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===Treatments===
===Treatments===
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> Early trials of the female sex hormone [[estriol]], led in part by [[Rhonda Voskuhl]], have generated interest in reducing symptoms in women with RRMS.<ref>{{Cite journal|last=Sicotte|first=Nancy L.|last2=Liva|first2=Stephanie M.|last3=Klutch|first3=Rochelle|last4=Pfeiffer|first4=Paul|last5=Bouvier|first5=Seth|last6=Odesa|first6=Sylvia|last7=Wu|first7=T. C. Jackson|last8=Voskuhl|first8=Rhonda R.|date=2002-10-01|title=Treatment of multiple sclerosis with the pregnancy hormone estriol|url=http://onlinelibrary.wiley.com/doi/10.1002/ana.10301/abstract|journal=Annals of Neurology|language=en|volume=52|issue=4|pages=421–428|doi=10.1002/ana.10301|issn=1531-8249}}</ref><ref>{{Cite journal|last=Gold|first=Stefan M.|last2=Voskuhl|first2=Rhonda R.|title=Estrogen treatment in multiple sclerosis|url=https://doi.org/10.1016/j.jns.2009.05.028|journal=Journal of the Neurological Sciences|volume=286|issue=1-2|pages=99–103|doi=10.1016/j.jns.2009.05.028|pmc=2760629}}</ref><ref>{{Cite journal|last=Voskuhl|first=Rhonda R|last2=Wang|first2=HeJing|last3=Wu|first3=T C Jackson|last4=Sicotte|first4=Nancy L|last5=Nakamura|first5=Kunio|last6=Kurth|first6=Florian|last7=Itoh|first7=Noriko|last8=Bardens|first8=Jenny|last9=Bernard|first9=Jacqueline T|title=Estriol combined with glatiramer acetate for women with relapsing-remitting multiple sclerosis: a randomised, placebo-controlled, phase 2 trial|url=https://doi.org/10.1016/S1474-4422(15)00322-1|journal=The Lancet Neurology|volume=15|issue=1|pages=35–46|doi=10.1016/s1474-4422(15)00322-1}}</ref> Similarly, several other studies are aimed to improve efficacy and ease of use of already existing therapies through the use of novel preparations.<ref>{{cite journal | last=Mendoza |first=RL | year = 2014 | title = Pharmacoeconomics and clinical trials in multiple sclerosis: baseline data from the European Union | url = https://link.springer.com/article/10.1007%2Fs10389-013-0561-z | journal = Journal of Public Health | volume = 22 | issue = 3| pages = 211–218 | doi=10.1007/s10389-013-0561-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 |last1=Kieseier |first1=BC |last2=Calabresi |first2=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|deadurl=yes|archiveurl=https://web.archive.org/web/20131004220459/http://www.biogenidec.com/press_release_details.aspx?ID=5981&ReqId=1777510|archivedate=2013-10-04|df=}}</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> Early trials of the female sex hormone [[estriol]], led in part by [[Rhonda Voskuhl]], have generated interest in reducing symptoms in women with RRMS.<ref>{{Cite journal|last=Sicotte|first=Nancy L.|last2=Liva|first2=Stephanie M.|last3=Klutch|first3=Rochelle|last4=Pfeiffer|first4=Paul|last5=Bouvier|first5=Seth|last6=Odesa|first6=Sylvia|last7=Wu|first7=T. C. Jackson|last8=Voskuhl|first8=Rhonda R.|date=2002-10-01|title=Treatment of multiple sclerosis with the pregnancy hormone estriol|journal=Annals of Neurology|language=en|volume=52|issue=4|pages=421–428|doi=10.1002/ana.10301|pmid=12325070|issn=1531-8249}}</ref><ref>{{Cite journal|last=Gold|first=Stefan M.|last2=Voskuhl|first2=Rhonda R.|title=Estrogen treatment in multiple sclerosis|journal=Journal of the Neurological Sciences|volume=286|issue=1–2|pages=99–103|doi=10.1016/j.jns.2009.05.028|pmid=19539954|pmc=2760629|year=2009}}</ref><ref>{{Cite journal|last=Voskuhl|first=Rhonda R|last2=Wang|first2=HeJing|last3=Wu|first3=T C Jackson|last4=Sicotte|first4=Nancy L|last5=Nakamura|first5=Kunio|last6=Kurth|first6=Florian|last7=Itoh|first7=Noriko|last8=Bardens|first8=Jenny|last9=Bernard|first9=Jacqueline T|title=Estriol combined with glatiramer acetate for women with relapsing-remitting multiple sclerosis: a randomised, placebo-controlled, phase 2 trial|journal=The Lancet Neurology|volume=15|issue=1|pages=35–46|doi=10.1016/s1474-4422(15)00322-1|pmid=26621682|year=2016|url=http://www.escholarship.org/uc/item/8zz3v374}}</ref> Similarly, several other studies are aimed to improve efficacy and ease of use of already existing therapies through the use of novel preparations.<ref>{{cite journal | last=Mendoza |first=RL | year = 2014 | title = Pharmacoeconomics and clinical trials in multiple sclerosis: baseline data from the European Union | journal = Journal of Public Health | volume = 22 | issue = 3| pages = 211–218 | doi=10.1007/s10389-013-0561-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 |last1=Kieseier |first1=BC |last2=Calabresi |first2=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|deadurl=yes|archiveurl=https://web.archive.org/web/20131004220459/http://www.biogenidec.com/press_release_details.aspx?ID=5981&ReqId=1777510|archivedate=2013-10-04|df=}}</ref> Request for approval of ''peginterferon beta-1a'' is expected during 2013.<ref name=PEG/>


