The international ECTRIMS conference, which takes place every year, is dedicated to basic and clinical research in the field of MS. Here is a summary of presented data that we found interesting at the September 2019 meeting in Stockholm, Sweden.

Changes in diagnosis of MS

The MS community is continuing to evaluate the impact of the 2017 revisions to the McDonald criteria for the diagnosis of MS. At ECTRIMS 2019, Stawiarz and colleagues presented promising data showing that, in Sweden, adoption of the new criteria led to a shortening in the time to MS diagnosis: with the first McDonald criteria, 50% of patients received a diagnosis within 1.4 years and with the second, this duration was reduced to 4 months. Moreover, with the revised criteria, almost 90% of patients received a diagnosis within a year of onset of symptoms. 1,2

Changes in the diagnostic criteria have played an important role in altering the long-term prognosis of MS, as shown in a study by the Cemcat group in Barcelona that was presented at ECTRIMS 2019: the investigators found that from 1994 to 2017, there was a 70% reduction in the risk of reaching EDSS 3.0 among people with MS (pwMS). They looked at factors that could have contributed to this change and found that simply changing the diagnostic criteria from the Poser criteria (used 1994–2000) to McDonald 2017 reduced the risk of EDSS 3.0 by 32%. This meant that the group of patients considered as having MS is now ‘enriched’ with patients with milder disease than before. In addition to this phenomenon, the investigators also found that mean time from CIS diagnosis to starting a DMT was reduced by 85% and concluded that this reduction, as well as changes in environment and healthcare standards, could have contributed to the improvement in prognosis.3

“There was a dramatic shortening of time from MS onset to MS diagnosis in Sweden, in recent decades”
– Prof. Leszek Stawiarz

In the highlights session, Aksel Siva observed that MS misdiagnosis is a universal problem and, in the future, increased use of PET, the MRI central vein sign and paramagnetic phase rims / iron rings may help to reduce misdiagnosis.4

Retinal biomarkers in MS

Optic nerve pathology and abnormal retinal ganglion cell loss is evident in almost all pwMS. Therefore, retinal parameters are potentially useful to quantify and track neurodegeneration in MS. Optical coherence tomography (OCT) parameters are among the most promising biomarkers, as highlighted by a scientific session at this year’s ECTRIMS that summarised data from several ECTRIMS abstracts. Notably, Bsteh and colleagues presented data showing that serum neurofilament light (sNfL) predicts retinal thinning in patients with RRMS – further evidence to strengthen the value of sNfL as a biomarker of neuroaxonal damage and prognosis. However, only 15–20% of annual peripapillary retinal nerve fibre layer (pRNFL) variance could be predicted from annual sNfL levels.5 During this session, the presenters discussed how to combine biomarkers to generate a network of information to overcome shortcomings that each biomarker has in isolation and allow for a more comprehensive overview of the disease state.6

Two abstracts at ECTRIMS presented conflicting data on the association of OCT measures and cognitive performance in pwMS. In the first abstract, Dreyer-Alster and colleagues reported that, among 896 pwMS, neither retinal nerve fibre layer (RNFL) thickness nor ganglion cell thickness had a significant association with global cognitive score, which included assessment of memory, executive function, visual–spatial measures, attention, information processing speed, motor skills and verbal function. They concluded that OCT was not a useful tool to assess CNS neurodegeneration associated with cognitive performance. In the second abstract, 51 pwMS had five different retinal parameters measured: pRNFL, macular RFNL, macular ganglion cell-inner plexiform layer, inner retinal layer and inner nuclear layer. The authors found a correlation between cognitive function as measured using the Brief International Cognitive Assessment for MS (BICAMS) and some parameters, particularly pRNFL and inner nuclear layer. The group concluded that OCT is a valuable tool for alerting the clinician to potential cognitive impairment in MS. Variation in these results could be partially be explained by the variation in the retinal layers analysed and the cognitive assessment tools used.7,8

Further to OCT parameters, visual evoked potentials can be used as predictive tools. An abstract at ECTRIMS showed that, among 112 patients with optic neuritis (ON), multifocal visual evoked potentials (mfVEP) in the unaffected eye have predictive value in determining whether patients with ON will develop MS.9

Epigenetics in MS: a novel look at MS pathogenesis

Dysregulation in epigenetics, the ability of the cell to adapt gene expression depending on environmental pressures, has been implicated in the pathophysiology of MS. At this year’s ECTRIMS, Kular and colleagues aimed to profile DNA methylation changes in the post-mortem brain tissue of pwMS compared with healthy controls. They identified methylation changes in, and therefore dysregulation of, genes involved in CREB signalling, axonal guidance and synaptic activity. These variations are novel potential contributors to MS disease pathophysiology. A further study highlighted the ability of a synthetic version of vitamin D3, calcitriol, to produce CD14+ cells that have different DNA methylation and expression profiles. This could partly explain the beneficial effect of vitamin D in preventing MS and the latitudinal variation in MS prevalence.10–12

In another study presented at ECTRIMS, Olsen and colleagues found a characteristic signature of demethylated myelin oligodendrocyte glycoprotein circulating free DNA in the sera of patients with active RRMS compared with patients with inactive disease and with healthy controls. This epigenetic biomarker, using methylation-specific probes, represents a minimally invasive measure of oligodendrocyte cell death that may be useful for monitoring disease progression in the future.13

Overview of the highlights session

ECTRIMS 2019 concluded with the highlights session, where Prof. Young and Prof. Siva presented their pick of new and interesting data from this year’s conference. Prof. Young started by presenting new data on MS and pregnancy and some of her take-home messages were:

– MS in the mother is associated with a small increase in neonatal risk, apart from any drug exposure
– Pregnancy delays clinically isolated syndrome and RRMS onset
– Pregnancy in active MS increases risk of disease progression

Prof. Young went on to highlight that elevated serum neurofilament levels are associated with worse neurological function and certain comorbidities, e.g. diabetes. Also, age, EDSS, and MRI at onset and at 2 years may allow predict risk of converting to SPMS.14

During Prof. Siva’s presentation he mentioned that radiologically isolated syndrome (RIS) may now allow clinicians to make a pre-clinical diagnosis of MS at a very early stage, and while it is clear that not all individuals with RIS develop MS, sNfL may allow prediction of clinical conversion to MS. Prof. Siva concluded his presentation with some treatment-related take-home messages, including:

– B-cell therapies have been shown to reduce IgG, IgM and IgA levels, and this is also a side effect of other immunosuppressive MS therapies. It is suggested that IgG monitoring should be performed in pwMS using these therapies
– Discontinuation of disease-modifying therapies in pwMS over 60 years of age may not influence clinical outcome in terms of relapse risk or risk of confirmed disability progression4

“Some patients are risk takers, and some are not, so it’s up to us to take a personalised approach”
– Prof. Emmanuelle Waubant

Conclusions

This year’s ECTRIMS in Stockholm contained interesting insights in diagnosis of MS, retinal biomarkers, epigenetics, pregnancy in pwMS and disease-modifying therapy. Many of these data promise to change clinical practice in the coming years.

BE/NEUR/19/0009a/TevaPharmaBelgium/10.2019