New Directions and Practice-Impacting Recommendations in Multiple Sclerosis

By Erin Longbrake, MD, PhD

The field of multiple sclerosis (MS) research and treatment is constantly evolving. As we continue to learn more about the pathogenesis of MS and gain access to new agents and treatment modalities, we can continually refine our treatment approaches and considerations. Nevertheless, despite the speed of advances in the space, many unmet needs remain when it comes to understanding the mechanisms of the disease and identifying effective pathways to target to halt its progression.

In late 2023, MJH Life Sciences Global Medical Affairs hosted a panel of thought leaders in neurology and neuroimmunology to identify and assess emerging updates and trends in MS diagnosis, imaging, and treatment that are influencing and shaping the future of patient care. The panel evaluated advances in the field and reviewed evolving standards of care through a survey of the most current research with the aim of elucidating the impact and implications of paradigm shifts that are pushing the field in new directions.

The panel focused on 4 areas. The first was the clinical and biological spectrum of the disease, considering in particular the emergence of preclinical MS as a recognized entity as well as the blurring of the lines between relapsing and progressive MS. The second area of focus examined current and emerging serologic and imaging biomarkers for MS diagnosis as well as for monitoring disease activity and progression. The third focus was new and emerging disease-modifying therapies, and the fourth evaluated strategies for starting, switching, or stopping immunotherapy.

This publication presents a collection of insights and takeaways from these presentations with the goal of bridging the gaps between these new developments and their application in practice. Each article represents a summary of presented material on the core areas of focus and contains insights that stemmed from the discussion among the contributors. Each article also includes recommendations for translating the latest innovations in research and treatment into clinical practice. We hope that you find the content practical and useful.

The Changing Paradigm of Multiple Sclerosis

THE LUBLIN-REINGOLD classification for multiple sclerosis (MS), initially developed in 1996, categorized MS as following 1 of 3 distinct clinical courses: relapsing-remitting (RRMS; acute bouts of disease activity followed by clinical recovery), secondary progressive (SPMS; relapsing-remitting disease followed by ongoing progression later in the disease course), and primary progressive (PPMS; ongoing progression from the start).¹

Although these classifications helped to standardize patient groups for MS trials and facilitated dialogue between patients and clinicians, these divisions of MS into relapsing and progressive categories is an artificial distinction without a biological basis. In response to this, Lublin and colleagues revised their classification system in 2013 to separately describe 2 separate pathophysiologic mechanisms contributing to MS. Inflammatory disease activity was reflected by clinical relapses, new T2 lesions, and/or gadolinium-enhancing magnetic resonance imaging (MRI) lesions. It coincides with breakdown of the blood-brain barrier and infiltration of peripheral immune cells into the central nervous system (CNS). In contrast, disease progression referred to slow accumulation of physical disability, usually in the absence of new MRI lesions. It likely represented a mismatch between chronic/ongoing injury (inflammation trapped behind a closed blood brain barrier, oxidative injury, axonal loss) and failure of regeneration/remyelination. This change in terminology allowed practitioners to more accurately identify individuals whose disease might respond to disease-modifying therapies (DMTs).¹

The categories of relapsing and progressive MS persist, and this frequently generates confusion among patients and practitioners, as many fail to realize that MS exists on a continuum and that both inflammation (disease activity) and neurodegeneration (progression) co-exist within each patient regardless of whether that person carries a label of relapsing or progressive MS. The relative contribution of each of these pathologic processes varies depending on the individual patient. Younger patients usually exhibit a high degree of inflammation, while older patients are more likely to exhibit clinical manifestations of neurodegeneration. Nevertheless, new data have shown that even young MS patients with relapsing disease can still exhibit slow accumulation of neurologic disability. Correspondingly, patients who are chronologically older may still exhibit signs of neuroinflammation.^2-4 Patient-specific factors such as age (with accompanying decreases in neuroplasticity and immunosenescence), genetic background, comorbidities, and individual environmental exposures likely influence the balance between inflammation and neurodegeneration in MS.

Existing MS treatment strategies are highly impactful for ameliorating inflammatory disease activity. Few treatment strategies have been shown to similarly impact the neurodegenerative biology that underlies clinical disease progression. Additional MS treatments are needed to impact this aspect of MS pathogenesis.

