The third day at MS Milan 2023 offered again lots of interesting topics. This time I selected the following ones:
- Paediatric MS
- Female health
- Prodromic MS
- HSCT in MS
Remark: As for the summaries before, I took most of the data and statements directly from the speakers presentations without any rewording.
Klicken Sie auf den unteren Button, um den Podcast zu laden.
Table of Contents
Scientific Session 15: Paediatric MS - updates on diagnosis, prognostic and treatment
Diagnostic work-up and prognosis of pediatric MS by Barbara Kornek
The classical approach is used for children as is for grown ups to get a correct diagnosis or differential diagnosis including:
- Clinical tests
- an MRI
- lumbal puncture to check the cerebrospinal fluid (CSF)
- Serum / blood
- (Optical coherence tomography – OCT)
- (Serum neurofilament light chains -sNfl)
The McDonald critieria from 2017 is used as diagnostic criteria for pediatric-onset of multiple sclerosis:
- Dissemination in space (one or more lesions in minimum two areas):
- Periventricular
- Juxta/cortical
- Infratentorial
- Spinal cord
- Dissemination in time
- Simultaneous presence of enhancing and non-enhancing lesions
- Further T2 or contrast-enhancing-lesion on a follow-up scan
- Presence of CSF-specific oligoclonal bands
It is important to make sure, that it is not an aquaporin-4 NMOSD or MOGAD disease, as they are treated differently.
It is very important that all involved parties working together smoothly to guarantee the best possible treatment and outcome of a child or teenager with multiple sclerosis including the health care professional (HCP), the family, the patient, and the society. The prognosis is influenced by the following factors:
- Physical disability caused by the relapse-associated worsening (RAW) and progression-independent-of-relapse-acitivity (PIRA)
- Cognitive deficits
- Neuropsychological problems
- Quality of life (QoL)
- Education
- Socioeconomic outcomes
Indicators for a negative prognosis
Relapses and relapse associated worsening (RAW)
- Recovery from relapse
- Incomplete recovery from the first attack
- Pattern of relapse
- Spinal cord and brainstem attacks
- Number of relapses
- Frequent attacks during the first years
The just mentiond factors indicate an earlier accumulation of irreversible deficits and an earlier conversion to SPMS.
Even so the recovery after a relapse is better in children and youngsters due to the earlier start of MS in life and often a higher MS activity, they tend to convert at a younger age into SPMS.
Progression independent of relapse activity (PIRA)
The overall clinical disability accumulation is less common in children and youngsters compared to adults. And PIRA contributes to a lower extent to the disability accrual compared to RAW.
Cognitive impairement is found in 30-50% of pediatric MS patients including information processing speed, memory and attention. When they are matched with people with MS onset as adults of the same age, disease duration, sex and EDSS they ones with paediatric onset are more severly affected. MRI controls of brain volume provide additional evidence of this. The percentage of Fatigue and psychiatric comorbidities like depression and anxiety is higher as well.
And of course, all of this contributes to worse socio-economic outcomes for later adult life. But, the good thing is, that the prognosis for paedetric onset of MS is improving more and more since DMTs are in use, especially high-efficacy DMTs.
Treatments for pediatric MS by Tanuja Chitnis
The overall goal is to support these children and teenagers in having a healthy and fulfilling life despite the pediatric onset of MS.
Unlike adults, the majority of pediatric patients acquire disability through relapse and relapse-associated worsening (RAW). So health care professionals need to focus mainly on preventing relapses and new MRI lesions in order to prevent disease progression (PIRA, SPMS). Furthermore, it is the goal to improve existing neurological symptoms, cognitive outcomes, and quality of life.
Shared decision making plays a crucial role in pediatric MS and besides the pediatric patient and clinician, the parents or caregivers are involved in this process as well. Choices need to be introduced and options described. HCPs need to help patients explore their preferences and make decisions.
Potential barriers on this path are:
- Available expertise
- Medical literacy
- All parties invovled in decision-making
- Availability of DMT options
- Adverse events
- Adherence
Information can be provided by the use of clinical trials, prospective observational studies and the experience of the clinician.
As of October 2023 regulatory administration approval exists for the following disease-modifying therapies:
- Yes in the EU, no in the U.S.:
- Beta-interferon
- Copaxone
- Aubagio (Phase 3)
- Tecfidera (Phase 2)
- Yes for both the EU and the U.S.:
- Gilenya (Phase 3)
- No for both the EU and the U.S.:
- Tysabri (Phase 1)
- Lemtrada (halted)
- No decision from regulatory:
- Ocrevus (ongoing)
- Kesimpta (ongoing)
From what is known so far, high efficacy disease-modifying drugs should be the first choice in pediatric MS given the highly inflammatory nature of the disease and short and long-term impacts of relapses.
