer to the "tissue type". This "type" is actually the MHC molecule, which protrudes from cells to present its proteins. A transplanted organ is obviously foreign to the rest of your body, so your body will work against its better interests (you need that organ) and mount an immune attack. This is commonly referred to as "rejection". In other words, your body has assessed this new tissue and decided it isn’t compatible. That is why people who receive an organ transplant need to take anti-rejection drugs, which suppress the immune system so it can no longer attack the new organ.

What is an Autoimmune Reaction?

An organ transplant is just one example of an immune response that ends up doing more harm than good. Another is anaphylaxis, when your body has such a severe overreaction to a foreign protein (antigen) that it can be fatal. No doubt you have heard of people who have died following a bee sting or after being exposed to peanuts (bee venom and peanuts are both proteins).

Another type of harmful reaction is an autoimmune response. This happens when your body mistakes its own proteins ("self") as something foreign and attacks them. There are many different types of autoimmune diseases. For example, in diabetes (Type 1), the immune system attacks the cells in the pancreas that are needed to produce insulin.

Multiple sclerosis is also thought to be an autoimmune disease, although how it occurs is still not understood. To trigger an immune response, you need an antigen but it is not entirely clear what this triggering antigen might be. One theory is that in MS, the antigen is myelin, the protein coat that "insulates" the nerves in the central nervous system (the brain and spinal cord). The body attacks the myelin, mounting an immune system flare-up that causes inflammation and damage to the delicate nerve fibres. Where this nerve damage occurs will determine, in part, the type of MS symptoms. If the sensory nerves are affected, this can cause sensory symptoms, such as pain or tingling. Damage to the optic nerve can cause vision problems, and so on.

Since MS is characterized by an immune system flare-up, or relapse, the traditional approach has been to use drug therapies that target this overreactive immune response. This can be accomplished with medications that readjust or modulate the immune response, which are called immunomodulatory (or disease-modifying) drugs; and with medications that suppress the immune response, which are called immunosuppressants.

First-Line Therapy

While MS is considered to be a problem of the immune system, most of the immune system is actually functioning normally. People with MS are able to fight off infections, such as the common cold or the flu, and their bodies continue to repair damaged tissue. So the ideal approach in treating MS would be to target the specific problems and leave the rest of the immune system to function normally.

This thinking led to the development of two different classes of medication that modulate, or adjust, the immune system: the beta-interferons and glatiramer acetate. These medications work in different ways to influence the way the immune system reacts in MS.

In MS, it appears that there are two key immune-system problems. The first is that T cells become activated when they should not. They go into "attack mode" and mount an immune response that damages the body’s own tissues. The second problem is that these activated T cells manage to cross the blood-brain barrier (BBB), a physical barrier of tightly-packed cells that keeps many molecules from entering the central nervous system. When these activated T cells get into the brain and spinal cord, the result is inflammation and damage to the nerves.

Now we’ll look at these two classes of medication in greater detail to see how they try to correct these immune-system problems.

Treatment: glatiramer acetate

Copaxone^® is a mixture of synthetic polypeptides (proteins) consisting of four naturally-occurring amino acids (the building blocks of proteins). About three decades ago, researchers discovered that the protein structure of glatiramer acetate (then called copolymer 1) was similar to the structure of a myelin protein (called Myelin Basic Protein, or MBP).

Like other proteins, glatiramer acetate is taken up by MHC molecules and "presented" to Th cells by specialized cells (called antigen-presenting cells, or APCs). The glatiramer acetate/APC complex stimulates the immune-system Th cells to proliferate.

All Th cells are not alike and several subtypes have been identified. The Th1 subtype favours an inflammatory response, whereas the Th2 subtype has anti-inflammatory effects. Normally these two Th types are equally matched so the body can respond with a pro-inflammatory or an anti-inflammatory effect, depending on the situation. However, in MS, the immune system appears to be biased to the pro-inflammatory Th1 subtype.

Current research indicates that when glatiramer acetate reacts with the T cells, there is a shift in this balance toward the Th2 type. As these Th2-biased T cells enter the brain, they are believed to react with similar myelin proteins in the CNS, a process called bystander suppression. The result is an alteration in the quality of the immune response: the T cells release anti-inflammatory chemicals and downregulate the inflammatory response in the CNS. This effect can be seen on MRI, which shows a reduction in inflammatory lesions in the brain and spinal cord.

Treatment: beta-interferons

Interferons are proteins that cells in the body produce in order to "interfere" with viruses. An infected cell produces interferon, which acts as a signal to neighbouring cells to release chemicals that will stop the virus from spreading.

