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Disease Modifying Treatment in Multiple Sclerosis
Desired treatment vs. Currently Available – Relapse Prevention in MS – Is it Possible to Prevent Disability in Multiple Sclerosis?
Multiple Sclerosis Treatment
Treatment of multiple sclerosis can be divided into three groups: acute relapse treatment, disease modifying and symptomatic treatments. Disease modifying treatment is meant to decrease the number, frequency, and severity of relapses. Ideally, it is expected to prevent or delay the overall disability accumulated over years.
There is no known proven disease modifying treatment for primary progressive MS. All available disease modifying treatment options are developed for relapsing-remitting form of multiple sclerosis.
MS relapses are treated with high dose of corticosteroids. This treatment does speed up the recovery, but there is no prove that steroids affect the outcome or the long term prognosis on MS.
Symptomatic treatments alleviate symptoms produced by the disease with no effect on the underlying disease process. Treatment of spasticity, pains, urinary urgency belongs to this group.
Disease Modifying Treatment in Multiple Sclerosis
First of all, you have to understand that there is no “multiple sclerosis specific treatment”. None of the treatments directly affects the cause of MS, since the exact target of the autoimmune attack in multiple sclerosis is not known.
All the disease modifying agents are interfering with the immune system function. Most of them cause some degree of immune deficiency, or immunosuppression. Side effects of this interference are infections, cancers, or other than MS autoimmune conditions. Better drug effect on the disease progression is inevitably associated with more severe side effects.
This is simply because suppression of the autoimmune process is not selective. Normal function of the immune system is suppressed as well.
As I said before, “We fight a sniper with a nuclear bomb”. Collateral damage is inevitable in all modern treatment modalities.
All the disease modifying agents are proven to decrease short term MS relapse rate. They prevent new MS lesions on the MRI, also short term. However, scientific proof of change in future disability is lacking. It does not mean that these medications do not change the long term disease prognosis. They possibly do but we have no scientific proof.
One of problems in MS research is related to the limitations in study design. Modern patients are usually compared with the patients from the past. It is hard to design a comparable groups of patients because the criteria for MS diagnosis are less strict now and lighter forms of MS are usually treated as well. It is hard to create a placebo group either. How can you offer a sugar pill instead of potentially life changing treatment? So, for now we are in the dark regarding the full spectrum of modern MS treatment benefits.
Desired Effect of Multiple Sclerosis Treatment vs. Currently Available
“Disease modifying” term refers to the idea of changing the natural course of multiple sclerosis, which includes relapse prevention, delaying or preventing long term disability, and control over wide-spread whole brain degenerative changes.
There is a wide gap between the desired effect of treatment, or expectations, and the real outcome of disease modifying treatment choices available at the moment.
This article will compare the “desired” and the “actual” in respect to the modern disease modifying strategies. I will not analyze short term statistical data because it is simply irrelevant in chronic disease.
Relapse Prevention in Multiple Sclerosis
Desired: In ideal case scenario, preventive treatment has to completely control any future relapses.
Actual: None of the available treatment options is able to guarantee a complete control of relapses.
- Relatively long term data is available only for Interferon betta-1b, which decreases relapse rate 30% relative to placebo over 5 years. There is significant reduction of incidence of disease progression over 5 year period of time. Decease progression means presence on new MS symptoms. This effect was found to be dose dependent. Low dose interferon betta-1b reduced disease progression 35% and high dose reduced the rate 46% vs. placebo over 5 years. Effect on the MRI detectable MS plaque load was even more dramatic. Plaque load grew only 3.6% in interferon treated group and 30% in placebo treated group. Longer term data regarding effects of interferon betta-1b on the relapse rate and the disease progression incidence is not available. On the other hand, mortality rate for any reason in interferon treated patients was reduced 18% vs. 30.6% in placebo controlled group at a median 21 year follow up. The effect was not dose dependent.
- Interferon betta-1a and Copaxone provided similar or inferior benefits over 2 years period of time but no longer studies were performed.
