Multiple Sclerosis: Diagnostic and Treatment Frontiers

Resources

General

European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS)
Largest professional organization for MS treatment and research; holds yearly MS conference

ECTRIMS Tip sheet: 2010 Revised McDonald Diagnostic Criteria for MS
At-a-glance version of current MS diagnostic criteria

International Multiple Sclerosis Genetics Consortium
Research consortium for scientists working on MS and MS-related diseases

Magnetic Resonance in Multiple Sclerosis (MAGNIMS)
European network of academics that share a common interest in the study of MS using MRI

Multiple Sclerosis Discovery Forum
Online community with news and resources intended to accelerate advances in MS research

Multiple Sclerosis Discovery Forum Drug Development Pipeline
Comprehensive information on compounds under investigation for treatment of MS

National Multiple Sclerosis Society
US nonprofit organization dedicated to supporting patients, clinicians, and researchers in MS

National Multiple Sclerosis Society Professional Resource Center: Managing MS: Disease Modification
Comprehensive information on the thirteen FDA-approved disease-modifying therapies for MS; includes information on emerging therapies

National Multiple Sclerosis Society Publications & Resources for Healthcare Professionals
One page list of resources available for professionals who treat patients with MS

Revised Recommendations of the Consortium of MS Centers Task Force for a Standardized MRI Protocol and Clinical Guidelines for the Diagnosis and Follow-Up of Multiple Sclerosis
Revised guidelines for MRI imaging of the brain and spinal cord in MS developed by an international group of neurologists and radiologists

Journal Articles

Arnason

Arnason BG, Berkovich R, Catania A, et al. 2013. Mechanisms of action of adrenocorticotropic hormone and other melanocortins relevant to the clinical management of patients with multiple sclerosis. Mult Scler. 19: 130-6.

Jensen MA, Yanowitch RN, Reder AT, et al. 2010. Immunoglobulin-like transcript 3, an inhibitor of T cell activation, is reduced on blood monocytes during multiple sclerosis relapses and is induced by interferon beta-1b. Mult Scler. 16: 30-8.

Comi

Baroncini D, Ghezzi A, Annovazzi PO, et al. 2016. Natalizumab versus fingolimod in patients with relapsing-remitting multiple sclerosis non-responding to first-line injectable therapies. Mult Scler. 22: 1315-26.

Comi G, Freedman MS, Kappos L, et al. 2016. Pooled safety and tolerability data from four placebo-controlled teriflunomide studies and extensions. Mult Scler Relat Disord. 5: 97-104.

Iaffaldano P, Lucisano G, Pozzilli C, et al. 2015. Fingolimod versus interferon beta/glatiramer acetate after natalizumab suspension in multiple sclerosis. Brain. 138: 3275-86.

Montalban X, Comi G, Antel J, et al. 2015. Long-term results from a phase 2 extension study of fingolimod at high and approved dose in relapsing multiple sclerosis. J Neurol. 262: 2627-34.

O'Connor P, Comi G, Freedman MS, et al. 2016. Long-term safety and efficacy of teriflunomide: Nine-year follow-up of the randomized TEMSO study. Neurology. 86: 920-30.

De Jager

Bove R, White CC, Giovannoni G, et al. 2015. Evaluating more naturalistic outcome measures: A 1-year smartphone study in multiple sclerosis. Neurol Neuroimmunol Neuroinflamm. 2: e162.

Esposito F, Sorosina M, Ottoboni L, et al. 2015. A pharmacogenetic study implicates SLC9a9 in multiple sclerosis disease activity. Ann Neurol. 78: 115-27.

Replogle JM, De Jager PL. 2015. Epigenomics in translational research. Transl Res. 165: 7-11.

Xia Z, White CC, Owen EK, et al. 2016. Genes and environment in multiple sclerosis project: a platform to investigate multiple sclerosis risk. Ann Neurol. 79: 178-89.

Gauthier

Chen W, Gauthier SA, Gupta A, et al. 2014. Quantitative susceptibility mapping of multiple sclerosis lesions at various ages. Radiology. 271: 183-92.

