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Tuesday, January 7, 2020

New multiple sclerosis treatment trial compares stem cell transplantation to best available drugs

NIH-funded study focuses on severe forms of relapsing MS.

A clinical trial has begun testing an experimental stem cell treatment against the best available biologic therapies for severe forms of relapsing multiple sclerosis (MS). The trial, sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, will compare the safety, efficacy and cost-effectiveness of the two therapeutic approaches.

MS is an autoimmune disease in which a person’s own immune cells attack the central nervous system. The experimental treatment involves using a mixture of four chemical agents to remove these immune cells. Some of the person’s own blood-forming stem cells, which were extracted before treatment, are then infused back into the individual. These cells repopulate the immune system, allowing it to reset itself so that the new immune cells no longer attack the central nervous system. This form of treatment is called autologous hematopoietic stem cell transplantation, or AHSCT. 

“For many people with MS — a chronic, debilitating, unpredictable and currently incurable disease — daily life can be a challenge,” said NIAID Director Anthony S. Fauci, M.D. “AHSCT has the potential to halt the progress of relapsing MS, eliminate the need for a person to take lifelong medication, and allow the body to partially regain function. However, we need to be certain that the benefits of this form of treatment outweigh its serious risks.”  

It is estimated that MS affects more than 2.3 million people worldwide, mostly women, including more than one million people in the United States. Symptoms of the disease vary widely and may include motor and speech difficulties, weakness, fatigue and chronic pain. The most common form of the disease is relapsing-remitting MS, which is characterized by periods of mild or no symptoms interspersed with symptom flare-ups, or relapses. Incomplete recovery from relapses often leads to increasing disability. Over years, the disease can worsen and shift to a progressive form that may also include relapses. 

The Food and Drug Administration has approved more than a dozen drugs for the treatment of relapsing forms of MS. These drugs vary in efficacy, safety and cost. For many people with severe forms of relapsing MS, first- and second-line drugs fail to adequately control the disease. Previous studies have suggested that AHSCT may be an effective and durable treatment for these individuals, but it has never been formally compared head-to-head with the available third-line drugs, which are highly effective but can have harsh side effects. AHSCT also carries the risks of serious side effects, and even death.

Given these risks and benefits, investigators aim to determine whether AHSCT is an appropriate treatment option for people with severe forms of relapsing MS who would otherwise receive one of the best available third-line biologic drugs.

The trial is called BEAT-MS (BEst Available Therapy versus autologous hematopoietic stem cell transplant for Multiple Sclerosis). It is being conducted by the NIAID-funded Immune Tolerance Network (ITN) in collaboration with the Blood and Marrow Transplant Clinical Trials Network (BMT CTN). The BMT CTN is funded by the National Heart, Lung, and Blood Institute and the National Cancer Institute, both components of NIH. Leading the trial is Jeffrey A. Cohen, M.D., a professor of neurology at the Cleveland Clinic Lerner College of Medicine and the director of the Experimental Therapeutics Program in the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic.

BEAT-MS will enroll 156 adults ages 18 to 55 years at 19 sites in the United States and the United Kingdom. Participants will be randomly assigned to receive either AHSCT or one of the best available high-efficacy biologic drugs, and then will be followed for 6 years. The neurologists who periodically examine the participants and assess their level of disability will not know which type of treatment they were assigned.

The main outcome investigators will measure is how much time elapses between a participant’s assignment to a treatment strategy and MS relapse or death from any cause, if either of these occur, during the first three years of the follow-up period. The researchers also will examine the mechanisms of action of the two treatment strategies and will compare the newly developing immune systems of participants who receive AHSCT with the immunologic features of participants who receive the best available biologic drugs. In addition, investigators will compare the effects of the two treatment strategies on other measures of disease activity and severity, cost-effectiveness in terms of health care costs and individual productivity, and participants’ quality of life.  

“We hope that BEAT-MS will clarify the best way to treat people with relapsing MS,” said Dr. Cohen. 

BEAT-MS is being sponsored by NIAID, NIH, and conducted by the ITN under award number AI109565 and by the NIAID-funded statistical and clinical coordinating center under award number AI117870. The ClinicalTrials.gov identifier for the Phase 3 study Best Available Therapy Versus Autologous Hematopoietic Stem Cell Transplant for Multiple Sclerosis (BEAT-MS) is NCT04047628 .

Additional information about the study, including how to enroll, is available at www.BEAT-MS.org .

NIAID conducts and supports research — at NIH, throughout the United States, and worldwide — to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID website .

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov .

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Is There a Cure for Multiple Sclerosis (MS)?

• Finding a Cure

Research Progress

Ms treatment options, emerging ms treatments, frequently asked questions.

There is no cure for multiple sclerosis (MS) . However, medications called disease-modifying therapies (DMTs) can help prevent MS relapses and slow the progress of the disease. And research on other experimental therapies is steadily advancing with the goals of stopping the condition, reversing the damage, and even preventing MS in the first place.

This article will discuss MS discoveries and treatments that can help people with this potentially disabling disease.

Morsa Images / Getty Images

How Close Is Science to Finding a Cure for MS?

There is tremendous hope that a cure for MS will be found one day. However, the timeline for putting an end to MS forever remains unknown.

As scientists throughout the world pursue a cure for MS, the National MS Society has named three goals, which are:

• No MS disease activity : This goal involves stopping the disease (no more disease lesions or progression) in those who are already diagnosed with MS. A lesion is an area of MS-related inflammation or damage within the brain or spinal cord.
• Reverse MS symptoms and disabilities : This goal involves finding treatments to repair myelin as well as lifestyle/rehabilitation strategies to restore normal functioning.
• No new MS diagnoses : This goal involves eliminating or reducing risk factors in those who are vulnerable to developing MS. Risk factors are triggers or exposures that may increase your chances of developing a disease.

In their search for a cure, researchers dig deep to learn everything they can about MS. The good news is that much progress has been made. Examples of this progress include:

Various factors have been identified that may make you more vulnerable to developing MS, including smoking , low vitamin D levels, and obesity in adolescence.

Research has also uncovered a possible connection between your gut microbiome (the organisms in your digestive tract) and MS development.

Lastly, around 200 genes have been identified that may contribute (typically on a small level) to MS risk.

Advances in magnetic resonance imaging (MRI) techniques to diagnose and monitor MS have been made. MRI involves the use of magnetic fields and radio waves to create three-dimensional images of the body's soft tissues.

Treatment/Rehabilitation

The emergence of targeted, highly effective DMTs has reduced the number and severity of relapses that people experience.

Moreover, the discovery of several compounds that can promote remyelination in animal models offers hope that function can be restored one day for people living with MS. Remyelination is the formation of new myelin sheaths around nerve fibers.

DMTs are "big-picture" drugs. They work to decrease the number and severity of MS relapses and slow the disease down.

There are nine classes of DMTs available. The vast majority are approved by the Food and Drug Administration (FDA) to treat relapsing forms of MS.

Relapsing MS includes:

• Relapsing-remitting MS (RRMS) : This is the most common type of MS. In RRMS, people experience worsening neurological symptoms, or relapses , that eventually go away or improve.
• Active  secondary progressive MS : People with RRMS may transition to this type. They experience gradually worsening symptoms with occasional relapses.
• Clinically isolated syndrome : This is a first-time episode of symptoms that does not yet meet the criteria for an official diagnosis of MS.

Some of the approved DMTs include:

• Mavenclad (cladribine) is taken by mouth in two yearly treatment courses. It works by temporarily decreasing the number of immune system cells.
• Vumerity (diroximel fumarate) is a pill taken twice daily by mouth that is believed to have anti-inflammatory and antioxidant properties.
• Bafiertam (monomethyl fumarate) is similar to Vumerity and is taken by mouth twice daily.
• Ponvory (ponesimod) , Mayzent (siponimod), and Zeposia (ozanimod) work by trapping white blood cells in the lymph nodes so they cannot enter the brain and spinal cord and attack myelin.
• Kesimpta  (ofatumumab) is an injectable DMT administered once monthly. It's a monoclonal antibody that targets B cells (infection-fighting cells) that have a specific CD20 marker on their surface.
• Ocrevus (ocrelizumab) is an infused DMT administered once every six months. It works similar to Kesimpta but is approved to treat both relapsing MS and primary progressive MS .

DMTs Have Unique Safety Profiles

While some side effects of DMTs are unpleasant, others are more serious, like an increased risk of infection. Be sure to carefully discuss with your MS healthcare provider whether the potential benefits of the DMT you are considering outweigh any risks involved.

Stem cell therapies and a drug called ibudilast are two emerging strategies for treating MS. Both of these therapies are experimental, meaning they are not yet approved by the Food and Drug Administration (FDA) for treating MS.

Stem Cell Therapies

Stem cells are self-replicating cells, or cells that have the unique ability to turn into multiple cell types (e.g., blood cells, nerve cells, fat cells, and bone cells). They are found in embryos and adults and are sometimes created in a laboratory. An autologous stem cell transplant uses the person's own stem cells.

Different stem cell therapies are being used or explored in MS care, including:

• An autologous hematopoietic stem cell transplant attempts to reboot a person's immune system using their own blood-forming stem cells. Research suggests this treatment is a potentially effective option for people with highly active relapsing-remitting MS not responding to DMTs.
• An autologous mesenchymal stem cell transplant involves removing a person's own mesenchymal stem cells, modifying them in a laboratory, and injecting them back into their bloodstream or spinal canal. Mesenchymal stem cells are tissue-protecting/anti-inflammatory cells found throughout your body, including in your bone marrow , fat, and dental tissues.
• An autologous   induced pluripotent stem cell-derived transplantation involves taking a person's own cells (usually skin or blood), turning them into specialized cells (including cells that make myelin) in a laboratory, and re-introducing them back into the body.

Ibudilast is an experimental oral medication that was found to slow the progression of brain shrinkage (compared to placebo) in people with primary or secondary progressive MS.

In the phase 2 clinical trial that revealed the above finding, no major safety issues were reported. However, the participants taking ibudilast did experience more depression and gastrointestinal-related side effects (e.g., nausea, diarrhea, stomach pain, vomiting) than those taking placebo.

Ibudilast works by blocking an enzyme called phosphodiesterase and has been found to protect nerve cells from damage and encourage myelin repair. It's currently used in Asia as a treatment for asthma and post-stroke dizziness.

Enrolling in a Clinical Trial

Under the guidance of your MS healthcare provider, you might consider trying an experimental therapy within the context of a clinical trial . If interested, the National MS Society allows you to search for clinical trials in your state .

As of yet, there is no cure for MS. However, experts have made significant progress in learning about the disease and developing targeted, more effective disease-modifying therapies.

Current research focuses on reducing potential risk factors, stopping disease activity, and promoting myelin repair. Two experimental MS treatments on the horizon are stem cell therapies and the oral drug ibudilast.

A Word From Verywell

The recent knowledge gained about MS, and the advances made in treatment, are encouraging. They offer hope and are a potential step forward to finding a cure for MS.

As you remain devoted to your MS care, take heart in knowing that researchers continue to work tirelessly to find a cure. This entails keeping in touch with your healthcare team, taking your medication as prescribed, and engaging in healthy lifestyle habits like getting enough sleep and maintaining a healthy weight.

MS is a complex disease, and its symptoms vary greatly from person to person. The good news is that with the right medical care, social support, healthy coping strategies, and a proactive attitude, many people with MS are able to live fulfilling, happy lives.

There is no cure for MS; however, the disease can be slowed, and disability can be delayed. Also, early detection, diagnosis, and treatment of MS with a DMT may put patients into long-term remission.

MS cannot be reversed, but it can be managed. There are numerous disease-modifying drugs available that can help decrease both relapses and disease progression.

While some people with MS experience long periods of remission, MS is a chronic (lifelong) condition that will not go away on its own.

One possible exception is those diagnosed with clinically isolated syndrome (a first-time episode of neurological symptoms). These individuals may or may not go on to develop MS.

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By Colleen Doherty, MD Dr. Doherty is a board-certified internist and writer living with multiple sclerosis. She is based in Chicago.

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• Published: 13 January 2023

Neurodegenerative disease

A neural stem-cell treatment for progressive multiple sclerosis

• Valentina Fossati   ORCID: orcid.org/0000-0003-1825-9371 1 ,
• Luca Peruzzotti-Jametti   ORCID: orcid.org/0000-0002-9396-5607 2 &
• Stefano Pluchino   ORCID: orcid.org/0000-0002-6267-9472 2  

Nature Medicine volume  29 ,  pages 27–28 ( 2023 ) Cite this article

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• Stem cells in the nervous system

A phase 1 trial using an allogeneic stem-cell-based therapy in people with progressive multiple sclerosis (MS) shows the feasibility and tolerability of the approach; rigorous evaluation of this and other regenerative strategies for MS is now urgently needed.

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REVIEW article

Therapeutic advances in multiple sclerosis.

• 1 Department of Neurosciences, University of California San Diego, San Diego, CA, United States
• 2 Department of Neurology, University of Florida, Gainesville, FL, United States

Multiple sclerosis (MS) is an autoimmune disease affecting the central nervous system that causes significant disability and healthcare burden. The treatment of MS has evolved over the past three decades with development of new, high efficacy disease modifying therapies targeting various mechanisms including immune modulation, immune cell suppression or depletion and enhanced immune cell sequestration. Emerging therapies include CNS-penetrant Bruton's tyrosine kinase inhibitors and autologous hematopoietic stem cell transplantation as well as therapies aimed at remyelination or neuroprotection. Therapy development for progressive MS has been more challenging with limited efficacy of current approved agents for inactive disease and older patients with MS. The aim of this review is to provide a broad overview of the current therapeutic landscape for MS.

Introduction

Multiple sclerosis (MS) is the most common autoimmune disease of the central nervous system (CNS) affecting >900,000 people in the United States and >2 million people worldwide ( 1 , 2 ). Epidemiologically, MS is a heterogenous disease influenced by genetic factors, such as the association with HLA-DRB1 * 15:01 , and environmental factors, including vitamin D level, obesity, smoking and Epstein Barr Virus (EBV) infection ( 3 , 4 ). The diagnosis is made when patients present with a typical clinical syndrome coupled by evidence of lesion dissemination in space and time. The revised 2017 McDonald's criteria allows for earlier diagnosis in the setting of a single clinical attack and corresponding MRI findings of symptomatic or asymptomatic, enhancing T1 or non-enhancing T2 lesions typical of MS, and/or presence of cerebrospinal fluid (CSF) specific oligoclonal bands ( 5 ). The historical clinical subtypes include clinically isolated syndrome (CIS), relapsing-remitting MS (RRMS), primary progressive MS (PPMS), and secondary progressive MS (SPMS) ( 5 ). A CIS is defined as a first demyelinating episode with features typical of an MS attack such as optic neuritis, brainstem or spinal cord lesion, but not yet fulfilling full criteria for MS. A more recent refinement of MS disease subtype classification proposed by Lublin et al. is similar with the additional caveat of modifying MS subtypes as “active” or “not active” based clinical relapse and/or MRI activity ( 6 ). There is growing evidence that phenotype in MS (relapsing vs progressive) is likely driven by “host factors” most notably patient age, with younger patients having greater frequency of relapses and older patients more likely to have progressive phenotypes ( 7 ).

Pathogenesis

Alterations in the peripheral immune system, blood brain barrier permeability, and intrinsic CNS immune cells (such as microglia) contribute to MS pathogenesis. Current therapeutic strategies target these three elements of MS pathogeny. Acute and chronic inflammation as well as neurodegeneration occur throughout the disease course, with prominence of acute inflammation in the relapsing phase of disease. The inflammatory process in MS has been studied in experimental autoimmune encephalomyelitis (EAE) animal models and pathological observations from patients with MS demonstrating the roles of both innate and adaptive immune responses ( 4 , 8 , 9 ). Innate immune cells with prominent roles in MS include myeloid-derived macrophages and microglia. Adaptive immune cells involved in MS include autoreactive CD4+ T cells, in particular Th1 cells, against myelin proteins and CD8+ cytotoxic T cells ( 10 – 12 ). Recent studies of specific T cell subtypes from MS patients demonstrated varying myelin targets that may correlate with different patterns of inflammation ( 13 ). Although B cells have not been shown to be critical for EAE in animal models, they play a key role in the pathogenesis of human MS by means of proinflammatory cytokine and chemokine production, antibody formation, and antigen presentation to T cells ( 14 ). The presence of oligoclonal bands (CSF-restricted IgG immunoglobulins) and antibody-complement depositions in MS lesions further implicate mature B cells in both relapsing and progressive forms of the disease ( 15 ). Though MS lesions are commonly recognized as focal areas of demyelination in white matter, the inflammatory injury also involves gray matter and the subpial/meningeal layers ( 9 , 16 ). Progressive MS is suspected to result from cumulative injury due to chronic inflammation and neurodegeneration stemming from multiple pathogenic mechanisms including activated microglia, leptomeningeal inflammatory infiltrates causing subpial demyelination, and mitochondrial dysfunction and oxidative injury driven by macrophages and microglia ( 17 , 18 ).

Therapeutic Goals

There are no curative treatments for MS. Given the disease heterogeneity, there is no single therapeutic target for MS. The main goal of current disease modifying therapy (DMT) is to quiet the disease by reducing inflammation, myelin injury and relapses. A meta-analysis of various DMTs demonstrated that all studied DMTs reduced relapse rate within 2 years ( 19 ). Additionally, cohort studies have demonstrated that earlier treatment with a DMT reduced onset of disability with some suggestion that earlier high-efficacy therapy may be more successful at reducing disability than traditional therapies ( 20 – 24 ). Treatments for progressive MS remain elusive and challenging, further suggesting that the pathogenesis of MS evolves from the pro-inflammatory relapsing stage to the neurodegenerative stage of the disease less responsive to immune-based therapies.

In this review, we will discuss the therapeutic advances in MS treatment over the last 30 years with a focus on new high-efficacy DMTs as well as current developments in progressive MS treatment. Figure 1 illustrates the mechanisms of different DMT groups, and Table 1 summarizes their mechanisms of action along with dosing, pivotal clinical trials, adverse effects and laboratory monitoring recommendations. Table 2 summarizes the current recommendation for DMT use in pregnancy.

Figure 1 . DMT mechanism of action.

Table 1 . Current therapeutic treatments for MS.

Table 2 . Recommendations on DMT use during pregnancy ( 25 ).

Early “Traditional” Injectable DMTS

Interferon beta.

In 1993, interferon therapy was the first FDA approved DMT for MS. Current interferon beta therapies include both subcutaneous and intramuscular formulations with different injection frequencies ranging from every other day (interferon beta-1b) to every 2 weeks (pegylated interferon beta-1a). Interferon beta is a cytokine with several functions, which include downregulation of antigen presentation, thereby suppressing T cell activity, induction of IL10, which skews the differentiation of CD4+ T cells toward a Th2 phenotype, blockade of T cell migration by decreasing adhesion molecules and matrix metalloproteinase 9 ( 26 , 27 ). Clinical trials assessing interferon therapy have shown to delay the onset of clinically definite MS in patients with CIS and reduce the severity and frequency of attacks ( 26 , 28 ). The PRISMS randomized, double-blind, placebo-controlled trial demonstrated reduced relapse rate with interferon beta-1a (1.82 in the 22 microg group, 1.73 in the 44 microg group) compared to 2.56 in the placebo group with a relative risk reduction of 27–33% ( 29 ). In the ADVANCE phase 3 randomized trial for pegylated interferon beta-1a, there was a reduced annualized relapse rate in the treatment groups (0.256 in every 2 week group, 0.288 in every 4 weeks) compared to 0.397 in the placebo group, which resulted in a hazard ratio of 0.62 (95% CI 0.40–0.97) for both the every 2 week and every 4 week groups ( 30 ).

The PRISMS-15 study evaluated long-term outcomes of 290 patients enrolled in the original PRISMS study 15 years after initial randomization, 145 of whom had data on conversion to SPMS. The conversion to SPMS were lower in patients who had higher cumulative doses of interferon than those with lower cumulative doses, and each cycle of 5 years on interferon treatment, SPMS risk was reduced by 28% (HR 0.72, 95% CI 0.60–0. 86) ( 31 ). The main side effects of interferon therapy are injection site reactions and post-injection flu-like symptoms. Long-term safety data from the PRISMS-15 study demonstrated that 9–12% patients reported serious adverse events though the details of those adverse events were not reported. The annualized relapse rate was 0.50 (95% CI 0.46–0.54) for the lower cumulative IFN dose group, and 0.37 (95% CI 0.33–0.40) for the higher cumulative IFN dose group ( 31 ).

Glatiramer Acetate

Glatiramer acetate (GA) was FDA approved in 1997 for the treatment of RRMS. It is a mixture of four amino acid polymers that bind to myelin-specific autoantibodies to reduce autoreactivity and promote a predominant Th2 phenotype ( 32 ). Although used originally to induce EAE in animal models, it was found to prevent EAE after injection of purified myelin basic protein ( 33 ). A phase III dose-comparison study demonstrated that both 20 and 40 mg GA dosing reduced the annualized relapse rate and mean number of gadolinium-enhancing lesions ( 34 ). GA has also been studied in primary progressive MS. Although a double-blind, placebo-controlled trial did not demonstrate a significant treatment effect in terms of the primary outcome of accumulated disability, it did significantly reduce T1 enhancing lesions at 1 year and T2 lesion burden at years 2–3 ( 35 ). Overall, GA is generally well-tolerated and safe to use during pregnancy ( 25 ). The main side effects include local injection reactions of the skin and more rarely panic-attack like episodes (flushing, chest pain, palpitations, dyspnea) that are usually transient and self-limiting.

Long-term outcomes for up to seven years for relapsing MS patients enrolled in the Glatiramer Acetate Low-frequency Administration (GALA) study demonstrated a 0.26 adjusted annualized relapse rate in the early-start GA group (randomized to GA in the placebo-controlled trial) compared to 0.31 in the delayed start GA group (switched to GA in the open label phase), with a risk ratio of 0.83 (95% CI 0.70–0.99, p = 0.04) with no differences between the two groups in terms of EDSS (expanded disability status scale) progression ( 36 ). The long-term safety profile was similar to those reported in the clinical trials, with the most common being injection site reactions (40%) and immediate post-injection reactions (12%); 11% patients had serious adverse events with 4 deaths that were deemed not related to the treatment drug ( 36 ).

