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By Bardia Nouriziabari

Multiple sclerosis (MS) modifying treatments play an important role in controlling the course of MS. Although they are not a permanent cure, they increase patient's ability to execute daily tasks with little or no help. Treatments can be divided into three different groups based on their effects. The first category of drugs facilitate recovery from an acute attack by decreasing T-cells response sensitivity to myelin and by retaining them in lymph nodes. The second category of drugs reduce the number and severity of the attacks by repairing blood brain barrier (BBB) and by inhibiting the adhesion of T-lymphocytes on endothelial surface of the BBB. The third group of treatments can reduce MS symptoms by blocking K+ channels on the exposed axonal surface resulting in enhancement of signal conduction along the damaged axon. MS therapeutic drugs can cause a range of undesirable side effects such as flu-like symptoms of interferons or cardiotoxicity of mitoxantrone. Also, the medications do not have a permanent effect on MS and discontinuing them reverts MS to its original course of progression.[1]

1_Treatments for attacks


1.1 Fingolimod

Fingolimod is a oral receptor modulator that works on sphingosine-1-phosphate receptor (S1P). It is shown
fingolimod.jpg
Figure1. Effect of fingolimod on lymphocyte egress
to be effective in patients with relapse-remitting multiple sclerosis (RRMS) by selectively retaining certain types immune cells in the lymph nodes.(Figure1)

Data from phase III FREEDOMS study in caucasian patients with RRMS under fingolimod treatment showed a 50% decrease in blood lymphocyte count. The decrease was followed by a reduction of disease activity in brain and spinal chord which was detected in MRI. Further, patients acquired a stable score on expanded disease status scale (EDSS).

Upon ceasing fingolimod administration patients exhibited escalated disease activity after 3 to 7 months. In some patients increased disease activity was followed by severe relapses due to fast influx of immune cells into the cerebrospinal fluid (CSF) and brain.[2]

A study by Saida et al. on 171 Japanese RRMS patients during a period of 6 months also provided good evidence of fingolimod effectiveness and safety. At the end of this study patients treated with fingolimod showed fewer gadolinium (Gd)-enhanced lesions than patients receiving the placebo.[3] (Figure2)

fingolimod_saida.jpg
Figure2. Numbers of gadolinium (Gd)-enhanced lesions at baseline and six months
The main adverse effect of fingolimod is transient dose dependent bradycardia which is usually asymptomatic and resolves in 24 hours without treatments. [4] However, In a rare clinical case a 26 year old woman being treated for RRMS with fingolimod showed sudden worsening of her symptoms which caused the treatment to stop. This incident enabled the idea that fingolimod might also inhibit T regulatory cells besides T memory cells which in patients with active MS can result in the worsening of the disease state.[5] A less serious side effect of fingolimod is upper respiratory tract infection. The risk of adverse effects increases in higher dosage of fingolimod.[6]

1.2 Corticosteroids

Coticosteroids are used to help patients recover from an accute attack and are most commonly used for RRMS. They help by reducing the amount of inflammation in the brain and spinal chord that has been caused by the attack. The most commonly administered corticostreoids are prednisone, dexamethason, and methylprednisolone. High doses of methylprednisolone is administered intravenously after the attack for three to five days. After the intravenous treatment, prednisone can be given by mouth for several days.[7]

Corticostreoids are effective for short term recovery from the attacks but show no efficiency for extended recovery from the disease. Further, both oral and intravenous treatments are concluded to be equally effective for recovery of the attacks. [8]

The short term use of corticostreoids can cause adverese effects such as sleep disorders, anxiety, and depression. Use of high doses of corticostreoids for longer periods of time can give rise to more serious side effects such as insulin resistance, diabetes mellitus, and osteoprosis.[9]
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1.3 Alemtuzumab

Alemtuzumab is a humanized monoclonal antibody which targets the surface protein CD52 on T cells and B cells and results in reduction of their numbers via antibody-dependent cell-mediated cytotoxicity (ADCC).[1] (Figure3)
alemtuzumab.gif
Figure 3. Alemtuzumab targeting the surface protein CD52 on a T cell


Based on the early clinical studies alemtuzumab was found to be effective in decreasing the relapse rate and lesion formation in secondary progressive multiple sclerosis (SPMS) patients, however no reduction in disease progression was observed.[10]

A recent study by Fox et al. compared the effectiveness of alemtuzumab versus interferon beta-1a(IFN-B1a) in 45 RRMS patients. The results of a 3 year follow up exhibited a 74% decrease in chance of having a new relapse and
71% reduction in risk of sustained accumulation of disability (SAD) in patients treated with alemtuzumab versus IFN-B1a. Further, patients treated with alemtuzumab showed an improved score for EDSS by 6.2 times versus patients treated with IFN-B1a. Alemtuzumab also decreased the annalized relapse rate (ARR) in RRMS patients by 94% by its second annual cycle.