Scientists discovered how to manufacture interferons using genetic recombination techniques. An early use for these drugs was to treat viral infections, such as hepatitis. One theory that developed in the 1970s and 1980s was that a viral infection might be the initial triggering event in MS, so researchers started to investigate if the anti-viral effects of interferons might be useful in MS.

Preliminary studies of one type of interferon, beta-interferon, produced promising results. This led to the first beta-interferon (Betaseron^®) approved for use in Canada for the treatment of relapsing-remitting MS. Two other beta-interferons, Avonex^® and Rebif^®, were subsequently approved. These drugs are slightly different subtypes of each other: Betaseron^® is called a beta-interferon-1b, whereas Avonex^® and Rebif^® are beta-interferon-1a drugs. However, their effects on the body are very similar.

It isn't entirely clear how beta-interferons work in the body. While they were initially investigated for their anti-viral effects, these effects don't seem to be the reason why they are beneficial in MS. One of the principal modes of action of the beta-interferons appears to be a stabilization of the BBB. In MS, this barrier is "leaky", which allows activated T cells to enter the central nervous system (CNS) and cause inflammation and damage. Beta-interferons, in effect, "plug the holes", reducing the flow of damaging cells into the brain and spinal cord. They do this in several ways. To cross over into the CNS, T cells have to attach to the BBB. Beta-interferons appear to interfere with this attachment. The body also produces enzymes (called MMPs, or matrix metalloproteinases), which degrade the barrier and make it easier for T cells to cross over. Beta-interferons inhibit these enzymes, which makes the BBB less porous and better defended against the T cell invasion.

The net effect is that fewer activated T cells make it across into the CNS, which results in less inflammation and less damage to myelin and nerve cells. These effects can be seen on magnetic resonance imaging (MRI), which allows doctors to see areas of inflammation and swelling (edema) in the brain and spinal cord. MRI shows that with a beta-interferon, the areas of inflammatory lesions (or plaques) are less pronounced.

Two modes of action

To summarize, there are two classes of medication for MS that work by two different means. Glatiramer acetate appears to alter the nature of the immune response so that it is less damaging to myelin and nerve fibres. Beta-interferons appear to act primarily at the blood-brain barrier, reducing the influx of activated T cells into the central nervous system.

Theory into practice: the clinical trial

Many medications seem to be effective in treating different illnesses, but appearances can be deceiving. That is why a clinical trial is needed. It is a more rigorous method of evaluating the effectiveness and safety of a medication.

The most rigorous study is the randomized controlled trial (RCT). "Controlled" means that a group of people receiving the study drug is compared to a second group of people receiving something else (which may include no drug treatment). In an RCT, the comparison treatment is usually a placebo. Most new drugs are required to show that they are effective compared to placebo before they can be approved for use by Health Canada (or the Food and Drug Administration in the U.S.).

A drawback with placebo-controlled trials is that one group of subjects will receive no treatment for the duration of the study. This has led to ethical concerns. Since researchers now recognize the importance of early treatment of MS, delaying treatment for the duration of a study is problematic when effective treatment with glatiramer acetate or a beta-interferon is available. As a result, many MS studies, notably those of long duration, do not use a placebo-controlled design.

If an effective medication is available, it may be used as the benchmark against which newer drugs can be compared. This is called an "active control" study, since the control group receives a therapeutically active agent (rather than placebo). For example, if there were a new medication to relieve headaches, the active control might be Aspirin or Motrin if either was considered to be the standard therapy. Similarly, in MS, the effectiveness of a new drug might be examined by comparing it to glatiramer acetate or one of the beta-interferons. This would enable researchers to determine if the new drug was equivalent to established therapies.

A treatment can also be compared to "historical controls". For example, if you wanted to know if a new drug prolonged survival after a heart attack, the survival data of people on the study drug could be compared to historical survival data obtained from the general population before any treatment was available.

"Randomized" means that the people who receive either the study drug or the control group are randomly assigned to a group. The main goal of randomization is to eliminate bias. For example, in a study on the effects of a drug on disability, it would not be a fair comparison if all the more disabled people ended up in one group. So randomization is intended to balance out the many variables, such as the age and sex of the study subjects, their level of disability, and so on.

Finally, RCTs are often "double-blinded". This means that neither the physician nor the patient knows whether the treatment being given is the study drug or the control. This measure is intended to eliminate bias as well. A doctor or patient might be more likely to "see" treatment effects if they knew that the drug was not a placebo.

Designing trials in MS

To obtain the most accurate and informative data, it is essential that a study be well-designed. Ideally, it should be an RCT. This is how new drugs are normally approved by government agencies, such as Health Canada or the Food and Drug Administration in the U.S.

