Research in multiple sclerosis

Several previous MS variants have been recently separated from MS after the discovery of a specific auto-antibody, specially autoantibodies against AQP4, MOG and Neurofascin proteins.{{cite journal | author = Kazutoshi Sato Douglas | date = Feb 2014 | title = Distinction between MOG antibody-positive and AQP4 antibody-positive NMO spectrum disorders | journal =Neurology| volume = 82 | issue = 6| pages = 474–481 | doi = 10.1212/WNL.0000000000000101 | pmid = 24415568 |display-authors=etal| pmc = 3937859}}

Previously recognized variants of MS like Optic-Spinal MS is now classified as a phenotype of the anti-AQP4 spectrum, and some tumefactive cases of MS as anti-MOG associated encephalomyelitis. Some researchers think that there could exist also an overlapping between Anti-NMDA receptor encephalitis cases and neuromyelitis optica or acute disseminated encephalomyelitis.{{cite journal |vauthors=Gahr M, Lauda F, Wigand ME, Connemann BJ, Rosenbohm A, Tumani H, Reindl M, Uzelac Z, Lewerenz J | year = 2015 | title = Periventricular white matter lesion and incomplete MRZ reaction in a male patient with anti-N-methyl-D-aspartate receptor encephalitis presenting with dysphoric mania | journal =BMJ Case Reports| volume = 2015| pages = bcr2014209075| doi = 10.1136/bcr-2014-209075 | pmid = 25917068 | pmc = 4422915 }}

The following previous MS variants are now considered apart from MS:

• Optic-Spinal MS: Now it is considered inside the Anti-AQP4 diseases spectrum.{{cite journal |vauthors=Li Y, Xie P, Lv F, etal |title=Brain magnetic resonance imaging abnormalities in neuromyelitis optica |journal=Acta Neurologica Scandinavica|volume= 118|issue= 4|pages= 218–25|year=2008 |pmid=18384459 |doi=10.1111/j.1600-0404.2008.01012.x|s2cid=22270592 }}{{cite journal |vauthors=Reindl M, Di Pauli F, Rostásy K, Berger T | date = Aug 2013 | title = The spectrum of MOG autoantibody-associated demyelinating diseases | journal =Nature Reviews Neurology| volume = 9 | issue = 8| pages = 455–61 | doi = 10.1038/nrneurol.2013.118 | pmid = 23797245 | s2cid = 7219279 }}{{cite journal |vauthors=Jarius S, Metz I, König FB, Ruprecht K, Reindl M, Paul F, Brück W, Wildemann B | date = Feb 2016 | title = Screening for MOG-IgG and 27 other anti-glial and anti-neuronal autoantibodies in 'pattern II multiple sclerosis' and brain biopsy findings in a MOG-IgG-positive case | journal =Multiple Sclerosis Journal| volume = 22 | issue = 12| pages = 1541–1549 | doi = 10.1177/1352458515622986 | pmid = 26869529 | s2cid = 1387384 }}{{cite journal |vauthors=Kitagawa S, Osada T, Kaneko K, Takahashi T, Suzuki N, Nakahara J | date = Nov 2018 | title = Clinical analysis of opticospinal multiple sclerosis (OSMS) presentation detecting anti-myelin oligodendrocyte glycoprotein (MOG) antibody | journal =Rinsho Shinkeigaku| volume = 58 | issue = 12 | pages = 737–744 | pmid = 30487359 | doi = 10.5692/clinicalneurol.cn-001184 | doi-access = free }}
• Anti-MOG associated MS and some cases of tumefactive multiple sclerosis{{Cite journal |doi = 10.2169/internalmedicine.50.4295|pmid = 21532234|title = Repeated Non-enhancing Tumefactive Lesions in a Patient with a Neuromyelitis Optica Spectrum Disorder|journal =Internal Medicine|volume = 50|issue = 9|pages = 1061–1064|year = 2011|last1 = Ikeda|first1 = Ken|last2 = Ito|first2 = Hirono|last3 = Hidaka|first3 = Takanobu|last4 = Takazawa|first4 = Takanori|last5 = Sekine|first5 = Tokinori|last6 = Yoshii|first6 = Yasuhiro|last7 = Hirayama|first7 = Takehisa|last8 = Kawabe|first8 = Kiyokazu|last9 = Kano|first9 = Osamu|last10 = Iwasaki|first10 = Yasuo|doi-access = free}} currently considered inside the anti-MOG spectrum.{{cite journal | vauthors = Pröbstel AK | display-authors = etal | date = Mar 2015 | title = Anti-MOG antibodies are present in a subgroup of patients with a neuromyelitis optica phenotype | journal =Journal of Neuroinflammation| volume = 12 | issue = 1| page = 46 | doi=10.1186/s12974-015-0256-1| pmid = 25889963 | pmc = 4359547 | doi-access = free }}{{cite journal | author = Spadaro Melania| year = 2015 | title = Histopathology and clinical course of MOG-antibody-associated encephalomyelitis | journal =Annals of Clinical and Translational Neurology| volume = 2 | issue = 3| pages = 295–301 | doi = 10.1002/acn3.164 |display-authors=etal | pmid=25815356 | pmc=4369279}}{{cite journal |vauthors=Spadaro M, etal | year = 2016 | title = Autoantibodies to MOG in a distinct subgroup of adult multiple sclerosis | journal =Neurology: Neuroimmunology & Neuroinflammation| volume = 3 | issue = 5| page = e257 | doi = 10.1212/NXI.0000000000000257 | pmid = 27458601 | pmc = 4949775 }}{{cite journal | vauthors = Ya Y | display-authors = etal | year = 2015 | title = Autoantibody to MOG suggests two distinct clinical subtypes of NMOSD | journal =Science China Life Sciences| volume = 59| issue = 12| pages = 1270–1281 | doi = 10.1007/s11427-015-4997-y | pmid = 26920678 | pmc = 5101174 }}
• Anti-neurofascin associated MS and CIDP: Some Anti-neurofascin demyelinating diseases were previously considered a subtype of Multiple Sclerosis but now they are considered a separate entity, as it happened before to anti-MOG and anti-AQP4 cases. Around 10% of MS cases are now thought to be anti-Neurofascin disease in reality.Marcus Vinicius, Magno Goncalves, Yara Dadalti Fragoso, The involvement of anti-neurofascin 155 antibodies in central and peripheral demyelinating diseases, Neuroimmunol Neuroinflammation, 8 Apr 2019;6:6.10.20517/2347-8659.2019.08 Anti-neurofascin autoantibodies have been reported in atypical cases of MS and CIDP, and a whole spectrum of Anti-neurofascin demyelinating diseases has been proposed.{{Cite journal |doi = 10.1016/j.neuint.2018.12.011|pmid = 30582947|title = Anti-neurofascin autoantibody and demyelination|journal =Neurochemistry International|volume = 130|pages = 104360|year = 2019|last1 = Kira|first1 = Jun-Ichi|last2 = Yamasaki|first2 = Ryo|last3 = Ogata|first3 = Hidenori|doi-access = free}} Some cases of CIDP are reported to be produced by auto-antibodies against several neurofascin proteins. These proteins are present in the neurons and four of them have been reported to produce disease: NF186, NF180, NF166 and NF155. Antibodies against Neurofascins NF-155 can also appear in MS{{cite journal |vauthors=Stich O, Perera S, Berger B, Jarius S, Wildemann B, Baumgartner A, Rauer S |title=Prevalence of neurofascin-155 antibodies in patients with multiple sclerosis |journal=Journal of the Neurological Sciences|date=March 2016 |doi=10.1016/j.jns.2016.03.004 |pmid=27084211 |volume=364 |pages=29–32|s2cid=29204735 }} and NF-186 could be involved in subtypes of MS{{Cite web|url=https://www.mssociety.org.uk/research/latest-research/latest-research-news-and-blogs/progressive-ms-a-new-perspective |archiveurl=https://archive.today/20070621025917/http://www.mssociety.org.uk/news_events/news/research/linington_resear.html|url-status=dead|archive-date=2007-06-21|title=Progressive MS: a new perspective | Multiple Sclerosis Society UK|website=www.mssociety.org.uk}} yielding an intersection between both conditions. Summarising, autoantibodies against several neurofascins can produce MS: neurofascin186 (NF186), neurofascin155 (NF155), contactin 1 (CNTN1), contactin associated protein 1 (CASPR1) and gliomedin. All of them nodal and paranodal proteins.
• Anti-TNF associated MS: Several anti-TNF drugs like adalimumab{{cite journal | doi = 10.1177/1756286419895155 | volume=13 | title=PPMS onset upon adalimumab treatment extends the spectrum of anti-TNF-α therapy-associated demyelinating disorders | year=2020 | journal=Therapeutic Advances in Neurological Disorders | page=175628641989515 | vauthors=Engel S, Luessi F, Mueller A, Schopf RE, Zipp F, Bittner S | pmid=31921355 | pmc=6940603 | doi-access=free }}{{cite journal | doi = 10.1155/2016/1423131 | volume=2016 | title=Adalimumab Induced or Provoked MS in Patient with Autoimmune Uveitis: A Case Report and Review of the Literature | year=2016 | journal=Case Reports in Medicine | pages=1–6 | author=Alnasser Alsukhni Rana | author2=Jriekh Ziena | author3=Aboras Yasmin | pmid=27840642 | pmc=5093248 | doi-access=free }} are commonly prescribed by a number of autoimmune conditions. Some of them have been reported to produce a CNS-demyelination compatible with, and by current knowledge indistinguishable from, standard MS.{{cite journal | doi = 10.1093/neuonc/now188.085 | volume=18 | title=P04.07 Relapse in a paucisymptomatic form of multiple sclerosis in a patient treated with nivolumab | year=2016 | journal=Neuro-Oncology | page=iv25 | author=Vicente L. Gómez | author2=Viqueira B. Rubio | author3=Cobos R. Garcia | author4=Moreno J. Pardo | author5=Gonzalez R. Arroyo | doi-access=free | pmc=5782583 }}{{cite journal |vauthors=Höftberger R, Leisser M, Bauer J, Lassmann H | date = Dec 2015 | title = Autoimmune encephalitis in humans: how closely does it reflect multiple sclerosis? | journal =Acta Neuropathologica Communications| volume = 3 | issue = 1| page = 80 | doi = 10.1186/s40478-015-0260-9 | pmid = 26637427 | pmc=4670499 | doi-access = free }} Several other monoclonal antibodies like pembrolizumab,Marzia Anita Lucia Romeo et al, Multiple sclerosis associated with pembrolizumab in a patient with non-small cell lung cancer, Journal of Neurology, pp 1–4, 04 October 2019 nivolumab{{cite journal | author = Lassman Hans | title = Acute disseminated encephalomyelitis and multiple sclerosis | journal =Brain| volume = 133| issue = 2| pages = 317–319 | doi = 10.1093/brain/awp342 | pmid=20129937 | date=Feb 2010| doi-access = free}} and infliximab{{Cite journal |title=Pathological findings in central nervous system demyelination associated with infliximab|first1=Alicja|last1=Kalinowska-Lyszczarz |first2=Mahboobeh |last2=Fereidan-Esfahani|first3=Yong|last3=Guo|first4=Claudia F|last4=Lucchinetti |first5=W Oliver|last5=Tobin|date=December 17, 2019|journal=Multiple Sclerosis Journal|volume=26|issue=9 |pages=1124–1129 |doi=10.1177/1352458519894710|pmid=31845616|pmc=7297659}} have been also reported to produce MS artificially. This has given birth to the Anti-TNF-α therapy-associated demyelinating disorders. The reactions have been diverse according to the source of the disease. Some of these cases can be classify as ADEM, using the confluent demyelination as barrier between both conditions.{{cite journal |vauthors=Young NP, Weinshenker BG, Parisi JE, Scheithauer B, Giannini C, Roemer SF, Thomsen KM, Mandrekar JN, Erickson BJ, Lucchinetti CF | year = 2010 | title = Perivenous demyelination: association with clinically defined acute disseminated encephalomyelitis and comparison with pathologically confirmed multiple sclerosis | journal =Brain| volume = 133| issue = 2| pages = 333–348 | doi = 10.1093/brain/awp321 | pmid=20129932 | pmc=2822631}} In most cases, the damage fulfills all pathological diagnostic criteria of MS and can therefore be classified as MS in its own right. The lesions were classified as pattern II in the Lassman/Lucchinetti system. Some lesions also showed Dawson fingers, which is supposed to be a MS-only feature.
• LHON-associated MS: Also a previous subtype of MS associated to LHON has been described (LHON-MS).{{Cite journal|title=Mitochondria in neuroinflammation – Multiple sclerosis (MS), leber hereditary optic neuropathy (LHON) and LHON-MS |first1=David|last1=Bargiela|first2=Patrick F|last2=Chinnery|date=September 25, 2019 |journal=Neuroscience Letters|volume=710|pages=132932|doi=10.1016/j.neulet.2017.06.051 |pmid=28668384|s2cid=38817368|doi-access=free}} It is a presentation of LHON with MS-like CNS damage. It used to satisfy McDonalds definition for MS, but after demonstration that LHON can produce this kind of lesions, the "no better explanation" requirement does not hold anymore. It is not due to auto-antibodies, but to defective mitochondria instead.{{cite journal |vauthors=Nikoskelainen EK, Marttila RJ, Huoponen K, etal |title=Leber's "plus": neurological abnormalities in patients with Leber's hereditary optic neuropathy |journal=J. Neurol. Neurosurg. Psychiatry |volume=59 |issue=2 |pages=160–4 |date=August 1995 |pmid=7629530 |pmc=485991 |doi= 10.1136/jnnp.59.2.160}} The symptoms of this higher form of the disease include loss of the brain's ability to control the movement of muscles, tremors, and cardiac arrhythmia.{{Cite web |url=http://heart-disease.health-cares.net/cardiac-arrhythmia.php |title=cardiac arrythmia |access-date=2020-02-05 |archive-date=2020-01-30 |archive-url=https://web.archive.org/web/20200130171040/http://heart-disease.health-cares.net/cardiac-arrhythmia.php |url-status=dead }} and the lack of muscular control.{{Cite web|title=Mayo Clinic: Multiple Sclerosis |url=http://www.mayoclinic.com/health/multiple-sclerosis/DS00188}}