Gauthier SA, Berger AM, Liptak Z, et al. 2009. Rate of brain atrophy in benign vs early multiple sclerosis. Arch Neurol. 66: 234-7.

Gauthier SA, Glanz BI, Mandel M, et al. 2009. Incidence and factors associated with treatment failure in the CLIMB multiple sclerosis cohort study. J Neurol Sci. 284: 116-9.

Gauthier SA, Mandel M, Guttmann CR, et al. 2007. Predicting short-term disability in multiple sclerosis. Neurology. 68: 2059-65.

Kuceyeski AF, Vargas W, Dayan M, et al. 2015. Modeling the relationship among gray matter atrophy, abnormalities in connecting white matter, and cognitive performance in early multiple sclerosis. AJNR Am J Neuroradiol. 36: 702-9.

Hafler

Axisa PP, Hafler DA. 2016. Multiple sclerosis: genetics, biomarkers, treatments. Curr Opin Neurol. 29: 345-53.

Cao Y, Goods BA, Raddassi K, et al. 2015. Functional inflammatory profiles distinguish myelin-reactive T cells from patients with multiple sclerosis. Sci Transl Med. 7: 287ra74.

Farh KK, Marson A, Zhu J, et al. 2015. Genetic and epigenetic fine mapping of causal autoimmune disease variants. Nature. 518: 337-43.

Housley WJ, Fernandez SD, Vera K, et al. 2015. Genetic variants associated with autoimmunity drive NFkappaB signaling and responses to inflammatory stimuli. Sci Transl Med. 7: 291ra93.

Housley WJ, Pitt D, Hafler DA. 2015. Biomarkers in multiple sclerosis. Clin Immunol. 161: 51-8.

Kofler DM, Farkas A, von Bergwelt-Baildon M, et al. 2016. The link between CD6 and sutoimmunity: genetic and cellular associations. Curr Drug Targets. 17: 651-65.

Marson A, Housley WJ, Hafler DA. 2015. Genetic basis of autoimmunity. J Clin Invest. 125: 2234-41.

Lublin

Katz Sand IB, Lublin FD. 2013. Diagnosis and differential diagnosis of multiple sclerosis. Continuum (Minneap Minn). 19: 922-43.

Lublin FD. 2012. Disease activity free status in MS. Mult Scler Relat Disord. 1: 6-7.

Lublin FD. 2014. New multiple sclerosis phenotypic classification. Eur Neurol. 72 Suppl 1: 1-5.

Lublin FD, Reingold SC, Cohen JA, et al. 2014. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology. 83: 278-86.

Polman CH, Reingold SC, Banwell B, et al. 2011. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 69: 292-302.

Okuda

Kantarci OH, Lebrun C, Siva A, et al. 2016. Primary progressive multiple sclerosis evolving from radiologically isolated syndrome. Ann Neurol. 79: 288-94.

Okuda DT. 2016. Incidental lesions suggesting multiple sclerosis. Continuum (Minneap Minn). 22: 730-743.

Okuda DT, Melmed K, Matsuwaki T, et al. 2014. Central neuropathic pain in MS is due to distinct thoracic spinal cord lesions. Ann Clin Transl Neurol. 1: 554-61.

Okuda DT, Mowry EM, Cree BA, et al. 2011. Asymptomatic spinal cord lesions predict disease progression in radiologically isolated syndrome. Neurology. 76: 686-92.

Okuda DT, Siva A, Kantarci O, et al. 2014. Radiologically isolated syndrome: 5-year risk for an initial clinical event. PLoS One. 9: e90509.

Thouvenot

Hinsinger G, Galeotti N, Nabholz N, et al. 2015. Chitinase 3-like proteins as diagnostic and prognostic biomarkers of multiple sclerosis. Mult Scler. 21: 1251-61.

Renard D, Castelnovo G, Bouly S, et al. 2015. Cortical abnormalities on MRI: what a neurologist should know. Pract Neurol. 15: 257-65.

Vidal-Jordana

Perez-Miralles FC, Sastre-Garriga J, Vidal-Jordana A, et al. 2015. Predictive value of early brain atrophy on response in patients treated with interferon beta. Neurol Neuroimmunol Neuroinflamm. 2: e132.

