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Treatments for MS
In 1993, based on the results of a large multi-center placebo-controlled trial, IFNβ-1b (Betaseron) was approved by the Food and Drug Administration (FDA) for the treatment of relapsing/remitting (RR)MS in the United States (US). Subsequently, based on an independent multi-center placebo-controlled trials, IFNβ-1a (Avonex) and IFNβ-1a (Rebif) have also been approved for use in the US.
The Betaseron trial demonstrated that, compared to treatment with placebo, treatment with 250 μg of IFNβ-1b subcutaneously every other day (qod) reduced the clinical attack rate, the MRI attack rate, and the volume of white matter disease seen on MRI. This trial also showed a reduction in confirmed one-point progression rate on the extended disability status scale (EDSS), however, this change was not statistically significant. Treatment with 50 μg of Betaseron on alternate days was also better than placebo on several outcome measures but was, in general, not as beneficial as the higher dose. The results of the Avonex trial published in 1996 were substantially similar to the earlier Betaseron trial. After two years, compared to placebo, treatment with 50 μg per week of Avonex intramuscularly produced a reduction in the clinical attack rate, the MRI attack rate, and the confirmed one-point EDSS progression rate. The total volume of white matter disease seen on MRI was also reduced in the treated group but this was not statistically significant.
The European trial of Rebif in RRMS augments these two earlier studies of IFNβ and demonstrated a significant benefit on each of the four major outcome measures in current use. Thus, compared to placebo, treatment with 44 μg three times per week of Rebif subcutaneously was associated with a reduction in clinical attack rate, the MRI attack rate, the confirmed one-point EDSS progression rate, and the volume of white matter disease seen on MRI. Moreover, although treatment with 22 μg of Rebif subcutaneously three time per week was also highly effective, the higher dose of Rebif did better than lower dose on each of these outcome measures. In addition, two head-to-head trials (Rebif vs. Avonex and Betaseron vs. Avonex) have demonstrated a short-term advantage of more frequently administered (or higher dose) IFNβ in the management of patients with RRMS. Another very large trial of Betaseron at the standard dose (250 μg, qod) and double this amount (500 μg, qod) failed to show any additional benefit from the higher dosed formulation. Presumably, this indicates that the frequency of administration is more important than total dose as an explanation for the earlier head-to-head data.
Three published trials (Avonex, Betaseron, and Rebif) have demonstrated that the early treatment with IFNβ of patients who have had a single attack of suspected MS delays significantly their progression to clinically definite MS. In each of these studies, the magnitude of the benefit seemed larger than that reported in the trials of RRMS. Such findings offer considerable empirical support for the notion that MS patients should be offered treatment early in the course of their illness.
Side effects of IFNβ (e.g., flu-like symptoms, fevers, muscle pains, and injection site reactions) are not uncommon although these typically subside with continued therapy. Flu-like side effects are often more severe and more persistent with less frequent administration of IFNβ, but they can usually be managed effectively with instructions on proper injection technique and with the use of concomitant non-steroidal anti-inflammatory medications at the time of injection. Some patients experience injection-site reactions (e.g., pain, redness, and hardening) with subcutaneous administration. These reactions are typically mild but, on occasion, they can be quite severe. Injection site reactions don’t occur with the intramuscular route of administration. Sometimes mild abnormalities are found on routine laboratory evaluation (e.g., mild elevation in liver function tests or a mild lymphopenia). These can usually be simply followed with discontinuation of the medication but, rarely, the elevations of liver function tests is marked enough to require the medication to be stopped. All of these side effects to IFNβ typically subside with continued therapy although in some patients they persist and alternative therapy is required.
Also, some patients develop neutralizing antibodies to IFNβ. These antibodies may be associated with a loss of therapeutic benefit with any of the IFNβ preparations. The actual clinical importance of these antibodies is, however, controversial. Thus, some patients who develop neutralizing antibodies to IFNβ seem to continue responding favorably to treatment and many patients who are antibody positive at one point in time will revert to being antibody negative at a future time point.
