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International Committee Proposes MS Disease Progression Framework Driven by Pathophysiological Mechanisms, Not Clinical Phenotype

SAP Partner | <b>National MS Society</b>

Through a culmination of previous research, the International Advisory Committee on Clinical Trials in Multiple Sclerosis suggests that multiple sclerosis disability progression is not caused by a single uniform disease mechanism but a combination of several mechanisms that play out variably over time.

For years, multiple sclerosis (MS) has been defined by 3 clinical courses: relapsing-remitting, primary progressive, and secondary progressive. Now, though, a newly published paper from the International Advisory Committee on Clinical Trials in Multiple Sclerosis suggests that patients with MS share qualitatively similar pathology features independent of clinical course, and that disability progression is neither dichotomous nor genetically determined, ultimately implying the need for a new framework from which to view the disease.1

The paper was authored by Tanja Kuhlmann, MD, an associate professor at the Institute of Neuropathology at University Hospital Münster, and part-time adjunct professor in the Department of Neurology and Neurosurgery at McGill University, and colleagues. It offers a major first step toward the elimination of the phenomenological classification of MS. Notably, Kuhlmann et al acknowledged that until the underlying mechanisms of the disease are better clarified, any new view of MS disease course will be flexible, and the adoption of biologically based definitions will present operational challenges, "as the existing descriptors are deeply embedded in clinical research and health-care systems" as well as in regulatory processes.

"The goal is to move away from purely clinical descriptions of separate phases, like relapsing or progressive MS, and toward understanding MS as a continuous process that is driven by mechanisms of nervous system injury counter-balanced by reserve and repair," coauthor Tim Coetzee, PhD, the chief advocacy, services, and science officer at the National MS Society, told NeurologyLive®. "Any new framework for classifying MS will require a sea change in how all stakeholders understand and describe the disease. It will take several years and international collaborative efforts, but this would enable the development and approval of more biologically based treatment approaches for each individual with MS."

The paper focused on clarifying the 1996 and 2013 clinical course descriptors, commonly referred to as the Lublin-Reingold classification, with the goal of determining an approach to developing a new framework for describing the disease. Overall, the thought is that disease evolution to a progressive course reflects a partial shift from predominantly localized acute injury to widespread inflammation and neurodegeneration, coupled with the failure of compensatory mechanisms such as neuroplasticity and remyelination.

A previously published study showed that the existence of an ongoing intrathecal immune response is usually shown at the time of diagnosis by the presence of central nervous system-specific oligoclonal bands.2 In the acute phase of disease, activation of microglia and infiltrates of macrophages and lymphocytes accompany demyelination and plaque formation; however, these inflammatory mechanisms do not resolve in approximately 20% of lesions. Nonresolving inflammation not only drives injury, but might also prevent repair, the study investigators noted.

Kuhlmann et al noted, "An open and crucial question is whether inflammation needs to resolve before tissue repair can commence. The development of sensitive and specific non-invasive imaging markers that detect non-resolving inflammation, such as the paramagnetic rim sign, along with future development of robust [cerebrospinal fluid] and blood biomarkers of the same processes, might allow this question to be answered."1

Inflammation has also been closely linked to axonal and neuronal injury in patients with MS. Although it remains a challenge to measure cellular, molecular, and metabolic mechanisms of neuroaxonal damage, the resulting global and regional brain atrophy—detectable from early in the disease course—has been associated with a heightened risk of progressive disability accumulation.3 Long-term disability progression independent of relapse activity, otherwise known as silent progression, is also correlated with accelerated brain atrophy. The international committee noted that, in line with this thinking, several phase 2 trials that include patients with progressive MS have begun to use atrophy induces as primary outcome measures.

Oxidative stress and mitochondrial dysfunction, another major theme brought up in the paper, have been shown to contribute to glial and neuronal injury, axonal energy loss, and loss of neuronal network function. Additionally, high levels of oxidative stress can induce injury of axons, neurons, dendrites, and oligodendroglia in MS lesions.4 Mitochondria, typically perturbed in MS, moves from cell soma to the demyelinated axon after demyelination; however, the peak of this potentially beneficial mitochondrial response is reached only after axonal degeneration has begun.5

"Energy failure can in practice be assayed in vivo using magnetic resonance spectroscopy, but a combination of laboratory and imaging techniques that can reliably assess ongoing oxidative injury and mitochondrial dysfunction in lesions is needed," Kuhlmann et al wrote.1 "As such, evidence of associations between molecular mechanisms of injury and multiple sclerosis progression mostly comes from small proof-of-concept studies, and standardization of methods will be necessary for implementation in clinical trials and practice."

Aging is another important factor that plays a role in the progression of MS. In adults, older age at diagnosis is associated with faster accumulation of ambulatory disability, which is currently a defining feature of progressive MS, and greater impairment. Telomere attrition length, a prototypical biological marker of aging, has been associated with greater disability in both cross-sectional and longitudinal analyses independent of disease duration and chronological age.6

Reproductive aging can also affect MS progression. Whereas women are at increased risk for developing MS, men with MS can have earlier and faster disability development. Although not fully understood, several studies have suggested that progressive MS pathology and disability accelerate in the perimenopausal period.7 Additionally, the loss of sex-specific steroid production might explain the phenomenon of women with MS appearing to catch up with men in terms of disability in later decades of life, the study authors noted.

Looking forward, the investigators concluded that, "In keeping with current trends throughout medicine, we envision a future in which clinical benefit accrues directly from biomarker-based, biologically informed treatment decisions," noting that in addition to the ongoing modifications this new framework will require, "comprehensive patient education efforts will also be required. As such, development of a roadmap for implementation of any new framework will be a key future focus of the International Advisory Committee on Clinical Trials in Multiple Sclerosis."1

REFERENCES
1. Kuhlmann T, Moccia M, Coetzee T, et al. Multiple sclerosis progression: time for a new mechanism-driven framework. Lancet Neurol. Published online November 18, 2022. doi:
2. Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol.2018;17(2):162-173. doi:10.1016/S1474-4422(17)30470-2
3. Chard DT, Alahmadi AAS, Audoin B, et al. Mind the gap: from neurons to networks to outcomes in multiple sclerosis. Nat Rev Neurol.2021;17(3):173-184. doi:10.1038/s41582-020-00439-8
4. Lassmann H, van Horssen J. Oxidative stress and its impact on neurons and glia in multiple sclerosis lesions. Biochim Biophys Acta.2016;1862(3):506-510. doi:10.1016/j.bbadis.2015.09.018
5. Licht-Mayer S, Campbell GR, Canizares M, et al. Enhanced axonal response of mitochondria to demyelination offers neuroprotection: implications for multiple sclerosis. Acta Neuropathol.2020;140(2):143-167. doi:10.1007/s00401-020-02179-x
6. Krysko KM, Henry RG, Cree BAC, et al. Telomere length is associated with disability progression in multiple sclerosis. Ann Neurol. 2019;86(5):671-682: doi:10.1002/ana.25592
7. Kalincik T, Vivek V, Jokubaitis V, et al. Sex as a determinant of relapse incidence and progressive course of multiple sclerosis.Brain 2013;136(pt 12):3609-3617. doi:10.1093/brain/awt28