Tur C, Tintore M, Vidal-Jordana A, et al. 2013. Risk acceptance in multiple sclerosis patients on natalizumab treatment. PLoS One. 8: e82796.

Tur C, Tintore M, Vidal-Jordana A, et al. 2012. Natalizumab discontinuation after PML risk stratification: outcome from a shared and informed decision. Mult Scler. 18: 1193-6.

Vidal-Jordana A, Sastre-Garriga J, Perez-Miralles F, et al. 2016. Brain volume loss during the first year of interferon-beta treatment: baseline inflammation and tissue-specific volume dynamics. J Neuroimaging. 26(5): 532-8.

Vidal-Jordana A, Sastre-Garriga J, Rovira A, et al. 2015. Treating relapsing-remitting multiple sclerosis: therapy effects on brain atrophy. J Neurol. 262: 2617-26.

Vidal-Jordana A, Tintore M, Tur C, et al. 2015. Significant clinical worsening after natalizumab withdrawal: predictive factors. Mult Scler. 21: 780-5.

Multiple sclerosis (MS) is an autoimmune disorder in which the body's immune system attacks myelinated nerve axons in the central nervous system (CNS). These unpredictable attacks create demyelinated lesions, or plaques, which slow or halt nerve conduction. The attacks lead to disabling symptoms that correspond to areas of the CNS where neurologic function is disturbed. Symptoms can include visual disturbances, limb weakness, bladder or bowel dysfunction, pain, fatigue, and cognitive deficits. Attacks can recur over many years, severely affecting quality of life and leading to permanent disability in many cases.

The past two decades have seen the development of new methods to detect MS lesions, new diagnostic guidelines, and new disease-modifying therapies that can slow development of disability in patients with MS. While new therapies have improved prognosis for these patients, researchers continue to work towards a more permanent cure. On June 28th, 2016, MS researchers gathered at the Academy to discuss cutting edge approaches to diagnosis and treatment. Topics included research on susceptibility genes and environmental triggers that might determine who is likely to develop MS, methods to predict disease progression and risk, and identification of underlying differences that may determine which patients respond to which therapy.

Two distinguished researchers in this field, Barry Arnason and Giancarlo Comi, provided their perspectives on the future of drug development in MS in keynote presentations that bookended the symposium. Angela Vidal-Jordana presented a historical perspective on MS treatment, highlighting the complex risk/benefit trade-offs that patients and physicians must make when selecting treatments. Fred Lublin discussed current diagnostic algorithms for MS, as well as updated disease categories that have allowed for more focused research strategies. Eric Thouvenot presented recent progress in the search for biomarkers that might allow MS diagnosis at earlier stages, resulting in earlier treatment and potentially better outcomes. David Hafler and Philip de Jager described genetic approaches to understanding MS that are intended to improve diagnosis, prediction of disease course, and prediction of therapeutic response, while also providing insight into the underlying molecular pathophysiology. Susan Gauthier and Darin Okuda gave an overview of the strengths and weaknesses of magnetic resonance imaging (MRI) of the brain and spinal cord, which has emerged in recent years as a key tool in diagnosis and evaluation. Overall, these presentations highlighted that while much progress has been made over the past two decades, considerable work is needed to continue improving the lives of these patients.

Highlights

Recent insights into immunologic, inflammatory, and neurologic mechanisms underlying MS provide clues for novel therapeutic approaches.

Selecting from among available therapeutic options for MS requires carefully assessing each therapy's risks and benefits as they apply to each patient's clinical circumstances.

Strategies for unmet needs in MS

Keynote speaker Barry G. Arnason of the University of Chicago summarized recent research on MS pathophysiology that illuminates potential new targets for MS treatment.

