The end of MS phenotypes?


The International Advisory Committee on Clinical Trials in Multiple Sclerosis is recommending that the clinical course descriptions of MS – relapsing-remitting (RRMS), secondary-progressive (SPMS) and primary-progressive (PPMS) – be discarded in favour of a more biology-based approach (Kuhlmann et al. Lancet Neurol 2022; epublished November 18, 2022).

Clinical phenotypes date back to 1996 when an earlier version of the committee surveyed 125 MS experts about how clinical courses might be defined (Reingold & Lublin. Neurology 1996;46;907-911). Consensus definitions were reached for RRMS, SPMS and PPMS, as well as for progressive-relapsing MS (officially eliminated in 2013). There was no consensus on relapsing-progressive MS or for severity definitions (benign vs. malignant).

This phenotypic approach was taken primarily to standardize recruitment into clinical trials. A subsequent revision in 2013 maintained the basic scheme but added modifiers (active vs. non-active with/without progression), which largely served to differentiate active patients who would respond to disease-modifying therapy (Lublin et al. Neurology 2014;83:278-286).

The new ‘One MS’ approach acknowledges that the underlying disease mechanisms operate similarly across disease phenotypes, such that pathological features differ in degree but not in kind. Individual patients may have differing degrees of non-resolving CNS inflammation, tissue damage/remodelling and repair, and activation of CNS resident cells (microglia, astrocytes) that contribute to neurodegeneration and disability progression.

The current revision is a recognition that neurodegenerative processes are evident, if not clinically apparent, from the outset. It also puts greater emphasis on targeting progressive biology as the most pressing unmet need as MS research moves forward.

In the short term, this shift away from MS phenotypes may have implications for drug approval. It remains to be seen if regulators such as Health Canada will agree to authorize DMTs for any MS patient ( RRMS and PMS) without trials demonstrating a benefit in all phenotypes.

In the longer term, the group noted that there will be a need to identify biomarkers and other measures that can reliably identify and monitor the pathological changes that are occurring and how they interrelate and correlate with outcomes. The stage would then be set for an era of personalized treatment targeting the unique pathological features of an individual patient with MS.

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