The world’s largest congress dedicated to research on the pathogenesis, diagnosis and treatment of multiple sclerosis and related neurological disorders, ECTRIMS, once again brought together renowned experts in MS research, neurology, physical therapy, nursing and related fields to discuss innovative research in their respective disciplines.
This year’s congress has been divided into the four main topics of therapy, pathogenesis, clinic, and imaging and non-imaging biomarkers to help users find their way around. The processes underlying MS lesion development, progression, and remyelination are poorly understood. In addition, the neuropathological and immunopathological appearance of lesions in the central nervous system is very heterogeneous. New imaging techniques are improving our understanding of the molecular mechanisms involved in lesion initiation and progression and development [1]. These imaging techniques have highlighted the role of specific genes and certain cell subsets, which could make them new therapeutic targets. By focusing on lesion margins and spatial gene activity profiles, in situ sequencing confirmed apolipoprotein C1 (APOC1), secreted phosphoprotein 1 (SPP1), and ferritin light chain (FTL) as margin markers in mixed active/inactive and active lesions, with higher expression levels in such lesions than in controls. When looking at these lesion margins with the goal of predicting lesion development, it became clear that not all appearing white matter is actually normal, and that there is overlap in the gene signatures of the different lesion types.
Imaging mass cytometry (IMC) is an imaging technique that reproduces immunofluorescence-equivalent staining patterns. It can distinguish demyelinating macrophages from the resident microglia pool and identify the types of lymphocytes present and subsets of T and B cells. This quantitative approach holds promise to better understand how meningeal inflammation relates to cortical pathology in MS patients and has the potential to identify novel therapeutic targets. A new imaging technique called FIND-seq (Focused Interrogation of cells by Nucleic acid Detection and Sequencing), which focuses on communication between microglia and astrocytes, allows characterization of pathogenic subsets of astrocytes. First, using a zebrafish model, SigmaR1-IRE1α-XBP1s were identified as drivers of pathogenic astrocytes. This new technique captures the entire cell cDNA and DNA and was able to show that the mineralocorticoid receptor (NR3C2) is a negative regulator of XBP1-driven astrocytes and that signaling through nuclear receptor co-repressor 2 (Ncor2) is a negative regulator that limits XBP1-driven pathogenic astrocytes. FIND-seq enables in-depth investigation of rare cell subsets of interest based on the expression of nucleic acid markers.
Personalized therapy management
There are many predictors of poor prognosis in patients with relapsing-remitting multiple sclerosis (RRMS), including low vitamin D levels, high relapse rate, presence of spinal cord lesions, male gender, and higher EDSS. Compared with low-impact treatments, high-impact treatments (HETs) have been shown to be more effective but carry potentially more serious side effects because disease activity and response to treatment vary from patient to patient. The guidelines for MS recommend treatment with a HET as early as possible. Because the majority of disability occurs independently of relapses and magnetic resonance imaging (MRI) activity, treatment early in MS disease should focus on the pathologic processes that contribute to the slow loss of neurologic function. To plan timely sequencing and escalation of treatment, vaccination status and immunologic effects of disease-modifying treatments (DMTs) should be considered [2].
Strategies for early intensive therapy in MS include continuous intensive therapies (natalizumab, fingolimod, ocrelizumab) or induction therapies (mitoxantrone, alemtuzumab, cladribine) [3]. A 10-year follow-up of 100 consecutive patients with early, active, RRMS who received mitoxantrone (3- or 6-monthly) showed that most patients did not require additional therapy or were treated with a first-line DMT; the mean annual relapse rate (ARR) was low and the mean EDSS score remained significantly improved. In patients with aggressive RRMS, alemtuzumab demonstrated sustained low ARR up to eight years and stable mean EDSS. Relapse rates were associated with a low risk of severe lymphopenia or clinical relapse even after induction with oral cladribine (weight-based dosing annually for 2 years). The need to consider de-escalation of therapy was highlighted during the COVID-19 pandemic, when some MS treatments were associated with an attenuated response to COVID-19 vaccination and a higher risk of severe COVID-19 infection. The NOVA study in RRMS showed that most patients on a 4-weekly dosing regimen of natalizumab can be switched to a 6-weekly dosing regimen without impacting efficacy. Similarly, a large retrospective study showed that delaying an anti-CD20 (ocrelizumab) by 4 weeks was as effective as standard dosing every 6 months.
