We know that relapses, being a defining clinical feature of MS, contribute to meaningful neurological disability over the short term. However, their contribution towards long-term disability progression is controversial: long-term disability progression studies and natural history studies have delivered conflicting results. In a recent large MSBase study, a high annualised relapse rate, particularly on-treatment relapse, was an indicator for disease progression.1,2 Did data from this year’s EAN support this possibility? Here we discuss this and other emerging predictors of disease progression and how these advances will determine treatment approaches.

What causes disease progression in MS?

As mentioned above, relapses are thought to play an important part is disease progression.1 Data from 2,015 patients with RRMS enrolled in the Danish MS Registry treated with disease-modifying therapies (DMTs) were presented by Dr Magyari at this year’s EAN congress. The researchers observed that the mean adjusted EDSS increase was 0.205 units in study intervals with relapses and only 0.065 without relapses, confirming a significant role for relapses on disability progression. However, the contribution of relapses to disease progression depended on the stage of disease progression in which the relapse occurred. For example, for patients whose EDSS scores were ≥ 4.0 at the start of the study interval, there was no clear effect of relapses on disability worsening. Data from another study of patients with secondary progressive MS (SPMS), suggest that relapses that occur in the early years (first 3 years and 3–5 years) after SPMS onset increased the risk of irreversible EDSS worsening. In contrast, no such association between relapses and EDSS worsening was observed in the later years (after 5 years) of SPMS.3,4

Relapse-dependent progression can be contrasted with so-called ‘silent’ progression, a term suggested by the MS-EPIC Team at the University of San Francisco, USA, to describe long-term worsening that is independent of relapse or new lesion formation in patients who are considered to have RRMS. This silent loss of function may be so gradual that it is not noticed by the patient or the physician and only becomes apparent at higher levels of EDSS. It is possible that there are two simultaneous pathological process – one causing focal demyelinating lesions and correlating with relapses and a separate, more diffuse, process that contributes to brain atrophy and leads to ‘silent’ progression in RRMS and is responsible for SPMS when clinical worsening is more evident.1

Other correlates of progression

Looking to other correlates of progression, Dr Dalla Costa presented data from 255 patients diagnosed with MS in a long-term follow-up study considering clinical and paraclinical markers of disability progression. Patients who presented with clinically isolated syndrome suggestive of MS with a minimum follow up of 2 years were included in the study. Factors that were predictive of disability progression over medium- and long-term follow up included low serum levels of 25-OH-vitamin D, smoking, female gender and, in particular, presence of spinal cord lesions at disease onset. A further study found that higher vitamin D levels over 10 years were associated with lower long-term disability progression. With these two studies in agreement, vitamin D seems an attractive tool for predicting both short- and long-term disease progression.5,6

A fresh look at monitoring disease progression

Novel data presented at this year’s EAN has brought to light some promising ways for measuring disease progression at different stages of the MS disease course. A fresh view on disease progression measures was presented that combined measures of both cognitive processing speed (Symbol Digit Modalities Test) and physical disability (EDSS). When used individually, these measures mostly captured two distinct disability groups (patients tended to progress according to one but not the other measure and a minority progressed on both measures) and when combined into a composite endpoint, this provided a comprehensive measure of clinically relevant disease progression in SPMS.7

A further marker, a combination of different evoked potentials (EPs) in the form of a numerically scaled score, was shown to predict disease progression in early MS. An EP score > 13 was shown to be a significant predictor of sustained accumulation of disability (SAD), with those participants with an EP score ≤ 13 showing a 74% relative risk reduction for SAD.8 Data on the potential predictive value of the IgM index as a biomarker for disease prognosis were also presented: in a 1-year study, 88% of patients with RRMS had a negative IgM index and 42% of patients with PPMS had a positive IgM index. A positive IgM index was likely associated with a more severe form of MS and could be correlated with many aspects of MS disease evolution.9

What are the treatment implications of these advances in disease progression understanding?

“If we have reliable disease progression measures, then we would be able to choose those patients who require a more effective treatment from the start and those who can start with a more moderately effective treatment”

Per Soelberg Sørensen, Danish Multiple Sclerosis Center, Denmark

The confirmation that relapses are associated with worsening of disability in patients with RRMS beyond the recovery phase (EDSS ≥ 4.0) led Magyari and colleagues to make some recommendations. They concluded that a treatment strategy offering the best chance of preventing relapses should be used to maximise prevention of disease progression. Fortunately, evolving diagnostic criteria are allowing earlier diagnosis and treatment initiation with DMTs. This approach will allow attenuation of the frequency of these early relapses and subsequently long-term disability.3,1

Furthermore, the results showing an ability to define an individual’s disease progression risk profile at the first demyelinating event can potentially guide neurologists in their treatment decisions and personalise therapy for patients from the onset.5

Click here to see an expert opinion interview video on disease progression in MS 


  1. Cree, BAC, et al. Silent progression in disease activity–free relapsing multiple sclerosis. Ann Neurol 85, 653–666 (2019).
  2. Jokubaitis VG, et al. Predictors of long-term disability accrual in relapse-onset multiple sclerosis. Ann Neurol 80, 89–100 (2016).
  3. Magyari M, et al. Worsening of disability caused by relapses in multiple sclerosis: a different approach; in European Academy of Neurology EPO2208 (EAN, 2019).
  4. Ahrweiller K, et al. Decreasing impact of late relapses on disability worsening in secondary progressive multiple sclerosis. Mult Scler J 135245851984809 (2019).
  5. Dalla Costa G. Clinical And Paraclinical Markers Of Disability Progression After A First Neurological Event: A Long Term Follow-Up Study; in European Academy of Neurology EPO3332 (EAN, 2019).
  6. Wesnes K, et al. Vitamin D levels predict long-term disability in multiple sclerosis; in European Academy of Neurology EPO3216 (EAN, 2019).
  7. Kappos L, et al. Assessment of Disease Progression in Patients with Secondary Progressive Multiple Sclerosis (SPMS) Using a Novel Functional Composite Endpoint; in European Academy of Neurology EPR2075 (EAN, 2019).
  8. Crnošija L. The evoked potential score predicts disease progression in early multiple sclerosis; in European Academy of Neurology EPO1231 (EAN, 2019).
  9. Marsli, S. IgM levels in the cerebrospinal fluid as a prognosis biomarker in multiple sclerosis patients; in European Academy of Neurology POD180 (EAN, 2019).