The common side effects of alemtuzumab include fatigue, rash, and headache. More serious adverse effects of this drug include the development of an autoimmune thyroid disorders with similar symptoms to Grave's disease. Importantly, in rare incidents some patients under alemtuzumab treatment develop other serious adverse effects such as transient neutropenia and pneumonia.[11]

2_Treatments for disease progression



2.1 IFNβ Therapies: IFNβ-1a & IFNβ-1b

Interferons (INF) beta 1a and 1b were approved for treating RRMS in 1996. These drugs are highly effective in reducing the number of relapses in RRMS patients. It is believed that the anti-inflammatory abilities of interferons and their capability to enhance the integrity of BBB is responsible for their high efficiency.

The most common side effects of interferons include injection-site reaction and flu like symptoms which will resolve in few hours after the injection in most patients. Rarely some patients can develop neutralizing antibodies (NABs) during the treatment which results in reduction of INF beta's efficiency. A study by Giovannon et al. on NABs indicated that formation of NABs during the first year of INF beta treatment results higher number of MRI lesions similar to the placebo group.[12]

A study by La Mantina et al. was conducted to determine the effectiveness of IFNs versus placebo on the progression of MS in patients with SPMS. The study found that IFN beta 1a and 1b were ineffective in reducing the likelihood of disease progression after the disease had a continuous progression for six months. IFNs were however able to majorly reduce the risk of progression when they were used during the earlier stage of disease progression at three months. Based on the obtained results it was concluded that IFN beta can not stop the formation of physical disability in SPMS, and can not delay the rate of progression once it has been initiated. In general IFNs were ruled not useful in SPMS.[13]
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2.2 Glatiramer Acetate

Glatiramer acetate (GA) has been used to treat RRSM since 1996. GA can be prescribed for RRSM treatment after the exhibition of the first set of symptoms despite the clinical description of MS which requires exhibition of at least two occasions of symptoms.

The mechanism of action for GA is not yet fully understood. A proposed mechanism states that GA reduces the the number of CD4+ proinflammatory T cells and increases the number Th2 regulatory cells which results in reduced inflammation. Another mechanism proposes that GA acts as a decoy for autoimmune cells and attract them to itself by containing four amino acids found in the myelin protein.

A meta-analysis done by Qizilbash et al. assessed the benefits and the risks of GA compared to interferon (IFN) and placebo treatments in RRMS patients. The dosage of the drug was 20mg a day and was delivered via subcutaneous injection. The gathered data from eleven publications showed that GA is ineffective in helping patients to become relapse free, however GA effectively reduced the number of relapses in randomized controlled trials. GA also reduced the rate of clinical progression by 35%. The most common side effect of GA included injection-site reaction. The side effect was seen equally in IFN treatment group but lower in the placebo gorup.

GA was assessed to have higher effectiveness than IFN in reducing clinical progression but the same ability for relapses. The risks of GA were concluded to be equal to IFN.[14]

2.3 Mitoxantrone

Mitoxantrone (MX) is a cytotoxic agent which inserts into the DNA and disrupts it. Further, it blocks topoisomerase II to prevent DNA repair. MX targets CD4 T cells and B cells and suppresses their function. It also prevents macrophages from demyelinating axons.

A meta analysis of 14 studies done by Martinelli et al. was executed to determine the safety and the effectiveness of MX in RRMS, progressive relapsing multiple sclerosis (PRMS), and SPMS. Meta analysis showed MX to be effective in reducing the rate of disease progression and ARR in patients under MX treatment versus patients under placebo treatment. MX also reduced the number active lesions in 92% of patients.