Interferons vs. GA

A multi-center, randomized head-to-head comparison of subcutaneous interferon beta vs. GA (REGARD study) did not show significant differences between the two drugs in time to first relapse ( 37 ). A real-world study of a large United States healthcare claims database using propensity score matching showed mildly lower annualized relapse rate comparing pegylated interferon 1a and GA (least square means ratio 0.809, 95% CI 0.67–0.97, p = 0.027) but no difference in healthcare resource utilization (inpatient stays p=0.83, durable medical equipment p = 0.29) ( 38 ). Another comparison using MSBase registry data using propensity-score matching demonstrated slightly lower relapse incidence in patients treated with GA and subcutaneous interferon beta-1a compared to intramuscular IFN beta-1a and IFN beta-1b ( p < 0.001) though no differences in 12-month disability progression ( 39 ). Pegylated IFN was not included in the study.

FDA Approved Oral Medications

Sphingosine-1-phosphate (s1p) receptor modulators.

The S1P receptor modulator, fingolimod, was FDA approved in 2010 for the treatment of relapsing forms of MS. Since then, additional medications in this drug class have been approved, including siponimod (selective modulator of S1P1 and S1P5 receptors, contraindicated in patients with CYP2C9 * 3/ * 3 phenotype), ozanimod (selective modulator of S1P1 and S1P5 receptors), and ponesimod (selective modulator of S1P1). S1P is a phospholipid with five subtypes present in lymphoid tissue as well as endothelial cells, smooth muscles, atrial myocytes, spleen, and eyes. In the lymph nodes, S1P binding to S1P receptors is important for lymphocyte trafficking ( 40 ). S1P receptor modulator medications alter immune migration by binding to S1P receptors on lymphocytes, causing downregulation of S1P receptor expression and inhibiting lymphocyte egression from the lymph nodes ( 40 ).

In a phase 3, placebo-controlled double-blind trial (FREEDOMS II), there was a 48% reduction in annualized relapse rate for patients treated with fingolimod compared to placebo (rate ratio of 0.52, 95% CI 0.40–0.66) without a significant difference in disability progression ( 41 ). More recent trials with newer formulations include the SUNBEAM trial, comparing the safety and efficacy of ozanimod and interferon beta-1a which demonstrated lower annualized relapse rate in both 0.5 and 1.0 mg dosing with a 31% reduction in relapse rate, with a risk ratio 0.52 (95% CI 0.41–0.66) for the 1.0 mg dose and risk ratio of 0.69 (95% CI 0.55–0.86) for the 0.5 mg dosing ( 42 ). The OPTIMUM trial was a phase 3 study comparing ponesimod and teriflunomide, which demonstrated a relative reduction in annualized relapse rate by 30.5% (rate ratio 0.69, 99% CI 0.536–0.902) and a lower mean cumulative gadolinium enhancing lesions (relative risk 0.42, 95% CI 0.31–0.56) in the ponesimod group ( 43 ). Siponimod has been approved for both the treatment of RRMS and active SPMS ( 44 ).

S1P receptor modulators are associated with rare but serious side effects of macular edema, bradycardia, and AV blockade. Macular edema occurred in 0.3% of patients in clinical trials, which likely is the result of off-target effects, and patients with a history of diabetes uveitis or other risk factors for macular edema should avoid this class of medications ( 45 ). Earlier studies of less selective S1P receptor blockade such as fingolimod reported rare bradycardia and AV block, and patients are advised to obtain baseline EKG screening and assurance of no concomitant medications that affect heart rate or risk AV blockade prior to starting the medication. Fingolimod requires a 6-h first dose observation due to the risk for bradycardia as this risk is highest at 4–5 h. Treatment related adverse events from the SUNBEAM trial for ozanimod included nasopharyngitis, headache and upper respiratory tract infections without any clinically significant bradycardia or atrioventricular block ( 42 ). Treatment-related adverse events from the ponesimod OPTIMUM study were similar between the two arms, though more patients in the ponesimod group experienced bradycardia, hepatobiliary disorders, pulmonary events, macular edema and seizures ( 43 ). Because all S1P modulator drugs target the S1P1 receptor, which is expressed on lymph nodes as well as atrial myocytes, they all carry a theoretical cardiac risk. While newer formulations, particularly those with an up-titration over the first week, do not require a first dose observation period, the authors recommend exercising caution with screening for appropriate candidates for the S1P receptor modulators and warning patients against starting concomitant medications that can lower heart rates or cause AV blockade.

If fingolimod is stopped abruptly without effective transition to a new medication, rebound relapses with high number of enhancing lesions or tumefactive lesions can occur 4–16 weeks after discontinuation ( 46 , 47 ). Furthermore, there is a low risk for the development of progressive multifocal leukoencephalopathy (PML) ( 48 ). As of August 2021, a total of 51 cases of fingolimod-related PML have been reported that were not related to prior natalizumab treatment ( 49 ). Risk factors may include duration of therapy (>18 months) and older age (>50 years), though lymphopenia is not strongly associated with PML cases, unlike in other immunotherapies ( 50 ). Several strategies to mitigate rebound risk after fingolimod discontinuation have been proposed, including monthly intravenous steroid pulses to bridge to the next therapy and shortening the washout period ( 47 ). The authors generally transition patients from an S1P modulator to another high efficacy DMT by discontinuing medication for 4–6 weeks, rechecking lymphocyte count at the end of the washout period, and immediately administering the first dose of the new DMT. Monthly steroid pulses are given if there are unexpected delays in initiating the new DMT.

Teriflunomide

Teriflunomide was FDA approved in 2012, and it is currently approved for use in the treatment of relapsing forms of MS and active SPMS. Teriflunomide is the active metabolite of leflunomide that reversibly inhibits pyrimidine synthesis thereby preventing proliferation of activated T and B cells ( 51 ). The TEMSO randomized, double-blind, placebo-controlled study demonstrated a relative risk reduction of 31% in the annualized relapse rate as well as decreased disability progression and disease activity on MRI ( 51 ). Long-term efficacy from the 9-year TEMSO study follow up of 742 patients demonstrated an annualized relapse rate of 0.22 for the 14 mg BID dosing and 0.24 for the 7 mg BID dosing ( 52 ).

Teriflunomide should not be used in pregnancy or male or female patients planning a pregnancy as it may affect fetal development and remains in circulation for up to 2 years even after drug discontinuation. Accelerated elimination can be achieved with cholestyramine or activated charcoal. Additionally, teriflunomide carries a black box warning for severe liver injury; therefore, liver function testing should be monitored every month for the first 6 months and then every 6 months thereafter. Blood pressure and tuberculosis status should be checked before and after drug initiation. Other more common side effects include headache and hair loss. Long-term safety data from the TEMSO extension study reported 55% serious adverse events in the 14 mg BID dosing group and 62% in the 7 mg BID group; 11% of patients discontinued teriflunomide due to side effects, the most common being elevation in liver enzymes ( 52 ).

Among the fumaric acid derivatives, dimethyl fumarate was first approved for MS in 2013. Other oral formulations include diroximel fumarate and monomethyl fumarate. The mechanism of action is the activation of the nuclear factor-like (Nrf2) pathway and improvement of anti-inflammatory responses by shifting cytokine production from interferon gamma and TNFα to IL4 and IL5 ( 53 ). A phase 3 placebo-controlled trial demonstrated a 44% relative reduction in annualized relapse rate with twice daily dimethyl fumarate, but no difference in time to disability ( 54 ). Exposure to dimethyl fumarate for up to 13 years in 1,736 patients enrolled in the DEFINE, CONFIRM and ENDORSE extension trials was associated with an overall annualized relapse rate of 0.15 (95% CI 0.118–0.194) ( 55 ).

The main side effects reported in this class of medications include gastrointestinal (GI) problems and flushing though the newer oral formulations in this class have potentially better GI tolerance ( 56 , 57 ). About 30% of patients have reduced absolute lymphocyte count within the first year of treatment, and 2.5% of patients develop grade 3 lymphopenia, which increases their risk for PML or other severe infections. The PML risk is related to grade 3–4 lymphopenia (absolute lymphocyte count <500 x 10 6 /L) mostly affecting CD4/CD8 cells ( 48 ). As of September 2021, there are 12 confirmed cases of PML in dimethyl fumarate treated patients with an incidence of 1.07 cases per 100,000 person-years from post-marking reports ( 58 ). Most PML cases are linked to moderate to severe lymphopenia, but cases of mild lymphopenia have been reported ( 59 ). Thus far, there are no confirmed cases of PML in patients treated with diroximel fumarate. Long-term safety data from clinical trials have thus far reported 32% patients with serious adverse events, mostly MS relapses, with 14% discontinuing treatment due to other adverse events mainly related to GI intolerance ( 55 ).

Cladribine is an oral medication FDA approved in 2019 for the treatment of relapsing forms of MS except CIS. It is a pro-drug that is phosphorylated to the active metabolite cladribine 2-cholordeoxyadenosine triphosphate causing intracellular accumulation of the metabolite and disrupting cellular metabolism, DNA synthesis and repair ( 60 , 61 ). Unlike other oral DMTs, cladribine is not taken daily. It is dosed by weight (3.5 mg/kg), which is divided into two yearly treatment courses with two cycles per treatment course that are spaced 1 month apart. Cladribine disproportionately affects lymphocytes due to their high concentration of deoxycytidine kinase, which phosphorylates cladribine to the active metabolite, resulting in the apoptosis of CD4+ and CD8+ T cells as well as CD19+ B cells, while sparing other immune cells. The CLARITY study was a randomized, double-blind, placebo-controlled trial that demonstrated a lower annualized relapse rate (0.14–0.15 compared to 0.33 placebo) with a relative reduction of 54–57% ( p < 0.001) in the two dosing groups compared to placebo, and the relapse-free rate odds ratio was 2.53 (95% CI 1.87–3.43) for 3.5 mg/kg dosing and 2.43 (95% CI 1.81–3.27) for the 5.25 mg/kg dosing ( 61 ).

Caution should be made when selecting patients for cladribine, as it does carry an increased risk for malignancy, specifically benign uterine leiomyomas, melanoma, pancreatic and ovarian carcinomas ( 61 ). However, in a meta-analysis of 11 phase III trials comparing the cancer rate of cladribine reported in the CLARITY and ORACLE MS trials vs. other DMTs (dimethyl fumarate, fingolimod, teriflunomide, natalizumab, alemtuzumab, glatiramer acetate), there were no significant difference in cancer rates among the various DMTs studied ( 62 ). In terms of safety monitoring, about 86% of patients develop lymphopenia ~2–3 months after initiation; therefore, close monitoring of lymphocyte count is indicated shortly after treatment.

Oral Medications Under Investigation

Bruton's tyrosine kinase inhibitors (btki).

Bruton's tyrosine kinase inhibitors (BTKi) are emerging oral treatments for MS. BTKs are Tec family tyrosine kinases that are expressed in B cells, monocytes, neutrophils, and mast cells and are important for B cell maturation, proliferation, antigen presentation and differentiation to plasma cells. In myeloid cells (monocytes, granulocytes), BTK is important for cytokine and inflammatory mediator production and phagocytosis ( 63 ). BTK is also expressed in microglia, which are implicated in neuroinflammation of progressive as well as relapsing phenotypes, making it an attractive target for both forms of MS ( 64 ). Evobrutinib is a highly selective, irreversible oral BTKi shown in phase 2 trials to reduce T1 gadolinium-enhancing lesions without a significant difference in the annualized relapse rate between placebo and low and high Evobrutinib doses ( 65 ). In a phase 2b randomized, double-blind, placebo-controlled crossover study, Tolebrutinib, a CNS-penetrant BTKi, was shown to reduce T1 gadolinium-enhancing lesions in a dose-dependent manner at 12 weeks (1.03 placebo, 0.77 for 15 mg, 0.76 for 30 mg, 0.13 for 60 mg) ( 64 ). Orelabrutinib is another CNS-penetrant BTKi undergoing a phase 2 clinical trial for the treatment of RRMS. Several ongoing phase 3 clinical trials are underway and actively recruiting to investigate the efficacy of BTK inhibitors (clinicaltrials.gov: NCT04410991, NCT04410978, NCT04458051).

High Efficacy Infusion and Injectable DMTS

Natalizumab.

Natalizumab is a monthly infusion DMT that was FDA approved in 2004. A subcutaneous formulation is approved for use in Europe but has not yet gained FDA approval in the United States. Natalizumab is a monoclonal antibody against the alpha chain in α4β1 integrin, also known as very late-activation antigen-4 (VLA-4), and the therapeutic mechanism of action is through inhibiting leukocyte infiltration across the endothelium into the brain. Phase 3 clinical trials (AFFIRM and SENTINEL) showed that natalizumab reduced clinical relapses at 1 year by 68 with 83% reduction in new T2 lesions and had better efficacy in combination with interferon beta-1a compared to interferon alone ( 66 , 67 ). The Tysabri Observational Programme (TOP) using real-world data on the long-term efficacy of natalizumab reported an annualized relapse rate of 0.15 (95% CI 0.14–0.15) at 10 year follow up with lower relapse rates in participants with lower baseline EDSS scores <3.0. It is worth noting that in TOP these participants had exposure to fewer prior DMTs and fewer prior relapses (less active disease) ( 68 ).

Natalizumab manufacturing was briefly halted due to its link to PML which is related to JC virus reactivation as a consequence of impaired leukocyte migration and decreased T-cell mediated responses in the brain ( 69 ). However, PML risk can now be well stratified with the anti-JCV antibody index, duration of therapy and prior exposure to immunosuppressive medications ( 69 , 70 ). The overall incidence of PML with natalizumab use is 4.14/1,000 patients, which has remained stable since the mid-2016 as risk stratification strategies became more widely incorporated into clinical practice ( 71 ). As of August 2021, the overall global incidence of PML in natalizumab treated patients was 3.75/1,000 patients (95% CI 3.50–4.0 per 1,000) ( 72 ). Data from the Phase 3b NOVA study recently showed that patients who switched to every 6 week dosing after 1 year of every 4 week treatment had similar efficacy in terms for relapse and disease activity compared to patients who remained on every 4 week dosing ( 73 ). Additionally, the retrospective analysis from the Tysabri Outreach: Unified Commitment to Health (TOUCH) program that included 35,521 patients suggested that there is also a reduction in PML risk with extended 6 week interval dosing ( 74 ).

If a patient becomes higher risk for PML due to a conversion to JC virus seropositivity, several transition strategies may be employed to transition to a different DMT though more studies are needed to determine safety and efficacy of the washout period. The switch to fingolimod has been studied in a double-blind, placebo-controlled trial demonstrating lower risk for MRI active lesions after an 8–12 week washout period compared to 16 weeks, and potentially decreased risk with a 4-week washout period compared to 8 weeks ( 75 , 76 ). Several studies of patients with RRMS have demonstrated safe and effective transitions from natalizumab to anti-CD20 therapy (ocrelizumab or rituximab) ( 77 , 78 ). A retrospective observational study from an Italian MS cohort evaluated annualized relapse rate, MRI activity and EDSS after patients transitioned from natalizumab (standard and extended interval dosing) to either ocrelizumab, rituximab or cladribine. The washout period for ocrelizumab was 8 ± 4.2 weeks, rituximab 7 ± 3.9 weeks, and cladribine 6 ± 2.9 weeks. The estimated annualized relapse rate of 0.001, 0.308, 0.5 respectively for ocrelizumab, rituximab and cladribine (no confidence intervals were given for these point estimates), and no significant difference between ocrelizumab and rituximab ( 77 ). The authors generally transition patients to another high efficacy DMT after natalizumab with a 4-week washout period, similar to other practice recommendations ( 79 ).

Alemtuzumab

Alemtuzumab was FDA approved in 2014 for MS treatment. Two treatment cycles are completed 12 months apart with the first cycle consisting of 5 infusions and the second cycle consisting of 3 infusions. It functions by binding to CD52, a cell surface antigen on T cells, B cells, natural killer (NK) cells, monocytes, and macrophages. Following antibody binding to CD52, cellular lysis is induced by antibody-dependent cytolysis and complement-mediated mechanisms ( 80 ). In a phase 3 randomized controlled trial (CARE-MS I) comparing alemtuzumab to interferon beta-1a, patients treated with alemtuzumab had a 54.9% improvement in relapse rape with a 78% relapse free rate at 2 years ( 80 ). Additionally, 11% patients in the interferon arm had sustained disability accumulation compared to 8% in the alemtuzumab arm with a hazard ratio of 0.70 (95% CI 0.40–1.23, p = 0.22) ( 80 ). Long term efficacy over 9 years from the CARE-MS I and II trials showed that 62% (95% CI 54–69) were free of 6-month disability worsening and 50% (95% CI 41–59) had confirmed 6-month disability improvement ( 81 ).

Alemtuzumab requires long-term monitoring due to its risk for secondary autoimmune diseases (Graves' disease, immune thrombocytopenia, anti-glomerular basement membrane disease), malignancy (thyroid cancer, melanoma, lymphoproliferative disorders), bone marrow suppression and strokes ( 80 ). The risk for secondary autoimmunity could be related to higher serum IL21 levels with higher T-cell apoptosis and cell cycling ( 82 ). Other explanations for secondary autoimmunity are the early re-constitution of immature B cell types that are unchecked by T cells, and the imbalance between pro-inflammatory and regulatory lymphocyte subsets ( 83 , 84 ).

B-cell depleting therapy has emerged as a popular high efficacy class of MS medications. Rituximab is a monoclonal antibody targeting CD20, a cell surface marker of pre-B and B cells. Although not FDA-approved, rituximab has been commonly used off-label for almost 20 years. In a phase 2, double-blind trial in RRMS, patients who received rituximab had significantly reduced gadolinium-enhancing lesions and reduced relapses at 24 weeks (34.3% placebo and 14.5% rituximab) with a relative risk of 2.3 (90% CI 1.3–4.3) and 48 weeks (40% placebo and 20.3% rituximab, relative risk 1.9, 90% CI 1.1–3.2) ( 85 ). In a retrospective cohort study on prospectively collected data of 494 patients in Sweden, patients who received rituximab had significantly lowered relapse rate compared to injectable DMTs and decreased gadolinium-enhancing lesions compared to injectable DMTs and dimethyl fumarate ( 86 ).

Ocrelizumab

Ocrelizumab is an intravenous humanized monoclonal antibody therapy targeting CD20 that induces an antibody-dependent cytolysis and complement-mediated lysis of B cells ( 87 ). It was FDA approved in 2017 for the treatment of RRMS ( 87 ). The OPERA I and OPERA II clinical trials were two parallel phase 3 multicenter, randomized, double-blind studies comparing the efficacy of ocrelizumab to interferon beta-1a at 96 weeks, showing a lower annualized relapse rate for ocrelizumab in OPERA I (rate ratio 0.54, 95% CI 0.40–0.72) and OPERA II (rate ratio 0.53, 95% CI 0.40–0.71). Secondary endpoints for disability progression at 24 weeks demonstrated a pooled hazard ratio of 0.60 (95% CI 0.43–0.84) favoring ocrelizumab, a reduction in T1 gadolinium-enhancing lesions for both OPERA I (rate ratio 0.06, 95% CI 0.03–0.10) and OPERA II (rate ratio 0.05, 95% CI 0.03–0.09), and reduction in new T2 hyperintense lesions for both OPERA I (rate ratio 0.23, 95% CI 0.17–0.30) and OPERA II (rate ratio 0.27, 95% CI 0.13–0.23) ( 87 ). In the 5-year open label extension phase of pooled OPERA I and II for RRMS, patients who remained on ocrelizumab maintained a low annualized relapse rate (0.14, 0.13, 0.10, 0.08, 0.07 for years 1–5 respectively). Patients who switched from interferon beta-1a to ocrelizumab at the start of the open-label extension demonstrated a relative rate reduction of 52% (p < 0.001) and continued to maintain low relapse rates at years 3–5 with ocrelizumab ( 88 ). The Ocrelizumab Biomarker Outcome Evaluation study in patients with RRMS suggested that ocrelizumab reduced serum neurofilament light chain (NfL), CSF NfL and CSF B cells, and in patients with PPMS, CSF NfL ( p = 0.012) and CXCL13 ( p = 0.020) were reduced ( 89 , 90 ).

Ocrelizumab is the only FDA-approved medication for PPMS with a positive phase 3 trial (ORATORIO) with modest but significant reduction of confirmed disability progression at 24 weeks, 29.6% ocrelizumab vs. 35.7% placebo (HR 0.75, 95% CI 0.58–0.98, p = 0.04) and a reduction in total T2 lesion volume (HR 0.90, 95% CI 0.88–0.92) ( 65 ). In the open-label extension phase of at least 6.5 study years, patients who received ocrelizumab earlier had lower disability progression than those who received placebo (EDSS difference of 13.1%, 95% CI 4.9–21.3) and time to requiring a wheelchair (7.4% difference, 95% CI 0.8–13.9) ( 91 ). Similarly, those who received ocrelizumab earlier had a lower total change in T2 lesion volume (0.45 vs. 13%, p < 0.0001) and T1 hypointense lesion volume (36 vs. 61% initially placebo, p < 0.0001).

Ofatumumab is a monthly injectable subcutaneous therapy approved in 2020. It is a monoclonal antibody that also binds to CD20+ B cells resulting in B cell depletion. Distinguishing features from other CD20 therapies are its shorter half-life and its initial uptake into lymph nodes after subcutaneous absorption. Two major clinical trials have demonstrated its efficacy for the treatment of RRMS. The phase 2b MIRROR study demonstrated an overall 65% reduction in the mean rate of cumulative new gadolinium-enhancing MRI lesions compared to placebo after 12 weeks (rate ratio 0.36, p < 0.001) with post hoc analysis showing an accumulation rate of 0.07 to 0.25 (rate ratio 0.08–0.29 compared to placebo, p ≤ 0.02) ( 92 ). The ASCLEPIOS I and II studies were phase 3 double-blind, double-dummy, randomized controlled trials comparing ofatumumab to teriflunomide. The annualized relapse rates were 0.11 for ofatumumab arm and 0.22 for teriflunomide arm in trial 1 (rate difference −0.11, 95% CI −0.16, −0.06) and 0.10 for ofatumumab and 0.25 teriflunomide in trial 2 (rate difference −0.15, 95% CI −0.2, −0.09). A pooled hazard ratio of 0.66 favored ofatumumab for disability worsening and 1.35 hazard ratio (95% CI 0.95–1.92) favoring ofatumumab for disability improvement ( 93 ).

Safety and Monitoring Considerations in B Cell Depleting Agents

Side effects that should be considered for patients undergoing B cell depleting therapies include infusion reactions for rituximab and ocrelizumab, and injection site reactions for ofatumumab. All patients should have hepatitis (specifically HBV and HCV), HIV and latent tuberculosis (TB) screening prior to initiating therapy due to the risk for fulminant hepatitis and TB reactivation. Infusion-related reactions may include rash, itchiness, fever/chills, throat irritation, dyspnea, nausea, or headache, which can be improved with pre-treatment with diphenhydramine and methylprednisolone. The ENSEMBLE PLUS randomized study demonstrated similar rates of infusion related reactions in patients receiving the conventional 5–6 h infusion vs. a shorter 2 h infusion (proportional difference 2.44%, 95% CI −3.83, 8.71%) ( 94 ). Patients should be counseled on the risk for mild to severe infections as well as prolonged recovery from infections due to immunosuppression. There is concern for the risk of a potentially more severe COVID-19 course in MS patients treated with anti-CD20 therapy ( 95 ).