Monoclonal antibodies, which are biological 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 |vauthors=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=|bibcode=2012NYASA1247..117S }}</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"/><ref>Kappos L, [[Heinz Wiendl|Wiendl H]], Selmaj K, Arnold DL, Havrdova E, Boyko A, Kaufman M, Rose J, Greenberg S, Sweetser M, Riester K, O'Neill G, Elkins J. Daclizumab HYP versus Interferon Beta-1a in Relapsing Multiple Sclerosis. N Engl J Med. 2015;373(15):1418-28.#</ref>
Monoclonal antibodies, which are biological 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 |vauthors=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= 1|pages=117–37 |date=January 2012 |pmid=22224673 |doi=10.1111/j.1749-6632.2011.06272.x |url=|bibcode=2012NYASA1247..117S }}</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"/><ref>Kappos L, [[Heinz Wiendl|Wiendl H]], Selmaj K, Arnold DL, Havrdova E, Boyko A, Kaufman M, Rose J, Greenberg S, Sweetser M, Riester K, O'Neill G, Elkins J. Daclizumab HYP versus Interferon Beta-1a in Relapsing Multiple Sclerosis. N Engl J Med. 2015;373(15):1418-28.#</ref>


Another research strategy is to evaluate the [[combination therapy|combined effectiveness]] of two or more drugs.<ref name="pmid21111490">{{cite journal |vauthors=Milo R, Panitch H |title=Combination therapy in multiple sclerosis |journal=J. Neuroimmunol. |volume=231 |issue=1–2 |pages=23–31 |date=February 2011 |pmid=21111490 |doi=10.1016/j.jneuroim.2010.10.021 |url=}}</ref> 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.<ref name="pmid21111490"/> Moreover, [[Synergy#Drug synergy|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.<ref name="pmid21111490"/> 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.<ref name="pmid21111490"/>
Another research strategy is to evaluate the [[combination therapy|combined effectiveness]] of two or more drugs.<ref name="pmid21111490">{{cite journal |vauthors=Milo R, Panitch H |title=Combination therapy in multiple sclerosis |journal=J. Neuroimmunol. |volume=231 |issue=1–2 |pages=23–31 |date=February 2011 |pmid=21111490 |doi=10.1016/j.jneuroim.2010.10.021 |url=}}</ref> 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.<ref name="pmid21111490"/> Moreover, [[Synergy#Drug synergy|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.<ref name="pmid21111490"/> 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.<ref name="pmid21111490"/>
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There are several ways of research open about the cause of MS, ranging from metabolic disregulations to external infections.
There are several ways of research open about the cause of MS, ranging from metabolic disregulations to external infections.


Regarding the possibility of external infections, there are recent news about anti-CD20 monoclonal antibodies against EBV B-cells which are considered by some people as an important clue over pathogenesis<ref>{{cite journal |author=Michael P Pender |author2=Scott R Burrows |title=Epstein–Barr virus and multiple sclerosis: potential opportunities for immunotherapy |journal=Clin Trans Immunol |volume=3 |issue=e27 |date=31 October 2014 |doi=10.1038/cti.2014.25}}
Regarding the possibility of external infections, there are recent news about anti-CD20 monoclonal antibodies against EBV B-cells which are considered by some people as an important clue over pathogenesis<ref>{{cite journal |author=Michael P Pender |author2=Scott R Burrows |title=Epstein–Barr virus and multiple sclerosis: potential opportunities for immunotherapy |journal=Clin Trans Immunol |volume=3 |issue= |pages=e27 |date=31 October 2014 |doi=10.1038/cti.2014.25|pmid=25505955 }}
</ref>
</ref>


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While MRI is used normally for diagnosis and follow up, it has limitations. New [[MRI]] technologies like pulse sequences and post-processing are under study.
While MRI is used normally for diagnosis and follow up, it has limitations. New [[MRI]] technologies like pulse sequences and post-processing are under study.


Anyway some of the features of MS, like [[microglia]] activation, are invisible to MRI. Therefore [[positron emission tomography]] (PET) is preferred in the current studies<ref>{{cite journal | vauthors=Laura A, Eero R, Juha OR|title=Imaging neuroinflammation in multiple sclerosis using TSPO-PET |journal=Clinical and Translational Imaging |volume=3 |issue=6 |pages=461–473 |date=December 2015 |doi=10.1007/s40336-015-0147-6}}</ref>
Anyway some of the features of MS, like [[microglia]] activation, are invisible to MRI. Therefore [[positron emission tomography]] (PET) is preferred in the current studies<ref>{{cite journal | vauthors=Laura A, Eero R, Juha OR|title=Imaging neuroinflammation in multiple sclerosis using TSPO-PET |journal=Clinical and Translational Imaging |volume=3 |issue=6 |pages=461–473 |date=December 2015 |doi=10.1007/s40336-015-0147-6|pmid=27331049 |pmc=4887541 }}</ref>


===Personalized medicine===
===Personalized medicine===
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==Clinical measures of evolution==
==Clinical measures of evolution==


Currently it is accepted that the standard course of the disease presents three different clinical stages. A preclinical or prodromal stage, also termed RIS (radiologically isolated sindrome), a relapsing stage and finally a progressive stage.<ref name="pmid29470968">{{cite journal|vauthors=Baecher-Allan C, Kaskow B, Weiner HL |title=Multiple Sclerosis: Mechanisms and Immunotherapy. |journal=Neuron |volume=97(4) |pages=742–768 |date=Feb 2018|pmid=29470968 |doi=10.1016/j.neuron.2018.01.021}}</ref>
Currently it is accepted that the standard course of the disease presents three different clinical stages. A preclinical or prodromal stage, also termed RIS (radiologically isolated sindrome), a relapsing stage and finally a progressive stage.<ref name="pmid29470968">{{cite journal|vauthors=Baecher-Allan C, Kaskow B, Weiner HL |title=Multiple Sclerosis: Mechanisms and Immunotherapy. |journal=Neuron |volume=97 |issue=4 |pages=742–768 |date=Feb 2018|pmid=29470968 |doi=10.1016/j.neuron.2018.01.021}}</ref>


