The second day at MS Milan 2023 was again packed with lots of valuable information. And so many exciting presentations happened at the same time.
I will focus on the following topics:
- Burning Debate about Menopause: All women with MS should start hormone replacement therapy…
- Treatment Efficacy
- Satellite Symposium 5: How immune reconstitution therapy has transformed MS management
- Scientific Session 13: Healthy life-style for MS management
- Scientific Session 14: Pulmonary gut brain axis
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Table of Contents
Just a remark at the beginning. I used the provided content during the ECTRIMS 2023 presentations to a large extent and just added some explanations to make it more easy to understand.
Burning Debate about Menopause: All women with MS should start hormone replacement therapy...
This presentation was done in a pro and contra style, but not really comparable. Rhonda Voskuhl being on pro hormone replacement explained the importance of creating a different style of trials that focus on main cognitive issues that come with menopause and do them with the safer type of hormone replacement.
Melinda Magyari is contra hormone replacement and argues with lots of old data, where the risky hormone replacement was used and that was not looking into the specific issues but more on a broader generic view.
So I will concentrate on the presentation of Rhonda Voskuhl as her data and arguments were scientifically and statistically more reasonable from my point of view.
Pro Hormone replacement in Menopause
Rhonda Voskuhl is Professor at the Department of Neurology at the David Geffen School of Medicine at UCLA and holds the Jack H. Skirball Chair in MS Research and is the Director of the UCLA Multiple Sclerosis Program. She just won the Rachel Horne Prize for Women’s Research in MS for „her pioneering work that focuses on understanding the sexual differences in susceptibility and progression of MS, and she has been instrumental in identifying potential therapies to enhance outcomes for MS patients.“
Background
Sex hormones are neuroprotective – Estrogen and Testosteron. So when they are ending they influence the progression of Multiple Sclerosis. For men this starts around 30 and is a slow dropping until 75. For women this happens in a very short amount of time. Around the age of 50 the estrogen level drops abrupt twards zero within five years.
There has been used questionnaires for women which resulted all in a significant worsening of symptoms beginning of menopause. But not much was done so far. Within the last five to ten years objective exams were done with the same findings. Existing symptoms and neurodegeneration were worsening. A MRI study showed the connection of ovarian failure and disability worsening as well as a an increased cortical atrophy.
Menopause in Healthy Women
Neuropsychologists found clear proof for „Brain Fog“ related to menopause especially a drop in verbal memory and processing speed. Very specific domains are affected, not IQ or general intelligence. When women have surgical menopause early on and brain MRIs are done, they have a higher hippocampal-cortex atrophy.
So clear outcome: Menopause is bad subjectively, objectively, by MRI. Important for trial design is, that the atrophy is region specific on hippocampus and prefrontal cortex.
How to treat the abrupt in estrogen with menopause
Proper trial design should focus on the following primary outcomes:
- For cognition: domain-specific (processing speed, verbal memory)
- For brain atrophy: region-specific (hippocampus, frontal cortex)
Estrogen Timing: Need to be treated before 65 years (within 5-10 years)
Estrogen Type: Estriol is in favor, not the other options as they are not effective or dangerous due to possible severe side-effects
Estrogen Dose: Higher is better so Estriol is in favor as it can be given in high doses.
Recent paper in nature communications.
Hormone replacement with Estriol in MS models showed remyelination and axonal sparing in the spinal cord and corpus callosum. Furthermore it reduced the atrophy and synaptic loss in the cerebral cortex an hippocampus and improved remylination in the cerebral cortex and hippocampus.
There was a phase 2 trial, so small group of women with MS before menopause who received 12 month Estriol compared to placebo and the actual treated women had an improvement in processing speed, a reduced cerebral cortex atrophy and reduced serum neurofilament light chains (sNfL). Higher dose caused higher blood levels and which related to higher improvements. Dose matter.
Next step: Multicenter, Phase 2, Double-blind, Coparator-Controlled Trial in the United States at 7 sites
It will be Estriol (ERβ) treatment (with tailored progesterone) to Menopausal women with MS (ages 45-65)
Primary outcome: MRI (cerebral cortex atrophy)
Secondary outcome: Cognitive (domain-specific) & sNfL
Exploratory outcome: Other MRI (hippocampus, thalamus) & other MS disabilities
Remark
Please discuss with your MS neurologist and gynecologist if hormone replacement therapy is an option for you.