The long-term safety report for ocrelizumab up to 7 years for both relapsing MS and PPMS for adverse events were similar to the data from the phase 3 clinical trials. The rate per 100 patient years for serious adverse events was 7.3 (95% CI 7.0 −7.7), infusion reactions 25.9 (95% 25.9–26.6) and infections 76.2 (95% CI 74.9–77.4) with no increased risk for malignancy ( 96 ). Hypogammaglobulinemia from decreased IgG levels can occur after B cell depleting therapy, up to 30% in ocrelizumab, which can increase the risk for infections ( 97 ). Therefore, baseline then subsequent immunoglobulin levels should be obtained during therapy. Low immunoglobulin levels can be treated with maintenance intravenous or subcutaneous immunoglobulins if a critical level is reached–this level may differ by country but often considered to be <400 mg/dl.

In terms of lab monitoring, CD19, another B cell marker, is frequently used as a surrogate marker for CD20 B cell levels as the CD20 B cell therapies interfere with its direct detection in the blood. However, CD19 is expressed on a composite of B cell subsets, from immature to mature B cells, whereas the functional depletion of CD19+, CD27+ memory B cells are more important in reducing relapse in MS ( 98 ). Thus, another strategy is to monitor circulating CD27+ memory B cells in addition to CD19 counts, which can be ordered in commercially available B cell subset panels. CD19+ B cells are typically depleted within 2 weeks after rituximab and ocrelizumab and 12 weeks for ofatumumab. B cell repopulation occur around 6 months after infusion therapy, although some patients may have longer repletion periods and may be able to receive less frequent dosing, thereby reducing infection risk and allowing time for more effective vaccination responses ( 99 ). It is also important to note that certain T cell subsets also express CD20 and are depleted with anti-CD20 therapy, although the clinical significance of this is unknown ( 100 ). Additionally, anti-CD20 therapy, specifically rituximab, was found to partially reduce CD4+ and CD8+ T cells, though this reduction is transient ( 98 , 101 ).

Mitoxantrone

Mitoxantrone is an infusion therapy administered every 3 months that was FDA approved in 2000 for the use in RRMS and SPMS though it is rarely used today due to side effects. It functions by intercalating into DNA causing crosslinking and strand breaks thereby reducing the proliferation of T cells, B cells and macrophages as well as downregulating the inflammatory cascade ( 102 ). A double-blind, placebo-controlled trial in Europe (MIMS) demonstrated reduced mean number of relapses (0.4 compared to 1.20 in placebo) and reduced median time to relapse and decreased disability progression ( 102 , 103 ). However, it is associated with cardiotoxicity and malignancy (specifically leukemia) thus falling out of favor compared to other commercially available DMTs ( 102 , 104 ).

Autologous Hematopoietic Stem Cell Transplantation

An emerging new therapy is autologous hematopoietic stem cell transplantation (AHSCT), which has been studied for the treatment of MS as well as other inflammatory disorders such as systemic sclerosis, Crohn's disease and neuromyelitis optica. The rationale for AHSCT is to “reset” the immune system. First, autologous peripheral blood stem cells are mobilized using cyclophosphamide and filgastrim and collected for post-ablation transplantation. Then, existing autoreactive immune cells are eliminated with either fully or partially myeloablative conditioning (chemotherapy) regimen ( 105 , 106 ). Conditioning regimens may include cyclophosphamide (Cy) + anti-thymocyte globulin (ATG), Cy + alemtuzumab, or ATG + BEAM (carmustine, etoposide, cytarabine, melphalan) ( 106 , 107 ). After conditioning, peripheral blood stem cells are re-infused to shorten the aplastic phase and reconstitute a new immune system with more regulatory cell types (regulatory T cells and CD56 NK cells) and decreased pro-inflammatory T-cell profiles ( 105 , 108 ). Early toxicity is largely due to adverse reactions to the cytotoxic agents and myelosuppression. Late toxicity is more rare, but notable adverse effects include infertility, HSV, CMV and EBV reactivation, secondary autoimmune disorders and myelodysplastic syndromes ( 106 ).

There are as of this writing four retrospective studies, five single-arm clinical trials, and two randomized control studies evaluating the efficacy of AHSCT with promising results. In a meta-analysis of published studies using AHSCT for MS treatment, the pooled estimated transplant-related mortality was 2.1%, two-year disease progression rate was 17.1%, five-year progression rate of 23.3%, and a pooled 83% of patients with no evidence of disease activity at 2 years ( 109 ). Patients who had the most benefit and least mortality rate were patients with RRMS ( 106 , 109 ). The two randomized controlled trials were the ASTIMS and MIST trials. ASTIMS was a phase 2 trial comparing AHSCT to mitoxantrone in 21 patients. None of the AHSCT-treated participants had T1 gadolinium-enhancing lesions after 4 years with an annualized relapse rate of 0.19 compared to 0.6 (in the mitoxantrone group rate ratio 0.36, 95% CI 0.15–0.88) ( 110 ). The MIST trial was a phase 3 crossover study comparing lower intensity non-myeloablative immunoablation (Cy + ATG) followed by a nonmyeloablative AHSCT to DMT (excluding ocrelizumab and alemtuzumab). The primary outcome result was a 93% reduction in the hazard for disease progression at 4–5 years in the AHSCT group compared to the DMT group (hazard ratio 0.07, 95% CI 0.02–0.24). It should be noted that the patients in the clinical trial had a higher level of disease activity at baseline, and the majority of the DMT group were maintained on lower efficacy DMTs (interferon, glatiramer acetate) ( 111 ).

A pooled treatment-related mortality from a meta-analysis is estimated to be 2.1%, though the mortality rate was 3.6% in patients who underwent transplantation prior to 2005, and only 0.3% in patients who underwent transplantation after 2005. Additionally, higher mortality was reported in patients who had more severe baseline disability scores ( 106 , 107 ). Currently, there are several ongoing phase 2 and phase 3 AHSCT multi-center, randomized controlled trials comparing AHSCT to high-efficacy therapies such as alemtuzumab, natalizumab, ocrelizumab and rituximab (clinicaltrials.gov: NCT04047628 BEAT-MS, NCT03477500 RAM-MS). Both trials are enrolling patients with RRMS (age 18–55 for BEAT-MS and 18–50 for RAM-MS with high disease activity.

Overall, AHSCT seem to be a promising emerging therapy for MS especially as a one-time treatment rather than long-term immunosuppression. The patients who seem to benefit most are those with lower disability at baseline, more active/relapsing disease, and younger age ( 109 ). Therefore, at this time, AHSCT should generally be reserved for patients <45 years old with less disability, high disease activity, few or no comorbidities who have failed 1–2 high efficacy DMTs. The cost utility of AHSCT compared to DMT use should also be considered. Currently, the one-year cost of a myeloablative AHSCT regimen is approximately $181,933, most of which is incurred at the time of transplantation, and an adjusted $4,700 per quality-adjusted life year. Comparatively, the cost of DMT is approximately $70,000 per year due to rising costs of newer, higher efficacy DMTs with an estimated $73,000 per quality-adjusted life year ( 107 ). However, the data on the long-term effects on disease burden and morbidity/mortality with early AHSCT therapy are still limited ( 106 ).

Pediatric MS

Pediatric-onset MS differs from adult-onset MS in that pediatric patients have more than three times higher relapse rates ( 112 ). Overall, 99% of pediatric patients present with relapsing forms of MS ( 112 , 113 ). Few DMTs have been evaluated with completed double-blind, randomized phase 3 trials, but observational data have generally supported similar efficacy and safety of most DMTs in children <18 years old ( 114 ). DMTs that are frequently used include traditional injectables (interferon beta, glatiramer acetate), oral medications (dimethyl fumarate, teriflunomide), and infusion medications (natalizumab, rituximab and ocrelizumab). Prior cohort studies comparing injectable DMTs to newer higher-efficacy DMTs suggest that early treatment with newer DMTs result in lower relapse rate and lower rates of new/enlarging T2 lesions and gadolinium-enhancing lesions. In a multicenter cohort study of 741 patients in the United States Network of Pediatric MS centers, patients who received newer DMTs had fewer relapses with an adjusted annualized relapse rate of 0.22 compared to those who received traditional injectable DMTs with an annualized relapse rate of 0.49 (rate ratio 0.45, 95% CI 0.29 – 0.70) ( 115 ). In comparing oral to infusion DMTs, 25% relapsed on oral medications while 15% relapsed with infusions ( 115 ). A safety and efficacy study on the use of natalizumab in pediatric onset MS demonstrated in a small cohort of 19 patients a decline in median EDSS, with no new gadolinium-enhancing lesions during the treatment phase ( 116 ). Another phase 2 multi-center, non-randomized trial of dimethyl fumarate in 22 pediatric patients demonstrate a significant reduction in T2 hyperintense lesions after 8 weeks of treatment ( 117 ).

The first FDA approved DMT for the treatment of pediatric MS was fingolimod, which was studied in the PARADIGMS phase 3 randomized trial of patients ages 10–17 with pediatric onset MS with an absolute difference in annualized relapse rate of 0.55 (82% change) compared to interferon beta-1a ( 118 ). Safety profiles were similar between the two groups except for increased seizure frequency in the fingolimod arm (6 patients, 5.6%) compared to interferon (1 patients, 0.9%) ( 118 ). The TERIKIDS phase 3 randomized trial comparing teriflunomide and placebo did not show a significant difference in time to first relapse (hazard ratio 0.66, 95% CI 0.39–1.11, p = 0.29) though teriflunomide decreased the number of T2 lesions (RR 0.45, 95% CI 0.29–0.71), and T1 gadolinium-enhancing lesions (RR 0.25, 95% CI 0.13–0.51) ( 119 ). Pending pediatric trials include a phase 3 safety and efficacy study with dimethyl fumarate (clinicaltrials.gov: NCT02283853), and open-label safety and efficacy study with alemtuzumab (clinicaltrials.gov: NCT02283853). Currently, there is a phase 2 study and new phase 3 study on the use of ocrelizumab in pediatric patients, with the phase 3 trial comparing efficacy between ocrelizumab and fingolimod (clinicaltrials.gov: NCT04075266) and a phase 3 trial for siponimod and ofatumumab vs. fingolimod (clinicaltrials.gov: NCT04926818).

Treatments for Progressive MS

Primary progressive MS is defined as progression and worsening of disability from onset of disease without a clear history of relapses, while secondary progressive MS is defined as progressive accruement of disability with a prior history of relapsing disease ( 6 ). Progressive MS is further classified into active vs. non-active disease based on evidence of active disease (gadolinium-enhancing lesions) on MRI ( 120 ). The average onset of progressive MS is about 20 years after onset of relapsing-remitting disease while about 10–15% of MS patients present with primary progressive disease with rapid accruement of disability ( 121 ). The pathological features of progressive forms of MS include brain atrophy, cortical demyelination with subpial involvement, slowly expanding lesions, diffuse injury related to microglial activation in both gray and white matter, and meningeal lymphoid follicle-like aggregates composed of B cells within the subpial lesions ( 122 , 123 ). In the neurodegenerative phase, acute inflammatory processes are less prominent, while chronic active and slowly expanding lesions predominate. Chronic active lesions demonstrate accumulation of extracellular iron in the oligodendrocytes in an age-dependent manner ( 122 ). Reactive oxygen species and nitric oxide from microglia and mitochondrial injury and dysfunction also contribute to progressive MS pathology. Secondary mitochondrial injuries are caused by chronic oxidative stress, and cortical neurons develop energy failure from decreased respiratory chain function and changes to the mitochondrial DNA. Progressive MS phenotypes have a clear association with chronological age given decreased relapse rate over time and greater accumulation of disability with increasing age ( 124 ). There is now growing evidence on the effects of biological aging on MS phenotype. As an example, shorter leukocyte telomere length associated with increased disability and progressive forms of MS in multiple cohorts ( 125 – 127 ).

Clinical Trials Targeting Progressive Phenotypes

As discussed earlier, the only current FDA-approved DMT for PPMS is ocrelizumab. Several other phase 3 clinical trials involving DMTs in the treatment of progressive (primary progressive and secondary progressive) MS have resulted in positive results. These include interferon beta (reduced disability progression), mitoxantrone (reduced disease progression, relapse rate), ocrelizumab (reduced disability progression, brain volume loss), and siponimod (disability progression, relapse rate and functional scores) ( 44 , 103 , 123 , 128 , 129 ). However, efficacy was mostly seen in patients with active disease. A randomized double-blind, placebo-controlled trial with rituximab yielded similar results but no statistically difference in disease progression between the treatment arms. In a sub-analysis, disease progression was delayed in patients ages <51 years (hazard ratio 0.52, p = 0.010) and patients with active, gadolinium-enhancing lesions (hazard ratio 0.41, p = 0.007) ( 130 ). Data from the INFORMS phase 3 trial did not show a significant reduction in disability progression with fingolimod, and the ASCEND phase 3 trial with natalizumab did not reduce disability progression in patients with SPMS ( 131 , 132 ). Currently, phase 3 randomized, double-blind trials are underway investigating the use of BTKi's for the treatment of PPMS (clinicaltrials.gov, NCT04458051) and SPMS (clinicaltrials.gov, NCT04411641).

In addition to DMTs, vitamin and co-factor supplementations have been studied for progressive MS treatment. Biotin, a coenzyme for five major carboxylases, was hypothesized to promote remyelination and neuroprotective mechanisms ( 123 ). However, while promising in phase 2, the phase 3 randomized, double blind, placebo-controlled international SPI2 study did not show significant benefit of biotin on walking speed or disability in PPMS or SPMS ( 133 ). Lipoic acid is an endogenous antioxidant that is involved in reducing oxidative species, iron chelation, and functions as a co-factor for pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase in mitochondria. A single-center double-blind, randomized phase 2 trial of 1,200 mg/day of alpha-lipoic acid daily demonstrated promising results with a 68% reduction in annualized percent change in brain volume with good safety and tolerability in patients with SPMS ( 134 ). A current phase 2 placebo-controlled trial is enrolling adult patients with progressive MS to study the effects of daily lipoic acid on the time 25 foot walk along with brain volume and other mobility measures (clinicaltrials.gov, NCT03161028). Recently, an exploratory study was published showing that N-acetylcysteine (NAC), a supplement that increases glutathione stores with neuroprotective potential, led to increased cerebral glucose metabolism and subjective improved cognition in MS patients ( 135 ). Low vitamin D levels have been associated with increased risk for developing MS, with some suggestion that level 25(OH)D levels predict slower progression of disease and lower T2 lesion volume, though the latter was mostly studied in patients receiving interferon therapy ( 136 ). A more recent cross-sectional study did not show a clear association with 25(OH)D levels with brain volume and progressive MS. However, vitamin D is postulated to exert an immunomodulatory effect and serve as a neuroprotective mechanism in progressive phenotypes ( 137 ).

Emerging cell-based immunotherapies are also being developed for progressive MS. A phase 1/2 study is underway for the safety and tolerability of ATA188, an allogenic Epstein Barr virus (EBV) T-cell therapy targeting EBV, which is well recognized risk factor for MS (clinicaltrials.gov, NCT03283826). This is based on the observation that defective CD8+ T-cell responses to EBV infection result in an accumulation of autoreactive B cells in the CNS that contributes to progressive MS pathology ( 138 ). An open-label phase 1 study with 5 SPMS and 5 PPMS patients demonstrated improvement in neurological function and quality of life and reduction in fatigue and intrathecal IgG production in six patients ( 139 ).

Remyelination and Neuroprotective Strategies

Remyelination and neuroprotection in patients with MS are underway as additional therapeutic approaches. A phase 2b, multi-arm, double-blind, randomized, placebo-controlled trial in the United Kingdom studied the effect of three neuroprotective medications (amiloride 5 mg, fluoxetine 20 mg, riluzole 50 mg) on the percentage brain volume change at 96 weeks as well as T2 lesion burden, functional evaluations and time to first relapse in patients with SPMS, with no significant different in the primary or secondary outcomes ( 140 ). A previous randomized, double-blind study using clemastine fumarate to target oligodendrocyte precursor differentiation demonstrated improved latency delay using visual evoked potentials in patients with RRMS and chronic demyelinating optic neuropathy, suggesting that remyelination is possible following injury. The main side effect of clemastine was fatigue ( 141 ). A randomized, single-blind, parallel trial of 24 weeks of aerobic exercising with stationary cycling is underway to utilize somatosensory evoked potentials to measure functional remyelination in the spinal cord along with other functional outcomes such as timed 25-foot walk and 9 hole peg test (clinicaltrials.gov, NCT04539002). Metformin, a common medication used in diabetes mellitus, has been studied as a potential therapy to improve the regenerative potential of oligodendrocyte progenitor cells ( 142 ). A phase 1/2 randomized, double-blind trial will aim to investigate safety and tolerability of 3, 6 and 9 month dosing of metformin 500 mg/m2/day in children/young adults ages 10–25 years old in addition to optical coherence tomography and visual evoked potentials to investigate the effects of metformin on endogenous neuro progenitor cells (clinicaltrials.gov, NCT04121468). The SYNERGY trial using opicinumab, a monoclonal antibody targeting LINGO-1, a membrane protein that suppresses oligodendrocyte differentiation, was discontinued in a phase 2 trial due to not meeting primary and secondary endpoints.

DMTs: When to Treat, How to Choose and When to Stop

Both the European Committee of Treatment and Research in Multiple Sclerosis (ECTRIMS) and the European Academy of Neurology (EAN) as well as the American Academy of Neurology (AAN) published guidelines in 2018 for the pharmacological treatment of people living with MS ( 143 , 144 ). For CIS, the ECTRIMS/EAN committee recommended interferon or glatiramer acetate for patients with abnormal MRI suggestive of MS though not fulfilling full criteria for MS, though the AAN supports annual imaging for the first 5 years prior to initiating DMTs to screen to new disease activity. For confirmed relapsing MS, the recommendations from ECTRIMS/EAN and AAN align with the practices of most MS centers. Patients should be presented with all reasonable DMT options for their individual case taking into consideration their medical co-morbidities, disease severity, specific medication adverse effects, and medication adherence/ accessibility ( 143 ). In terms of relative efficacy among the various DMT options, although there are no head-to-head trials comparing all available DMTs, several studies have attempted to assess real-world efficacy among the various medications to decrease relapse rate and delay conversion to SPMS in relapsing MS patients.

Comparing Oral DMTs

Real-world data comparing efficacies of oral DMTs may offer further insight into DMT of choice when discussing options with patients. A 2-year prospective study of 1,770 patients with RRMS from the French Multiple Sclerosis Registry demonstrated similar efficacy between teriflunomide (TRF) and dimethyl fumarate (DMF) using an inverse probability weighing on propensity scores, with 30.4% (95% CI 26.9–33.9) patients who experienced at least one relapse at 2 years in the TRF group vs. 29.5% (95% CI 26.6–32.2) in the DMF group and an odds ratio of 0.96 (95% CI 0.78–1.19) comparing DMF versus TRF ( 145 ). However, the adjusted proportion of new T2 lesions were lower in the DMF group compared to TRF (OR 0.60, 95%CI 0.43–0.82), and fewer patients withdrew from treatment due to lack of effectiveness in the DMF group compared to TRF (OR 0.54, 95% CI 0.41–0.74) ( 145 ). The cohort included RRMS patients who were either treatment-naïve or previously received injectable DMTs. Data from the Danish Multiple Sclerosis Registry compared TRF and DMF at 48 months and found lower annualized relapse rate for DMF (OR 0.58, 95% CI 0.46–0.73) and a lower incidence of discontinuation with DMF due to inefficacy ( 146 ). In the Italian MS cohort, findings at 38 months comparing DMF and TRF showed similar time to first event for TRF and DMF (HR 0.73, CI 0.52–1.03) but higher relapse-free survival in the DMF group after 38 weeks, and discontinuation rates between TRF and DMF at 24 months were comparable ( 147 , 148 ).

Injectable vs. Oral DMTs vs. High-Efficacy DMT

A multi-center retrospective study from the Italian MS Register compared the relapse rate, time to first relapse in 3,919 patients treated with first-line injectables DMTs (IFN or GA) to 683 patients treated with first-line oral DMTs (dimethyl fumarate or teriflunomide) ( 149 ). In this study, the oral DMT group demonstrated a lower time to first relapse (HR 0.57, 95% CI 0.47, 0.69) and annualized relapse rate (0.65 incidence ratio, 95% CI 0.52, 0.82) but no difference in the disability progression between the injectable and oral DMT groups ( 149 ). A comparative effectiveness study used an MS research registry and the electronic health record of 1,535 patients in the registry to determine 1-year, 2-year relapse rate and time to relapse for patients treated with dimethyl fumarate, fingolimod, natalizumab and rituximab after adjusting for confounders and propensity scores ( 150 ). The study compared natalizumab with rituximab, and dimethyl fumarate with fingolimod. Based on their statistical algorithms, there was an increased 1-year (0.08 rate difference), 2-year (0.132 rate difference) and shorter time to related (0.903 rate difference) in natalizumab-treated patients compared to rituximab. Interestingly, there were no significant difference in relapses between dimethyl fumarate and fingolimod in all three outcome measures ( 150 ).

Conversion to SPMS

An international cohort study of 1,555 patients from the MSBase studied the risk of conversion to SPMS in patients treated with interferon beta, glatiramer acetate, fingolimod, natalizumab and alemtuzumab ( 21 ). The results demonstrated a delay in converting to SPMS for all drugs compared to untreated patients with a HR of 0.71 (95% CI 0.61–0.81) and 5-year absolute risk 12% for those treated with either IFN or GA, HR 0.37 (95% CI 0.22–0.62) and 5-year absolute risk of 7% for fingolimod, HR 0.61 (95% CI 0.43–0.86) and 5-year absolute risk of 19% for natalizumab, and HR 0.52 (95% CI 0.32–0.85) with 5-year absolute risk of 7% for alemtuzumab. Additionally, when patients were escalated from IFN or GA to fingolimod, natalizumab or alemtuzumab within 5 years, the HR was 0.76 (95% CI 0.66–0.88) with a 5-year absolute risk of 8% ( 21 ). Data for B cell therapies were not available at the time of the study.