The main measure of evolution of symptoms, specially important as an [[End point of clinical trials|endpoint]] in MS trials, is the EDSS (extended dissability status score). However, this and other measures used in clinical studies are far from perfect and suffer from [[Sensitivity and specificity|insensitivity]] or inadequate validation.<ref name="pmid22516081">{{cite journal|vauthors=Cohen JA, Reingold SC, Polman CH, Wolinsky JS |author-link4=Jerry Wolinsky|title=Disability outcome measures in multiple sclerosis clinical trials: current status and future prospects |journal=Lancet Neurol |volume=11 |issue=5 |pages=467–76 |date=May 2012|pmid=22516081 |doi=10.1016/S1474-4422(12)70059-5 |url=}}</ref> 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.<ref name="pmid22516081"/>
The main measure of evolution of symptoms, specially important as an [[End point of clinical trials|endpoint]] in MS trials, is the EDSS (extended dissability status score). However, this and other measures used in clinical studies are far from perfect and suffer from [[Sensitivity and specificity|insensitivity]] or inadequate validation.<ref name="pmid22516081">{{cite journal|vauthors=Cohen JA, Reingold SC, Polman CH, Wolinsky JS |author-link4=Jerry Wolinsky|title=Disability outcome measures in multiple sclerosis clinical trials: current status and future prospects |journal=Lancet Neurol |volume=11 |issue=5 |pages=467–76 |date=May 2012|pmid=22516081 |doi=10.1016/S1474-4422(12)70059-5 |url=}}</ref> 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.<ref name="pmid22516081"/>
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An example of a soon-to-be finished study is the ''[[Wellcome Trust]] [[Wellcome Trust Case Control Consortium|case control consortium]]'', a collaboration study including 120,000 genetic samples, of which 8000 are from individuals with MS.<ref name="pmid21247752">{{cite journal |author=Baranzini SE |title=Revealing the genetic basis of multiple sclerosis: are we there yet? |journal=Current Opinion in Genetics & Development |volume=21 |issue=3 |pages=317–24 |date=June 2011|pmid=21247752 |pmc=3105160 |doi=10.1016/j.gde.2010.12.006 |url=}}</ref> This study may presumably identify all the common genetic variants involved in MS.<ref name="pmid21247752"/> Further studies will probably involve full [[Genome project|genome sequencing of large samples]], or the study of structural genetic variants such as [[insertion (genetics)|insertions]], [[deletion (genetics)|deletions]] or [[polymorphism (biology)|polymorphisms]].<ref name="pmid21247752"/>
An example of a soon-to-be finished study is the ''[[Wellcome Trust]] [[Wellcome Trust Case Control Consortium|case control consortium]]'', a collaboration study including 120,000 genetic samples, of which 8000 are from individuals with MS.<ref name="pmid21247752">{{cite journal |author=Baranzini SE |title=Revealing the genetic basis of multiple sclerosis: are we there yet? |journal=Current Opinion in Genetics & Development |volume=21 |issue=3 |pages=317–24 |date=June 2011|pmid=21247752 |pmc=3105160 |doi=10.1016/j.gde.2010.12.006 |url=}}</ref> This study may presumably identify all the common genetic variants involved in MS.<ref name="pmid21247752"/> Further studies will probably involve full [[Genome project|genome sequencing of large samples]], or the study of structural genetic variants such as [[insertion (genetics)|insertions]], [[deletion (genetics)|deletions]] or [[polymorphism (biology)|polymorphisms]].<ref name="pmid21247752"/>


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.<ref>{{cite journal |author1=Sawcer S. |author2=Hellenthal G. |author3=Pirinen M. |author4=Spencer C.C.A. |author5=Patsopoulos N. A. |author6=Moutsianas L. | year = 2011 | title = Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis | url = | journal = Nature | volume = 476 | issue = 7359| pages = 214–219 | doi = 10.1038/nature10251 |display-authors=etal | pmid=21833088 | pmc=3182531|bibcode=2011Natur.476..214T }}</ref> Some genetic mutations have been associated with an increased risk to develop MS, like STK11-SNP.<ref>Mutation Identified as Genetic Marker for Multiple Sclerosis, Labmedica International staff writers [http://mobile.labmedica.com/genetic_testing/articles/294757745/mutation_identified_as_genetic_marker_for_multiple_scle_.html]</ref> The chronic [[demyelination]] may cause [[axons]] to be notably vulnerable to repetitive and increasing injury and destruction.<ref>{{cite journal |author1=Frischer J.M. |author2=Bramow S. |author3=Dal-Bianco A. |author4=Lucchinetti C.F. |author5=Rauschka H. | year = 2009 | title = The relation between inflammation and neurodegeneration in multiple sclerosis brains | url = | journal = Brain | volume = 132 | issue = 5| pages = 1175–89 | doi=10.1093/brain/awp070|display-authors=etal|pmc=2677799}}</ref>
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.<ref>{{cite journal |author1=Sawcer S. |author2=Hellenthal G. |author3=Pirinen M. |author4=Spencer C.C.A. |author5=Patsopoulos N. A. |author6=Moutsianas L. | year = 2011 | title = Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis | url = | journal = Nature | volume = 476 | issue = 7359| pages = 214–219 | doi = 10.1038/nature10251 |display-authors=etal | pmid=21833088 | pmc=3182531|bibcode=2011Natur.476..214T }}</ref> Some genetic mutations have been associated with an increased risk to develop MS, like STK11-SNP.<ref>Mutation Identified as Genetic Marker for Multiple Sclerosis, Labmedica International staff writers [http://mobile.labmedica.com/genetic_testing/articles/294757745/mutation_identified_as_genetic_marker_for_multiple_scle_.html]</ref> The chronic [[demyelination]] may cause [[axons]] to be notably vulnerable to repetitive and increasing injury and destruction.<ref>{{cite journal |author1=Frischer J.M. |author2=Bramow S. |author3=Dal-Bianco A. |author4=Lucchinetti C.F. |author5=Rauschka H. | year = 2009 | title = The relation between inflammation and neurodegeneration in multiple sclerosis brains | url = | journal = Brain | volume = 132 | issue = 5| pages = 1175–89 | doi=10.1093/brain/awp070|pmid=19339255 |display-authors=etal|pmc=2677799}}</ref>


