Multiple sclerosis research
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.
- 1 Research directions
- 2 Clinical measures of evolution
- 3 Geographical Causes
- 4 Genetics
- 5 Research into pathogenesis
- 6 Disease-modifying drugs
- 7 Biomarkers
- 8 References
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.
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. 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. Early trials of the female sex hormone estriol, led in part by Rhonda Voskuhl, have generated interest in reducing symptoms in women with RRMS. Similarly, several other studies are aimed to improve efficacy and ease of use of already existing therapies through the use of novel preparations. Such is the case the 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. Request for approval of peginterferon beta-1a is expected during 2013.
Monoclonal antibodies, which are drugs of the same family as natalizumab, have also raised high levels of interest and research. Alemtuzumab, daclizumab and CD20 monoclonal antibodies such as rituximab, ocrelizumab and ofatumumab have all shown some benefit and are under study as potential treatments for MS. 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.
Another research strategy is to evaluate the combined effectiveness of two or more drugs. 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. 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.
Finally, regarding research on the cause, there are several open possibilities under research, ranging from metabolic disregulations to external infections. Regarding to this last possibility, the recent news about anti-CD20 monoclonal antibodies against EBV B-cells are considered by some people like an important clue about the pathogenesis
Also there are some reports consider 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.
While MRI is used normally for diagnosis and follow up, it has limitations. New MRI technologies like pulse sequences and post-procesing are under study.
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 is currently an active field of research.
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.
The main measure of evolution of symptoms, specially important as an endpoint in MS trials, is the EDSS. However, this and other measures used in clinical studies are far from perfect and suffer from insensitivity or inadequate validation. 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.
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. 
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. 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. Some genetic mutations have been associated with an increased risk to develop MS, like STK11-SNP. The chronic demyelination may cause axons to be notably vulnerable to repetitive and increasing injury and destruction.
Research into pathogenesis
Research into pathogenesis focuses in explaining the ultimate causes of MS onset and progression, and explaining the heterogeneous behaviour
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.
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. An explanation of this effect could shed some light into the pathogenesis.
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.
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. 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.
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. 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. 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. This drug was expected to be in the market in 2011 for use in multiple sclerosis patients., but in 2011 the company decided to stop selling the tablets in Russia and Australia though it was already approved in this countries. Nevertheless, it seems that approval process continued in Europe and the EMEA has accepted a review process
Also are in phase III at least the following drugs (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, failing its primary target though in March 2008 was still performing good. After several financial troubles, a phase III trial has been granted in 2011
- 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.
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. 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 Later, a 2007 open label study found it equivalent to Mitoxantrone and in 2008 evidence appeared that it can reverse disability.
- Simvastatin has shown brain atrophy reduction in secondary progressive MS.
- Tcelna is currently under active research by Opexa, showing promising results.
- 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 or riluzole, and some reduction of spasticity was reported in a pilot Italian study on low dose naltrexone but there is nothing conclusive still.
A Statin, Simvastatin (Zocor), has shown good results in progressive variants 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 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.
Diagnosis of MS has always been made by clinical examination, supported by MRI or CSF tests. According with both the pure autoimmune hypothesis and the immune-mediated hypothesis, researchers expect to find biomarkers able to yield a better diagnosis, and able to predict the response to the different available treatments.
Some people focus on blood tests, given the easy availability for diagnosis. Among the studies for blood tests, the highest sensitivity and specificity reported to date is testing circulating erythrocytes (s=98.3%, e=89.5%). Also a good result was obtained using methylation patterns of circulating cell debris are specific for a number of conditions, including RRMS There are ongoing efforts to be able to diagnose MS by analysing myelin debris into the blood stream.
