MS: the coming (r)evolution (Part 3)
In Part 1 of this series we looked at ‘progression independent of relapse activity’(PIRA) – the idea that MS-related disability is the result of nerve damage that is occurring even in people who are experiencing no relapses. Relapses have traditionally been viewed as the key indicator of disease activity. What the PIRA concept suggests is that relapses are an important symptom (and a miserable one at that), but they are not a good reflection of the MS disease process itself. In fact, people with primary-progressive MS (PPMS) can develop significant disability while having few or no relapses.
PIRA has profound implications for the treatment of MS. In recent years, doctors have pursued the goal of ‘no evidence of disease activity’ (NEDA). ‘Disease activity’ in this context means relapses and new inflammatory lesions on magnetic resonance imaging (MRI). But if relapses have little impact on the course of disease, achieving NEDA will be largely meaningless. For example, a recent 12-year study found that 1 in 4 people were getting worse – despite achieving NEDA (Prosperini and collleagues. Neurol Neuroimmunol Neuroinflamm 2021;8:e1059). This suggests that the ‘real MS’ lies in the slow burn of nerve damage that occurs independently of inflammation (Giovannoni and colleagues. Ther Adv Neurol Disord 2022;15:17562864211066751).
The implication is that reducing relapses (the usual efficacy measure in drug trials) is not the best way to evaluate the effectiveness of a drug (the importance of preventing new MRI lesions is less clear since PIRA only looks at relapses). That is why trials are starting to look at other measures, although these methods (such as novel MRI scans and PET imaging) are not generally available at the moment. Much can also be learned from the people with MS themselves, something we will look at in a later installment in this series.
Current treatments do not appear to have much impact on PIRA (Dzau and colleagues. J Neurol Neurosurg Psychiatry 2023;94:984-991). But the higher-efficacy medications (e.g. Lemtrada, Ocrevus, Kesimpta) do benefit measures associated with PIRA, such as brain atrophy (shrinkage due to tissue damage), which is related to worsening physical and mental ability (Chylinska and colleagues. Mult Scler Int 2023, Aug 31:4130557). These effects result in sizeable gains. A recent study estimated that MS treatments (typically moderate-efficacy drugs) slowed the progression of disability: the time it typically took for people to progress from diagnosis to needing a cane was prolonged from 18 years to 21 years (Lublin and colleagues. Brain 2022;145:3147-3161). This is an important gain (although admittedly small) but the hope is that more potent therapies will prolong disability even longer.
PIRA has shown that other treatment approaches are needed. We will look at these new treatments in Part 4 of this series.
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