So before any of the immunomodulatory treatments were approved for use in Canada to treat MS, the drug manufacturers had to submit RCT data for review by Health Canada. These "pivotal trials" (studies used to obtain drug approval) will be reviewed later in this document.

As part of the design of the study, the investigators have to designate which questions they hope the study will answer. For example, in a drug trial for relapsing-remitting MS, the study question might be: will this drug reduce the frequency of MS relapses? The frequency of MS relapses would then be the primary endpoint – the main end result that is being investigated. That same study might also perform MRIs on subjects every few months, and this might yield some interesting information. However, MRI is not the primary focus of the study, so it would be a secondary endpoint of the study.

The safety of a drug would not necessarily be the objective of the study (unless it is a study intended to assess safety), but it is always an important consideration. So throughout a clinical trial, the investigators typically obtain a variety of samples (e.g. blood, urine, etc.) to determine the effects of the drug on blood cells, liver and kidney function, and other biological parameters. They also ask the study patients about any unusual or troubling experiences they might be having. While a troubling effect may not be attributable to the drug, it is important for investigators to obtain all the information they can so they can get a complete picture of any adverse effects.

Relapsing-remitting MS is a difficult disease to study. It is a fluctuating illness: relapses come and go as part of the natural course of the disease. What if a person were going into a relatively quiescent period of few relapses just as he/she was starting a drug? It might give a false impression that this relapse-free interval was due to the drug, rather than being part of the fluctuating course.

The chronic nature of MS is also challenging. Does a relatively short trial of 1-2 years’ duration give an accurate picture of how a treatment is affecting a life-long illness? A well-designed study can help to determine if a treatment is truly providing any benefits or not.

In assessing the effects of treatment, an important issue is whether the primary and secondary endpoints being studied are actually relevant. If the treatment was an antihypertensive medication in people with hypertension, measuring blood-pressure reduction would be a valid endpoint and so this issue would not arise. But MS is different. The standard measure that has traditionally been assessed with MS drugs is the effect on the frequency of relapses. While reducing relapses would certainly seem to be an important goal, it is not entirely clear if relapse frequency has an impact on the long-term course of the illness or on the degree or severity of disability down the road. Ideally, researchers would be able to determine if a drug prevented disability. But this is often not feasible since it generally requires studying a large group of people for several years.

Researchers sometimes elect to continue monitoring patients that were in a clinical trial even after the trial has ended. Such inquiries, called "extension studies" because they extend past the original trial, may continue for many years. While not as scientific as an RCT, these extension studies can provide valuable information on how well people are doing on a medication and whether the drug appears to be safe to take over the long term.

Trials of immunomodulatory drugs: the questions researchers ask

What questions have researchers asked when they have designed clinical trials of immunomodulatory drugs in MS? The following is a sampling of some of the questions that can be asked:

Effectiveness:

• Does the medication prevent relapses?
• How many people remain free of relapses?
• How long before a relapse occurred — did the medication delay the onset of a new relapse?
• Did individuals’ degree of disability get better, remain the same, or get worse during treatment?

Effect on other parameters:

• How does the medication appear to work?
• What are the effects of this drug on the immune system?
• Are the effects of the drug specific to one or more key immune system targets?
• How does the medication affect existing inflammatory lesions in the brain and spinal cord, as assessed by MRI?
• Does the medication influence the development of new MRI lesions?
• Does a medication impact the evolution of lesions to irreversible tissue damage?
• Does a medication impact neuronal integrity as seen on magnetic resonance spectroscopy (MRS)?
• Does a medication impact other symptoms of MS (i.e. fatigue, headache)?

Longer-term effects:

• Do the effects of the drug continue or do they wear off?
• Does there appear to be an ongoing benefit with the medication?
• Are patients able to keep taking the medication, or are there adverse or intolerable effects of the drug?

Tolerability:

• Does this drug cause any potentially toxic or damaging effects (e.g. to the blood or liver)? Do these effects need to be monitored on an ongoing basis (e.g. with regular blood tests)?
• What are the adverse effects caused by this drug?
• Do these adverse effects improve or worsen with time?

Examining the evidence: clinical trials of immunomodulatory drugs

RCTs were conducted for glatiramer acetate (Copaxone^®) and the beta-interferons (Avonex^®, Betaseron^®, Rebif^®), and all four of these agents have been approved by Health Canada for as first-line therapy treatment of relapsing-remitting MS.

Let’s look at the studies that were done.