MS as a Spectrum

The concept of relapsing MS can be misleading, because it fails to depict the presence of chronic inflammation and suggests a lack of disease progression. In fact, much of the disability progression in RRMS is not related to relapses.¹ Progression independent of relapse activity (PIRA) describes slow accumulation of clinical disability that is not associated with a relapse. PIRA can be identified in patients at the earliest stages of MS, including those who are on highly effective DMTs.⁵ A strong association exists between older age and PIRA. Age-related cellular processes that promote inflammation and decrease neuroplasticity, in addition to the burden of comorbidities and reproductive aging, may contribute to this association.¹

Looking even before the onset of clinical MS, accumulating evidence supports the existence of a preclinical disease state. Retrospective analysis of claims data found that individuals ultimately diagnosed with MS disproportionately accessed the health care system for more than 5 years before diagnosis, generally with nonspecific systemic complaints.⁶ Others were found to have MRI lesions strongly suggestive of MS yet had no neurologic symptoms that would suggest the disease. This phenomenon has been termed radiologically isolated syndrome (RIS). Over 50% of individuals with RIS go on to develop MS within a 10-year period, and careful evaluations can identify subtle yet nondiagnostic symptoms such as headaches, fatigue, or mild cognitive impairment in this patient population. Interestingly, RIS represents preclinical disease, but radiologic evidence suggests that some individuals with RIS may have had longstanding MS disease biology that may not be appropriately considered early MS. Some RIS patients, for example, exhibit numerous brain lesions along with thalamic atrophy; in these individuals, the underlying pathobiology has likely been longstanding in contrast to disease in some people with a first clinical demyelinating syndrome who have a low lesion burden and no significant atrophy.

Preclinical MS cannot yet be systematically identified, and management of patients with RIS is controversial since not all patients develop clinical disease. Ongoing research to help identify imaging markers or biomarkers associated with emerging disease may help to identify RIS patients who would benefit from treatment. At present, younger age at RIS diagnosis, presence of cerebrospinal fluid (CSF)-restricted oligoclonal bands, infratentorial/spinal cord lesions, and male sex are predictive of future disease. While RIS patients may have subtle neurocognitive deficits, many have limited resources that preclude testing. The decision about whether to treat a patient with RIS is nuanced, and it requires a high level of familiarity with the disease state. These patients will be best served by subspecialty trained neurologists (as opposed to receiving treatment from a general or community neurologist).

Measuring Disease Progression

The clinical phenomenon of disease progression, or slowly worsening disability in MS, is caused by a combination of multiple injurymechanisms (eg, nonresolving inflammation, neurodegeneration, oxidative stress, mitochondrial dysfunction) together with inad­equate compensatory mechanisms (eg, remyelination/repair and neuroplasticity) that occur to varying degrees within an individual and are influenced by the aging process.¹ Current methods of assessing disease progression in MS generally rely on demonstrating a persistently increased Expanded Disability Status Scale (EDSS) score, but this does not sufficiently or quan­titatively capture several important functional domains (eg, upper extremity function, bladder impairment, fatigue, and cognition). In particular, fatigue and cognition are very poorly assessed by EDSS; therefore, the score may not reflect disease worsening, even if the patient’s subjective symptoms and experienced disability have changed dramatically. Improved methods for detecting disease progression are needed. An objective biologic-or biomarker-based approach would be particularly desirable for optimizing treatment and enhancing clinical trial design. Several promising biomarkers, including radiologic measures (such as paramagnetic rim lesions and slowly expanding lesions) and serologic biomarkers (such as serum neurofilament light chain or glial fibrillary acidic protein) are under investigation and are discussed further in the next article. Ideally, objective biomarkers evaluating each mechanism contributing to progression (eg, chronic inflammation, demyelination, oxidative injury) would be identified and used in parallel to better delineate where each patient was on the spectrum of MS.

Patient-reported outcomes and wearable devices offer increas­ingly sensitive ways to improve the clinician’s understanding of the patient’s daily life experiences and objectively identify disease progression. Systemic symptoms including cognitive impairment, fatigue, depression, and insomnia are common among patients with MS, and the degree to which these comor­bidities are caused by the biologic mechanisms of MS-related injury, progression, and inflammation or by other comorbidities (eg, sleep disorders) and lifestyle factors (eg, sedentary behav­ior and lack of socialization) remains to be elucidated. These symptoms often have a strong effect on patients’ quality of life and psychiatric comorbidities.

