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Research directions on MS treatments include investigations of MS pathogenesis and heterogeneity; research of more effective, convenient, or tolerable new treatments for RRMS; creation of therapies for the progressive subtypes; neuroprotection strategies; and the search for effective symptomatic treatments.<ref name="pmid19597083">{{cite journal |author=Cohen JA |title=Emerging therapies for relapsing multiple sclerosis |journal=Arch. Neurol. |volume=66 |issue=7 |pages=821–8 |date=July 2009 |pmid=19597083 |doi=10.1001/archneurol.2009.104 |url=}}</ref>
Research directions on MS treatments include investigations of MS pathogenesis and heterogeneity; research of more effective, convenient, or tolerable new treatments for RRMS; creation of therapies for the progressive subtypes; neuroprotection strategies; and the search for effective symptomatic treatments.<ref name="pmid19597083">{{cite journal |author=Cohen JA |title=Emerging therapies for relapsing multiple sclerosis |journal=Arch. Neurol. |volume=66 |issue=7 |pages=821–8 |date=July 2009 |pmid=19597083 |doi=10.1001/archneurol.2009.104 |url=}}</ref>


Advancements during the last decades have led to the recent approval of several oral drugs. These drugs are expected to gain in popularity and frequency of use at the expense of previously existing therapies.<ref name="pmid21425270">{{cite journal |author=Miller AE |title=Multiple sclerosis: where will we be in 2020? |journal=Mt. Sinai J. Med. |volume=78 |issue=2 |pages=268–79 |year=2011 |pmid=21425270 |doi=10.1002/msj.20242 |url=}}</ref> Further oral drugs are still under investigation, the most notable example being [[laquinimod]], which was announced in August 2012 to be the focus of a third phase III trial after mixed results in the previous ones.<ref>{{cite news|last=Jeffrey|first=susan|title=CONCERTO: A Third Phase 3 Trial for Laquinimod in MS|url=http://www.medscape.com/viewarticle/768902|accessdate=21 May 2013|newspaper=Medscape Medical News|date=9 Aug 2012}}</ref> Similarly, Other studies are aimed to improve efficacy and ease of use of already existing therapies through the use of novel preparations. Such is the case the [[PEGylation|PEGylated]] version of interferon-β-1a, that has a longer life than normal interferon and therefore it is being studied if given at less frequent doses has a similar efficacy than the existing product.<ref name="pmid22201341">{{cite journal |author=Kieseier BC, Calabresi PA |title=PEGylation of interferon-β-1a: a promising strategy in multiple sclerosis |journal=CNS Drugs |volume=26 |issue=3 |pages=205–14 |date=March 2012 |pmid=22201341 |doi=10.2165/11596970-000000000-00000 |url=}}</ref><ref name=PEG>{{cite press release|url=http://www.biogenidec.com/press_release_details.aspx?ID=5981&ReqId=1777510|title=Biogen Idec Announces Positive Top-Line Results from Phase 3 Study of Peginterferon Beta-1a in Multiple Sclerosis|publisher=Biogen Idec |date=2013-01-24|accessdate=2013-05-21}}</ref> Request for approval of ''peginterferon beta-1a'' is expected during 2013.<ref name=PEG/>
Advancements during the last decades have led to the recent approval of several oral drugs. These drugs are expected to gain in popularity and frequency of use at the expense of previously existing therapies.<ref name="pmid21425270">{{cite journal |author=Miller AE |title=Multiple sclerosis: where will we be in 2020? |journal=Mt. Sinai J. Med. |volume=78 |issue=2 |pages=268–79 |year=2011 |pmid=21425270 |doi=10.1002/msj.20242 |url=}}</ref> Further oral drugs are still under investigation, the most notable example being [[laquinimod]], which was announced in August 2012 to be the focus of a third phase III trial after mixed results in the previous ones.<ref>{{cite news|last=Jeffrey|first=susan|title=CONCERTO: A Third Phase 3 Trial for Laquinimod in MS|url=http://www.medscape.com/viewarticle/768902|accessdate=21 May 2013|newspaper=Medscape Medical News|date=9 Aug 2012}}</ref> Similarly, Other studies are aimed to improve efficacy and ease of use of already existing therapies through the use of novel preparations.<ref>Roger Lee Mendoza (2014). Pharmacoeconomics and clinical trials in multiple sclerosis: baseline data from the European Union. ''Journal of Public Health'',
22 (3): 211-218, http://link.springer.com/article/10.1007%2Fs10389-013-0561-z.</ref> Such is the case the [[PEGylation|PEGylated]] version of interferon-β-1a, that has a longer life than normal interferon and therefore it is being studied if given at less frequent doses has a similar efficacy than the existing product.<ref name="pmid22201341">{{cite journal |author=Kieseier BC, Calabresi PA |title=PEGylation of interferon-β-1a: a promising strategy in multiple sclerosis |journal=CNS Drugs |volume=26 |issue=3 |pages=205–14 |date=March 2012 |pmid=22201341 |doi=10.2165/11596970-000000000-00000 |url=}}</ref><ref name=PEG>{{cite press release|url=http://www.biogenidec.com/press_release_details.aspx?ID=5981&ReqId=1777510|title=Biogen Idec Announces Positive Top-Line Results from Phase 3 Study of Peginterferon Beta-1a in Multiple Sclerosis|publisher=Biogen Idec |date=2013-01-24|accessdate=2013-05-21}}</ref> Request for approval of ''peginterferon beta-1a'' is expected during 2013.<ref name=PEG/>


Monoclonal antibodies, which are drugs of the same family as natalizumab, have also raised high levels of interest and research. [[Alemtuzumab]], [[daclizumab]] and [[CD20]] monoclonal antibodies such as [[rituximab]], [[ocrelizumab]] and [[ofatumumab]] have all shown some benefit and are under study as potential treatments for MS.<ref name="pmid22224673">{{cite journal |author=Saidha S, Eckstein C, Calabresi PA |title=New and emerging disease modifying therapies for multiple sclerosis |journal=Annals of the New York Academy of Sciences |volume=1247 |issue= |pages=117–37 |date=January 2012 |pmid=22224673 |doi=10.1111/j.1749-6632.2011.06272.x |url=}}</ref> Nevertheless their use has also been accompanied by the appearance of potentially dangerous adverse effects, most importantly opportunistic infections.<ref name="pmid21425270"/> Related to these investigations is the recent development of a test against [[JC virus]] antibodies which might help to predict what patients are at a greater risk of developing progressive multifocal leukoencephalopathy when taking natalizumab.<ref name="pmid21425270"/> While monoclonal antibodies are probably going to have some role in the treatment of the disease in the future, it is believed that it will be small due to the risks associated to them.<ref name="pmid21425270"/>
Monoclonal antibodies, which are drugs of the same family as natalizumab, have also raised high levels of interest and research. [[Alemtuzumab]], [[daclizumab]] and [[CD20]] monoclonal antibodies such as [[rituximab]], [[ocrelizumab]] and [[ofatumumab]] have all shown some benefit and are under study as potential treatments for MS.<ref name="pmid22224673">{{cite journal |author=Saidha S, Eckstein C, Calabresi PA |title=New and emerging disease modifying therapies for multiple sclerosis |journal=Annals of the New York Academy of Sciences |volume=1247 |issue= |pages=117–37 |date=January 2012 |pmid=22224673 |doi=10.1111/j.1749-6632.2011.06272.x |url=}}</ref> Nevertheless their use has also been accompanied by the appearance of potentially dangerous adverse effects, most importantly opportunistic infections.<ref name="pmid21425270"/> Related to these investigations is the recent development of a test against [[JC virus]] antibodies which might help to predict what patients are at a greater risk of developing progressive multifocal leukoencephalopathy when taking natalizumab.<ref name="pmid21425270"/> While monoclonal antibodies are probably going to have some role in the treatment of the disease in the future, it is believed that it will be small due to the risks associated to them.<ref name="pmid21425270"/>

Revision as of 03:57, 26 October 2014

Treatments under investigation for multiple sclerosis may improve function, curtail attacks, or limit the progression of the underlying disease. Many treatments already in clinical trials involve drugs that are used in other diseases or medications that have not been designed specifically for multiple sclerosis. There are also trials involving the combination of drugs that are already in use for multiple sclerosis. Finally, there are also many basic investigations that try to understand better the disease and in the future may help to find new treatments.