Glatiramer acetate studies

Copaxone^® is the only therapy that has been shown in three RCTs to be effective in relapsing-remitting MS. The first was a randomized, double-blind pilot study by Dr. Murray Bornstein and colleagues. A total of 50 patients received either Copaxone^® (20 mg subcutaneous injection once a day) or placebo for two years.

Results:

• The two-year average number of relapses was 0.6 (3 relapses every 5 years) per patient with Copaxone^® versus 2.7 in the placebo group. This represented a reduction in the relapse rate of 77% during the study period.
• 56% of patients in the Copaxone^® group had no relapses compared with 28% in the placebo group.
• 43 of 50 patients (86%) completed the study.

These preliminary results led to a larger two-year randomized trial of Copaxone^® in 251 patients by Dr. Kenneth Johnson and colleagues. The primary endpoint was the mean number of relapses. Secondary endpoints included the proportion of patients who experienced no relapses, and the proportion of patients with sustained disease progression, defined as an increase of 1 or more points on the EDSS scale for three months. After the initial two-year study period, patients were enrolled in a 1-year extension trial.

Results:

• In the initial two-year study, the mean relapse rate was 1.19 with Copaxone^® versus 1.68 with placebo, a reduction of 29%. When the extension data were included, the mean relapse rate was 1.34 with Copaxone^® versus 1.98 with placebo, a reduction in relapses of 32%.
• During the entire study period, 34% of patients receiving Copaxone^® experienced no relapses, compared with 25% on placebo.
• For disability, patients treated with Copaxone^® were stable during the initial two-year study and improved slightly during the extension phase. Patients in the placebo group worsened during the initial study and during the extension.
• At the end of the initial two-year study, there was a mean improvement in EDSS score of 0.05. Patients on placebo worsened by a mean of 0.21 points. Only Copaxone patients in pivotal RRMS trials with any immunomodulator did obtain an improvement of their EDSS score.
• At the end of the 33-month extension phase, the level of disability was slightly better in the Copaxone^® group: the average EDSS score improved by 0.11 points compared to a worsening in EDSS score of 0.34 points with placebo.
• At the end of the extension study, 82% of patients in the Copaxone^® group were unchanged or improved with respect to their level of disability compared with 69% in the placebo group.
• A total of 86% of patients completed the initial two-year treatment period and 77% completed the extension study.

At the end of the three-year extension period, all patients (including those on placebo) were invited to continue the study on Copaxone^®. These patients are still being monitored and the 8-year follow-up data have been published. In the subset of patients receiving Copaxone^® for the full eight years, the annual relapse rate is 0.2 (1 relapse every 5 years). Copaxone^® continues to be well-tolerated.

The study by Johnson and colleagues did not collect MRI data, so another trial was launched to specifically examine the effects of Copaxone^® on inflammatory lesions in the central nervous system. The European-Canadian MRI trial randomized 239 patients to Copaxone^® (20 mg injected once a day) or placebo for nine months. During the study, patients underwent MRI scans every month.

Results:

• The total number of MRI lesions was reduced by 35% with Copaxone^® compared to placebo. The mean number of MRI lesions per patient was reduced 29% with Copaxone^® versus placebo, indicating that Copaxone^®reduced the burden of illness as assessed by MRI.
• The annualized relapse rate was 0.51 with Copaxone^® versus 0.76 with placebo, a reduction of 33%.
• 94% of enrolled patients completed the study.

Beta-interferon studies

Avonex^® (Beta-interferon-1a)

The safety and efficacy of Avonex^® in relapsing MS was evaluated in a two-year randomized, double-blind trial by Dr. Lawrence Jacobs and colleagues. A total of 301 people were enrolled and received Avonex^® (30 micrograms byintramuscular injection once a week) or placebo. The primary endpoint was the time to sustained worsening of disability. "Worsening" was defined as a deterioration of 1 point on the Expanded Disability Status Scale (EDSS), which assesses disability. "Sustained" was defined as at least six months.

Results:

• There was a significant improvement with Avonex^® with respect to the time to sustained progression of disability. The proportion of people who had progression of disability was 21.9% with Avonex^® compared to 34.9% with placebo. The probability of progression was 12.5% with Avonex^® versus 22% with placebo.
• The annual relapse rate for all patients was 0.67 per year (about 2 relapses every 3 years) with Avonex^® and 0.82 per year (about 4 relapses every 5 years) with placebo – a reduction of 18% over the two-year period; the relapse rate reduction was 9.6% after one year, which was not statistically significant.
• A total of 23 patients (7.6%) discontinued treatment early. Two-year data were based on a subset of 172 patients (57% of the original sample) who completed two years of treatment.
• Among the 172 people who completed two years of therapy, the relapse rate was 0.61 per year with Avonex^® and 0.90 per year with placebo – a reduction of 32%.
• Avonex^® also reduced the number and volume of lesions seen on MRI.

