Treating Multiple Sclerosis Throughout the Life Cycle of Disease

Bridging the GapsNew Directions and Practice Impacting Recommendations in Multiple Sclerosis

Multiple sclerosis(MS) is a chronic, immune-mediated disease of the central nervous system (CNS) that typically pres­ents in people aged 20 to 40 years.1 At a cellular level, both peripheral immune cells (eg, T cells, B cells, and myeloid cells) and CNS cells (eg, neurons, microglia, oligodendrocytes, and astroglia) contribute to the disease. The relative contribution of inflammatory biology (caused by breakdown of the blood-brain barrier and influx of peripheral immune cells) and neurodegenerative biology vary across the lifetime of disease.

Clinically, inflammatory biology manifests as relapses: discrete, subacute neurologic events that localize within the CNS and associate with new/contrast enhancing lesions on magnetic resonance imaging (MRI). This phenomenon is termed disease activity. In contrast, neurodegenerative biology manifests as slow, chronic accumulation of physical disability over long periods of time associated with atrophy on MRI. This clinical phenomenon is termed disease progression.

Importantly, disease activity and disease progression are not mutually exclusive terms. Both processes occur in paral­lel throughout the disease, although the relative contribution of each varies over time. Younger patients frequently exhibit high levels of inflammation and disease activity. In contrast, aging patients have decreased neurologic reserve and repair capacity and are more likely to exhibit disability progression.2 This likely parallels disease pathobiology; MS appears to start in the periphery and then shifts more into the CNS behind a closed blood-brain barrier.

Most current therapies target peripheral inflammation. Their effectiveness is thus likely contingent on ongoing peripheral inflammatory changes. Since disease pathobiology is not constant and inflammatory activity wanes over time, these medicines may have less utility in aging patients or those with a progressive phenotype. Indeed, this theory parallels clinical experience. During early disease, when pathobiology is driven by inflam­mation, therapies that primarily work in the periphery (such as anti-CD20 monoclonal antibodies) are more effective. During other times, when the disease is more compartmentalized in the CNS, therapies that cross the blood-brain barrier and those with neuroprotective mechanisms of action are predicted to be more effective. Unfortunately, we have few drugs that meet these criteria.

Disease-Modifying Drugs

Peripheral Versus CNS Activity

Current disease-modifying therapies (DMTs) with activity limited to the periphery include interferons, glatiramer acetate, several oral immunomodulators (eg, dimethyl fumarate and teriflunomide), and monoclonal antibodies (eg, alemtuzumab, natalizumab, ocrelizumab, and ofatumumab). DMTs that are capable of crossing the blood-brain barrier include the cell-depleting purine analogue cladribine and the sphingosine 1-phosphate (S1P) receptor modulators (eg, fingolimod, siponimod, ponesimod, and ozanimod).3,4 Despite crossing into the CNS, these medi­cations also have a strong peripheral anti-inflammatory effect, and the degree to which they modulate the CNS microenviron­ment directly is unknown.

Highly Effective Therapies

The medications alemtuzumab, natalizumab, cladribine, and anti- CD20 monoclonal antibodies are all considered highly effective. While there is not consensus that all patients should start with highly effective therapy (HET), it is becoming increasingly clear that the benefit of HET is greatest in younger patients. HETs are therefore viable treatment options at the time of disease onset, and the specific agent used for a given patient will be a shared decision.

Anti-CD20 Agents: Depletion of B-Cell Reservoirs and Other Considerations

Anti-CD20 therapy is highly effective for relapsing MS; it has an overall acceptable safety profile overall. While ocrelizumab is the only DMT that has shown any clinical efficacy in primary progres­sive MS, anti-CD20 medications have only modest efficacy in progressive MS overall. Moreover, they do not seem to reduce paramagnetic rim lesions (PRLs), which are chronic active lesions associated with progressive disability and resistance to approved therapy options.5,6 Still, early use of anti-CD20s could alter the disease trajectory and, by preventing demyelinating injury, avert subsequent axonal degeneration that results in clinical progres­sion independent of relapse activity (PIRA), which involves a slow increase in clinical disability that is not related to relapse.7 Data suggest that once PIRA occurs, it keeps increasing despite treatment.8

Anti-CD20 medications rapidly lyse CD20-expressing cells in the circulation, effectively removing naïve, regulatory, and memory B cells. Interestingly, animal data suggest that anti-CD20 agents do not fully deplete lymphocyte reservoirs in secondary lymphoid tissue in the short term. For MS patients, B-cell ac­cumulations may be present in the meninges, and anti-CD20 drugs may not affect these cells due to poor penetrance into the CNS. If B-cell reservoirs are hidden in the CNS, these cells could continue to drive inflammation or progression despite use of an anti-CD20 medication.

