Treatment of multiple sclerosis (MS) with high-efficacy disease-modifying therapies (DMTs) offers a viable therapeutic option for many patients. Learn about the role of inflammation in MS pathology, treatment strategies for high-efficacy DMTs, their impact on cognition, and use in special populations.
Transforming Multiple Sclerosis Care Using High-Efficacy Disease-Modifying Therapies
High-efficacy disease-modifying therapies (DMTs) have fundamentally changed the therapeutic landscape of multiple sclerosis (MS) by offering superior control of disease activity and progression compared to traditional MS therapeutic approaches.1 These high-efficacy MS treatments significantly reduce relapse rates, MRI lesion activity, and disability progression.2,3 For example, natalizumab has been shown to reduce annualized relapse rates by up to 68% compared to placebo in patients with relapsing-remitting MS (RRMS).4 However, their use is not without risks; for instance, natalizumab carries a risk of progressive multifocal leukoencephalopathy, which requires vigilant patient monitoring.5 Integrating biomarkers such as neurofilament light chain (NfL) into clinical practice has enhanced the ability to tailor treatment strategies.6 Elevated NfL levels are predictive of future disability and brain atrophy, even in patients who appear clinically stable.7 This emphasizes the importance of using biomarkers to detect subclinical disease activity and optimize therapeutic interventions. Ongoing studies such as TREAT-MS and DELIVER-MS aim to determine whether early intensive therapy provides better long-term outcomes compared to the traditional or escalation approach.8,9 These trials are mainly focused on metrics such as sustained disability progression and preservation of brain volume, which are crucial for improving long-term quality of life (QoL) in patients with MS.
Addressing Progression Independent of Relapse Activity (PIRA)
PIRA remains one of the most challenging aspects of MS management because it reflects neurodegenerative processes that occur independently of overt inflammatory relapses or compartmentalized inflammation that is difficult to measure with current biomarkers.10 This form of progression is strongly associated with microglial activation, chronic oxidative stress, and mitochondrial dysfunction within the central nervous system (CNS).11 While current therapies effectively suppress relapses and MRI lesion activity in up to 90%–95% of cases, they often fail to address the compartmentalized CNS inflammation and the accompanied neurodegeneration driving PIRA.10,12 Pharmacological advancements that address PIRA demonstrate reduced sustained disability progression, including effects on patients with higher levels of disability.13 The MAGNIFY-MS study (NCT03364036) of the small molecule cladribine aligns with the possibility of addressing progression independent of relapses. Still, it is important to mention that it is a single-arm study that lacks a direct control group for comparison. Additionally, emerging BTK inhibitors are being investigated, and lifestyle modifications can be critical in mitigating PIRA.14 Regular physical activity has been shown to promote neuroplasticity and improve functional outcomes in patients with MS, while dietary interventions focused on anti-inflammatory options and the avoidance of processed foods may further support brain health. Smoking cessation is particularly important because smoking accelerates brain atrophy and worsens disability progression.15
Long-Term Safety of DMTs: Real-World Data and Clinical Challenges
Understanding the long-term safety profiles of DMTs is essential for optimizing their use in clinical practice. While randomized controlled trials provide initial safety data, real-world evidence from cohort studies and post-marketing surveillance offers valuable insights into rare or long-term adverse events.16 For example, cladribine was initially linked to an increased risk of malignancies during its trial phase when compared to placebo; however, subsequent long-term data from open-label extension studies did not detect a significant further increase in cancer risk over time.17 Similarly, real-world data on ocrelizumab have confirmed its generally favorable safety profile while highlighting rare risks such as infusion reactions and opportunistic infections.18 Long-term risks include autoimmune complications such as thyroid disorders or immune thrombocytopenia for B, T, and other immune cell-depleting agents such as anti-CD52 (alemtuzumab). These risks necessitate ongoing monitoring even after treatment discontinuation. Real-world evidence also informs strategies for managing these risks, such as preemptive screening for latent infections or autoimmune predispositions, before initiating therapy. Integrating long-term safety data into clinical decision-making ensures that patients receive treatment regimens with an optimal balance between therapeutic efficacy and tolerability.
