The New York Academy of Sciences
Multiple Sclerosis: Diagnostic and Treatment Frontiers
Posted January 13, 2017
Multiple sclerosis (MS) is an unpredictable autoimmune disorder with multiple, often disabling neurologic symptoms. Although many patients live nearly normal life spans, the consequences for quality of life can be profound. MS has a strong genetic component, but as yet unknown environmental factors are thought to trigger the disorder in susceptible individuals. In recent years, clinical and basic science researchers have made inroads into understanding this challenging disorder, with the hopes of improving clinicians' abilities to diagnose, assess risk, and select individualized treatment regimens for their patients. Multiple new therapies have been developed and approved, and more are on the way. On June 28th, 2016, the Academy presented Multiple Sclerosis: Diagnostic and Treatment Frontiers featuring a discussion of the current state of and future prospects for research on MS, including cutting edge genetics approaches and novel insights into the molecular pathophysiology of this complex disease.
Use the tabs above to find a meeting report and multimedia from this event.
Presentations available from:
Barry G. Arnason, MD (University of Chicago)
Giancarlo Comi, MD, (Università Vita-Salute San Raffaele)
Philip L. De Jager, MD, PhD (Brigham and Women's Hospital, Harvard University; Broad Institute of Harvard and Massachusetts Institute of Technology)
Susan A. Gauthier, DO, MPH (Weill Cornell Medical College)
David A. Hafler, MD, MSc (Yale School of Medicine; Broad Institute of Harvard and Massachusetts Institute of Technology)
Fred D. Lublin, MD (Icahn School of Medicine at Mount Sinai)
Darin Okuda, MD (University of Texas Southwestern Medical Center)
Eric Thouvenot, MD, PhD (Université Montpellier)
How to cite this eBriefing
The New York Academy of Sciences. Multiple Sclerosis: Diagnostic and Treatment Frontiers. Academy eBriefings. 2016. Available at: www.nyas.org/MS2016-eB
- 00:011. Panel discussion introduction by Fred D. Lublin
- 01:222. Giancarlo Comi on the timing of repair strategies
- 05:413. Susan A. Gauthier on repair
- 09:084. Giancarlo Comi on the right intervention and target
- 11:385. David Hafler on what worked and what didn't
- 14:226. Susan A. Gauthier on the next big thing in MRI and PET scanning biomarkers
- 16:227. Final thoughts by each panelis
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
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Barry G. Arnason, MD
Barry G. Arnason is the James Nelson and Anna Louise Raymond Professor of Neurology at the University of Chicago. He has studied immunologic aspects of Multiple Sclerosis (MS) for 5 decades including T-cell function and nervous system-immune system interactions, both in MS patients and in animal models. He has also participated in numerous clinical trials including the pivotal trial of Betaseron, the first drug to be approved for the treatment of MS. He was the recipient of the 2014 John Dystel prize for contributions to MS research. He is the author or co-author of close to 400 scientific publications, with the majority related to MS.
Giancarlo Comi, MD
Giancarlo Comi is a professor of neurology, chairman of the Department of Neurology, and director of the Institute of Experimental Neurology at Vita-Salute San Raffaele University, Milan, Italy. He is also president of the European Charcot Foundation, a member of the Board of Administration of the Italian Multiple Sclerosis Foundation and of the Scientific Committee of Associazione Italiana Sclerosi Multipla, co-chair of the Scientific Steering Committee of the Progressive MS Alliance, and a fellow of the European Academy of Neurology. He has served as a past president of the European Neurology Society, the Italian Society of Clinical Neurophysiology, and the Italian Society of Neurology.
Comi sits on the executive boards of various scientific associations and on the editorial boards of Clinical Investigation, European Journal of Neurology and Multiple Sclerosis. He is also the associate editor of Neurological Sciences. Most recently, he was awarded the Gold Medal of 'Benemeranza Civica' from the City of Milan.
Philip L. De Jager, MD, PhD
Philip De Jager is an associate professor of neurology at Harvard Medical School and director of the program in translational neuropsychiatric genomics within the Ann Romney Center for Neurologic Diseases in the Department of Neurology at Brigham and Women's Hospital. He is the first incumbent of the Steven R. and Kathleen P. Haley Distinguished Chair for the Neurosciences and a practicing clinical neuroimmunologist.