The most prominent adverse effect of MX is cardiotoxicity which prevents its long term use in MS patients. Cardiotoxicity can be detected and prevented by electrocardiogram and echocardiography. Also, a functionally equivalent drug to MX named pixantrone is currently under development and lacks the cardiotoxicity effect.[15] Data from 3220 Italian patients with MS showed that MX can also cause acute myeloid leukemia (AML) as the average incidence rate of AML was nine times higher in these patients than the general population of Italy under the age of 64. Further, study demonstrated that the occurrence of AML is dose dependent, as there was a positive correlation between the accumulative dosage of MX and the frequency of AML.[16] Less serious side effects of MX include amenorrhoea, alopecia, urinary tract infection, phlebitis, and headache.[15]

2.4 Natalizumab

Natalizumab is the first humanized monoclonal antibody that was approved for treating RRMS in 2004 in U.S. Natalizumab inhibits the migration of leukocytes through the BBB by selectively inhibiting alpha-4 subunit of very late activation antigen 4 (VLA4-A) on leukocytes.(Figure4) Based on a recent study by Harrer et al. natalizumab binds more prominently to NKT and NK cells due to their higher level of expressed alpha-4 integrin on their surface than to CD19+ B cells and CD3+ T cells with a lower expression.[17]
natalizumab2.jpg
Figure4. Natalizumab inhibits leukocytes migration through blood brain barrier by inhibiting VLA4-A


The results of AFFIRM study showed natalizumab's capability in treating RRMS. Natalizumab decreased the relapse rate by 68% and the rate of disease progression by 42% after one year of treatment.

An important potential side effect of Natalizumab is Progressive multifocal leukoencephalopathy (PML). 68 MS patients under natalizumab treatment developed PML during 2006 to 2010 from which 14 were fatal. PML can be diagnosed by detecting JV virus in CSF and using MRI. PML can be treated by plasmapheresis or immunoabsorbtion to clear natalizumab from patients body, however this can follow by a rare condition known as immune reconstitution inflammatory syndrome (IRIS) which results in an unexpected worsening of MS symptoms due to immune system recovery.[5]

The clinical effectiveness of natalizumab can be reduced by occurrence of NABs in some patience as it was seen in nine percent of RRMS patients under natalizumab treatment in AFFRIM study.[17]
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3_Treatments for symptoms



3.1 Dalfampridine

Dalfampridine was approved in 2010 for treating gate difficulties in MS patients. The active ingredient of dalfampridine is 4-aminoprydine (4-Ap) which is released in the body over an extended period of time. 4-Ap is a potassium (K+) channel blocker that blocks K+ channels on the exposed surface of the demyelinated axons in CNS and therefore results in a delayed repolirezation within the axon and an enhanced synaptic transmission.[18](Figure 5)
Dal_final.jpg
Figure5. A)Leakage of K+ from the unmyelinated axon B)Blockage of K+ channels by 4-Ap


Unspecific tendency of 4-Ap for its substrate type allows 4-Ap to bind and block a range of different voltage-activated K+ (Kv) channels that are found among different cells in the CNS and immune system. This allows dalfampridine to have three different mechanism of actions (MoA) for enhancing MS symptoms. Primarily 4-Ap blocks the K+ channels on exposed axonal surface which results in higher influx of Ca2+ into the presynaptic neuron and therefore a higher amount of neurotransmitter release. However, by its secondary mechanism of action 4-Ap can directly activate the high voltage-activated Ca2+ channels (HVACC) in neurons by attaching to the subunit of HVACC intracellularly and turning up its activity level. Increased function of HVACC results in an increased intracellular Ca2+ level and promoted glutamate release from the neuron. [19] 4-Ap can also act as an immunomodulatory factor by blocking Kv channels on T lymphocytes and inhibiting their antigen-specific and antigen-nonspecific mitogenic response.[20]

A study by Goodman et al. was done to determine the efficiency and safely of dalfampridine versus placebo in patients with all MS subtypes. The double-blind trial included total of 237 participants of which 119 were given 10mg dalfampridine twice daily and 118 were given the placebo. After 9 weeks patients under dalfampridine treatment showed 25% enhanced walking speed from the baseline compared to 4.7% improvement in the placebo group. In addition, dalfampridine treated patients exhibited increased leg strength and visual acuity.[21]

The common side effects of dalfampridine include headache, back pain, dizziness and insomnia. Over dose of the drug can lead to more severe adverse effects such as atrial fibrillation, hypothermia, and seizure.[22]

4_See Also


Summary of MS modifying treatments



5_External links

Multiple Sclerosis Society of Canada
Multiple Sclerosis International Federation

6_Further Reading


  1. MS theories of origin and risk factors
  2. Pathophysiology of Multiple Sclerosis
  3. MS clinical symptoms and diagnosis
  4. MS alternative therapies