The role of patient-centered outcomes
To ensure patient-centered care, the need for, acceptance of, and use of patient-centered outcomes (PROs) must be standardized. The PROMS project has initiated several working groups to explore how PROs might be integrated into health policy and into patients’ daily lives [4]. Patients should become researchers themselves, helping to improve care and find solutions to the challenges they face in living with MS. Through the use of digital health technologies, a more accurate picture of disease progression can be uncovered, highlighting the need for patients and normalizing the integration of PROs into clinical trials. Since the COVID-19 pandemic, digital health technologies have been increasingly used for digital assessments both in clinical trials and as a means to engage patients in their own care. The use of such devices to improve outcomes is common in diseases such as diabetes. In addition, MS patients can record and report daily clinical disease activity, psychological status, and quality of life using electronic diaries based on cell phones. Such devices can measure the impact of real-world factors on mobility and provide a more accurate assessment of deterioration in walking ability, which could predict the risk of falls or silent progression of the disease. Ultimately, the goal is to work with key stakeholders to ensure that PROs are an integral part of all aspects of health policy and practice for people with MS, and to determine how best to incorporate this information.
Off MS
Neuromyelitis optica spectrum disorder (NMO-SD) is a lifelong condition typically characterized by relapses rather than disease progression. The risk of relapse was about 30% with conventional treatments. However, the newly approved monoclonal antibody treatments for anti-aquaporin-4 antibody (AQP4)-positive NMO-SD have been shown to significantly reduce the risk of relapse, whether administered as monotherapy or as add-on therapy. Combined with the knowledge gained from immunological studies, it may be possible to develop more individualized treatment for patients with NMO-SD [5]. NMO-SD patients treated with older medications have about a one-third risk of relapse within a year. The new monoclonal antibodies satralizumab, inebilizumab, and eculizumab have different targets, including IL-6R, CD19, and complement. Comparison of results from randomized controlled trials of these three monoclonal antibodies showed that satralizumab and inebilizumab reduced the risk of relapse by three-quarters in patients with AQP4-positive NMO-SD, and the reduction in relapse risk was even greater for eculizumab (94%). However, it should be noted that cost, lack of direct comparative data with older therapies, risk of infection, and long-term risks may be disadvantages for these newer agents. Furthermore, none of these monoclonal antibodies is effective in AQP4-negative NMO-SD patients, and none is approved for the treatment of patients younger than 12 years of age. The selection of a new therapy may depend on several factors, including cost, availability, patient age, and previous treatments. Immunological studies of NMO-SD and MOGAD suggest that IL-6 signaling promotes the production of AQP4 autoantibodies from plasmablasts; therefore, it is possible that B-cell programming may be used for more individualized treatment of patients with demyelinating diseases. In turn, this expanded knowledge could enable de-escalation or cessation of immunosuppressive therapies.
Congress: ECTRIMS 2022
Literature:
- Eggen B, Ramaglia V, Quintana F. Pathogenesis Session 1. Hot Topic 4: New ways of imaging MS pathology. 10/26/2022, ECTRIMS 2022
- Montalban X, Rostein D, Giovannoni G. Therapy Session 1. Hot Topic 1: High efficacy therapies. 10/26/2022, ECTRIMS 2022
- Edan G, Waubant E, Strijbis E. Therapy Session 1. Hot Topic 5: Escalating and de-escalating DMTs. 27.10.2022. EVTRIMS 2022
- Weiland H, Battaglia MA, Leocani L, Khan U. Clinical Session 1. European Charcot Foundation Symposium: The patient at the centre – role of patient reported outcomes. 10/26/2022, ECTRIMS 2022
- Palace J, van Luijn M, Marignier R. Clinical Session 2. Hot Topic 2: NMO-SD. 26.10.2022. ECTRIMS 2022.
InFo NEUROLOGY & PSYCHIATRY 2022; 20(6): 26-27.