Although newer DMTs demonstrate higher efficacy compared to older injectable medications, it is still uncertain whether earlier initiation of high-efficacy DMTs will alter the natural history of non-relapse related disease progression since immunotherapy has been less successful in treating progressive forms of MS. Several ongoing studies are investigating these questions including the prospective traditional vs. early aggressive therapy for MS trials (clinicaltrials.gov; TREAT-MS, DELIVER-MS) studies, which randomizes patients to traditional first-line therapy vs. high-efficacy DMT. The TREAT-MS trial compares traditional injectable and oral medications to higher efficacy DMTs including ocrelizumab, natalizumab, alemtuzumab, rituximab, cladribine, and ofatumumab to evaluate disability progression. DELIVER-MS compares high efficacy DMTs (alemtuzumab, ocrelizumab, natalizumab, rituximab, ofatumumab) to traditional injectables or oral medications to evaluate brain volume loss.

Discontinuing DMTs

Due to a decline in overall inflammatory activity as patients enter the neurodegenerative stage of the disease, the effectiveness of DMTs directed at active disease activity diminish over time especially in patients with sustained absence of further disease activity. Considerations for stopping DMTs include increasing risks of complications from medication side effects with older age, increasing medical co-morbidities, and costs/expenses required for continuation of DMTs ( 151 ). Currently, the available data for DMT discontinuation in the later stages of the disease are based on retrospective analyses. A meta-analysis of 38 clinical trials assessed DMT efficacy on disability progression using a regression model, demonstrating that higher efficacy DMTs are most beneficial in younger patients in the earlier stages of disease but have limited benefit in the patients >53 years ( 152 ). A retrospective observational study from the Cleveland Clinic of 600 MS patients who were >60 years old evaluated clinical outcomes of discontinuing DMT after exposure to DMTs for at least 2 years ( 153 ). In this study, 29.7% of patients discontinued DMTs, of which 89% of patients remained off treatment, and only one clinical relapse occurred among those who discontinued DMTs. Performance scales, timed 25 foot walk, and nine hole peg tests did not differ among those who remained on and off DMT ( 153 ). Results from DISCO-MS, a randomized prospective study of patients >55 years evaluating relapse rate, MRI lesion burden, quality of life, and performance scales from stopping vs. continuing DMTs, will hopefully provide further insight into this topic (clinicaltrials.gov: NCT03073603).

Over the last three decades, there has been a rapid expansion of treatment options for MS as well as increasing efficacy of newer agents against relapses. Despite advances in our understanding of the biology of MS pathogenesis, there remains a scarcity of effective treatment for progressive disease. While newer DMTs have higher efficacy in reducing relapse rate and MRI disease activity, they also may carry higher side effect profiles due to increased levels of immunosuppression. Part of the difficulty in the management of MS is the heterogenous nature of the disease, which is influenced by environmental and genetic factors as well as the naturally adaptive and evolving nature of the immune system that changes with time and age. There is promising increased activity in the field for the development of neuroprotective and remyelinating therapies including mechanisms to support mitochondrial function and cell-based therapies targeting culprits of chronic inflammation. Additional therapeutic approaches include harnessing immunoprotective mechanisms such as supporting regulatory T-cell function and reparative microglial function. Further studies are needed to identify early risk factors for an increased inflammatory state, early neurodegeneration, or a combination of both. Early therapeutic interventions for both the neuroinflammatory and neurodegenerative aspects of the disease, used in tandem, will likely be key to further therapeutic advances and the ultimate goal of true remission of the disease.

Author Contributions

JHY contributed to the conception and drafting of the manuscript. TR, NW, AD-P, and JSG contributed to the editing and approval of the final manuscript. All authors contributed to the article and approved the submitted version.

Conflict of Interest

JY has received speaker fees for NeurologyLive. TR received grant funding from the National Multiple Sclerosis Society. JG has received grant or contract funding from Biogen, Octave, Novartis, and EMD-Serono and has served on advisory boards for Bayer and Genentech and has received speaker fees from BMS and Alexion.

The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher's Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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Keywords: multiple sclerosis, disease modifying therapy, demyelination, neurodegeneration, review

Citation: Yang JH, Rempe T, Whitmire N, Dunn-Pirio A and Graves JS (2022) Therapeutic Advances in Multiple Sclerosis. Front. Neurol. 13:824926. doi: 10.3389/fneur.2022.824926

Received: 29 November 2021; Accepted: 09 May 2022; Published: 03 June 2022.

Reviewed by:

Copyright © 2022 Yang, Rempe, Whitmire, Dunn-Pirio and Graves. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Jennifer H. Yang, jhy045@ucsd.edu

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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A New Approach to M.S. Could Transform Treatment of Other Diseases

By Rivka Galchen

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In 2014, Erin Storch looked in the mirror and felt as if she were drifting leftward. It was a feeling she didn’t know how to fully describe. She had been on maternity leave, and had recently returned to her job at a hospital consultancy in Washington, D.C. Storch had been promoted while on leave, so she was learning something new at work—and it seemed strangely difficult to absorb the information. She was also pumping milk three times a day. People suggested that what she was experiencing might be profound exhaustion; she disagreed. “I knew in my gut that the way I was feeling was not within the spectrum of what you would consider normal,” she said.

There were further unsettling sensations: “Coffee tasted like water. The left side of my body was weak and numb.” Storch went to see her ob-gyn, who sent her for a CT scan. Nothing unusual showed up.

Storch’s son was six months old when her symptoms manifested. When he was seven and a half months old, she walked down the stairs while holding him, and fell. Her son was O.K. “But then I knew that something was really wrong,” she said. She found a new doctor, who sat with her and her husband “for maybe forty minutes. It was just a conversation—there wasn’t even a physical exam. He said to me that he knew a lot of moms with demanding careers and that this was not that.” She started to cry from the relief of being believed. He scheduled an MRI for that evening. “But since there was some time to kill I decided, being me, to go to work,” she said. She crashed her car into a pole in a garage on M Street.

The MRI showed that Storch had several lesions, indicative of inflammation, in her brain. She was admitted to the hospital the next morning, where she was eventually told that she had multiple sclerosis, a chronic disease characterized by inflammation in the brain and the spinal cord. While Storch was in the hospital, her mother and her sister used breast milk from the freezer to feed her son, who had never had formula.

Despite her diagnosis, there was little clarity. In the hospital, she recalled, there was one doctor who, in response to her husband’s questions, replied, “Have you heard of Google?” (Storch says that she did go down “a Google rabbit hole, and I didn’t find anything that helped me.”)

After Storch went home, she started seeing a neurologist, who, she said, “was doing the best with the tools they had—this was not an M.S. specialist.” The neurologist put her on a pill that had recently been approved by the F.D.A. She began seeing a psychotherapist, too. “She wanted me to educate her on the disease,” Storch said. “She would ask questions like ‘Is it possible that you could be in a wheelchair?’ ” Storch realized that she didn’t know. Also, the medication she was taking didn’t seem to be helping.

Around that time, Storch received an e-mail from someone she knew at work, recommending a doctor. “That was how I found Dr. Sadiq,” Storch said.

Saud Sadiq is the director and chief research scientist of the Tisch Multiple Sclerosis Research Center of New York and the head of the adjacent clinical practice. Speaking with his patients can feel like speaking with devotees of one of those bands which border on being a religion. Patients told me that he talked with them until they ran out of questions, that he saw them on a Saturday so they could have their normal life, that he gave them his cell-phone number. Amelia Collins, who has been his patient for twenty-three years, told me that she once heard his cell phone ring while he was performing a spinal tap. He said to her, “You see, this is the only time I won’t answer my phone, because I have your spine in my hands—otherwise I would answer.”

Storch said, “We sat in his office, and everything that I thought a health-care experience should be—that was what it was. It felt like he had unlimited time.”

There are two main types of M.S.: a relapsing-remitting form (R.R.M.S.) and a progressive form. Both attack the brain and the spinal cord and can become debilitating if not treated, but R.R.M.S. usually responds well to current therapies. The progressive form, which often presents as what is called the primary-progressive type (P.P.M.S.), which affects about fifteen per cent of patients, tends not to. As their names suggest, R.R.M.S. is characterized by symptoms that flare up and then often spontaneously remit, and P.P.M.S. proceeds more inexorably. Sadiq told Storch that she likely had R.R.M.S., and advised her that an aggressive course of treatment could stave off further disability. Once damage is done, it is often irreversible. He told her that the medication she was taking may as well have been a water pill.

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“The other thing about Sadiq’s practice was that everything was there,” Storch said. Sadiq’s center, which he founded in 2006, has an unusual structure. Research, occupational therapy, social work, nutrition counselling, MRIs, physical therapy—they all take place on two floors of a building on Fifty-seventh Street, in Manhattan, and all are devoted almost exclusively to M.S. The center’s research arm, a nonprofit supported in part with funding from the Tisch family, has space for lab animals and for growing experimental tissues, and nearby there are rooms for working with weights, for speaking with a social worker, for receiving infusions of steroids—everything an M.S. patient, or an M.S. researcher, might need. Storch sees a nutritionist there, and for the first year she regularly sought counsel from a social worker on staff. “I needed help with my mental health very badly,” she said. Storch disbelieved Sadiq’s optimistic prognosis: “I would go to the social worker and say, ‘How do I know he’s not lying to me?’ She would reassure me and say that she had been there for ten years, and that if that was how he was practicing, we would probably know that by now.”

Sadiq told Storch that she would have no more disease progression, and, she said, “that has been the case.” She takes a drug, Ocrevus, that eliminates her B cells, an element of the immune system which, in M.S. patients, attacks the nervous system. Her Ocrevus infusions, given twice a year, are accompanied by an infusion of steroids. “I know that knocks me out for a couple days, so I plan on that,” she said. “I save a bad TV show to watch.” She also takes two medications that help with symptoms: gabapentin for numbness and tingling, and modafinil for fatigue. “I used to call the office so often, but now M.S. is less at the forefront of my life. It’s just something I manage like I manage everything else,” she told me. Storch struck me as professional, reserved, and put-together. She teared up only once, when she said she didn’t know what her life would be like today if she hadn’t met Sadiq.

I recently spent a couple of stressful months trying to get appointments for a close relative with a newly diagnosed neurodegenerative disease—appointments with neurologists and ophthalmologists and neuro-ophthalmologists and radiologists—and trying to find, as several of the neurologists suggested, a way to get an appointment with the right kind of neurologist. I often wished there were a practice organized like Sadiq’s, with all the players in one house, and clinical trials as well as basic scientific research happening there, too, where the researchers’ ambitions were influenced by the problems seen each day. “It happened not by careful thought but because, when I was the chairman of neurology at St. Luke’s-Roosevelt, I was frustrated with the bureaucracy, and the bureaucracy getting in the way of the research, so I decided to open an independent lab and practice,” Sadiq told me, when I visited the center not long ago. “If I had thought about it, I wouldn’t have done it, because there was no prototype to copy. In hindsight, it was unlikely to be successful.” Sadiq was especially eager to show me the backup ventilation system for the animal-care area—it was so large that it had to be installed through the windows. “If we want to do creative and innovative research—that’s very difficult to do when you’re under pressure to publish or secure more funding,” he said, explaining why he valued working outside a research hospital like those in which he trained.

The approach of housing all M.S. services together, as at Sadiq’s practice, can seem less than revolutionary, but at a recent “patients as teachers” session at the Barlo Multiple Sclerosis Center, at St. Michael’s Hospital, in Toronto, the patients spoke about the value of having care from different providers be coördinated. Providers want this, too—it is sometimes called comprehensive care—but the usual demons of funding and structural change are difficult to overcome. Even the Barlo center, a strong model for comprehensive care, is described by its director, Jiwon Oh, as “still a work in progress.”

Sadiq is gently boastful of how his center functions. “I saw a patient yesterday who was seen at an Ivy League M.S. center, and they told her she needed another MRI but couldn’t schedule it until two weeks later,” he told me, “and her treatment couldn’t start for another three weeks after that. When she came to see me yesterday, because we have two MRI facilities downstairs, we did it immediately and she’s starting treatment tomorrow.” A popular saying in the treatment of strokes is “Time is brain”—it’s important to get a clot dissolved as soon as possible. Today, with M.S., there is a similar emphasis on early treatment, since time is both brain and spinal cord. “She is going to get married in November, and I want her to have a good wedding, walk down the aisle,” Sadiq said.

Sadiq, who is sixty-eight, is fond of describing himself as a “very boring-in-general guy,” and “just an old man working” who occasionally attends a Yankees game. “But I am too busy, so mostly I give my tickets away,” he added. His wife died of ovarian cancer last year, and his son is in his thirties. Sadiq lives in New Jersey with his mother, who is a healthy ninety. “This is my dream, I love what I do, my life is this,” he said of his research and clinical practice. He feels that he has “limited time,” and told me, “I hope to find these things”—better treatments for M.S.—“quickly.”

Sadiq was born in Kenya, and graduated from the University of Nairobi’s medical school in 1979. He did his residency in internal medicine in Kenya and in the U.K. between 1981 and 1985, and so has witnessed the arc of how dramatically M.S. outcomes have changed in the past half century. “When I was in school, and in residency, M.S. was a dead-end disease. It overwhelmingly led to disability,” he told me in his office, which is decorated with model ships, Yankees paraphernalia, illuminated Torah passages, golden Virgin Mary icons, and other gifts he has received during his decades as a neurologist. The patient was often a young woman, since M.S. affects women three times as often as men and tends to present in a person’s twenties or thirties. Part of the terror of M.S. was not knowing when an attack—which might manifest as a loss of sensation, or a loss of vision, or a loss of strength, or any other number of troubling losses—would come. Patients were not unlikely to end up confined to a wheelchair, or to have a sense of pressure on their chest, a dread of warm days, trouble seeing or blindness, or difficulty controlling their bladder and bowel movements; sometimes holding a pencil was a challenge. “If the patient was young, you would not tell her about her prognosis for as long as you could,” Sadiq said. “That seems crazy to me now. But that was what was done. You told the parents or the spouse, but not the patient.”

In 1985, Sadiq moved to Galveston, for a residency in neurology at the University of Texas. It was, he said, “the year after MRIs came into widespread clinical use.” MRIs are now commonplace, but they’re still astonishing: after you’re slid into an MRI machine, all the water molecules in your body orient themselves along the lines of a magnetic field, as if saluting; radio energy is then pulsed through the body, which stimulates the protons of those water molecules to varying degrees, depending on the part of the body. MRIs are thus particularly good at imaging soft tissues, such as muscles, abdominal organs, and the brain, where the lesions typical of M.S. show up. “Previously, you were working with subjective complaints,” Sadiq explained. “Now you could objectively characterize the lesions.” In early years, MRIs were used only for diagnosis, because the machines were rare; now they’re also used to monitor disease progression.

MRI imaging is not just about helping a doctor “believe” a patient’s story, or giving a patient the validating feeling of “seeing” her illness—it also opens up research possibilities, by enabling physicians to share a common language that is quantitative and transmissible (if still limited, since MRIs are just fancy pictures, and cannot explain all that a patient experiences). Whereas the move to make more room for a patient’s subjective experience helps in individual cases, the ability to speak both generally and precisely helps when thinking of a disease across thousands, or hundreds of thousands, of cases. If you were to think of the research trajectory of M.S. as a nineteenth-century novel, then the arrival of the MRI would be a decisive plot turn; in the data-mining storytelling of the twenty-first century, the change comes from the networks of thousands of patients and researchers coördinating and building up a body of knowledge bit by bit.

Multiple sclerosis presents far more variously than most other illnesses; for that reason, it has been called “the great imitator.” Some of the conditions it can resemble are minor, and others are major. If you have ever Googled a random tingling or twinge or eyebrow twitch, you have probably spent at least one evening convinced that you have M.S. On the other hand, M.S. patients often think for a while that they don’t have much going on. One person’s first symptom might be numbness. A different patient might experience weakness. Or an unexplained fall, or fatigue, or difficulty urinating or walking. In the United States, the incidence is around three people in a thousand, which is either rare or common, depending on the emotional heft you ascribe to a third of one per cent of the population.

Until recently, patients weren’t given medication before they were in distress; now treatment tends to come early, with the highest-efficacy drugs available. Oh, of the Barlo center, told me, “When I went into neurology residency”—in 2005—“the field was still sometimes called ‘diagnose and adios,’ because it seemed like there was so little that could be done for patients with these chronic neurological diseases,” such as M.S., Parkinson’s, A.L.S., and Alzheimer’s. “M.S. is the only chronic neurological disease where there’s been a very dramatic change.” In 1993, there were no approved M.S.-specific drug therapies; now there are more than twenty. Some treatments broadly target a patient’s immune response, and others interfere with the production of particular elements of the immune response which attack the patient’s nervous system. A study from Turkey comparing the records of an M.S. clinic in 1996 with those at the same clinic twenty years later showed a dramatic decline in the number of wheelchair-dependent patients—a particularly visible measure of disease.

When I spoke with Oh, she had been asked to address an A.L.S. conference, so that A.L.S. researchers might learn from the M.S. community. I asked her what she thought accounted for the progress; she talked about how visible the disease is, especially because it most often hits young people. “I don’t want that to sound ageist,” she said. It’s not unusual to know someone for whom the course of family and work life has been remarkably altered by M.S.; that attracts funding. Oh’s center raised twenty-one million dollars for its launch, which her hospital matched. The facility, which treats nine thousand patients, has expanded from four clinic rooms to twenty; its research and clinical arms are now on adjacent floors, and physical therapy, occupational therapy, and social work are also integrated into the space.

Jeffrey Cohen, the director of experimental therapeutics at the Cleveland Clinic’s Mellen Center for Multiple Sclerosis Treatment and Research, said, “The field does seem to be a little more organized. We have a well-developed set of diagnostic criteria, and a well-developed methodology for testing treatments and deciding whether they work. But another part of it may be that success begets success.” When something goes well, funding tends to come your way to do more such work.

For centuries, the treatment of M.S. hardly advanced at all. In the fourteenth century, a physician wrote of a Dutch woman named Lidwina of Schiedam, “Believe me there is no cure for this illness, it comes directly from God.” Lidwina’s is one of the first documented instances of what was most likely multiple sclerosis. Her illness, at the time, was attributed not only to God but to a fall while ice skating; she is said to have celebrated her paralysis and pain as an offering to Him, and she is now the patron saint of ice skating. People tried to ameliorate M.S. with leeches, quinine, foxglove, tobacco, hemlock, valerian, coffee, tea, being suspended above the ground, vertically, for four minutes at a time, and being wrapped in sheets sprayed with cold water. The nineteenth-century German poet Heinrich Heine (“There are two kinds of rat / The hungry and the fat”) did not know what he was suffering from when he wrote to a friend, “My legs are like cotton and I am carried about like a child. . . . My right hand is beginning to wither and God knows whether I shall ever be able to write to you again. Dictation is painful because of my paralyzed jaw. My blindness is still the last of my ills.” Heine, who died at fifty-eight, had a gash on his neck, inflicted deliberately, to which various ointments were administered.

The underlying causes of the symptoms of M.S. began to be gleaned with the work of the nineteenth-century French physician Jean-Martin Charcot, who is today considered a founder of modern neurology. The son and the grandson of carriage-makers, and the oldest of four brothers, Charcot was chosen by his father as the child who would get a costly advanced education. He studied medicine at the University of Paris. His brothers kept his study cozy with a hot cannon ball resting in a bucket of sand. Upon becoming a physician, Charcot took a position at the Salpêtrière Hospital, an old ammunitions factory that had been turned into, in his words, a “great asylum (of human misery).”

Salpêtrière held some five thousand patients. They were affected by chronic diseases of many kinds, but especially those of the nervous system. “We are, in other words, in possession of some sort of museum of living pathology of great resources,” Charcot wrote. His great scientific move can seem, in retrospect, ordinary. He set about differentiating and classifying, by symptoms, the residents of Salpêtrière, and then following them over time—including after their deaths, by studying their cadavers.

One case in particular focussed his attention on the destruction he saw in the brains and the spinal cords of certain cadavers. Charcot had hired as a maid a woman named Luc, who had motor difficulties. Charcot noticed that Luc’s tremors worsened when she moved about, and subsided when she was at rest—a different pattern from that found in Parkinson’s. (Charcot, with his colleague Alfred Vulpian, was the first to distinguish the diseases.) Luc broke quite a few dishes. As her symptoms worsened, she had to be admitted to Salpêtrière. Did she have neurosyphilis? A tumor? When she died, in 1866, he studied her brain and her spinal cord. He saw what he called sclérose en plaque disseminée . His drawings of these lesions as he saw them under a microscope show droplets of myelin—the sheathing around a nerve—floating free from the axon, the body of the nerve. Charcot was a gifted artist, and often said that what made a good physician was the ability to see without preconceptions. We now understand that many of the varied symptoms of M.S. occur when the myelin around the axon frays. An analogy sometimes given is that the nervous system is like the wiring of a lamp, and the myelin like the wiring’s protective sheath; when that sheath wears away, so much can go wrong.

In 1868, Charcot gave a series of lectures on the condition, which remain the origin story for the field today. He said that he did not know the cause of the disease; that it was most common in females; that the symptoms were intermittent and could spontaneously improve and then worsen again; and that “the prognosis has hitherto been of the gloomiest.”

The physician T. Jock Murray, a specialist at Dalhousie University, in Nova Scotia, in his comprehensive book “Multiple Sclerosis: The History of a Disease,” from 2005, writes about how theories of the causes of M.S. have shifted in parallel with trends in medical science: “In the era of Pasteur”—the father of germ theory—“it seemed to be an infectious disease; in the era of environmental illness, it seemed a disease due to some toxin; when epidemiological techniques flourished, interest centered on mysterious demographic and environmental factors; as immunology flourished, it became an immunological disease, and in this age of genetics, gene probes, and the human genome, there is great interest in a genetic factor.” This makes it sound as if each theory were later debunked, but Murray explains that the process of discovery was in reality cumulative. Cohen, of the Cleveland Clinic, summed up the current understanding: “Ultimately, we don’t know the cause, but it’s generally the same as I was taught in medical school—some genetic predisposition to an autoimmune condition, and superimposed on that are some environmental factors, including infection, that either trigger the process or play an ongoing role.” Some research points to the Epstein-Barr virus, which virtually all M.S. patients have; yet it’s been estimated that more than ninety per cent of the general population has it, too.

“There have been many times where the field has undergone a paradigm shift in terms of what we think is important,” Oh, of the Barlo center, told me. Currently, the shift is toward trying to better understand the progressive aspects of the disease, and why it gets worse over time. Oh said, “Now we feel we really have gotten ahold of the acute inflammatory component”—the flare-ups that characterize R.R.M.S.—“and so that’s made it apparent that it’s the progressive component of the disease that we don’t really understand.” Oh is a lead researcher on a prospective study following a thousand M.S. patients in an effort to identify factors that cause progression.