Research directions

Research directions on MS treatments include investigations of MS pathogenesis and heterogeneity; research of more effective, convenient, or tolerable new treatments for RRMS; creation of therapies for the progressive subtypes; neuroprotection strategies; and the search for effective symptomatic treatments.[1]

Advancements during the last decades have led to the recent approval of several oral drugs. These drugs are expected to gain in popularity and frequency of use at the expense of previously existing therapies.[2] Further oral drugs are still under investigation, the most notable example being laquinimod, which was announced in August 2012 to be the focus of a third phase III trial after mixed results in the previous ones.[3] Similarly, Other studies are aimed to improve efficacy and ease of use of already existing therapies through the use of novel preparations.[4] Such is the case the PEGylated version of interferon-β-1a, that has a longer life than normal interferon and therefore it is being studied if given at less frequent doses has a similar efficacy than the existing product.[5][6] Request for approval of peginterferon beta-1a is expected during 2013.[6]

Monoclonal antibodies, which are drugs of the same family as natalizumab, have also raised high levels of interest and research. Alemtuzumab, daclizumab and CD20 monoclonal antibodies such as rituximab, ocrelizumab and ofatumumab have all shown some benefit and are under study as potential treatments for MS.[7] Nevertheless their use has also been accompanied by the appearance of potentially dangerous adverse effects, most importantly opportunistic infections.[2] Related to these investigations is the recent development of a test against JC virus antibodies which might help to predict what patients are at a greater risk of developing progressive multifocal leukoencephalopathy when taking natalizumab.[2] While monoclonal antibodies are probably going to have some role in the treatment of the disease in the future, it is believed that it will be small due to the risks associated to them.[2]

Another research strategy is to evaluate the combined effectiveness of two or more drugs.[8] The main rationale for polytherapy in MS is that the involved treatments target different mechanisms of the disease and therefore, their use is not necessarily exclusive.[8] Moreover synergies, in which a drug potentiates the effect of another are also possible. Nevertheless there can also appear important drawbacks such as antagonizing mechanisms of action or potentiation of deleterious secondary effects.[8] While there have been several clinical trials of combined therapy none has shown positive enough effects to merit the consideration as a viable treatment for MS.[8]

Finally, regarding neuroprotective and specially regenerative treatments such as stem cell therapy, while their research is considered of high importance at the moment they are only a promise of future therapeutic approaches.[9] Likewise, there are not any effective treatments for the progressive variants of the disease. Many of the newest drugs as well as those under development are probably going to be evaluated as therapies for PPMS or SPMS, and their improved effectiveness when compared with previously existing drugs may eventually lead to a positive result in these groups of patients.[2]

Clinical measures of evolution

The main measure of evolution of symptoms, specially important as an endpoint in MS trials, is the EDSS. However, this and other measures used in clinical studies are far from perfect and suffer from insensitivity or inadequate validation.[10] In this sense there is ongoing research to improve the EDSS and other measures such as the multiple sclerosis functional composite. This is important as the greater efficacy of existing medications force functional measures in clinical trials to be highly sensitive in order to adequately measure disease changes.[10]

Geographical Causes

Extensive research on multiple sclerosis is being done on what parts of the world have higher rates of MS compared to other regions. Researchers have studied MS mortality statistics in various latitudes of the earth and the pattern shows that MS mortality rates are lowest in equatorial regions, which contain the countries, Ethiopia and Jamaica. It increases towards the north and south showing that the highest MS rate is at a latitude of around 60 degrees, which are the countries Orkney, Shetland Islands, and Oslo, Norway. The next step for researchers would be to consider what factors are different at the latitudes of 60 degrees and the equatorial regions and continue to narrow down their theories for the exact cause of MS. [11]

Genetics

Advances in genetic testing techniques have led to a greater understanding of the genetics of MS. However, it is hard to predict how these future discoveries will impact clinical practice or research for new drugs and treatments.[2]

An example of a soon-to-be finished study is the Wellcome Trust case control consortium, a collaboration study including 120,000 genetic samples, of which 8000 are from individuals with MS.[12] This study may presumably identify all the common genetic variants involved in MS.[12] Further studies will probably involve full genome sequencing of large samples, or the study of structural genetic variants such as insertions, deletions or polymorphisms.[12]

Genetic Influence on Disease

Genetic factors are the primary cause to the more rapid progression and frequency of the disease. Although genetics is linked to multiple sclerosis, most of the prime perceptivity of the linkage has not been fully characterized as there has not been a big enough sample size available for the research needed.[13] The chronic demyelination may cause axons to be notably vulnerable to repetitive and increasing injury and destruction.[14]

Disease-modifying drugs and procedures

Disease-modifying drugs and procedures represent possible interventions able to modify the natural course of the disease instead of targeting the symptoms or the recovery from relapses.[15] Over a dozen clinical trials testing potential therapies are underway, and additional new treatments are being devised and tested in animal models.

Phase III

Phase III programs consist of studies on large patient groups (300 to 3,000 or more) and are aimed at being the definitive assessment of how effective and safe a test drug will be. It is the last stage of drug development and is followed by a submission to the appropriate regulatory agencies (e.g., European Medicines Agency (EMEA) for the European Union, the Food and Drug Administration (FDA) for the USA, Therapeutic Goods Administration (TGA) for Australia, etc.) to obtain approval for marketing. Treatment in MS phase III studies is usually 2 years per patient.

  • Alemtuzumab (injectable. brand names: Campath and Lemtrada; under development by Genzyme and Bayer Schering) is a monoclonal antibody currently already used in the treatment of chronic lymphocytic leukemia and T-cell lymphoma. Results from the phase II study comparing it to Rebif (interferon beta-1a) were published in May 2007 showing efficacy. However, the trial was halted after 3 cases [16] of immune thrombocytopenic purpura (ITP) were reported; later on, a further 3 more cases were found, and 1 patient died. This is a life-threatening side effect but is treatable if detected. Therefore, all patients receiving alemtuzumab should have their platelet count monitored.[17][18] Two phase 3 trials comparing with Rebif are due to end in 2011.[19][20] The results have been considered a success.[21] Though the drug has been submitted for approval on June 2012[22] under the name Lemtrada there are doubts about its approval.[23]
  • Tovaxin (injectable) A vaccine against self T-Cells, which consist of attenuated autoreactive T cells. It is developed by Opexa Therapeutics, (previously known as PharmaFrontiers), and finished a phase IIb September 2008,[30] failing its primary target though in March 2008 was still performing good.[31] After several financial troubles, a phase III trial has been granted in 2011[32]
  • Peginterferon Beta-1a, also known as Plegridy, recently submitted to FDA.[33] It can be considered a pharmaceutical formulation of interferon beta-1a in which the molecules are pegylated to extend their half-life.

Phase II

Phase II studies are performed on mid-sized groups of patients (20 to 300) and are designed to assess whether a drug may work in the targeted disease area, as well as to continue earlier safety assessments obtained in healthy volunteers. Treatment in MS phase II studies is with 4–12 months usually shorter than in phase III studies.