==Research into pathogenesis==
==Research into pathogenesis==
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Research into pathogenesis focuses on explaining the ultimate causes of MS onset and progression, and explaining the heterogeneous behaviour<ref name="pmid19597083"/>
Research into pathogenesis focuses on explaining the ultimate causes of MS onset and progression, and explaining the heterogeneous behaviour<ref name="pmid19597083"/>


[[Pathology of multiple sclerosis|Pathological research]] tries to obtain correlations for the observable biomarkers. Several important areas of study have been delimited, like Normal Appearing White Matter areas, which are the source of the lesions and under special MRI techniques like [[Magnetic Resonance Spectroscopy]] have been found to have a similar molecular composition.<ref>{{cite journal | author = Fleischer Vinzenz ''et al.'' | year = 2016 | title = Metabolic Patterns in Chronic MS Lesions and Normal-appearing White Matter: Intraindividual Comparison by Using Two-Dimensional MR Spectroscopic Imaging | url = | journal = Neuroradiology | volume = 281| issue = 2| pages = 536–543| doi = 10.1148/radiol.2016151654 }}</ref>
[[Pathology of multiple sclerosis|Pathological research]] tries to obtain correlations for the observable biomarkers. Several important areas of study have been delimited, like Normal Appearing White Matter areas, which are the source of the lesions and under special MRI techniques like [[Magnetic Resonance Spectroscopy]] have been found to have a similar molecular composition.<ref>{{cite journal | author = Fleischer Vinzenz ''et al.'' | year = 2016 | title = Metabolic Patterns in Chronic MS Lesions and Normal-appearing White Matter: Intraindividual Comparison by Using Two-Dimensional MR Spectroscopic Imaging | url = | journal = Neuroradiology | volume = 281| issue = 2| pages = 536–543| doi = 10.1148/radiol.2016151654 | pmid = 27243371 }}</ref>


Also some external agents can modify the disease course. Smoking is known to modify (for worse) the course of the disease, and recently this effect has been seen via MRI.<ref>Gamze Durhan, Sevda Diker, Arzu Ceylan Has, Jale Karakaya, Asli Tuncer Kurne, and Kader Karli Oguz, Influence of cigarette smoking on white matter in patients with clinically isolated syndrome as detected by diffusion tensor imaging, Diagn Interv Radiol. 2016 May; 22(3): 291–296. {{doi|10.5152/dir.2015.15415}}, {{PMC|4859748}}</ref> An explanation of this effect could shed some light into the pathogenesis.
Also some external agents can modify the disease course. Smoking is known to modify (for worse) the course of the disease, and recently this effect has been seen via MRI.<ref>Gamze Durhan, Sevda Diker, Arzu Ceylan Has, Jale Karakaya, Asli Tuncer Kurne, and Kader Karli Oguz, Influence of cigarette smoking on white matter in patients with clinically isolated syndrome as detected by diffusion tensor imaging, Diagn Interv Radiol. 2016 May; 22(3): 291–296. {{doi|10.5152/dir.2015.15415}}, {{PMC|4859748}}</ref> An explanation of this effect could shed some light into the pathogenesis.
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:main: [[Multiple sclerosis drug pipeline]]
:main: [[Multiple sclerosis drug pipeline]]


Disease-modifying drugs represent possible interventions able to modify the natural course of the disease instead of targeting the symptoms or the recovery from relapses.<ref>{{cite journal | author = Lee Mendoza R | year = 2014 | title = Pharmacoeconomics and clinical trials in multiple sclerosis: baseline data from the European Union | url = https://link.springer.com/article/10.1007%2Fs10389-013-0561-z | journal = Journal of Public Health | volume = 22 | issue = 3| pages = 211–218 | doi=10.1007/s10389-013-0561-z}}</ref> Over a dozen clinical trials testing potential therapies are underway, and additional new treatments are being devised and tested in animal models.
Disease-modifying drugs represent possible interventions able to modify the natural course of the disease instead of targeting the symptoms or the recovery from relapses.<ref>{{cite journal | author = Lee Mendoza R | year = 2014 | title = Pharmacoeconomics and clinical trials in multiple sclerosis: baseline data from the European Union | journal = Journal of Public Health | volume = 22 | issue = 3| pages = 211–218 | doi=10.1007/s10389-013-0561-z}}</ref> Over a dozen clinical trials testing potential therapies are underway, and additional new treatments are being devised and tested in animal models.


New drugs must pass several clinical trials in order to get approved by regulatory agencies. Phase III is normally the last testing phase and when results are as expected a formal approval request is submitted to the regulator. [[Clinical trial#Phase III|Phase III]] programs consist of [[Clinical trial|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 (United States)|Food and Drug Administration]] (FDA) for the United States, [[Therapeutic Goods Administration]] (TGA) for Australia, etc.) to obtain approval for marketing. Treatment in MS phase III studies is usually 2 years per patient.
New drugs must pass several clinical trials in order to get approved by regulatory agencies. Phase III is normally the last testing phase and when results are as expected a formal approval request is submitted to the regulator. [[Clinical trial#Phase III|Phase III]] programs consist of [[Clinical trial|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 (United States)|Food and Drug Administration]] (FDA) for the United States, [[Therapeutic Goods Administration]] (TGA) for Australia, etc.) to obtain approval for marketing. Treatment in MS phase III studies is usually 2 years per patient.
Line 92: Line 92:
Currently there are several ongoing phase III trials, and there are also some drugs that are waiting for approval after finishing theirs.
Currently there are several ongoing phase III trials, and there are also some drugs that are waiting for approval after finishing theirs.


