European Committee for Treatment and Research in Multiple Sclerosis

The 37^th congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) - the world’s largest meeting dedicated to MS - was held virtually from 13^th to 15^th October 2021. The congress was structured around a diverse scientific programme, with traditional interactive ECTRIMS sessions modified to accommodate the digital format.

Maria Pia Amato, ECTRIMS President

ECTRIMS President Maria Pia Amato, Florence, Italy, welcomed delegates and highlighted the key role which ECTRIMS has played for over 25 years in meeting the needs and expectations of people living with MS. Thomas Berger, Vienna, Austria, Chair of the Local Organising Committee, explained that this year’s annual congress would give special attention to the important topic of translational research. This approach involves harnessing neuropathological and immunopathogenic insights, as well as new fluid and imaging biomarkers, and translating this increased knowledge into a more individualised approach to the treatment and care of MS.

“During these unprecedented times, the power of connecting with colleagues from across the globe is more important than ever…this year’s congress plays a key role as a catalyst for meeting the needs of people living with MS.”

Maria Pia Amato, ECTRIMS President

This year’s ECTRIMS lecture was delivered by Roland Martin, Zürich, Switzerland, and focused on the gains achieved through translational research - moving from basic neuroimmunology to disease-modifying therapy (DMT). Describing MS as a ‘success story’ when it comes to treatment, Dr Martin noted that to achieve a cure we must address the disease in an antigen-specific manner.

T-cell cloning experiments have helped uncover new disease-associated autoantigens including GDP L-fructose synthase (GDPLFS), which shows homologies with the gut microbiota Akkermansia, and RAS guanyl-releasing protein 2 (RASGRP2). A multicentre phase II trial using GDPLFS and RASGRP2, plus other myelin-specific proteins, to induce immunotolerance in patients with MS is planned to commence in 2022.

“Hopefully this approach - induction of immune tolerance - will soon come to patients with MS and the dream will come true.”

Roland Martin, Zürich, Switzerland

Immunological and virological features of COVID-19 neurological complications were addressed by Renaud Du Pasquier, Lausanne, Switzerland. Although there is little direct evidence of SARS-CoV-2 entry into the central nervous system (CNS), with cerebral spinal fluid (CSF) polymerase chain reaction (PCR) and immunohistochemistry mostly negative, indirect findings from several groups showing the intrathecal synthesis of anti-SARS-CoV-2 antibodies suggest that the virus may be present in the CNS. What is clear, highlighted Dr Du Pasquier, is that the virus causes blood brain barrier (BBB) dysfunction as evidenced by endotheliitis and the presence of SARS-CoV-2 in the choroid plexus.

“My hypothesis is that SARS-CoV-2 stays at the gates of the brain, just at the border probably in the choroid plexus, and from there orchestrates a dysregulated innate immune response with activation of astrocytes and microglia.”

Renaud Du Pasquier, Lausanne, Switzerland

Maria Pia Sormani, Genoa, Italy, reviewed lessons learned from COVID-19 and MS registries noting that, despite the limitations and the challenges of combining data, results still provide useful insights. Consensus across different registries supports a correlation between anti-CD20 therapy and the development of more severe COVID-19 in MS patients. High-dose steroid use immediately prior to infection also appears to increase the risk of severe disease outcomes, while emerging evidence supports a protective role of interferon (IFN).

The impact of treatment with DMTs on response to vaccination for SARS-CoV-2 in MS patients was explored by Anat Achiron, Tel-Aviv, Israel. In a study of 179 COVID-19 vaccinees, SARS-CoV-2 specific memory B- and T-cell responses to the Pfizer/BioNTech vaccine were shown to occur only in healthy participants and untreated or cladribine-treated MS patients. With ocrelizumab, the SARS-CoV-2 specific B-cell response was impaired, although the T-cell response was present, while with fingolimod patients failed to develop either. Based on these findings, Dr Achrion suggested COVID-19 vaccination schedules may need to be amended based on DMT therapy and stressed the importance of ensuring all patients have an absolute lymphocyte count >1000 cells/m³ prior to vaccination.