As of 2014, the only fully specific biomarkers found were four proteins in the CSF: CRTAC-IB (cartilage acidic protein), tetranectin (a plasminogen-binding protein), SPARC-like protein (a calcium binding cell signalling glycoprotein), and autotaxin-T (a phosphodiesterase) This list was expanded on 2016, with three CSF proteins (Immunoglobulins) reported specific for MS. They are the following immunoglobulins: Ig γ-1 (chain C region), Ig heavy chain V-III (region BRO) and Ig-κ-chain (C region)
Biomarkers are expected to play an important role in the near future
Existing damage and disease evolution
During a clinical trial for one of the main MS drugs, a catheter was inserted into the brain's ventricles of the patients. Existing damage was evaluated and correlated with body fluids. Thanks to the courage of these volunteers, now we know that in PPMS, neurofilament light chain (NF-L) level, in CSF and serum, is a sensitive and specific marker for white matter axonal injury
About biomarkers for MRI images, Radial Diffusivity has been suggested as a biomarker associated with the level of myelination in MS lesions. However, it is affected also by tissue destruction, which may lead to exaggeration of diffusivity measures. Diffusivity can be more accurate. Distinct patterns of diffusivity in MS lesions suggest that axonal loss dominates in the T1 hypointense core and that the effects of de/remyelination may be better detected in the "T2-rim", where there is relative preservation of structural integrity.
Treatments and response to therapy
Currently the only clear biomarker that predicts a response to therapy is the presence of anti-MOG autoantibodies in blood. Anti-MOG seropositive patients do not respond to approved MS medications. In fact, it seems that MS patients with anti-MOG positivity could be considered a different disease in the near future.
Comparative Effectiveness Research (CER) is an emerging field in Multiple Sclerosis treatment. The response of the disease to the different available medications at this moment cannot be predicted, and would be desirable
But the ideal target is to find subtypes of the disease that respond better to a specific treatment. A good example could be the discovery that the presence of a gene called SLC9A9 appears in people who fail to respond to interferon β therapy or that the disregulation of some transcription factors define molecular subtypes of the disease Other good example could be the Hellberg-Eklund score for predicting the response to Natalizumab.
Though biomarkers are normally assumed to be chemical compounds in body fluids, image can also be considered a biomarker. For an example about research in this area, it has been found that fingolimod is specially suitable for patients with frequently relapsing spinal cord lesions with open-ring enhancement Anyway, patients with spinal cord lesions could have different T-helper cells patterns that those with brain lesions
Biomarkers are also important for the expected response to therapy. As an example of the current research, in 2000 was noticed that patients with pattern II lesions were dramatically responsive to plasmapheresis, and in February 2016, it was granted the first patent to test the lesion pattern of a patient without biopsy.
Other examples could be the proposal for protein SLC9A9 (gen Solute carrier family 9) as biomarker for the response to interferon beta, as it happens for serum cytokine profiles The same was proposed to MxA protein mRNA. The presence of anti-MOG, even with CDMS diagnosis, can be considered as a biomarker against MS disease modifying therapies like fingolimod
- Cohen JA (July 2009). "Emerging therapies for relapsing multiple sclerosis". Arch. Neurol. 66 (7): 821–8. doi:10.1001/archneurol.2009.104. PMID 19597083.
- 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.
- Jeffrey, susan (9 Aug 2012). "CONCERTO: A Third Phase 3 Trial for Laquinimod in MS". Medscape Medical News. Retrieved 21 May 2013.
- 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.
- Gold, Stefan M.; Voskuhl, Rhonda R. "Estrogen treatment in multiple sclerosis". Journal of the Neurological Sciences. 286 (1-2): 99–103. doi:10.1016/j.jns.2009.05.028. PMC .
- Voskuhl, Rhonda R; Wang, HeJing; Wu, T C Jackson; Sicotte, Nancy L; Nakamura, Kunio; Kurth, Florian; Itoh, Noriko; Bardens, Jenny; Bernard, Jacqueline T. "Estriol combined with glatiramer acetate for women with relapsing-remitting multiple sclerosis: a randomised, placebo-controlled, phase 2 trial". The Lancet Neurology. 15 (1): 35–46. doi:10.1016/s1474-4422(15)00322-1.
- Mendoza, RL (2014). "Pharmacoeconomics and clinical trials in multiple sclerosis: baseline data from the European Union". Journal of Public Health. 22 (3): 211–218. doi:10.1007/s10389-013-0561-z.