The goal of De Jager's work as a clinician–scientist is to apply modern methods of neuroimmunology, statistical genetics and computational biology to first delineate and then intervene in the sequence of events leading from health to neurodegenerative diseases.
Susan A. Gauthier, DO, MPH
Susan Gauthier received her DO degree from the Philadelphia College of Osteopathic Medicine. After completing her neurology residency at the Boston University Medical Center where she served as chief resident, Gauthier was a recipient of a three year National Multiple Sclerosis Society Clinical Trial Training Fellowship in which she completed at the Brigham and Women's Hospital in Boston and received a MPH from the Harvard School of Public Health. She is currently a member of the clinical staff at the Judith Jaffe Multiple Sclerosis Center at Weill Cornell Medical College, where she is an associate professor of clinical neurology and the director of clinical research. Her research is focused on the translation of early-stage imaging techniques to explore biological mechanisms at play in multiple sclerosis with a specific interest in quantification of myelin and inflammation.
Brooke Grindlinger, PhD
The New York Academy of Sciences
David A. Hafler, MD, MSc
David Hafler is the William S. and Lois Stiles Edgerly Professor, chair of the neurology department, and professor of immunobiology at Yale School of Medicine, and neurologist-in-chief of the Yale–New Haven Hospital. He graduated from Emory University with combined BS and MSc degrees in biochemistry and received his MD from the University of Miami School of Medicine. Hafler was trained in immunology at the Rockefeller University and at Harvard. He later held the Breakstone Professorship of Neurology at Harvard and was a founding associated member of the Broad Institute at MIT. In 2009, he moved to Yale. Hafler is a co-founder of the International MS Genetic Consortium, a group that identified the genes causing MS. He has been elected to membership in the American Society of Clinical Investigation, the Alpha Omega Society, and was a Weaver Scholar of the National Multipole Sclerosis Society.
Fred D. Lublin, MD
Fred D. Lublin is the Saunders Family Professor of Neurology at The Icahn School of Medicine at Mount Sinai and director of the Corinne Goldsmith Dickinson Center for Multiple Sclerosis at that institution. Lublin received his medical degree from Jefferson Medical College, Philadelphia, PA. He completed his internship in Internal Medicine from the Bronx Municipal Hospital, Albert Einstein Medical Center, and his residency at the New York Hospital, Cornell Medical Center.
Lublin and his colleagues were among the first in the country involved with studies of Interferon beta-1b, which was approved by the Food & Drug Administration in 1993 to treat the relapsing-remitting form of Multiple Sclerosis. He is a member of the WHO Advisory Group for the Revision of ICD-10 Diseases of the Nervous System working group on demyelinating diseases of the central nervous system. He is a co-chief editor of the journal Multiple Sclerosis and Related Disorders.
Darin Okuda, MD
Darin Okuda is a clinician-scientist and associate professor specializing in multiple sclerosis within the Department of Neurology and Neurotherapeutics at UT Southwestern Medical Center. Okuda completed his undergraduate, graduate, and medical education at the University of Hawaii. He completed his residency training at the Barrow Neurological Institute and fellowship training in neuroimmunology at the University of California, San Francisco Multiple Sclerosis Center. Within UT Southwestern, he currently serves as director of the Multiple Sclerosis and Neuroimmunology Imaging Program, director of Neuroinnovation, and the deputy director of the MS Program and Clinical Center for Multiple Sclerosis.
Okuda's current research focuses on improving our diagnostic capabilities in multiple sclerosis. He currently directs scientific strategies within the Radiologically Isolated Syndrome Consortium (RISC), a multi-national working group, involving 10 countries, aimed at advancing the science in the very early forms of multiple sclerosis.