Alternative delivery and dosing strategies are being evalu­ated to see whether the efficacy of anti-CD20 medications can be enhanced. Higher doses may achieve deeper tissue depletion; these doses are being studied. Alternatively, the use of brain shuttles could deliver anti-CD20 medications to the CNS to affect cells there. The potential incremental clinical impact achieved with these alternative strategies, however, remain to be defined.

All immunomodulatory agents, including anti-CD20 medica­tions, can increase the risk of infection. The risk of infection is hard to predict. It has been observed that some patients are susceptible to repeated infections, while others never developinfections. Similarly, with advancing age, patients may become more likely to develop infections, yet many do not. Regarding anti-CD20 medications, low immunoglobulin G (IgG) levels (eg, 1.5 g/L to 2.5 g/L, up to 4.5 g/L) that result from B-cell depletion have been associated with increased risk of infection, although most people with infections have normal IgG values.

Patients with hypogammaglobulinemia who are doing well on anti-CD20 therapy and have no clinically significant infec­tions may choose to remain on treatment. For patients with hypogammaglobulinemia with recurrent or serious infections, intravenous Ig (IVIG) or subcutaneous Ig could be considered as an adjunctive therapy. Alternatively, a DMT with a different mechanism of action could be selected. It can take a long time before IgG levels normalize after treatment discontinuation; in some patients, this may take several years.

Emerging Treatments

Bruton Tyrosine Kinase Inhibitors

Bruton tyrosine kinase (BTK) is believed to play a role in both peripheral and CNS-compartmentalized inflammation in MS.9 Targeting this molecule may therefore affect both inflammatory disease biology (eg, relapses) as well as neurodegenerative biology (eg, slow progression). BTK inhibitors (BTKis) affect both B cells and myeloid cells. Results from phase 2 clinical trials demonstrated that they reduced new focal MRI lesion activity and PRLs. BTKis may also reduce the risk of PIRA. Three BTKis—tolebrutinib, fenebrutinib, and remibrutinib—are currently in phase 3 development. A fourth BTKi, evobrutinib, recently underwent phase 3 investigation but failed to meet the trial end points.10,11

Implications for Clinical Practice

BTKis are expected to affect inflammatory disease biology (relapses), but they may have additional mechanisms of action by directly affecting CNS microglia. This could translate to an impact across a wider spectrum (or just a different spectrum) of disease biology compared to existing treatment options. At present, results of phase 2 trials suggest that these medications will likely impact inflammatory disease biology, but their relative impact on progressive MS biology is still hypothetical. Phase 3 clinical trials are underway to establish their relative efficacy in relapsing and progressive MS. Top-line data from the first phase 3 studies with evobrutinib were recently communicated; a low relapse rate not significantly different than that seen with use of control treatment (teriflunomide) was noted. Whether there is a superior effect on the risk of disability accrual with BTKis compared to regular therapies is still unknown.

As a class of medications, BTKis may be associated with safety concerns, such as elevations in liver enzymes, that may necessitate frequent monitoring. Moreover, unlike other families of MS medications, each BTKi is functionally distinct in terms of its specificity and mechanism of binding and, hence, possibly has different effects. This may mean that BTKis cannot be lumped together as a family of interchangeable medica­tions. The optimal role of BTKis in treatment strategies remains to be determined; possibly, these could be sequenced with other high efficacy medications (like anti-CD20s) to achieve an optimal balance of safety and efficacy.

Disability, Risk Factors, and Other Considerations Affecting Treatment Selection

All DMTs for MS offer benefits to appropriately selected patients, but they also introduce risk. Balancing risk and benefit is an important consideration over the course of MS. This balance changes over time (eg, early disease vs 10 years into treatment), and it may be affected by the degree of physical disability and comorbidities within a given patient.

