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The 38th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) took place from 26-28 October 2022, in Amsterdam, The Netherlands. The world’s largest international congress dedicated to multiple sclerosis (MS) news brought together over 240 speakers who shared state-of-the-art updates on the most relevant issues impacting the MS community.
In this feature, we spotlight hot topics in MS discussed at ECTRIMS 2022, from the inclusion of optic nerve lesions in McDonald criteria to pregnancy and treatment options. Read on to hear from experts about the highlights from the meeting.
The McDonald criteria provides guidance for clinicians to ensure an accurate and early diagnosis for multiple sclerosis (MS) patients. The earliest set of criteria were devised by McDonald et al. and mainly focused on the objective demonstration of dissemination of lesions in both time and space, integrating magnetic resonance imaging (MRI) with clinical and paraclinical diagnostic methods.1 However, following extensive research, new evidence has led to the criteria being revised multiple times. In 2017, the International Panel on Diagnosis of Multiple Sclerosis reviewed the 2010 McDonald criteria and recommended revisions. The 2017 McDonald criteria still apply mainly to patients with a typical clinically isolated syndrome (CIS), define what is needed to fulfil dissemination in time and space of lesions in the central nervous system (CNS), and highlight there is no need for better explanation for the presentation.2 The changes made to the criteria include: the presence of CSF-specific oligoclonal bands allows a diagnosis of MS in patients with a typical (CIS); symptomatic lesions can demonstrate dissemination in space or time in patients with supratentorial, infratentorial, or spinal cord syndrome; and cortical lesions can demonstrate dissemination in space.
Considering the extensive revisions already made to the McDonald criteria, researchers argue that further refinement should focus on including optic nerve lesions. Inflammation of the optic nerve can result in optic neuritis (ON), an acute demyelinating disorder that can cause painful visual loss. ON is associated with demyelinating disorders of the CNS; specifically, it is known to be a principal manifestation of MS in 25% to 35% of patients with CIS and will present in approximately 70% of patients over the course of the disease.3 Therefore, recent evidence suggests that the inclusion of symptomatic ON involvement in dissemination in space in patients with ON could potentially improve the overall performance of the McDonald criteria, thereby, improving the accuracy of early MS diagnosis. This could be implemented in clinical practice by utilizing paraclinical tests such as: MRI, visual evoked potentials (VEPSs) and optical coherence tomography (OCT). MRIs and VEPs can both identify optic nerve lesions, whilst OCTs are also important for identifying the presence of a unilateral ON in MS patients.4
At the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), Angela Vidal-Jordana, MD, PhD, Vall d’Hebron University Hospital, Barcelona, Spain, spoke about the delay of diagnosis and treatment access for MS patients presenting with ON. There are currently discussions concerning different ways of measuring optic nerve damage, and how these methods can be implemented to advance MS diagnosis for specific patients. Dr Vidal-Jordana states, “The addition of optic nerve topography will improve the diagnostic criteria for patients presenting with ON”.
Despite the arguments favoring the inclusion of optic nerve involvement, the literature debates the role of optic nerve lesions and whether they should be added to the criteria. The European network MAGNIMS (Magnetic Resonance Imaging in Multiple Sclerosis) proposed to the international panel that there was no fundamental reason to treat a symptomatic optic nerve lesion differently from a brainstem or cord lesion, which are included in the 2017 criteria. The data presented by MAGNIMS as evidence showed a promising increase in sensitivity on MRI.5 However, when considering techniques other than MRI, it seemed that more normative and standardized data are needed for OCT and VEP before optic nerve lesions are included in the McDonald criteria in the future.