Improving Quality of Life in MS

In addition to managing progression and disease activity in MS, clinicians should consciously evaluate and address symptoms that impact quality of life. MS management tends to focus heavily on DMT, and while this is incredibly important for long-term disease management, it has a relatively small impact on how patients experi­ence MS on a day-to-day basis. Intentionally discussing modifiable factors including comorbidity management, exercise strategies, sleep hygiene, and diet can help improve quality of life and empower patients to take ownership in how they feel. Having a multidisciplinary team may facilitate addressing these lifestyle factors and managing the patient’s condition in a holistic way. Community-based activities in which people with MS gather together and engage in physical activity and brain health activities may also help build community and improve physical and mental health.

Environmental and geographic factors may also contribute to a patient’s ability to make beneficial lifestyle changes and a patient’s quality of life. For example, patients in colder climates may stay indoors if they are concerned about slipping on ice and thus become more deconditioned than are patients in warmer climates who are able to walk outside more frequently. On the other hand, patients who are highly heat sensitive may avoid going outdoors when the weather is warm and thus be susceptible to deconditioning. Understanding patients’ individual symptomatology and discussing personalized strategies to work around environmental barriers to exercise may be beneficial.

Conclusions

MS occupies a spectrum that includes overlapping pathologic and reparative processes that contribute to varying degrees; inflammation, neurodegeneration, and repair are simultaneously active for any given patient. Future research will need to focus on developing and standardizing biologically-based biomarkers of MS inflammation, progression, and repair and using them to develop personalized treatment approaches and algorithms.¹

Faculty presenters: Stephen Krieger, MD; and Carrie M. Hersh, DO, MSc, FAAN.This article was reviewed, edited, and approved by Dr Krieger, Dr Hersh, and Dr Longbrake.

References

1. Kuhlmann T, Moccia M, Coetzee T, et al. Multiple sclerosis progression: time for a new mechanism-driven framework. Lancet Neurol. 2023;22(1):78-88. doi:10.1016/S1474-4422(22)00289-7

2. Kawachi I, Lassmann H. Neurodegeneration in multiple sclerosis and neuromyelitis optica. J Neurol Neurosurg Psychiatry. 2017;88(2):137-145. doi:10.1136/jnnp-2016-313300

3. Hauser SL, Oksenberg JR. The neurobiology of multiple sclerosis: genes, inflammation, and neurodegeneration. Neuron. 2006;52(1):61-76. doi:10.1016/j.neuron.2006.09.011

4. Spain RI, Cameron MH, Bourdette D. Recent developments in multiple sclerosis therapeutics. BMC Med. 2009;7:74. doi:10.1186/1741-7015-7-74

5. Tur C, Carbonell-Mirabent P, Cobo-Calvo Á, et al. Association of early progression independent of relapse activity with long-term disability after a first demyelinating event in multiple sclerosis. JAMA Neurol. 2023;80(2):151-160. doi:10.1001/jamaneurol.2022.4655

6. Wijnands JMA, Kingwell E, Zhu F, et al. Health-care use before a first demyelinating event suggestive of a multiple sclerosis prodrome: a matched cohort study. Lancet Neurol. 2017;16(6):445-451. doi:10.1016/S1474-4422(17)30076-5

The Role of Biomarkers in Multiple Sclerosis

Sensitive biomarkers for multiple sclerosis (MS) can help improve diagnosis, predict disease activity (eg, relapse activity or progression), and assess treatment response; however, identifying useful biomarkers for MS has been difficult due in part to the high heterogeneity of the disease and variation in immune signatures among patients.¹ Several blood- and magnetic resonance imaging (MRI)-based biomarkers are in late stages of development. Clinically useful biomarkers will be noninvasive, easy to obtain, accurate, reproducible, and cost effective.¹

