The trend to the early use of higher-efficacy disease-modifying therapies (DMT) in the management of MS was put on pause during the pandemic due to concerns about the effects of these agents on the immune response to SARS-CoV-2 and, latterly, to COVID-19 vaccination. However, as the pandemic dragged on, it became impractical to interrupt or delay treatment, and current DMT recommendations now emphasize that the risks of undertreated MS outweigh the possible risks of COVID, especially in a younger population.
The usual rationale for early, effective treatment is the limited time window during which DMTs may change the slope of disability worsening. However, ‘early’ may be something of a misnomer. ‘Early’ is generally defined as within two years of disease onset, although time of onset is poorly defined. RIS/CIS and the emerging concept of the MS prodrome have further muddied when MS can be said to have begun (Wijnands et al. Eur J Neurol 2019;26:1032-1036).
Moreover, patients’ recall of symptom onset is likely to be unreliable and may not prompt a physician visit. In the NOVO study, the median time from symptom onset to physician visit was 19 months (Fernandez et al. J Neurol 2010;257:1500-1507). The overall time from onset to diagnosis was 24.9 months. This likely underestimates the problem. Health Canada estimates that the mean time from symptom onset to MS diagnosis is five years; the mean age at diagnosis is 37 years (Gilmour et al. Health Canada, Health Reports, 17 January 2018). While this later age at diagnosis runs contrary to expectations, it is consistent with patient populations enrolled in RMS trials over the past decade, such as ASCLEPIOS and FREEDOMS (Hauser et al. N Engl J Med 2020;383:546-557. Kappos et al. N Engl J Med 2010;362:387-401). This suggests the window of opportunity is already partially closed when treatment is initiated, mitigating some of the expected benefits of early treatment (Chalmer et al. Eur J Neurol 2018;25:1262-e110).
Most of these earlyish patients initiate treatment with a modestly effective DMT, a strategy that has been called the conservative approach (Grand’Maison et al. Neural Regen Res 2018;13:1871-1874). This conservatism is generally associated with poor long-term outcomes, as long-term studies have shown, and some authors have recently noted (Stankiewicz & Weiner. Neurol Neuroimmunol Neuroinflamm 2020;7:e636). With glatiramer acetate, 23% of patients reached EDSS 6.0 after a mean of 5.6 years (Ford et al. Mult Scler 2010;16:342-350). In the PRISMS trial, 19.7% on high-dose interferon-β-1a progressed to EDSS 6.0 within 7 years (Kappos et al. Neurology 2006;67:944-953). With interferon-β-1b, 35.7% reached EDSS 6.0 after a median exposure to high-dose therapy of 8 years (Ebers et al. J Neurol Neurosurg Psychiatry 2010;81:907-912).
The more assertive approach that has emerged in recent years is to escalate to a higher-efficacy therapy within the first two years in patients with breakthrough disease activity (Freedman et al. Can J Neurol Sci 2020;47:437-455). A concern, however, is that the benchmark of breakthrough disease activity may not adequately predict worsening disease. Sormani and colleagues stratified risk according to a modified Rio scoring system (Sormani et al. Mult Scler 2013;19:605-612). In the lowest risk group (score 0: no relapses, < 4 T2 lesions at 1 year), 24% progressed over the next three years; in the modest risk group (score 1: 1 relapse and ≤ 4 T2 lesions or 0 relapses and >4 T2 lesions), one-third had early worsening. Studies have shown that clinically stable patients switched to a higher-efficacy DMT will have significant reductions in disease activity and neurofilament-light levels (de Flon et al. Neurology 2016;87:141-147). Even achieving no evidence of disease activity (NEDA) does not appear to be highly predictive of long-term outcomes (Rotstein et al. JAMA Neurol 2015;72:152-158). Indeed, in the EPIC study, there was a trend to worse EDSS scores over the long term in patients with early NEDA (Cree et al. Ann Neurol 2016;80:499–510).
An escalation approach may result in significant delays in effective treatment. This was evident in a study comparing escalation (ESC) versus early intensive therapy (EIT) (Harding et al. JAMA Neurol 2019;76:536-541). Despite close monitoring of the ESC group, 60% experienced sustained accumulation of disability and a mean worsening in EDSS score of 1.2 points before they were escalated. The authors concluded that clinical/MRI surveillance may not be sufficiently responsive, and that current criteria for justifying more intensive therapy are too stringent.
Over a decade ago, the concept emerged that the clinical course of MS was dependent on age rather than disease activity (Confavreux & Vukusic. Brain 2006;129:606-616). In that natural history study, the time to reach disability milestones was determined by the patient’s age, not by their relapses. With subsequent observations on the effect of MS on the aging brain, some authors have suggested that an age-related treatment strategy would be appropriate. According to this view, a more rational strategy would be to initiate a high-efficacy DMT in patients younger than age 40 to obtain the maximal treatment benefit, with the plan to de-intensify therapy in older patients to reduce the risk of infections and other complications related to immune senescence (Stankiewicz & Weiner, 2020). During a pandemic, such an approach might be especially appropriate in younger patients, even those with apparently stable disease, whose risk of early MS worsening is greater than it is for severe COVID-19.