  • Estradiol and estrogen receptors(ER): Both have been shown to be antiinflammatory and neuroprotective in a variety of neurological disease models and now is known that they work also in presence of inflammation[35][36][needs update]
  • Ibudilast: A phase II trial shows that Ibudilast does not reduce lesion rate, but prevents them to turn into black holes. They classify its action as class III evidence of delay on disease activity[37]
  • Inosine: Inosine is a compound that has shown interesting preliminary results in phases I and II clinical trials.[38][39] Two different mechanisms of action have been proposed. First, it produces uric acid after ingestion,[40] which is a natural antioxidant;[41] second, it has been shown to induce axonal rewiring in laboratory animals with stroke,[42] and spinal cord injury.[43] However it can cause health problems in a long-term treatment,[44] mainly kidney stones.[45] It seems that its mechanism of action is peroxynitrite inactivation[46]
  • Ocrelizumab, Anti-CD20 humanized monoclonal antibody, whose mechanism of action targets B-Cells, like Rituximab, currently in phase II.[47]
  • Ofatumumab, other anti-CD20 monoclonal antibody, also in phase II for MS, and phase III for others autoimmune diseases
  • Stem cell transplantation was found feasible in a phase I/II study in 21 patients with relapsing-remitting MS not responsive to interferon beta. It involves collecting some of the patient's own peripheral blood stem cells, giving low-intensity chemotherapy to eliminate auto-reactive lymphocytes, and then reinfusing the stem cells.[48] Earlier studies in the secondary-progressive stage of MS have failed to shown reversal of neurological symptoms.
  • BAF312, NOVARTIS' BAF312 is a sphingosine-1-phosphate receptor modulator for oral use that is currently (June 8, 2009) in Phase II trial. "A back-up compound for Fingolimod, BAF 312" is in Phase II studies.[49] It is being tested for the first time on people having multiple sclerosis. Worldwide 275 patients will participate in this phase II trial the outcome of which is to establish what the optimal dosage of BAF312 is for patients affected with Multiple Sclerosis for use in further trials. In order to identify "the optimal dosage", participants in group I will be randomly selected to take either placebo, or BAF312 in doses of 0.5 mg/day, 2 mg/day, or 10 mg./day and will be regularly controlled in order to measure and determine the effectiveness, the tolerability and the safety of the dosages. BAF312 acts on the lymphocytes to inhibit their migration to the location of the inflammation. BAF312, though information about it is extremely limited, may be very similar to Fingolimod but preventing lymphopenia, one of its main side effects, by preventing egress of lymphocytes from lymph nodes. BAF312 may be more selective in the particular sphingosine-1-phosphate receptors (8 in number) that it modulates.[50] Expected name: Siponimod

Phase I and animal models

Phase I and medicaments used in animal models would make a huge list. Here only some of them with special interest are listed.

  • GIFT15 is a treatment which suppresses the immune system, and has been successfully used in the treatment of mice. The immune system attacks the central nervous system in Multiple Sclerosis patients. Specifically a "granulocyte-macrophage colony–stimulating factor (GM-CSF) and interleukin-15 (IL-15) 'fusokine]' (GIFT15) exerts immune suppression via aberrant signaling through the IL-15 receptor on lymphomyeloid cells. We show here that ex vivo GIFT15 treatment of mouse splenocytes generates suppressive regulatory cells of B cell ontogeny (hereafter called GIFT15 Breg cells)."[51][52][53]
  • Bosentan, endothelin-1 antagonist, has been proposed to lower the ET1 levels, which are involved in brain hypoperfusion[54]

Other possible treatments

  • Antimicrobial agents against Chlamydophila pneumoniae: MS patients are more likely to have detectable levels of Chlamydophila pneumoniae DNA in their cerebrospinal fluid, compared to other patients with neurological diseases; however these findings are insufficient to establish an etiologic relation.[55] Anecdotal reports of the use of antimicrobial agents against Chlamydophila pneumoniae are favorable, but only one double-blind placebo-controlled trial has been published, in which the number of patients studied was too small (four in each arm of the trial) to reach statistical significance in the primary outcome measure (volume of gadolinium-enhancing lesions, as viewed on MRI).[56]
  • Antioxidants, available as supplements, are reported to reduce the blood–brain barrier permeability.[57] Related to this, MS patients have been reported to have low levels of uric acid, which is a natural antioxidant,[58] and has been observed that raising uric acid levels protects against blood–brain barrier destruction (through peroxynitrite scavenging ).[59] Peroxynitrite has been correlated with the axons degeneration and its removal can protect neurons from further damage after an attack. They can also remove other reactive oxygen species[60]
  • Bilirubin has been found to have immunomodulatory properties, apart from the already known antioxidant properties, and is a possible future treatment.[61]
  • Use of drugs to suppress myelin-reactive effector memory T cells by blocking voltage-gated Kv1.3 channels in these cells.[62][63][64][65][66]
  • Helminthic therapy: A study showed a negative association between multiple sclerosis and infection with intestinal parasites, such as hookworm indicating that parasites may protect against multiple sclerosis.[68][69] Helminth therapy involves ingesting helminth eggs by the names of Trichuris suis, which are non parasitic worms. This is done in hopes that the body will redirect the immune response away from attacking the myelin, which produce lesions, and target the helminths. The study by Dr Fleming shows this is affective in reducing the extent of lesions seen through MRI’s taken before and after the study.[70]
  • BCG vaccine: The common, live, attenuated vaccine against tuberculosis, has substantially reduced recurrence of symptoms in multiple sclerosis patients.[71] The frequency of new enhancing lesions as detected by Gd-enhanced MRI was reduced by more than half in 12 patients, comparing the six-month run-in phase to the six-month post BCG phase of the experiment. Persistence at subsequent MR scan was reduced from 18 to 1 lesion, and evolution to black holes was reduced from 28 to 6 lesions.[72] The conventional explanation of such protection is that parasites (including bacteria) modulate the sensitivity of the immune system. BCG appears safe as a treatment for multiple sclerosis.[71][73]
  • Low dose naltrexone is also known as LDN. Naltrexone, a pure opiate antagonist, licensed by the FDA for the treatment of alcohol and opioid addictions, is currently being studied at a lower dosage for MS patients. A small, short-duration clinical trial[74] with MS patients was recently conducted at the University of California, San Francisco. In October 2007 data was presented at the European Congress of MS in Prague regarding safety findings of a pilot study of low dose naltrexone therapy in multiple sclerosis by neurological researchers in Milan, Italy.[75] However, no compelling efficacy results for LDN in MS therapy have been published. LDN is currently available to MS patients in the USA by off-label prescription.
  • Minocycline: the antibiotic minocycline has shown an effect on clinical and magnetic resonance imaging (MRI) outcomes and serum immune molecules in MS patients over 24 months of open-label minocycline treatment. Despite a moderately high pretreatment relapse rate in patients in the study prior to treatment, no relapses occurred between months 6 and 24. The only patient with gadolinium-enhancing lesions on MRI at 12 and 24 months was on half-dose minocycline. Clinical and MRI outcomes in this study were supported by systemic immunological changes and call for further investigation of minocycline in MS.[76][77][78]
  • Pixantrone: pixantrone (BBR2778) is an analogue of mitoxantrone devoid of toxic effects on cardiac tissue. It is as potent as mitoxantrone in animal models of MS; however results of human trials had not been published in 2007.[79]
  • Plasmapheresis. Pattern II MS lesions have been reported to respond to plasmapheresis,[80] which points to something pathogenic into the blood serum, and the percentaje reported of pattern II is very close to the 47% reported in Kir4.1 MS cases,[81] turning Kir4.1 patients into candidates for plasma exchange.
  • Prolactin:In 2007 it was published that the hormone prolactin can ease the effects of demyelination in animal models of MS.[82] This effect of prolactin may be the reason why pregnancy tends to reduce the effects of multiple sclerosis in women.[83]
  • Statins: a family of cholesterol-lowering drugs, the statins, have shown anti-inflammatory effects in animal models of MS.[84] However there is no evidence that statins are beneficial in the treatment of human MS patients, and concerns exist that, if ever shown to be effective, the high doses needed would prevent long-term use due to the potential for liver damage and muscle-wasting disease. One of them, Atorvastatin, has been tried in combination with several approved treatments, though with little success. Other, Simvastatin (Zocor) has shown good results in progressive variants[85]
  • Testosterone has been studied for its potential benefits in men with Multiple Sclerosis, but the results are preliminary.[86]
  • Venous stents, based on the contentious hypothesis that defects in the blood drainage system (CCSVI) can debilitate the blood–brain barrier,[25][26] and the problems with angioplasties to treat CCSVI, mainly restenosis after angioplasties.
  • Vitamin D: a 2004 study found that women who took vitamin D supplements were 40% less likely to develop MS than women who did not take supplements. However, this study does not provide enough data to conclude that vitamin D has a beneficial influence on ongoing MS. Furthermore, it could not distinguish between a beneficial effect of vitamin D and that of multivitamin supplements including vitamin E and various B vitamins, which may also exert a protective effect.[87] A new study in the same sense was published in 2013[88]
  • Omega-3 fatty acid: A study found that Omega-3 fatty acid supplementation decreases matrix metalloproteinase-9 production in relapsing-remitting multiple sclerosis[89]