Medical research is a strange salad of astonishing, horrifying, life-saving, intriguing, confusing, even sometimes boring activities. Charcot refused to experiment on animals, and famously had on his office door a sign that read “ Vous ne trouverez pas une clinique des chiens chez moi ” (“You won’t find a dog clinic here”). What kind of research methods are being used today?

Several papers that emerged recently from lab research at Sadiq’s center make this question vivid. Jamie Wong, a neuroscience researcher, was a lead author of a paper in Brain , published in February, which examined a number of antibodies found in the spinal fluid of P.P.M.S. patients. Wong had injected the spinal fluid of those patients into the spinal sac of mice, and determined that this provoked P.P.M.S.-like symptoms—weakness, in this case—in the animals. (The strength of the mice is measured by having them hold on to the tiny silver bar of a grip-testing machine.) When the antibodies were removed from patients’ spinal fluid prior to its injection into the mice, the animals showed no symptoms of M.S. Of the many small advances that lead to interventions, this was a pretty big one.

Wong’s background is in spinal-cord injury. She came to the center’s lab because she wanted to do work that was integrated with a clinical practice—she meets patients. “That reminds me why I’m doing this research,” she said.

At the time that Wong was performing her mouse studies, Sadiq was recruiting Nicolas Daviaud, a French neuroscientist, who then began an organoid research project at the center’s lab. Organoids are the almost impossibly strange thing you might guess they are: tiny organs, not connected to bodies, grown, sometimes in clusters of ninety-six, in what look like doll-house ice trays. Since M.S. is a disease of the central nervous system, the relevant organoid for research is a brain. Daviaud grows miniature brains, each of which bears the DNA of a patient. He and other researchers can then study how M.S. progresses differently—which neural tissue is affected, and when—according to an individual’s genetic background, using these miniature brains.

Or, sort of brains. I spoke with Madeline Lancaster, a developmental biologist who runs a team at the M.R.C. Laboratory of Molecular Biology and who developed cerebral organoids. “They are not really brains—they are simplified brain tissues,” she said. She brought out some preserved cerebral organoids that she keeps in her purse to help people understand what they are. Their containers looked like dice for playing Dungeons & Dragons. She observed that, unlike a human brain, which has one cerebral cortex, an organoid can have more than twelve—but that it still has three layers of neural tissue around a fluid-filled ventricle, like a developing human brain. I asked—of course I did—if she worried that the organoids might achieve consciousness. She was patient. She said, “It’s hard to define consciousness, but it’s relatively easy to say what some of the prerequisites are.” She mentioned needing neural connections between parts of the brain, as well as a way for information to get into the brain and out of it: “An animal that can’t interact with its environment but that can still see—functionally it’s blind.” Basically, a brain needs a body.

Daviaud has a similarly untroubled relationship to the cerebral organoids he has nourished and grown. He explained his process to me: he takes hematopoietic stem cells, which we all have in our blood, and helps them multiply, then reprograms them into pluripotent stem cells, which are able to become any kind of cell at all. You may remember the controversy around whether researchers should be allowed to use stem cells from unwanted embryos. What few people seem to know is that this ethical conundrum was circumvented when a Japanese researcher named Shinya Yamanaka found a way to turn any old cell—hair, skin, blood—into a cell that, like an embryonic stem cell, can become almost any other kind of cell. (He was awarded the Nobel Prize for this work.) The process is “surprisingly simple,” Daviaud said. He grows the organoids for about forty-five days, at which point they are a few millimetres in diameter.

Sadiq and Daviaud intend to use cerebral organoids to try to answer a number of questions, including how the Epstein-Barr virus affects neural tissue. Scientists also believe that organoids might be used to test drugs directly on human nervous tissue, and to produce spinal fluid or other cells that might be useful in therapies. “But we have so much we’d need to know before then, like what if these cells keep developing and become cancers?” Sadiq said.

M.S. researchers have also begun to dream about actually repairing damage from the disease. Several early-stage clinical trials in the U.S. are exploring the use of mesenchymal stem cells, modified in the lab and injected into the spinal fluid of patients with progressive forms of M.S., in the hope of reversing the disease’s progression. Lauren Louth, a forty-four-year-old nurse, recently participated in a two-year clinical trial at Sadiq’s center that was based on work by the researcher Violaine Harris, who has been affiliated with the center since its founding. The trial had what is called a compassionate crossover structure: half the patients received the stem-cell injections while the other half received a placebo; then, after a year, the treatments were switched, so that all the patients had access to the potential treatment. Louth first learned of her M.S. when she was working in an emergency room in 2005; she remembers looking at a patient and seeing double. She mentioned this to the doctor she was working with, and received an MRI and a probable diagnosis before her shift was over. “I told my fiancé, ‘The wedding is cancelled, we’re not getting married, you’re not changing my diapers,’ ” she said. (She is now married to that fiancé and has two kids.)

Her symptoms worsened over time. Walking became difficult, her cognition declined, and she experienced a tightness known as an “M.S. hug.” She lost some dexterity in her left hand, which is her dominant hand. “I would wake up and feel so heavy-headed, thinking, What will I lose today?” she said. She lived with the disease, sometimes taking medications for it and sometimes not, for many years. Then, in a particularly low moment, she travelled from her home in Rhode Island to see Sadiq, whom she had not met before. She wanted to ask his opinion about stem-cell therapies.

Louth ended up being Patient 48 in the stem-cell trial run by Sadiq’s center. On paper, only small benefits over the placebo were seen, and only in patient groups with higher disability scores; for that subgroup, walking times improved, and also bladder function. Louth told me about her subjective experience of the treatment: “I feel sharper. That brain fog, that feeling of flightiness, where you’re everywhere but where you’re supposed to be”—she felt that it had lifted, and that her heat intolerance became “pretty much nonexistent.” For the first time in a long time, she enjoyed rather than feared summer. Many doctors and patients say that the more difficult-to-measure symptoms—those that affect mood or cognitive function—are more important. Oh said that they are sometimes termed “silent symptoms,” but “they are not at all silent for patients.”

After the stem-cell trial, Louth “started having stability of symptoms,” she said. “I don’t wake up every morning thinking about what I will lose.” Subjective reports are both more and less reliable than objective ones, in that they capture hope and happiness, and the state of our inner lives, which most humans agree are among the highest priorities.

Sadiq isn’t all reason and numbers. Louth recalled that he told her he had prayed that he would be able to help her. Different emotional narratives coalesce around different diseases: it is not unusual to think of cancer as an invader; to think of autoimmune diseases as a betrayal of self; to think of neurological diseases as a sort of ghost or a supernatural takeover. It’s not surprising, in that narrative, to learn that Charcot tried to hypnotize patients who had been diagnosed as hysterics. He held Tuesday-afternoon demonstrations, equipped with theatre lighting and a stage, which were akin to exorcisms. His most famous patient, Blanche Wittman, would go onstage and, in front of an audience that sometimes included Guy de Maupassant and Degas, cower as if seeing a snake, or bark orders as if directing troops—and then later have no memory of these acts. Some of Charcot’s colleagues were appalled by the scenes, which they saw as a return to the pseudoscience of mesmerism. Charcot himself was also disturbed. That humans were so suggestible seemed like something science would need to account for. “In the last analysis, we see only what we are ready to see, what we have been taught to see,” Charcot, the teacher of Sigmund Freud, said. After Charcot died, of heart disease that he had self-diagnosed, Blanche Wittman never had an attack of hysteria again. ♦

An earlier version of this article misstated the city to which Sadiq moved in 1985.

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Expert Voices: Current state of MS treatments and cure research

by BioNews Staff | February 9, 2022

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In this installment of our “Expert Voices” series, Multiple Sclerosis News Today asked Tim Coetzee, PhD, some of your questions related to the current state of multiple sclerosis (MS) treatment and cure research.

Coetzee serves as the National MS Society’s chief advocacy, services, and science officer. In this capacity, he leads the society’s work in state and federal advocacy, delivery of services and connection programs, healthcare professional engagement and training, and the society’s global research programs.

Most recently, he served as the president of Fast Forward , a venture philanthropy of the National MS Society where he was responsible for strategic funding of biotechnology and pharmaceutical companies as well as partnerships with the financial and business communities. Prior to Fast Forward, he led the society’s global research initiatives on nervous system repair and protection in multiple sclerosis as well as the society’s fellowship and faculty award programs. 

Prior to joining the society, Coetzee held faculty appointments at the University of Connecticut Health Sciences Center where he conducted research into the structure and function of myelin. He received his PhD in molecular biology from Albany Medical College in 1993 and has since been involved in the field of MS research. Coetzee has been with the National MS Society since fall 2000. 

What in the MS therapy development pipeline most excites you?

Tim Coetzee’s role at the National MS Society includes organizing funding for innovative MS research conducted across the globe. (Photo courtesy of Tim Coetzee)

I am very excited by progress being made in the MS therapy development pipeline overall. Because of the advances in the science of MS, we now have a large number of treatments in various stages of testing for relapsing and progressive MS. One of the most exciting developments is with a group of treatments known as Bruton’s tyrosine kinase inhibitors , or BTKi. These treatments have shown great promise in Phase 2 clinical trials and now there are multiple Phase 3 clinical trials for various types of BTKi molecules. There’s reason to think that this type of approach may hold promise for stopping MS progression, but we won’t know until the larger trials are completed.

What has been most disheartening in the field of MS treatment research?

While I’m excited by the momentum in MS treatment development overall, I am also frustrated by the continued challenges in finding effective treatments for progressive MS. The recent approval of some modestly effective treatments for progressive MS is encouraging, but we have to do more. That’s why the National MS Society joined with other MS societies from around the world to launch the International Progressive MS Alliance . Recently, we published a scientific strategy paper where we discussed the challenges and opportunities in progressive MS. I am optimistic that by coming together, we can accelerate progress and find solutions for people with progressive MS.

It is also becoming clear that people from diverse backgrounds may not respond to MS therapies the same way. That’s why there’s a big push to make sure that clinical trials include participants of diverse races and ethnicities, and for more information from these trials about the backgrounds of participants and any differences seen in trial outcomes based on these characteristics.

Are there any specific aspects of MS that make finding a cure particularly difficult?

Finding cures for everyone with MS is our top priority, but as you note, this is also a big challenge. A big part of finding a cure is understanding what causes MS. To do that, we need to identify all relevant risk factors for MS, what windows of risk are, and determine whether any risk factor is necessary and sufficient to cause disease. We also need to understand contributions of genetic factors and environmental interactions to MS risk, along with understanding how the roles of sex, ethnicity, and race contribute to MS risk . Other key aspects focus on stopping disease activity in people living with the disease; in other words, putting it into permanent remission, and also restoring functions that have been lost through regenerative medicine and rehabilitation, wellness, and exercise strategies. Tackling these and other issues is a central part of the society’s Pathways to Cures Research Roadmap .

Which treatment research frontiers would you like to see get more funding?

There are a few areas that require additional focus by the global funding community. Progressive MS is a top priority given the major gaps in treatments. There is also a great need to address the lack of progress in developing effective treatments for managing symptoms and improving quality of life. The good news is that there are more researchers focused on symptom management and quality of life. This research has shown that by focusing on things like sleep, nutrition, and psychosocial behaviors, among others, people with MS may have less disease progression and better quality of life. Nevertheless, more needs to be done to accelerate the turning of these research advances into treatments.

What challenges typically impede trials in progressing from animal to human testing?

Often the biggest challenge in progressing a treatment from animal to human testing is our poor understanding of the biological target of the treatment. The animal models (most often, rodents) used for developing treatments don’t represent the full complexity of MS, and thus, something that works in animals may fail when it’s evaluated in people with MS. The research community has recognized this challenge and is working diligently to find new model systems that more accurately reflect MS disease mechanisms.

Many people with MS ask if there’s realistic hope to be found in stem cell therapies. Do you have thoughts on that?

Stem cell therapies hold promise, and there’s been significant progress made, but continued research is needed to determine the effectiveness and safety of different stem cells in treating MS and restoring function. The National MS Society reviewed evidence on the use of a particular type of stem cell therapy — autologous hematopoietic stem cell transplant (aHSCT) — for the treatment of MS and concluded that aHSCT is a good treatment option for some people, specifically for people who have very aggressive relapsing-remitting MS who have not benefited from disease-modifying therapies.

Stem cell therapy is an active area of research, and I encourage individuals to stay informed by visiting the society’s online resources on stem cells . There’s often a lot of hype around stem cell therapies, and it’s important to be informed to be able to separate facts from hype.

Are there any avenues of treatment or cure research that you feel people should have their eye on?

I am very excited by the research community’s continued focus on myelin repair to protect nerve connections and restore function. There are several clinical trials of myelin repair treatments underway and I am confident more are coming. While there have been some disappointments in this line of research, we are making breakthroughs, and I expect that myelin repair treatments will soon be part of what doctors use to treat MS.

Expert Voices is a monthly series involving a Q&A with an expert in the MS space about a specific topic. These topics and questions are curated from a survey in which we ask readers what they want to learn more about from experts. 

Multiple Sclerosis News Today  is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.

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• Patient Care & Health Information
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• Multiple sclerosis

Neurological exam

A complete neurological exam and medical history are needed to diagnose MS .

• Multiple sclerosis FAQs

Neurologist Oliver Tobin, M.B., B.Ch., B.A.O., Ph.D., answers the most frequently asked questions about multiple sclerosis.

So people who are overweight have a higher chance of developing MS and people who have MS who are overweight tend to have more active disease and a faster onset of progression. The main diet has been shown to be neuroprotective is the Mediterranean diet. This diet is high in fish, vegetables, and nuts, and low in red meat.

So this question comes up a lot because patients who have multiple sclerosis can sometimes get a transient worsening of their symptoms in heat or if they exercise strenuously. The important thing to note is that heat does not cause an MS attack or MS relapse. And so it's not dangerous. You're not doing any permanent damage if this occurs. Exercise is strongly recommended and is protective to the brain and spinal cord.

Scientists do not yet know which stem cells are beneficial in MS, what route to give them or what dose to give them or what frequency. So at the moment, stem cell treatments are not recommended outside of the context of a clinical trial.

Neuromyelitis optica spectrum disorder or NMOSD and MOG-associated disorder can give features similar to multiple sclerosis. These are more common in people of Asian or African-American ethnicity. And your doctor may recommend blood tests to exclude these disorders.

Well, the first drug approved by the FDA for treatment of multiple sclerosis was in 1993. Since then, over 20 drugs have become available for treatment of MS. And the potency of these drugs has increased over time to the point where we can almost completely suppress the inflammatory component of the disease. This would not be possible if patients like you did not enroll in research studies. There are many different types of research studies, not just drug trials, but also observational studies, as all of these enhance our understanding of the disease, hopefully to lead to even better cures for multiple sclerosis.

Well, the most important thing about having a diagnosis of multiple sclerosis is that you are at the center of your medical team. A comprehensive MS center is the best place for management of multiple sclerosis, and this typically includes physicians with expertise in multiple sclerosis, neurologists, but also urologists, physiatrists or physical medicine and rehabilitation providers, psychologists, and many other providers who have specialty interest in multiple sclerosis. Engaging this team around you and your particular needs will improve your outcomes over time.

There are no specific tests for MS . Instead, a diagnosis of multiple sclerosis often relies on ruling out other conditions that might produce similar signs and symptoms, known as a differential diagnosis.

Your doctor is likely to start with a thorough medical history and examination.

• Lumbar puncture (spinal tap)

During a lumbar puncture, also known as a spinal tap, you typically lie on your side with your knees drawn up to your chest. Then a needle is inserted into your spinal canal — in your lower back — to collect cerebrospinal fluid for testing.

• MRI multiple sclerosis lesions

Brain MRI scan showing white lesions associated with multiple sclerosis.

Your doctor may then recommend:

• Blood tests, to help rule out other diseases with symptoms like MS . Tests to check for specific biomarkers associated with MS are currently under development and may also aid in diagnosing the disease.
• Spinal tap (lumbar puncture), in which a small sample of cerebrospinal fluid is removed from your spinal canal for laboratory analysis. This sample can show abnormalities in antibodies that are associated with MS . A spinal tap can also help rule out infections and other conditions with symptoms like MS . A new antibody test (for kappa free light chains) may be faster and less expensive than previous spinal fluid tests for multiple sclerosis.
• MRI, which can reveal areas of MS (lesions) on your brain, cervical and thoracic spinal cord. You may receive an intravenous injection of a contrast material to highlight lesions that indicate your disease is in an active phase.
• Evoked potential tests that record the electrical signals produced by your nervous system in response to stimuli may be done. An evoked potential test may use visual stimuli or electrical stimuli. In these tests, you watch a moving visual pattern, as short electrical impulses are applied to nerves in your legs or arms. Electrodes measure how quickly the information travels down your nerve pathways.

In most people with relapsing-remitting MS , the diagnosis is straightforward and based on a pattern of symptoms consistent with the disease and confirmed by brain imaging scans, such as an MRI.

Diagnosing MS can be more difficult in people with unusual symptoms or progressive disease. In these cases, further testing with spinal fluid analysis, evoked potentials and additional imaging may be needed.

Brain MRI is often used to help diagnose multiple sclerosis.

• Care at Mayo Clinic

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Multiple sclerosis care at Mayo Clinic

• Explaining multiple sclerosis

There is no cure for multiple sclerosis. Treatment typically focuses on speeding recovery from attacks, reducing new radiographic and clinical relapses, slowing the progression of the disease, and managing MS symptoms. Some people have such mild symptoms that no treatment is necessary.

Multiple sclerosis research laboratory at Mayo Clinic

Treatments for MS attacks

• Corticosteroids, such as oral prednisone and intravenous methylprednisolone, are prescribed to reduce nerve inflammation. Side effects may include insomnia, increased blood pressure, increased blood glucose levels, mood swings and fluid retention.
• Plasma exchange (plasmapheresis). The liquid portion of part of your blood (plasma) is removed and separated from your blood cells. The blood cells are then mixed with a protein solution (albumin) and put back into your body. Plasma exchange may be used if your symptoms are new, severe and haven't responded to steroids.

Treatments to modify progression

There are several disease modifying therapies (DMTs) for relapsing-remitting MS . Some of these DMTs can be of benefit for secondary progressive MS , and one is available for primary progressive MS .

Much of the immune response associated with MS occurs in the early stages of the disease. Aggressive treatment with these medications as early as possible can lower the relapse rate, slow the formation of new lesions, and potentially reduce risk of brain atrophy and disability accumulation.

Many of the disease-modifying therapies used to treat MS carry significant health risks. Selecting the right therapy for you will depend on careful consideration of many factors, including duration and severity of disease, effectiveness of previous MS treatments, other health issues, cost, and child-bearing status.

Treatment options for relapsing-remitting MS include injectable, oral and infusions medications.

Injectable treatments include:

Interferon beta medications. These drugs used to be the most prescribed medications to treat MS . They work by interfering with diseases that attack the body and may decrease inflammation and increase nerve growth. They are injected under the skin or into muscle and can reduce the frequency and severity of relapses.

Side effects of interferons may include flu-like symptoms and injection-site reactions. You'll need blood tests to monitor your liver enzymes because liver damage is a possible side effect of interferon use. People taking interferons may develop neutralizing antibodies that can reduce drug effectiveness.

• Glatiramer acetate (Copaxone, Glatopa). This medication may help block your immune system's attack on myelin and must be injected beneath the skin. Side effects may include skin irritation at the injection site.
• Monoclonal antibodies. Ofatumumab (Kesimpta, Arzerra) targets cells that damage the nervous system. These cells are called B cells. Ofatumumab is given by an injection under the skin and can decrease multiple sclerosis brain lesions and worsening symptoms. Possible side effects are infections, local reactions to the injection and headaches.

Oral treatments include:

• Teriflunomide (Aubagio). This once-daily oral medication can reduce relapse rate. Teriflunomide can cause liver damage, hair loss and other side effects. This drug is associated with birth defects when taken by both men and women. Therefore, use contraception when taking this medication and for up to two years afterward. Couples who wish to become pregnant should talk to their doctor about ways to speed elimination of the drug from the body. This drug requires blood test monitoring on a regular basis.
• Dimethyl fumarate (Tecfidera). This twice-daily oral medication can reduce relapses. Side effects may include flushing, diarrhea, nausea and lowered white blood cell count. This drug requires blood test monitoring on a regular basis.
• Diroximel fumarate (Vumerity). This twice-daily capsule is similar to dimethyl fumarate but typically causes fewer side effects. It's approved for the treatment of relapsing forms of MS .
• Monomethyl fumarate (Bafiertam) was approved by the FDA as a delayed release medicine that has a slow and steady action. Because of its time release, it is hoped that side effects will be decreased. Possible side effects are flushing, liver injury, abdominal pain and infections.

Fingolimod (Gilenya). This once-daily oral medication reduces relapse rate.

You'll need to have your heart rate and blood pressure monitored for six hours after the first dose because your heart rate may be slowed. Other side effects include rare serious infections, headaches, high blood pressure and blurred vision.

• Siponimod (Mayzent). Research shows that this once-daily oral medication can reduce relapse rates and help slow progression of MS . It's also approved for secondary-progressive MS . Possible side effects include viral infections, liver problems and low white blood cell count. Other possible side effects include changes in heart rate, headaches and vision problems. Siponimod is harmful to a developing fetus, so women who may become pregnant should use contraception when taking this medication and for 10 days after stopping the medication. Some might need to have the heart rate and blood pressure monitored for six hours after the first dose. This drug requires blood test monitoring on a regular basis.
• Ozanimod (Zeposia). This oral medication decreases the relapse rate of multiple sclerosis and is given once a day. Possible side effects are an elevated blood pressure, infections and liver inflammation.
• Ponesimod (Ponvory). This oral medication is taken once a day with a gradually increasing dosing schedule. This medicine has a low relapse rate and has demonstrated fewer brain lesions than some other medications used to treat multiple sclerosis. The possible side effects are respiratory tract infections, high blood pressure, liver irritation and electrical problems in the heart that affect heart rate and rhythm.
• Cladribine (Mavenclad). This medication is generally prescribed as a second line treatment for those with relapsing-remitting MS . It was also approved for secondary-progressive MS . It is given in two treatment courses, spread over a two-week period, over the course of two years. Side effects include upper respiratory infections, headaches, tumors, serious infections and reduced levels of white blood cells. People who have active chronic infections or cancer should not take this drug, nor should women who are pregnant or breastfeeding. Men and women should use contraception when taking this medication and for the following six months. You may need monitoring with blood tests while taking cladribine.

Infusion treatments include:

Natalizumab (Tysabri). This is a monoclonal antibody that has been shown to decrease relapse rates and slow down the risk of disability.