The DMTs are working more effectively in pediatric patients, but there are as well more serious adverse events. so it is important to inform the patients and parents / caregivers about potential side-effects, but also about the prognosis if the MS is not treated or just treated with platform therapies. Careful monitoring for disease activity and progression independent of disease acitivity (PIRA) is key. The recommendation is to do another MRI six month after starting the DMT. The role of serum / blood biomarkers is not 100% clear yet. Mitigation strategies for adverse events are important.
DMT should be started as early as possible. So DMT screening tests should be started right at diagnosis including antibody screening tests and starting to vaccinate if necessary. Communication with the insurance is important to avoid logistic barriers. Patient and parents need to get educational material and the option to ask their questions and discuss potential concerns.
If there is a need to change the drug, it has to be done rapidly for the ones that might cause rebounds, as the rebounds appear much earlier in younger patients. And maybe shorter intervalls are needed for B cell depleting therapies due to the young bone marrow and earlier return of B cells.
Non-DMT management
The patient and family should be offered a psychologist or family counselor. Cognitive testing every 1-2 years makes sense and support from a neuropsychologist. For teenagers contraceptive use is important.
Transitional care happens normally between the ages of 16 to 22, depending on the country. Early preparation of this transition is beneficial. Besides demanding college or work schedules, young adults face challenges with fatigue, cognitive issues, and physical deficits. Continued educational and psychosocial support are helpful to overcome independent care challenges like appintment scheduling, adherence to and renewing medication, and MRI monitoring.
More information on optimal symptomatic treatments for pediatric MS is needed as well as innovation in safe, effective therapies for the earliest form of the disease.
Scientific Session 20: Female health
Lessons learned from RCTs, registries and real world experiences for breastfeeding by Kristen Krysko
Postpartum MS relapses
The individual risk of mothers depends on the relapses in the year before or during pregnancy, the radiological activity before pregnancy, the disability status (higher disability is associated with a higher risk), and the discontinuation of certain high efficacy DMTs like natalizumab or fingolimod.
Good prevention options for relapses include breastfeeding and DMT resumption.
Potential mechanisms for the benefit include hormonal changes. These protection is lost when supplemental feeding begins. But these positive effects of breatfeeding are limited in time and have only a modest benefit. That’s why many women would benefit from also resuming/starting a DMT.
The safety of DMTs for babies depends on the type of DMT. Injectables are considered safe and monoclonal antibody therapies as well due to the large molecular size that results in a low transfer to the breastmilk.
With Cladribine mothers can breastfeed 7 days (Europe) to 10 days (North America) after last tablet. Breastmilk meanwhile need to be pumped and thrown away in order to avoid stopping of the breastmilk.
Effect of DMT initiation on postpartum relapses
Platform injectables do not reduced the risk of early postpartum relapses. Higher efficacy DMTs like natalizumab may reduce the risk of postpartum relapses at month 3-4. Anti-CD20 / B cell depleting therapies before / after pregnancy result in a well controlled disease activity.
Summary
Exclusive breastfeeding should be encouraged. If mothers don’t plan to breastfeed a rapid resumption of DMT within 2-4 weeks postpartum is recommended.
If mothers plan to breastfeed platform injectables or monoclonal antibody therapies for higher active MS should be considered starting at 2 weeks postpartum once the breastmilk is mature. Or these mothers remain off DMT with rapid weaning and re-initiation of DMT when stopped.
There is emerging data on new DMTs for use during lactation.
Compatibility with breatfeeding:
- Yes
- Glatiramer acetate
- Interferon-beta
- Yes, if needed:
- Natalizumab
- Rituximab
- Ocrelizumab
- Ofatumumab
- No:
- Dimethyl fumarate
- Fingolimod
- Teriflunomide
- Cladribine
Conclusion
MS therapy decision before, during and after pregnancy are complex and need to be tailored to each individual woman and her level and risk of activity. It is best to talk openly about the options with a MS specialist. The pregnancy itself lowers the activity of the disease but it is going back sooner or later to the level from before the pregancy postpartum. Breastfeeding is good for mother and child and should be recommended and supported and there are lots of options to do so and keep the MS under control.
Hot Topic 8: Prodromic MS - can we reduce the risk of MS conversion and progression?
The prodromic phase by Helen Tremlett
Healthcare use is higher in the five years before onset defined as a first demyelinating event or MS symptom onset (study in four Canadian provinces with 14,428 MS cases compared with 72,059 matched healthy controls). Especially the last two years before MS onset show increasing healthcare need. The numbers are fore the last year of onset:
- 78% higher rate of hospitalizations
- 88% higher rate of physician service use
- 49% relative increase in drug prescriptions numbers (drug classes dispensed)
Complexity of the MS prodrome include a myriad of issues, without a single feature specific to MS:
- Depression and anxiety
- Psychatry visits
- Irritable bowel syndrome
- Urologist visits
- Headaches and migraine
- Sleep disturbances
- Dermatologist visits
Similar findings came up to ten years pre first MS record for another study done in UK and a third study done in Sweden and Canada showing even higher rates of physician visits up to 15 years pre-MS onset with 46,727 MS patients and 194,493 matched healthy controls.