For example, '''[[Cladribine]]''' (under development by [[Merck Serono]]; anticipated brand name: ''Movectro'') is a [[antineoplastic]] oral [[Chemical compound|drug]] with immunosuppressive effects. It is already currently used as an [[Intravenous therapy|intravenous infusion]] to treat [[hairy cell leukemia]] (leukemic reticuloendotheliosis). An oral version of cladribine is in phase III.<ref>[http://www.clinicaltrial.gov/ct2/show/NCT00213135?term=clarity&rank=3 clinicaltrial.gov CLARITY Study.] Retrieved on 25 November 2007.</ref> The completion of the phase III program took place in early 2009 meeting its main endpoint with 58% relative reduction in annualized relapse rates with respect to placebo.<ref>[http://www.tradingmarkets.com/.site/news/Stock%20News/2146783/ Merck Serono's Phase III multiple sclerosis trial meets endpoint]</ref> Formal submission to European EMEA took place in middle 2009. In January 2010, researchers published in [[NEJM]] significant results of cladribine use in reducing relapsing course of multiple sclerosis.<ref>{{cite journal | doi = 10.1056/NEJMoa0902533 | pmid = 20089960 | title = A Placebo-Controlled Trial of Oral Cladribine for Relapsing Multiple Sclerosis | journal = New England Journal of Medicine | volume = 362 | issue = 5 | pages = 416–26 | year = 2010 | last1 = Giovannoni | first1 = Gavin | last2 = Comi | first2 = Giancarlo | last3 = Cook | first3 = Stuart | last4 = Rammohan | first4 = Kottil | last5 = Rieckmann | first5 = Peter | last6 = Sørensen | first6 = Per Soelberg | last7 = Vermersch | first7 = Patrick | last8 = Chang | first8 = Peter | last9 = Hamlett | first9 = Anthony | last10 = Musch | first10 = Bruno | last11 = Greenberg | first11 = Steven J. }}</ref> This drug was expected to be in the market in 2011 for use in multiple sclerosis patients.,<ref>Merck KGaA Submits Application For Cladribine Tablets As Multiple Sclerosis Therapy In Europe [http://www.medicalnewstoday.com/articles/158796.php]</ref><ref>[http://news.bbc.co.uk/2/hi/health/8470138.stm Hope for MS pill after cladribine and fingolimod trials, BBC News;Published 20-January-2010]</ref> but in 2011 the company decided to stop selling the tablets in Russia and Australia though it was already approved in this countries.<ref>http://www.genengnews.com/gen-news-highlights/merck-serono-gives-up-on-getting-drug-candidate-for-multiple-sclerosis-approved/81245334/</ref> Nevertheless, it seems that approval process continued in Europe and the [[EMEA]] has accepted a review process<ref>[http://www.prnewswire.com/news-releases/merck-receives-european-medicines-agency-acceptance-for-review-of-marketing-authorization-application-for-cladribine-tablets-587207901.html Press release]</ref>
For example, '''[[Cladribine]]''' (under development by [[Merck Serono]]; anticipated brand name: ''Movectro'') is a [[antineoplastic]] oral [[Chemical compound|drug]] with immunosuppressive effects. It is already currently used as an [[Intravenous therapy|intravenous infusion]] to treat [[hairy cell leukemia]] (leukemic reticuloendotheliosis). An oral version of cladribine is in phase III.<ref>[http://www.clinicaltrial.gov/ct2/show/NCT00213135?term=clarity&rank=3 clinicaltrial.gov CLARITY Study.] Retrieved on 25 November 2007.</ref> The completion of the phase III program took place in early 2009 meeting its main endpoint with 58% relative reduction in annualized relapse rates with respect to placebo.<ref>[http://www.tradingmarkets.com/.site/news/Stock%20News/2146783/ Merck Serono's Phase III multiple sclerosis trial meets endpoint]</ref> Formal submission to European EMEA took place in middle 2009. In January 2010, researchers published in [[NEJM]] significant results of cladribine use in reducing relapsing course of multiple sclerosis.<ref>{{cite journal | doi = 10.1056/NEJMoa0902533 | pmid = 20089960 | title = A Placebo-Controlled Trial of Oral Cladribine for Relapsing Multiple Sclerosis | journal = New England Journal of Medicine | volume = 362 | issue = 5 | pages = 416–26 | year = 2010 | last1 = Giovannoni | first1 = Gavin | last2 = Comi | first2 = Giancarlo | last3 = Cook | first3 = Stuart | last4 = Rammohan | first4 = Kottil | last5 = Rieckmann | first5 = Peter | last6 = Sørensen | first6 = Per Soelberg | last7 = Vermersch | first7 = Patrick | last8 = Chang | first8 = Peter | last9 = Hamlett | first9 = Anthony | last10 = Musch | first10 = Bruno | last11 = Greenberg | first11 = Steven J. }}</ref> This drug was expected to be in the market in 2011 for use in multiple sclerosis patients.,<ref>Merck KGaA Submits Application For Cladribine Tablets As Multiple Sclerosis Therapy In Europe [http://www.medicalnewstoday.com/articles/158796.php]</ref><ref>[http://news.bbc.co.uk/2/hi/health/8470138.stm Hope for MS pill after cladribine and fingolimod trials, BBC News;Published 20-January-2010]</ref> but in 2011 the company decided to stop selling the tablets in Russia and Australia though it was already approved in this countries.<ref>{{Cite web | url=http://www.genengnews.com/gen-news-highlights/merck-serono-gives-up-on-getting-drug-candidate-for-multiple-sclerosis-approved/81245334/ | title=Merck Serono Gives up on Getting Drug Candidate for Multiple Sclerosis Approved| date=2011-06-22}}</ref> Nevertheless, it seems that approval process continued in Europe and the [[EMEA]] has accepted a review process<ref>[http://www.prnewswire.com/news-releases/merck-receives-european-medicines-agency-acceptance-for-review-of-marketing-authorization-application-for-cladribine-tablets-587207901.html Press release]</ref>