Disease Management at Different Ages and Stages of Disease

A variety of patients appear to be on the spectrum of MS but do not meet the full diagnostic criteria for the disease. For example, patients with radiologically isolated syndrome (RIS) have MRI lesions consistent with MS but have never experi­enced classic symptoms of disease. Patients with clinically isolated syndromes (CIS) have experienced a single event but have not (yet) experienced demyelination. The overall disease burden evident on MRI results may give a clue about where on the MS spectrum these individuals lie; a patient with CIS and a very small lesion burden may be close to true pathologic onset. Conversely, a patient with RIS who has no frank clinical symptoms but a large volume of T2 hyper­intensities on MRI and evident brain atrophy has likely had longstanding pathobiology. The role of ongoing immuno­modulatory therapy is unclear for these patient populations.

Treating Radiologically Isolated Syndrome

RIS may evolve into either relapsing or progressive MS. Whether, when, and how to treat RIS patients is not yet deter­mined; while DMTs delayed the onset of clinical symptoms in clinical trials,12 this impact at the individual level needs to be balanced against the ethics of instituting chronic immunosup­pression in an asymptomatic patient. Patients with RIS who likely warrant treatment include those with MRI lesions with a central vein sign characteristic of MS, cortical lesion distri­butions, or cerebrospinal fluid-restricted oligoclonal bands. For others, observation may be a more appropriate manage­ment strategy. Much work remains to better understand and appropriately stratify those with preclinical MS.


A majority of patients with MS switch DMTs at least once over the lifetime of their disease, usually due to adverse effects or breakthrough disease. Insurance changes, access issues, and cost considerations can also contribute to the decision to switch. Occasionally, patients switch from 1 DMT to another within the same family of medications. This sort of switch is usually driven by the need for an improved adverse effect profile or improved insurance coverage; patients who need to switch because of new disease activity should switch to a medication with a different mechanism of action. In these cases, an escalation approach is usually adopted, with an HET replacing one that is less efficacious.

Potential Role of Biomarkers

Biomarkers are measurable, quantitative ways to objectively determine patients’ disease status or the effectiveness of treat­ment. Reliable biomarkers for patients with MS are lacking. Ongoing work has been focusing on imaging biomarkers and soluble biomarkers as discussed in detail in the prior article.

Among the emerging biomarkers, changes in serum neurofila­ment light chain (sNfL) levels, which reflect neuronal injury, are likely closest to clinical implementation. sNfL levels are associ­ated with lesion development and relapse, therapy response, disease progression, and the probability of long-term disability.13,14 However, increases in sNfL values are less pronounced in pro­gressive disease.13 Although these group-level associations have been established, the utility of individual-level sNfL monitoring has not yet been established.13,14

Discontinuation or De-Escalation

Immunosenescence describes the biological process by which the immune system becomes less reactive with age. Aging is related to a decrease in inflammatory MS biology (disease activity), increased risk of infection, more medical comorbidities, and an increased number of comedications. The patient’s age, along with their personal MS history, is a major consideration when thinking about de-escalating or discontinuing MS treatment. In some patients, particularly those with many years of stable disease, de-escalation or discontinuation may be appropriate.

One recent study exploring treatment discontinuation in older patients was the DISCOMS trial (NCT03073603). This study enrolled patients who were aged at least 55 years with MS of any subtype, who had no clinical relapses for 5 years and no new or enlarging MRI lesions for 3 years, and who had been continuously treated with DMT for at least 5 years.15 The results showed overall low relapse rates for all study participants (0.8% and 2.3% of study participants continuing and discontinuing study drug, respectively), with a trend for increased MRI activity in those who stopped their DMT. The investigators concluded that discontinuing DMT is a reasonable option for a selected population of older MS patients.15

Notably, some individuals may experience ongoing risk of MS activity in their sixth decade and beyond and therefore should continue on high-efficacy DMTs.

Discussing Treatment Discontinuation With Patients

Results from the DISCOMS trial provide neurologists with data to discuss with patients who may be considering discontinuing their DMT. These patients may be understandably concerned about both discontinuing a DMT that they have been on for many years and the risks of infection or adverse events. The DISCOMS trial results may make it easier for people to decide whether to discontinue therapy without feeling like they could be making a decision that could harm them. It is important to point out that these DISCOMS results primarily apply to patients on platform (ie, first-line self-injectable and oral) medications. The risk/benefit is unknown for discontinuation of other agents. As the DMT landscape continues to evolve in the coming years, the relative benefits versus risks of DMT discontinuation will continue to evolve as well.