Advancements during the last decades have led to the recent approval of several oral drugs. In March 2019 for example the Food and Drug Administration approved cladribine tablets (Mavenclad) to treat relapsing forms of multiple sclerosis (MS) in adults, to include relapsing-remitting disease and active secondary progressive disease.{{cite web|url=https://www.fda.gov/news-events/press-announcements/fda-approves-new-oral-treatment-multiple-sclerosis|archive-url=https://web.archive.org/web/20191124223530/https://www.fda.gov/news-events/press-announcements/fda-approves-new-oral-treatment-multiple-sclerosis|url-status=dead|archive-date=November 24, 2019|title=FDA approves new oral treatment for multiple sclerosis|work=fda.gov|access-date=2019-05-11}} These drugs are expected to gain in popularity and frequency of use at the expense of previously existing therapies.{{cite journal |vauthors=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 |doi-access=free }}

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.{{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}}{{Cite journal|last1=He|first1=Dian|last2=Han|first2=Kai|last3=Gao|first3=Xiangdong|last4=Dong|first4=Shuai|last5=Chu|first5=Lan|last6=Feng|first6=ZhanHui|last7=Wu|first7=Shan|editor1-first=Lan|editor1-last=Chu|date=2013-08-06|title=Laquinimod for multiple sclerosis|journal=The Cochrane Database of Systematic Reviews|issue=8|pages=CD010475|doi=10.1002/14651858.CD010475.pub2|issn=1469-493X|pmid=23922214|pmc=11696216}} Early trials of the female sex hormone estriol, led in part by Rhonda Voskuhl, have generated interest in reducing symptoms in women with RRMS.{{Cite journal|last1=Sicotte|first1=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|s2cid=5000678|issn=1531-8249}}{{Cite journal|last1=Gold|first1=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}}{{Cite journal|last1=Voskuhl|first1=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|s2cid=30418205|url=http://www.escholarship.org/uc/item/8zz3v374}} Similarly, several other studies are aimed to improve efficacy and ease of use of already existing therapies through the use of novel preparations.{{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|s2cid=25533962 }}

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.{{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 |s2cid=34290702 }}{{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|url-status=dead|archive-url=https://web.archive.org/web/20131004220459/http://www.biogenidec.com/press_release_details.aspx?ID=5981&ReqId=1777510|archive-date=2013-10-04}} Peginterferon beta-1a was approved for use in the United States in August 2014.{{cite web | title=Drug Approval Package: Plegridy (peginterferon beta-1a) prefilled syringe) NDA #125499 | website=U.S. Food and Drug Administration (FDA) | date=17 September 2014 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/125499Orig1s000TOC.cfm | access-date=30 March 2020}}

Preliminary data have suggested that mycophenolate mofetil, an anti-rejection immunosuppressant medication, might have benefits in people with multiple sclerosis. However, a systematic review found that the limited evidence available was insufficient to determine the effects of mycophenolate mofetil as an add‐on therapy for interferon beta-1a in people with RRMS.{{Cite journal|last1=Xiao|first1=Yousheng|last2=Huang|first2=Jianyi|last3=Luo|first3=Hongye|last4=Wang|first4=Jin|date=2014-02-07|title=Mycophenolate mofetil for relapsing-remitting multiple sclerosis|journal=The Cochrane Database of Systematic Reviews|issue=2|pages=CD010242|doi=10.1002/14651858.CD010242.pub2|issn=1469-493X|pmid=24505016|doi-access=|pmc=10875409}}

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.{{Cite journal|last1=Gray|first1=O.|last2=McDonnell|first2=G. V.|last3=Forbes|first3=R. B.|date=2003|title=Intravenous immunoglobulins for multiple sclerosis|journal=The Cochrane Database of Systematic Reviews|volume=2010|issue=4|pages=CD002936|doi=10.1002/14651858.CD002936|issn=1469-493X|pmid=14583956|pmc=8407393}}{{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 |bibcode=2012NYASA1247..117S |s2cid=10837693 }} Nevertheless, their use has also been accompanied by the appearance of potentially dangerous adverse effects, most importantly opportunistic infections. 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. 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.{{Cite journal |last1=Kappos |first1=Ludwig |last2=Wiendl |first2=Heinz |author-link2=Heinz Wiendl |last3=Selmaj |first3=Krzysztof |last4=Arnold |first4=Douglas L. |last5=Havrdova |first5=Eva |last6=Boyko |first6=Alexey |last7=Kaufman |first7=Michael |last8=Rose |first8=John |last9=Greenberg |first9=Steven |year=2015 |title=Daclizumab HYP versus Interferon Beta-1a in Relapsing Multiple Sclerosis |journal=New England Journal of Medicine |volume=373 |issue=15 |pages=1418–1428 |doi=10.1056/nejmoa1501481 |pmid=26444729 |last10=Sweetser |first10=Marianne |last11=Riester |first11=Katherine |last12=o'Neill |first12=Gilmore |last13=Elkins |first13=Jacob|doi-access=free }}

Another research strategy is to evaluate the combined effectiveness of two or more drugs.{{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 |s2cid=31753224 }} 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. 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. 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.

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.{{cite journal |vauthors=Luessi F, Siffrin V, Zipp F |title=Neurodegeneration in multiple sclerosis: novel treatment strategies |journal=Expert Rev Neurother |volume=12 |issue=9 |pages=1061–76; quiz 1077 |date=September 2012 |pmid=23039386 |doi=10.1586/ern.12.59 |doi-access=free }} 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.

{{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.{{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| s2cid = 25533962 }} 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 two years per patient.