Eric Thouvenot, MD, PhD
Eric Thouvenot entered the Ecole Normale Supérieure, Paris, France, and then the Faculté de Médecine Pitié-Salpêtrière. Resident in Montpellier Hospitals from 2000, he graduated MD in 2005 and PhD in 2009 at the Université Montpellier. Professor of neurology and head of the neurology department at Nîmes University Hospital, France, Thouvenot has received several grants from pharmaceutical companies (Novartis, Biogen-Idec, Genzyme) and charities and coordinates a French national clinical research project aimed at evaluating the clinical efficacy of Vitamin D to reduce conversion to MS after a Clinically Isolated Syndrome in 316 patients. He performs his basic research at the Institut de Génomique Fonctionnelle (Université Montpellier, France), where he actively participated in the implementation of the proteomics platform. He has developed several multicentric biomarker studies in France and participated in the European biomarker consortium.
Angela Vidal-Jordana, MD
Multiple Sclerosis Centre of Catalonia (Cemcat), Vall d'Hebron University Hospital
Angela Vidal-Jordana obtained her medical degree at the Universitat Autònoma de Barcelona in 2005. She specialized in the neurology department of Santa Creu i Sant Pau University Hospital (Barcelona). From 2011 to 2013, she received a research-training contract from the Spanish Ministry of Health at the Multiple Sclerosis Centre of Catalonia (Cemcat) and Vall d'Hebron University Hospital, and she continued working as a neurologist in the same institution afterwards. As part of this contract, she held a six-month research fellowship in neurology–neurinmunology at Johns Hopkins Hospital. Since joining Cemcat, she has participated as an investigator in numerous research projects. During this time, she also gained experience in optical coherence tomography and non-conventional brain MRI techniques to be applied in patients with multiple sclerosis. She is currently writing her doctoral thesis. Her areas of scientific interest are non-conventional neuroimaging techniques, mainly volumetric analysis, and optical coherence tomography in patients with multiple sclerosis.
Megan Stephan studied transporters and ion channels at Yale University for nearly two decades before giving up the pipettor for the pen. She specializes in covering research at the interface between biology, chemistry, and physics. Her work has appeared in The Scientist and Yale Medicine. Stephan holds a PhD in biology from Boston University.
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.
Barry G. Arnason, Keynote Speaker
University of Chicago
Multiple Sclerosis Center of Catalonia (Cemcat), Vall d'Hebron University Hospital
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.
Most patients with RRMS progress to secondary progressive (SP) MS, which is characterized by progressively increasing disability with fewer discernable relapses and remissions. Several lines of evidence suggest that progressive MS involves widespread activation of microglia. Microglia carry a number of neurotransmitter receptors, including beta-2 adrenergic receptors. Beta-2 adrenergic agonists, including terbutaline and albuterol, have shown therapeutic effects in animal models of SPMS. However, most beta-2 adrenergic agonists do not cross the blood brain barrier well, with the exception of clenbuterol, which is banned in the U.S. and European Union because it improves motor performance in athletes. Arnason suggested that a beta 2-agonist that crosses the blood-brain barrier would be of potential interest as an experimental therapy for SPMS.
Lastly, Arnason summarized recent studies of neuropathic pain in MS, which appears to involve the activities of at least six neurotransmitters, eight receptors, pro-inflammatory cytokines, neurotransmitter transporters, and neurotrophins. These findings suggest that combination therapies that target multiple mechanisms may be most effective at relieving neuropathic pain from MS. Such an approach might be safer than using a single therapy because it would involve lower doses of each individual drug.
Parsing current treatment options
Angela Vidal-Jordana of Vall d'Hebron University Hospital, Barcelona, Spain described the expansion of therapeutic options for RRMS in recent years. While having more treatment options allows for more individualized management, neurologists must understand the unique risk/benefit profile of each medication to work with patients towards optimal treatment decisions. All currently available RRMS therapies have shown efficacy in reducing clinical disease activity, but they differ considerably in toxicity profiles and monitoring requirements. Therapeutic decision-making must take into account disease severity, the efficacy and safety profiles of each therapeutic agent, and patients' preferences and treatment expectations.
Vidal-Jordana described the natural history of RRMS and the evolution of treatment options with the case of patient who was first treated for MS in 2001. At the time, available therapies for RRMS were three forms of interferon-beta, which reduces relapse rate and slows disability progression, and glatiramer acetate, which also reduces relapse rate but has no effect on disability. This patient elected for initial treatment with glatiramer acetate to avoid the flu-like symptoms associated with interferons. However, after developing five new MS lesions in the course of a year, she switched to interferon beta.