A second form of immunomodulatory treatment, glatiramer acetate (Copaxone), has also been approved for use in the US based on the results of a multicenter placebo-controlled trial published in 1995. Thus, 20 mg of Copaxone administered subcutaneously every day was associated with a reduction in clinical attack rate over a two year period. The confirmed one-point EDSS progression rate was also slightly reduced but this was not statistically significant. An earlier small pilot trial of 20 mg Copaxone subcutaneously daily reported a reduction in both the clinical attack rate and the confirmed one-point EDSS progression rate. MRI outcomes were not included either in the multicenter trial or in this earlier pilot trial. In a subsequent short-duration trial of Copaxone looking specifically at MRI outcome measures, both MRI attack rate and the volume of white matter disease seen on MRI have been reported preliminarily to be significantly reduced in the group receiving active drug.
As was the case for the interferons, early treatment with GA of patients who have had a single attack of suspected MS delays significantly their progression to clinically definite MS. Also, again, the magnitude of the benefit seemed larger than that reported in the trials of RRMS suggesting that MS patients should be offered treatment early in the course of their illness.
Two very large head-to-head clinical trials (Copaxone vs. Rebif) and (Copaxone vs. Betaseron) showed no difference in clinical outcomes (either relapses ore sustained disability) between these IFNβ preparations and GA. By contrast, another head-to-head trial (Copaxone vs. Avonex) has demonstrated a short-term advantage of GA. This last trial also included patients who received both Copaxone and Avonex and there didn’t seem to be any further benefit of the combination over Copaxone alone.
Side effects to Copaxone are generally minimal. These include injection site reactions (e.g., pain, redness, and hardness), which are typically mild and often subside with continued therapy. Treatment-associated changes in liver function tests or other laboratory abnormalities seem not to occur with Copaxone. A few patients treated with Copaxone experience a so-called ‘systemic reaction’. This reaction consists of flushing and/or chest pain together a variable secondary symptom complex including rapid heart beats, anxiety and/or shortness of breath. It comes on within minutes of injection, usually lasts less than 30 minutes. Its cause is unknown and it is without serious consequences. Indeed, in the majority of patients, it does not occur more than once or twice. Remarkably, in the original trial of Copaxone, it also occurred in patients receiving placebo. Lipoatrophy (localized wasting of fat tissue under the skin) can sometimes occur in patients receiving Copaxone. This side effect can often be lessened by improvements in injection technique but, in some cases, it can be disfiguring and, therefore, prompt a change in therapy.
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However, the results of the American trial of Betaseron, the results of the European trial of Rebif, and of the American trial of Avonex in SPMS all failed to confirm the benefit of IFNβ on reducing the confirmed one-point EDSS progression despite benefits seen for the clinical attack rate, the MRI attack rate, and the volume of white matter disease seen on MRI. Similarly, a trial of Copaxone in primary progressive (PP)MS failed to demonstrate a benefit to therapy on disability outcome. Taken together, these trials suggest that IFNβ and GA therapy (possibly also other current therapies) are not as useful in progressive forms of the disease as they are during the so-called “inflammatory phase” of the illness.
Conclusions about immunomodulating treatments
The therapeutic efficacy of IFNβ and GA in the treatment of MS is now well established. Indeed, several large independent multi-center controlled trials have demonstrated a remarkable consistency in the therapeutic benefits provided by these agents. Moreover, these agents have now been in use for over two decades and they have been proven to be remarkably safe ion the setting of long-term administration. Nevertheless, their therapeutic effectiveness in SPMS and PPMS has not been demonstrated.
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Considering all of the evidence, and despite the often robust effects of these agents on MRI outcome measures, the clinical success rate for these approaches to the management of MS patients has been disappointing. Often, initially optimistic reports of success with a particular agent or method are followed by larger clinical trials that have failed to confirm the original findings. Some agents (e.g., glucocorticoids, azathioprine) have been studied extensively and with repeatedly equivocal findings or demonstrating minimal benefits. Other approaches (e.g., total lymphoid radiation or bone marrow transplants) may carry either large or unknown short-term risks for patients. Some of the chemotherapeutic agents (e.g., cyclosporin. cyclophosphamide) are both acutely toxic and, if used for prolonged periods, carry uncertain long-term risks to health. As a result of such difficulties, in addition to the lack of unequivocal evidence for efficacy, the clinical use of these agents has remained limited and, indeed, many of the currently available agents should be considered only in very selected circumstances.