Lower cognitive performance up to two years before MS symptom onset versus age matched controls from Norway. For PPMS a lower cognitive performance was measurable up to 20 years before symptom onset.
Implications
Cognitive decline is measurable during the MS prodrome. PPMS could start decades before first apparent progressive symptoms.
Summary
Neurodegeneration is already present in the prodromal period up to 6 years pre-MS onset, proven by high serum neurofilament light chains that are measurable.
Early recognition could help with secondary / disability prevention. That suggests an earlier window of opportunity to identify MS. It could help to alleviate uncertainty, start with DMT use right away, and identify „prodromal MS for novel neuroprotective randomized controlled trials.
But is it important to balance prompt recognition and diagnosis against over or misdiagnosis of MS.
Radiologically Isolated Syndromes by Christine Lebrun-Frenay
Can we prevent MS onset for patients with very clear MRI findings, who are fully asymptomatic?
After two years 19% will have MS, after five years 35% and 51% after ten years.
Risk factors for a clinical event include:
- Age below 37 years
- Presence of oligoclonal bands (OCBs)
- Presence of gadolinum enhancing lesions
- Presence of infratentorial lesions
- Presence of spinal cord lesions
Risk stratification is important to identify, whether early treatment with DMT might be reasonable to prevent or delay MS onset. The risk increases to develop MS within ten years with the amount of risk factors:
- 0-1 factor: 29% converted
- 2 factors: 54% converted
- 3 factors: 68% converted
- 4 factors: 87% converted
ARISE Study – earlier treatment strategy for future MS patients
Early treatment for at-risk people may have profound effect on long-term disability progression. In this 96-week study, treatment with dimethyl fumarate resulted in over 80% risk reduction relative to placebo in the prevention of a first clinical event related to CNS demyelination.
TERIStudy – confirmation with another mode of action
Teriflunomid brought a 63% risk reduction
Summary of the two studies
Two prospective, double-blinded, randomsied studies in 2009 RIS, with two DMTs showing that we can have an impact on MS.
Conclusion
RIS is very rare as it happens accidently. MRI expertise is crucial. At ten years, a majority of people with 2009 RIS criteria will develop clinical MS. The risk of MS increases with the number of risk factors. Two phase three studies have demonstrated the beenfit of early intervention. And for all other cases please stay close and see if changes happen that suggest to become active on early treatment.
Hot Topic 9: HSCT in MS - a long story with new perspectives
Immunological rationale for HSCT in MS by Paolo Muraro
Highly targeted treatment strategies are quite „selective“
- Strength: Fewer off-target effects: better tolerability and safety
- Weakness: Less effective, or effective only in a subset of patients
Autologous HSCT strategy is „non-selective“
- Strength: More effective, in a larger proportion of subjects
- Weakness: Worse tolerability and higher front-loaded risk
Immune ‚resetting‘ for treatment of autoimmunity
Rationale: Lymphoid ablation allows destruction of mature lymphocytes, regardless of their specificity. Homeostatic regeneration of the immune system erases the ‚memory‘ of previous dys-immune activation.
The expected evidence is:
- Ablation of ‚old‘ adaptive immunity, including the pathogenic.
- Re-instatement or potentiation of immune regulation
- Repopulation with ’new‘ adaptive immune repertoire.
Is this a real immune resetting?
- Depletion of inflammatory cells or downregulation of inflammatory molecules. Evidence of suppression of circulating proinflammatory cytokines in MS patients after HSCT.
- Improvement of immune regulation. The frequency of ‚regulatory natural killer cells increases post-aHSCT. Changes in natural killer cells inversely correlate with changes in pro-inflammatory Th cells after aHSCT.
- Regeneration of the adaptive immune system. Removal of pre-existing blood CD4 and CD8 T cell repertoires after aHSCT. Removal of pre-existing T cell clones following aHSCT for multiple sclerosis. The effect increases over time. Study done where it was checked pre-therapy to month 12, 24 ánd 48 after aHSCT.
Conclusion
- The evidence of regeneration of adaptive immunity following HSCT grows.
- More data is needed on effects on B cells and related molecules
- Further studies are required to demonstrate relevance of immune changes to clinical outcomes
- RCTs of HSCT versus high-efficacy disease-modifying therapies are ongoing/planned and include mechanistic studies
HSCT as an early rescue strategy after DMTs failure by Lars Bø
Open questions:
- When to switch from a standard treatment?