Most patients with MS have the relapsing–remitting (RR) form, in which short episodes of neurologic deficits, or relapses, are interspersed with periods of remission. Glucocorticoids are a mainstay of therapy for RRMS. While these therapies reduce the severity of relapses, they do not prevent disease progression. In addition to their immunosuppressive properties, Arnason noted that these agents up-regulate expression of the Na/K ATPase, a membrane transport protein that maintains the electrical excitability of neurons, providing another explanation for glucocorticoid efficacy and another potential treatment target. He also suggested that mineralocorticoid receptor antagonists such as spironolactone, which is already approved to treat other conditions, could be useful in MS patients who are glucocorticoid-refractory, given the close evolutionary relationship between mineralocorticoid and glucocorticoid receptors.

Multiple lines of evidence suggest that MS remission is an active rather than a passive state. One factor involved in maintaining remission is increased cell-surface expression of immunoglobulin-like transcript-3 (ILT3), a receptor found on dendritic cells, monocytes, and macrophages. ILT3 inhibits immune responses, including the CD4+ T cells that are active in MS. Patients with active MS have low levels of ILT3, while those with stable MS have levels similar to healthy controls. ILT3 is upregulated by interferon beta-1b, an approved MS therapy. In peripheral monocytes isolated from patients with MS, this upregulation is potentiated by a number of agents including vitamin D and the beta-2 adrenergic agonist albuterol, a commonly used asthma therapy. Agents such as these could be tested as potential adjuvant therapies to lengthen remissions.

Highlights

The inclusion of MRI and new subtype definitions has considerably changed how MS is diagnosed. Diagnosis will likely continue to change with new guidelines expected in 2017.

Biomarkers that may allow clinicians to diagnosis MS early have been identified, but further validation studies are needed.

Genetic and epigenetic mapping have identified candidate genes and pathways that contribute to the underlying molecular pathophysiology of MS.

Current diagnostic paradigms in MS

Neurologic deficits such as those observed in MS can arise from a wide range of pathologic causes, and an MS diagnosis is one of exclusion. Traditionally, a clinical diagnosis of MS has required observing neurologic episodes that are separated by time—that is, occur more the once—and by space—occurring in at least two areas of the body. There should be objective evidence, and after clinical investigation, no better explanation available. Fred Lublin, of the Icahn School of Medicine at Mount Sinai in New York City, discussed refinements to this diagnostic paradigm, which have focused on developing better methods for detecting and characterizing suspected MS lesions in the CNS.

Highlights

Brain and spinal cord lesions detected by MRI can provide important diagnostic and prognostic information in MS, although the association between detected lesions and clinical symptoms is often unclear.

Clinicians using MRI lesions to diagnose and evaluate treatment efficacy in patients with MS should be aware that such lesions can be caused by other conditions and/or may reflect factors other than disease severity or progression.

The value of MRI

Susan Gauthier of Weill Cornell Medical College described the essential role that MRI plays in diagnosing, evaluating, and monitoring patients with MS. Conventional brain MRI has played a role in MS diagnosis since 2001 and can be used to identify patients with subclinical disease. However, MRI has limitations. Often, the clinical presentation does not match the locations of the lesions. Lesion morphology can also be non-specific, and it may be difficult to rule out other conditions as their cause. Nevertheless, MRI is a valuable tool in MS when correlated with a patient's clinical history and neurological findings.

MRI studies can serve as a prognostic biomarker in MS. Longitudinal studies suggest that early presence of inflammatory lesions on brain MRI correlates with the subsequent degree of neurodegeneration and long-term disability. About 74% to 85% of MS cases include spinal cord involvement, and the number of cervical spinal cord lesions and loss of cervical spinal cord volume are both independently associated with later disability. MRI analysis of spinal cord lesions can also predict CIS to CDMS conversion as well as subsequent disease subtype.

In addition to detecting CNS lesions, MRI can measure loss of brain tissue, which occurs in normal aging and is accelerated in patients with MS. Brain atrophy is thought to represent a loss of grey matter and may be associated with the cognitive deficits that occur in MS. Faster brain atrophy correlates with faster development of disability in patients as well. In general, patients with a large burden of inflammatory lesions in the brain have more atrophy, suggesting that the two are related. However, patients with similar disease duration or level of disability do not always have the same level of brain atrophy, and extent of atrophy among patients with MS overlaps substantially with that of healthy controls. Although brain atrophy can be measured using conventional MRI techniques, it requires special software and is not currently reimbursed by insurance companies. It is thus not a routine clinical tool for assessing patients with MS at this time.