The following drugs, at least, are also in phase III (for a complete list see [[Multiple sclerosis drug pipeline]]):
The following drugs, at least, are also in phase III (for a complete list see [[Multiple sclerosis drug pipeline]]):
Line 113: Line 113:
Most Progressive-Onset variants does not have any approved disease-modifying treatment currently. Some possible treatments have been published, such as [[methylprednisolone]] pulses<ref>{{cite journal |doi=10.1590/S0004-282X2008000300013 |vauthors=de Araújo EA, de Freitas MR |title=Benefit with methylprednisolone in continuous pulsetherapy in progressive primary form of multiple sclerosis: study of 11 cases in 11 years |journal=Arq Neuropsiquiatr |volume=66 |issue=2B |pages=350–3 |date=June 2008 |pmid=18641870 |url=http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0004-282X2008000300013&lng=en&nrm=iso&tlng=en}}</ref> or [[riluzole]],<ref>{{cite journal |vauthors=Killestein J, Kalkers NF, Polman CH |title=Glutamate inhibition in MS: the neuroprotective properties of riluzole |journal=J Neurol Sci |volume=233 |issue=1–2 |pages=113–5 |date=June 2005 |pmid=15949499 |doi=10.1016/j.jns.2005.03.011 }}</ref> and some reduction of spasticity was reported in a pilot Italian study on [[low dose naltrexone]]<ref name="pmid18728058">{{cite journal |vauthors=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 |title=A pilot trial of low-dose naltrexone in primary progressive multiple sclerosis |journal=Multiple Sclerosis |volume=14 |issue=8 |pages=1076–83 |year=2008 |pmid=18728058 |doi=10.1177/1352458508095828}}</ref> but there is nothing conclusive still.
Most Progressive-Onset variants does not have any approved disease-modifying treatment currently. Some possible treatments have been published, such as [[methylprednisolone]] pulses<ref>{{cite journal |doi=10.1590/S0004-282X2008000300013 |vauthors=de Araújo EA, de Freitas MR |title=Benefit with methylprednisolone in continuous pulsetherapy in progressive primary form of multiple sclerosis: study of 11 cases in 11 years |journal=Arq Neuropsiquiatr |volume=66 |issue=2B |pages=350–3 |date=June 2008 |pmid=18641870 |url=http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0004-282X2008000300013&lng=en&nrm=iso&tlng=en}}</ref> or [[riluzole]],<ref>{{cite journal |vauthors=Killestein J, Kalkers NF, Polman CH |title=Glutamate inhibition in MS: the neuroprotective properties of riluzole |journal=J Neurol Sci |volume=233 |issue=1–2 |pages=113–5 |date=June 2005 |pmid=15949499 |doi=10.1016/j.jns.2005.03.011 }}</ref> and some reduction of spasticity was reported in a pilot Italian study on [[low dose naltrexone]]<ref name="pmid18728058">{{cite journal |vauthors=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 |title=A pilot trial of low-dose naltrexone in primary progressive multiple sclerosis |journal=Multiple Sclerosis |volume=14 |issue=8 |pages=1076–83 |year=2008 |pmid=18728058 |doi=10.1177/1352458508095828}}</ref> but there is nothing conclusive still.


Currently, good results using the [[monoclonal antibody]] [[Ocrelizumab]] in primary progressive MS (PPMS)<ref>{{cite journal | author = Gajofatto A, Turatti M, Benedetti MD | year = 2016 | title = Primary progressive multiple sclerosis: current therapeutic strategies and future perspectives | url = | journal = Expert Rev Neurother | volume = | issue = | pages = 1–14| doi = 10.1080/14737175.2017.1257385 | pmid = 27813441 }}</ref> have put the focus into depleting [[B cells]] targeting [[CD20]] proteins<ref>{{cite journal | author = Castro-Borrero Wanda ''et al.'' | year = 2012 | title = Current and emerging therapies in multiple sclerosis: a systematic review | url = | journal = Therapeutic Advances in Neurological Disorders | volume = 5 | issue = 4| pages = 205–220 | doi = 10.1177/1756285612450936 | pmc = 3388530 }}</ref>
Currently, good results using the [[monoclonal antibody]] [[Ocrelizumab]] in primary progressive MS (PPMS)<ref>{{cite journal | author = Gajofatto A, Turatti M, Benedetti MD | year = 2016 | title = Primary progressive multiple sclerosis: current therapeutic strategies and future perspectives | url = | journal = Expert Rev Neurother | volume = 17| issue = 4| pages = 1–14| doi = 10.1080/14737175.2017.1257385 | pmid = 27813441 }}</ref> have put the focus into depleting [[B cells]] targeting [[CD20]] proteins<ref>{{cite journal | author = Castro-Borrero Wanda ''et al.'' | year = 2012 | title = Current and emerging therapies in multiple sclerosis: a systematic review | url = | journal = Therapeutic Advances in Neurological Disorders | volume = 5 | issue = 4| pages = 205–220 | doi = 10.1177/1756285612450936 | pmid = 22783370 | pmc = 3388530 }}</ref>


