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CME / ABIM MOC

Bringing the Immune System to Life in Multiple Sclerosis: What Does Mechanism Have to Do With It?

  • Authors: Heinz Wiendl, MD
  • CME / ABIM MOC Released: 10/13/2021
  • THIS ACTIVITY HAS EXPIRED
  • Valid for credit through: 10/13/2022
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Target Audience and Goal Statement

This activity is intended for neurologists, obstetricians/gynecologists, and primary care physicians.

The goal of this activity is to provide a better understanding of the role of specific, targeted immune mediators when selecting an appropriate disease-modifying therapies (DMTs) for the management of multiple sclerosis (MS). 

Upon completion of this activity, participants will:

  • Have increased knowledge regarding the
    • Immune targets of DMTs used in the management of MS 
  • Have greater competence related to
    • Selecting an appropriate therapy for a patient with MS based on the mechanism of action of available DMTs 


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Medscape, LLC encourages Authors to identify investigational products or off-label uses of products regulated by the US Food and Drug Administration, at first mention and where appropriate in the content.


Faculty

  • Heinz Wiendl, MD

    Professor of Neurology
    Chair, Department of Neurology
    University Hospital Muenster
    Muenster, Germany

    Disclosures

    Disclosure: Heinz Wiendl, MD, has the following relevant financial relationships:
    Advisor or consultant for: Actelion; Argenx; Biogen; Bristol Myers Squibb; EMD Serono; Idorsia; IGES; Immunic; Immunovant; Janssen; Johnson & Johnson; Novartis; Roche; Sanofi; Swiss Multiple Sclerosis Society; UCB
    Grants for clinical research from: Biogen; Deutsche Forschungsgemeinshaft; Fresenius Foundation; GlaxoSmithKline; Hertie Foundation; Interdisciplinary Center for Clinical Studies; NRW Ministry of Education and Research; Roche Pharma AG; Sanofi-Genzyme

Editors

  • Lisette Arnaud-Hevi, PhD

    Medical Education Director, WebMD Global, LLC 

    Disclosures

    Disclosure: Lisette Arnaud-Hevi, PhD, has disclosed no relevant financial relationships.

  • Frances McFarland, PhD, MA

    Associate Medical Education Director, Medscape Education, LLC

    Disclosures

    Disclosure: Frances McFarland, PhD, MA, has disclosed no relevant financial relationships.

CME Reviewer

  • Esther Nyarko, PharmD

    Associate Director, Accreditation and Compliance, Medscape, LLC

    Disclosures

    Disclosure: Esther Nyarko, PharmD, has disclosed no relevant financial relationships.

None of the nonfaculty planners for this educational activity have relevant financial relationship(s) to disclose with ineligible companies whose primary business is producing, marketing, selling, reselling, or distributing healthcare products used by or on patients.

Peer Reviewer

This activity has been peer reviewed and the reviewer has disclosed no relevant financial relationships.


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CME / ABIM MOC

Bringing the Immune System to Life in Multiple Sclerosis: What Does Mechanism Have to Do With It?

Authors: Heinz Wiendl, MDFaculty and Disclosures
THIS ACTIVITY HAS EXPIRED

CME / ABIM MOC Released: 10/13/2021

Valid for credit through: 10/13/2022

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INTRODUCTION

Multiple sclerosis (MS) is a chronic, inflammatory disease characterized primarily by the accumulation of demyelinating lesions on the brain and spinal cord.[1] It has a heterogeneous presentation, depending on the dissemination of lesions within the central nervous system (CNS).[2] A small group of patients, approximately 5% to 10%, experience primary progressive MS (PPMS), which is progressive from onset.[1] In most cases, however, patients initially experience relapsing-remitting MS (RRMS), in which a clinically isolated syndrome (CIS) is followed by relapses of neurological deficits that last days or even weeks.[1] This is usually followed by the secondary progressive MS (SPMS), or the development of permanent neurological damage and progressive clinical disability.[1]