Combined therapies

Several combinations of drugs have been tested. Some of them are couples of approved drugs. Other tests try one approved drug with one experimental substance. Finally, at some point there could appear some trials testing couples of non-approved drugs.

Combination of approved drugs

  • Mitoxantrone & Copaxone: A recent study in the United Kingdom revealed interesting results when using a combination of mitoxantrone and copaxone. In an open-label study of 27 patients with RRMS, the results suggested a rapid and sustained suppression of relapses. A three year controlled study of 60 patients is now being launched at 10 centres across the UK.[90] In another clinical trial, glatiramer acetate (Copaxone) has been combined with Mitoxantrone in such a way that every course of Mitoxantrone is followed by GA treatment. It has yielded promising results twice, in a consistent way.[91][92]
  • Tysabri & Copaxone This combination has been found to be safe and well tolerated after six months.[93]
  • Mitoxantrone & beta-interferon: This combination has worked in some cases but not in others[94]
  • Avonex & Copaxone: Currently in phase III, with good results published[95]
  • Interferon beta 1a & Tysabri: Dangerous but effective.[96] Linked with PML, but is remarkable that Natalizumab alone is also linked with it.
  • Natalizumab and Fingolimod. No formal research has been done, but some problems have been reported.[97]
  • Interferon beta 1a & Glatimer acetate: No additional benefits found[98]

Approved and experimental drugs combined

  • Copaxone & Minocycline. Good results[99]
  • Avonex & Atorvastatin: Avonex (beta-1a) has also been combined with Atorvastatin in a clinical trial showing that is safe in its conditions,[100] even though high-dose statins are expected to produce liver problems and muscle-wasting disease over the long-term.[101] Other clinical trials have found problems combining IFN beta with Atorvastatin[102]
  • Betaseron & Atorvastatin: Betaseron (beta-1b) has also been combined with Atorvastatin with good safety results but poor performance. The combined treatment did not have any beneficial effects on RRMS compared to IFNB-1b monotherapy.[103]
  • Cyclophosphamide & Beta-interferon has been tried on IFNbeta-unresponsive patients with success, but it is still under study.[104]
  • Avonex & Inosine: Avonex (interferon beta-1a) was combined with Inosine. Available data suggests that this combination is safe and well tolerated, though with no improvements respect interferon beta alone.[105][106] Recently the lack of additional benefits respect Avonex have been confirmed, and it has been reported that 2gr/day should be considered as the maximum safe dosage.[107]

Summary table

Summarizing in a table which combinations have been tried:

Interferon beta-1a Betaseron (beta-1b) Copaxone Mitoxantrone Tysabri Fingolimod (Gylenya) Teriflunomide Dymethil Fumarate BG12
Interferon beta-1a — — — — — — — —
Betaseron NO — — — — — — —
Copaxone YES[98] NO — — — — — —
Mitoxantrone NO NO YES[91][92] — — — — —
Tysabri YES (linked to PML) NO YES[93] NO — — — —
Fingolimod NO NO NO NO NO — — —
Teriflunomide NO NO NO NO NO NO — —
Dymetyl Fumarate BG12 NO NO NO NO NO NO NO —
Atorvastatin YES YES[103] NO NO NO NO NO NO
Cyclophosphamide NO YES NO NO NO NO NO NO
Inosine YES[105][106] NO NO NO NO NO NO NO

Research in biomarkers and tailored treatments

Comparative Effectiveness Research (CER) is an emerging field in Multiple Sclerosis treatment. The response of the disease to the different available medications at this moment cannot be predicted, and would be desirable[108]

Research is on its way. For example, a biomarker recently proposed is vitamin D. Apart from its possible involvement in disease patogenesis, it has been proposed as a biomarker of the disease evolution[109]

But the ideal target is to find subtypes of the disease that respond better to a specific treatmet. A good example could be the discovery of the disregulation of some transcription factors,[110] or the promising report about autoantibodies against the potasium channel Kir4.1 appearing with high specificity in MS patients (they have shown to be pathogenic in models).

Aggressive variants

Progressive variants have proved more difficult to treat than RRMS. This is the status of the research into progressive variants.

Highly active relapsing remitting

Highly Active Relapsing Remitting, sometimes called Rapidly Worsening relapsing remitting, is a clinical form considered distinct from standard RR during clinical trials, being normally non responsive to standard medication.

As of 2011, fingolimod has been approved as the first disease modifying therapy for this clinical course.[111] Cyclophosphamide is currently used off-label for Rapidly Worsening MS (RWMS).[112]

Primary progressive

This variant does not have any approved treatment currently. Some possible treatments have been published, such as methylprednisolone pulses[113] or riluzole,[114] and some reduction of spasticity was reported in a pilot Italian study on low dose naltrexone[75] but there is nothing conclusive still.

A Statin, Simvastatin (Zocor), has shown good results in progressive variants[85]

Secondary progressive and progressive-relapsing

Only Mitoxantrone has been approved, but most of the previous pipeline drugs have been or will be tried on it at some point.

