MS Milan 2023 was the 9th joint meeting of the European ECTRIMS and American ACTRIMS congress. Over 8,600 participants from 108 countries joined and had the chance to listen to 240 faculty members and diggest the input from 1,915 abstracts.
Ten hot topics where defined:
- MS and EBV
- Treatment screening and monitoring
- MS in the elderly
- Which biomarker and when?
- Future therapeutic strategies
- PIRA and silent progression
- New technologies for MS patients
- Prodromic MS
- HSCT in MS
- Biomarkers of damage and recovery
I will try to pick some interesting outcomes on most of them during my summary of the three days starting with the ECTRIMS lecture by Dr. Stephen L. Hauser and continuing with MS and EBV, and MS in the elderly.
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Table of Contents
Opening Session and ECTRIMS lecture: Multiple Sclerosis: Path to a Cure by Stephen L. Hauser, MD
Director, UCFS Weill Institute for Neurosciences; Professor, Department of Neurology; University of California, San Francisco, USA
More and more MS experts go for the strategy of treating MS the earliest possible and Stephen Hauser agrees with that strategy. The earlier we counteract in the course of multiple sclerosis, the better the long-term results seem to be and might lead one day to controlling the disease completly which is very near to a cure.
Unfortunately, however, we do not yet know what the initial triggers for MS are. And so far, we don’t know the specific MS signature. we have to look for either.
And cure would be dependent on our definition and that stage of disease progression somebody is. For example, in an established MS, treatment would have to target multiple cell types.
But take a step back and look at the disease from the vey beginning to the end. Stephen Hauser used the metapher of a disease in three acts. The first act or phase is the one that comes before the first monitoring, the so-called prodromal phase, in which changes already occur, but about which we do not yet know much. Followed by a mostly relapsing phase with high inflammatory activity, which can now be treated well with immunotherapies. And the third act is the neurodegenerative phase, when you are in the progressive course of MS.
From act 1 to act 2, the benign autoimmunity becomes pathogenic and starts to destroy CNS tissue.
As we know today, more or less from the beginning of the relapsing course, neurodegeneration already starts. The intensity depends on the severity of the disease and is at the beginning normally very mild, but later increases in intensity while the inflammatory activity decreases.
How to detect early signs of MS
We know that MS is not a typical inherited disease, as more than 230 sites in the gene code are associated with increased susceptibility to MS. These gene changes contribute only 19 percent of the risk of disease, while 81 percent are due to other causes. Furthermore, certain genetic alterations affect the central nervous system and are responsible for the aggressiveness of the disease.
We know from other autoimmune diseases such as systemic lupus, insulin-dependent diabetes mellitus and rheumatoid arthritis that a very specific reaction becomes more nonspecific over time and becomes more widespread, leading to the onset of the actual disease.
If these changes are detected and treated early, it appears that the onset of the disease can be delayed. At least that is what small studies have shown.
MS patients have now been found to have a certain common autoantibody signature that is the same before and after the onset of the disease.
However, this profile has only been found in 12-15% of patients.
The questions that arise are when does this pattern first appear? Already in the phase of benign changes or only in the pathogenic preliminary phase of MS?
Is this signature only found in high-risk families or is there a correlation between genes or disease expression?
Treatment strategies: Earlier is better
Early acquired impairments often remain permanent and are an indicator of SPMS.
The benefits of early treatment have already been demonstrated in studies of clinically isolated syndrome and radiologically isolated syndrome, as well as in evaluations of registry data on RRMS patients.
Highly effective therapies have been shown to be more protective against later disability. This represents an opportunity to move from suppression of the disease to a cure.
Stephen Hauser’s speech was very inspiring, and it’s nice to know that for the first subsets of patients who don’t have MS today, this strategy could work. Nevertheless, we have not yet reached this goal. It’s a vision, but one that I think is worth sharing.
Since Stephen Hauser has been dedicated to multiple sclerosis from the beginning of his scientific career a few decades ago and has seen the community of scientists and practitioners grow steadily, his vision seems quite realistic to me. However, the timetable remains unclear for the time being.