Currently there are several ongoing phase III trials, and there are also some drugs that are waiting for approval after finishing theirs. 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,{{Cite web|url=https://www.forbes.com/feeds/ap/2008/09/19/ap5448876.html|title=Opexa shares lose most of value on study data|website=Forbes}}{{Dead link|date=June 2022 |bot=InternetArchiveBot |fix-attempted=yes }} failing its primary target though in March 2008 was still performing well.{{Cite web|url=http://www.medicalnewstoday.com/articles/100415.php|title=Opexa Therapeutics Announces Completion Of Mid Study Descriptive Analysis On Phase IIb Trial Of Tovaxin|access-date=2008-03-14|archive-date=2009-01-03|archive-url=https://web.archive.org/web/20090103102120/http://www.medicalnewstoday.com/articles/100415.php|url-status=dead}} After several financial troubles, a phase III trial was granted in 2011.{{Cite web|url=http://www.opexatherapeutics.com/?page=release§ion=news&article=010511|title=Opexa Therapeutics - Home|website=www.opexatherapeutics.com}}

{{Further|Neurovax}}

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.{{Cite web|url=https://www.pharmacytimes.com/view/spt-npp-0211|archiveurl=https://web.archive.org/web/20160819035841/http://www.pharmacytimes.com/publications/specialty-pt/2011/february-2011/spt-npp-0211|url-status=dead|title=Significant Advances in Multiple Sclerosis Treatment|archivedate=August 19, 2016|website=Pharmacy Times}} 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{{cite journal |vauthors=Gladstone DE, Zamkoff KW, Krupp L, etal |title=High-dose cyclophosphamide for moderate to severe refractory multiple sclerosis |journal=Arch. Neurol. |volume=63 |issue=10 |pages=1388–93 |year=2006 |pmid=16908728 |doi=10.1001/archneur.63.10.noc60076|doi-access= }} Later, a 2007 open label study found it equivalent to mitoxantrone{{cite journal |vauthors=Zipoli V, Portaccio E, Hakiki B, Siracusa G, Sorbi S, Pia Amato M |title=Intravenous mitoxantrone and cyclophosphamide as second-line therapy in multiple sclerosis: An open-label comparative study of efficacy and safety |journal= Journal of the Neurological Sciences|volume= 266|issue= 1–2|pages= 25–30|year=2007 |pmid=17870094 |doi=10.1016/j.jns.2007.08.023 |s2cid=24283817 }} and in 2008 evidence appeared that it can reverse disability.{{cite journal |vauthors=Krishnan C, Kaplin AI, Brodsky RA, etal |title=Reduction of Disease Activity and Disability With High-Dose Cyclophosphamide in Patients With Aggressive Multiple Sclerosis |journal=Arch. Neurol. |volume= 65|issue= 8|pages= 1044–51|date=June 2008 |pmid=18541787 |doi=10.1001/archneurol.65.8.noc80042 |pmc=2574697}}
• Simvastatin has shown brain atrophy reduction in secondary progressive MS.{{cite journal | last=Chataway |first=J | year = 2014 | title = Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial | journal = The Lancet | volume = 383 | issue = 9936| pages = 2213–2221 | doi=10.1016/s0140-6736(13)62242-4 | pmid=24655729| doi-access = free | hdl = 10044/1/26298 | hdl-access = free }}
• 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.

Most Progressive-Onset variants does not have any approved disease-modifying treatment currently. Some possible treatments have been published, such as methylprednisolone pulses{{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 |doi-access=free }} or riluzole,{{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 |s2cid=20607353 }} and some reduction of spasticity was reported in a pilot Italian study on low dose naltrexone{{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 |s2cid=3548490 }} but there is nothing conclusive still.

Currently, good results using the monoclonal antibody ocrelizumab in primary progressive MS (PPMS){{cite journal |vauthors=Gajofatto A, Turatti M, Benedetti MD | year = 2016 | title = Primary progressive multiple sclerosis: current therapeutic strategies and future perspectives | journal = Expert Rev Neurother | volume = 17| issue = 4| pages = 1–14| doi = 10.1080/14737175.2017.1257385 | pmid = 27813441 | s2cid = 24034132 }} have put the focus into depleting B cells targeting CD20 proteins{{cite journal | author = Castro-Borrero Wanda |display-authors=etal| year = 2012 | title = Current and emerging therapies in multiple sclerosis: a systematic review | journal = Therapeutic Advances in Neurological Disorders | volume = 5 | issue = 4| pages = 205–220 | doi = 10.1177/1756285612450936 | pmid = 22783370 | pmc = 3388530 }}

A statin, simvastatin (Zocor), has shown good results in progressive variants{{Cite web|url=http://ccsvi-ms.ning.com/profiles/blogs/statin-may-slow-progressive-ms|title=Statin may slow progressive MS}}{{Dead link|date=July 2022 |bot=InternetArchiveBot |fix-attempted=yes }} 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{{cite journal | last=Wang |first=Z | year = 2016| title = Nuclear Receptor NR1H3 in Familial Multiple Sclerosis | journal = Neuron | volume = 90 | issue = 5| pages = 948–954 | doi = 10.1016/j.neuron.2016.04.039 | pmid=27253448 | pmc=5092154}} 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, 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.First Oral Treatment For Highly Active Relapsing Remitting Multiple Sclerosis Provides New Choice For UK Patients Failing On Injections, [http://www.medicalnewstoday.com/releases/222803.php] Cyclophosphamide is currently used off-label for Rapidly Worsening MS (RWMS).{{cite journal | pmid = 11990872 | volume=8 | issue=2 | title=Treatment of multiple sclerosis with cyclophosphamide: critical review of clinical and immunologic effects |date=April 2002 |vauthors=Weiner HL, Cohen JA | journal=Mult. Scler. | pages=142–54 | doi=10.1191/1352458502ms790oa| s2cid=35767740 }}

Pediatric patients constitute a particularly interesting MS population since the clinical onset of the disease is likely very close to the biological one. Therefore, this population offers the possibility of studying the MS pathogenesis closer to its root. Grey matter lesions were observed in the cerebellum of almost all (93.3%) adolescents with pedMS and significantly outnumbered WML, suggesting that the cerebellar cortex is a main target of MS-related pathology in teens.{{cite journal |last1=Margoni |first1=Monica |last2=Franciotta |first2=Silvia |last3=Poggiali |first3=Davide |last4=Riccardi |first4=Alice |last5=Rinaldi |first5=Francesca |last6=Nosadini |first6=Margherita |last7=Sartori |first7=Stefano |last8=Anglani |first8=Maria Giulia |last9=Causin |first9=Francesco |last10=Perini |first10=Paola |last11=Gallo |first11=Paolo |title=Cerebellar gray matter lesions are common in pediatric multiple sclerosis at clinical onset |journal=Journal of Neurology |date=5 March 2020 |volume=267 |issue=6 |pages=1824–1829 |doi=10.1007/s00415-020-09776-6|pmid=32140864 |s2cid=212404981 }}