This medication is designed to block the movement of potentially damaging immune cells from your bloodstream to your brain and spinal cord. It may be considered a first line treatment for some people with severe MS or as a second line treatment in others.

This medication increases the risk of a potentially serious viral infection of the brain called progressive multifocal leukoencephalopathy (PML) in people who are positive for antibodies to the causative agent of PML JC virus. People who don't have the antibodies have extremely low risk of PML .

Ocrelizumab (Ocrevus). This treatment reduces the relapse rate and the risk of disabling progression in relapsing-remitting multiple sclerosis. It also slows the progression of the primary-progressive form of multiple sclerosis.

This humanized monoclonal antibody medication is the only DMT approved by the FDA to treat both the relapse-remitting and primary-progressive forms of MS . Clinical trials showed that it reduced relapse rate in relapsing disease and slowed worsening of disability in both forms of the disease.

Ocrelizumab is given via an intravenous infusion by a medical professional. Infusion-related side effects may include irritation at the injection site, low blood pressure, a fever and nausea, among others. Some people may not be able to take ocrelizumab, including those with a hepatitis B infection. Ocrelizumab may also increase the risk of infections and some types of cancer, particularly breast cancer.

Alemtuzumab (Campath, Lemtrada). This treatment is a monoclonal antibody that decreases annual relapse rates and demonstrates MRI benefits.

This drug helps reduce relapses of MS by targeting a protein on the surface of immune cells and depleting white blood cells. This effect can limit potential nerve damage caused by the white blood cells. But it also increases the risk of infections and autoimmune disorders, including a high risk of thyroid autoimmune diseases and rare immune mediated kidney disease.

Treatment with alemtuzumab involves five consecutive days of drug infusions followed by another three days of infusions a year later. Infusion reactions are common with alemtuzumab.

The drug is only available from registered providers, and people treated with the drug must be registered in a special drug safety monitoring program. Alemtuzumab is usually recommended for those with aggressive MS or as second line treatment for patients who failed another MS medication.

Recent developments or emerging therapies

Bruton's tyrosine kinase (BTK) inhibitor is an emerging therapy being studied in relapsing-remitting multiple sclerosis and secondary-progressive multiple sclerosis. It works by mostly modulating B cells, which are immune cells in the central nervous system.

Stem cell transplantation destroys the immune system of someone with multiple sclerosis and then replaces it with transplanted healthy stem cells. Researchers are still investigating whether this therapy can decrease inflammation in people with multiple sclerosis and help to "reset" the immune system. Possible side effects are fever and infections.

Researchers are learning more about how existing disease modifying therapies work to lessen relapses and reduce multiple sclerosis-related lesions in the brain. Further studies will determine whether treatment can delay disability caused by the disease.

For primary-progressive MS , ocrelizumab (Ocrevus) is the only FDA-approved disease-modifying therapy (DMT). Those who receive this treatment are slightly less likely to progress than those who are untreated.

For secondary progressive MS , some might consider the use of FDA-approved disease modifying therapies such as ozanimod, siponimod and cladribine, which can potentially slow down disabilities.

Treatments for MS signs and symptoms

Physical therapy can build muscle strength and ease some of the symptoms of MS .

Therapy. A physical or occupational therapist can teach you stretching and strengthening exercises and show you how to use devices to make it easier to perform daily tasks.

Physical therapy along with the use of a mobility aid, when necessary, can also help manage leg weakness and other gait problems often associated with MS .

• Muscle relaxants. You may experience painful or uncontrollable muscle stiffness or spasms, particularly in your legs. Muscle relaxants such as baclofen (Lioresal, Gablofen), tizanidine (Zanaflex) and cyclobenzaprine may help. Onabotulinumtoxin A treatment is another option in those with spasticity.
• Medications to reduce fatigue. Amantadine (Gocovri, Osmolex), modafinil (Provigil) and methylphenidate (Ritalin) have been used to reduce MS -related fatigue. However, a recent study did not find amantadine, modafinil or methylphenidate to be superior to a placebo in improving MS -related fatigue and caused more frequent adverse events. Some drugs used to treat depression, including selective serotonin reuptake inhibitors, may be recommended.
• Medication to increase walking speed. Dalfampridine (Ampyra) may help to slightly increase walking speed in some people. Possible side effects are urinary tract infections, vertigo, insomnia and headaches. People with a history of seizures or kidney dysfunction should not take this medication.
• Other medications. Medications also may be prescribed for depression, pain, sexual dysfunction, insomnia, and bladder or bowel control problems that are associated with MS .
• Acetyl-L-carnitine: Can it relieve MS fatigue?
• Emerging treatments for multiple sclerosis

Clinical trials

Explore Mayo Clinic studies testing new treatments, interventions and tests as a means to prevent, detect, treat or manage this condition.

Lifestyle and home remedies

To help relieve the signs and symptoms of MS , try to:

• Get plenty of rest. Look at your sleep habits to make sure you're getting the best possible sleep. To make sure you're getting enough sleep, you may need to be evaluated — and possibly treated — for sleep disorders such as obstructive sleep apnea.
• Exercise. If you have mild to moderate MS , regular exercise can help improve your strength, muscle tone, balance and coordination. Swimming or other water exercises are good options if you have intolerance to heat. Other types of mild to moderate exercise recommended for people with MS include walking, stretching, low-impact aerobics, stationary bicycling, yoga and tai chi.
• Cool down. MS symptoms may worsen when the body temperature rises in some people with MS . Avoiding exposure to heat and using devices such as cooling scarves or vests can be helpful.
• Eat a balanced diet. Since there is little evidence to support a particular diet, experts recommend a generally healthy diet. Some research suggests that vitamin D may have potential benefit for people with MS .
• Relieve stress. Stress may trigger or worsen your signs and symptoms. Yoga, tai chi, massage, meditation or deep breathing may help.
• Exercise and multiple sclerosis
• Vitamin D and MS: Any connection?
• Vitamins for MS: Do supplements make a difference?

Alternative medicine

Many people with MS use a variety of alternative or complementary treatments or both to help manage their symptoms, such as fatigue and muscle pain.

Activities such as exercise, meditation, yoga, massage, eating a healthier diet, acupuncture and relaxation techniques may help boost overall mental and physical well-being in patients with MS .

According to guidelines from the American Academy of Neurology, research strongly indicates that oral cannabis extract (OCE) may improve symptoms of muscle spasticity and pain. There is a lack of evidence that cannabis in any other form is effective in managing other MS symptoms.

Daily intake of vitamin D3 of 2,000 to 5,000 international units daily is recommended in those with MS . The connection between vitamin D and MS is supported by the association with exposure to sunlight and the risk of MS .

Coping and support

Living with any chronic illness can be difficult. To manage the stress of living with MS , consider these suggestions:

• Maintain normal daily activities as best you can.
• Stay connected to friends and family.
• Continue to pursue hobbies that you enjoy and are able to do.
• Contact a support group, for yourself or for family members.
• Discuss your feelings and concerns about living with MS with your doctor or a counselor.

Preparing for your appointment

You may be referred to a doctor who specializes in disorders of the brain and nervous system (neurologist).

What you can do

• Write down your symptoms, including any that may seem unrelated to the reason why you scheduled the appointment.
• Make a list of all your medications, vitamins and supplements.
• Bring any clinical notes , scans, laboratory test results or other information from your primary care provider to your neurologist.
• Write down your key medical information, including other conditions.
• Write down key personal information, including any recent changes or stressors in your life.
• Write down questions to ask your doctor.
• Ask a relative or friend to accompany you, to help you remember what the doctor says.

What to expect from your doctor

Your doctor is likely to ask you questions. Being ready to answer them may reserve time to go over points you want to spend more time on. You may be asked:

• When did you begin experiencing symptoms?
• Have your symptoms been continuous or occasional?
• How severe are your symptoms?
• What, if anything, seems to improve your symptoms?
• What, if anything, appears to worsen your symptoms?
• Does anyone in your family have multiple sclerosis?

Questions to ask your doctor

• What's the most likely cause of my symptoms?
• What kinds of tests do I need? Do they require any special preparation?
• Is my condition likely temporary or chronic?
• Will my condition progress?
• What treatments are available?
• I have these other health conditions. How can I best manage them together?

In addition to the questions that you've prepared to ask your doctor, don't hesitate to ask other questions during your appointment.

• What is multiple sclerosis? National Multiple Sclerosis Society. https://www.nationalmssociety.org/What-is-MS. Accessed June 2, 2022.
• Daroff RB, et al. Multiple sclerosis and other inflammatory demyelinating diseases of the central nervous system. In: Bradley's Neurology in Clinical Practice. 7th ed. Philadelphia, Pa.: Elsevier Saunders; 2012. https://www.clinicalkey.com. Accessed June 2, 2022.
• Ferri FF. Multiple sclerosis. In: Ferri's Clinical Advisor 2019. Philadelphia, Pa.: Elsevier; 2019. https://www.clinicalkey.com. Accessed June 2, 2022.
• Olek MJ. Clinical presentation, course, and prognosis of multiple sclerosis in adults. https://www.uptodate.com/contents/search. Accessed June 2, 2022.
• Wingerchuk DM (expert opinion). Mayo Clinic, Phoenix/Scottsdale, Ariz. Jan. 21, 2019.
• Ciccarelli O. Multiple sclerosis in 2018: New therapies and biomarkers. The Lancet. 2019; doi: 10.1016/S14744422 (18)30455-1.
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• Lotze TE. Pathogenesis, clinical features, and diagnosis of pediatric multiple sclerosis. https://www.uptodate.com/contents/search. Accessed June 2, 2022.
• Kantarci OH, et al. Novel immunomodulatory approaches for the management of multiple sclerosis. Clinical Pharmacology & Therapeutics. 2014; doi:10.1038/clpt.2013.196.
• Olek MJ. Disease-modifying treatment of relapsing-remitting multiple sclerosis in adults. https://www.uptodate.com/contents/search. Accessed June 2, 2022.
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• Wingerchuk DM. Multiple sclerosis: Current and emerging disease-modifying therapies and treatment strategies. Mayo Clinic Proceedings. 2014; doi:10.1016/j.mayocp.2013.11.002.
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• National MS Society. Network of Pediatric MS Centers. https://www.nationalmssociety.org/What-is-MS/Who-Gets-MS/Pediatric-MS/Care-for-Pediatric-MS. Accessed June 2, 2022.
• Rodriguez M. Plasmapheresis in acute episodes of fulminant CNS inflammatory demyelination. Neurology. 1993; doi:10.1212/wnl.43.6.1100.
• Deb C. CD8+ T cells cause disability and axon loss in a mouse model of multiple sclerosis. PLoS One. 2010; doi:101371/journal.pone.0012478.
• FDA approves new drug to treat multiple sclerosis. U.S. Food & Drug Administration. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm549325.htm. Accessed June 1, 2022.
• Keegan BM (expert opinion). Mayo Clinic, Rochester, Minn. January 15, 2019.
• FDA approves new oral drug to treat multiple sclerosis. U.S. Food and Drug Administration. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm634469.htm. Accessed June 2, 2022.
• Kappos L, et al. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): A double-blind, randomized, phase 3 study. The Lancet. 2018; doi: 10.1016/S0140-6736(18)30475-6.
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• AskMayoExpert. Multiple sclerosis. Mayo Clinic; 2020.
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• Vumerity. National MS Society. https://www.nationalmssociety.org/Treating-MS/Medications/Vumerity. Accessed March 16, 2020.
• Gianfrancesco M, et al. Obesity during childhood and adolescence increases susceptibility to multiple sclerosis after accounting for established genetic and environmental risk factors. Obesity Research and Clinical Practice. 2014; doi.org/10.1016/j.orcp.2014.01.002.
• Pantavou KG, et al. Season of birth and multiple sclerosis: A systematic review and multivariate meta-analysis. Journal of Neurology. 2020; doi:10.1007/s00415019-09346-5.
• Cifu DX, et al., eds. Multiple sclerosis. In Braddom's Physical Medicine and Rehabilitation. 6th ed. Elsevier; 2021 https://www.clinicalkey.com. Accessed Jun. 2, 2022.
• Langer-Gould AM, et al. Racial and ethnic disparities in multiple sclerosis prevalence. Neurology. 2022; doi:10.1212/WNL.0000000000200151.
• Kasper LH, et al. Immunomodulatory activity of interferon-beta. Annals of Clinical and Translational Neurology. 2014; doi:10.1002/acn3.84.
• Goldschmidt CH, et al. Re-evaluating the use of IFN-B and relapsing multiple sclerosis: Safety, efficacy and place in therapy. Degenerative Neurological and Neuromuscular Disease. 2020; doi:10.2147/DNND.S224912.
• Kieseie BC. The mechanism of action of interferon-B in relapsing multiple sclerosis. Central Nervous System Drugs. 2011; doi:10.1007/s10067-008-0972-3.
• Betaseron. Bayer AG; 1993. www.bayer.com. Accessed Jun. 1, 2022.
• Hauser SL, et al. Ofatumumab versus teriflunomide in multiple sclerosis. The New England Journal of Medicine. 2020; doi:10.1056/NEJMoa1917246.
• Kesimpta. Novartis; 2020. www.novartis.com. Accessed Jun. 1, 2022.
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• Olek MJ. Treatment of progressive multiple sclerosis in adults. https://www.uptodate.com/contents/search. Accessed Jun. 2, 2022.
• Wingerchuk DM, et al. Disease modifying therapies for relapsing multiple sclerosis. British Medical Journal. 2016; doi:10.1136/bmj.i3518.
• Saadeh RS, et al. CSF kappa free light chains: Cutoff validation for diagnosing multiple sclerosis. Mayo Clinic Proceedings. 2022; doi:10.1016/j.mayocp.2021.09.014.
• Goldschmidt C, et al. Advances in the treatment of multiple sclerosis. Neurologic Clinics. 2021; doi:10.1016/j.ncl.2020.09.002.
• Bafiertam. Banner Life Sciences LLC; 2013. www.bannerls.com. Accessed Jun. 1, 2022.
• Baliertam delayed release capsule. Banner Life Sciences LLC; 2013. www.bannerls.com. Accessed Jun. 1, 2022.
• Oral ponesimod versus teriflunomide in relapsing multiple sclerosis (OPTIMUM). ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02425644. Accessed Jun. 2, 2022.
• Ponvory. Janssen Pharmaceuticals; 2021. www.janssen.com. Accessed Jun. 1, 2022.
• Torke S, et al. Inhibition of Bruton's tyrosine kinase as a novel therapeutic approach in multiple sclerosis. Expert Opinion on Investigational Drugs. 2020.
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• Reston, et al. Autologous hematopoietic cell transplantation for multiple sclerosis: A systematic review. Multiple Sclerosis. 2011; doi:10,1177/1352458510383609.
• Petrou P, et al. Beneficial effects of autologous mesenchymal stem cell transplantation in active progressive multiple sclerosis. Brain. 2020; doi:10.1093/brain/awaa333.
• Liang J, et al. Allogenic mesenchymal stem cell transplantation in the treatment of multiple sclerosis. Multiple Sclerosis. 2009; doi:10.1177/1352458509104590.
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• Multiple sclerosis information page. National institute of neurological disorders and stroke. https://www.ninds.nih.gov/Disorders/All-Disorders/Multiple-Sclerosis-Information-Page. Accessed Jun. 2, 2022.
• Sadovnick AD. Genetic background of multiple sclerosis. Autoimmunity Reviews. 2012; doi:10.1016/j.autrev.2011.05.007.
• Demyelinating disease: What can you do about it?
• Infographic: Multiple Sclerosis
• Multiple sclerosis: Can it cause seizures?
• Myelin damage and the nervous system
• Physical therapy for multiple sclerosis
• What is multiple sclerosis? An expert explains

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Research Funded by the National MS Society

Pathways to cures.

• Read more about our funded research on STOPPING MS
• Read more about our funded research on RESTORING function
• Read more about our funded research on ENDING MS through prevention

Track Record of Progress

• Recruited and provided training to more than 1,000 new MS researchers to the field
• Provided early career support and funding to many thought leaders in MS research
• Set standards in diagnosis, symptom management, pediatric MS, integrative therapies, rehabilitation and wellness research, clinical trial strategies and stem cell research
• Targeted highly promising areas of research, such as race and gender differences — to expedite progress and set the stage for clinical trials
• Helped launch the MS field of nerve and myelin repair, which resulted in trials of repair strategies to restore function for people living with MS
• Drove research uncovering genes that contribute to MS susceptibility and new treatment avenues, and funded pivotal findings on the role of EBV and other viral triggers of MS
• Funded a groundbreaking study that produced a scientifically sound measure of the prevalence of MS to help us better understand the disease and find solutions
• Paved the way for the development of disease-modifying therapies for MS and launched a unique commercial research funding program to support the creation of new treatment strategies

Global Collaboration

• We fostered the creation of the International Progressive MS Alliance , an unprecedented global collaboration of MS organizations, researchers, health professionals, the pharmaceutical industry, companies, trusts, foundations, donors and people affected by progressive MS — working together to address the unmet needs of people with progressive MS.
• We led the MS Outcome Assessments Consortium , working toward creating robust clinical outcome measures to improve and speed MS clinical trials of new therapies.
• Our funding supported the International MS Genetics Consortium in completing the largest MS genetics study to date .
• We provided seed funding to create the International MS Microbiome Consortium to understand how gut bacteria influence MS and seek probiotic solutions
• With ECTRIMS, the Society supports the International Advisory Committee on Clinical Trials in MS, which provides guidance on planning clinical trials for new agents for the treatment of MS, improving diagnosis and other critical issues
• We held the first-ever Pathways to Cures Global Summit, convening nearly 200 participants from 15 countries. The summit reviewed recent scientific advances, refined the Pathways roadmap and developed a global strategy of collaboration and alignment of investments into areas of high opportunity to speed the development of MS cures.

Multiple Sclerosis Diagnoses Are Rising—And Doctors Don’t Know Why

The risk of an American developing MS is now roughly 1 in 333.

“It all looks normal,” Rebeckah Price’s first optometrist told her on January 3, 2023. Inside of the small, sterile room, the then-46-year-old, single mother of three was hunting for answers after the vision in her left eye rapidly deteriorated over the previous 30 days, leaving her scared and shaken. The vision in her eye was like a fogged bathroom mirror post-shower, one she wasn’t able to wipe clear.

“My heart sank,” Price says. “I do all these wellness things. I didn’t want to receive this [news], and so I told them ‘maybe it’s just stress,’ and I went home.”

By Valentine’s Day she was officially diagnosed with relapsing-remitting MS (RRMS)—one of four different types of MS, which includes clinically isolated syndrome (CIS), primary progressive MS (PPMS), and secondary progressive MS (SPMS).

The Toronto-based yoga teacher and Nike trainer is certainly not alone in her diagnosis, as cases are on the rise domestically and abroad.

As of 2023, 2.9 million people across the globe are living with the disease—up from 2.3 million in 2013, according to the International MS Federation . In the U.S., an estimated 1 million people had MS in 2019, which is about two times greater than previous reports from the previous national study done way back in 1975, according to a National MS Society –funded Multiple Sclerosis Prevalence Workgroup. (Just FYI, the population has not also doubled in this time period; it went from roughly 216 million in ’75 to 328 million in 2019.) This means the risk of an American developing MS is now roughly 1 in 333.

On a global scale, the number of people living with MS increased in every World Health Organization (WHO) region in the world between 2013 and 2020, according to a review published in the National Library of Medicine using the Atlas of MS data .

Yet doctors and experts still don’t have a super clear answer as to why the rates are increasing so noticeably and so fast.

“That’s the billion dollar question,” says Michelle Fabian, MD, associate professor of neurology at the Icahn School of Medicine at Mount Sinai. “It’s been a tough nut to crack for the research community.

Here's a quick primer on multiple sclerosis.

MS is an autoimmune disease that attacks myelin—the fatty insulation that surrounds the nerves in the spinal cord and brain. In severe cases, MS can attack the axon, the nerve fibers responsible for transmitting electrical impulses. Think of your nerves like an iPhone charging cord (with the external insulation playing the role of myelin), says Dr. Fabian. If a cord is simply frayed, you can probably still use it. But if the smaller wires within the cord’s casing are affected, the cord will be almost useless.

Myelin degeneration can result in scarring, or lesions on the nerves, most commonly in the brain and spinal cord, which in turn can cause coordination issues, dizziness, muscular weakness, sensation loss, and slurred speech. One of the most common symptoms is vision changes (like the one Price experienced), when the immune system attacks the optic nerve connecting the eye to the brain.

Something to note: MS symptoms typically last for at least 24 hours, typically longer, according to Elena Grebenciucova, MD, assistant professor of neurology at Northwestern University in Chicago. So, if you’re experiencing a light tingling for a minute or so, it’s not necessarily something that should make you rush to your doctor.

Experts think there could be multiple factors at play when it comes to the baffling rise in cases.

There’s no magic bullet or clear answer just yet, but experts like Marwa Kaisey, MD, assistant professor of neurology at Cedar-Sinai Medical Center, attribute the increase to greater life expectancy and the adoption of more specific in-depth diagnostic criteria, which offers a really clear picture of what conditions must be present to indicate that a person has MS.

For example, in order for a doctor to confirm a patient has MS, they must do three things: Find evidence of damage in at least two separate areas of the central nervous system (hence, the “multiple” in “multiple sclerosis”) which includes the spinal cord and brain, find evidence that the damage occurred at different points in time, and rule out all other possible diagnoses. This diagnostic criteria, which was written in 2017, is helping doctors diagnose more patients with MS, when originally, they might have been diagnosed with another condition.

And, for reasons that are also still unclear and currently being studied, MS is more prevalent in women than men, Dr. Kaisey says. In fact, MS affects two to three times as many women as men, the International MS Federation estimates. (Dr. Fabian points out that women are, in general, more prone to other autoimmune conditions like lupus and rheumatoid arthritis .)

Another possible factor impacting this rise in MS rates? Fewer women are having children.

“Women are waiting longer to have kids, and we’ve seen that pregnancy actually can decrease the risk of MS,” says Dr. Fabian. The biological changes that occur during pregnancy include tamping down a lot of inflammation in the body which can trigger MS. Additionally, pregnancy hormones can, at times, positively affect the immune system, which can lessen the symptoms of MS, according to the National Multiple Sclerosis Society .

One review out of the University of California, Berkeley, also cites childhood obesity as a contributing factor to higher rates of MS in women (rates currently sit around 19.7 percent in the U.S., according to the CDC). Having childhood obesity often results in getting a first period at a younger age, and according to Dr. Kaisey, this, along with many other factors like diet and gut microbiome health , increases the risk of developing MS.

This rise in diagnoses does have a surprising upside.