Brain atrophy in a patient with long-standing RRMS. These images were taken at different levels within the brain and show the large open crevices created by brain atrophy. (Image courtesy of Susan Gauthier)

MRI can also be used to monitor treatment response in MS. A recent meta-analysis of a large number of clinical trials found that the presence of new and/or enlarging brain lesions on MRI correlates strongly with a lack of treatment effect. As a validated marker for relapse activity, MRI has been instrumental in facilitating the development and approval of multiple FDA-approved therapies for MS. Combined with clinical measures, MRI also plays an important role in defining No Evidence of Disease Activity (NEDA) in MS. MRI has also evolved as a tool to monitor for early detection of opportunistic infections like PML. Preclinical detection by MRI can improve patient survival from this infection.

Gauthier recommended that clinicians consult a recent consensus statement on standardized clinical sequences for MRI from the Consortium of MS Centers Task Force, which includes a standardized MRI protocol and guidelines for the use of MRI in diagnosis and follow-up of patients with MS.

MRI pitfalls

Darin Okuda of the University of Texas Southwestern Medical Center provided further insight on the limitations of MRI in MS. Both Gauthier and Okuda mentioned the diagnostic paradox of MRI—a patient with a heavy burden of brain lesions by MRI can have few or no neurologic symptoms. Okuda said that there are about 10 MRI attacks, i.e. the appearance of one or more new lesions, for every clinical attack of MS, suggesting that MRI is a valuable tool for detecting subclinical disease.

MRI is highly sensitive and scans can be difficult to interpret. Okuda showed many examples of lesions resulting from other conditions that looked similar to MS lesions. A patient may also have lesions caused by MS together with lesions from other conditions at the same time. Although MRI shows the location of MS lesions, the extent of underlying tissue injury is often unclear. In addition, the use of differing MRI protocols and different manufacturers' hardware can make it challenging to compare MRI studies done at different locations or times. Another limitation is that MRI studies often involve a 20% coinsurance payment, so not all patients will receive this imaging.

Conditions with brain MRI lesions that resemble those of MS. (Image courtesy of Darin Okuda)

MRI is of particular value in establishing dissemination of MS events in space, an important component of MS diagnosis. Okuda said that repeated imaging is also an important way to detect changes in the distribution, morphology, and characteristics of MS lesions over time. In patients with CIS, gradual accumulation of brain lesions correlates with long-term risk of developing CDMS as well as a risk of increased disability. Rapid increases in brain lesion volume early in the disease course are also associated with a much higher risk of having SPMS at 20 years after CIS diagnosis. Okuda also noted the correlation between spinal cord lesions and development of future disability and recommended spinal cord imaging for all patients, if possible given financial constraints. He and his colleagues have gained insights into the underlying pathophysiology of pain in patients with MS by studying spinal cord lesions.

Okuda discussed some of the challenges involved in using MRI to evaluate treatment efficacy in patients with MS. Newly observed lesions might indicate treatment failure, or they may be caused by technical differences in how the MRI is performed. New lesions might also be attributable to other conditions, including recreational drug use, hypertension, or type 2 diabetes. Increased lesion activity may also reflect disease activity that began before treatment was started or before the onset of full therapeutic effect. Clinicians should also consider that treatment may have been interrupted or that patient adherence may have been less than optimal when evaluating MRI studies for treatment response.

Back to basic science

Two junior researchers presented late-breaking abstracts describing preclinical work on MS pathophysiology. Yonghao Cao, of Yale University School of Medicine, presented his work on the heterogeneity of myelin-reactive T cells in patients with MS. He showed that these cells differ between patients with MS and healthy individuals in cytokine production, chemokine receptor expression, and RNA transcriptional profiles. This work improves our understanding of MS pathophysiology and may provide new therapeutic targets. Bridget Shafit-Zagardo, of Albert Einstein College of Medicine, presented her work on the Gas6/Axl signaling pathway, which is involved in the innate immune response. By knocking out this pathway in mice, she showed that it may play an important role in remyelination and in maintaining axonal integrity. This pathway may also represent a future therapeutic target in MS.