Special Discontinuation Considerations

Natalizumab and the S1P receptor modulators (eg, fingolimod) have been associated with clinical disease rebound after treat­ment discontinuation. De-escalation is not advised with these medications, even in the absence of activity, but switches can be done safely, especially if an alternative medication is started timely (eg, anti-CD20 or cladribine). Data support switching the patient to rituximab or ocrelizumab.16

Pregnancy represents an important, discrete time period during which disease-modifying drug (DMD) discontinuation or switching decisions arise. Treatment standard of care should involve discussing product safety and discontinuation or switch­ing plans prior to DMD initiation in individuals of childbearing potential with appropriate considerations for vaccination as well.17 Real-world and phase 4 data are being collected on an ongoing basis and summarized regularly to support updated evidence-based decision-making.18,19

Patient Monitoring

All patients taking DMT require close monitoring. Clinical, radiologic, and laboratory monitoring helps assure the safety and efficacy of the treatment choice. For those who are nonadherent or have meaningful adverse effects to their DMT, clinicians should initiate discussions about alternate treatment options, as no treatment will effectively control MS if it is not taken by the patient. Given the richness of treatment options, a tolerable and effective medi­cation should be identifiable for all patients.

A subset of patients may be reluctant to start MS therapy despite counseling. For these patients, it is important to build a therapeutic relationship and continue to monitor them over time so that this decision can be re-evaluated if the disease evolves.

Washout and Drug Holiday Guidance

Clinical opinions regarding a drug holiday (or washout periods) vary and depend on the drug in question. In the case of anti-CD20 medi­cations, a drug holiday or an extended dosing interval may allow for some B-cell repletion, which could be important if the patient was experiencing frequent infections. Drug holidays also offer a window during which there may be a more robust immunologic response to vaccination. For other medications, such as S1P receptor modulators and natalizumab, drug holidays increase risk of relapse and should not be considered. A washout (using activated charcoal or cholestyr­amine) is recommended for patients taking teriflunomide who are planning pregnancy or who unexpectedly become pregnant. Other­wise, washouts and drug holidays are generally not recommended.

The Value of Real-World Data

Real-world data (RWD) enables the evaluation of more diverse patient populations outside of clinical trials. As recruitment for randomized clinical trials may result in younger, healthier, and less diverse trial participants compared to the general MS population, RWD can be used to inform the effects of age, race, and comorbidities. RWD also examines unique scenarios and allows for drug comparisons. Statistical tools such as propensity score matching can be used to computationally derive comparable patient populations, allowing researchers to assess how these medications perform outside of clinical trials. For example, clinical trials have exclusion criteria related to adiposity. However, in the real world, adiposity influences drug concentrations and related variables as well as disease progres­sion; therefore, it is important to understand how DMDs perform in individuals with adiposity. Patients should understand that clinical trials cannot answer all questions and that RWD can help explore questions that are outside the boundaries of clinical trials.

Importance of Shared Decision-Making With DMDs

Patients often have questions about when it is acceptable to delay treatment (ie, if interested in having children). Patients may have reservations about starting treatment, such as mistrust, risk aversion, or bad experiences with medicines or people within the health care system. It is important to build a therapeutic rela­tionship with these individuals and to explore their concerns. For patients wanting to pursue lifestyle modifications only, discussion about how both DMT and lifestyle modifications are key to living one’s best life with MS may be effective. Communication is key to understanding a patient’s concerns and keeping the dialogue open.


MS is an immune-mediated, neurodegenerative disease of complex pathophysiology. A greater understanding of the disease suggests that pathophysiology involves both peripheral activity and processes confined within the CNS. Despite the availability of HET, unmet needs remain in the treatment of MS. New therapies under inves­tigation aim to address current therapeutic limitations. Clinical trial results and RWD will continue to inform best practices for starting, switching, de-escalating, and discontinuing MS therapies. Shared decision-making is important for patients and neurologists to ensure the best outcomes in MS.

Faculty presenters: Robert T. Naismith, MD; Fredrik Piehl, MD; Riley Bove, MD; and Ahmed Z. Obeidat, MD. This article was reviewed, edited, and approved by Dr Naismith, Dr Piehl, Dr Bove, Dr Obeidat, and Dr Longbrake.

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