Hello and welcome to another summary of ECTRIMS 2024, this time on the topic of de-escalation and discontinuation of therapy. There was a scientific session on this topic with six lectures, moderated by Dr. Melinda Magyari and Prof. Bernhard Hemmer. And there were also individual posters. Except for one talk about NMOSD and MOGAD, all scientific contributions were about multiple sclerosis.
I will present all the contributions and their results, some of which are still preliminary. After all, it is a topic that probably affects most of us. Can or should I switch my therapy from a high efficacy to a lower one or even stop it altogether at some point, and when is that a safe approach?
Table of Contents
What does de-escalation of therapy mean?
That the intensity of treatment is reduced, i.e. from a highly effective therapy (HET) to a medium or only slightly effective therapy. This is something that is of interest to us patients, but of course also to doctors. On the one hand, nobody wants to risk a reactivation of MS or a progressive worsening that accelerates. On the other hand, our immune system ages over time.
Most studies on disease-modifying therapies were only conducted in the age group from 18 to 55 years. When it comes to patients aged 56 and older, the only studies that can be used are registry studies, i.e. databases in which the condition of people with MS is recorded. Depending on the database, more or less extensive and meaningful data can be found there to assess the effectiveness and benefits of therapies.
What is certain is that the older we get, the more the innate immune system takes the lead again, as our adaptive immune system, which is able to adapt to new pathogens, loses some of its effectiveness. Since the current highly effective immunotherapies are precisely targeted at this adaptable immune system, the benefits decrease above a certain age. But when is that? How much does this point vary from person to person and are there ways to find out when an attempt at de-escalation or even a discontinuation trial will do more good than harm? These are many questions to which the following studies provide at least initial answers, but much research still needs to be done and is increasingly being done.
Why is de-escalation a topic?
Many people with MS are treated with strong medications, so-called highly effective immunotherapies (disease-modifying therapies = DMTs). These are very successful in stopping inflammatory activity and preventing relapses, but they can also have severe side effects, increase the risk of long-term complications and drive up costs. Therefore, some of us and our doctors are considering whether it is possible to switch to a less potent drug after a certain period of time. However, so far there have been few studies that really show whether and when this is safe.
Strategies for de-escalation with anti CD20 therapies
by Dr. Chiara Starvaggi Cucuzza et al.
Why might it be necessary to de-escalate anti-CD20 therapies?
Because the risk of infections, decreased immune responses, and diseases characterized by an incomplete absence of gamma globulins, particularly immunoglobulins, increases with the duration of treatment.
How can the effectiveness of the therapy be balanced with safety concerns?
The older a person is and the higher their degree of disability, the greater the risk of serious side effects. For this group of patients, it is worth considering de-escalation or even a complete halt to immunotherapy. A third option is to extend the intervals, as B-cell depletion can have a long-term effect that extends well beyond the intervals tested in the pivotal trials. In trials, intervals of 12 to 18 months were tested, which showed positive results in terms of relapses and MRI activity.
The following studies are currently ongoing on this topic:
- RIDOSE-MS: Rituximab 500 mg, 6 vs. 12 months dosing interval (completed: Q2 2025
- BLOOMS: ocrelizumab (Ocrevus) every 6 months vs. B-cell-directed reinfusion (completed: Q1 2026)
- WINDCORE: ocrelizumab (Ocrevus), 6 vs. 12-month dosing intervals (completed: Q4 2027)
A higher level of ocrelizumab in the blood is associated with less progression in relapsing and primary progressive MS patients. Thus, a lower level could mean faster worsening. However, this still needs to be tested in clinical trials.
Switching to a less effective treatment
It would be useful to have a personal risk-benefit assessment of disease activity compared to side effects at each visit. If it comes into consideration, patient and doctor should actively discuss scenarios for de-escalation. There seems to be no clear age at which de-escalation should be considered; rather, biological age seems to be important. To continue to benefit from the efficacy of B-cell therapy while minimizing the risk of side effects, administration cycles can be extended.
Further studies are needed to understand the role of B cells in the pathogenesis and development of MS and their effects on infections. It is necessary to investigate whether disease activity is progressing in secret or is also dormant and what effects the change of therapy has on the increase in disability and whether the most sensible step is perhaps one towards a progression-oriented immunotherapy that primarily seeks to prevent the increase in disability independent of relapses.
Discontinuation and de-escalation in NMOSD and MOGAD
by Dr. Arlette Bruijstens
Why and when is de-escalation interesting?
Because the risk-benefit profile can change over time, especially in certain situations, such as pregnancy or the desire to have children, due to infections or cancer, and because of the reduced effectiveness of vaccinations. Other reasons may include side effects or a lack of compliance with the prescribed treatment plan. In addition, highly effective therapies are usually associated with high costs and are therefore closely analyzed in terms of their benefits.