- Kieseier, BC; Calabresi, PA (March 2012). "PEGylation of interferon-β-1a: a promising strategy in multiple sclerosis". CNS Drugs. 26 (3): 205–14. doi:10.2165/11596970-000000000-00000. PMID 22201341.
- "Biogen Idec Announces Positive Top-Line Results from Phase 3 Study of Peginterferon Beta-1a in Multiple Sclerosis" (Press release). Biogen Idec. 2013-01-24. Archived from the original on 2013-10-04. Retrieved 2013-05-21.
- Saidha S, Eckstein C, Calabresi PA (January 2012). "New and emerging disease modifying therapies for multiple sclerosis". Annals of the New York Academy of Sciences. 1247: 117–37. Bibcode:2012NYASA1247..117S. doi:10.1111/j.1749-6632.2011.06272.x. PMID 22224673.
- Kappos L, 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.#
- Milo R, Panitch H (February 2011). "Combination therapy in multiple sclerosis". J. Neuroimmunol. 231 (1–2): 23–31. doi:10.1016/j.jneuroim.2010.10.021. PMID 21111490.
- Luessi F, Siffrin V, Zipp F (September 2012). "Neurodegeneration in multiple sclerosis: novel treatment strategies". Expert Rev Neurother. 12 (9): 1061–76; quiz 1077. doi:10.1586/ern.12.59. PMID 23039386.
- Michael P Pender; Scott R Burrows (31 October 2014). "Epstein–Barr virus and multiple sclerosis: potential opportunities for immunotherapy". Clin Trans Immunol. 3 (e27). doi:10.1038/cti.2014.25.
- Ichiro Nakashima (December 2015). "Anti-myelin oligodendrocyte glycoprotein antibody in demyelinating diseases". Neuroimmunology. 6 (S1): 59–63. doi:10.1111/cen3.12262.
- Laura A, Eero R, Juha OR (December 2015). "Imaging neuroinflammation in multiple sclerosis using TSPO-PET". Clinical and Translational Imaging. 3 (6): 461–473. doi:10.1007/s40336-015-0147-6.
- Paul M. Matthews, Decade in review—multiple sclerosis: New drugs and personalized medicine for multiple sclerosis, Nature Reviews Neurology volume 11, pages 614–616 (2015)
- Baecher-Allan C, Kaskow B, Weiner HL (Feb 2018). "Multiple Sclerosis: Mechanisms and Immunotherapy". Neuron. 97(4): 742–768. doi:10.1016/j.neuron.2018.01.021. PMID 29470968.
- Cohen JA, Reingold SC, Polman CH, Wolinsky JS (May 2012). "Disability outcome measures in multiple sclerosis clinical trials: current status and future prospects". Lancet Neurol. 11 (5): 467–76. doi:10.1016/S1474-4422(12)70059-5. PMID 22516081.
- Geographical Clues about Multiple Sclerosis. Jonathan D. Mayer, Annals of the Association of American Geographers Vol. 71, No. 1 (Mar., 1981), pp. 28-39 Published by: Taylor & Francis, Ltd. on behalf of the Association of American Geographers
- Baranzini SE (June 2011). "Revealing the genetic basis of multiple sclerosis: are we there yet?". Current Opinion in Genetics & Development. 21 (3): 317–24. doi:10.1016/j.gde.2010.12.006. PMC . PMID 21247752.
- Sawcer S.; Hellenthal G.; Pirinen M.; Spencer C.C.A.; Patsopoulos N. A.; Moutsianas L.; et al. (2011). "Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis". Nature. 476 (7359): 214–219. Bibcode:2011Natur.476..214T. doi:10.1038/nature10251. PMC . PMID 21833088.
- Mutation Identified as Genetic Marker for Multiple Sclerosis, Labmedica International staff writers 
- Frischer J.M.; Bramow S.; Dal-Bianco A.; Lucchinetti C.F.; Rauschka H.; et al. (2009). "The relation between inflammation and neurodegeneration in multiple sclerosis brains". Brain. 132 (5): 1175–89. doi:10.1093/brain/awp070. PMC .