MS Therapeutic Immune Reconstitution vs Continuous Immune Suppression
Immune reconstitution therapies (IRTs) offer a unique approach to MS treatment by inducing durable disease control through short-term immunosuppression followed by immune system reconstitution.19 Cladribine and alemtuzumab are prime examples of IRTs that provide prolonged remission with minimal ongoing treatment burden. This makes them particularly suitable for patients who may not tolerate continuous immunosuppression due to comorbidities or life circumstances such as pregnancy planning. Unlike continuous immune suppression therapies like fingolimod or dimethyl fumarate—which require daily or regular administration—IRTs reduce cumulative immunosuppressive exposure over time.20,21 This approach minimizes long-term risks such as infections or malignancies while maintaining high efficacy in controlling disease activity. However, careful patient selection is critical for maximizing the benefits of IRTs while minimizing potential complications such as secondary autoimmunity or a short-term increased risk of infections or malignancy.20
The Role of Inflammation and Microglia in MS Pathology
Inflammation is central to MS pathogenesis and involves both peripheral immune activation and CNS-resident processes mediated by microglia and astrocytes. While current therapies effectively target peripheral inflammation driven by T and B cells, they have limited impact on CNS-compartmentalized inflammation.22 Microglia play a dual role in MS pathology in that they contribute to demyelination and axonal damage during active disease phases, but they also facilitate repair processes under certain conditions.23 Novel therapeutic approaches aim to modulate microglial activity to reduce neuroinflammation while promoting remyelination. BTK inhibitors represent a promising class of drugs capable of crossing the blood-brain barrier to target microglia directly. Early-phase clinical trials have demonstrated their potential to slow disease progression by reducing chronic CNS inflammation, which is a key driver of PIRA.24
Advances in Biomarkers: Fluid and Imaging Innovations
Biomarkers are transforming the way MS is diagnosed, monitored, and treated. Fluid biomarkers such as NfL provide a noninvasive measure of axonal damage and correlate strongly with disease activity on MRI scans.7 Advanced assays such as Simoa (single molecule array) enable clinicians to track NfL levels over time and offer valuable insights into treatment efficacy and disease progression. Imaging biomarkers are also advancing rapidly, with techniques like MRI-based volumetric analysis providing detailed assessments of gray matter atrophy, which is a key predictor of long-term disability in patients with MS.25 Paramagnetic rim lesions detected on susceptibility-weighted imaging are emerging as markers of chronic active lesions associated with progressive disease stages.26 The central vein sign (CVS) and corpus callosum volume are also gaining attention as important imaging biomarkers. The CVS, visible on advanced MRI sequences, is highly specific for MS because it highlights small veins that are centrally located within demyelinating lesions, which is a feature that helps differentiate MS from mimicking conditions like small vessel disease or other inflammatory disorders.9,27 Meanwhile, atrophy of the corpus callosum, measurable through indices like the corpus callosum index (CCI), correlates strongly with brain atrophy, disability progression, and cognitive impairment in MS, making it a valuable marker for disease severity and progression.28,29 The integration of AI into imaging analysis holds promise for dramatically improving diagnostic accuracy and enabling personalized treatment strategies based on individual disease trajectories. Together, these tools can enhance diagnostic accuracy and provide insights into disease pathology and prognosis.
Personalized Care for Diverse MS Populations
Special populations such as pediatric patients, elderly individuals, and those with advanced disability face unique challenges that require tailored approaches to care. Pediatric-onset MS often presents with higher relapse rates but slower overall progression compared to adult-onset disease; however, treatment decisions within this group are complicated by limited trial data. Similarly, elderly patients may experience greater risks from immunosuppressive therapies due to age-related comorbidities or immunosenescence and are often excluded from clinical trials.30 Trials like CHARIOT-MS are addressing unmet needs in advanced MS populations by evaluating the effects of cladribine on hand function preservation in patients with severe disability (EDSS 6.5–8.5) due to the high prevalence of wheelchair usage within this population of patients.31 Personalized care strategies incorporating biomarkers such as NfL levels or imaging findings can help optimize treatment plans based on individual risk profiles and therapeutic goals.