NMOSD (AQP4+)
The natural history of the disease is almost always relapsing, with severe relaps-related disability. In adults, relapsing activity remains high for at least five years. Studies have shown that 82% of patients experienced a relapse when treatment was stopped and 9-38% experienced a relapse when de-escalation was used. Therefore, the recommendation is to continue treatment at all costs and de-escalation may be an option for certain subgroups of patients, but these require further research.
MOGAD
The natural course of the disease is relapsing in 30-50% of cases, with a high degree of variability. Patients often recover well or completely from the relapses. In adults, relapse activity subsides within the first five years. So far, there are no evidence-based studies. Both de-escalation and discontinuation of therapy can always be considered.
Further research needed
More research is needed on both NMOSD and MOGAD to identify successful de-escalation strategies and risk factors for relapses. In addition, it is necessary to find out which biomarkers are suitable for monitoring the process and adjusting it if necessary. sGFAP seems suitable for this, and other new biomarkers are being sought.
Guiding Treatment Deescalation in Relapsing Remitting Multiple Sclerosis
by Dr. Jannis Müller et al
This study examined 880 people with MS who had either maintained their highly effective therapy or switched to a less effective one. The aim was to find out whether de-escalation increases the risk of future relapses and disability worsening. Researchers used data from over 87,000 people with MS from multiple centers worldwide to compare the results.
Study results
- Increased risk of relapses: Patients who de-escalated their medication (switched to a less potent drug) had a 2.4 times higher risk of future relapses than those who continued their highly effective therapy.
- Increase in disability: The study also showed that the risk of disability worsening (as measured by the EDSS score) was 1.6 times higher in patients who de-escalated their medication.
- Patients aged 50 years and older: Interestingly, patients aged 50 years and older did not have a significantly increased risk of relapsing when de-escalating medication, but it was shown that the risk increased with repeated relapses.
What does this mean?
The results show that de-escalation is not suitable for all people with MS. In fact, the decision should be made on an individual basis. Specifically, if you are younger or still have very active disease, you may be at higher risk of relapses and progressive disability if you switch to a less effective therapy. For older patients, switching may be safer, but it should be well monitored to adjust the decision as needed.
What should you do?
If you are considering de-escalation, it is important to discuss it in detail with your neurologist. It depends on many factors – for example, how active your MS is, how you have responded to your current treatment, and what risks you are willing to take.
Conclusion
The decision to de-escalate therapy should not be taken lightly. This study shows that there are situations where it can work, but there are also risks. It is important to be well informed, consult with your medical team and think carefully about what is best for you.
The study’s power is limited due to its retrospective design. The subgroups were affected by within-group variability and small sample sizes. No detailed analyses of specific immunotherapy pathways. No measurements of hidden disease activity. No other de-escalation methods such as dose reduction or extension of application intervals. No clear thresholds for age, gender, EDSS, disease duration, or time since last relapse.
Alternate-Day Fingolimod Tapering: Impact on Rebound Disease Activity in Patients with Multiple Sclerosis
by Assoc. Prof. Dr. Tuncay Gündüz et al.
If you are taking fingolimod or considering a treatment switch, you have probably already heard that suddenly stopping the medication can sometimes lead to a rebound in disease activity – meaning your MS could flare up, possibly even worse than before you started the medication, as immune cells that have been held back in the lymph nodes are suddenly free to do damage. But there appears to be a better way to manage this transition.
The study: What is the best way to stop fingolimod?
Researchers looked at 148 MS patients who stopped taking fingolimod. Some of these patients stopped the drug abruptly, while others took it every other day for a period of time before stopping it completely. The goal was to find out if tapering the drug helps to reduce the risk of a flare-up.
Why tapering works
The researchers found the following:
- Tapering helps: In the group that tapered fingolimod every other day (called the T group), only 30% of people experienced a relapse, compared to 67% in the group that stopped abruptly (the A group).
- Severity matters: Although tapering did not completely stop relapses, the relapses were less severe.
- Timing is important: the study also found that people who had been stable on fingolimod for a long period of time without relapses were more likely to have a relapse when they stopped the medicine, suggesting that it is very important to choose the timing of a treatment change carefully.
What does this mean for you?
If you are considering stopping fingolimod, tapering off the medication gradually – by taking it every other day for a period of time – could make a real difference. It might not stop the risk of a relapse completely, but it could reduce the chances of severe relapses and give you a better chance of staying stable during the transition to your next treatment. Always talk to your medical team about the safest way to handle any changes to your medication.