The impact of treatment with DMTs on response to vaccination for SARS-CoV-2 in MS patients

The power of big data to improve MS management was examined by Jan Hillert, Stockholm, Sweden. Broadly speaking, MS registries between different countries are similar enough in terms of variables, definitions and governance to allow sharing of data. Collaborations are therefore possible in spite of the challenges. Analytical methods are also under development including improved statistical methodology and alternatives to data pooling to enable better sharing of big registry data. However, novel outcome measures are still needed, Dr Hillert concluded, which could include socioeconomic and device-generated data.

MS registry collaborations are possible in spite of the challenges

The pitfalls and opportunities of multinational registries were discussed by Helmut Butzkueven, Melbourne, Australia. Dr Butzkueven highlighted the major pitfall as disparity between medical record data and registry data, with the latter requiring a minimum dataset with clear and validated dates as well as repeat codified measures. Other challenges include data security and handling (general data protection regulation [GDPR] and its many interpretations), in addition to funding. However, multinational registries also offer important opportunities including long-term affordable and clinically relevant monitoring of drug safety, collection of pregnancy outcomes data at scale and the definition of surrogate endpoints and biomarkers for disease progression in progressive MS trials.

Peter Alping, Stockholm, Sweden, showcased findings from the COMBAT-MS trial which used registry data to evaluate the effectiveness of the most common initial MS therapies used in Sweden. In total, 1938 first-ever therapy episodes were included for injectables (IFNs and glatiramer acetate), dimethyl fumarate, natalizumab and rituximab. In treatment-naïve patients, rituximab was found to be associated with the lowest risk of relapses and magnetic resonance imaging (MRI) lesions and the lowest probability of switching therapy. Dr Alping suggested this ‘somewhat surprising’ difference in efficacy between rituximab and natalizumab may be due to the vulnerable period after switching from natalizumab due to JC virus positivity. Expanded Disability Status Scale (EDSS) outcomes at 3 years were similar for rituximab, dimethyl fumarate and natalizumab, and only slightly higher for injectables, despite differences in MRI lesions and relapses.

Risk of hospitalisation with any DMT

A dynamic scoring system for improving the decision to switch from first- to second-line therapy in MS was proposed by Camille Sabathe, Nante, France. This system was developed by applying an original statistical methodology to 12,823 relapsing/remitting MS (RRMS) patients from the OFSEP (Observatoire Français de la Sclérose En Plaques) cohort. Using the system, it proved possible to compute the individual hazard ratio (iHR) for time to first relapse at any time after treatment initiation. Internal validation identified a sub-population at higher benefit from switching, with one third of patients potentially able to delay relapse as a result.

Huah Shing Ng, Vancouver, Canada, presented findings from a population-based Canadian study examining the relationship between DMT exposure and subsequent health service use in a cohort of 35,894 MS patients. Treatment with any first- or second-generation DMT reduced the hazard ratio (HR) for hospitalisation by 24% and 29%, respectively. Within the second generation DMTs, reduction in hospitalisation risk ranged from 20% with natalizumab to 44% with fingolimod. DMT exposure was generally not associated with differences in the number of physician visits. These findings provide real-world evidence of a beneficial relationship between DMT exposure and hospitalisations in MS, Dr Ng concluded.

“Fewer hospitalisations could represent a major reduction in healthcare costs and a lower disease burden for people with MS and their families.”

Huah Shing Ng, Vancouver, Canada

Mattia Fonderico, Florence, Italy, presented findings from a real-world, multicentre cohort study evaluating progression independent of relapse activity in 5287 patients with clinically isolated syndrome (CIS) or early RRMS. Progression independent of relapse activity (PIRA) was found to account for approximately two thirds of confirmed disability worsening events. The main determinant of confirmed disability accumulation (CDA) was age, with relapse-associated worsening (RAW) events being more frequent in younger patients and PIRA predominant in older patients. Early treatment with DMT was effective in preventing the occurrence of any CDA, both RAW and PIRA.

“For a considerable number of patients, underlying disease progression is already relevant in the earliest stages of relapsing MS.”