A former problem with pediatric patients is that some variants of anti-MOG disease were considered MS before 2016. Therefore, publications before this date have to be considered with caution. Currently the only approved treatment for pediatric MS is fingolimod.{{cite journal |last1=Eshaghi |first1=Arman |title=First approved treatment in children with multiple sclerosis slows brain atrophy |journal=Journal of Neurology, Neurosurgery & Psychiatry |date=4 March 2020 |pages=jnnp-2019-322519 |doi=10.1136/jnnp-2019-322519|pmid=32132223 |volume=91 |issue=5 |s2cid=212416856 |url=https://discovery.ucl.ac.uk/id/eprint/10096568/ }}

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.{{Cite journal |doi = 10.1038/nrneurol.2015.200|pmid = 26503926|title = New drugs and personalized medicine for multiple sclerosis|journal = Nature Reviews Neurology|volume = 11|issue = 11|pages = 614–616|year = 2015|last1 = Matthews|first1 = Paul M.|s2cid = 40121167 }}

{{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 established:

• 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.{{Cite journal |doi=10.1186/s12987-015-0024-8 |pmc=4677451 |pmid=26652013|year=2015 |last1=Hottenrott |first1=T. |title=The intrathecal, polyspecific antiviral immune response in neurosarcoidosis, acute disseminated encephalomyelitis and autoimmune encephalitis compared to multiple sclerosis in a tertiary hospital cohort |journal=Fluids and Barriers of the CNS |volume=12 |pages=27 |last2=Dersch |first2=R. |last3=Berger |first3=B. |last4=Rauer |first4=S. |last5=Eckenweiler |first5=M. |last6=Huzly |first6=D. |last7=Stich |first7=O. |doi-access=free }} In some reports the MRZR showed a lower sensitivity than OCB (70% vs. 100%), but a higher specificity (69% vs. 92%) for MS.
• free light chains (FLC). Several authors have reported that they are comparable or even better than oligoclonal bands.{{Cite journal |last1=Duranti |first1=Fabio |last2=Pieri |first2=Massimo |last3=Zenobi |first3=Rossella |last4=Centonze |first4=Diego |last5=Buttari |first5=Fabio |last6=Bernardini |first6=Sergio |last7=Dessi |first7=Mariarita |title=kFLC Index: a novel approach in early diagnosis of Multiple Sclerosis |url=http://worldwidejournals.in/ojs/index.php/ijsr/article/download/6571/6613 |journal=International Journal of Scientific Research |volume=4 |issue=8 |access-date=2018-08-27 |archive-date=2016-08-28 |archive-url=https://web.archive.org/web/20160828121810/http://worldwidejournals.in/ojs/index.php/ijsr/article/download/6571/6613 |url-status=dead }}

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.

Some of the features of MS, like microglia activation, are invisible to MRI. Therefore positron emission tomography (PET) is preferred in the current studies.{{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 }}

Patients with multiple sclerosis (MS) routinely undergo serial contrast-enhanced MRI checks. Given concerns regarding tissue deposition of gadolinium-based contrast agents (GBCAs){{cite web|url=https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-warns-gadolinium-based-contrast-agents-gbcas-are-retained-body|archive-url=https://web.archive.org/web/20190813004320/https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-warns-gadolinium-based-contrast-agents-gbcas-are-retained-body|url-status=dead|archive-date=August 13, 2019|title=fda-drug-safety-communication-fda-warns-gadolinium-based-contrast-agents-gbcas-are-retained-body; requires new class warnings|date=2018-05-16|website=USA FDA}} and evidence that enhancement of lesions is only seen in patients with new disease activity on noncontrast imaging,

research is now being carried out to understand and implement what intravenous contrast agents would be reserved for patients with evidence of new disease activity on non-contrast images.{{cite journal|title=Initiative to Reduce Unnecessary Gadolinium-Based Contrast in Multiple Sclerosis Patients|journal = Journal of the American College of Radiology |volume = 16|issue = 9 Pt A|pages = 1158–1164|date=2018-05-01|pmid = 31092348|pmc = 6732018|last1 = Rudie|first1 = J. D.|last2 = Mattay|first2 = R. R.|last3 = Schindler|first3 = M.|last4 = Steingall|first4 = S.|last5 = Cook|first5 = T. S.|last6 = Loevner|first6 = L. A.|last7 = Schnall|first7 = M. D.|last8 = Mamourian|first8 = A. C.|last9 = Bilello|first9 = M.|doi = 10.1016/j.jacr.2019.04.005}}{{cite journal|title=Imaging biomarkers in multiple sclerosis|journal = Journal of Magnetic Resonance Imaging |volume = 31|issue = 4|pages = 770–88|date=2010-04-01|pmid = 20373420|last1 = Filippi|first1 = M.|last2 = Agosta|first2 = F.|doi = 10.1002/jmri.22102|s2cid = 15893040 |doi-access = }}

The main measure of evolution of symptoms, specially important as an endpoint in MS trials, is the EDSS (extended disability status score). However, this and other measures used in clinical studies are far from perfect and suffer from insensitivity or inadequate validation.{{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 |s2cid=19562110 }} 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.

Currently there are two main criteria coexisting:

• EDSS (disability status scale), the first scale to monitor MS progression.
• NEDA (No evidence of disease activity), the new one.

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.{{Cite journal |doi = 10.1177/1756286418805713|pmid = 30386435|pmc = 6204617|title = NEDA-3 status including cortical lesions in the comparative evaluation of natalizumab versus fingolimod efficacy in multiple sclerosis|journal = Therapeutic Advances in Neurological Disorders|volume = 11|pages = 175628641880571|year = 2018|last1 = Puthenparampil|first1 = Marco|last2 = Cazzola|first2 = Chiara|last3 = Zywicki|first3 = Sofia|last4 = Federle|first4 = Lisa|last5 = Stropparo|first5 = Erica|last6 = Anglani|first6 = Mariagiulia|last7 = Rinaldi|first7 = Francesca|last8 = Perini|first8 = Paola|last9 = Gallo|first9 = Paolo}}

In MS usually the clinical course is referred to as "type", while radiological and pathological types are referred to as "variants".