Fluid Biomarkers

Neurofilament Light Chain

Neurofilament light chain (NfL) is a neuron-specific cytoskeletal protein that increases in the blood with any neuroaxonal injury. High serum and/or cerebrospinal fluid (CSF) levels have been linked with higher T2 lesion load and greater number of gadolinium-enhancing T1 lesions in relapsing-remitting MS ([RMSS] of note, concentrations also rise with other diseases affecting the neuroaxonal compartment).^2,3 Additionally, higher serum NfL (sNfL) levels were associated with a greater number of new or enlarging T2 lesions, loss of brain volume, and risk for confirmed disability worsening over a 1- to 2-year period.³ sNfL is reduced by effective treatment, with lower sNfL concentrations observed 6 and 24 months after starting treatment with fingolimod and significant, durable reductions in sNfL concentrations observed in patients with RRMS and primary progressive MS (PPMS) who received ocrelizumab.² After suppression of disease activity with ocrelizumab, a persistently high on-treatment NfL level at 48 weeks was associated with an increased risk for long-term disability progression and an approximately 2-fold increased likelihood of confirmed disability progression over approximately 8 years.² sNfL is therefore a leading serologic biomarker for evaluating MS disease activity. sNfL appears to measure a combination of inflammatory disease biology as well as slowly progressive neurodegeneration.

The sNfL values increase with age and decrease with higher body mass index (BMI); therefore, adjusted normal ranges are needed.⁴ Additionally, several platforms are available for quantifying sNfL, and while results are tightly correlated between the platforms, the absolute values returned can vary depending on the platform used. Based on large reference datasets, cross-sectional interpretation of the degree of abnormality of sNfL levels as compared to those of controls is informative and supplemented by following individual patient trends over time (using a consistent testing platform).

As sNfL measurements are incorporated into clinical practice, understanding the kinetics of change in sNfL values with disease activity and treatment will help determine the appropriate frequency for measuring this biomarker and the degree to which changes in or levels of normalization for sNfL represent an actionable item. In evaluating a 3-parameter end point for no evidence of disease activity, patients' increased sNfL levels were prognostic of disease activity in the following year.⁴ High sNfL values while on disease-modifying therapy reflect ongoing neuroaxonal injury and an insufficient response to treatment, likely indicating that treatment should be changed if other relevant comorbidities (eg, at least moderately severe renal impairment or insufficiently controlled diabetes) have been excluded.

Octave Panels

The Octave panel is a first-in-class, multiprotein, serum-based assay for assessment of disease activity in MS.⁵ The panel includes 18 serum biomarkers that were selected based on research and development studies and included into an algorithm that calculates 4 disease pathway scores (immunomodulation, neuroinflammation, myelin biology, and neuroaxonal integrity).⁵ In a clinical validation study, the scores on this 18-protein, serum-based assay were strongly associated with the presence of T1 gadolinium-enhancing lesions, new or enlarging T2 lesions, and active vs stable disease, and the model performed better than the single-protein model based on demographically corrected NfL.⁵ However, combining multiple biomarkers into a single score may eliminate the nuance of the multidimensional pathologic components involved in MS progression. Additionally, many of the correlations between Octave scores and disease indices appear to be driven by 3 to 4 of the markers (primarily NfL), and the added value of the remaining biomarkers appear to be relatively small with a lack of data on how to use the information.

For other markers, it is not clear how useful the serum measurements are; for example, while CSF levels of CXCL13 have been promising as an MS biomarker, serum CXCL13 levels are much higher and likely indicate general systemic inflammation rather than the central nervous system (CNS)-specific inflammation that is more relevant to MS. Some neurologists use the Octave panel as a 1-time test, because it is accessible and relatively inexpensive and provides a snapshot of the patient’s disease status, but understanding how to interpret and use the test to guide clinical decision-making is still evolving.

Imaging Biomarkers

Central Vein Sign

The central vein sign (CVS) was first identified on ultra high‑field MRI; it is defined radiologically as a hypointense vessel located in the middle of an MS lesion with a diameter of greater than 3 mm and pathologically as a perivenular, inflammatory, demyelinated focal lesion.^6-8 Because the location of this vein in the lesion is highly specific to MS, it has been proposed as an imaging biomarker to differentiate MS from other CNS conditions with white matter lesions.⁶ The CVS is also common in patients along the MS spectrum, including those with clinically isolated syndrome (CIS)9 and radiologically isolated syndrome (RIS).¹⁰ Two prospective trials evaluating CVS as a diagnostic tool are ongoing: the DECISIve trial (NCT04024969) is comparing the diagnostic accuracy between CVS on T2-weighted MRI and lumbar puncture with oligoclonal band examination in patients presenting with possible MS, and the CAVS-MS trial (NCT04495556) is evaluating the agreement between CVS and McDonald criteria for diagnosis of MS, the sensitivity of CVS to identify MS in patients with typical presentations, and the specificity of CVS for patients with atypical presentations.^11,12