Mattia Fonderico, Florence, Italy

Johannes Lorschneider, Basel, Switzerland, introduced active and passive methods and devices for biosensing in MS. In MS, current clinical monitoring tools only allow for low temporal resolution and do not reflect the entire spectrum of symptoms. Sensor-based measurements have the potential to create more objective functional outcomes (digital biomarkers) with increased sensitivity to change over time. Passive biosensing, where data is collected while the user is performing their usual daily activities, is a promising approach in MS but still faces major challenges. The use of consumer wearables and smartphones will hopefully improve the availability and scalability of biosensor-based measurements. However, Dr Lorschneider cautioned that much work is required for validation before outcomes based on sensor data can be used in clinical practice or trials.

Definition of biosensor

“Biosensors can address unmet needs in the clinical monitoring of patients affected by MS.”

Johannes Lorschneider, Basel, Switzerland

The application of biosensors for disease activity monitoring in clinical trials was reviewed by Jennifer Graves, La Jolla, USA. Currently over 80% of MS biosensing studies focus on accelerometery, but other sensors are quickly becoming incorporated into devices and clinical trial outcomes.

Examples of biosensing in clinical trials include the ARTIOS (NCT04353492) phase IIIb trial of ofatumumab which employed actigraphy (daily activity) and the CONSONANCE (NCT03523858) phase IIIb trial of ocrelizumab which utilized the Floodlight suite of apps. Moving forward, multisensors incorporating accelerometer, gyroscope and surface electromyography (EMG) are also planned for inclusion in future MS clinical trials.

Tanuja Chitnis, Boston, USA, explored the role of biosensing in MS clinical practice, highlighting how COVID-19 has accelerated the need for at-home biosensing with 50–90% of patients seen via telehealth during the pandemic. Biosensing provides the opportunity to capture patient function and symptoms in free-living (in between healthcare visits) and may provide more sensitive measures of patient function. Biosensors also have the potential to improve measurement of patient disability and prognostication. Studies have shown that gyroscopic measurements during turns are correlated with disease severity scores and that ambient gait tracking may be used to predict falls.

Biosensors in MS and their applications

Ilya Kister, New York, USA, explained that older age (>55 years) and longer duration of no evidence of disease activity (NEDA-3, >5 years) have proved consistent predictors of successful DMT stop in patients with relapsing MS based on retrospective analysis of studies to date. A combination of these variables may therefore help identify subgroups of patients with a very low risk of disease reactivation after stopping DMTs. To advance the field further, three randomised discontinuation trials are underway. The most advanced of these is the USA DISCOMS (Discontinuation of DMTs in MS) study (NCT03073603) from which data read out is expected within the next year.

There is no biological difference between relapsing and progressive forms of MS, explained Gavin Giovannoni, London, UK. Older patients are more likely to have progressive MS and less likely to have evident disease activity on stopping DMTs. De-risking treatments therefore becomes increasingly important in these more advanced, older patients and may involve timely stopping/switching of DMTs or use of an induction-maintenance protocol. Moving forward, we need to develop a new evidence base for stopping DMTs in MS, which is lacking in current guidelines, stressed Dr Giovannoni. Accruing new data and DMT specific knowledge is therefore crucial.

Deborah Miller, Cleveland, USA, summarised the benefits and risks of sustained DMT discontinuation and noted that the decision to stop treatment must be a collaborative, iterative process between patients and healthcare providers. Discontinuation means a transition, not an end, to MS care and key considerations for post-treatment monitoring should include location, timing and outcome measures.

The benefits and risks of sustained DMT discontinuation

The role of meningeal layers in CNS autoimmunity was discussed by Francesca Odoardi, Goettingen, Germany. Unlike the leptomeninges, the dura is marginally involved in CNS autoimmunity. The difference between these layers is due to their distinct vascular properties, differences in antigen availability and the limited exchange between the CNS and the dura.

Translational research focused on the role of microglia and complement as key components of neural circuit degeneration in MS was presented by Dorothy Schafer, Worcester, USA. C3 but not C1q is localised to synapses in the lateral geniculate nucleus (LGN) at onset of experimental autoimmune encephalomyelitis (EAE), which suggests activation of the alternative complement cascade. Although C1q is not present at the synapses, it could still play a role in neurodegeneration, postulated Dr Schafer, with complement therefore providing a potential therapeutic target. Experiments have shown that C1q regulates microglial transition into a disease-associated cell.