- Autologous hematopoietic stem cell transplantation (HSCT) needs special attention. This approach reserved for very aggressive cases of multiple sclerosis. Besides, it is expensive, has relatively high mortality rate, and may only be performed at major institutions proficient in this type of procedures. At the same time, the survivors have a very high rate of long lasting remission and even reversal of some already accumulated disability.
- Both, interferons and Copaxone delay conversion of clinically isolated syndrome into definite multiple sclerosis short term. Over years, the benefit either fade away (Interferon betta-1b) or unknown (Interferon betta-1a and Copaxone).
Delay or Prevention of Disability in Multiple Sclerosis
Desired: Prevention, or at least delay and reversal of the accumulated disability long term.
Actual: No treatment has ever been proven to affect disability long term.
Treatment of Progressive MS or Prevention of “Degenerative” changes in MS
Desired: Causing remission in progressive MS and preventing wide spread brain degenerative changes.
Actual: There is no evidence that any of the available treatments prevents diffuse brain degenerative changes long term. No disease modifying treatment is available for progressive form of MS.
There are multiple newer medications with sometimes spectacular effect on the multiple sclerosis rate of progression short term. Unfortunately, until sufficient evidence is accumulated short term success cannot be translated into life time benefit for a few reasons:
- It is not known if the effect on the disease progression will be sustainable
- It is not known if long term treatment for years is practical due to side effect profiles of the newer medications. Most common concerns are PML and other infections, cancers, and other autoimmune diseases. As an example, Alemtuzumab causes autoimmune diseases (usually thyroid) in 30%!
- Some of medications after withdrawal may lead to sever rebound effect with fulminant progression of MS whipping off all the prior benefits of treatment (Fingolimod and Natalizumab).
The following sections briefly describes some of the drugs, which are most commonly used for disease modification treatment in multiple sclerosis.
There are 3 types of interferon preparations. All of them are injectable.
Interferon beta-1b, 0.25 mg (Betaseron) is injected subcutaneously every other day was first marketed in 1993. Interferon beta-1a is available in 2 formulations. Avonex 30 mcg is injected intramuscularly once a week. Rebif has two doses of 22 mcg or 44 mcg injected subcutaneously 3 times a week.
They all have comparable effect on the relapse rate, disability progression, MS lesion load on the MRI and the side effects. Interferons decrease relapse rate in the range of 30% over 5 year period of time. They decrease disability and MRI lesion load over the same period of time. Long term benefits are unknown. It appears that early treatment is more beneficial than the one that was started later in the course of the disease.
Interferons are generally well tolerated. They are given by autoinjector. Flu-like symptoms (fever, chills, malaise, body aches) are most common and usually subside over time. Other less common side effects are injection site reactions (skin necrosis is rare), liver problems, depression, decreased white blood cell count, thyroid disorders, and other autoimmune disorders. Preexisting headache disorders and spasticity may worsen on interferon therapy.
Another issue is formation of antibodies to the injected interferons. Antibody may neutralize the beneficial effect of these drugs, which leads to increased MS attack relapse rate. The rate of neutralizing antibody formation may be as high as 60% for high dose interferons (Rebif and Betaseron) and 20% for Avonex. Detection of antibodies in association with increased relapse rate often necessitates changes in the management.
Glatiramer Acetate (Copaxone, copolymer 1)
Copaxone is a mixture of random synthetic polymers made out of 4 amino acids common for myelin (L-alanine, L-glutamic acid, L-lysine, and L-tyrosine). This mixture is antigenically similar to myelin basic protein. Copaxone is a potent stimulant of special T-cells which produce some anti-inflammatory effects in the brain. It also has effect on the detection and processing of antigens (foreign cell components). Glatiramer acetate may also stimulate myelin repair mechanisms.
Overall beneficial effects are very similar to interferons (around 30% relapse rate reduction). Copaxone 20mg is administered daily and Copaxone 40 mg is administered 3 times a week as subcutaneous injections.
It is usually well tolerated. Local injection site reaction is the major problem. Most common reactions are pain, itching, or injection site hardening. Prolonged use may cause cosmetic issues due to scarring and local subcutaneous fat loss. The above described skin changes may be permanent. Copaxone does not produce neutralizing antibodies, blood or liver problems, depression, worsening headaches or spasticity, or flu-like symptoms.