A subsequent trial, called CHAMPS (for Controlled High-risk subjects Avonex Multiple sclerosis Prevention Study), examined whether Avonex^® (30 micrograms by intramuscular injection once a week) could delay the onset of MS in people who had experienced one demyelinating event (such as a relapse) but did not meet the full criteria for a diagnosis of MS. This was a three-year randomized, double-blind placebo-controlled study involving 383 patients.

Results:

• During the three-year study period, the cumulative probability of developing MS was 35% among people on Avonex^® compared to 50% among people on placebo.
• People in the Avonex^® group also had fewer new or enlarging lesions on MRI compared to people in the placebo group.
• 15% of patients discontinued early for reasons other than the development of clinically definite MS.

Betaseron^® (beta-interferon-1b)

The efficacy of Betaseron^® was evaluated in a double-blind study by researchers in the U.S. and Canada. The study randomized 372 patients with relapsing-remitting MS to receive one of two doses of Betaseron^® (1.6 or 8 MIU by subcutaneous injection every other day) or placebo. Treatment continued for a median of 45-48 months. The primary endpoint was the relapse rate.

Results:

• After two years of therapy, the annual relapse rate was 0.90 (just under 1 relapse per year) with the higher dose of Betaseron^® compared with 1.31 (4 relapses every 3 years) with placebo. This represented a 31% decrease in the rate of relapses.
• The cumulative MRI lesion burden was decreased with high-dose Betaseron^®, but increased with low-dose Betaseron^® and with placebo.
• Fewer people in the Betaseron^® groups experienced progression compared to those on placebo, but this difference was not significant.
• 86 people (23%) had dropped out of the study by the end of year 2, and 125 (34%) had stopped by the end of year 3. At the end of 48 months of treatment, only 47% of people taking the higher dose of Betaseron, 42% taking the lower dose of Betaseron, and 46% on placebo remained in the study.

Betaseron^® (8 MIU every other day) was also investigated in secondary-progressive MS in a randomized, double-blind study involving 718 patients. The trial duration was for up to three years. The primary endpoint was the time to confirmed progression of disability, defined as an increase of one point on the EDSS in less disabled people (baseline EDSS score of 3.0 to 5.5), or an increase of 0.5 points in more disabled people (baseline EDSS score of 6.0 or 6.5).

Results:

• The time to progression of disability was delayed 9-12 months with Betaseron^® versus placebo.
• The proportion of patients with confirmed progression was 39% with Betaseron^® and 50% with placebo.
• A total of 25% of patients in the Betaseron^® group and 27% on placebo dropped out of the study or discontinued therapy early.

Another study of secondary-progressive MS was conducted by the North American Study Group. This was a three-year randomized, double-blind trial in which 939 subjects with secondary-progressive MS were randomized to low- or high-dose Betaseron^® or placebo. The primary outcome was time to progression confirmed at six months; secondary outcomes included the mean change in EDSS score from baseline, MRI activity and relapse-related measures.

Results:

• There was no significant difference between Betaseron and placebo in terms of time to confirmed progression.
• Betaseron^® was associated with a reduced relapse rate and improvements on MRI.

Rebif^® (beta-interferon-1a)

The pivotal study of Rebif^® was called PRISMS (Prevention of Relapses and disability by Interferon-1a Subcutaneously in Multiple Sclerosis). This was a two-year randomized, double-blind trial involving 560 patients who received one of two doses of Rebif^® (22 or 44 micrograms three times a week) or placebo. The primary endpoint was the number of relapses. Secondary endpoints included the time to first relapse, disability and the lesion burden on MRI. The study was later extended to four years (PRISMS-4). There was no placebo group for this phase. All patients received one of the two doses of Rebif^®.

Results:

• The mean number of relapses was 1.73 with the higher dose and 1.82 with the lower dose of Rebif^®, compared to 2.56 with placebo. This represented a reduction in relapses of 32% and 29% with high- and low-dose Rebif^®, respectively.
• The time to first relapse was prolonged 3-5 months with Rebif^® compared to placebo.
• The proportion of people experiencing no relapses was higher with Rebif^® versus placebo.
• A higher proportion of people on placebo showed progression of disability, defined by an increase of 1 point on the EDSS scale sustained for more than three months. During the first two years, about 40% of placebo-treated patients progressed compared to 29% in the Rebif^® groups.
• The burden of disease and the number of active lesions seen on MRI were lower with both doses of Rebif^® compared to placebo.
• 90% of patients in PRISMS completed the two years of treatment.
• The PRISMS-4 extension found that the lowest rate of disease progression was with the highest cumulative dose of Rebif^®. The time to confirmed EDSS progression was significantly prolonged only in patients receiving the higher (44 microgram) dose.