MS affects approximately 2.3 million people worldwide, and its prevalence is increasing, particularly among females.[1] It is the primary cause of nontraumatic disability in young adults.[1] The typical age of onset is 20 years to 35 years for RRMS and around 40 years of age for PPMS, but up to 10% of patients experience a demyelinating lesion during childhood or adolescence.[1]

The immune system contributes significantly to the pathophysiology of MS, which has implications for disease management and the selection of disease-modifying therapies. In this article, Dr Heinz Wiendl, Professor of Neurology and Chair of the Department of Neurology at the University Hospital of Muenster, in Muenster, Germany, discusses the role of the immune system in MS and how that influences considerations for management.

HOW IS THE IMMUNE SYSTEM INVOLVED IN MS PATHOLOGY?

One key hallmark of MS is immune cell infiltration into the CNS, which leads to inflammatory demyelination or inflammatory neurodegeneration.[1] The involvement of these cells, however, starts outside of the CNS (Figure 1). Basic tolerance mechanisms or immune regulatory networks seem to be disturbed, activating peripheral T cells, B cells, and myeloid cells and causing them to migrate across the blood-brain barrier into the CNS, where they recognize components of the CNS.[1,3] These cells and residents of the CNS secrete inflammatory factors that bring inflammatory cells into the CNS, promoting demyelination followed by oligodendrocyte and neuroaxonal injury.[1,2]

Figure 1. Immune System Dysregulation Outside the CNS[2]

BCR, B-cell receptor; MAIT, mucosa-associated invariant T; TCR, T-cell receptor; TH, T helper; TReg, regulatory T cell.

Both peripheral inflammation and neuroinflammation, a compartmentalized part of the immune system within the CNS, contribute to MS pathology (Figure 2).[1] The key players are adaptive immune cells, including B cells; CD8+, CD4+ TH1, and CD4+ TH17 T cells; and the soluble factors they secrete.[2] These factors include cytokines, such as interferon (IFN)-γ interleukin (IL)-2, IL-17, and granulocyte-macrophage colony-stimulating factor (GM-CSF), that mediate damage or contribute to the initiation and continuation of neuroinflammation.[1,2] Within the CNS, microglia and macrophages target other CNS cells, leading to oligodendrocyte damage and axon demyelination.[1,4]

Figure 2. Immune Dysregulation in the CNS During Early MS[1]

DC, dendritic cell; SAS, subarachnoid space.

At later stages of MS, immune cell infiltration in the CNS declines, but neuroinflammation and neurodegeneration continue, most likely as a result of mechanisms such as oxidative stress and CNS-compartmentalized inflammation (Figure 3).[1]

Figure 3. Immune dysfunction in the CNS during late MS[1]

APC, antigen-presenting cell; CCL2, CC-chemokine ligand 2; NO, nitric oxide; RNS, reactive nitrogen species; ROS, reactive oxygen species.

HOW DO THESE IMMUNE MECHANISMS INFLUENCE DISEASE PROGNOSIS AND SEVERITY?

Overall, we know that age, sex, the number of spinal cord lesions, and the extent of brain abnormalities predict outcomes.[5] As far as the immune system, we know that the degree of inflammation -- as well as the microenvironment in the CNS, including its capacity for repair -- contributes to relapse activity and maybe relapse severity. We see a higher degree of inflammation in RRMS and active SPMS than we do in PPMS.[4,6] What we call an inflammatory relapse involves a wave of infiltration by activated immune cells into the CNS.[1] And we know that the type and the quantity of cells invading the CNS, along with the CNS micromilieu and factors determining repair processes, contribute to the development of MS lesions, determining the outcomes of lesions and their clinical sequelae. But at present, there are no reliable circulating biomarkers of prognosis.[6] One of the most widely studied potential markers is neurofilament, which measures the extent of neuroaxonal damage.[6,7] Another one is glial fibrillary acid protein (GFAP), which correlates with clinical severity and magnetic resonance imaging (MRI) lesion count.[7] These are markers that can be measured in serum,[7] which suggests that immune-mediated damage in the CNS can be measured in the periphery.