With greater awareness around the disease, more people are finding answers to their health symptoms sooner, says Dr. Grebenciucova. And that’s a good thing.

Megan Monahan, who was diagnosed with RRMS in her late 30s, first experienced health issues at 22, triggering gallstones and surgery, leaving her without a gallbladder and with chronic hives for over eight months. The Los Angeles–based meditation teacher doesn’t know if there’s any correlation between her MS and the events of her 20s, but she’s thankful to finally be getting answers, empowering her on a path to health and healing—physically and emotionally.

“I spent the first 20-some years of my life kind of like, ‘I’m fine-ing’ my way through,” she says . “I can’t help but wonder if I had [received] an MRI 10 years ago, would the lesions have been there?”

Monahan and Price would do almost anything to reverse the damage MS has wreaked on their bodies and lives. “I don’t wish this disease on anyone. It’s one of the most awful things I’ve ever had to endure,” Price says. “Whether you have MS or not, I hope that women everywhere learn how to hold space for themselves—on their terms. Every day is a fight, don’t give up.”

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Advances in multiple myeloma treatment

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By Jason Howland

Multiple myeloma is a blood cancer that most often occurs in people over age 45. It's the second-most common blood cancer and the most common blood cancer in Black people.

Right now, there is no cure for the disease. But as Dr. Joselle Cook, a Mayo Clinic  hematologist , explains, recent advances in treatment are helping people live longer. And as multiple myeloma research continues, a cure may someday be on the horizon.

Watch this "Mayo Clinic Minute" video to hear Dr. Cook discuss multiple myeloma:

Multiple myeloma is a cancer that forms in a type of white blood cell called a plasma cell that builds up in bone marrow.

"Some of these plasma cells develop mutations over time and become abnormal and produce an abnormal protein. We call it an immunoglobulin, or in our world, we call it a monoclonal protein. And so that can cause damage over time," says Dr. Cook.

The damage caused by multiple myeloma can lead to  anemia , bone pain, frequent infections and  kidney failure .

"The treatment involves … we call it plasma cell directed therapy," says Dr. Cook. "It's treatments that are specifically directed at the immune system. So it's usually a combination of three or four drugs."

Other advances in treatment include  bone marrow transplant , in which a person's own stem cells are infused after high-dose chemotherapy to rebuild and regenerate healthy bone marrow.

"We've seen new therapies like  CAR-T , or chimeric antigen receptor-T cell therapy, where we're taking people's T cells, we're engineering them to specifically recognize a myeloma cell," says Dr. Cook.

Because of advances like these, the prognosis for patients with multiple myeloma continues to improve.

"Several years ago, people would say that the survival was three to five years. And I would say now, median or average survival is about 10 years or even longer," says Dr. Cook. "Hopefully, we can extend the expected survival beyond 20 years and maybe eventually find a cure in my lifetime, I hope."

Learn more about multiple myeloma and find a clinical trial at Mayo Clinic.

Join the Blood Cancers and Disorders Support Group on Mayo Clinic Connect , an online community moderated by Mayo Clinic for patients and caregivers.

Also, read these articles:

• Hope, time and new options after CAR-T cell therapy for multiple myeloma
• Multiple myeloma: Its evolution, treatment and the quest to catch it early
• No place like home: David Elder’s post-transplant care a ‘blessing’

A version of this article was originally published on the Mayo Clinic News Network .

Related Posts

After receiving CAR-T cell therapy at Mayo Clinic, Welsh-born John Cadwallader achieved remission and found new hope. He now receives care in the U.K. and is monitored by Mayo in the U.S. and London.

Dr. Joselle Cook discusses how multiple myeloma evolves, its treatment and research into screening methods.

Mayo Clinic's Advanced Care at Home program helped David Elder recover at home from a bone marrow transplant to treat his multiple myeloma.

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Pathways to cures for multiple sclerosis: A research roadmap

Bruce f bebo, jr.

National Multiple Sclerosis Society 733 3rd Ave New York, NY 10017 USA

Mark Allegretta

Douglas landsman, kathy m zackowski, fiona brabazon, walter a kostich, timothy coetzee, alexander victor ng.

Department of Physical Therapy, Marquette University, Milwaukee, WI, USA

Ruth Ann Marrie

Department of Internal Medicine (Neurology), University of Manitoba, Winnipeg, MB, Canada

Kelly R Monk

Vollum Institute, Oregon Health & Science University, Portland, OR, USA

Amit Bar-Or

Center for Neuroinflammation and Neurotherapeutics, Multiple Sclerosis Division, Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

Caroline C Whitacre

Background:.

Multiple Sclerosis (MS) is a growing global health challenge affecting nearly 3 million people. Progress has been made in the understanding and treatment of MS over the last several decades, but cures remain elusive. The National MS Society is focused on achieving cures for MS.

Objectives:

Cures for MS will be hastened by having a roadmap that describes knowledge gaps, milestones, and research priorities. In this report, we share the Pathways to Cures Research Roadmap and recommendations for strategies to accelerate the development of MS cures.

The Roadmap was developed through engagement of scientific thought leaders and people affected by MS from North America and the United Kingdom. It also included the perspectives of over 300 people living with MS and was endorsed by many leading MS organizations.

The Roadmap consist of three distinct but overlapping cure pathways: (1) stopping the MS disease process, (2) restoring lost function by reversing damage and symptoms, and (3) ending MS through prevention. Better alignment and focus of global resources on high priority research questions are also recommended.

Conclusions:

We hope the Roadmap will inspire greater collaboration and alignment of global resources that accelerate scientific breakthroughs leading to cures for MS.

Introduction

Multiple Sclerosis (MS) is a growing global health challenge affecting nearly 3 million people with significant public health and economic impacts. 1 While substantial progress has been made in the development of more than a dozen effective disease-modifying treatments (DMTs) for relapsing forms of MS, we still lack a fundamental understanding of all the pathological processes driving disease, we lack effective treatments for progressive forms of MS, and cures remain elusive. The National Multiple Sclerosis Society is focused on achieving breakthroughs to cures for MS. Progress toward this goal will be hastened by having a roadmap that describes the knowledge gaps, milestones, and research priorities that will lead to cures for everyone living with this condition.

In this report, we share the Society’s Pathways to MS Cures Research Roadmap. The Roadmap was developed with input from scientific experts, health care providers, and people affected by MS from the United States, Canada, and the United Kingdom ( Table 1 ). The Roadmap has also been endorsed by leading MS patient and professional organizations ( Table 2 ). We hope the Roadmap will inspire greater collaboration and alignment of global resources that accelerate scientific breakthroughs leading to cures for MS. Achievement of this ambition will require enhanced engagement of global stakeholders and implementation of a range of new approaches.

Pathways to cures roadmap advisors.

Organizations endorsing the Roadmap.

MS: multiple sclerosis.

Development of the roadmap

The Roadmap was developed through a consensus building process that included the National MS Society’s Scientific Advisory Committee, National Board of Directors, and the Pathways to Cures Task Force-composed of scientific thought leaders and people affected by MS ( Table 1 ). In addition, the perspectives of over 300 people with MS were obtained and incorporated in the Roadmap through a survey conducted in collaboration with the Accelerated Cure Project for Multiple Sclerosis. This survey established that the definition of a cure was different depending on an individual’s perspective, but the responses could be grouped into three main categories: (1) stopping the MS disease process, (2) restoring lost function by reversing damage and symptoms, and (3) ending MS through prevention. These perspectives are consistent with what we and others have learned through various outreach efforts and largely align with findings of other MS organizations.

The scientific foundations of the Roadmap were developed and refined by the Task Force and Scientific Advisory committees. Subsequently, the Roadmap was endorsed by many leading global MS patient and professional organizations, research funders, and other stakeholders ( Table 2 ). We hope that the Roadmap and the stakeholder endorsements will inspire greater alignment of resources on research that accelerates progress toward scientific breakthroughs that lead to cures for MS. In the following paragraphs, we outline the key objectives, barriers, potential solutions, and recommendations for implementation of strategies to advance each of the pathways in the Roadmap.

The stop pathway

The Roadmap defines stopping MS as achieving a state of no new disease activity or central nervous system (CNS) injury, no worsening of daily living or quality of life, and no change in disease manifestations. By stopping all forms of disease activity and tissue injury, we prevent the accumulation of disability and create a permissive environment for myelin and axonal repair and other pathways that promote restoration of function. The opportunities for stopping MS disease activity span from the sub-clinical to later stages of disease ( Figure 1 ). The Stop pathway includes two major objectives: (1) Early Detection and (2) Precision Medicine.

The evolution of MS and opportunities for the discovery of cures.

Current knowledge

Much has been learned about the role of the immune system in MS pathogenesis, aiding the development of more than a dozen effective DMTs that target different cells, mediators, and pathways, with tremendous improvements in the quality of life for people with MS. 2 Most of these therapies directly modulate the adaptive immune system or impact immune cell trafficking. In addition, cell depletion/reconstitution therapies have shown promise in clinical studies of aggressive forms of relapsing MS. 3 Having many treatment options with different mechanisms of action and efficacy, adverse event profiles, and routes of administration creates an opportunity for health care providers to tailor their treatment approach for individuals with MS.

Despite successes in relapsing MS, there are far fewer therapeutic options for people living with progressive forms of MS. The lack of a full understanding of the pathophysiologic mechanisms driving progression is arguably the main reason why there are not better treatment options for this form of disease. Attention is turning to CNS-compartmentalized inflammation as a promising area of study. It is becoming clear that there are both protective and destructive interactions taking place between cells of the immune system and neurons and glia in the CNS. This knowledge is starting to reveal targets for possible interventions. In addition, there is a need for more sensitive and specific endpoints that would facilitate rapid proof-of-concept clinical trials and better animal models that more closely recapitulate the disease course and pathology of progressive MS.

Efforts at biological phenotyping are starting to lead to a better understanding of both relapsing and progressive disease heterogeneity and the identification new therapeutic targets. Recent single cell profiling studies have led to the discovery of multiple populations of peripheral immune cells as well as microglial cells, astrocytes, and oligodendrocytes that may allow more precise interventions to be developed. A recent machine learning study using data derived from thousands of MRI scans obtained from well-controlled clinical trials and cohort studies identified three MRI-defined MS subtypes that are independent of the clinically defined forms of disease. 4 The subtypes predict disability progression and may also have value in predicting treatment responses. While much attention has been focused on stopping MS with DMTs, certain comorbidities such as obesity and smoking have been shown to negatively impact disease progression. 5 Identifying approaches that promote lasting lifestyle changes and address comorbidities are also components of the this pathway.

Early detection

There is growing consensus on the importance of early application of disease-modifying interventions to minimize CNS damage, potentially delay the accumulation of disability, and maximize function. 6 This suggests that an earlier MS diagnosis or the identification of individuals at high risk for a future diagnosis could improve long-term outcomes. As many as 85% of individuals with clinically isolated syndrome (CIS) are diagnosed with MS within 2 years. 7 Early treatment of CIS with interferons, 7 , 8 glatiramer acetate, 9 or teriflunomide 10 has been reported to delay the ascertainment of MS and provide persistent long-term benefits. Identifying features of those who ultimately are diagnosed with MS will improve precision and enable early treatment of the high-risk subset.

There is emerging evidence that the MS disease process starts many years before it becomes clinically apparent and includes a prodromal phase characterized by non-disease-specific clinical symptoms. 11 Retrospective reviews of medical records and health utilization have uncovered evidence of increased healthcare usage 5 to 10 years before a first clinically evident demyelinating event or MS diagnosis. The types of symptoms reported such as pain, anxiety, and others do not provide the specificity needed for diagnosis but may be reflections of an underlying early disease process. Recent studies also provide evidence of axonal injury occurring years before an MS diagnosis. Longitudinal sampling from a cohort of US military veterans revealed that elevated serum neurofilament light chain (NfL) levels preceded MS diagnosis by 6 years. 12 Some individuals without clinical signs of MS are found to have brain lesions characteristic of MS. These asymptomatic individuals with so-called radiologically isolated syndrome (RIS) are also at an increased risk for an MS diagnosis. 13 More recently, an increased cerebrospinal fluid NfL concentration in RIS has been identified as a risk factor for diagnosis. 14 Not everyone with RIS or CIS will go on to develop an ascertained diagnosis of MS. The earliest phases of MS onset and development of biological markers, health data, and sociological features to help identify onset, define biology-based phenotypes, and improve the diagnostic process are needed. Identification of the prodromal period of MS necessitates a set of diagnostic tools with defined thresholds. There is an opportunity to intervene during this pre-clinical phase of MS and delay, reduce, or perhaps even stop the subsequent development of disability. While the focus of much of this work is on the adult population, we must not lose sight of the importance of addressing issues and opportunities for early detection in the pediatric population.

Precision medicine

MS is a heterogeneous disease, and each person with MS experiences the disease differently. Treatment choice is a personal decision balancing risk and efficacy and may also be influenced by the policies of payers. Early treatment is desirable and has been shown to impact long-term disease trajectory. 7 Research is underway to determine whether an escalation or higher-efficacy first-line treatment approach offers better long-term outcomes. Analysis of lesions over time and space suggests that different immune-effector mechanisms may predominate in individuals at different times. 15

Given that heterogeneity may also exist at the patient level, an evidence-driven approach that could prognosticate outcomes would help frame the full benefits and risks of any specific treatment and help guide the selection of an optimal therapy for a given patient at a given point in time. 16 , 17 In certain settings, nonclinical measures such as serum NfL and new MRI activity can discriminate between treatment and placebo groups, suggesting that monitoring treatment response is possible. 18 Learnings from other disease areas such as oncology, where precision medicine approaches have been incorporated as standard of care, could be helpful. MS clinicians already have experience utilizing precision medicine in clinical practice. The determination of JC virus status prior to and during treatment with natalizumab is an example of precision medicine used to risk-stratify and monitor safety. 19 In addition, MRI is commonly used to track brain lesion activity as part of ongoing disease management. Additional non-invasive biomarkers are needed that will allow the tracking of different aspects of disease activity. Consideration should also be given to how precision medicine tools that improve MS treatment will be implemented by general neurologists and non-MS specialists.

The most advanced fluid biomarker in development is NfL. NfL is a neuronal structural protein released through any cause of neuroaxonal injury and can be monitored with a blood test. Numerous retrospective studies 20 , 21 and prospective analyses of phase 3 trials in relapsing MS 22 suggest that the concentration of NfL in serum, plasma, or cerebrospinal fluid can serve as a useful predictor of disease worsening at the population level. Correlations have been observed for acute disease activity and prediction of subsequent MRI lesion activity, brain volume loss, relapse rate, and worsening of disability. Recent studies on age and sex effects in normal adults show increased and more variable sNfL in subjects over 60 years of age. 22 Understanding normative characteristics for sNfL is essential to enable clinical utility. Other proteins such as glial fibrillary acidic protein (GFAP), released by astrocytes, are also being investigated as potential biomarkers.

Additional imaging and fluid biomarker approaches are needed that will further inform and possibly predict disease course and will allow tracking of neuroinflammation, myelination status, cortical lesions, and the distinct pathologies of relapsing and progressive MS. An improved understanding of genetic and environmental factors that influence disease course is also highly desirable. Data-driven algorithms combining clinical data and known genetic and environmental risk factors with biological and imaging biomarker data may present a pathway to optimized diagnosis, prognosis, disease activity monitoring and response to therapy that will lead us to stopping MS.

Recommendations

The relationship between acute inflammation, compartmentalized inflammation, and neurodegeneration needs to be better understood to allow more precise intervention and the development of new therapeutic approaches ( Table 3 ). Health data and sociological features collected from representative cohorts may help identify earlier onset and defining the variability of MS disease expression biologically may further improve the diagnostic process to allow treatment prior to accumulation of disability. Better biological markers and tools, including improved predictive models, will lead to a better understanding of the biology and heterogeneity of MS. Biomarkers informed by research into disease mechanisms, powered by carefully monitored cohorts with improved outcome measures, high-quality longitudinal samples, and curated data may enable an understanding of the prodromal phase. Finally, better coordination of properly collected longitudinal cohorts that include diverse populations of people with MS will be needed to answer these key epidemiological questions.

Stop pathway recommendations and research priorities.

The restore pathway

The Roadmap defines the Restore pathway as reversing symptoms and recovering function to enable full participation in society. While DMTs can limit the occurrence of relapses and in some cases delay disability worsening, they have limited capacity to enhance or restore function. This pathway explores the opportunity to enhance regeneration and remyelination, as well as focus on strategies to reverse symptoms and improve quality of life.

One focus is to integrate the study of pathophysiological mechanisms and their association with functional capacity, as well as rigorously evaluate the potential to enhance neuroplasticity, remyelination, and restoration of function. An integrated approach is needed that enhances remyelination, neural regeneration, and neuroplasticity, while optimizing the extent to which wellness behaviors, rehabilitation, self-care, and exercise promote reversal or diminution of symptoms. The development and improvement of outcomes that can measure or even identify patients who have the necessary substrate for regeneration, as well as the advancement of clinical intervention trials that measure neural recovery and its impact on a person’s life after diagnosis and during disease is critical to enable full participation in society. Opportunities for advancing the Restore Pathway span from the subclinical through later stages of disease, although it is likely that earlier interventions will be more successful ( Figure 1 ). The Restore Pathway includes two main objectives: (1) Regeneration and (2) Restoration of Functional Activity.

Regeneration

Remyelination requires myelin producing oligodendrocytes that create new myelin sheaths in the CNS. The brain generates oligodendrocytes from oligodendrocyte precursor cells (OPCs) throughout life, but the efficiency of remyelination declines with age. Strategies for promoting remyelination by restoring a youthful milieu in the CNS and targeting CNS-endogenous cells with remyelination-enhancing therapies hold much promise. 23 Mechanisms that underlie remyelination failure in MS are not fully understood and are thought to occur through a combination of inhibitory factors. Recent evidence suggests that inhibition from secreted factors released by both infiltrating immune cells and resident glia play a role in suppressing remyelination. In addition, certain oligodendroglia subtypes may also negatively impact remyelination. 24 While much attention has been focused on OPCs, recent studies suggest that adult oligodendrocytes can also participate in remyelination. 25

Removing impediments to myelin repair, stimulating endogenous OPC differentiation, and transplanting cells with the potential to promote repair 26 provide opportunities for immune modulation, neuroprotection, or repair in people with MS. Further studies are needed to focus on the cell biology of remyelination and evaluate emerging molecular pathways that could be leveraged for repair therapies.

The use of animal models such as experimental autoimmune encephalomyelitis, cuprizone and lysolecithin have strengths as well as limitations, and need to be optimized, or new tools need to be developed, to better represent MS. Most DMTs for MS target inflammatory processes, yet we know there is an urgent need for therapies that provide neuroprotection and/or promote axonal growth and/or remyelination in the setting of an inflammatory or non-inflammatory tissue environment. Clarifying the functional heterogeneity of OPCs, the remyelinating capacity of mature oligodendrocytes, the role of aging, and the roles of other neural cells in repair offer promising opportunities to expose additional new targets for regeneration.

Promoting neuroprotection, synaptic plasticity, and strategies to limit neurodegeneration are also promising approaches for reducing disability and restoring function in MS. Studies of neuroprotection and synaptic plasticity have primarily involved rodent models and show considerable involvement of neural networks of the hippocampus, basal ganglia, and cerebellum. 27 Pathology studies in MS show significant declines in the number of synapses in the hippocampus, as well as receptors and molecules involved in synaptic plasticity and glutamate neurotransmission. 28 Recent work shows that CNS inflammation affects synaptic transmission and that immune-mediated alterations to synaptic plasticity may be a contributing factor to the pathogenesis of MS-related cognitive impairment; reversing any of these areas could offer functional benefits. 29 , 30 Understanding how to protect neurons and why some clusters of neurons are more resilient than others provide new opportunities for therapeutic approaches.

Restoration of functional activity

Accurately evaluating disease progression and disability is important for understanding the biology of regeneration, testing therapeutic approaches, guiding treatment, and informing personalized care. Imaging measures have expanded substantially and have proved to offer a quantitative and objective way to evaluate MS disease progression but have limited ability to track myelin changes over time in the brain or spinal cord. 31 Brain imaging methods such as magnetization transfer imaging and diffusion tensor imaging offer opportunities to evaluate the evolution of acute white matter lesions, whereas other methods such as myelin water imaging, susceptibility-weighted imaging and positron emission tomography allow for the evaluation of chronic white matter lesions. 32 Studies are needed that target remyelination more precisely and develop better imaging tools that specifically measure changes in myelination.

To different extents, imaging measures have been shown to relate broadly to disability; 33 however, these studies have almost entirely focused on the Expanded Disability Status Scale (EDSS) as the measure of disability. The EDSS is a rating scale that assesses overall disability, placing a greater emphasis on walking function over other symptoms such as spasticity, fatigue, cognitive dysfunction, or hand dysfunction. 34 Impairment-based outcome measures that detect disability worsening and provide specific information about the impairment can be used to tailor treatment interventions for each person based on the specific symptom or based on patient-reported feedback, as in the Fatigue Severity Scale. While these clinical outcome measures can describe and, in some cases, predict disability, they are not sensitive enough to detect either early disease progression or the results of regeneration. Emerging technologies using remote monitoring wearable devices may offer insights into early detection of disease worsening and/or progression as well as responses to regenerative therapies. Biomarkers that relate to the disease process, or symptoms could also be important tools for managing MS. Development of appropriate outcome measures that singularly or in combination quantify neural regeneration, identify patients who have the necessary substrate for regeneration and are associated with specific measures of impairment would improve clinical decision making and expedite the study of clinical interventions.

Clinical trials are already underway exploring pharmaceutical approaches and cell-based therapies to facilitate remyelination and neural repair. Up to now, none of these trials have provided definitive positive results, highlighting deficits in both measurement tools and validated targets. A phase 2b, multi-arm trial of three putative neuroprotective drugs 35 failed to provide evidence for neuroprotection in patients with secondary progressive MS; this trial followed mixed results from two highly anticipated clinical trials interrogating the remyelinating effects of anti-LINGO antibodies in optic neuritis and relapsing-remitting MS. 36 Data from early clinical trials evaluating the safety and efficacy of autologous mesenchymal stem cells delivered intrathecally reported improvements in physical abilities, vision, and cognition along with a decrease in inflammatory biomarkers. 37 , 38 Data are needed from larger studies to provide additional evidence.