Another important study of Rebif^® was OWIMS (Once Weekly Interferon beta-1a for Multiple Sclerosis), a two-year study that looked at the effectiveness of two lower doses of Rebif^® (22 or 44 micrograms injected once a week; the usual injection frequency is three times a week). These lower doses reduced inflammation on MRI but did not improve the frequency of relapses. These effects did not change when the study was subsequently extended to three years, indicating that less frequent dosing with Rebif^® is not clinically effective.

Adverse effects with approved first-line therapies for RRMS

Glatiramer acetate

Approximately 8% of patients treated with Copaxone^® in clinical trials discontinued treatment because of an adverse effect. The adverse effects most commonly associated with discontinuation were injection site reactions and flushing. About 10% of patients experience an immediate post-injection reaction, with symptoms such as flushing, chest pain, palpitations, anxiety, breathlessness, constriction of the throat and urticaria. These reactions typically resolved on their own and did not require specific treatment.

Other adverse effects may include pain, redness or itchiness at the site of injection, chest pain, facial swelling and gastrointestinal upset.

Contraindications:

Copaxone^® should not be used in people with a known hypersensitivity to glatiramer acetate or mannitol.

Warnings:

• Copaxone^® must be injected subcutaneously. It should not be injected intravenously (into the vein).
• Copaxone^® has been associated with an immediate post-injection reaction, a constellation of symptoms that can include flushing, chest pain, palpitations, anxiety, shortness of breath, constriction of the throat and urticaria (skin reactions).
• Approximately 26% of people taking Copaxone^® (compared to 10% on placebo) experienced at least one episode of temporary chest pain. While some of these episodes occurred in the context of the immediate post-injection reaction (see above), many did not. The cause of this is unknown.
• Copaxone^® has not been studied in people with a history of severe anaphylactoid reactions, obstructive pulmonary disease or asthma. Caution is advised when Copaxone^® is used in these types of patients.

Precautions:

There are no adequate and well-controlled studies of Copaxone^® in pregnant women. It is not known if Copaxone^® is excreted in breast milk, so nursing women should only be treated with Copaxone^® after a careful assessment of the risks and benefits, and treatment should be used with caution. Copaxone^® is an antigenic substance and thus it is possible that detrimental host responses can occur with its use.

Beta-interferons

The three beta-interferons produce similar adverse effects. All may cause flu-like symptoms, such as fatigue, fever, chills, muscle or joint pain and headache. In the Betaseron^® trial, flu-like symptoms were initially reported by 76% of patients receiving the higher dose. The frequency of this adverse effect declined after three months, although 10% reported persistent symptoms in the last six months of the study. Nonprescription pain/fever medications may help to relieve some of these symptoms.

Less frequent adverse reactions include cold sores, stuffy nose, light-headedness, blood disorders and alterations in liver function tests.

Beta-interferons may also cause mild-to-moderate injection site reactions, such as itchiness, rash and redness where the drug is injected. Subcutaneous injections of Betaseron^® and Rebif^® may cause severe skin damage (necrosis); this may be minimized by regular rotation of the injection site. Intramuscular injection of Avonex^® may cause absesses or fibrosis at the injection site.

Beta-interferons may be associated with anaphylaxis, difficulty breathing, bronchospasm, swelling of the tongue, skin rash, and hives. These effects are rare but should be reported immediately to a physician.

Thyroid dysfunction may occur during the first year of treatment, particularly in people with a pre-existing thyroid condition.

Contraindications:

• Beta-interferons should not be used in people with a known hypersensitivity to beta-interferon or albumin.
• Beta-interferons should not be taken during pregnancy or breastfeeding. Beta-interferons may cause abortion if taken during pregnancy.