In 2007, the patient wished to become pregnant and stopped her therapy until she had a postpartum relapse, after which she resumed interferon beta treatment. Within a year, brain MRI showed 10 new MS lesions, indicating a suboptimal treatment response and a high risk of progressive disease. Her options now included therapies that were not available when she was first diagnosed, including the monoclonal antibody natalizumab and the immunomodulatory agent mitoxantrone, or enrolling in a clinical trial. Natalizumab and mitoxantrone have similar efficacies in RRMS, but their toxicity profiles are quite different. Mitoxantrone is associated with high rates of serious adverse events including cardiotoxicity, leukemia, and amenorrhea. Natalizumab is associated with less serious adverse events apart from a low risk of developing a devastating brain infection known as progressive multifocal leukoencephalopathy (PML).
Vidal-Jordana described best practices for monitoring patients on natalizumab and assessing the risk of PML. PML risk is much higher in patients who carry antibodies to the JC virus (JCV). Although this patient was JCV-negative when she started on natalizumab, after four years she became JCV-positive, prompting reassessment of her treatment regimen. Discontinuing natalizumab carries a high risk of disease reactivation, and seven months after stopping treatment, she had developed 60 new brain MRI lesions. At this juncture, in 2015, she began treatment with fingolimod, which is effective but has its own set of potential toxicities that must for accounted for and monitored.
Today, a newly diagnosed patient with RRMS in the U.S. has five first-line treatment options: interferon beta, glatiramer acetate, teriflunomide, dimethyl fumarate, and fingolimod. Second-line therapies include natalizumab, alemtuzumab, and fingolimod. As this patient's case demonstrates, selecting from among these treatment options requires weighing efficacy against potential treatment toxicities and the need for monitoring, which can be quite burdensome for the patient. Neurologists must consider patient characteristics such as age, disease severity, and disability status, and work together with their patients to select treatment options with toxicities and monitoring schedules that are acceptable to the patient. Vidal-Jordana noted that the expansion of treatment options for RRMS has made treatment decisions considerably more complex but allows for more personalized, patient-centered medicine.
Fred D. Lublin
Icahn School of Medicine at Mount Sinai
David A. Hafler
Yale School of Medicine; Broad Institute of Massachusetts Institute ofTechnology and Harvard University
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.
The most recent diagnostic guidelines for MS are the 2010 Revised McDonald MS Diagnostic Criteria (MAGNIMS), which are used to distinguish between actual MS, suspected MS, and neurologic conditions that are most likely not MS. The majority of patients with MS have abnormalities that can be detected by MRI, which led to inclusion of MRI criteria in the MAGNIMS guidelines. However, MRI detection of lesions alone is not sufficient to make a diagnosis, and two or more episodes of clinical symptoms should also be documented. The presence of spinal fluid abnormalities, known as IgG oligoclonal bands, can also be used to support an MS diagnosis.
In 2013, the MS disease spectrum was reorganized into four major subtypes, based on their clinical characteristics. These are 1) clinically isolated syndrome (CIS), a single neurologic episode that appears characteristic of MS but is not diagnostic without another episode; 2) RRMS, which involves clearly defined attacks followed by periods of partial or complete remission; 3) primary progressive (PP) MS, in which the disease progresses slowly but continuously from the start without distinct relapses or remissions; and 4) SPMS, the steadily worsening disease course that is eventually experienced by most patients with RRMS. These new definitions are used by regulatory agencies to better define the MS subtypes targeted by experimental therapies in clinical trials.
MS clinical research has advanced since the release of the MAGNIMS guidelines, and new diagnostic criteria are likely to be included in the new guidelines expected in 2017. New criteria may include changes in brain volume (discussed in more detail in a subsequent talk by Susan Gauthier) as well as changes in cognitive status. Lublin said that MRI will likely continue to be used as an objective measure of MS disease severity, progression, and treatment response; however, more refined imaging techniques and/or fluid biomarkers are also needed.