In 1996, the US National Multiple Sclerosis Society (NMSS) Advisory Committee on Clinical Trials in Multiple Sclerosis (ACCTMS) standardized four clinical courses for MS (Remitent-Recidivant, Secondary Progressive, Progressive-Relapsing and Primary progressive). Later, these were considered subtypes of the disease and this is known as the Lublin classification.{{cite journal |last1=Giovannoni |first1=Gavin |last2=Hawkes |first2=Christopher H. |last3=Lechner-Scott |first3=Jeannette |last4=Levy |first4=Michael |last5=Yeh |first5=E. Ann |title=Multiple sclerosis is one disease |journal=Multiple Sclerosis and Related Disorders |date=1 July 2022 |volume=63 |page=103961 |doi=10.1016/j.msard.2022.103961|pmid=35714573 }}{{cite journal |last1=Pitt |first1=David |last2=Lo |first2=Chih Hung |last3=Gauthier |first3=Susan A. |last4=Hickman |first4=Richard A. |last5=Longbrake |first5=Erin |last6=Airas |first6=Laura M. |last7=Mao-Draayer |first7=Yang |last8=Riley |first8=Claire |last9=Jager |first9=Philip Lawrence De |last10=Wesley |first10=Sarah |last11=Boster |first11=Aaron |last12=Topalli |first12=Ilir |last13=Bagnato |first13=Francesca |last14=Mansoor |first14=Mohammad |last15=Stuve |first15=Olaf |last16=Kister |first16=Ilya |last17=Pelletier |first17=Daniel |last18=Stathopoulos |first18=Panos |last19=Dutta |first19=Ranjan |last20=Lincoln |first20=Matthew R. |title=Toward Precision Phenotyping of Multiple Sclerosis |journal=Neurology: Neuroimmunology & Neuroinflammation |date=1 November 2022 |volume=9 |issue=6 |pages=e200025 |doi=10.1212/NXI.0000000000200025|pmid=36041861 |pmc=9427000 |doi-access=free }}

Some reports state that those "types" were artificially made up for classifying RRMS as a separate disease. In this way, the number of patients in this group was low enough to get the interferon approved by the FDA under the orphan drugs act.

Later revisions of this report removed the progressive-relapsing course and added CIS.{{Cite journal | doi=10.1212/WNL.0000000000000560| pmid=24871874| pmc=4117366| title=Defining the clinical course of multiple sclerosis: The 2013 revisions| journal=Neurology| volume=83| issue=3| pages=278–286| year=2014| last1=Lublin| first1=F. D.| last2=Reingold| first2=S. C.| last3=Cohen| first3=J. A.| last4=Cutter| first4=G. R.| last5=Sorensen| first5=P. S.| last6=Thompson| first6=A. J.| last7=Wolinsky| first7=J. S.| last8=Balcer| first8=L. J.| last9=Banwell| first9=B.| last10=Barkhof| first10=F.| last11=Bebo| first11=B.| last12=Calabresi| first12=P. A.| last13=Clanet| first13=M.| last14=Comi| first14=G.| last15=Fox| first15=R. J.| last16=Freedman| first16=M. S.| last17=Goodman| first17=A. D.| last18=Inglese| first18=M.| last19=Kappos| first19=L.| last20=Kieseier| first20=B. C.| last21=Lincoln| first21=J. A.| last22=Lubetzki| first22=C.| last23=Miller| first23=A. E.| last24=Montalban| first24=X.| last25=O'Connor| first25=P. W.| last26=Petkau| first26=J.| last27=Pozzilli| first27=C.| last28=Rudick| first28=R. A.| last29=Sormani| first29=M. P.| last30=Stuve| first30=O.| display-authors=29}} Nevertheless, regulatory agencies often refer to unofficial subtypes in their recommendations, like "active SPMS" {{Cite web|url=https://www.fda.gov/news-events/press-announcements/fda-approves-new-oral-treatment-multiple-sclerosis|archive-url=https://web.archive.org/web/20191124223530/https://www.fda.gov/news-events/press-announcements/fda-approves-new-oral-treatment-multiple-sclerosis|url-status=dead|archive-date=November 24, 2019|title=FDA approves new oral treatment for multiple sclerosis|first=Office of the|last=Commissioner|date=March 24, 2020|website=FDA}} "highly active",{{Cite web|url=https://www.ema.europa.eu/en/medicines/human/EPAR/mavenclad|title=Mavenclad | European Medicines Agency|date=17 September 2018 }} or "rapidly progressive".

These types have proven to be unspecific. In the days in which NMO was considered a kind of MS (optic-spinal MS), the four clinical types model on widespread usage, and it was nevertheless unable to yield any clue about all the important differences.{{Citation needed|date=June 2020}}

Currently it is accepted that the "types" are not exclusive. 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.{{Cite journal |date=Feb 2018 |title=Multiple Sclerosis: Mechanisms and Immunotherapy. |journal=Neuron |volume=97 |issue=4 |pages=742–768 |doi=10.1016/j.neuron.2018.01.021 |pmid=29470968|last1=Baecher-Allan |first1=C. |last2=Kaskow |first2=B. J. |last3=Weiner |first3=H. L. |s2cid=3499974 |doi-access=free }}

In 1996, the US National Multiple Sclerosis Society (NMSS) Advisory Committee on Clinical Trials in Multiple Sclerosis (ACCTMS) standardized four clinical courses for MS (remittent-recidivant, secondary progressive, progressive-relapsing and primary progressive).{{Cite journal | doi=10.1111/ene.13819| pmid=30300457| title=Multiple sclerosis - a review| journal=European Journal of Neurology| volume=26| issue=1| pages=27–40| year=2019| last1=Dobson| first1=R.| last2=Giovannoni| first2=G.| doi-access=free| pmc=1589931}}

Some reports state that those "types" were artificially made up trying to classify RRMS as a separate disease so that the number of patients was low enough to get the interferon approved by the FDA under the orphan drugs act. Revisions in 2013 and 2017 removed the Progressive-Relapsing course and introduced CIS as a variety/course/status of MS, stabilising the actual classification (CIS, RRMS, SPMS and PPMS). Nevertheless, these types are not enough to predict the responses to medications and several regulatory agencies use additional types in their recommendations, such as highly active MS, malignant MS, aggressive MS or rapidly progressive MS.Díaz C, Zarco LA, Rivera DM, Highly active multiple sclerosis: An update, Mult Scler Relat Disord. 2019 May;30:215-224. doi: 10.1016/j.msard.2019.01.039. Epub 2019 Jan 24 [https://www.sciencedirect.com/science/article/pii/S2211034819300380?via%3Dihub]

Research into pathogenesis focuses on explaining the fundamental causation of MS onset and progression, and explaining its heterogeneous behaviour. There are several open lines of research as to the cause of MS, ranging from metabolic disregulation to infection.