  • Cyclophosphamide (trade name Revimmune) is currently in Phase III for secondary progressive MS.[115] It was also studied for RRMS but the company does not pursue actively this path. After a 2006 study for refractory cases it showed good behaviour[116] Later, a 2007 open label study found it equivalent to Mitoxantrone[117] and in 2008 evidence appeared that it can reverse disability.[118]
  • Tcelna is currently under active research by Opexa, showing promising results.[119]

References

  1. ^ Cohen JA (July 2009). "Emerging therapies for relapsing multiple sclerosis". Arch. Neurol. 66 (7): 821–8. doi:10.1001/archneurol.2009.104. PMID 19597083.
  2. ^ a b c d e f Miller AE (2011). "Multiple sclerosis: where will we be in 2020?". Mt. Sinai J. Med. 78 (2): 268–79. doi:10.1002/msj.20242. PMID 21425270.
  3. ^ Jeffrey, susan (9 Aug 2012). "CONCERTO: A Third Phase 3 Trial for Laquinimod in MS". Medscape Medical News. Retrieved 21 May 2013.
  4. ^ Roger Lee Mendoza (2014). Pharmacoeconomics and clinical trials in multiple sclerosis: baseline data from the European Union. Journal of Public Health, 22 (3): 211-218, http://link.springer.com/article/10.1007%2Fs10389-013-0561-z.
  5. ^ Kieseier BC, Calabresi PA (March 2012). "PEGylation of interferon-β-1a: a promising strategy in multiple sclerosis". CNS Drugs. 26 (3): 205–14. doi:10.2165/11596970-000000000-00000. PMID 22201341.
  6. ^ a b "Biogen Idec Announces Positive Top-Line Results from Phase 3 Study of Peginterferon Beta-1a in Multiple Sclerosis" (Press release). Biogen Idec. 2013-01-24. Retrieved 2013-05-21.
  7. ^ Saidha S, Eckstein C, Calabresi PA (January 2012). "New and emerging disease modifying therapies for multiple sclerosis". Annals of the New York Academy of Sciences. 1247: 117–37. doi:10.1111/j.1749-6632.2011.06272.x. PMID 22224673.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  8. ^ a b c d Milo R, Panitch H (February 2011). "Combination therapy in multiple sclerosis". J. Neuroimmunol. 231 (1–2): 23–31. doi:10.1016/j.jneuroim.2010.10.021. PMID 21111490.
  9. ^ Luessi F, Siffrin V, Zipp F (September 2012). "Neurodegeneration in multiple sclerosis: novel treatment strategies". Expert Rev Neurother. 12 (9): 1061–76, quiz 1077. doi:10.1586/ern.12.59. PMID 23039386.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  10. ^ a b Cohen JA, Reingold SC, Polman CH, Wolinsky JS (May 2012). "Disability outcome measures in multiple sclerosis clinical trials: current status and future prospects". Lancet Neurol. 11 (5): 467–76. doi:10.1016/S1474-4422(12)70059-5. PMID 22516081.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  11. ^ Geographical Clues about Multiple Sclerosis. Jonathan D. Mayer, Annals of the Association of American Geographers Vol. 71, No. 1 (Mar., 1981) , pp. 28-39 Published by: Taylor & Francis, Ltd. on behalf of the Association of American Geographers
  12. ^ a b c Baranzini SE (June 2011). "Revealing the genetic basis of multiple sclerosis: are we there yet?". Current Opinion in Genetics & Development. 21 (3): 317–24. doi:10.1016/j.gde.2010.12.006. PMC 3105160. PMID 21247752.
  13. ^ Sawcer, S., &, Hellenthal, G., & Pirinen, M., & Spencer, C.C.A., & Patsopoulos, N. A., & Moutsianas, L., & et al (2011). Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature. Aug 10, 2011; 476(7359): 214–219. doi:10.1038/nature10251
  14. ^ Frischer J.M., & Bramow S., & Dal-Bianco A., & Lucchinetti C.F., & Rauschka H., et al. (2009) The relation between inflammation and neurodegeneration in multiple sclerosis brains. Brain 132: 1175–89.
  15. ^ Roger Lee Mendoza (2014). Pharmacoeconomics and clinical trials in multiple sclerosis: baseline data from the European Union. Journal of Public Health, 22 (3): 211-218, http://link.springer.com/article/10.1007%2Fs10389-013-0561-z.
  16. ^ Hader, Walter J., and Irene M. Yee. "The Prevalence of Familial Multiple Sclerosis in Saskatoon, Saskatchewan." Multiple Sclerosis International 2014 (2014).
  17. ^ Information from GenZyme on its clinical trial for Alemtuzumab
  18. ^ Coles AJ, Compston DA, Selmaj KW; et al. (October 2008). "Alemtuzumab vs. interferon beta-1a in early multiple sclerosis". N Engl J Med. 359 (17): 1786–801. doi:10.1056/NEJMoa0802670. PMID 18946064. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  19. ^ clinicaltrial.gov Phase III Alemtuzumab Study 1;vs Rebif. Enrollment: 81, Start Sept 2007, Est' end date May 2011
  20. ^ clinicaltrial.gov Phase III Alemtuzumab Study 2;vs Rebif Enrollment: 840, Start Date: Oct 2007, Est End Date: Sept 2011.
  21. ^ Sanofi Reports Positive Top-Line Results From First Phase 3 Study Of Alemtuzumab (Lemtrada™) In Multiple Sclerosis, [1] L
  22. ^ Lemtrada submitted for approval on June 2012
  23. ^ Sanofi’s Lemtrada Drug May Be Too Risky, FDA Staff Says
  24. ^ clinicaltrials.gov
  25. ^ a b Zamboni P, Galeotti R, Menegatti E; et al. (April 2009). "Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis". Journal of Neurology, Neurosurgery & Psychiatry. 80 (4): 392–9. doi:10.1136/jnnp.2008.157164. PMC 2647682. PMID 19060024. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  26. ^ a b Zamboni P. et al.: Rationale and preliminary results of endovascular treatment of multiple sclerosis, the liberation procedure [2]
  27. ^ Montalban X, Wynn D, Kaufman M et al. Preliminary CHOICE results. ECTRIMS 2007
  28. ^ Rose JW, Burns JB, Bjorklund J, Klein J, Watt HE, Carlson NG (2007). "Daclizumab phase II trial in relapsing and remitting multiple sclerosis: MRI and clinical results". Neurology. 69 (8): 785–9. doi:10.1212/01.wnl.0000267662.41734.1f. PMID 17709711.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  29. ^ ClinicalTrials.gov: Identifier NCT01064401. Updated on 7. April 2011.
  30. ^ Opexa shares lose most of value on study data
  31. ^ Opexa Therapeutics Announces Completion Of Mid Study Descriptive Analysis On Phase IIb Trial Of Tovaxin
  32. ^ Tovaxin phase III announced http://www.opexatherapeutics.com/?page=release&section=news&article=010511
  33. ^ [3]
  34. ^ clinicaltrial.gov CDP323 Phase II Study. Retrieved on 25 November 2007.
  35. ^ Tiwari-Woodruff S, Morales LB, Lee R, Voskuhl RR (2007). "Differential neuroprotective and antiinflammatory effects of estrogen receptor (ER){alpha} and ER{beta} ligand treatment". Proceedings of the National Academy of Sciences. 104 (37): 14813–8. doi:10.1073/pnas.0703783104. PMC 1976208. PMID 17785421.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  36. ^ Palaszynski KM, Liu H, Loo KK, Voskuhl RR (April 2004). "Estriol treatment ameliorates disease in males with experimental autoimmune encephalomyelitis: implications for multiple sclerosis". J Neuroimmunol. 149 (1–2): 84–9. doi:10.1016/j.jneuroim.2003.12.015. PMID 15020068.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  37. ^ Barkhof F, Hulst HE, Drulovic J, Uitdehaag BM, Matsuda K, Landin R (March 2010). "Ibudilast in relapsing-remitting multiple sclerosis: a neuroprotectant?". Neurology. 74 (13): 1033–40. doi:10.1212/WNL.0b013e3181d7d651. PMID 20200338.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  38. ^ "Treatment of Multiple Sclerosis Using Over the Counter Inosine". ClinicalTrials.gov. March 16, 2006. Retrieved 2006-05-10.