The study’s validity is limited due to its retrospective design and the lack of laboratory data. There is a need for a randomized control study to confirm the results.
Short-term B cell depletion results in medication-free, long-term freedom from disease activity and correction of immune tolerance defect in a subset of people with relapsing MS
by Dr. Bardia Nourbakhsh et al.
What is B cell therapy?
B cells are one type of immune cell that plays a role in MS by mistakenly attacking the body’s own nervous system. B-cell-depleting therapies like ocrelizumab work by clearing these harmful cells from your system. While these treatments are highly effective at stopping MS activity, there has always been concern that using them for too long could suppress the immune system too much, leaving patients vulnerable to infection.
But what if you didn’t have to take the drugs forever? What if a short course of treatment could keep MS in check for the long term?
What did the study show?
Researchers followed 19 patients with relapsing forms of MS who received only two courses of ocrelizumab and then stopped taking the medicine. These patients were monitored for about two and a half years (30 months) after their last dose. Here’s what happened:
- Most patients (14 out of 19) remained completely free of relapses or new disease activity for over two years – without ongoing medication!
- In 5 patients, MS returned after 19–37 months, but the rest remained in control.
- The key seemed to be the health of their immune systems, particularly a part of their immune response known as B cell tolerance. Patients with healthy B cell tolerance were more likely to remain in remission.
A brief detour into the depths of immunology
In MS patients, peripheral selection of autoreactive B cells is impaired. Misfired B cells that attack the body’s own structures are not eliminated. Four of the seven patients tested had impaired central B cell tolerance. All four experienced MS reactivation during the treatment-free period. The other three had reduced numbers of autoreactive B cells leaving the bone marrow and remained free of disease activity. In the three patients who had functional central B cell tolerance, anti-B cell therapy restored impaired peripheral selection of autoreactive B cells one year after the second ocrelizumab treatment, whereas in the four patients with defective central B cell tolerance, anti-B cell therapy led to the accumulation of autoreactive B cells in the mature naive B cell compartment.
Conclusion
MS is a heterogeneous disease that can be divided into two distinct entities based on a specific pattern of defects in early B cell tolerance. Long-term freedom from disease activity after a short course of B cell-depleting therapy is associated with normal central B cell tolerance and elimination of autoreactive B cells.
What does this mean and what are the next steps?
This study is very exciting as it suggests that for some people with MS, a short course of B cell therapy such as ocrelizumab could be enough to achieve long-term freedom from disease activity.
The next step is to test the results on a larger patient group to see if they can be repeated. A biomarker must be found that can be used to determine whether a patient has a functioning or impaired central B cell tolerance. In addition, research is needed to determine whether it makes a difference how long and deep the B cells are depleted, i.e. whether fewer or more infusions are needed and whether the strategy needs to be adapted to the specific drug. It is also not yet clear whether autoreactive B cells eventually return in patients with intact central B cell tolerance. And another open question is what influence the procedure has on the smoldering inflammation that is responsible for disability progression independent of relapses.
As so often, more research is needed.
B-cell tailored dosing versus standard interval dosing of ocrelizumab in relapsing-onset MS –Interim analysis of a randomized controlled trial (BLOOMS trial)
by Dr. Laura Hogenboom et al.
Why personalized dosing?
Ocrelizumab works by targeting B cells, which are part of the immune system and can mistakenly attack nerves in people with MS. Usually, ocrelizumab is given every six months to keep MS under control, but not every body works the same way. For some people, it takes longer for B cells to return after treatment, meaning they may not need infusions as often.
The idea behind personalized interval dosing (PID) is to extend the time between infusions for people whose B-cell levels remain low, thereby reducing the number of infusions needed. This could lead to the following benefits:
- Fewer side effects from infusions,
- lower risk of infection by reducing the frequency of immunosuppression,
- lower healthcare costs and an overall reduced treatment burden.
The study so far
This study, the BLOOMS study, is taking place in the Netherlands and includes 119 patients with relapsing MS. They were divided into two groups: one that continues with standard dosing (every 6 months) and another that receives personalized dosing, in which infusions are delayed until B cells return (measured by blood tests).
So far, the study shows no signs of increased disease activity in either group – no new lesions on MRI scans or relapses. This suggests that extending the time between infusions based on personal B-cell levels may work just as well as the regular 6-month schedule.
In the personalized dosing group, a median of 8.4 months passed between infusions, with some going as long as 13 months without treatment.
What does this mean?
The initial results from this study suggest that in the future, people may not have to stick to the same rigid dosing schedule if their B cells don’t return quickly. This could mean fewer infusions, less frequent side effects, and more flexibility in their treatment plan – all while keeping their MS under control.
