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Optimizing Multiple Sclerosis Treatment
Translating Progress Into Practice: Optimizing MS Treatment and Patient Outcomes

Released: January 12, 2026

Patricia K. Coyle
Patricia K. Coyle, MD, FAAN, FANA
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Key Takeaways
  • Multiple Sclerosis (MS) is considered an immunoinflammatory pathology of the central nervous system (CNS) involving 2 overlapping processes: (1) a peripheral immune cell-mediated focal inflammation that produces relapses and MRI lesions, and (2) a CNS-intrinsic smoldering inflammation that drives chronic injury and progression.
  • The recognition of a prodromal phase and radiologically isolated syndrome supports the concept that MS can exist in a silent form for years before clinical diagnosis, reinforcing the importance of early detection strategies, including imaging and predictive analytics.
  • Relapses contribute to short-term disability, but long-term progression in MS is more often due to progression independent of relapse activity, a process linked to smoldering intra-CNS inflammation, highlighting the need to treat beyond relapse prevention.
  • Advances in biologic classification and novel delivery systems may help close the gaps between the arsenal of disease-modifying therapies, which mostly target the relapsing forms of MS and its progressive form, which remains inadequately treated.

Multiple sclerosis (MS) is the most common disabling neurologic disease of young adults. Our understanding of multiple subtypes of MS has changed, and it is now considered to be a homogeneous spectrum disorder involving 2 overlapping central nervous system (CNS) immunoinflammatory pathologies: One acute and localized underlying relapsing MS, and the other chronic and diffuse underlying progressive MS. Both pathologies are believed to be present in virtually all individuals with MS from a very early disease time point. Focal inflammation involves the perivenular trafficking of systemic adaptive immune cells, predominantly lymphocytes. It results in clinical relapses, contrast lesion activity, and the development of new macroscopic MRI lesions. This component is maximal at an early age and early in disease progression, tending to diminish over time. As it fades, it may even burn out with age. This has been the basis for considering disease-modifying therapy (DMT) discontinuation in elderly individuals with relapsing MS. The second immunopathology is smoldering intra-CNS inflammation, with toxic glial and mitochondrial changes. This process involves innate immune cells within the CNS and underlies the progressive neurodegenerative aspects of MS, including microscopic injury and marked damage to synapses, neurons, and axons. Subjects show slow clinical progression with slowly expanding lesions but no enhancement on MRI images. Often, such lesions contain an expanding rim of microglia and macrophages that have phagocytized iron. Iron is known to enhance oxidative injury. Although present early, this aspect of MS typically presents clinically at midlife (ages 45-55 years). The current interpretation is that CNS reserves mask the subtle clinical sequelae until sufficient loss has accumulated over time to become apparent.

The spectrum component of MS lies in the fact that MS can exist yet be clinically silent and undetected. Limited data have suggested that silent MS may account for 20% to 25% of individuals identified with MS at autopsy. The radiologically isolated syndrome with abnormal imaging suggestive of MS is now recognized and diagnosed as MS according to the revised 2024 McDonald diagnostic criteria. In addition, there is now a recognized MS prodrome, spanning 5-10+ years prior to the initial neurologic presentation recognized as MS. During this prodrome, healthcare system resources are used significantly more than in matched controls. It is hoped that studies will allow identification of these future individuals with MS.

There is also interest in understanding how MS progresses, as this is a first step towards effective preventative treatment. MS can lead to disability due to relapse-associated worsening, or due to progression independent of relapse activity, with the latter appearing to predominate over the former. Age, comorbidities, and poor CNS reserve can also contribute to disability, together with rampant MS symptoms.

Multiple DMTs encompassing 10 distinct mechanisms of action and including generics and biosimilars have been developed over the past 3 decades. They are predominantly immunosuppressive agents aimed at relapsing forms of MS, with only 1 DMT approved for primary progressive MS. Progressive MS, with its smoldering intra-CNS inflammation and neurodegenerative damage, is a clear area of need with limited therapeutic options. In addition, there are no CNS repair agents to improve fixed deficits and recovery from a relapse. Nevertheless, the vigorous and ongoing development of novel agents and delivery systems, including CNS penetrant and intranasal drug delivery, makes us hopeful that major MS breakthroughs can be expected in the next few years.

Finally, the classification of MS based on clinical features is being revisited, using artificial intelligence to achieve a more meaningful biologic classification, which may usher in a new way to think about MS.

Your Thoughts
When a patient with relapsing MS has breakthrough disease activity on their current DMT, how do you decide between so many options of DMT therapies? Share your approach or a case that challenged your thinking.

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