- Fleischer Vinzenz; et al. (2016). "Metabolic Patterns in Chronic MS Lesions and Normal-appearing White Matter: Intraindividual Comparison by Using Two-Dimensional MR Spectroscopic Imaging". Neuroradiology. 281 (2): 536–543. doi:10.1148/radiol.2016151654.
- 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
- Zurawski Jonathan, Lassmann Hans, Bakshi Rohit (2016). "Use of Magnetic Resonance Imaging to Visualize Leptomeningeal Inflammation in Patients With Multiple Sclerosis: A Review". JAMA Neurol. 74 (1): 100–109. doi:10.1001/jamaneurol.2016.4237. PMID 27893883.
- Lee Mendoza R (2014). "Pharmacoeconomics and clinical trials in multiple sclerosis: baseline data from the European Union". Journal of Public Health. 22 (3): 211–218. doi:10.1007/s10389-013-0561-z.
- clinicaltrial.gov CLARITY Study. Retrieved on 25 November 2007.
- Merck Serono's Phase III multiple sclerosis trial meets endpoint
- Giovannoni, Gavin; Comi, Giancarlo; Cook, Stuart; Rammohan, Kottil; Rieckmann, Peter; Sørensen, Per Soelberg; Vermersch, Patrick; Chang, Peter; Hamlett, Anthony; Musch, Bruno; Greenberg, Steven J. (2010). "A Placebo-Controlled Trial of Oral Cladribine for Relapsing Multiple Sclerosis". New England Journal of Medicine. 362 (5): 416–26. doi:10.1056/NEJMoa0902533. PMID 20089960.
- Merck KGaA Submits Application For Cladribine Tablets As Multiple Sclerosis Therapy In Europe 
- Hope for MS pill after cladribine and fingolimod trials, BBC News;Published 20-January-2010
- Press release
- Opexa shares lose most of value on study data
- Opexa Therapeutics Announces Completion Of Mid Study Descriptive Analysis On Phase IIb Trial Of Tovaxin
- Tovaxin phase III announced http://www.opexatherapeutics.com/?page=release§ion=news&article=010511
- Exploring the Efficacy and Safety of Siponimod in Patients With Secondary Progressive Multiple Sclerosis (EXPAND)
- Significant Advances in Multiple Sclerosis Treatment http://www.pharmacytimes.com/publications/specialty-pt/2011/February-2011/SPT-NPP-0211
- Gladstone DE, Zamkoff KW, Krupp L, et al. (2006). "High-dose cyclophosphamide for moderate to severe refractory multiple sclerosis". Arch. Neurol. 63 (10): 1388–93. doi:10.1001/archneur.63.10.noc60076. PMID 16908728.
- Zipoli V, Portaccio E, Hakiki B, Siracusa G, Sorbi S, Pia Amato M (2007). "Intravenous mitoxantrone and cyclophosphamide as second-line therapy in multiple sclerosis: An open-label comparative study of efficacy and safety". Journal of the Neurological Sciences. 266 (1–2): 25–30. doi:10.1016/j.jns.2007.08.023. PMID 17870094.
- Krishnan C, Kaplin AI, Brodsky RA, et al. (June 2008). "Reduction of Disease Activity and Disability With High-Dose Cyclophosphamide in Patients With Aggressive Multiple Sclerosis". Arch. Neurol. 65 (8): 1044–51. doi:10.1001/archneurol.65.8.noc80042. PMC . PMID 18541787.
- Chataway, J (2014). "Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial". The Lancet. 383 (9936): 2213–2221. doi:10.1016/s0140-6736(13)62242-4. PMID 24655729.
- Opexa Initiates Late Stage Clinical Study of Tcelna in Patients with Secondary Progressive Multiple Sclerosis 
- de Araújo EA, de Freitas MR (June 2008). "Benefit with methylprednisolone in continuous pulsetherapy in progressive primary form of multiple sclerosis: study of 11 cases in 11 years". Arq Neuropsiquiatr. 66 (2B): 350–3. doi:10.1590/S0004-282X2008000300013. PMID 18641870.