HOW IS THE IMMUNOPATHOLOGY OF MS TARGETED BY APPROVED DISEASE-MODIFYING THERAPIES (DMTS)?

All the approved DMTs interfere with the immune system, primarily the peripheral immune system, and they interfere in different ways.[2,3] I generally classify these therapies into 4 groups: 1) general or selective immunosuppressors, 2) immunomodulators, 3) agents that interfere with leukocyte trafficking, and 4) those that promote lymphocyte depletion (Table 1).[4,5,8-10] All those groups include platform and higher-efficacy treatments. Bottom line, these agents selectively target immune regulatory networks and thus the key players in the immunopathogenesis of MS.

Table 1. Approved DMTs for MS

Agent

Mechanism of Action

Efficacy

Immunomodulators

Glatiramer acetate[4,5,8]

Induces proliferation of anti-inflammatory lymphocytes

Modest

IFNs[4,8]

Changes cytokine balance in favor of anti-inflammatory cytokines

Modest

Dimethyl fumarate[4,8]

Changes cytokine balance by inhibiting nuclear factor erythroid 2-related factor 2 (NrF2)

Modest to moderate

Teriflunomide[4,8,10],*

Mitochondrial dihydroorotate dehydrogenase inhibitor

Modest

     

Classical General Immunosuppressants

Mitoxantrone[4,8,11],**

Type II topoisomerase inhibitor

High

Agents That Interfere With Leukocyte Trafficking

Fingolimod[4,8]

Sphingosine-1-phosphate receptor modulator that retains memory T cells in the lymph nodes and secondary lymphatic tissues

Moderate

Ozanimod[8]

Sphingosine-1-phosphate receptor modulator

Moderate

Siponimod[4,8]

Sphingosine-1-phosphate receptor modulator

Moderate

Natalizumab[4,5,8]

Monoclonal antibody that blocks α-4 integrin; prevents lymphocytes from crossing the blood-brain barrier into the CNS

High

Agents That Promote Lymphocyte Depletion

Cladribine[4,8,9],**

Synthetic deoxyadenosine analogue; transiently reduces B and T cells

Moderate

Alemtuzumab[4,8],**

Anti-CD52 monoclonal antibody

High

Ocrelizumab[4,8]

Anti-CD20 monoclonal antibody

High

Ofatumumab[8]

Anti-CD20 monoclonal antibody

High


*Based on its mode of action, teriflunomide can also be classified as an immunosuppressant. However, because of the selectivity of the immune suppression, and based on recent evidence about its mode of action, including its shorter- and longer-term safety profiles, teriflunomide is regarded as a selective immunosuppressant and by some experts as an immunomodulator.

**Used infrequently. Based on its mode of action, cladribine can also be classified as an immunosuppressant. However, because of the selectivity of the immune suppression, and based on recent evidence about its mode of action, including its shorter- and longer-term safety profiles, cladribine is regarded as a selective immunosuppressant.

HOW DOES OUR KNOWLEDGE ABOUT THE IMMUNOPATHOLOGY OF MS AND THE ACTION OF DMTs HELP US IN SELECTING AN APPROPRIATE TREATMENT?

When we think about treatment, we think about clinical control, which you can measure by looking at relapse rate, disability progression, inflammatory lesion development, or "no evidence of disease activity" (NEDA). But it's also about preventing the accumulation of neurological defects and later disability. The key goal is to stop or try to stop the neuroinflammation and the processes that are kicked off through inflammatory degeneration, and DMTs generally target neuroinflammation, with an indirect effect on neurodegeneration.[5]

But early intervention with the dysfunctional immune system is key. The earlier you intervene and the more completely you silence or dampen inflammation in the CNS, the better you can prevent or delay axonal injury and neuronal loss.[4,12] This is supported by data showing that initial treatment with higher-efficacy therapies, such as alemtuzumab or natalizumab, is associated with a lower risk of conversion from RRMS to SPMS and less disability.[13,14] However, we do not yet have a personalized approach where we can tailor treatments based on the individual patient's phenotype.