Treatment Efficacy
Sequencing and Escalation by Tomas Kalincik
The escalation strategy has changed. So for a long time people used to start with low effective therapy and only were escalated to higher therapies when the therapy was not working. Nowadays more and more clinicians and countries start with level two or even level three of effectiveness.
When registry data compared the groups starting with a higher efficacy earlier the risk of progression is lower. But it is not easy to compare, because the patients who never had to go on high efficacy therapies are not included in the data.
Clear message here:
When there is indication for a an active or even highly active MS it is better to start early on high efficacy treatments as they are clearly outperforming the slowly escalating therapy strategy when it comes to long-term progression.
If all indicators show a very mild course of MS it is still okay to start with a low efficacy treatement.
Sequencing of DMTs
Autologous Hematopoietic stem-cell transplantation (aHSCT) outperforms Natalizumab in a highly active relapsing MS on reduction of relapses and confirmed disability improvement.
But there is no significant difference between aHSCT versus Natalizumab in a progressive MS.
So the clinical disease phenotype is very helpful to predict the response to escalation of immunotherapy.
Sequencing of DMTs
Keeping the wash-out period as short as possible is smart and has a positive impact on the long-term progression. So starting fast with another treatment keeps the MS better under control.
Triggers of treatment escalation
There are four indicators that suggest to start a high efficacy treatment:
- Relapses
- Increase in EDSS (Expanded Disability Status Scale)
- New / enhancing / enlarging brain lesions
- Higher neurofilament light chains in the serum
Conclusion
Early use of high-efficacy therapies for people with indication of an active to very aggressive disease results in clearly better control of the disease and improved disability outcome than does their delayed use. This is true for relapsing-remitting MS (RRMS). Treatment is still a big challenge for progressive MS (PMS).
Don’t wait long, when the therapy of level one or level two is not being effective to surpress multiple sclerosis sufficently. Be proactive and change to a higher efficacy level.
We start to get a better understanding of latent disease worsening and its pathogenesis. And this will allow for more precise choice of high-efficacy therapies early in the disease course.
Evaluating age dependent efficacy of multiple sclerosis treatments in a real-life cohort by Matteo Betti
Efficacy of DMTs on disability progression is signitficantly reduced in people with MS over 40 to 45 years.
A metaanalysis from 2017 of 38 randomized controlled trials (RCTs) in people with MS showed that beyond the age of 40,5 years there is no greater efficacy of high effective treatement than platform therapies so level one in terms of disability accrual prevention.
A real world observational study comparing infusible DMTS, like Natalizumab and Rituximab, versus oral DMTs like Dimethyl Fumarate and Fingolimod in 1,246 people with MS did not find differences in terms of disease activity reduction beyond the age of 45.
Another metanalyises from 2022 of RCTs of depleting agents like Cladribine, Anti-CD20 and Alemtuzumab showed a greater risk of developing neoplasms after the age of 45 years.
Objectives
Evaluating the effect of age on the efficacy of high efficacy DMTs in a real worl reaplsing MS population, by comparing the risk of disability accumualtion in immediate initiation of high efficacy versus platform DMTs, before and after the age of 45.
Methods
Italian MS Registry was used with a defined minimum baseline dataset. All patients were either CIS (Clinically Isolated Syndrom) or RR course at the first evaluation and followed-up minimum two years.
The outcome was defined as a 24-week confirmed disability accumulation (CDA): Expanded Disability Status Scale (EDSS).
Patients were matched so that were comparable on sex, age, disease duration and severity of the disease and more.
At the end out of 82,197 registered patients, 5,259 patients could be matched. 3.477 of them starting a platform DMT and 1,782 starting a high efficacy DMT.
Conclusion
Age sub-group below 45 years had a clear beenfit of starting high efficacy treatments. But the age sub-group of patients older than 45 years had on a group-level no advantage of high efficacy treatments when compared to platform DMTs.
So when taking the long-term course into account there was a clear benefit of high efficacy treatment started earlier in life and even any DMT started earlier in life compared to no DMT or shorter DMT usage before the age of 45.
However at the individual level, early high efficacy treatment could be still more effective, reliable biomarkers identifying this subgroup of patients are needed.
Satellite Symposium 5: How immune reconstitution therapy has transformed MS management
Why time matters in MS by Gavin Giovannoni
Smouldering MS or Neurodegeneration is there from the very beginning of the MS disease course and can begin before MS is detected clinically.