A [[Statin]], Simvastatin (Zocor), has shown good results in progressive variants<ref name="Statin may slow progressive MS">[http://ccsvi-ms.ning.com/profiles/blogs/statin-may-slow-progressive-ms Statin may slow progressive MS]</ref> Also [[Masitinib]] and [[Ibudilast]], mainly targeted to SPMS have recruited PPMS patients in their clinical trials with good results.
A [[Statin]], Simvastatin (Zocor), has shown good results in progressive variants<ref name="Statin may slow progressive MS">[http://ccsvi-ms.ning.com/profiles/blogs/statin-may-slow-progressive-ms Statin may slow progressive MS]</ref> Also [[Masitinib]] and [[Ibudilast]], mainly targeted to SPMS have recruited PPMS patients in their clinical trials with good results.

Revision as of 01:22, 6 January 2019

Research in multiple sclerosis may find new pathways to interact with the disease, 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]

Treatments

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] Early trials of the female sex hormone estriol, led in part by Rhonda Voskuhl, have generated interest in reducing symptoms in women with RRMS.[4][5][6] Similarly, several other studies are aimed to improve efficacy and ease of use of already existing therapies through the use of novel preparations.[7] 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.[8][9] Request for approval of peginterferon beta-1a is expected during 2013.[9]

Monoclonal antibodies, which are biological 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.[10] 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][11]

Another research strategy is to evaluate the combined effectiveness of two or more drugs.[12] 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.[12] 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.[12] 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.[12]

Regarding neuroprotective and 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.[13] 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]

Etiology

There are several ways of research open about the cause of MS, ranging from metabolic disregulations to external infections.

Regarding the possibility of external infections, there are recent news about anti-CD20 monoclonal antibodies against EBV B-cells which are considered by some people as an important clue over pathogenesis[14]

There are also some reports considering that current diagnostic methods are confusing several disease entities into the same clinical entity "multiple sclerosis". For example, neuromyelitis optica, formerly considered a kind of MS, was separated in 2006 with the discovery of AQP4-IgG, and currently a second variant has been separated, antiMOG associated encephalomyelitis. Some other conditions are expected to be distinguished from MS following the discovery of specific pathogens.[15]

Imaging

While MRI is used normally for diagnosis and follow up, it has limitations. New MRI technologies like pulse sequences and post-processing are under study.

Anyway some of the features of MS, like microglia activation, are invisible to MRI. Therefore positron emission tomography (PET) is preferred in the current studies[16]

Personalized medicine

Personalized medicine refers to the expected possibility of classifying patients as good or bad responders before starting a therapy. Given the side effects of all MS medications, this is currently an active field of research.[17]

About this, in 2013 appeared reports of a new kind of multiple sclerosis without white matter demyelination that affects 12% of the patients and could behave differently from the rest of patients[18] Later its existence was confirmed (2018)[19]

Biomarkers

Main:Multiple sclerosis biomarkers

Several biomarkers for diagnosis, disease evolution and response to medication (current or expected) are under research. While most of them are still under research, there are some of them already well stablished:

  • oligoclonal bands: They present proteins that are in the CNS or in blood. Those that are in CNS but not in blood suggest a diagnosis of MS.
  • MRZ-Reaction: A polyspecific antiviral immune response against the viruses of measles, rubella and zoster found in 1992.[20] In some reports the MRZR showed a lower sensitivity than OCB (70% vs. 100%), but a higher specificity (69% vs. 92%) for MS.[20]
  • free light chains (FLC). Several authors have reported that they are comparable or even better than oligoclonal bands.[21]

Clinical measures of evolution

Currently it is accepted that the standard course of the disease presents three different clinical stages. A preclinical or prodromal stage, also termed RIS (radiologically isolated sindrome), a relapsing stage and finally a progressive stage.[22]

The main measure of evolution of symptoms, specially important as an endpoint in MS trials, is the EDSS (extended dissability status score). However, this and other measures used in clinical studies are far from perfect and suffer from insensitivity or inadequate validation.[23] 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.[23]

NEDA

Currently the criteria for testing the evolution is moving from raw EDSS (dissability status) to NEDA (No evidence of disease activity). Several NEDA criteria have been published. NEDA-3 means that EDSS remains constant, MRI shows no activity and no relapses have appeared. NEDA-4 means NEDA-3 plus that brain atrophy has not increased. Some authors speak about a NEDA-3+ which is a NEDA-3 plus no cortical lesions.[24]

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. [25]

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.[26] This study may presumably identify all the common genetic variants involved in MS.[26] Further studies will probably involve full genome sequencing of large samples, or the study of structural genetic variants such as insertions, deletions or polymorphisms.[26]

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.[27] Some genetic mutations have been associated with an increased risk to develop MS, like STK11-SNP.[28] The chronic demyelination may cause axons to be notably vulnerable to repetitive and increasing injury and destruction.[29]

Research into pathogenesis

Research into pathogenesis focuses on explaining the ultimate causes of MS onset and progression, and explaining the heterogeneous behaviour[1]

Pathological research tries to obtain correlations for the observable biomarkers. Several important areas of study have been delimited, like Normal Appearing White Matter areas, which are the source of the lesions and under special MRI techniques like Magnetic Resonance Spectroscopy have been found to have a similar molecular composition.[30]

Also some external agents can modify the disease course. Smoking is known to modify (for worse) the course of the disease, and recently this effect has been seen via MRI.[31] An explanation of this effect could shed some light into the pathogenesis.

GDP-L-fucose synthase

GDP-L-fucose synthase is the only autoantigen reported to date in a subset of MS patients[32][33] It is currently unknown if it is pathogenic or a side effect of the disease.