Highlights

The International Multiple Sclerosis Genetics Consortium is integrating genetic and clinical data into an MS model to improve diagnosis and prognosis as well as understanding of the underlying pathophysiology.

Current therapies for RRMS show good efficacy, although toxicity profiles are highly variable; effective therapies for progressive MS subtypes have yet to be developed.

An Integrative Approach

MS is highly heterogeneous, which can make it difficult to determine an individual's prognosis. Although genetic susceptibility factors for MS have been identified, there are no genetic variants that are associated with different courses of disease progression (i.e. RRMS vs PPMS) or with a patient's likelihood of responding to one of the currently available therapies. Philip de Jager, of Brigham and Women's Hospital and Harvard University, and his colleagues involved in the International Multiple Sclerosis Genetics Consortium (IMSGC), are working on integrating genetic, imaging, biometric, and immunologic data into a single analytic model to provide clinicians with this type of prognostic information and allow for more individualized patient management.

De Jager provided an update on genetic studies that shed light on MS prognosis. Available evidence suggests that gene variants involved in MS susceptibility are not involved in determining disease subtype or progression. Studies of CD4+ T cells and peripheral blood mononuclear cells show distinct gene expression patterns that divide patients with MS into two to four subgroups with differing mortality risks. Gene expression data from CD4+ T cells have also identified a patient subgroup that is more likely to convert from CIS to CDMS.

Gene expression studies can divide patients with MS into at least two subpopulations. (Image courtesy of Philip De Jager)

Many candidate genes have been identified as potentially affecting treatment response in MS. Three moderately sized GWAS studies have been published for response to interferon beta treatment, although larger confirmatory studies are needed. IMSGC researchers are working to correlate identified SNPs with MS pathophysiology by examining which SNPs occur on genes that are expressed together, and whether these genes cluster together in specific pathways that may be involved in MS. Using this method, researchers have identified groups of genes whose expression is perturbed by interferon beta treatment, or that appear to be related to brain volume changes. These gene groups will be examined for their internal relationships as well as their relationships with other groups of co-expressed genes to produce causal models of MS pathophysiology and progression.

The IMSGC is pursuing novel study designs in a wide range of areas. The MS CODES3 consortium is attempting to define more naturalistic MS outcomes measures by using cell phones to collect longitudinal data on patients' abilities to complete the Trails A test, a neuropsychological test that measures visual, motor, and cognitive function. Another study, known as Genes and Environment in MS (GEMS), will prospectively follow asymptomatic family members of patients with MS using a large variety of clinical measures. This study, which hopes to enroll 10,000 individuals, is testing whether the Genes and Environment Risk Score (GERS) can identify individuals at high risk of developing MS. Thus far, researchers have identified subtle neurologic deficits in family members with high GERS scores that are not present in those with low GERS scores. Next-generation genetics studies are also underway to identify genes involved in MS susceptibility and pathophysiology.

New Treatments on the Horizon

The final presentation, and second keynote, was given by Giancarlo Comi of Università Vita-Salute San Raffaele in Milan, Italy. Comi provided a discussion of novel and emerging therapies for relapsing-remitting and progressive forms of MS.

Comi presented clinical trial results on current and emerging therapies for RRMS, including three monoclonal antibodies, alemtuzumab, daclizumab, and ocrelizumab. Alemtuzumab, which was FDA approved in 2014, targets CD52, a protein found abundantly on B-cell and T-cell surfaces. Alemtuzumab treatment selectively depletes these cells, thus rebalancing the immune cell population. Daclizumab, which was approved in 2016, is directed against the high-affinity alpha subunit of the IL2 receptor, also known as CD25, and exerts its immunomodulatory effects primarily through natural killer (NK) cells. Ocrelizumab, which is not yet FDA approved, is directed against CD20, which is expressed on B cells. Phase 3 trials have shown that these three agents reduce annualized relapse rates by about 45% to 55% compared to interferon beta 1a, and all three have effects on brain atrophy and MRI evidence of disease activity. Comi also presented recent clinical trial results for cladribine, an antileukemic agent that reduces B-cell and CD4+ T-cell populations, and for the approved MS therapies glatiramer acetate and peg-interferon beta-1a.