Multiple sclerosis (MS) is more commonly diagnosed in women than in men and these women are usually of reproductive age in young adulthood and, therefore, could be wanting to have children. It has become clear in recent years that discussions about planning a family and pregnancy ought to be considered proactively due to the time pressure of starting disease modifying therapies (DMTs). Recent research clarifies the importance of early intervention with DMTs since they have been shown to reduce/delay long-term disability caused by neuroaxonal damage, which starts early in relapsing–remitting MS.6 However, despite the growing interest in managing MS during pregnancy, there is still a lack of evidence regarding safety of DMT use preconception, during pregnancy, and post-partum.
There are highly effective DMTs available for the treatment of MS, such as natalizumab and fingolimod, although these are not FDA-approved for use during pregnancy; thus, regulatory agencies recommend to avoid pregnancy during treatment and to respect a 2–3-month washout period before conception.7 However, research also suggests that suspension of natalizumab and fingolimod can result in severe disease reactivation post-partum. This, therefore, elucidates the dilemma currently facing women with MS who want to become pregnant whilst on DMT, whilst also highlighting the importance of preconception counseling to advise MS patients on whether to take DMT and the implications of this during pregnancy and post-partum.
At ECTRIMS 2022, Celia Oreja-Guevara, MD, PhD, University Hospital San Carlos, Madrid, Spain, discussed the findings of her study investigating pregnancy and infant outcomes in women receiving ocrelizumab for the treatment of MS. Dr Oreja-Guevara explains that in this study the in utero fetal exposure time was 3 months before the last menstrual period or during pregnancy. The results demonstrated that only 0.8% of pregnancies resulted in malformation, which is lower than the general population at approximately 3%. Moreover, patients treated with ocrelizumab experienced fewer spontaneous abortions (11%) than the general population (15%). There were more elective abortions in patients exposed to ocrelizumab; however, Dr Oreja-Guevara states, “ocrelizumab is not causing malformations so now that physicians and patients are more aware of ocrelizumab and less afraid, there are now fewer elective abortions in comparison to last year”. Furthermore, this is the largest dataset of pregnancy outcomes for an anti-CD20 therapy in MS and the cumulative data do not suggest an increased risk of preterm birth, major congenital anomalies or other adverse outcomes with ocrelizumab in utero exposure.
In the past, treatment for multiple sclerosis (MS) was based on the use of various immunosuppressive drugs. However, since the approval of interferon (IFN) beta-1b, disease modifying therapies (DMTs) have become an increasingly popular treatment option for MS. As DMT popularity has increased, 19 different drugs have been approved for use and they are categorized according to their efficacy: moderate-intermediate efficacy and high-efficacy therapies (HET).8 Different categories of DMT are used depending on the treatment strategy chosen for the patient. The escalation strategy involves the initial use of moderate-intermediate efficacy drugs, such as IFN, which have low side-effect profiles, and progressing to HET with more complex side-effect profiles, following treatment failure. Whereas, early intense therapy involves initiating treatment from the onset of MS in the so-called “window of opportunity” with HET. HET drugs include monoclonal antibodies such as: natalizumab, alemtuzumab and ocrelizumab.8 Despite the high-efficacy of such DMTs and potential for preventing disability from progressing over time, they are also associated with a higher risk profile and adverse side-effects. Thus, there is controversy surrounding which method should be used to treat MS patients, since the principal treatment goal is to prevent long-term disability accumulation, whilst also considering whether the benefits outweigh the risks.
Extensive research has been carried out to investigate which therapeutic strategy is most effective in treating MS. Despite these studies finding that escalation therapy can reduce inflammatory activity and reduce relapses in the early stages of MS, they have evidenced that escalation fails to prevent conversion to secondary progressive MS (SPMS).8 Considering this, research suggests that one major disadvantage of escalation therapy is the risk of lesion accumulation if first-line DMTs are ineffective, which could result in disability accumulation. Conversely, Harding et al. carried out a comparative study of 592 people, looking at disability outcomes of MS patients who received early intensive therapy and those who received escalation therapy, after 5 years. Their findings suggested that long-term outcomes were more favorable following early intensive therapy in comparison to escalation therapy.9 Nonetheless, the literature remains inconclusive, and further research is necessary to ascertain which therapy option is most effective for treating MS.