Methotrexate (Rheumatrex) is relatively mild immunosuppressant in widespread use for other inflammatory neurological conditions such as myasthenia gravis or demyelinating peripheral neuropathies. In MS, it has been reported to slow the progression of upper extremity dysfunction in patients with SPMS, although a comparable benefit on the progression of lower extremity dysfunction was not demonstrated in this study. It is generally well tolerated by patients at single weekly doses ranging from 7.5 to 20 mg orally. Some patients experience nausea, headache, or diarrhea but these side effects rarely necessitate discontinuation of treatment, particularly at the lower doses used for treating MS. Complete Blood Counts (CBCs), in addition to tests of hepatic and renal function, should be followed in all patients. Some patients will develop irreversible liver damage following prolonged treatment (>2 years) and many experts recommend a blind liver biopsy in that setting so that drug-related hepatic toxicity can be detected early. There also may be an increased long-term risk of developing non-Hodgkins lymphoma following therapy.
Azathioprine (Imuran) is another relatively mild immunosuppressant that has been used primarily in SPMS. Meta-analysis of published trials suggests that azathioprine (Imuran) is marginally effective. It is generally administered at a total daily dose of 2-3 mg/kg with the therapeutic goal of lowering the white blood cell count to between 3,500 and 4,000 cells/ml. This treatment is also generally well tolerated although some patients will experience abdominal pain or nausea.
Cyclophosphamide (Cytoxan) is a potent immunosuppressant. It often has prominent short-term side effects such as hair loss, nausea, vomiting, and bleeding into the urine. The published experience using this agent in SPMS is mixed. Initial reports were favorable suggesting a short-term benefit from a single course of the drug administered intravenously. However, a large multi-center trial in Canada failed to confirm any long-term benefit of a single course of treatment. Because of the known toxicity of this agent, however, it is probably best reserved for very highly selected patients (e.g., patients in otherwise in good health, ambulatory, and aged less than 40 years) who have unusually aggressive disease or who continue to progress despite other therapies.
Cladribine (Leustatin) is also a potent immunosuppressive agent that is relatively selective for lymphocytes compared to other cell types. It has been used successfully to treat a variety of lymphoid malignancies but it is especially effective in the treatment of hairy-cell leukemia. The Scripps Clinic, in two small studies, reported fairly modest benefits to treatment in patients with either SPMS or RRMS. A recent, large, phase III trial demonstrated a more convincing benefit to therapy on both clinical and MRI outcomes. Nevertheless, the FDA declined to approve this agent on the basis of this single trial and the future use of this therapy is in doubt.
Mitoxantrone (Novantrone) is an immunosuppressive agent, which has been reported to be of value in the treatment of MS. This agent has been studied in a combined RRMS and SPMS population at doses of 12 mg and 5 mg per square meter, administered by IV infusion every 3 months for 2 years. Compared to placebo, treatment with high dose mitoxantrone resulted in a significant reduction in the clinical attack rate, as well as marginally significant reductions in MRI attack rate, the one-point EDSS progression, and the total lesion load on MRI. On the basis of this trial the FDA has already approved this agent for use in MS. In general, mitoxantrone was well tolerated, although, because of a concern about its cardiac toxicity, the recommended total life-time dose of mitoxantrone (Novantrone) is limited such that continuous treatment with quarterly mitoxantrone (Novantrone) at a dose of 12 mg per square meter beyond 2-3 years is not recommended. Clearly, such a limitation will be problematic for patients expected to require treatment over many years. In addition, its use has been associated with and increased the risk of leukemia (blood cancer) developing in the future (even after the drug has been stopped) and it can cause permanent sterility in some patients. For all of these reasons, this therapy has been used only sparingly in MS patients, at least in the US. Nevertheless, it may be a reasonable alternative in selected patients who are continuing to deteriorate despite optimal management with other agents.
Intravenous immunoglobulin G (IVIg) has also been used of in the treatment of RRMS. Several trials have reported a beneficial effect of treatment on reducing the clinical attack rate. The findings, however, have been less consistent for MRI measures and for effects on clinical disability. Moreover, the available trials have often studied only small numbers of patients, lacked complete clinical and MRI outcome data, or have used methods, the validity of which has been challenged. In addition, the treatment regimens used have been so variable between reports that the optimal manner in which to administer IVIg is impossible to determine. At present, therefore, the use of IVIg in MS should be reserved for only selected patients or for research settings.
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The drug was initially approved by the FDA in 2004, but was subsequently withdrawn from the market when it was discovered that some patients developed a brain virus infection called progressive multifocal leukoencephalopathy (PML) on therapy. The drug was reintroduced to the market in 2006 under a formal prescribing program (called the TOUCH program).