Comi said that the overall goal of RRMS treatment should be to reach NEDA, and that early, adequate, and individually risk-stratified approaches are needed to use current treatment options optimally. Each of the currently available MS therapies has its own toxicity profile, and the more efficacious agents generally have higher toxicities. He said that patients with a poorer prognosis should initially receive higher efficacy therapies even if the treatment burden, in terms of convenience, monitoring, tolerability, and safety, is high, in order to prevent permanent loss of neurologic function. This approach requires the ability to risk stratify patients with MS, which can be done using currently available clinical and epidemiologic data. This approach would be a departure from the usual step-up approach, in which less toxic therapies are tried first, followed by more toxic but potentially more effective second-line treatments.

Relationship between efficacy and treatment burden in current and emerging MS therapies. (Image courtesy of Giancarlo Comi)

Effective therapies have been much harder to come by for the progressive forms of MS. A large number of agents, some of which are effective in RRMS, have been tried but failed. These include fingolimod in PPMS and natalizumab in SPMS, both of which were anticipated to succeed based on preclinical and early clinical studies. Among older therapies, the interferons and mitoxantrone have shown limited activity in SPMS. The novel agent ocrelizumab has shown modest activity in PPMS, reducing confirmed disability progression at 12 weeks and 24 weeks of treatment. Ocrelizumab appears to be more effective in patients with active rather than stable PPMS, as defined by the presence of MRI lesions before the start of treatment.

Progressive forms of MS appear to involve somewhat different pathophysiological mechanisms than RRMS, including more prominent roles for mitochondrial dysfunction and oxidative injury. Experimental therapies that target these mechanisms include biotin, phenytoin for optic neuritis of MS, and statins. In a phase 2 trial, simvastatin significantly reduced disability rates and brain atrophy in patients with SPMS. A newer immunomodulatory therapy, laquinimod, reduced disability in patients with PPMS, but its development has been troubled by cardiovascular safety concerns. Comi suggested that other CNS cell types besides neurons and immune cells, such as microglia or astrocytes, might make more productive targets for new therapies for progressive MS.

Comi's talk was followed by a panel discussion that included himself, Fred Lublin, Barry Arnason, and Susan Gauthier. Panel members discussed three topics based on attendee's questions: optimal strategies for promoting remyelination in patients with MS, whether the mechanisms of inflammation differ in PPMS compared to RRMS, and what types of imaging are likely to emerge as important in MS in the future. Remyelination occurs in other neurologic conditions but not MS, and participants suggested that treatment of actively forming lesions, rather than stable lesions, might be more successful, particularly if the neurons involved had not had a chance to degenerate. On the topic of imaging, panelists discussed positron emission tomography (PET) molecular imaging, which could provide more sensitive and specific imaging of MS pathophysiological processes, improving diagnosis, evaluation, therapeutic monitoring, and drug discovery.

Will the use of newer, more sophisticated techniques allow the discovery of genes directly responsible for MS susceptibility and severity?

What are the differences between RRMS and PPMS at the molecular level and how do they influence disease course?

How does the underlying molecular pathophysiology of MS change with disease severity and progression?

Will it be possible to develop biomarkers that allow for a definitive diagnosis of MS rather than one of exclusion?

Will it be possible to develop biomarkers that allow MS disease severity to be assessed more objectively?

Will it be possible to develop biomarkers that predict MS disease course or response to treatment?

Can PET imaging be used to make identification of MS lesions more specific and sensitive?

Will it be possible to develop more effective treatments for progressive forms of MS?

Will it be possible to develop preventive therapies for MS that could be used in individuals who are at-risk based on their genetic background?

Will it be possible to develop therapies that reverse the course of MS?

Are there ways of reducing the toxicities associated with currently available MS therapies to improve quality of life and allow more prolonged treatment of MS patients?