Glatiramer Acetate occasionally causes allergy-like reactions. The symptoms are sweating, chest tightness, shortness of breath, palpitations, anxiety, flushing. They start within minutes after injection and last from 1 to 30 minutes. The cause is not known, because the symptoms do not progress to anaphylactic shock. These reactions have tendency to happen only once (or maximum a few times) in a given patient.
Vitamin D has a profound effect on immune system function. Long before antibiotics were invented, tuberculosis was treated by moving to more southern latitudes. Curative effect was probably caused by sun exposure and vitamin D production (this is my speculation).
Level of vitamin D has correlation with MS incidence progression rate according to some studies on children and adults. Daily Vitamin D supplementation of 400 IU or more is associated with 40% reduction of MS rate in women. Patients who are diagnosed with MS and have higher vitamin D levels have better prognosis regarding relapse rate and disability progression. Higher levels of vitamin D are associated with lower rate of new MRI brain MS lesions. The rate of conversion of clinically isolated syndrome into MS over 4 years period is lower in patients with higher blood levels of 25OH-Vit D.
The amount vitamin D of 400 IU supplementation without sun exposure is probably too low. Skin exposure for 15 minutes on a sunny day may produce as much as 20,000 IU of Vitamin D. It is hard to say what the ideal supplementation dose is. Please bear in mind that an excessive amount of vitamin D is toxic.
I would take as a reference point the vitamin D amount that produces a currently considered normal blood level of 25OH-Vit D (30.0 to 74.0 ng/mL).
Statistically Natalizumab produces the highest relapse (68%), disability (42%), and new MRI lesions rate reduction over 2 years.
There are strings attached, though.
The major safety concern is a serious viral brain infection – progressive multifocal leukoencephalopathy (PML). It is caused by JC virus. The virus infects oligodendrocytes (myelin producing cells) leading to severe brain damage. This infection may be fatal. Diagnosis of PML requires an immediate discontinuation of the drug. Plasma exchange speeds up immune system function recovery.
Natalizumab is a special antibody to alpha 4-integrin. Once the antibody attaches to this protein on the leukocyte (type of white blood cell) membrane, the leukocyte has difficulty migrating into the brain tissue. While it prevents damage to the brain tissue, it also inhibits normal immune responses to invaders.
Natalizumab is injected intravenously once a month. Besides potential infections it is generally well tolerated. The most common side effects are anxiety, fatigue, headache, nausea, dizziness, flushing, nose congestion, sore throat, edema. Allergic reactions occur in 4%. About 6% develops neutralizing antibody.
This drug is reserved for severe MS cases and for patients who don’t respond to other types of treatment.
Discontinuation of the drug causes a rebound of MS activity. The rebound may be so severe that it might be fatal.
Oral Drugs for Multiple Sclerosis
Fingolimod is the first oral drug approved as a disease modifying agent for relapsing-remitting MS. It prevents lymphocyte migration into the tissues. Fingolimod is proven to prevent relapses and new MRI visible lesions. The effect is somewhat better than low dose interferon.
Side effect profile is not so favorable. Oral administration advantage is offset by potential serious complications. The most concerning are severe herpes infections, heart conduction abnormalities with conduction block, cancers, respiratory problems, and retinal disease (macular swelling with higher dose).
A few patient’s deaths were reported during trials (some were unexplained). There is a suspicion it might cause MS exacerbation in severe cases.
The most common side effects are headache, flue, back pain, cough, diarrhea and liver abnormalities (increased liver enzymes).
Discontinuation of Fingolimod leads to a gradual reactivation of multiple sclerosis.
Dimethyl Fumarate (DMF, BG-12)
Dimethyl fumarate is another oral drug. It was FDA approved for relapsing-remitting MS treatment in 2013 and in European Union in 2014. It appears to be a promising first line MS drug.
Studies demonstrated about 53% relapse rate reduction and 85%-90% new MRI lesions reduction. Reports on disability progression are controversial.