Natalizumab is considered by some to be one of the most effective therapies currently available for MS, but this risk of progressive multifocal leukoencephalopathy from JC virus infection must be carefully balanced and individualized. Other important adverse effects that can occur include infusion reactions and liver toxicity.
Natalizumab is often reserved for patients who have had breakthrough disease activity despite treatment with first-line agents or those with very aggressive disease.
The JC virus antibody test is a new blood test that appears to predict whether people at are higher or much lower risk of PML on natalizumab. This test is now widely available. People who test positive for the antibody on this blood test are at a substantially higher risk of developing PML on natalizumab, whereas people who test negative appear to be at a significantly lower risk. In general, about half of MS patients test positive and half test negative on this test. The “false negative” rate is about 2%; the chance of converting from a negative to positive test over time is about 2-3% per year. Other major risk factors for PML with natalizumab are prior immunosuppressant use and length of treatment (the risk is greater after 2 years of therapy; the risk is very low within the first year of therapy).
Fingolimod (Gilenya) is an oral disease modifying therapy for treatment of MS that is taken as a pill once daily. It was approved by the FDA in September 2010. Fingolimod targets a receptor in lymph nodes (the sphingosine-1-phosphate receptor) that prevents white blood cells involved in the immune system from leaving the lymph node and entering the blood; the drug may also have direct effects on neurons and support cells in the nervous system.
Major risks with Fingolimod include infection (particularly herpesvirus and varicella zoster (the virus that causes Chicken Pox and shingles)), liver toxicity, macular edema (leakage of fluid in the retina) and, potentially, skin cancer. The drug also causes a slow heart rate (bradycardia) after initial dosing, so the first time patients take this drug must be in a monitored setting with heart monitoring (first-dose monitoring is also recommended if patients stop the drug for more than a few days and wish to restart). In April 2012, the FDA put out new guidelines about cardiac safety related to fingolimod. Patients with an abnormal ECG or known history of heart disease require extra-monitoring – the specifics should be discussed with your doctor. We have formal protocols in place at the UCSF MS center for screening and safety monitoring with fingolimod therapy.
Fingolimod may also be more effective than some first-line agents for MS, but seems to carry more risk. For this reason, this drug is often used as a second-line therapy for patients who have had breakthrough disease activity despite first-line therapy or have more aggressive disease.
Teriflunomide (Aubagio) was approved by the FDA in September 2012 as an oral disease modifying therapy for MS. It is taken as a pill once daily. The drug is an active metabolite of leflunomide, a drug (now generic) used for treatment of arthritis. The drug is thought to work by affecting DNA synthesis (a pyrimidine synthesis inhibitor), which targets rapidly dividing cells in the immune system, leading to immunomodulation.
Major adverse effects of Teriflunomide include liver toxicity, diarrhea and possible teratogenicity (toxic effects during pregnancy on the developing fetus). It carries a pregnancy category X rating. (unique among currently licensed MS therapies). While the drug’s effect on sperm is unclear, the official recommendation from the FDA is that men should also be advised against impregnating a woman and fathering a child while actively taking this medication and men must also be counseled to use reliable contraception. The drug can last in the system for up to 2 years; an accelerated elimination procedure is available for women and men who wish to pursue pregnancy.
Teriflunomide appears to be about as effective as existing first-line injectable therapies.
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Monoclonal antibodies (MAB's) are one of the newer strategies for modulating the body's immune system. In general, MABs work by interfering with specific targets involved in the development of an MS attack. This approach differs from traditional immunosuppression by virtue of its marked selectivity. There is no question that this approach offers considerable promise, both now and into the future. Natalizumab (Tysabri), an MAB against a protein that permits immune cells to enter the brain, is highly effective and is already FDA approved for use in MS. Rituximab, an MAB against certain immune cells called B-cells, is FDA approved (but not for MS) and has also been shown to be highly effective. Other MABs directed against this same target (ocrelizumab and ofatumimab) also seem to be highly effective and are currently under investigation. Alemtuzimab, a MAB directed against both B-cells and another set of immune cells (T-cells), is also highly effective and is currently under consideration for approval by the FDA.
Stem Cells are as a possible means of inducing repair of the myelin sheath that has been injured during the course of MS. One approach would be for stem cells (cells that have the potential to become oligodendrocytes) to be transplanted into an individual. A second approach would be to induce stem cells already present in a persons body to develop into oligodendrocytes. Both approaches are currently being explored.
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