Warnings:

• Patients treated with a beta-interferon should be informed that depression and suicidal ideation [thinking about suicide] may be a side effect of treatment and should report these symptoms immediately to their physician. Patients exhibiting depression need to be monitored closely and cessation of therapy should be considered if depressive symptoms emerge.
• Rare cases of serious liver injury, including hepatitis and hepatic failure, have been reported with beta-interferons. Liver function tests are recommended before starting treatment and every month for the first six months, and at 6-month intervals thereafter. Beta-interferon therapy should be initiated with caution in patients with a history of significant liver disease or alcohol abuse, and in patients with clinical evidence of acute liver disease. Caution is needed when taking a beta-interferon in combination with a drug with documented liver toxicity. Patients should be informed of the symptoms suggesting liver dysfunction, such as jaundice, malaise, fatigue, nausea, vomiting, abdominal pain, dark urine and pruritus (skin itching). Patients should be advised to consult their physician immediately if such symptoms arise.
• Regular blood tests are required at the start of treatment with a beta-interferon, and after 1, 3 and 6 months. Repeat blood tests are required every six months thereafter.
• Anaphylaxis has been reported as a rare complication. Other allergic reactions include rash and urticaria. Allergic reactions, some severe, may occur after long-term use.

Precautions:

Rare cases of heart damage (cardiomyopathy), thyroid dysfunction and seizures have been reported. Patients with heart disease should be monitored closely. Beta-interferons should be used with caution in people with a history of seizure disorders.

Recommendations on the use of immunomodulatory therapies

The 24 members of the Canadian MS Clinics Network and the MS Society of Canada have recommended the use of an immunomodulatory therapy as early as possible in the MS disease course. Immunomodulatory drug treatment should be continued long-term unless there is a clear lack of benefit or intolerable side effects.

The recommended treatments for relapsing-remitting MS are glatiramer acetate (Copaxone^®) or any of the three beta-interferons (Avonex^®, Betaseron^®, Rebif^®).

Betaseron^® can also be used for the slowing of progression in disability and the reduction in the frequency of relapses in patients with secondary-progressive MS. Rebif^® is used to decreases the frequency of relapses and slows the progression of disease in relapsing forms. Avonex is used for the treatment of relapsing forms of MS, to slow progression of disability, and decrease frequency of clinical exacerbations.

No treatment is currently indicated for use in people with primary-progressive MS. Selecting a therapy

No individual therapy will be the best choice for everyone so MS patients, in consultation with their neurologist and MS clinic nurse, will need to weigh the relative advantages and disadvantages of each of the available treatments.

A number of factors may be compared:

Efficacy: Two classes of treatments used for relapsing-remitting MS — glatiramer acetate and the three beta-interferons — are efficacious.

Side effects:

• Glatiramer acetate (Copaxone^®) may produce pitting of the skin, and has the potential to cause an immediate post-injection reaction.
• Beta-interferons (Avonex^®, Betaseron^®, Rebif^®) often produce flu-like symptoms, which may or may not be troubling to an individual patient. People taking a beta-interferon will need to have regular blood tests to monitor the effects of the drug on the liver. A beta-interferon may not be the optimal choice in a patient suffering from clinical depression; this issue should be discussed with the doctor.

Self-injection: All four medications are given by injection. There is no oral (pill) formulation. Avonex^® has the advantage of requiring less frequent injections (once a week). However, these are intramuscular and are intended to be used only under the guidance and supervision of a physician; a doctor may permit self-injection once the patient has been trained in intramuscular injections. The other three medications are injected subcutaneously (just under the skin). Betaseron^® is taken every other day, Rebif^® is taken three times per week, and Copaxone^® is injected daily.

Convenience: Betaseron^®, Copaxone^® and Rebif^® are available with an autoinjector, which can make self-injection more convenient. Avonex^® is not available with an autoinjector. In addition, Copaxone^® and Rebif^® come as pre-mixed solutions. Avonex^® and Betaseron^® must be reconstituted prior to use.

Switching medications

During treatment with an immunomodulatory drug, some people may decide that the medication isn’t fully effective or produces intolerable side effects. As a result, some people, in consultation with their neurologist, may decide to modify the dose or switch to a different class.

According to a recent statement by the Canadian MS Working Group, a change in medication may be advisable if relapses persist, if recovery following a relapse is slowed, there is progression of disability or worsening on MRI.

A poor response to a beta-interferon may be due to the development of neutralizing antibodies. Beta-interferons are genetically-engineered proteins, so they can trigger the body to produce antibodies. Persistent neutralizing antibodies appears to be associated with a loss of clinical effect, i.e. they neutralize the drug and prevent it from producing a beneficial effect on relapses and MRI findings. Betaseron^® and Rebif^® are reported to be more immunogenic (capable of inducing an immune reaction) than Avonex^®. However, these three drugs are cross-reactive: when persistent antibodies develop with one drug they are highly likely to develop again if that patient is switched to another beta-interferon.

Antibodies to glatiramer acetate are not neutralizing antibodies and are not cross-reactive with the beta-interferons. As a result, they do not affect the clinical effectiveness of the medication.