- Killestein J, Kalkers NF, Polman CH (June 2005). "Glutamate inhibition in MS: the neuroprotective properties of riluzole". J Neurol Sci. 233 (1–2): 113–5. doi:10.1016/j.jns.2005.03.011. PMID 15949499.
- Gironi M, Martinelli-Boneschi F, Sacerdote P, Solaro C, Zaffaroni M, Cavarretta R, Moiola L, Bucello S, Radaelli M, Pilato V, Rodegher M, Cursi M, Franchi S, Martinelli V, Nemni R, Comi G, Martino G (2008). "A pilot trial of low-dose naltrexone in primary progressive multiple sclerosis". Multiple Sclerosis. 14 (8): 1076–83. doi:10.1177/1352458508095828. PMID 18728058.
- Gajofatto A, Turatti M, Benedetti MD (2016). "Primary progressive multiple sclerosis: current therapeutic strategies and future perspectives". Expert Rev Neurother: 1–14. doi:10.1080/14737175.2017.1257385. PMID 27813441.
- Castro-Borrero Wanda; et al. (2012). "Current and emerging therapies in multiple sclerosis: a systematic review". Therapeutic Advances in Neurological Disorders. 5 (4): 205–220. doi:10.1177/1756285612450936. PMC .
- Statin may slow progressive MS
- Wang, Z (2016). "Nuclear Receptor NR1H3 in Familial Multiple Sclerosis". Neuron. 90 (5): 948–954. doi:10.1016/j.neuron.2016.04.039. PMC . PMID 27253448.
- First Oral Treatment For Highly Active Relapsing Remitting Multiple Sclerosis Provides New Choice For UK Patients Failing On Injections, 
- Weiner HL, Cohen JA (April 2002). "Treatment of multiple sclerosis with cyclophosphamide: critical review of clinical and immunologic effects". Mult. Scler. 8 (2): 142–54. doi:10.1191/1352458502ms790oa. PMID 11990872.
- Carlson NG, Rose JW (2013). "Vitamin D as a clinical biomarker in multiple sclerosis". Expert Opin Med Diagn (Review). 7 (3): 231–42. doi:10.1517/17530059.2013.772978. PMID 23480560.
- Wootla B, Eriguchi M, Rodriguez M (2012). "Is multiple sclerosis an autoimmune disease?". Autoimmune Dis. 2012: 969657. doi:10.1155/2012/969657.
- Buck Dorothea; Hemmer Bernhard (2014). "Biomarkers of treatment response in multiple sclerosis". Expert Review of Neurotherapeutics. 14 (2): 165–172. doi:10.1586/14737175.2014.874289. PMID 24386967.
- Comabella Manuel; Montalban Xavier (2014). "Body fluid biomarkers in multiple sclerosis". The Lancet Neurology. 13 (1): 113–126. doi:10.1016/S1474-4422(13)70233-3. PMID 24331797.
- Zahra Salehi, Rozita Doosti, Masoumeh Beheshti, Ehsan Janzamin, Mohammad Ali Sahraian, Maryam Izad, Differential Frequency of CD8+ T Cell Subsets in Multiple Sclerosis Patients with Various Clinical Patterns, July 28, 2016, https://dx.doi.org/10.1371/journal.pone.0159565
- Sarah Y et al. An In Vitro Diagnostic for Multiple Sclerosis Based on C-peptide Binding to Erythrocytes, EBioMedicine, August 2016, doi:10.1016/j.ebiom.2016.07.036
- Lehmann-Werman et al. Identification of tissue-specific cell death using methylation patterns of circulating DNA. Proc Natl Acad Sci U S A. 2016 Mar 29;113(13):E1826-34. doi:10.1073/pnas.1519286113. Epub 2016 Mar 14
- Hammack, B. N.; Fung, K. Y.; Hunsucker, S. W.; Duncan, M. W.; Burgoon, M. P.; Owens, G. P.; Gilden, D. H. (Jun 2004). "Proteomic analysis of multiple sclerosis cerebrospinal fluid". Mult Scler. 10 (3): 245–60. doi:10.1191/1352458504ms1023oa. PMID 15222687.