Short term, it appears lacking any serious side effects. It has to be taken twice a day. Most common side effects are flushing, diarrhea, nausea, and abdominal pain, which tend to subside over time.
Similar medications may cause PML, but no such side effect is reported on BG-12. BG-12 is an enteric-coated formulation intended to reduce stomach upset.
The exact mechanism of anti-inflammatory effect is unknown.
Teriflunomide is an anti-metabolite, which blocks cell division, hence affecting the immune system cells as well many other cells in the body. The exact mechanism of effect in MS is not known. It is taken orally once a day.
The most common side effects are hair thinning, diarrhea, nausea, and elevated liver enzymes (ALT).
The overall effect on MS is comparable with interferons.
It may produce birth defects. Teriflunomide may stay in the body as long as 2 years after the last dose, so it is not recommended for couples who are planning pregnancy.
Accelerated elimination entails an 11 days treatment with cholestyramine or activated charcoal.
Laquinimod does produce statistically significant reduction in in MS relapse rate, but it is inferior to all other drugs.
Treatment of Aggressive Multiple Sclerosis
There is no universal protocol for the management of frequently relapsing multiple sclerosis and/or MS with rapid accumulation of disability. The approaches described below are typically reserved for aggressive MS.
Alemtuzumab is more popular in Europe and is perceived by many as the most useful agent for aggressive multiple sclerosis.
The drug is a monoclonal antibody to CD52 antigen, present on the surface of T and B lymphocytes. It rapidly produces a sustained depression of lymphocyte level for up to a year.
The treatment consists of 5 consecutive daily IV infusions on the first year and the second treatment of 3 infusions a year later.
Studies showed that 80% of patients with nonaggressive MS did not require retreatment on the third year.
The most common issue with Alemtuzumab is precipitation of other autoimmune diseases in up to 30% of treated patients. Thyroid suffers most often. A new autoimmune disorder might occur as late as 4 years after the last treatment with Alemtuzumab.
Cladribine is an antineoplastic and antimetabolite that reduces CD4+ and CD8+ lymphocytes. In studies it was also proven to be effective in oral form, but only infusion form is currently available on the market.
It is given as a 2 year course of 4 daily infusions every 6 months. Due to side effect profile it is better to be administered by hematologist.
Cladribine does not cause fertility issues, which might be an important advantage over other chemotherapeutic agents.
Immunoablation and Autologous Hematopoietic Stem Cell Transplantation
This approach is reserved exclusively for severe refractory MS.
The whole idea of this approach is a total immune system “reset”. It is like getting a new immune system. The procedure is similar to bone marrow transplantation. The difference is that in bone marrow transplantation patient’s bone marrow is replaced with the donor’s one. In autologous transplantation, own stem cells are harvested, followed by chemotherapy. Then stem cells are “replanted” back.
There is no established level of Immunoablation. Both medium-intensity protocols and high-intensity protocols in this procedure are effective. Medium intensity impact on the immune system is associated with fewer complications. On the other hand, it might be less efficient.
Overall, all studies report very high success rate with mortality around 1%. Depending on the protocol, the rate of relapse control and new MRI lesions freedom ranges from 80% to 100%, with follow up for 10 years in one of the studies. There is even some neurological improvement.
In spite of lack of any inflammation in the brain and the spinal cord, 30% of patients continued to progress. This is understandable, since some degenerative processed in multiple sclerosis are likely independent of the autoimmune attacks.
- None of the available disease modifying strategies in multiple sclerosis targets the underlying cause of the disease, since it is still unknown.
- All medications have a broad, sometimes profound, effect on the immune system function and are associated with side effects, which sometimes may be devastating.
- Only short-to-medium term relapse prevention effect of modern treatment is proven.
- There is no proof that disease modifying treatment delays or prevents MS related disability long term
- There is no treatment for progressive MS or chronic degenerative changes in the brain.
- There are more than 800 ongoing trials for MS treatment. Many more new drugs will hit the market over the following years.
- Further research of multiple sclerosis underlying mechanism and future statistical data about currently utilized treatment will shed more light on the best management of multiple sclerosis.
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