Experimental evidence supporting a role for fibrin as a driver of neurodegeneration and inhibition of myelin repair in MS was reviewed by Katerina Akassoglou, San Francisco, USA. Dr Akassoglou explained that fibrin is one of the key signals that programs innate immune cells at sites of vascular damage towards neurotoxic phenotypes. Upstream and downstream treatments may target these effects of fibrin in the brain. For example, blockade of bone morphogenic protein (BMP) receptor signaling has been shown to overcome extrinsic inhibition of remyelination and restore neurovascular homeostasis.

“In the CNS, fibrinogen acts as a bloody brake on myelin repair and a gas pedal for toxic inflammation.”

Katerina Akassoglou, San Francisco, USA

Jaume Sastre-Garriga, Barcelona, Spain, considered the question of whether every relapsing MS patient should be treated, noting that the case in favour of widespread use of therapy is very strong as unnoticed MS disease-related damage remains ongoing in many cases. The efficacy and safety profile of available drugs is also improving and becoming more well-known to clinicians, and improvement in prognostic tools is enabling better selection of the right therapy at the right time. Moving forward, it remains important to still strive for a personalised approach for each patient, Dr Sastre-Garriga added.

Frauke Zipp, Mainz, Germany, outlined recommendations on treatment switching from the recent MS Treatment Consensus Group (MSTKG) white paper. Non-response may be assessed after 6–9 months (at the earliest) and a DMT switch must be considered in the case of disability-relevant relapses, rapid disability progression or severe side effects. The switch from a DMT for a mild/moderate disease course to a DMT for a (highly) active course should be made if there is ≥1 relevant relapse or ≥2–3 new or enlarged MRI lesions or an increase in disability ≥0.5–1 EDSS points within 1 year. Beyond disease severity/activity and safety, it is also important to consider individual patient factors when selecting therapy, stressed Dr Zipp.

Factors influencing therapy choice in MS

Induction therapy with high-efficacy DMTs such as alemtuzumab and cladribine is currently still reserved for patients with very active or aggressive MS. However, growing evidence suggests that maximum patient benefit can be achieved with early initiation of high efficacy DMTs in all patients with RRMS, explained Maria Trojano, Bari, Italy.

For example, long-term comparisons from observational studies have demonstrated the superiority of HE versus moderate efficacy treatments in reducing disability progression. A shift in the current treatment paradigm for RRMS is also supported by the existence of the MS prodrome, with neurodegeneration present years before onset of the first MS symptom, and the detection of ‘silent progression’ in relapsing MS associated with ongoing brain atrophy. Pragmatic clinical trials - TREAT-MS (NCT03400328) and DELIVER-MS (NCT03535298) - comparing early high-efficacy therapy versus a traditional escalation approach are ongoing and results will shed further light on this important clinical question.

“Growing evidence suggests improved patient outcomes with early initiation of highly effective DMTs, calling for a change in the management approach of MS and questioning the current escalation strategies.”

Maria Trojano, Bari, Italy

Estimated number of people worldwide with progressive MS

Treatment of progressive MS (PMS) was reviewed by Xavier Montalban, Barcelona, Spain, who explained that effective treatment is complicated by the multifaced and complex underlying mechanisms of disease. Only one drug is approved for PMS - ocrelizumab - which produced a 24% reduction in 3-month confirmed disability progression (CDP) in the pivotal ORATORIO trial, with increasing effects seen over time in the open-label extension. Due to labelling changes, a number of RRMS drugs are now indicated for use in secondary progressive MS (SPMS) but positive trials have only been achieved with IFN-beta and siponimod. In the EXPAND trial (NCT01665144), siponimod met the primary endpoint of reduction in 3-month CDP and slowed sustained progression to EDSS ≥7 (wheelchair use) versus placebo. Unfortunately, the few medications currently approved for the treatment of PMS are typically limited in their efficacy to active forms of the disease, have little impact on slowing degeneration and fail to promote repair, Dr Montalban acknowledged.

What are the factors associated with improved response to siponimod in SPMS?

