Is all MS progressive?


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A recent debate in the literature addressed the question of whether all cases of multiple sclerosis are progressive. The discussion highlighted some of the challenges of diagnosing secondary-progressive MS (SPMS) and the limitations of viewing the MS disease process as distinct phenotypes.

Supporting the position that the primary disease process in MS is progressive, Dr. Antonio Scalfari noted that there is no biological rationale for segmenting a clinical course into phenotypes (Scalfari A. Mult Scler 2021;27:1002-1004). The underlying pathophysiology of inflammation and neurodegeneration co-occurs in all phenotypes. Early progression may go undetected in CIS/early MS, in part because disease activity and neuroplasticity mask neurodegenerative changes. However, this focus on clinical appearance may be misplaced: CNS inflammation may be only an epiphenomenon (the Inside-Out model); and compensatory mechanisms relate to the response to disease rather than disease itself.

Scalfari noted that the recent analysis of the OPERA trials demonstrated that even in MS patients early in their disease course (6 years) and with little disability (mean EDSS 2.8), a high proportion of 24-week confirmed disability accumulation (81-89%) was attributable to progression independent of relapse activity (PIRA) (Kappos et al. JAMA Neurol 2020;77:1132-1140). Other PIRA analyses have also reported that most disability worsening is PIRA (see Progression independent of relapses (PIRA) in MS, NeuroSens, November 21, 2019). Thus, PIRA is an early development although it may only become clinically apparent as focal inflammatory activity declines due to immunosenescence, and disability becomes evident as compensatory mechanisms are exhausted. Despite these findings of early PIRA onset, one proposed definition of SPMS requires an EDSS score of 4.0 before a diagnosis can be made (Lorscheider et al. Brain 2016;139:2395-2405), which is likely to result in a considerable delay. The OPERA analysis suggests that the onset of progression frequently occurs in patients with EDSS <3.0.

The contrary view is that MS is not invariably progressive, as shown by a proportion of patients with benign MS (Cross & Naismith. Mult Scler 2021;27:1004-1005). The estimated prevalence of benign MS, defined as EDSS <2.5 after 15-20 years, has been reported to be about 15% (Pittock et al. Ann Neurol 2004;56:303-306. Zivadinov et al. BMC Neurol 2016;16:102). The authors also noted that a subset of MS patients have little or no radiological evidence of progression using various imaging techniques (Benedetti  et al. Mult Scler 2009;15:789-794. Calabrese et al. Mult Scler 2009;15:36-41. De Stefano et al. Brain 2006;129(Pt8):2008-2016). Moreover, these estimates presume that there are no mild MS cases in the community that remain undiagnosed; this population would be overlooked by MS registries and natural history studies.

The classification scheme proposed almost a decade ago argued for PPMS and SPMS to remain separate phenotypes, although it acknowledged that the two entities are not pathologically distinct (Lublin et al. Neurology 2014;83:278-286). The two progressive phenotypes share the modifiers of active with and without progression, progression without activity, and no activity or progression (stable disease). However, the recent debate suggests that from a pathophysiological perspective, MS may be viewed as a spectrum rather than as distinct categories. Most patients may be viewed as having inflammation and neurodegeneration from onset or thereabouts. At either end of the spectrum would be the subtype of benign MS (inflammation without neurodegeneration), and the subtype of what has been described as myelocortical MS (neurodegeneration in the absence of inflammation or white-matter demyelination) (Trapp et al. Lancet 2018;17:870-884).

The Scalfari model of MS proposes a one-stage disease process of a progressive course with or without overlapping relapses. As such, treatment would ideally be directed at the pathophysiological processes that drive PIRA, such as chronic slowly-expanding lesions and microglial activation. In the OPERA analysis, there was a 15% reduction in the number of patients with PIRA events with ocrelizumab versus interferon-β (13.9 vs. 16.4%) (Kappos 2020). A greater benefit may be achievable with small-molecule DMTs that can cross the blood-brain barrier. A post-hoc analysis of the EXPAND study reported a 29-33% reduction in 6-month confirmed disability progression with siponimod versus placebo in the subgroup without on-study relapses; the relative risk was significant at 12 months but not at later time points (Cree et al. Mult Scler 2020, epublished November 18, 2020). It remains to be determined if other small-molecule DMTs in development, such as Bruton’s tyrosine kinase inhibitors, will have an effect on the primary neurodegenerative process.

Is all MS progressive? – Survey

Do you believe that neurodegeneration is evident at lower EDSS scores (<3.0)?

Do you believe that an EDSS >4.0 is required before SPMS can be diagnosed?

In your estimation, what proportion of RRMS patients have suspected SPMS at 15 years after disease onset?

In your estimation, what proportion of your RRMS patients have been diagnosed with SPMS at 15 years after disease onset?

What criterion for an SPMS diagnosis do you find most useful in practice?

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