CVS may be useful for monitoring disease if it helps to distinguish inflammatory lesions related to MS from those caused by other conditions. It may also help avoid MS misdiagnosis. At present, the utility of this tool is limited by heterogeneity in MRI scanners and sequence acquisition protocols, and the degree to which these variables affect the readout should be elucidated in future research.⁶ Tailoring the MRI to maximize specificity (as opposed to sensitivity) can help optimize the clinical utility of the CVS as a biomarker. Presently, high resolution T2* relaxation with 3-dimensional echo-planar imaging may represent the optimal sequence for detecting CVS, but this is not widely available on clinical MRI scanners. Susceptible weighted-imaging protocols can also reveal a subset of CVS lesions.

Paramagnetic Rim Lesions

Paramagnetic rim lesions (PRLs) are defined radiologically as persistently hyperintense MRI lesions with a surrounding hypointense rim and pathologically as chronically active lesions with iron accumulation in microglia and macrophages at the edge of the demyelinated area.^13,14 PRLs have been correlated with CSF markers of neurodegeneration, including higher age-adjusted NfL percentiles and optical coherence tomography parameters (eg, lower peripapillary retinal nerve fiber layer and ganglion cell-inner plexiform layer thicknesses).^13,15

PRLs are present across the spectrum of MS and in all age groups. High numbers of PRLs appear to be correlated with more aggressive disease, positioning PRLs as a promising imaging biomarker. Optimizing and standardizing the image quality, protocols, and algorithms will be important to effectively use this biomarker in the clinical setting. Communication between neurologists and radiologists about optimal image parameters and protocols is also important for improving the utility of this biomarker.

Slowly Expanding Lesions

Slowly expanding lesions (SELs), which are radiologically defined as gradual and constant radial expansion of T2 lesions for at least 3 time points, may be more prevalent than PRL in patients with MS (92% with SEL vs 56% with PRL in 1 retrospective study), and higher SEL counts have been correlated with greater increases in Expanded Disability Status Scale (EDSS) scores over time. The EDSS measures disability on a scale of 0 to 10, with a higher score indicating greater disability.^16,17 Additionally, presence of both SELs and PRLs was associated with worsening disability over time compared with detection of SEL alone.¹⁷ This finding could be useful for predicting future disease severity, although the SEL designation is currently based on a mathematical construct—rather than a pathologic mechanism—and further characterization of the pathologic relevance of the SEL finding will be helpful for refining the SEL definition. The reliance on computational algorithms to detect SELs also limits the clinical applicability, at least in current practice. A recent federal research grant (DOD W81XWH-21-1-0787) was awarded to to investiga­tors at the Cleveland Clinic to study the pathology of SEL in MS.

Conclusions

Advances have been made in the search for MS biomarkers that predict MS relapse and disability progression, but it is unlikely that any single measure can comprehensively evaluate patients with MS because of the complexity of the disease and high heterogeneity in disease behavior.¹ Additionally, the MRI protocols and computational tools used to measure image-based biomarkers are largely unstandard­ized, and future work is needed to standardize these protocols, train algorithms to adjust for technical differences across MRI platforms, and retrain those who use them as the technology evolves. Using rational combinations of biomarkers that reflect the diversity of MS pathology will help optimize the diagnostic and prognostic value of these measures.¹

Faculty presenters: Jens Kuhle, MD, PhD; and Pascal Sati, PhD. This article was reviewed, edited, and approved by Dr Kuhle, Dr Sati, and Dr Longbrake.

References

1. Yang J, Hamade M, Wu Q, Wang Q, Axtell R, Giri S, Mao-Draayer Y. Current and Future Biomarkers in Multiple Sclerosis. Int J Mol Sci. 2022 May 24;23(11):5877. doi:10.3390/ijms23115877. PMID: 35682558; PMCID: PMC9180348.

2. Bar-Or A, Thanei G-A, Harp C, et al. Blood Neurofilament Light Levels Predict Non-Relapsing Progression Following Anti-CD20 Therapy in Relapsing and Primary Progressive Multiple Sclerosis: Findings From the Ocrelizumab Randomized, Double-Blind Phase 3 Clinical Trials. Poster presented at the 38th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS); Amsterdam, The Netherlands and virtual. October 26-28, 2022. Abstract P256.