  39. ^ Toncev G (October 2006). "Therapeutic value of serum uric acid levels increasing in the treatment of multiple sclerosis". Vojnosanit Pregl. 63 (10): 879–82. doi:10.2298/VSP0610879T. PMID 17121380.
  40. ^ Koch M, De Keyser J (2006). "Uric acid in multiple sclerosis". Neurol. Res. 28 (3): 316–9. doi:10.1179/016164106X98215. PMID 16687059.
  41. ^ Rentzos M, Nikolaou C, Anagnostouli M; et al. (2006). "Serum uric acid and multiple sclerosis". Clinical neurology and neurosurgery. 108 (6): 527–31. doi:10.1016/j.clineuro.2005.08.004. PMID 16202511. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  42. ^ Chen, Peng; David E. Goldberg; Bryan Kolb; Marc Lanser; Larry I. Benowitz (June 25, 2002). "Inosine induces axonal rewiring and improves behavioral outcome after stroke". PNAS. 99 (13): 9031–9036. doi:10.1073/pnas.132076299. PMC 124418. PMID 12084941. Retrieved 2006-05-10.
  43. ^ Liu F, You SW, Yao LP; et al. (2006). "Secondary degeneration reduced by inosine after spinal cord injury in rats". Spinal Cord. 44 (7): 421–6. doi:10.1038/sj.sc.3101878. PMID 16317421. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  44. ^ McNaughton L, Dalton B, Tarr J (1999). "Inosine supplementation has no effect on aerobic or anaerobic cycling performance". International journal of sport nutrition. 9 (4): 333–44. PMID 10660865.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  45. ^ Markowitz CE, Spitsin S, Zimmerman V; et al. (June 2009). "The Treatment of Multiple Sclerosis with Inosine". The Journal of Alternative and Complementary Medicine. 15 (6): 619–25. doi:10.1089/acm.2008.0513. PMC 3189001. PMID 19425822. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  46. ^ Markowitz CE, Spitsin S, Zimmerman V; et al. (June 2009). "The treatment of multiple sclerosis with inosine". J Altern Complement Med. 15 (6): 619–25. doi:10.1089/acm.2008.0513. PMC 3189001. PMID 19425822. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  47. ^ Hutas G (November 2008). "Ocrelizumab, a humanized monoclonal antibody against CD20 for inflammatory disorders and B-cell malignancies". Current Opinion in Investigational Drugs. 9 (11): 1206–15. PMID 18951300.
  48. ^ Burt RK; Loh, Yvonne; Cohen, Bruce; Stefosky, Dusan; Balabanov, Roumen; Katsamakis, George; Oyama, Yu; Russell, Eric J; Stern, Jessica; Muraro, Paolo; Rose, John; Testori, Alessandro; Bucha, Jurate; Jovanovic, Borko; Milanetti, Francesca; Storek, Jan; Voltarelli, Julio C; Burns, William H; et al. (2009). "Autologous non-myeloablative haemopoietic stem cell transplantation in relapsing-remitting multiple sclerosis: a phase I/II study". Lancet Neurol. 8 (3): 244–53. doi:10.1016/S1474-4422(09)70017-1. PMID 19186105. {{cite journal}}: Explicit use of et al. in: |author= (help)
  49. ^ Multiple sclerosis and the pharmaceutical industry/Medicines in development for MS: abpi.org.uk
  50. ^ WO 2008000419, Hiestand, Peter C; Schnell, Christian, "S1P Receptor modulators for treating multiple sclerosis", assigned to Novartis  [non-primary source needed]
  51. ^ "McGill/JGH researchers successfully reverse multiple sclerosis in animals New immune-suppressing treatment forces the disease into remission in mice". McGill University. August 11, 2009. Retrieved 2009-08-12.
  52. ^ "Multiple Sclerosis Successfully Reversed In Mice: New Immune-suppressing Treatment Forces The Disease Into Remission". Science Daily. August 12, 2009.
  53. ^ Moutih Rafei, Jeremy Hsieh, Simone Zehntner, MengYang Li, Kathy Forner, Elena Birman, Marie-Noëlle Boivin, Yoon Kow Young, Claude Perreault, Jacques Galipeau. (August 9, 2009). "A granulocyte-macrophage colony–stimulating factor and interleukin-15 fusokine induces a regulatory B cell population with immune suppressive properties". Nature Medicine. 15 (9). Nature Medicine: 1038–45. doi:10.1038/nm.2003. PMID 19668193. Retrieved 2009-08-12.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  54. ^ D'haeseleer M, Beelen R, Fierens Y, Cambron M, Vanbinst AM, Verborgh C, Demey J, De Keyser J. Cerebral hypoperfusion in multiple sclerosis is reversible and mediated by endothelin-1, Proc Natl Acad Sci U S A. 2013 Apr 2;110(14):5654-8. doi: 10.1073/pnas.1222560110, PMID 23509249
  55. ^ Bagos PG, Nikolopoulos G, Ioannidis A (2006). "Chlamydia pneumoniae infection and the risk of multiple sclerosis: a meta-analysis". Mult Scler. 12 (4): 397–411. doi:10.1191/1352458506ms1291oa. PMID 16900753.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  56. ^ Sriram S, Yao SY, Stratton C, Moses H, Narayana PA, Wolinsky JS (2005). "Pilot study to examine the effect of antibiotic therapy on MRI outcomes in RRMS". J. Neurol. Sci. 234 (1–2): 87–91. doi:10.1016/j.jns.2005.03.042. PMID 15935383.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  57. ^ Oztaş B, Kiliç S, Dural E, Ispir T (November 2001). "Influence of antioxidants on the blood–brain barrier permeability during epileptic seizures". J Neurosci Res. 66 (4): 674–8. doi:10.1002/jnr.10023. PMID 11746387.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  58. ^ "Uric Acid In Multiple Sclerosis". 01/02/2006. Archived from the original on 2005-05-07. Retrieved 2006-05-10. {{cite web}}: Check date values in: |year= (help)CS1 maint: year (link)
  59. ^ Kean RB, Spitsin SV, Mikheeva T, Scott GS, Hooper DC (December 1, 2000). "The peroxynitrite scavenger uric acid prevents inflammatory cell invasion into the central nervous system in experimental allergic encephalomyelitis through maintenance of blood-central nervous system barrier integrity". Journal of Immunology. 165 (11): 6511–8. doi:10.4049/jimmunol.165.11.6511. PMID 11086092.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  60. ^ Schreibelt G, van Horssen J, van Rossum S, Dijkstra CD, Drukarch B, de Vries HE (2007). "Therapeutic potential and biological role of endogenous antioxidant enzymes in multiple sclerosis pathology". Brain Research Reviews. 56 (2): 322–30. doi:10.1016/j.brainresrev.2007.07.005. PMID 17761296.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  61. ^ Liu Y, Li P, Lu J; et al. (August 2008). "Bilirubin possesses powerful immunomodulatory activity and suppresses experimental autoimmune encephalomyelitis". Journal of Immunology. 181 (3): 1887–97. doi:10.4049/jimmunol.181.3.1887. PMID 18641326. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  62. ^ Beeton C, Wulff H, Barbaria J; et al. (November 2001). "Selective blockade of T lymphocyte K+ channels ameliorates experimental autoimmune encephalomyelitis, a model for multiple sclerosis". Proceedings of the National Academy of Sciences. 98 (24): 13942–7. doi:10.1073/pnas.241497298. PMC 61146. PMID 11717451. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  63. ^ Wulff H, Calabresi PA, Allie R; et al. (June 2003). "The voltage-gated Kv1.3 K+ channel in effector memory T cells as new target for MS". Journal of Clinical Investigation. 