Almost 80% of respondents to an International Advisory Committee on Clinical Trials in Multiple Sclerosis survey supported a change to current MS clinical course descriptors.[1]
Instead, they would prefer a mechanism-driven framework that reflects recent advances in the understanding of long-term disability progression – specifically, that it results from a combination of pathological processes that vary between and within individuals over time. Yet while implementing such a shift in thinking has precedent in neurology, notably in Huntington and Alzheimer’s disease, 1 it is not without its challenges.
Here, we take a look at the argument for change, the results of the survey, and the committee’s recommendations for making the transition.
Evolving understanding
Clinical course descriptors have been a hotly debated topic in MS for decades. Since the Lublin–Reingold clinical course descriptors for MS were published in 1996, and revised in 2013, some sections of the community have been calling for them to be replaced with a biological mechanisms-based framework. [1]
Explaining the current ubiquity of terms such as relapsing-remitting, primary and secondary progressive MS, the authors of Do the current MS clinical course descriptors need to change and if so how? A survey of the MS community write: “The emergence of clinical course descriptors for MS resulted in a consistent approach to patient selection for clinical trials. This reduction in patient heterogeneity presaged nearly three decades of successful clinical trials and a transformation in the clinical management of relapsing MS. Along the way, the course descriptors were widely integrated in the MS healthcare ecosystem.”[1]
As a result, people living with MS rely on them to understand their status in the disease course, clinicians employ them in disease management, and regulatory authorities and health technology assessment agencies have incorporated them into drug approvals and reimbursement schemes.
However, our understanding of the condition has evolved greatly in recent years. We now know that disability progression can occur from the early phases of relapsing MS, is partially independent of relapse activity, and is associated with accelerated brain, spinal cord, and retinal atrophy.[1]
“The recognition of shared underlying biology between relapsing and progressive MS blurs the distinction between these forms of the disease as expressed in the current clinical course descriptors, raising important questions about how the descriptors should evolve, or whether they should be replaced with a new approach,” the authors continue. [1]
Earlier this year, the committee, which is sponsored by ECTRIMS and the US National Multiple Sclerosis Society, proposed a new mechanism-driven framework of MS progression in The Lancet.[2] They have since also conducted a survey designed to help them better understand the implications of adoption.
The survey [1]
A total of 502 people from 49 countries responded to the survey, 86.8% of whom were healthcare professionals and researchers. Only 53% said they found the current course descriptors useful, and 77% said they supported changing them.
Asked about the role of any new framework, 90.4% said it should inform treatment decisions, 87.5% said it should guide the design and conduct of clinical trials, and 84.7% said it should allow patients to understand their disease. The majority, 80.1%, said it should link disease mechanisms and clinical expression of disease.
Respondents were also asked which disease mechanisms should be included. A total of 90.9% said it was “very important” or “extremely important” to measure axonal degeneration, 83.6% said demyelination, 83.2% non-resolving inflammation, and 81.4% remyelination.
When asked which tools and measures could be deployed to aid in classification, respondents considered magnetic resonance imaging (MRI) for lesion volume and count, cerebrospinal fluid (CSF) oligoclonal bands, and MRI for global and regional brain atrophy to have “the highest readiness for use”. They thought others, including serum nerve fibre layer (NfL), genetic tests, and MRI for central vein sign, required more research.
Most respondents, 81%, also said they expected any new framework to be clinically validated before dissemination.
Path ahead [1]
While there is a clear desire for a new course descriptors framework, the widespread use of the current approach poses “considerable challenges”.
“Attention will need to be paid to engaging all the affected stakeholders in developing and adopting a change process… In addition, stakeholders will need to be engaged in the development of strategies to clinically validate the proposed framework. Concerted efforts by researchers, clinicians, patients and funders will be essential to success,” the paper says.
Based on the landscape assessing survey, the authors propose six principles to guide development of a new framework, saying it should:
- reflect the currently understood domains of biological mechanisms of disease
- acknowledge that knowledge gaps exist, and plan to address them as new information emerges
- drive and stimulate advances in knowledge and therapeutic innovations
- be easily understood by, and facilitate communication with, people living with MS
- have equity at their core, to enable the feasibility of global application
- be meaningful, useful, and applicable to all stakeholders
“A shift from strict labels towards characterizing how biological disease is connected to clinical presentation would mark an important advance in current practice,” the authors conclude.
“The application of a mechanism-driven framework to MS could potentially address biologic and pathologic heterogeneity in patients at variable stages of disease and ages, and offer promise to treat early and, ideally, ahead of irreversible deficits. It is reasonable to expect that it would also improve current clinical practice and contribute to development of precision medicine approaches to MS.”
Read the full paper here
References
[1] Thompson, A. J., Moccia, M., Amato, M. P., Calabresi, P. A., Finlayson, M., Hawton, A., … & Coetzee, T. (2023). Do the current MS clinical course descriptors need to change and if so how? A survey of the MS community. Multiple Sclerosis Journal, 13524585231196786.
[2] Kuhlmann, T., Moccia, M., Coetzee, T., Cohen, J. A., Correale, J., Graves, J., … & Waubant, E. (2023). Multiple sclerosis progression: time for a new mechanism-driven framework. The Lancet Neurology, 22(1), 78-88.