- Zbysek, Pavelek (2016). "Proteomic analysis of cerebrospinal fluid for relapsing-remitting multiple sclerosis and clinically isolated syndrome". Biomedical Reports. doi:10.3892/br.2016.668.
- Serafeim, Katsavos; Anagnostouli Maria (2013). "Biomarkers in Multiple Sclerosis: An Up-to-Date Overview". Multiple Sclerosis International. 2013: 340508. doi:10.1155/2013/340508.
- Joakim Bergman et al. Neurofilament light in CSF and serum is a sensitive marker for axonal white matter injury in MS. August 2, 2016 doi:10.1212/NXI.0000000000000271, Neurol Neuroimmunol Neuroinflamm October 2016 vol. 3 no. 5 e271
- Klistornera Alexander; et al. (2016). "Diffusivity in multiple sclerosis lesions: At the cutting edge?". NeuroImage Clinical. 12: 219–226. doi:10.1016/j.nicl.2016.07.003.
- Spadaro Melania; et al. (2016). "Autoantibodies to MOG in a distinct subgroup of adult multiple sclerosis". Neurol Neuroimmunol Neuroinflamm. 3 (5): e257. doi:10.1212/NXI.0000000000000257.
- Happe, LE (Nov 2013). "Choosing the best treatment for multiple sclerosis: comparative effectiveness, safety, and other factors involved in disease-modifying therapy choice". Am J Manag Care. 19 (17 Suppl): S332–42. PMID 24494634.
- Esposito et al., Gene Variant Associated with Non-Response to Interferon β, Annals of Neurology on April 25, 2015
- Parnell, GP (Jan 2014). "The autoimmune disease-associated transcription factors EOMES and TBX21 are dysregulated in multiple sclerosis and define a molecular subtype of disease". Clin Immunol. 151 (1): 16–24. doi:10.1016/j.clim.2014.01.003. PMID 24495857.
- Sandra Hellberg et al. Dynamic Response Genes in CD4+ T Cells Reveal a Network of Interactive Proteins that Classifies Disease Activity in Multiple Sclerosis, Cell, Volume 16, Issue 11, p2928–2939, 13 September 2016
- Warabi Yoko; et al. (2016). "Spinal cord open-ring enhancement in multiple sclerosis with marked effect of fingolimod". Images in Neuroimmunology. doi:10.1111/cen3.12322View (inactive 2017-02-24).
- Gross; et al. (2016). "Distinct pattern of lesion distribution in multiple sclerosis is associated with different circulating T-helper and helper-like innate lymphoid cell subsets". Mult Scler. doi:10.1177/1352458516662726. PMID 27481205.
- Mark C Johnson et al. Distinct T cell signatures define subsets of multiple sclerosis patients" The Journal of Immunology May 1, 2016 vol.196 (1 Supplement) 54.19
- while others were irresponsive
- United States patent US9267945
- Esposito F et al. A pharmacogenetic study implicates SLC9A9 in multiple sclerosis disease activity. Ann Neurol. 2015; doi:10.1002/ana.24429. PMID 25914168
- Hegen, Harald; et al. (2016). "Cytokine profiles show heterogeneity of interferon-β response in multiple sclerosis patients". Neurol Neuroimmunol Neuroinflamm. 3 (2): e202. doi:10.1212/NXI.0000000000000202.
- Matas et al. MxA mRNA expression as a biomarker of interferon beta response in multiple sclerosis patients. J Neuroimmunol. 2016 Feb 15;291:73-7. doi:10.1016/j.jneuroim.2015.12.015. Epub 2015 Dec 30.
- Miyazaki, T; Nakajima, H; Motomura, M; Tanaka, K (2016). "A case of recurrent optic neuritis associated with cerebral and spinal cord lesions and autoantibodies against myelin oligodendrocyte glycoprotein relapsed after fingolimod therapy". Clinical Neurology. 56 (4): 265–269. doi:10.5692/clinicalneurol.cn-000756. PMID 27010093.