Cognitive and Brain Health in MS
Cognitive dysfunction affects up to 70% of individuals with MS over their disease course and impacts memory, attention, processing speed, and executive function.32 Addressing cognitive impairment requires a multidisciplinary approach that integrates pharmacological interventions with lifestyle modifications such as regular exercise, cognitive training programs, and dietary adjustments aimed at reducing systemic inflammation and optimizing brain health. Untreated comorbidities like hypertension or diabetes exacerbate cognitive decline by contributing to cerebrovascular damage and neuroinflammation. Managing these comorbidities alongside MS-specific treatments is essential for preserving brain health in all MS patient populations over the long term.33,34
MS Therapies That Help With Disease Progression, Cognition, and Cognitive Function
The management of MS has significantly advanced with the development of DMTs that not only slow disease progression but also show potential in preserving or improving cognitive function and brain health. Cognitive impairment is primarily driven by neuroinflammation, brain atrophy, and demyelination. While DMTs are primarily designed to reduce relapses and disability progression, emerging evidence suggests they have a role in mitigating cognitive decline through mechanisms such as reducing neuroinflammation, preventing brain atrophy, and promoting neuroprotection.
Cladribine is an oral IRT approved for RRMS and active secondary-progressive MS (SPMS) that selectively depletes B and T cells while sparing innate immune cells, thus reducing chronic inflammation without prolonged immunosuppression. Clinical trials have demonstrated cladribine’s ability to reduce relapse rates and slow disability progression. Importantly, cladribine has been shown to significantly reduce brain volume loss, a key marker of neurodegeneration associated with cognitive decline. In the CLARITY trial, cladribine reduced annualized brain atrophy rates compared to placebo (−0.56% vs −0.81%), highlighting its neuroprotective effects. By reducing inflammatory activity within the CNS, cladribine indirectly supports cognitive health. Its ability to protect gray matter integrity, which is a critical factor for cognitive performance, makes it a valuable option for patients at risk of cognitive decline. Additionally, cladribine’s short-term immunosuppressive effects allow for durable disease control with minimal long-term exposure to immunosuppressive agents, which may further support brain health.35,36
Siponimod is a selective sphingosine-1-phosphate (S1P) receptor modulator that has demonstrated significant benefits in slowing disability progression and improving cognitive processing speed in patients with SPMS. The pivotal EXPAND trial showed that siponimod reduced the risk of disability progression by up to 26% and provided clinically meaningful improvements in cognitive performance, as measured by the Symbol Digit Modalities Test (SDMT), highlighting its potential to address both physical and cognitive impairments in patients with SPMS.37
Ozanimod is another S1P receptor modulator that has shown promise in improving and preserving cognitive function in patients with relapsing MS, particularly in early stages. Interim results from the ENLIGHTEN clinical trial demonstrated that after one year of treatment, nearly half (47.4%) of participants experienced clinically meaningful improvements in cognitive processing speed, as measured by the SDMT, while 25.9% maintained stable cognitive function. Additionally, ozanimod was associated with minimal brain volume loss and significant reductions in MRI-detected lesions, suggesting its potential to protect against both cognitive decline and disease progression.
Beta interferons,such as interferon beta-1a and -1b, have long been used as platform therapies for MS. While their primary role is reducing relapse rates and lesion activity on MRI, studies suggest they may also benefit cognitive function by reducing neuroinflammation and promoting the production of neurotrophic factors like brain-derived neurotrophic factor (BDNF). For example, a two-year study found that patients treated with interferon beta-1a showed significant improvements in information processing speed and memory compared to placebo.38
Patient-Reported Outcomes (PROs): A New Era in MS Care
PROs are increasingly recognized as vital tools for capturing the real-world impact of MS on patients’ lives. These measures provide insights into areas often overlooked by traditional clinical metrics, such as fatigue severity, sleep quality, emotional well-being, and QoL. Web-based platforms have streamlined PRO collection during routine care visits or clinical trials while enabling longitudinal tracking of patient experiences.39 Incorporating PROs into routine practice fosters a patient-centric care approach by aligning treatment strategies with individual preferences and priorities. For example, addressing fatigue—a common yet under-recognized symptom—can significantly improve QoL even if traditional metrics like EDSS scores remain unchanged.39
Clinical Impact: High-efficacy DMTs have revolutionized MS management by significantly reducing relapse rates, MRI lesion activity, and disability progression while also preserving brain volume and cognitive function. Emerging evidence emphasizes the importance of biomarkers and PROs in tailoring treatments to detect subclinical disease activity and address patients’ real-world challenges. Ongoing trials aim to define optimal strategies for early intensive therapy versus traditional escalation approaches and are focusing on long-term outcomes such as sustained disability progression and brain health. Novel therapies, including cladribine, S1P modulators, and BTK inhibitors, may further enhance neuroprotection by addressing PIRA and improving QoL in all MS populations.
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