Progressive variants

Cortical atrophy and demyelination along the subpial surface appear early in the disease course but accelerate in progressive stage. Inflammatory infiltrates appear in the meninges, in some cases with B cell follicles. Leptomeningeal enhancement under MRI is common in patients with progressive forms of MS and shows a relationship to subpial cortical lesions and cortical atrophy.[34]

Disease-modifying drugs

main: Multiple sclerosis drug pipeline

Disease-modifying drugs represent possible interventions able to modify the natural course of the disease instead of targeting the symptoms or the recovery from relapses.[35] Over a dozen clinical trials testing potential therapies are underway, and additional new treatments are being devised and tested in animal models.

New drugs must pass several clinical trials in order to get approved by regulatory agencies. Phase III is normally the last testing phase and when results are as expected a formal approval request is submitted to the regulator. 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 United States, Therapeutic Goods Administration (TGA) for Australia, etc.) to obtain approval for marketing. Treatment in MS phase III studies is usually 2 years per patient.

Relapsing-remitting MS

Currently there are several ongoing phase III trials, and there are also some drugs that are waiting for approval after finishing theirs.

For example, Cladribine (under development by Merck Serono; anticipated brand name: Movectro) is a antineoplastic oral drug with immunosuppressive effects. It is already currently used as an intravenous infusion to treat hairy cell leukemia (leukemic reticuloendotheliosis). An oral version of cladribine is in phase III.[36] The completion of the phase III program took place in early 2009 meeting its main endpoint with 58% relative reduction in annualized relapse rates with respect to placebo.[37] Formal submission to European EMEA took place in middle 2009. In January 2010, researchers published in NEJM significant results of cladribine use in reducing relapsing course of multiple sclerosis.[38] This drug was expected to be in the market in 2011 for use in multiple sclerosis patients.,[39][40] but in 2011 the company decided to stop selling the tablets in Russia and Australia though it was already approved in this countries.[41] Nevertheless, it seems that approval process continued in Europe and the EMEA has accepted a review process[42]

The following drugs, at least, are also in phase III (for a complete list see Multiple sclerosis drug pipeline):

  • 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,[43] failing its primary target though in March 2008 was still performing good.[44] After several financial troubles, a phase III trial has been granted in 2011[45]
  • Siponimod, (BAF312) is a sphingosine-1-phosphate receptor modulator for oral use for MS. A phase III trial should run from Dec 2012 to Dec 2016.[46]

Secondary progressive variants

Relapsing-Onset variants (RO), even when they turn into progressive, have proved easier to treat than Progressive-Onset variants. Though difficult to treat, Secondary progressive and Progressive-Relapsing are easier to treat than PPMS. Only Mitoxantrone has been approved for them, but there is nothing for PPMS. At this moment several therapies are under research:

  • Cyclophosphamide (trade name Revimmune) is currently in Phase III for secondary progressive MS.[47] 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[48] Later, a 2007 open label study found it equivalent to Mitoxantrone[49] and in 2008 evidence appeared that it can reverse disability.[50]
  • Simvastatin has shown brain atrophy reduction in secondary progressive MS.[51]
  • Tcelna is currently under active research by Opexa, showing promising results.[52]
  • Masitinib, a tyrosine kinase inhibitor, is in late-stage testing for the treatment of patients with secondary and primary progressive MS (PPMS). It is a twice-daily oral medication that targets mast cells and inhibits several biochemical processes.14
  • Ibudilast: MediciNova, Inc., announced that MN-166 (ibudilast) has been approved for "fast track" development by the U.S. Food and Drug Administration (FDA) as of 2016, as a potential treatment for progressive multiple sclerosis (MS). Progressive MS in this case means both the primary progressive (PPMS) and secondary progressive (SPMS) forms of the disease.

Treatment for Primary Progressive variants

Most Progressive-Onset variants does not have any approved disease-modifying treatment currently. Some possible treatments have been published, such as methylprednisolone pulses[53] or riluzole,[54] and some reduction of spasticity was reported in a pilot Italian study on low dose naltrexone[55] but there is nothing conclusive still.

Currently, good results using the monoclonal antibody Ocrelizumab in primary progressive MS (PPMS)[56] have put the focus into depleting B cells targeting CD20 proteins[57]

A Statin, Simvastatin (Zocor), has shown good results in progressive variants[58] Also Masitinib and Ibudilast, mainly targeted to SPMS have recruited PPMS patients in their clinical trials with good results.

Respect the etiological research, a special genetic variant named rapidly progressive multiple sclerosis[59] has been described. It is due to a mutation inside the gene NR1H3, an arginine to glutamine mutation in the position p.Arg415Gln, in an area that codifies the protein LXRA.

Highly active relapsing remitting variant

Highly Active Relapsing Remitting, sometimes called Rapidly Worsening relapsing remitting, is a clinical form considered distinct from standard RRMS 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.[60] Cyclophosphamide is currently used off-label for Rapidly Worsening MS (RWMS).[61]

References

  1. ^ a b 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. ^ Sicotte, Nancy L.; Liva, Stephanie M.; Klutch, Rochelle; Pfeiffer, Paul; Bouvier, Seth; Odesa, Sylvia; Wu, T. C. Jackson; Voskuhl, Rhonda R. (2002-10-01). "Treatment of multiple sclerosis with the pregnancy hormone estriol". Annals of Neurology. 52 (4): 421–428. doi:10.1002/ana.10301. ISSN 1531-8249. PMID 12325070.
  5. ^ Gold, Stefan M.; Voskuhl, Rhonda R. (2009). "Estrogen treatment in multiple sclerosis". Journal of the Neurological Sciences. 286 (1–2): 99–103. doi:10.1016/j.jns.2009.05.028. PMC 2760629. PMID 19539954.
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