If an individual with MS is dissatisfied with a treatment, it is essential that he/she discuss any concerns with the neurologist and MS clinic nurse. The neurologist can assess if the medication is still effective (by looking at the frequency of relapses or disability or by ordering a new MRI), safe and/or well tolerated and can discuss alternative treatments.

Immunosuppressants

A second category of medications that may be used to control MS is the immunosuppressants. These are potent drugs that were originally developed to treat different types of cancer and to prevent rejection during organ transplantation.

As the name implies, immunosuppressants suppress the function of the immune system. These effects are not selective but global, affecting all aspects of the immune response. Because they lower the body’s defence system, people taking an immunosuppressant are at risk of contracting a variety of infections. People on an immunosuppressant should generally avoid vaccinations as well.

Because of their potent effects and potentially severe side effects, immunosuppressants are generally reserved for specific instances when rapid downregulation of the immune system is required, such as severe relapses or progressive forms of MS. Immunosuppressants should only be used under the close supervision of a physician.

Immunosuppressants in MS

Let’s take a look at some of the immunosuppressants used to treat relapsing-remitting or progressive forms of MS. It should be noted that none of these agents has been specifically approved in Canada for the treatment of MS but they are commonly employed by physicians. Mitoxantrone (Novantrone^®) has been approved to treat worsening RRMS or SPMS in the U.S.

Cyclosporine

This medication is commonly used as an anti-rejection drug following organ transplantation. While a potent immunosuppressive agent, several studies have shown that is not highly effective in MS. For example, a two-year double-blind study randomized 547 patients with progressive MS to cyclosporine or placebo. Cyclosporine did have a modest effect in delaying the progression of disability but many people were unable to tolerate the therapy. Common side effects included kidney toxicity and high blood pressure. As a result, cyclosporine is not commonly employed to treat progressive MS.

Azathioprine

Azathioprine is an immunosuppressant used in organ transplantation and autoimmune diseases, such as rheumatoid arthritis and Crohn’s disease. Unfortunately, its beneficial effects in MS appear to be modest. A meta-analysis of seven studies involving 793 patients found that the drug produced a small improvement in disability scores after two years of therapy, but questioned whether these benefits outweighed the drug’s side effects, which include bone marrow suppression.

Methotrexate

Methotrexate is commonly used to treat different types of cancer, as well as autoimmune diseases, such as rheumatoid arthritis, Crohn’s disease and psoriatic arthritis.

Few RCTs have specifically investigated methotrexate in MS. A double-blind trial randomized 60 patients with chronic progressive MS to low-dose oral methotrexate or placebo for two years. Methotrexate did produce a nonsignificant reduction in disease progression and relapses. It was relatively well-tolerated medication, although long-term use has been shown to cause liver damage. A second, smaller uncontrolled trial reported that methotrexate appeared to stabilize disease progression in 10 of 20 patients over a one-year study period.

Mitoxantrone

Mitoxantrone is an immunosuppressant first used to treat prostate cancer and leukemia, and several studies have examined its safety and efficacy in MS. The drug is not approved in Canada for use in MS but physicians often employ the drug "off-label". A two-year Italian trial randomized 51 patients with relapsing-remitting MS to monthly infusions of mitoxantrone or placebo. Mitoxantrone reduced the mean number of relapses versus placebo, and slowed confirmed disease progression, defined as a 1-point change on the EDSS, in the second year of the trial.

In secondary-progressive MS, regular infusions of mitoxantrone (13 in 32 months) significantly improved disability scores, reduced the number of relapses and decreased disease activity on MRI compared to regular infusions of methylprednisolone.

Despite this effectiveness in progressive MS, mitoxantrone use is limited by its toxicity. Side effects include nausea, vomiting, hair loss and bone marrow suppression. Higher cumulative doses are associated with heart damage, so use of the drug is often limited to two years, after which it must be discontinued. Secondary acute myelogenous leukemia has also been reported in MS and cancer patients treated with mitoxantrone.

Evolving role of immunosuppressants

Immunosuppressants are often poorly tolerated by people with MS and these potent agents can produce significant side effects. So they cannot be used routinely as first-line agents. However, the potential exists to combine these agents with other therapies, such as the immunomodulatory medications or other immunosuppressants. This combination approach might enable doctors to use lower, less toxic doses of an immunosuppressant to achieve a rapid control of the disease process. For example, a patient with relapsing-remitting MS who starts to progress might benefit from immunosuppression followed by long-term maintenance with an immunomodulatory drug. This is one of the approaches to treatment that is now being investigated.