At ECTRIMS 2022, Dalia Rotstein, MD, MPH, St. Michael’s Hospital and the University of Toronto, Toronto, ON, gave an overview of which patients would be eligible for escalation therapy. Dr Rotstein stated that “An escalation approach is not appropriate for every patient with MS and a key step is prognostication at baseline”. When a patient is diagnosed with MS, it is important to consider their prognostic factors, for example, indications of more severe disease can include: clinical, radiographic, demographic features, and biomarkers such as NfL. In terms of demographic features, male patients, older patients, and non-white patients tend to have a more severe course. In terms of clinical features, if a patient has a motor, cerebellar, or sphincter relapse, that can be an indication of a more severe course.
Lastly, regarding MRI features, if there are gadolinium-enhancing lesions, a high T2 lesion load, or a high burden of spinal cord disease, then these are considered poor prognostic indicators and should be considered at baseline. If a patient lacks these factors and has a generally good prognostic profile, then an escalation approach should be considered. Additionally, a conversation should be had with the patient about their preferences in terms of comfort level with risk and the route of administration of the medication, whilst also considering the cost. Furthermore, the efficacy of each medication must be weighed against the safety profile and the potential for adverse events.
Autologous hematopoietic stem cell transplantation (aHSCT) is a routine part of clinical hematological practice, which is traditionally a treatment for malignant diseases, such as myeloma. However, in recent decades, research has evidenced that aHSCT can also be used to treat severe autoimmune diseases (ADs), specifically multiple sclerosis (MS). Since the known pathophysiology of MS involves the abnormal activation of CD4+ and CD8+ T-cells and the induction of inflammatory responses in the CNS, the mechanisms by which aHSCT is involved in MS remission include: regulation of lymphocyte hemostasis, induction of Treg activity, suppression of inflammation, and suppression of auto-reactive lymphocytes.10
In contrast, disease-modifying therapies (DMTs) are frequently used as an immunosuppressive or immunoregulatory treatment for MS, and have been shown to reduce relapse rates in patients with relapsing-remitting MS (RRMS). However, this treatment option can pose high risk to patients by causing adverse side effects and DMTs have not been shown to be particularly effective for progressive MS patients.11 Burt et al. recently compared the efficacy of aHSCT against standard DMTs as a treatment for highly active RRMS in the MIST trial (NCT00273364). The results of the trial demonstrated that aHSCT was significantly more effective than continued DMTs and can be administered safely.12
Despite the advantages of aHSCT as a treatment method for MS, emerging evidence suggests that there are some safety concerns regarding previous treatment, and therefore the patients eligible for aHSCT should be considered carefully. In various studies the success of aHSCT was dependent on the intensity of conditioning regimens administrated before transplant, with high density of these regimens being associated with higher mortality rates in the transplanted patients.10 Shevchenko et al. therefore investigated the efficiency and safety of aHSCT together with a reduced intensity BEAM-like conditioning regimen in patients with different forms of MS. The results elucidated that the administration of low-density regimens of immunoablation was safer and had higher efficiency in the treatment of MS patients.13
Riccardo Saccardi, MD, Careggi University Hospital, Florence, Italy, discussed the rationale of aHSCT for the treatment of MS patients at ECTRIMS 2022. Transplantation was already a common procedure for patients affected by oncological disease, particularly leukemia and lymphoma, when research suggested that it could also be used in autoimmune diseases, such as MS. The treatment works by using the side-effects of the transplantation, which causes suppression of the immune system. Dr Saccardi explains, “when the immune system is recovering after the transplant, the autoimmune disease would usually disappear”. Furthermore, in most MS patients, the disease is silent for many years following aHSCT. Consequently, aHSCT has become a treatment option for patients who are resistant to DMTs.
Written by Annabel Tordoff
Reviewed by Marta Palhas