Tools to screen compounds that promote remyelination 39 also provide promise for identifying new therapies. High-throughput screening resulted in the first randomized clinical trial to show evidence of remyelination in MS using clemastine fumarate. 40 Other high-throughput screening approaches have identified molecules that enhance the formation of oligodendrocytes and ultimately remyelination. 41 Future screens should also look for compounds that promote remyelination in potentially inhibitory environments. 42 Ongoing clinical trials of Bruton tyrosine kinase inhibitors (BTK) 43 and early phase trials of new drugs exploring novel pathways that block neurite growth inhibition 44 provide promising avenues for limiting MS progression. Clinical trials using biologic outcomes sensitive to regeneration and behavioral markers sensitive to functional recovery are critical components for optimizing recovery and guiding clinical care.

Studies have shown that in MS, exercise is safe, can improve strength, cardiorespiratory fitness, walking, symptomatic fatigue, and cognition, and overall is an effective symptomatic treatment in MS. 45 Clinical trials have begun to evaluate combining exercise with other symptomatic treatments such as cognitive rehabilitation and/or medications, with positive results. 45 The effects of exercise in modifying the disease or even reducing the risk of MS is also being evaluated. 46 Exercise studies provide preliminary evidence of the potential impact of exercise on neuroprotection and regeneration in animal models and humans. 46 , 47 Studies of cardiac rehabilitation provide a powerful example of how rehabilitation can improve quality of life and drive recovery. This evidence highlights the perspective that long-term and large-scale human studies in MS can be tailored to assess and measure the neuroprotective and neurodegenerative benefits of exercise and other rehabilitation interventions.

There are a variety of rehabilitation strategies to support preventive, restorative, compensatory, and maintenance strategies to address symptoms of MS. Balance and gait dysfunction are a leading concern for people with MS, with increasingly pronounced impairments in persons with progressive MS. 48 The evidence supporting rehabilitative strategies is growing but varies in methodological quality and is largely confined to small cohorts with mixed phenotypes of MS included, making translation difficult. 49 Wearable technology has emerged as a useful tool to collect long-term data assessing function in the real-world setting. 50 Further research is needed to develop effective rehabilitation approaches incorporating appropriate study design and outcome measurement and evaluating type and intensity of interventions. Integrating mechanistic studies and rehabilitation approaches through novel collaborations can inform and expand our understanding of regeneration and rehabilitation and their impact on each other.

Growing evidence suggests that neuro-regeneration and restoration of function are possible in MS. Mechanisms underlying the eventual failure of repair are not fully understood in MS, thus limiting generalizability and application to clinical trials. Preserving and repairing myelin is likely to be one of the best ways to prevent neurodegeneration ( Table 4 ). Translation of knowledge from basic mechanisms to functional impact is needed to optimize treatment, manage symptoms, and ultimately restore function for people with MS. In sum, it is important to build the knowledge base integrating mechanisms with rehabilitation so that they inform one another and drive breakthroughs for restoring functional activity.

Restore pathway recommendations and research priorities.

The end pathway

The Roadmap defines the End Pathway as no new cases of disease. There is a growing appreciation that along with some other autoimmune and neurological conditions, MS may be preventable. One of the objectives of the End pathway is to prevent MS in the general population, commonly referred to as primary prevention. Primary prevention of MS will require population-based public health initiatives that reduce or eliminate exposure to putative risk factors and perhaps could also involve more targeted measures among individuals considered to be at high risk for developing MS (e.g. first degree family members). The second objective of the End pathway focuses on identifying MS in its earliest (prodromal) stages to delay or prevent onset of classical clinical manifestations, defined as secondary prevention. Some of the approaches for achieving secondary prevention overlap with the early detection approaches described in the Stop pathway. Opportunities for preventing MS precede exposures to environmental risk factors and extend through the subclinical stages of disease ( Figure 1 ).

Primary prevention

The goal of primary prevention is to prevent MS in the general population before it occurs by limiting exposure to modifiable MS risk factors. The cause of MS is not yet known, but progress has been made in identifying contributing factors and biological pathways that increase the risk of developing MS. Environmental risk factors such as low serum levels of vitamin D, 51 adolescent obesity, 52 tobacco smoking, 53 infection with Epstein Barr virus (EBV) and in particular, symptomatic primary EBV infection, 54 , 55 while not yet proven to be causal, have been consistently associated with an increase in MS risk.

A family history of MS is among the strongest risk factors, and more than 230 common gene variants have been identified that contribute to MS risk, with the strongest being multiple risk alleles in the major histocompatibility complex. 56 , 57 The genetics and environmental exposures driving MS risk have mostly been studied in adult Caucasian populations. There is a strong need to determine whether these same factors are driving the risk for MS in other racial and ethnic groups. Furthermore, since the latency between exposure to MS risk factors and the onset of MS is shorter in pediatric MS, studying risk factors in this population could also reveal important insights.

Even in the absence of full knowledge of the cause of MS, strategies for preventing MS may be achievable in the next few years. Compelling evidence currently exists to support preventive, near-term, public health approaches such as vitamin D supplementation, 55 childhood obesity prevention, 58 and EBV vaccination. 59 , 60 A better understanding of all factors and their interactions that can trigger MS, as well as cooperation and buy-in by public health agencies and policy makers to the concept of MS as a preventable disease are needed. Public health initiatives such as these are likely to also help prevent other disorders and could more effectively be advanced by collaboration and coordination with other disease-specific advocacy organizations. It is also worth considering whether higher-risk primary prevention strategies could be deployed for those with a greater risk for developing MS. Substantial gaps also exist in our understanding of MS risk in non-European populations and addressing these gaps will need to be prioritized so that prevention strategies can be developed that benefit diverse populations of people with MS.

Secondary prevention

The goal of secondary prevention is to identify individuals in whom the biologic processes driving the disease have begun, but in whom classical clinical manifestations have yet to emerge. With this knowledge, one could intervene during the pre-clinical and/or prodromal stages of MS, including in asymptomatic people with radiological findings highly suggestive of MS. Because secondary prevention interventions are likely to have greater risks and side effects, it would be ideal to identify individuals at the highest risk for MS for whom early intervention is most likely to be beneficial.

Prodromal periods are recognized in other autoimmune and neurodegenerative conditions like type-1 diabetes, rheumatoid arthritis, Alzheimer’s disease, and Parkinson’s disease, and trials testing interventions designed to delay or perhaps prevent the onset of clinical disease in some of these conditions are underway. 61 Evidence supporting an MS prodrome is also emerging. 62 , 63 Biomarkers like serum NfL are being studied that could help identify individuals in the prodromal stage of MS. It is likely that a Bayesian approach to estimating risk for developing MS that incorporates clinical, radiological, and laboratory data could be developed and deployed that would establish the MS prodromal period with enough confidence that a low-to-moderate risk disease-modifying approach could be used to treat MS in the very earliest stages with significantly improved outcomes. As our knowledge of the prodromal period of disease improves, it might also be possible to deploy high efficacy or even induction therapies that could re-establish tolerance to CNS antigens and prevent MS from occurring in the first place.

Accelerating research that leads to a better understanding of all the factors that contribute to the risk for MS in all populations, including environmental exposures, the microbiome, social determinants of health, and genetics and epigenetics, as well as the interactions among them that may increase risk will help get us closer to realizing primary prevention ( Table 5 ). The cost-effectiveness of some public health initiatives for preventing MS may need to be proven to convince policy makers of their value.

End pathway recommendations and research priorities.

MS: multiple sclerosis; EBV: Epstein Barr virus.

Biomarkers that indicate risk should be identified and made widely available. Although the presence of multiple biomarkers may increase the accuracy of risk detection, the practicality of detection in an individual will need to be considered. A better understanding of the age at which risk factors act and when prevention interventions should begin will facilitate intervention. More information is needed about how to identify high-risk individuals, stratify risk, and select interventions that are tiered according to the strength of risk. Interventions should balance risk/benefit and be stratified according to the degree of an individual’s risk, ranging from low-risk, long-term strategies such as vitamin D supplementation, dietary approaches, and vaccination against EBV, to higher-risk strategies such as immune-modulatory therapy. More evidence is needed for the causative role of known risk factors. Most of what is known about MS risk factors has been derived from largely white populations, leaving a gap in understanding how risk factors may differ across other racial or ethnic groups that will need to be addressed so that prevention strategies can be developed that benefit everyone at risk for MS.

Tremendous progress has been made in understanding of the pathogenesis and treatment of MS since the Institute of Medicine published their strategic review of MS research in 2001. 64 This progress has led to the development of numerous DMTs and improved quality of life for many people with MS. Furthermore, it has led to optimism that we are close to breakthroughs that will lead to cures for MS. The Pathways to Cures Roadmap includes carefully considered recommendations of a large group of leaders in MS research and clinical care, as well as people affected by MS from North America and the United Kingdom. We hope this report will inspire a heightened sense of urgency among research funders to support research that leads to cures for MS. We also look forward to engaging with the key stakeholders in the MS movement to help promote improved coordination of global research efforts focused on answering the key questions that will lead to cures.

Research breakthroughs leading to MS cures will require strategic investments in research priorities and increased multidisciplinary collaboration. We are hopeful that the Roadmap could be a starting point for a dialogue with our fellow MS organizations that leads to improved coordination and optimization of MS research investments. Over the last decade, we have made significant progress toward better global collaboration through efforts like the International Progressive MS Alliance and the Patient Reported Outcomes in MS initiative. We encourage MS research funders and advocates to build on this progress by seeking more opportunities to collaborate, align, and leverage their collective investments on research that addresses areas of high opportunity identified in the Roadmap. This could potentially be accomplished through improved data sharing among global research funders and the development of platforms to encourage prioritization, coordination, and leveraging of research investments (e.g. the EU-funded MULTI-ACT project).

The lack of diversity in the MS research workforce and in clinical research studies is a critical issue limiting the generalizability of research breakthroughs and the translation of these breakthroughs for everyone with MS, including underrepresented groups. To achieve cures for everyone with MS, we encourage all stakeholders in the MS movement to implement strategies to increase participation of underrepresented groups in the MS research workforce and clinical studies. 64 Improved engagement of these groups will lead to improvements in the quality of scientific data, facilitate the discovery of important efficacy and safety information and help to identify population specific differences in disease course and treatments and accelerate the development of cures for everyone with MS.

It will also be important to update the Roadmap on a regular basis to reflect advances in our understanding of the Pathways and to account for the development of new technologies and approaches. We propose that a biennial meeting of global MS stakeholders that reviews progress on the Pathways to Cures milestones and updates the Roadmap to reflect contemporary knowledge of MS be organized in collaboration with other MS organizations. A regular meeting could also serve as a platform for data sharing between MS advocacy and research funding organizations and be a venue for developing better coordination of MS research activities that accelerate progress toward badly need cures for MS.

Finding cures for MS has taken much longer than initially anticipated, and while significant obstacles remain, we are optimistic that (1) a passionate and committed global research community, (2) a growing spirit of international collaboration and coordination of resources, (3) a highly motivated and talented research workforce, and (4) a dedicated and well-organized network of activists will speed development of MS cures. We look forward to partnering with other global stakeholders in the MS movement to make the hopes and dreams of people with MS around the world come true.

Acknowledgments

The National MS Society is deeply grateful to Jim and Kathleen Skinner for their $10 million lead investor gift to fund Pathways to MS Cures. The authors would like to acknowledge Howard Weiner who first introduced the concept of the three cures for MS. Medical writing assistance provided by Kristine De La Torre, PhD and Cathy Carlson.

Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Bruce Bebo, Mark Allegretta, Douglas Landsman, Kathy Zackowski, Fiona Brabazon, Walter Kostich, and Timothy Coetzee are employees of the National MS Society and have no other relevant conflicts to disclose. Alexander Ng has no relevant conflicts to disclose. Ruth Ann Marrie is a co-investigator on a study funded by Roche and Biogen (no funds to Dr. Marrie or her institution). Kelly Monk has no relevant conflicts to disclose. Amit Bar-Or has received research grants and consulting fees from Biogen, grants, and consulting fees from Genetech/Roche, consulting fees from GlaxoSmithKlein, research grants and consulting fees from Merck/EMD Serono, consulting fees from Medimmune, research grants and consulting fees from Novartis, consulting fees from Celgene/Receptos, consulting fees from Sanofi-Genzyme, consulting fees from Atara Biotherapeutics, and Jansen/Actelion. None of these disclosures are related to this work. Caroline Whitacre has no relevant conflicts to disclose.

Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Activities supporting the development of the Roadmap were funded by the National Multiple Sclerosis Society.

Contributor Information

Bruce F Bebo, Jr, National Multiple Sclerosis Society 733 3rd Ave New York, NY 10017 USA.

Mark Allegretta, National Multiple Sclerosis Society 733 3rd Ave New York, NY 10017 USA.

Douglas Landsman, National Multiple Sclerosis Society 733 3rd Ave New York, NY 10017 USA.

Kathy M Zackowski, National Multiple Sclerosis Society 733 3rd Ave New York, NY 10017 USA.

Fiona Brabazon, National Multiple Sclerosis Society 733 3rd Ave New York, NY 10017 USA.

Walter A Kostich, National Multiple Sclerosis Society 733 3rd Ave New York, NY 10017 USA.

Timothy Coetzee, National Multiple Sclerosis Society 733 3rd Ave New York, NY 10017 USA.

Alexander Victor Ng, Department of Physical Therapy, Marquette University, Milwaukee, WI, USA.

Ruth Ann Marrie, Department of Internal Medicine (Neurology), University of Manitoba, Winnipeg, MB, Canada.

Kelly R Monk, Vollum Institute, Oregon Health & Science University, Portland, OR, USA.

Amit Bar-Or, Center for Neuroinflammation and Neurotherapeutics, Multiple Sclerosis Division, Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Caroline C Whitacre, National Multiple Sclerosis Society 733 3rd Ave New York, NY 10017 USA.

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Western researchers’ breakthrough paves way for ALS cure

Fueled by a $10-million gift from the temerty foundation, a possible new als treatment could move to clinical trials within five years.

By Prabhjot Sohal

In a groundbreaking Canadian discovery powered by philanthropy, a team of Western University researchers led by Dr. Michael Strong has uncovered a potential path toward a cure for amyotrophic lateral sclerosis (ALS). 

The breakthrough, which illustrates how protein interactions can preserve or prevent the nerve cell death that is a hallmark of ALS, is the culmination of decades of Western research backed by the Temerty Foundation.

“As a doctor, it’s been so important for me to be able to sit down with a patient or their family and say to them, ‘we're trying to stop this disease,’” said Strong, a clinician-scientist who has devoted his career to finding a cure for ALS. “It's been 30 years of work to get here; 30 years of looking after families and patients and their loved ones, when all we had was hope. This gives us reason to believe we've discovered a path to treatment.”

ALS, also known as Lou Gehrig’s disease, is a debilitating neurodegenerative condition that progressively impairs nerve cells responsible for muscle control, leading to muscle wastage, paralysis and, ultimately, death. The average life expectancy of an ALS patient post-diagnosis is a mere two to five years.

In a study recently published in the journal Brain , Strong’s team found that targeting an interaction between two proteins present in ALS-impacted nerve cells can halt or reverse the disease’s progression. The team also identified a mechanism to make this possible.

“ This gives us reason to believe we've discovered a path to treatment.” —Dr. Michael Strong

“Importantly, this interaction could be key to unlocking a treatment not just for ALS but also for other related neurological conditions, like frontotemporal dementia,” said Strong, who holds the Arthur J. Hudson Chair in ALS Research at Western’s Schulich School of Medicine & Dentistry. “It is a gamechanger.”

In virtually all ALS patients, a protein called TDP-43 is responsible for forming abnormal clumps within cells, which causes cell death. In recent years, Strong’s team discovered a second protein, called RGNEF, with functions that are opposite to TDP-43.

The team’s latest breakthrough identifies a specific fragment of that RGNEF protein, named NF242, that can mitigate the toxic effects of the ALS-causing protein. The researchers discovered that when the two proteins interact with each other, the toxicity of the ALS-causing protein is removed, significantly reducing damage to the nerve cell and preventing its death.

In fruit flies, the approach notably extended lifespan, improved motor functions and protected nerve cells from degeneration. Similarly, in mouse models, the approach led to enhanced lifespan and mobility, along with a reduction in neuroinflammation markers.

“The investment – and foresight – of the Temerty Foundation has accelerated progress in finding an effective treatment for ALS.” —Western President Alan Shepard

The team’s path to discovery was paved by the Temerty family’s long-standing investment in ALS research at Western – support Strong calls “truly transformational.” Now Strong and his team have set a goal to bring their potential treatment to human clinical trials in five years, a mission that is fueled by a new gift from the Temerty Foundation.

The foundation, established by James Temerty, founder of Northland Power Inc., and Louise Arcand Temerty, is investing $10 million over five years to power the next steps to bring this treatment to ALS patients.

“Finding an effective treatment for ALS would mean so much to people living with this terrible disease and to their loved ones,” said James Temerty. “Western is pushing the frontiers of ALS knowledge, and we are excited for the opportunity to contribute to the next phase of this groundbreaking research.”

The new gift by the Temerty Foundation brings the family’s total investment in neurodegenerative disease research at Western to $18 million.

“Dr. Strong's relentless dedication to his field is matched only by the Temerty family’s deep desire to make a difference for the thousands of people around the world diagnosed with this devastating disease,” said Western President Alan Shepard.  “The investment – and foresight – of the Temerty Foundation has accelerated progress in finding an effective treatment for ALS. We are grateful for the Temerty family’s commitment to life-changing research.”

“This is a pivotal moment in ALS research that could truly transform patient lives,” said Dr. John Yoo, dean at Schulich Medicine & Dentistry. “With Dr. Strong’s leadership, our continued investment in the best tools and technology and the visionary support of the Temerty Foundation, we are thrilled to be heralding in a new era of hope for patients with ALS.”

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New treatment could reverse hair loss caused by an autoimmune skin disease

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Researchers at MIT, Brigham and Women’s Hospital, and Harvard Medical School have developed a potential new treatment for alopecia areata, an autoimmune disorder that causes hair loss and affects people of all ages, including children.

For most patients with this type of hair loss, there is no effective treatment. The team developed a microneedle patch that can be painlessly applied to the scalp and releases drugs that help to rebalance the immune response at the site, halting the autoimmune attack.

In a study of mice, the researchers found that this treatment allowed hair to regrow and dramatically reduced inflammation at the treatment site, while avoiding systemic immune effects elsewhere in the body. This strategy could also be adapted to treat other autoimmune skin diseases such as vitiligo, atopic dermatitis, and psoriasis, the researchers say.

“This innovative approach marks a paradigm shift. Rather than suppressing the immune system, we’re now focusing on regulating it precisely at the site of antigen encounter to generate immune tolerance,” says Natalie Artzi, a principal research scientist in MIT’s Institute for Medical Engineering and Science, an associate professor of medicine at Harvard Medical School and Brigham and Women’s Hospital, and an associate faculty member at the Wyss Institute of Harvard University.

Artzi and Jamil R. Azzi, an associate professor of medicine at Harvard Medical School and Brigham and Women’s Hospital, are the senior authors of the new study , which appears in the journal Advanced Materials . Nour Younis, a Brigham and Women’s postdoc, and Nuria Puigmal, a Brigham and Women’s postdoc and former MIT research affiliate, are the lead authors of the paper.

The researchers are now working on launching a company to further develop the technology, led by Puigmal, who was recently awarded a Harvard Business School Blavatnik Fellowship.

Direct delivery

Alopecia areata, which affects more than 6 million Americans, occurs when the body’s own T cells attack hair follicles, leading the hair to fall out. The only treatment available to most patients — injections of immunosuppressant steroids into the scalp — is painful and patients often can’t tolerate it.

Some patients with alopecia areata and other autoimmune skin diseases can also be treated with immunosuppressant drugs that are given orally, but these drugs lead to widespread suppression of the immune system, which can have adverse side effects.

“This approach silences the entire immune system, offering relief from inflammation symptoms but leading to frequent recurrences. Moreover, it increases susceptibility to infections, cardiovascular diseases, and cancer,” Artzi says.

A few years ago, at a working group meeting in Washington, Artzi happened to be seated next to Azzi (the seating was alphabetical), an immunologist and transplant physican who was seeking new ways to deliver drugs directly to the skin to treat skin-related diseases.

Their conversation led to a new collaboration, and the two labs joined forces to work on a microneedle patch to deliver drugs to the skin. In 2021, they reported that such a patch can be used to prevent rejection following skin transplant. In the new study, they began applying this approach to autoimmune skin disorders.

“The skin is the only organ in our body that we can see and touch, and yet when it comes to drug delivery to the skin, we revert to systemic administration. We saw great potential in utilizing the microneedle patch to reprogram the immune system locally,” Azzi says.

The microneedle patches used in this study are made from hyaluronic acid crosslinked with polyethylene glycol (PEG), both of which are biocompatible and commonly used in medical applications. With this delivery method, drugs can pass through the tough outer layer of the epidermis, which can’t be penetrated by creams applied to the skin.

“This polymer formulation allows us to create highly durable needles capable of effectively penetrating the skin. Additionally, it gives us the flexibility to incorporate any desired drug,” Artzi says. For this study, the researchers loaded the patches with a combination of the cytokines IL-2 and CCL-22. Together, these immune molecules help to recruit regulatory T cells, which proliferate and help to tamp down inflammation. These cells also help the immune system learn to recognize that hair follicles are not foreign antigens, so that it will stop attacking them.

Hair regrowth

The researchers found that mice treated with this patch every other day for three weeks had many more regulatory T cells present at the site, along with a reduction in inflammation. Hair was able to regrow at those sites, and this growth was maintained for several weeks after the treatment ended. In these mice, there were no changes in the levels of regulatory T cells in the spleen or lymph nodes, suggesting that the treatment affected only the site where the patch was applied.

In another set of experiments, the researchers grafted human skin onto mice with a humanized immune system. In these mice, the microneedle treatment also induced proliferation of regulatory T cells and a reduction in inflammation.

The researchers designed the microneedle patches so that after releasing their drug payload, they can also collect samples that could be used to monitor the progress of the treatment. Hyaluronic acid causes the needles to swell about tenfold after entering the skin, which allows them to absorb interstitial fluid containing biomolecules and immune cells from the skin.

Following patch removal, researchers can analyze samples to measure levels of regulatory T cells and inflammation markers. This could prove valuable for monitoring future patients who may undergo this treatment.

The researchers now plan to further develop this approach for treating alopecia, and to expand into other autoimmune skin diseases.

The research was funded by the Ignite Fund and Shark Tank Fund awards from the Department of Medicine at Brigham and Women’s Hospital.

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MIT researchers have developed microneedle patches that are capable of restoring hair growth in alopecia areata patients, reports Ernie Mundell for HealthDay . The team’s approach includes a, “patch containing myriad microneedles that is applied to the scalp,” writes Mundell. “It releases drugs to reset the immune system so it stops attacking follicles.” 

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• Institute for Medical Engineering and Science

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