Hot Topic 1: MS and EBV – implications for management and treatment
Background
The Epstein-Barr-Virus or short EBV seems to be one of the triggers for MS onset. The virus stays in the body for the rest of the lifetime. The later one gets the first EBV infection, i.e., the older one is, the more intense the effects are and the association with the onset of MS seems to increase. While babies and young children usually take the infection well, in adolescents and young adults, mononucleosis can be quite intense and make you very sick. But please remember that more than 90 percent become infected with EBV during their lifetime and only a fraction of them develop MS. So, the infection can by no means be the sole trigger.
The EBV infection seems to be an autoimmune potentiator, not only for Multiple Sclerosis. We don’t know yet which potential mechanism plays a role. If it is molecular mimicry, some kind of B cell transformation, lytic reaction or a second hit.
There is also evidence that resurgent infections of EBV contribute to MS activity and thus have a negative impact on progression. That’s why EBV is one defined target of future treatment strategies.
What strategies might emerge from the association of EBV infection and MS onset?
- An EBV vaccination followed by exposure to EBV would lead to few or no latently infected B cells. Therefore, reduced likelihood of antibodies or T cells cross-reacting with the nervous systems proteins which ends up in a reduced risk of MS
- Killing EBV- infected cells in patients with MS by infusion of EBV-specific T cells or a therapeutic EBV vaccine or special inhibitors. Most infected B cells would die and only few latently infected B cells would survive. Reduced antigenic stimulus for EBV-specific antibodies or T cells to recognize nervous systems proteins. Results in reduced MS disease activity.
Unfortunately, finding an effective, durable vaccine against MS is not easy. If we get a working EBV vaccine at one point in the future, we would theoretically have to vaccinate babies and then wait 20 years to see if multiple sclerosis and other EBV-triggered diseases occur less.
However, the approach of killing EBV-infected T cells might show results more quickly.
Clinical progression and decision making
Traditional view of MS progression is active versus progressive, whereas the progressive disease occurs in the absence of relapses (PIRA – progression independent of relapse activity). Disability Accumulation happens due to relapse activity and neurodegeneration (PIRA) right from the beginning. Relapse activity is driven by the periphery and neurodegeneration by processes happening in the central nervous system itself.
Progression independent of disease activity (PIRA) accounts for half or more of MS patients who experience confirmed disability worsening.
Cognitive disability seems to happen at the very beginning of MS onset and can be detected by brain atrophy measurements. Please keep in mind that it depends on the severity of your disease and is not the same for every patient. Brain atrophy itself happens already in the phase of CIS = clinically isolated syndrome and keeps ongoing during the relapsing phase and in the progressive phase as well. So brain atrophy and cognitive disfunction seem to start from the very beginning often even before motion disability is recognized by the patients. And again, the earlier the treatment with a DMT that stops MS inflammation and maybe has additional a positive effect on neurodegeneration, the better it seems to slow down progression. Healthy lifestyle should always be taken into account as it has quite some effects on our body.
For measuring MS, it seems a good idea to take brain atrophy and cognitive function into account right from the beginning and not just concentrate on physical disabilities.
Hot Topic 3: MS in the elderly
For the topic of MS in the elderly I choose two abstracts that were presented on the efficacy of MS treatments and the safety of discontinuation.
Abstract O068 (Betti M. et al., MSMilan2023): Evaluating age dependent efficacy of multiple sclerosis treatments in a real-life cohort
- The Peak age prevalence of pwMS is shifting towards 55-59 years.
- A meta-analysis of 38 clinical trials published in 2017 showed that DMTs efficacy decreased with age and that after age of 53 there was no predicted benefit
- However, nation-wide registry data show that DMTs continue to be commonly prescribed in pwMS >60 years
The aim of this abstract was to estimate age-dependent efficacy (in terms of disability progression) of DMTs = disease-modifying treatments in a real-world population of RRMS patients.
Some details on the methods:
It was a multicentric, retrospective, cohort study based on prospectively acquired data from the Italian Multiple Sclerosis Register.