Regarding the possibility of a viral cause, there are reports of monoclonal antibodies against Epstein–Barr virus–infected B-cells.{{cite journal |author=Michael P Pender |author2=Scott R Burrows |title=Epstein–Barr virus and multiple sclerosis: potential opportunities for immunotherapy |journal=Clin Transl Immunol |volume=3 |issue= 10|pages=e27 |date=31 October 2014 |doi=10.1038/cti.2014.25|pmid=25505955 |pmc=4237030 }} These reports have been recently complemented by reported interactions between Epstein–Barr virus (EBV) and human endogenous retroviruses (HERVs), and experiments in vitro showing how HERVs can activate microglia into an active state that produces demyelination. A longitudinal study showed the risk of MS increased 32-fold after infection with EBV, suggesting EBV is a primary cause of MS,{{Cite journal|vauthors=Bjornevik K, Cortese M, Healy BC, Kuhle J, Mina MJ, Leng Y et al|date=2022-01-21|title=Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis|url=https://www.science.org/doi/abs/10.1126/science.abj8222|journal=Science|volume=375|issue=6578|pages=296–301|language=EN|pmid=35025605|doi=10.1126/science.abj8222|bibcode=2022Sci...375..296B |s2cid=245983763|url-access=subscription}}{{cite news |first=Gina |last=Kolata |date=13 January 2022 |title=Common Virus May Play Role in Debilitating Neurological Illness |url=https://www.nytimes.com/2022/01/13/health/multiple-sclerosis-epstein-barr-virus.html |archive-url=https://web.archive.org/web/20220114054710/https://www.nytimes.com/2022/01/13/health/multiple-sclerosis-epstein-barr-virus.html |work=The New York Times |archive-date=14 January 2022 |url-status=live}}{{cite journal |last1=Robinson |first1=WH |last2=Steinman |first2=L |title=Epstein-Barr virus and multiple sclerosis. |journal=Science |date=13 January 2022 |volume=375 |issue=6578 |pages=264–265 |doi=10.1126/science.abm7930 |pmid=35025606 |bibcode=2022Sci...375..264R |s2cid=245978874 |doi-access=free }} although only a very small proportion of those infected with EBV will later develop MS.

Pathological research tries to obtain correlations for the observable biomarkers. Several important areas of study have been delimited, such as 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.{{cite journal |author=Fleischer Vinzenz |display-authors=etal | year = 2016 | title = Metabolic Patterns in Chronic Multiple Sclerosis Lesions and Normal-appearing White Matter: Intraindividual Comparison by Using 2D MR Spectroscopic Imaging| journal = Radiology| volume = 281| issue = 2| pages = 536–543| doi = 10.1148/radiol.2016151654 | pmid = 27243371 | doi-access = }}

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.{{Cite journal |doi=10.5152/dir.2015.15415 |pmid=27015443|pmc=4859748|year=2016|last1=Durhan|first1=G.|title=Influence of cigarette smoking on white matter in patients with clinically isolated syndrome as detected by diffusion tensor imaging|journal=Diagnostic and Interventional Radiology (Ankara, Turkey)|volume=22|issue=3|pages=291–296|last2=Diker|first2=S.|last3=Has|first3=A. C.|last4=Karakaya|first4=J.|last5=Kurne|first5=A. T.|last6=Oguz|first6=K. K.}} An explanation of this effect could shed some light into the pathogenesis.

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.{{Cite journal |doi = 10.1111/j.1467-8306.1981.tb01338.x|title = Geographical Clues about Multiple Sclerosis|journal = Annals of the Association of American Geographers|volume = 71|pages = 28–39|date = March 1981|last1 = Mayer|first1 = Jonathan D.}}

Another important research field in MS is over its heterogeneity. There are also some reports considering that several disease entities are confused 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 and a third one was separated as anti-neurofascin disease.

This research is not closed and some other conditions could be separated from MS following the discovery of specific pathogens.{{cite journal |author=Ichiro Nakashima |title=Anti-myelin oligodendrocyte glycoprotein antibody in demyelinating diseases |journal=Neuroimmunology |volume=6 |issue=S1 |pages=59–63 |date=December 2015 |doi=10.1111/cen3.12262|doi-access=free }}

MS has been historically a clinically defined entity including several atypical presentations. Some auto-antibodies have been found in atypical MS cases, giving birth to separate disease families and restricting the previously wider concept of MS.

The research in MS heterogeneity is trying to set apart all the pathogenically unrelated conditions that are currently included in the spectrum. It is an ongoing research and the list of separated conditions could grow in the future.

First of all, anti-AQP4 autoantibodies were found in neuromyelitis optica (NMO), which was previously considered a MS variant. After that, a whole spectrum of diseases named NMO spectrum diseases (NMOSD) or anti-AQP4 diseases has been accepted.{{Cite journal |doi = 10.1111/cen3.12491|title = Neuromyelitis optica spectrum and myelin oligodendrocyte glycoprotein antibody‐related disseminated encephalomyelitis|journal = Clinical and Experimental Neuroimmunology|volume = 10|pages = 9–17|year = 2019|last1 = Misu|first1 = Tatsuro|last2 = Fujihara|first2 = Kazuo|doi-access = }}

Later, it was found that some cases of MS were presenting anti-MOG autoantibodies, mainly overlapping with the Marburg variant. Anti-MOG autoantibodies were found to be also present in ADEM, and now a second spectrum of separated diseases is being considered. At this moment, it is named inconsistently across different authors, but it is normally something similar to anti-MOG demyelinating diseases.

Finally, a third kind of auto-antibodies is accepted. They are several anti-neurofascin auto-antibodies which damage the Ranvier nodes of the neurones. These antibodies are more related to the peripheral nervous demyelination, but they were also found in chronic progressive PPMS and combined central and peripheral demyelination (CCPD, which is considered another atypical MS presentation).

Other auto-antigens are under study, such as GDP-L-fucose synthase which is reported in a subset of MS patients.{{Cite news |url=http://neurosciencenews.com/multiple-sclerosis-gut-flora-10003/ |title=Link Between Gut Flora and Multiple Sclerosis Discovered |date=2018-10-11 |work=NeuroscienceNews}}{{Cite journal |doi=10.1126/scitranslmed.aat4301|pmid=30305453|title=GDP-l-fucose synthase is a CD4+ T cell–specific autoantigen in DRB3*02:02 patients with multiple sclerosis|journal=Science Translational Medicine|volume=10|issue=462|pages=eaat4301|year=2018|last1=Planas|first1=Raquel|last2=Santos|first2=Radleigh|last3=Tomas-Ojer|first3=Paula|last4=Cruciani|first4=Carolina|last5=Lutterotti|first5=Andreas|last6=Faigle|first6=Wolfgang|last7=Schaeren-Wiemers|first7=Nicole|last8=Espejo|first8=Carmen|last9=Eixarch|first9=Herena|last10=Pinilla|first10=Clemencia|last11=Martin|first11=Roland|last12=Sospedra|first12=Mireia|s2cid=52959112|url=https://www.zora.uzh.ch/id/eprint/158835/1/2018_Planas_GDP_L-Fucose_Sci_Transl._Med._in_press.pdf|doi-access=free}} It is currently unknown if it is pathogenic or a side effect of the disease.