*Stem Cell Therapies in Neurodegenerative Diseases

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7_References



1. Fox, E.J., Sullivan, H.C., Gazda, S.K., et al. (2012). A single-arm, open-label study of alemtuzumab in treatment-refractory patients with multiple sclerosis. European Journal of Neurology, 19, 307-311.
2. Havla, J., Pelkofer, H., Meinl, I., et al. (2012). Rebound of Disease Activity After Withdrawal of Fingolimod (FTY720) Treatment. Arch Neurol, 69, 262-264.
3. Saida, T,. Kikuchi, S., Itoyama, Y., et al. (2012). A randomized, control trial of fingolimod (FTY720) in Japanese patients with multiple sclerosis. Multiple Sclerosis Journal, 1, 1-9.
4. Hla, T., Brinkmann, H. (2011). Sphingosine 1-phosphate (S1P): physiology and the effects of S1P receptor modulation. Neurology, 76, S3-S8.
5. Castrop, F., Kowarik, M.C., Albrecht, H., et al. (2012). Severe multiple sclerosis relapse under fingolimod therapy: incident or coincidence? Neurology, 78, 928-930.
6. Wipfler, P., Harrer, A., Pilz, G,. et al. (2011). Recent development in approved and oral multiple sclerosis treatment and an update on future treatment options. Drug Discovery Today, 16, 8-21.
7. Compston, A., Coles, A. (2008). Multiple Sclerosis. The Lancet, 372, 1502-1517.
8. Burton, J.M., O'Connor, P.W., Hohol, M., et al. (2009). Oral versus intravenous steroids for treatment of relapses in multiple sclerosis. Cochrane Database of systematic review, 3, 1-47.
9. Donihi, A.C., Raval, D., Saul, M. et al. (2006). Prevalence and predictors of corticosteroid-related hyperglycemia in hospitalized patients. Endocrine Practice, 4, 358-362.
10. Coles, A.J., CAMMS223 Study Group., Compston, D.A., et al. (2008). Alemtuzumab vs. Interferon Beta-1a in Early Multiple Sclerosis. The New England journal of medicine, 359, 1786–1801.
11. Fox, E.J., Sullivan, H.C., Gazda, S.K., et al. (2012). A single-arm, open-label study of alemtuzumab in treatment-refractory patients with multiple sclerosis. European Journal of Neurology, 19, 307-311.
12. Giovannoni, G., Munschauer, F.E., Deisenhamme F. (1996). Neutralizing antibodies during treatment of multiple sclerosis with interferon beta-1b: experience during the first three years. The IFNB Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group. Neurology, 4, 889-894.
13. La Mantia, L., Vacchi, L., Di Pietrantonj, C,. et al. (2012). Interferon Beta for secondary progressive multiple sclerosis. Cochrane Database of systematic review, 1, 1-56.
14. Qizilbash, N., Mendez, I. (2012). Benefit-risk analysis of glatiramer acetate for relapsing-remitting and clinically isolated syndrome multiple sclerosis. Clinical Therapeutics, 34, 159-176.
15. Martinelli F., Rovaris, M., Carpa, R,. et al. (2009). Mitoxantrone for multiple sclerosis. Cochrane Database of systematic review, 1, 1-29.
16. Martinelli, V., Cocco, E., Salemi, G., et al (2012) Acute myeloid leukemia in Italian patients with multiple sclerosis treated with mitoxantrone. Neurology, 78, 933-934.
17. Harrer, A., Pilz, G., Einhaeupl, M., et al. (2012). Lymphocyte subsets show different response patterns to in vivo bound natalizumab-a flow cytometric study on patients with multiple sclerosis. Plosone, 7, 1-7.
18. Judge S.I., Bever C.T. Jr. (2006). Potassium channel blockers in multiple sclerosis: neuronal Kv channels and effects of symptomatic treatment. Pharmacology and Therapeutics, 111, 224–259.
19. Wu, Z.Z. Li, D.P., Chen, S.R., et al. (2009). Aminopyridines potentiate synaptic and neuromuscular transmission by targeting the voltage-activated calcium channel beta subunit. The Journal of biological chemistry, 284, 36453–36461.
20. Espejo, C., Montalban, X. (2011). Dalfampridine in multiple sclerosis: From symptomatic treatment to immunomodulation. Clinical Immunology, 142, 84-92.
21. Goodman, A.D., Brown, T.R., Edwards, K.R., et al. (2010). A phase 3 trial of extended release oral dalfampridine in multiple sclerosis. Annals of Neurology, 68, 494–502.
22. Johnson, N.C., Morgan, M.W. (2006). An unusual case of 4-aminopyridine toxicity. The Journal of emergency medicine, 30, 175-175.