Losses in productivity have been reported in patients with early MS in a real-world prospective cohort study from Canada. In that study with 512 all participants showed no or mild disability at baseline (EDSS score below 3.5), except for 15 with a higher EDSS score. However, the time and cost burden of MS was evident over three months. 55% reported a loss in work productivity that caused work time lost and therefore real money. The performance indicators have been associated with unemployment and loss of productivity, including:
- Impaired visual acuity
- Impaired cognitive processing
- Impaired manual dexterity
Preventing disability accumulation is the main argument for treating early. In the CLARITY and CLARITY EXT trials it made a difference, if people started right away with Cladribine tablets or two years later.
Brain health can be preserved that way and brain atrophy limited.
Immune reconstitution treatment in MS; what we have learned by Jiwon Oh
Optimizing treatment sequencing is important when considering disease duration and evolving patient needs.
Most patients will require more than one DMT throughout the disease course taking into account that a patient spends on average over 40 years living with MS. Therefore treatment should be selected to address the immidiate clinical problem and keep subsequent therapeutic options open. And please remember early treatment with a high-efficacy DMT is important in reducing the risk of neuronal injury which comes with the cost of increasing disabilty.
MS treatment approachs impact the immune system in different ways:
- Chronic immune depleting therapies are giving regularly and the clinical efficacy stays during the active dosing more or less, maybe a bit longer.
- When using immune reconstitution therapy the drug is administered very seldom and with big time intervals in between while providing a long-term clinical efficacy that extends beyond the active dosing.
Starting patients on DMTs that cause continuous immune depletion may increase the risk of some adverse events developing over time, but doesn’t have to. The risk of serious infection is increase with continious immune depletion and is higher than in the general population.
When using immune reconstitution therapy there is a reduction phase at the beginning, followed by a repopulation and later on reconstitution phase. But the mixture of immune cells that come back are different from before. They are in a better immune balance. So fewer immune cells that want to destroy healthy tissue in the central nervous system.
Based on MRI acitviiy already in month 2 of administration Cladribine tablets, so when the cycle of the first year is finished, there is a clear reduction of immune cells that may contribute to early onset of action. And the re-population of immune cells may reduce the risk of adverse events over time.
Of the patients who experience adverse events 53% report them within 45 days following the initation of Cladribine tablets. The most frequent treatment-related adverse events happen to be:
- Headache (2.2 %9
- Gastrointestinal disorders (2 %)
- Skin and subcutaneous tissue disorders (1.8 %)
- Lymphopenia = having an abnormally low level of lymphocytes in the blood (1.2 %)
- Medication error (1.2 %)
- Fatigue (0.8 %)
The low frequency of adverse events occuring after 45 days may allow more flexibility for life-long MS care. The reconstitution of immune cells may result in sustained efficacy, even so the tablets are just taken in month one and month two of year one and year two, but not in year three or year four, while still providing benefits.
Conclusion
Immune reconstitution therapies (IRTs) may be most beneficial when used early in the disease course to delay the progression of disease in the absence of continuous immunosupression and reducing inflammation in the most inflammatory phase of the disease.
But they are not suitable for everyone and detailed consultation by an neurologist preferably specialised on MS is needed.
Summary - how immune reconstitution therapy has transformed MS management
Early treatment with cladribine tablets was associated with better clinical outcomes.
Cladribine tablets selectively target pathological (disease triggering) memory B cells, while maintaining protective immune function.
Real-world data support the long-term management of patients on cladribine tablets including continued treatment in year five and beyond.
Cognitive function and employment remained stable and health related quality of life increased during treatment with cladribine tablets.
Remark
This session was sponsered by Merck who are poducing cladribine tablets, so it was extremely focussing on research regarding cladribine. Please keep in mind, that therapy choices need to be made on your individual disease course and personal preferences.
Scientific Session 13: Healthy life-style for MS management
Diet and vitamin D by Ilana Katz Sand
The immunomodulatory effects of vitamin D are relevant to MS and include impacts on the following types of immune cells:
- Monocytes and macrophages
- Dendritic cells
- Memory T cells
- B cells
There are neuroprotective effects of vitamin D. And there has been a lot of research done with clear effidence that a low vitamin D Level increases the risk of getting MS. So low vitamin D levels during pregnancy increase the risk of MS for the babies to be born.
There was more research done on the association between vitamin D levels and MS severity, disease activity, and progression.
But interventional vitamin D supplementation trials have failed to meet their primary endpoints.