Other example could be 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.{{Cite journal |last=Hendrickson |first=Megan |title=Myelocortical multiple sclerosis: a subgroup of multiple sclerosis patients with spinal cord and cortical demyelination |journal=Onlinelibrary.ectrims-congress.eu |url=http://onlinelibrary.ectrims-congress.eu/ectrims/2013/copenhagen/34294/megan.hendrickson.myelocortical.multiple.sclerosis.a.subgroup.of.multiple.html}} Later its existence was confirmed (2018){{Cite journal |doi = 10.1016/S1474-4422(18)30245-X|pmid = 30143361|pmc = 6197820|title = Cortical neuronal densities and cerebral white matter demyelination in multiple sclerosis: A retrospective study|journal = The Lancet Neurology|volume = 17|issue = 10|pages = 870–884|year = 2018|last1 = Trapp|first1 = Bruce D.|last2 = Vignos|first2 = Megan|last3 = Dudman|first3 = Jessica|last4 = Chang|first4 = Ansi|last5 = Fisher|first5 = Elizabeth |author-link5=Elizabeth Fisher (neuroscientist) |last6 = Staugaitis|first6 = Susan M.|last7 = Battapady|first7 = Harsha|last8 = Mork|first8 = Sverre|last9 = Ontaneda|first9 = Daniel|last10 = Jones|first10 = Stephen E.|last11 = Fox|first11 = Robert J.|last12 = Chen|first12 = Jacqueline|last13 = Nakamura|first13 = Kunio|last14 = Rudick|first14 = Richard A.}}

Besides all this autoantibodies found, four different patterns of demyelination have been reported in MS, opening the door to consider MS as an heterogeneous disease.{{Cite journal | doi=10.1212/01.CON.0000433291.23091.65| pmid=23917093| pmc=3915566| title=Pathology of Multiple Sclerosis| journal=Continuum: Lifelong Learning in Neurology| volume=19| issue=4 Multiple Sclerosis| pages=901–921| year=2013| last1=Popescu| first1=Bogdan F. Gh.| last2=Pirko| first2=Istvan| last3=Lucchinetti| first3=Claudia F.}}

Epstein–Barr virus has been the focus of heavy research. A cross-reactivity between GlialCam and EBNA1 has been reported on 25% of MS cases{{cite journal |last1=Wekerle |first1=Hartmut |title=Epstein–Barr virus sparks brain autoimmunity in multiple sclerosis |journal=Nature |date=15 February 2022 |volume=603 |issue=7900 |pages=230–232 |doi=10.1038/d41586-022-00382-2 |pmid=35169323 |bibcode=2022Natur.603..230W |s2cid=246866517 }}

Human endogenous retroviruses (HERVs) have been reported in MS for several years. In fact, one of the families, human endogenous retrovirus-W, was first discovered while studying MS patients.

Recent research as of 2019 point to one of the HERV-W viruses (pHEV-W), and specifically one of the proteins of the viral capside that has been found to activate microglia in vitro. Activated microglia in turn produces demyelination.{{Cite journal |doi = 10.1073/pnas.1901283116|pmid = 31213545|pmc = 6660731|title = PHERV-W envelope protein fuels microglial cell-dependent damage of myelinated axons in multiple sclerosis|journal = Proceedings of the National Academy of Sciences|volume = 116|issue = 30|pages = 15216–15225|year = 2019|last1 = Kremer|first1 = David|last2 = Gruchot|first2 = Joel|last3 = Weyers|first3 = Vivien|last4 = Oldemeier|first4 = Lisa|last5 = Göttle|first5 = Peter|last6 = Healy|first6 = Luke|last7 = Ho Jang|first7 = Jeong|last8 = Kang t. Xu|first8 = Yu|last9 = Volsko|first9 = Christina|last10 = Dutta|first10 = Ranjan|last11 = Trapp|first11 = Bruce D.|last12 = Perron|first12 = Hervé|last13 = Hartung|first13 = Hans-Peter|last14 = Küry|first14 = Patrick| bibcode=2019PNAS..11615216K |doi-access = free}} Some interactions between the Epstein–Barr virus and the HERVs could be the trigger of the MS microglia reactions.{{Cite journal |doi = 10.1073/pnas.1909786116|pmid = 31289223|pmc = 6660775|title = Human retrovirus pHEV-W envelope protein and the pathogenesis of multiple sclerosis|journal = Proceedings of the National Academy of Sciences|volume = 116|issue = 30|pages = 14791–14793|year = 2019|last1 = Lisak|first1 = Robert P.| bibcode=2019PNAS..11614791L |doi-access = free}} Supporting this study, a monoclonal antibody against the viral capside (Temelimab) has shown good results in trials in phase IIb.Hans-Peter Hartung et al, Efficacy and Safety of Temelimab, an Antibody Antagonist of the Human Endogenous Retrovirus Type-W env Protein, in Participants with Relapsing Remitting Multiple Sclerosis: A Double-Blind, Randomised, Placebo-Controlled Phase 2b Clinical Trial, The Lancet 17 May 2019 {{SSRN|3388820}}

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.

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.{{cite journal |vauthors=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 }} This study may presumably identify all the common genetic variants involved in MS. Further studies will probably involve full genome sequencing of large samples, or the study of structural genetic variants such as insertions, deletions or polymorphisms.

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.{{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 | journal = Nature | volume = 476 | issue = 7359| pages = 214–219 | doi = 10.1038/nature10251 |display-authors=etal | pmid=21833088 | pmc=3182531|bibcode=2011Natur.476..214T }} Some genetic mutations have been associated with an increased risk to develop MS, like STK11-SNP.{{Cite news | url=https://www.labmedica.com/genetic_testing/articles/294757745/mutation_identified_as_genetic_marker_for_multiple_scle_.html | title=Mutation Identified as Genetic Marker for Multiple Sclerosis| date=2015-03-16}} The chronic demyelination may cause axons to be notably vulnerable to repetitive and increasing injury and destruction.{{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 | journal = Brain | volume = 132 | issue = 5| pages = 1175–89 | doi=10.1093/brain/awp070|pmid=19339255 |display-authors=etal|pmc=2677799}}

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.{{cite journal | author=Zurawski Jonathan |author2=Lassmann Hans |author3=Bakshi Rohit | year = 2016 | title = Use of Magnetic Resonance Imaging to Visualize Leptomeningeal Inflammation in Patients With Multiple Sclerosis: A Review | journal = JAMA Neurol | volume = 74| issue = 1| pages = 100–109| doi = 10.1001/jamaneurol.2016.4237 | pmid = 27893883 | s2cid = 11268426 }}

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