Defining treatment response in PMS is challenging, explained Daniel Ontaneda, Cleveland, USA, but should capture both inflammatory and neurodegenerative measures. Patients should be counselled not to expect stability of their disease, but rather a slowing of disability progression. Clinical monitoring measures include well-established scales, performance measures, cognitive function and patient-reported outcomes. Imaging and fluid biomarkers, principally neurofilament light, also hold promise as they may reflect neurodegenerative processes and show strong treatment effects.

Jeremy Chataway, London, UK, gave a ‘whistlestop tour’ of potential future treatment options for PMS. Active phase III trials are ongoing for Bruton’s tyrosine kinase inhibitors as a novel therapeutic approach in PMS. The existing drugs ocrelizumab and cladribine are also undergoing evaluation for impact on upper limb function. Agents that have been investigated in the area of neuroprotection include ibudilast, lipoic acid and high-dose biotin (failed at phase III). Recruitment of ~1900 patients into the MS-STAT2 phase III trial (NCT03387670) repurposing high-dose simvastatin in SPMS has just been completed. A range of targets also exist for remyelination in MS, including clemastine fumarate which is currently under evaluation in the phase II ReCOVER study (NCT02521311) in optic neuritis.

Five therapeutic targets for remyelination in MS

MS diagnosis in clinical practice was reviewed by Georgina Arrambide, Barcelona, Spain, who emphasised that McDonald diagnostic criteria were not developed to differentiate MS from other conditions. No specific diagnostic biomarker exists for MS so diagnosis is based on clinical work-up of patients with typical MS presentations. Diagnosis is supported by MRI findings showing key MS lesion characteristics (disseminated in space and time), the presence of oligoclonal bands and exclusion of alternative diagnoses.

Typical presentations for MS diagnosis

The question of ‘when does progression start?’ in MS was addressed by Johannes Lorscheider, Basel, Switzerland. Growing evidence indicates that disability progression occurs independent from relapses in MS (PIRA), begins early in the disease course and is probably underestimated (so-called silent progression). Whether PIRA constitutes the beginning of SPMS remains a matter of debate and improved tools for detecting disability progression are urgently needed. The transition from RRMS to SPMS appears gradual and it remains questionable if defining a clear-cut onset is even possible, Dr Lorscheider concluded.

Clinical and MRI-related red flags to suggest alternative diagnoses to MS

Pierre Laubauge, Montpellier, France, reviewed red flag clinical findings and MRI features which suggest alternative diagnoses to MS. The MS phenotype can also be extended to include patients with atypical MS presentations. These classifications include cavitations, solitary sclerosis, tumoral demyelinating lesions (TDLs), MS that mimics acute disseminated encephalomyelitis (ADEM), pseudo luecodystrophies or even normal brain MRI.

Mechanisms and potential triggers of inflammatory reactions occurring within the CNS of MS patients were explored by Inge Huitinga, Amsterdam, Netherlands. Focal white matter inflammation is present and relevant in advanced MS as evidenced by a study of 182 patients (disease duration: 29 years) which revealed unexpected, high innate inflammatory activity in progressive MS. Both T- and B-cells may play a role in this focal white matter inflammation in advanced MS, explained Dr Huitinga, notably, CD8+ TRM cells which are reactivated in MS lesions and upregulate inhibitory GPR56. Collectively, the changes that occur in late MS create a state of ‘locked in inflammation’ that may not be easily reached by current therapies.

“We should focus on the surface molecules, the TRM cells, to block them from infiltrating the CNS and stop them from driving this smouldering inflammation.”

Inge Huitinga, Amsterdam, Netherlands

MS inflammation persists in compartmentalised brain niches including meningeal infiltrates in the subarachanoid space which are linked with grey matter lesions. Meningeal inflammation may be associated with cortical demyelination which in turn influences CSF inflammation. Roberta Magliozzi, Verona, Italy, presented research findings illustrating how this intrathecal inflammatory profile can predict disease activity in MS after several years of follow-up. CSF biomarkers offer the best in vivo surrogate markers of meningeal inflammation which imaging cannot detect.