111 (11): 1703–13. doi:10.1172/JCI16921. PMC 156104. PMID 12782673. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  64. ^ Vennekamp J, Wulff H, Beeton C; et al. (June 2004). "Kv1.3-Blocking 5-Phenylalkoxypsoralens: A New Class of Immunomodulators". Molecular Pharmacology. 65 (6): 1364–74. doi:10.1124/mol.65.6.1364. PMID 15155830. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  65. ^ Rus H, Pardo CA, Hu L; et al. (August 2005). "The voltage-gated potassium channel Kv1.3 is highly expressed on inflammatory infiltrates in multiple sclerosis brain". Proceedings of the National Academy of Sciences. 102 (31): 11094–9. doi:10.1073/pnas.0501770102. PMC 1182417. PMID 16043714. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  66. ^ Matheu MP, Beeton C, Garcia A; et al. (October 2008). "Imaging of Effector Memory T Cells during a Delayed-Type Hypersensitivity Reaction and Suppression by Kv1.3 Channel Block". Immunity. 29 (4): 602–14. doi:10.1016/j.immuni.2008.07.015. PMC 2732399. PMID 18835197. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  67. ^ Leung, G; Sun W; Zheng L; Brookes S; Tully M; Shi R (2010). "Anti-acrolein treatment improves behavioral outcome and alleviates myelin damage in experimental autoimmune enchephalomyelitis mouse". Neuroscience. 173: 150–155. doi:10.1016/j.neuroscience.2010.11.018. PMC 3034379. PMID 21081153.
  68. ^ Correale J, Farez M (2007). "Association between parasite infection and immune responses in multiple sclerosis". Annals of Neurology. 61 (2): 97–108. doi:10.1002/ana.21067. PMID 17230481.
  69. ^ Correale J, Farez M, Razzitte G (August 2008). "Helminth infections associated with multiple sclerosis induce regulatory B cells". Annals of Neurology. 64 (2): 187–99. doi:10.1002/ana.21438. PMID 18655096.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  70. ^ Fleming, JO; Isaak, A.; Lee, J.; Luzzio, C.; Carrithers, M.; Cook, T.; Field, A.; Boland, J.; Fabry, Z. (3 March 2011). "Probiotic helminth administration in relapsing-remitting multiple sclerosis: a phase 1 study". Multiple Sclerosis Journal. 0: 1–12. doi:10.1177/1352458511398054. {{cite journal}}: Invalid |display-authors=9 (help)
  71. ^ a b Ristori, G (Oct 1999). "Use of Bacille Calmette-Guèrin (BCG) in multiple sclerosis". Neurology. 53 (7): 1588–1589. doi:10.1212/wnl.53.7.1588. PMID 10534275. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  72. ^ Paolillo, A; Buzzi MG; Giugni E; Sabatini U; Bastianello S; Pozzilli C; Salvetti M; Ristori G. (February 2003). "The effect of Bacille Calmette-Guérin on the evolution of new enhancing lesions to hypointense T1 lesions in relapsing remitting MS". J Neurol. 250 (2): 247–248. doi:10.1007/s00415-003-0967-6. PMID 12622098.
  73. ^ Rutschmann, OT; McCrory, DC; Matchar, DB; Immunization Panel of the Multiple Sclerosis Council for Clinical Practice Guidelines (Dec 2002). "Immunization and MS: a summary of published evidence and recommendations". Neurology. 59 (12): 1837–1843. doi:10.1212/wnl.59.12.1837. PMID 12499473.
  74. ^ 2007 clinical trial using LDN
  75. ^ a b Gironi M, Martinelli-Boneschi F, Sacerdote P, Solaro C, Zaffaroni M, Cavarretta R, Moiola L, Bucello S, Radaelli M, Pilato V, Rodegher M, Cursi M, Franchi S, Martinelli V, Nemni R, Comi G, Martino G (2008). "A pilot trial of low-dose naltrexone in primary progressive multiple sclerosis". Multiple Sclerosis. 14 (8): 1076–83. doi:10.1177/1352458508095828. PMID 18728058.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  76. ^ Zabad RK, Metz LM, Todoruk TR; et al. (2007). "The clinical response to minocycline in multiple sclerosis is accompanied by beneficial immune changes: a pilot study". Mult. Scler. 13 (4): 517–26. doi:10.1177/1352458506070319. PMID 17463074. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)"It has been available for over 30 years and, in the United Kingdom alone, more than 6.5 million people have been treated with minocycline for an average of 9 months, mostly for acne." Minocycline is probably the most cost effective, and effective treatment available for MS, but its low cost, means that large pharmaceutical companies will fight to prevent its introduction as an MS treatment.
  77. ^ May 2003 Emerging Therapies for MS
  78. ^ Tilley BC, Alarcón GS, Heyse SP; et al. (January 1995). "Minocycline in rheumatoid arthritis. A 48-week, double-blind, placebo-controlled trial. MIRA Trial Group". Annals of Internal Medicine. 122 (2): 81–9. doi:10.1001/archinte.122.1.81. PMID 7993000. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  79. ^ Gonsette RE, Dubois B (2004). "Pixantrone (BBR2778): a new immunosuppressant in multiple sclerosis with a low cardiotoxicity". J. Neurol. Sci. 223 (1): 81–6. doi:10.1016/j.jns.2004.04.024. PMID 15261566.
  80. ^ Wilner AN, Goodman (March 2000). "Some MS patients have "Dramatic" responses to Plasma Exchange". Neurology Reviews. 8 (3).
  81. ^ Srivastava R. et Al, Potassium channel KIR4.1 as an immune target in multiple sclerosis, N Engl J Med. 2012 Jul 12;367(2):115-23. doi: 10.1056/NEJMoa1110740, PMID 22784115
  82. ^ Gregg C, Shikar V, Larsen P; et al. (2007). "White matter plasticity and enhanced remyelination in the maternal CNS". J. Neurosci. 27 (8): 1812–23. doi:10.1523/JNEUROSCI.4441-06.2007. PMID 17314279. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  83. ^ Vukusic S, Confavreux C (2006). "[Multiple sclerosis and pregnancy]". Rev Neurol. (Paris) (in French). 162 (3): 299–309. PMID 16585885.
  84. ^ Weber MS, Prod'homme T, Steinman L, Zamvil SS (2005). "Drug Insight: using statins to treat neuroinflammatory disease". Nature Clinical Practice Neurology. 1 (2): 106–12. doi:10.1038/ncpneuro0047. PMID 16932506.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  85. ^ a b Statin may slow progressive MS
  86. ^ Sicotte NL, Giesser BS, Tandon V; et al. (2007). "Testosterone treatment in multiple sclerosis: a pilot study". Arch. Neurol. 64 (5): 683–8. doi:10.1001/archneur.64.5.683. PMID 17502467. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  87. ^ Munger KL, Zhang SM, O'Reilly E; et al. (2004). "Vitamin D intake and incidence of multiple sclerosis". Neurology. 62 (1): 60–5. doi:10.1212/01.wnl.0000101723.79681.38. PMID 14718698. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  88. ^ Mowry EM, Waubant E, McCulloch CE, Okuda DT, Evangelista AA, Lincoln RR, Gourraud PA, Brenneman D, Owen MC, Qualley P, Bucci M, Hauser SL, Pelletier D., Vitamin D status predicts new brain magnetic resonance imaging activity in multiple sclerosis [4]
  89. ^ Shinto L, Marracci G, Baldauf-Wagner S; et al. (2009). "Omega-3 fatty acid supplementation decreases matrix metalloproteinase-9 production in relapsing-remitting multiple sclerosis,☆☆☆". Prostaglandins, Leukotrienes and Essential Fatty Acids. 80 (2–3): 131–6. doi:10.1016/j.plefa.2008.12.001. PMC 2692605. PMID 19171471. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  90. ^ United Kingdom early Mitoxantrone Copaxone trial