3. Kuhle J, Kropshofer H, Haering DA, et al. Blood neurofilament light chain as a biomarker of MS disease activity and treatment response. Neurology. 2019;92(10):e1007-e1015. doi:10.1212/WNL.0000000000007032

4. Benkert P, Meier S, Schaedelin S, et al. Serum neurofilament light chain for individual prognostication of disease activity in people with multiple sclerosis: a retrospective modelling and validation study. Lancet Neurol. 2022;21(3):246-257. doi:10.1016/S1474-4422(22)00009-6

5. Chitnis T, Foley J, Ionete C, et al. Clinical validation of a multi-protein, serum-based assay for disease activity assessments in multiple sclerosis. Clin Immunol. 2023;253:109688. doi:10.1016/j.clim.2023.109688

6. Castellaro M, Tamanti A, Pisani AI, Pizzini FB, Crescenzo F, Calabrese M. The Use of the Central Vein Sign in the Diagnosis of Multiple Sclerosis: A Systematic Review and Meta-analysis. Diagnostics (Basel). 2020;10(12):1025. Published 2020 Nov 29. doi:10.3390/diagnostics10121025

7. Sati P, Oh J, Constable RT, et al. The central vein sign and its clinical evaluation for the diagnosis of multiple sclerosis: a consensus statement from the North American Imaging in Multiple Sclerosis Cooperative. Nat Rev Neurol. 2016;12(12):714-722. doi:10.1038/nrneurol.2016.166

8. Adams CW. The onset and progression of the lesion in multiple sclerosis. J Neurol Sci. 1975;25(2):165-182. doi:10.1016/0022-510x(75)90138-0

9. Clarke MA, Pareto D, Pessini-Ferreira L, et al. Value of 3T Susceptibility-Weighted Imaging in the Diagnosis of Multiple Sclerosis. AJNR Am J Neuroradiol. 2020;41(6):1001-1008. doi:10.3174/ajnr.A6547

10. Suthiphosuwan S, Sati P, Absinta M, et al. Paramagnetic Rim Sign in Radiologically Isolated Syndrome. JAMA Neurol. 2020;77(5):653-655. doi:10.1001/jamaneurol.2020.0124

11. Allen CM, Morgan P, Craner M, et al222 DECISIve – DiagnosE using the Central veIn SIgn. A study comparing T2* MRI and lumbar puncture. JNNP. 2022;93:A77.

12. Ontaneda D, Sati P, Raza P, et al. Central vein sign: A diagnostic biomarker in multiple sclerosis (CAVS-MS) study protocol for a prospective multicenter trial. Neuroimage Clin. 2021;32:102834. doi:10.1016/j.nicl.2021.102834

13. Maggi P, Kuhle J, Schädelin S, et al. Chronic White Matter Inflammation and Serum Neurofilament Levels in Multiple Sclerosis. Neurology. 2021;97(6):e543-e553. doi:10.1212/WNL.0000000000012326

14. Dal-Bianco A, Grabner G, Kronnerwetter C, et al. Slow expansion of multiple sclerosis iron rim lesions: pathology and 7 T magnetic resonance imaging. Acta Neuropathol. 2017;133(1):25-42. doi:10.1007/s00401-016-1636-z

15. Krajnc N, Dal-Bianco A, Leutmezer F, et al. Association of paramagnetic rim lesions and retinal layer thickness in patients with multiple sclerosis. Mult Scler. 2023;29(3):374-384. doi:10.1177/13524585221138486

16. Elliott C, Wolinsky JS, Hauser SL, et al. Slowly expanding/evolving lesions as a magnetic resonance imaging marker of chronic active multiple sclerosis lesions. Mult Scler. 2019;25(14):1915-1925. doi:10.1177/1352458518814117

17. Calvi A, Clarke MA, Prados F, et al. Relationship between paramagnetic rim lesions and slowly expanding lesions in multiple sclerosis. Mult Scler. 2023;29(3):352-362. doi:10.1177/13524585221141964

Treating Multiple Sclerosis Throughout the Life Cycle of Disease

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.

Switching

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.

Conclusions

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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