Just a side note from me, the ultra-high dose approach with the Coimbra protocol is not part of it as Dr. Coimbra has never used a scientific based study to prove his concept. He is convinced that his approach works and trains doctors for money, but does not provide scientific data. This is scientifically questionable. Observational studies, i.e. real-world data, would be an opportunity to show whether the approach has potential without great financial expense. There is at least one such observational study underway at the Charité in Berlin, Germany, which was initiated by patients themselves. Results are expected in 2024 at the earliest. Please don’t try to do ultra-high does on your own without a good clinician and expert on your side as this can cause severe damage to your health.
Potential mechanisms for dietary effects include:
- indirect effects mediated by comorbidities associated with worse outcomes, e.g. obesity, cholesterol levels, other vascular risk factors
- effects directly related to diet, e.g. on the dietary metabolism, mediated through gut microbiota
There has been a study that showed an inverse association between Mediterranean diet and the risk of multiple sclerosis.
Dietary components in MS
- Grains and gluten
- Dairy
- Meat
- Salt
- Fruits and vegetables
There are many popular dietary patterns out there and under investigation. For sure is a balanced diet like the Mediterranean-style a gooid choice and has proven the following benefits:
- Better general health
- Positive effect on cognitive aging
- Reasonable to aim for long-term adherence as it is a lifestyle change rather than a „diet“, budget friendly and household involvement
Practical recommendations
Prepare meals at home as much as possible. Incorporate colorful fresh fruits and vegetables daily. If you choose to eat grains, choose whole graines over refined grains. Avoid or at least limit processed foods and added sugars as much as possible.
Physical activity by Ulrik Dalgas
The human genom is made to move, but we don’t do that much anymore. That has an effect on the health for everybody and for MS patients even more. MS patients move less and is realated to early deficits.
The physical inactivity and deconditioning directly interacts with the disease process and progression and both factors contribute to a worsening of symptoms. But the physical activity can be modified to a certain amount.
To start with the definitions first:
- „Physical acitvity is any bodily movement produced by skeletal muscles that results in energy expenditure.“
- „Exercise is a subset of physical activity that is planned, structured, and repetitive and has as a final or an intermediate objective the improvement or maintenance of physical fitness.“
There has been proven evidence that exercise therapy can improve aerobic capacity, muscle strength, balance, cognition and walking capacity as well as reducing pain, fatigue and depressive symptoms.
But please choose exercises that are beneficial for the brain, so no hits on the head as happens during boxing, american football or soccer when doing a header. Most other acitivites are fine and it is probably more important that you enjoy the sport and doing it with great pleasure on a regular basis.
Summary
- The physical acitivty level of persons with MS is still markedly lower that the general population.
- Adhering to the physical activity recommendations is important already at early disese stages.
- Exercise is a safe and beneficial symptomatic treatement in MS.
- Numerous challenges still lies ahead of us.
If you want to know more about the importance and positive effect of exercise, please check out my interview with Prof. Ulrik Dalgas: #022: Exploring exercise’s immune benefits and MS symptom relief: Prof. Ulrik Dalgas shares insights
Scientific Session 14: Pulmonary gut brain axis
Pulmonary microbioma and CNS autoimmunity by Francesca Odoardi
Central nervous systems autoimmuity is classical seen as a matter between the brain and the immune system. But new players showed up on the field, like the gut, but also the lung.
Why the lung?
Environmental risk factors include lung infections and smoking and COPD (chronic obstructive pulmonary disease).
Research has showed that a massive infiltration of myelin reactive T cells happen in the lung. The lung is a hub for autoreative T cells on their way to the central nervous system (CNS).
Can the lung serve as an initiation site of CNS autoimmunity?
Yes, it is possible and with a very low dose. So the lung is not just capable but also very efficient in triggering autoimmunity.
What is the link between lung microbiota and microglia?
It can affect the microglia which are cells very important for MS processes. When they become reactive this is causing a higher diasease activity.
Summary
The lung microbiota may influence susceptibility to relapse and may also play a role in the chronic phase of autoimmunity.
I did an interview with Prof. Dr. Alexander Flügel for the German podcast which has a coressponding blog article you might find interesting and want to read using a translation option like Google Translate: #202: Basic research on T cells to better treat MS. Interview with Prof. Dr. Alexander Flügel
I hope the summary of Day 2 of the ECTRIMS provided you with some valuable information. A take home message would be to discuss your therapy choices with a MS specialist that is up-to-date on the newest research data to best treat your individual pathway with the disease and to use the possibilities to lower the severity of the disease by a healthy lifestyle from exercise, to diet all the way to a lung-friendly life.
See you soon and try to make the best out of your life,
Nele
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