  91. ^ a b Vollmer T, Panitch H, Bar-Or A; et al. (June 2008). "Glatiramer acetate after induction therapy with mitoxantrone in relapsing multiple sclerosis". Mult Scler. 14 (5): 663–70. doi:10.1177/1352458507085759. PMID 18424479. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  92. ^ a b Arnold DL, Campagnolo D, Panitch H; et al. (October 2008). "Glatiramer acetate after mitoxantrone induction improves MRI markers of lesion volume and permanent tissue injury in MS". J Neurol. 255 (10): 1473–8. doi:10.1007/s00415-008-0911-x. PMID 18854910. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  93. ^ a b Goodman AD, Rossman H, Bar-Or A; et al. (March 2009). "GLANCE: Results of a phase 2, randomized, double-blind, placebo-controlled study". Neurology. 72 (9): 806–12. doi:10.1212/01.wnl.0000343880.13764.69. PMC 2821836. PMID 19255407. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  94. ^ Zaffaroni M, Rizzo A, Baldini SM, Ghezzi A, Comi G (September 2008). "Induction and add-on therapy with mitoxantrone and interferon beta in multiple sclerosis". Neurol Sci. 29 (Suppl 2): S230–2. doi:10.1007/s10072-008-0946-x. PMID 18690501.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  95. ^ NIH Deepens Investment In Combination Study Of MS Drugs
  96. ^ Radue EW, Stuart WH, Calabresi PA; et al. (May 2010). "Natalizumab plus interferon beta-1a reduces lesion formation in relapsing multiple sclerosis". J. Neurol. Sci. 292 (1–2): 28–35. doi:10.1016/j.jns.2010.02.012. PMID 20236661. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  97. ^ http://ccsvi-ms.ning.com/profiles/blogs/severe-relapses-under-fingolimod-treatment-prescribed-after-natal
  98. ^ a b Common MS Drugs Taken Together Do Not Reduce Relapse Risk
  99. ^ Metz LM, Li D, Traboulsee A; et al. (October 2009). "Glatiramer acetate in combination with minocycline in patients with relapsing--remitting multiple sclerosis: results of a Canadian, multicenter, double-blind, placebo-controlled trial". Multiple Sclerosis. 15 (10): 1183–94. doi:10.1177/1352458509106779. PMID 19776092. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  100. ^ Paul F, Waiczies S, Wuerfel J; et al. (2008). Gwinn, Katrina (ed.). "Oral high-dose atorvastatin treatment in relapsing-remitting multiple sclerosis". PLoS ONE. 3 (4): e1928. doi:10.1371/journal.pone.0001928. PMC 2276246. PMID 18398457. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  101. ^ Patient Management in Multiple Sclerosis: A Canadian Expert Viewpoint, Mark S. Freedman [5]
  102. ^ Birnbaum G, Cree B, Altafullah I, Zinser M, Reder AT (October 2008). "Combining beta interferon and atorvastatin may increase disease activity in multiple sclerosis". Neurology. 71 (18): 1390–5. doi:10.1212/01.wnl.0000319698.40024.1c. PMID 18525027.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  103. ^ a b Kamm CP et al. Atorvastatin Added to Interferon Beta for Relapsing Multiple Sclerosis: 12-Month Treatment Extension of the Randomized Multicenter SWABIMS Trial, PLoS One. 2014 Jan 30;9(1):e86663. doi: 10.1371/journal.pone.0086663. eCollection 2014., PMID 24497963
  104. ^ Perini P, Calabrese M, Rinaldi L, Gallo P (September 2008). "Cyclophosphamide-based combination therapies for autoimmunity". Neurol Sci. 29. Suppl 2 (S2): S233–4. doi:10.1007/s10072-008-0947-9. PMID 18690502.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  105. ^ a b Patient Management in Multiple Sclerosis: A Canadian Expert Viewpoint, Mark S. Freedman
  106. ^ a b Gonsette RE, Sindic C, D'hooghe MB; et al. (April 2010). "Boosting endogenous neuroprotection in multiple sclerosis: the ASsociation of Inosine and Interferon beta in relapsing- remitting Multiple Sclerosis (ASIIMS) trial". Mult. Scler. 16 (4): 455–62. doi:10.1177/1352458509360547. PMID 20200198. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  107. ^ Muñoz García D et al. Associated Inosine to interferon: results of a clinical trial in multiple sclerosis. Acta Neurol Scand. 2014 Oct 14. doi: 10.1111/ane.12333
  108. ^ Happe LE. Choosing the best treatment for multiple sclerosis: comparative effectiveness, safety, and other factors involved in disease-modifying therapy choice, Am J Manag Care. 2013 Nov;19(17 Suppl):s332-42., PMID 24494634
  109. ^ ni en el bitcoind, et al. Vitamin D as an Early Predictor of Multiple Sclerosis Activity and Progression, JAMA Neurol. 2014 Jan 20. doi: 10.1001/jamaneurol.2013.5993, PMID 24445558
  110. ^ Parnell GP et al. The autoimmune disease-associated transcription factors EOMES and TBX21 are dysregulated in multiple sclerosis and define a molecular subtype of disease, Clin Immunol. 2014 Jan 15;151(1):16-24. doi: 10.1016/j.clim.2014.01.003. PMID 24495857
  111. ^ First Oral Treatment For Highly Active Relapsing Remitting Multiple Sclerosis Provides New Choice For UK Patients Failing On Injections, [6]
  112. ^ Weiner HL, Cohen JA (April 2002). "Treatment of multiple sclerosis with cyclophosphamide: critical review of clinical and immunologic effects". Mult. Scler. 8 (2): 142–54. doi:10.1191/1352458502ms790oa. PMID 11990872.
  113. ^ de Araújo EA, de Freitas MR (June 2008). "Benefit with methylprednisolone in continuous pulsetherapy in progressive primary form of multiple sclerosis: study of 11 cases in 11 years". Arq Neuropsiquiatr. 66 (2B): 350–3. doi:10.1590/S0004-282X2008000300013. PMID 18641870.
  114. ^ Killestein J, Kalkers NF, Polman CH (June 2005). "Glutamate inhibition in MS: the neuroprotective properties of riluzole". J Neurol Sci. 233 (1–2): 113–5. doi:10.1016/j.jns.2005.03.011. PMID 15949499.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  115. ^ Significant Advances in Multiple Sclerosis Treatment http://www.pharmacytimes.com/publications/specialty-pt/2011/February-2011/SPT-NPP-0211
  116. ^ Gladstone DE, Zamkoff KW, Krupp L; et al. (2006). "High-dose cyclophosphamide for moderate to severe refractory multiple sclerosis". Arch. Neurol. 63 (10): 1388–93. doi:10.1001/archneur.63.10.noc60076. PMID 16908728. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  117. ^ Zipoli V, Portaccio E, Hakiki B, Siracusa G, Sorbi S, Pia Amato M (2007). "Intravenous mitoxantrone and cyclophosphamide as second-line therapy in multiple sclerosis: An open-label comparative study of efficacy and safety". Journal of the Neurological Sciences. 266 (1–2): 25–30. doi:10.1016/j.jns.2007.08.023. PMID 17870094.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  118. ^ Krishnan C, Kaplin AI, Brodsky RA; et al. (June 2008). "Reduction of Disease Activity and Disability With High-Dose Cyclophosphamide in Patients With Aggressive Multiple Sclerosis". Arch. Neurol. 65 (8): 1044–51. doi:10.1001/archneurol.65.8.noc80042. PMC 2574697. PMID 18541787. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  119. ^ Opexa Initiates Late Stage Clinical Study of Tcelna in Patients with Secondary Progressive Multiple Sclerosis [7]
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