Hans Lassman, Vienna, Austria, outlined key similarities and differences between MS and myelin oligodendrocyte glycoprotein (MOG) antibody associated demyelinating disease (MOGAD) in terms of clinical disease, pathology and inflammatory features.

While MS is a progressive disease, MOGAD is not - residual damage results from destructive acute lesions with no active progressive tissue damage. Dr Lassman noted that the pathology of MOGAD closely reflects that of MOG-EAE, with demyelination induced by a combination of CD4+ T-cells and pathogenic anti-MOG antibodies. In contrast, MS inflammation is driven largely by T- and B-cells.

The available evidence shows that MS is not a ‘genuine risk’ for SARS-CoV-2 infection, explained Thomas Berger, Vienna, Austria, with risk more dependent on factors such as age and comorbidities. In general, DMTs have a good safety profile in the context of SARS-CoV-2, although agents such as anti-CD20 monoclonal antibodies (mAbs) and alemtuzumab may confer a slightly higher risk for infection and/or an altered humoral immune response. MS patients may receive any of the approved SARS-CoV-2 vaccines and vaccine-related AEs are similar to those seen in the general population, he concluded.

Currently used treatments for MS are immune-modifying (predominately suppressive) potentially increasing patients’ susceptibility to infections and blunting their response to vaccinations said Anna Fogdell-Hahn, Stockholm, Sweden. Data on 6421 MS patients from the COMBAT-MS real-world study (NCT03193866) revealed a higher incidence of infections in MS patients, including serious infection - with second-line treatments (notably rituximab) conferring the highest risk. MS patients were also at higher risk for COVID-19 hospitalisation, but fatality rate was not increased. Overall immunity against infections in MS is broad, noted Dr Fogdell-Hahn and what does not develop on the B-cell side may be rescued with the T-cell response.

“To make sure that patients on DMT develop sufficient protection by vaccinations, monitoring of antibodies might be needed.”

Anna Fogdell-Hahn, Stockholm, Sweden

Renaud Du Pasquier, Lausanne, Switzerland, discussed the impact of opportunistic infections in MS, focusing on the key risk posed by progressive multifocal leukoencephalopathy (PML). PML incidence ranges from 0.2 per 10,000 patients with dimethyl fumarate to 1.44 for fingolimod and 38.6 with natalizumab. Other opportunistic infections have also been linked to specific DMTs: herpes simplex and varicella zoster viruses (all DMTs bar IFN-beta, glatiramer acetate and teriflunomide); cryptococcal meningitis (sphingosine-1-phosphate [SP1] receptor modulators) and listeria rhombencephalitis (alemtuzumab). However, except for PML and natalizumab where risk mitigation is now well-established, the identification of risk factors for opportunistic infection with other DMTs remains difficult, conceded Dr Du Pasquier. Staying alert for opportunistic infection - not just PML - is therefore important with all DMTs (with the exception of the platform therapies). Age (≥50 years) and duration of treatment seem to contribute to increased risk.

Key risks posed by PML

The closing Charcot Lecture delivered by Alan Thompson, London, UK, covered historical perspectives and recent advances in the field of progressive MS. Improved knowledge of the mechanisms that underpin disease progression in MS has opened up new avenues for therapeutic intervention, moving beyond immune modulation to neuroprotection and repair. Above all it is important to start effective treatment early in the course of MS to stem disease progression, before compensatory CNS mechanisms are lost and the impact of ageing becomes more pronounced, Dr Thompson concluded.

Historical perspectives and recent advances in the field of progressive MS

“If we wait until progression becomes clinically manifested and particularly disabling then the therapeutic window has probably already shut.”

Alan Thompson, London, UK

Overview of ECTRIMS 2021

Clinical highlights included the elucidation of key factors driving relapse and disability progression in MS and increased understanding of the importance of progression independent of relapse activity (PIRA). In the era of COVID-19, registry data and national studies have helped shed further light on risk in MS populations and underscored the critical role of vaccination. Scientific highlights from this year’s congress included the identification of important disease-relevant cellular interactions in the CNS and further evidence confirming the key role of microglia. Important advances in MS imaging have come in the form of clinical MRI, molecular imaging and the use of ultra-high field MR.