In principle, 3 main scenarios can be considered when treating MS as early as possible to achieve the most effective disease control possible: 1) complete prevention of secondary progression by preventing neurodegeneration from the beginning; 2) delay and attenuation of secondary progression by delaying and attenuating neurodegeneration from the beginning; and 3) delay of secondary progression with progression rates remaining unchanged.

HOW DO THE DIFFERENT CLASSES OF DMTS DIFFER IN SAFETY AND TOLERABILITY?

Platform therapies such as IFN-β or glatiramer acetate are characterized by excellent safety but only moderate efficacy.[1] The higher the efficacy of a DMT, the more intense is its intervention with the immune system, and therefore the higher the risk of (partially serious) adverse events.[1] One of the most critical adverse events is interference with immunocompetence, and a prime example of this is progressive multifocal leukoencephalopathy (PML), an opportunistic brain infection by the John Cunningham virus.[1] Theoretically, all immune therapies carry a risk of PML, but in MS, this risk is seen to be higher, especially with leukocyte trafficking agents such as fingolimod and the monoclonal antibody natalizumab.[1,5,11] Alemtuzumab has been associated with secondary autoimmune-related adverse events that can be severe.[5]

WHAT SHOULD WE CONSIDER WHEN SELECTING OR MODIFYING DMTS FOR A PATIENT WITH MS?

There are 2 key considerations: 1) disease control and 2) safety, including tolerability.[5] With respect to disease control, one important aspect highlighted in many guidelines and recommendations is the efficacy switch, also called escalation therapy or treatment optimization, where a patient is switched to a higher-efficacy therapy because of suboptimal or insufficient disease control.[5] With respect to safety, each treatment decision requires individual risk stratification and continuous pharmacovigilance.[11] Risk mitigation for DMTs should be considered right from the beginning, when a patient is diagnosed, in what we call a de-risking strategy.[11] Mitigation steps might include certain baseline diagnostics, steps to address infusion-related reactions, and monitoring, which will depend on the DMT that's used.[11] It should be noted that only IFNs and glatiramer acetate are currently approved for patients who are pregnant.[15]

One should also consider the mode of action of the current therapy when considering a switch. This is a key consideration in switching and treatment sequence recommendations.[15,16] Yet another consideration in treatment is the therapeutic concept, or whether the treatment will be administered as chronic, maintenance therapy or as pulse therapy.[11,15]

Decisions about treatment and treatment modification should always have the best possible disease control as a goal, but this must be considered in the context of the mode of action, treatment concept, and issues of safety and tolerability, and all of this must be balanced with patient preferences and implications for the patient's quality of life.[15-17] The key goal here is: 1) best possible disease control with 2) highest quality of life for the patient. That will include such issues as mode of application and whether it's feasible for the patient.

WHAT ABOUT PATIENTS WITH PPMS?

Most of what we have talked about applies primarily to RRMS, where we know more about the immunological activity as a key driver. The immune system appears to be less relevant in PPMS, and the inflammatory mechanisms seem to be different,[1] even though the genetic basis and the lesions within the CNS do not differ significantly from those seen with RRMS. Most of the treatments we have are not as effective, if at all.[1] Patients with this form of MS continue to progress whether we treat them or not.[1] However, the data suggest that while treatments generally targeting the immune system do not significantly modify disease progression, treatment with anti-CD20 DMTs such as ocrelizumab or rituximab might have some effect on this endpoint, and ocrelizumab currently is approved for PPMS.[1,4]