The hunt for MS biomarkers
Eric Thouvenot of Université Montpellier, Montpellier, France, described research on biomarkers that might allow for an earlier MS diagnosis, specifically, biomarkers that would allow clinicians to predict earlier or later conversion from CIS to clinically definite (CD) MS. Such biomarkers would allow earlier, more individualized treatment based on patient risk of conversion. Epidemiologic research has identified numerous factors that influence the risk of conversion of CIS to CDMS, including gender, age, the presence of antibodies to Epstein-Barr virus, and serum vitamin D levels. The presence of oligoclonal bands and more than one lesion on MRI also strongly predict conversion.
Clinical research has identified a large number of candidate biomarkers for conversion in cerebrospinal fluid (CSF) of patients with MS, which largely reflect the inflammatory and neurodegenerative processes associated with the disease. Novel biomarkers include IgM oligoclonal bands in addition to the already used IgG oligoclonal bands, and molecules involved in inflammation, particularly the combination of CXCL-13, interleukin 8, and interleukin 12p40. One study found that the presence of CD5+ B cells in the CSF quadrupled the risk of early CIS to CDMS conversion. Increased levels of neurofilaments, a marker of neurodegeneration, in CSF may also be associated with conversion risk.
Novel, unbiased 'omics approaches, including proteomics and genomics, have emerged as powerful strategies to identify novel candidate biomarkers in MS. Thus far, proteomic analyses of CSF from patients with CIS have identified high levels of chitinase 3-like protein 1 (CHI3L1) as a predictor of earlier conversion to CDMS. Chitinase 3-like protein 2 and chitotriosidase are also increased in patients with MS compared with healthy controls. These molecules, which are secreted by macrophages and astrocytes, are increased in other inflammatory conditions, like rheumatoid arthritis and sarcoidosis, and in neuropsychiatric conditions like Alzheimer's disease and schizophrenia. In addition to their potential as biomarkers, these molecules and other members of their associated pathways may represent new therapeutic targets in MS.
Genetic insights into MS mechanisms
David Hafler of the Yale University School of Medicine described his work on genetic and epigenetic changes that might drive the development of MS in susceptible individuals. He and his group are identifying genetic variants that occur in people with MS, mapping these variants to cell types and transcription factors likely to be involved in MS pathophysiology, and using genome-wide association studies (GWAS) to elucidate the roles of immunologic and environmental factors in the development of MS.
MS has a strong genetic component. Relatives of patients with MS have an increased risk of developing the condition, and identical twins of patients with MS have about a 25% chance of being affected. Studies have identified hundreds of genetic variations associated with developing MS, but most have relatively weak effects on disease risk. However, by comparing these variants with those found in patients with other autoimmune diseases, researchers have been able to narrow them down to a subset of shared, and thus potentially causative mutations. Many of these genetic changes are grouped within specific signaling cascades, and most are associated with genes that regulate immune function, supporting an immunologic etiology for this disease.
Hafler and his group are mapping both genetic and epigenetic variations in patients with MS and other autoimmune diseases to specific cell types and regulatory pathways. Using a systems-based approach, they have identified single nucleotide polymorphisms (SNPs) that have a higher probability of being causal in MS because the affected genes are expressed in key immune cell types, including CD4+ and CD8+ T cells, FoxP3+ regulatory cells, B cells, and monocytes. Often these genetic variations map to binding sites for immune-related transcription factors, including NFkappaB, IRF4, Pu.1, and AP-1, and to noncoding regulatory elements, such as transcription enhancers, involved in immune system regulation. By mapping epigenetic modifications, they identified H3 lysine 27 acetylation as a marker of active promoters and enhancers in cells that participate in MS pathophysiology. These mapping efforts provide a better understanding of the immunoregulatory pathways involved in MS. Further comprehensive genetic analyses using newer methods, such as the gene-editing technique CRISPR, will be needed to identify new biomarkers and new therapeutic targets for this disorder.
Susan A. Gauthier
Weill Cornell Medical College
University of Texas Southwestern Medical Center
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.
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.
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.
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.
Philip L. De Jager
Brigham and Women's Hospital, Harvard University; Broad Institute ofHarvard and Massachusetts Institute of Technology
Giancarlo Comi, Keynote Speaker
Università Vita-Salute San Raffaele
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.
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.
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?