Of course, this is still preliminary data, and the full results won’t be available until 2027. But it shows that personalized medicine is the way of the future for MS treatment, helping to determine exactly the right amount of therapy for each individual person.
An important question in this context is whether the time interval remains the same for each individual. In other words, whether the drug is always needed only after an assumed ten months or whether the interval is subject to fluctuations because other factors influence when the B cells return. Because then the monthly testing effort and the poorer plannability for the infusion would be an unpleasant factor.
De-escalation treatment strategies in patients with relapsing-remitting multiple sclerosis in Austria
by Dr. Michael Guger et al.
You have probably heard of highly effective MS medications, such as natalizumab (Tysabri), ocrelizumab (Ocrevus) or ofatumumab (Kesimpta). These therapies work very well, but sometimes patients or doctors want to switch to more moderate therapies. This is exactly what is meant by “de-escalation”. This study examined how this affects the disease.
The idea behind the study
The researchers wanted to find out how safe it is to switch from highly to moderately effective drugs and what needs to be considered when doing so. They looked at how long patients remained without relapses and whether their disability (measured by the EDSS score) changed after switching to a less aggressive therapy.
How was the study conducted?
A total of 389 MS patients from a registry in Austria who switched from highly effective therapies (such as natalizumab, ocrelizumab or ofatumumab) to moderately effective drugs were examined. These moderate therapies include, for example, dimethyl fumarate (Tecfidera), fingolimod (Gilenya) or teriflunomide (Aubagio). The researchers divided the patients into three groups: those who switched to a moderate therapy in less than three months, those who switched in three to six months, and those who switched in six to twelve months.
Results of the study
The results show the following:
- Patients who made the switch after less than 3 months had the lowest risk of relapse, at just 5.2%.
- However, if the switch took 3 to 6 months, the risk rose to 15.7%, and if it took 6 to 12 months, the risk was as high as 39.4%. This means that a quick switch is safer!
- Disability (measured by the EDSS score) increased slightly from 2.8 to 3.1, which shows that it is important to plan the switch well.
What does this mean for you?
If you are considering switching from a high-efficacy DMT to a moderate-efficacy one, it is important not to delay the transition for too long. The study shows that a rapid switch within 3 months reduces the risk of relapses and minimizes disability worsening.
It’s also important to keep your neurologist closely involved during this transition period to ensure you’re well monitored and get the right support.
The bottom line
This study provides important insights that de-escalation – switching to a less intensive therapy – can be a safe option if it is well planned and implemented quickly. It gives certain patients the chance to take fewer medications and still maintain control over their MS. If you are considering this, talk to your doctor about whether this scenario is an option for you and what the best plan is for you.
Stay active and positive – we have more options than ever before for living a good life with MS!
Classification of the risk of disease reactivation after de-escalation/discontinuation of disease-modifying therapy in relapsing-remitting MS using the VIAADISC score
by Prof. Dr. Gabriel Bsteh et al.
In addition, researchers have developed a VIAADISC score that can predict the risk of a relapse after a change in therapy. This score takes into account age, activity on MRI, and the duration of the stable phase before the change in therapy.
129 MS patients participated in the VIAADISC study, and the results showed the following:
- The risk of relapse was significantly higher in patients with a high VIAADISC score (3-6). A high VIAADISC score was associated with a 2.63-fold higher risk of relapse. In contrast, patients
with a low score (0-1) had a very low risk of relapse of only 4.8%. - Switching natalizumab (Tysabri) and fingolimod (Gilenya) was particularly problematic, with a higher risk of relapses, even with moderate VIAADISC values.
- De-escalation of dimethyl fumarate (Tecfidera) or teriflunomide (Aubagio) appeared to be the safest. Here, patients with low VIAADISC values had the lowest risk of the disease becoming active again.
What does this mean for everyday life with MS?
It is important that if you are switching from a highly effective therapy to a moderate therapy, you do not delay this change for too long. A quick change within 3 months can significantly reduce the risk of a relapse while also halting the progression of your disability. The researchers also emphasize that it is crucial to keep a close eye on the disease during the transition.
In addition, the VIAADISC score can be helpful in better estimating the risk of relapse after a change in therapy. For example, if you are switching from a highly effective therapy such as natalizumab or Fingolimod, it may be advisable to discuss your risk with your doctor.
Conclusion
These studies give us important clues as to how we can make the transition between different medications safe. If you are considering a change of therapy, talk to your neurologist about how quickly this should be done and what risk you are taking. It turns out that a speedy change can help minimize the risk of relapses and disability progression, and the VIAADISC score can be a useful guide.
I hope these insights give you a good feeling of being well informed. I will, of course, report on any new research findings in this area.
See you soon and try to make the best out of your life,
Nele
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