- From a low efficacy treatment?
- From one previous high efficacy treatment?
- From two or more previous high efficacy treatments?
There is no general agreement on this.
It seems that there is not much time to make this decision as the early impact of an aggressive MS course is having long-term impacts on disability. It is important to start high efficacy treatment very early.
Proportion of MS patients with NEDA (no evidence of disease activity) at year two is rather low, even with high-efficacy treatments that reach up to 50% while data from older aHSCT studies reach levels of 70-90%.
A new study from 2023 showed the association of aHSCT with preventing relapses and facilitating recovery from disability was considerably superior to fingolimod and marginally superior to natalizumab. This study did not find evidence for difference in the effictiveness of aHSCT and ocrelizumab over a shorter available follow-up time.
There is a need for randomized trials with newer and high-effective treatments.
Conclusion
- aHSCT should be available for RRMS patients when standard treatment is no longer effective and when treatment options are limited.
- HSCT is more likely to have a good effect in younger patients with a shorter disease duration, with a low disability.
- There is an increasing use of high efficacy treatment early in the disease course of RRMS
- The subgroup with indication for HSCT as a rescue therapy may grow smaller.
- Cost/benefit: Need for data from long term follow up.
- Demonstrating a higher efficacy may require larger studies / a combined analysis of data from several ongoing studies.
HSCT in highly-active naïve patients: protocols, evidence for efficacy and safety by Richard Nicholas
aHSCT in RRMS: the story so far
- Historically used in late MS with less benefit and more side effects.
- In UK NHS practice available if failed a high effective DMT with new disease activity
- RRMS trials versus high efficacy DMTs are ongoing.
- It can be used in naive RRMS (STAR-MS study)
Naive RRMS: the rationale
- „The choice of younger patients, earlier in their course of disease with less disability along with actively inflammatory disease has resulted in better outcomes with aHSCT than had been seen in the earlier studies.“
- Younger and less prior therapies.
- Lower treatment related mortality (TRM) over time.
Highly active MS (HAMS) – aggressive / malignant
- 4-15% of MS patients have an active disease from onset
- The most important features include:
- frequent relapses with incomplete recovery (two or more)
- high radiological burden of disease (new T2/gadolinum enhancing lesions
- rapid accrual of disability after disease onset (EDSS of 4 at 5 years despite treatment with 1 or more DMTs
- otherwise typical features of MS
- Difficult to target those at-risk before permanent disability has accrued.
aHSCT as a first-line DMT in ‚aggressive‘ MS: Five European and North American centres retrospectively evaluated
- Median interval between diagnosis and aHSCT was 5 (1-20) months.
- 20 patients, median age 28 years (17-47); 50% female
- Multiple poor prognostic factors:
- 8 patients with 2 relapses; 9 patients with 3-4 relapses; 3 patients with more than 4 relapses
- All 20 patients had inclomplete recovery
- Median pre-transplan EDSS score was 5.0 (1.5-9.5)
- Three different treatment regimes were used
Outcomes:
- Median follow-up of 30 months (12-118)
- Median EDSS score improved to 2.0 (0-6.5)
- No patient had further relapses
- 3 had residual MRI disease activity six months post-transplant, but no further new or enhancing lesions were observed in subsequent scans.
Naive RRMS – the decisions
- MS is a long disease.
- Is really highly active treatment better?
- Induction therapies: do they really work?
- Are we trading short-lasting efficacy for lifelong cumulative toxicity?
Naive RRMS – conclusions to date
- Long term treatment strategies for MS are continuing to evolve
- The efficacy and side effect profile of aHSCT is similar to its use in active RRMS despite DMT
- Optimal treatment protocols are still being tested
- aHSCT is gaining traction as an option for those with ongoing RRMS despite high efficacy DMT treatment.
- Multiple RCTs (randomized controlled trials) are testing whether aHSCT is superior to high-efficacy DMTs.
- aHSCT has been a possible treatment option in aggressive MS without treatment with benefit if used early on.
- Use in naive patients who do not have aggressive MS should be within the context of clinical trials.
With that I’m at the end of my summary of MSMILAN 2023. I hope the selected topics were interesting for you. There are still lots of open questions and many fields where research needs to find solutions. But with each step of understanding the disease better it is more likely to find ways to avoid the onset, find better symptomatic therapies and hopefully ways to reduce disability burden. As mentioned before, I’ll try to get some of the experts for detailed interviews.
See you soon and try to make the best out of your life,
Nele
For more information and positive thoughts, subscribe to my newsletter for free.
Click here for an overview of all podcast episodes published so far.
And at many more places.
* This text contains affiliate links. This means that I get a small compensation if you buy the product recommended by me through the link. For you nothing changes in the price of the product. And it helps me to pay for the blog and to write new posts.