The main outcome was the confirmed diasability worsening defined by an increase of the EDSS score. The higher the EDSS score, the lower points it had to be.
Increase of:
- 1.5 points if baseline EDSS=0;
- 1.0 point if EDSS>1.0
- and <5.5; 0.5 point if EDSS>6.0
Determinants of confirmed disability accumulation (CDA) after 2 years follow up assessed using a logistic regression model including the following covariates:
- Age
- Sex
- Type of onset (monofocal vs. multifocal)
- Disease course
- Disease duration and EDSS at baseline
- Number of relapses before baseline
- Class of first DMT = disease-modifying treatment (platform vs. high efficacy)
Results
- 22,196 pwMS were included
- After 2 years follow up 3178 (14.3%) pwMS had a CDA = confirmed disability worsening
- In the logistic regression analysis, CDA was associated with:
- Older age at baseline (OR 1,29, CI 1,25-1,35, p<0,001)
- A multifocal onset (OR 1,24, CI 1,1-1,39, p<0,001)
- A greater number of relapses before baseline (OR 1,07, CI 1,06-1,09, p<0,001)
- Platform therapies (OR 1,26, CI 1,04-1,51, p=0,016)
Conclusions
- In this real-world population of CIS and RRMS patients, older age at DMT start was associated with decreased efficacy in terms of disability worsening prevention
- Early treatment with high efficacy DMTs reduced the risk of disability accrual independently of age
Abstract 0099, Coerver E. et al., MSMilan2023: Discontinuation of first-line disease-modifying therapy in stable multiple sclerosis (DOT-MS): An early-terminated multicenter randomized controlled trial
The consequences of discontinuing first-line DMT in MS have not fully been established. So the aim of this trial was to investigate whether first-line DMT can be discontinued in people with stable MS without recurrence of inflammatory disease activity.
Methods
This multicenter randomized controlled non-inferiority trial included 89 people with relapse onset MS aged ≥18 years without any relapses or substantial MRI activity in the previous 5 years.
45 discontinued first-line DMT and 44 continued first-line DMT.
The primary outcome was the number of patients with inflammatory disease activity, defined as a confirmed relapse or significant MRI activity during follow-up (≥3 new T2-lesions or ≥2 contrast-enhancing lesions on MRI).
Premature discontinuation of the trial was considered if the proportion of patients with inflammatory disease activity in the ‘discontinuation’ group was higher than in the ‘continuation’ group, and the 95% CI of this difference did not include zero.
Results
- 67.4% female, 32.6% male
- Mean age at inclusion: 53.5 years (SD 7.8)
- Median follow-up: 12.0 months (IQR 7.0-20.0)
- The trial was prematurely discontinued because during follow-up, 6/45 participants in the ‘discontinuation’ group experienced inflammatory disease activity that fulfilled the predefined criteria vs. 0/44 participants in the ‘continuation’ group (95% CI of difference in patient proportion: 0.04-0.27)
- Median time to disease activity was 9.0 months (IQR 5.3-13.5)
- Of the 6 participants with inflammatory disease activity, 2 experienced a relapse
- Mean age of these 6 patients: 48.7 years (SD 8.6)
- All restarted DMT, which resulted in stabilization of disease
- In addition to these 6 patients, 5 patients in the ‘discontinuation’ group and 1 patient in the ‘continuation’ group experienced radiological disease activity not fulfilling our criteria for significant disease activity
Conclusion
- Significant inflammatory disease activity returned in 6/45 participants (13.3%) who discontinued DMT
- Based on our pre-planned interim-analysis the trial was discontinued in its current design
The speech by Stephen L. Hauser was very inspiring. EBV remains an interesting therapeutic goal, but it seems to be difficult and a long way to come up with trial scenarios that would have an impact on the MS burden. MS in the elderly is a burning topic and will become more crucial year to year as the MS population is aging. I’m glad scientists are starting to look into this topic more and more. And on the aspect of personal medicine it would be great to find out how to best treat each individual, when to stop DMTs and to find effictive ways to tackle progression in MS.
See you soon and try to make the best out of your life,
Nele
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