Prof. Dr. med. Özgür Yaldizli

Managing MS during pregnancy and post-partum (PP) is challenging as multiple treatment strategies exist.

Aim of this study is to describe all pregnancies observed from 2012 to 2023 in the Swiss MS cohort, including disease modifying treatments (DMTs), relapses, MRI activity and serum neurofilament light chain (sNfL) levels. Anti-CD20-monoclonal antibodies (anti-CD20) and natalizumab are defined as high-efficacy DMT (HET). Disease activity was assessed by relapse rate during pregnancy or PP, number of new/enlarging T2w lesions on the first cMRI after birth or sNfL levels during pregnancy and PP. We will compare patients continuously exposed to HET during pregnancy to patients who stopped DMT or were treatment-naive before and remained untreated during pregnancy. We will estimate odds ratios with generalized estimating equation models (GEEs) adjusted for age, disease duration, EDSS and relapse rate in the year before pregnancy. For new/enlarging T2w lesions a sensitivity analysis using Firth logistic regression will be performed. sNfL z-scores during pregnancy and PP will be compared between HET, oral DMT, platform DMT and untreated patients at blood sampling using GEEs. This study will show whether or not continuous exposure to HET during pregnancy is associated with a lower risk of disease activity compared to women who were untreated or had not been continuously exposed to HET during pregnancy.

Multiple sclerosis (MS) is a chronic, progressive and disabling disease of the central nervous system where the immune system attacks the myelin sheet of the axons. MS is also the most common non-traumatic cause of disability in young adults. The most common form of the disease is relapsing-remitting MS (RRMS). It is characterized by attacks with new or exacerbating old neurological symptoms followed by remissions. Patients with RRMS increasingly use disease modifying therapies to modulate/suppress the pathogenic

activity of the immune system. The most effective therapies almost completely suppress acute disease activity. However, higher efficacy increases the risk for infectious diseases. No consensus exists on how to adapt such therapies to treat patients as little as possible but as much as necessary. More personalized treatment and care strategies in MS are urgently needed. The Swiss MS Cohort study (SMSC) was established in 2012 and has 8 centers across Switzerland. In September 2021, the SMSC included >1300 of the estimated 15,000 patients living with MS in Switzerland. Every 6 to 12 months patients come for standardized evaluations of relapses and disability status, blood sampling and magnetic resonance imaging (MRI) to detect disease activity in the brain or spinal cord. The applicants have critical expertise in standardizing and integrating high-quality clinical, imaging and

biomarker assessments within the SMSC and conducted extensive research on the novel biomarker serum neurofilament light chain (sNfL). NfL is a neuroaxonal protein released in the cerebrospinal fluid and then the blood when neurons are damaged. Higher levels of sNfL are associated with disease activity and higher risk of relapses; conversely, patients under effective treatment have lower levels of sNfL. sNfL offers a novel way to monitor and even predict disease activity, and to personalize MS therapy. We believe that intensive

sNfL monitoring in addition to usual care could 1) improve patients’ quality of life by reducing their treatment burden (e.g., by reducing the drug dose) and risk for side effects (e.g., infections) and 2) result in fewer patients with disease activity by early and more sensitive biomarker-guided treatment escalation. We propose the Multiple SClerosis pRagmatIc Platform Trial (MultiSCRIPT) embedded in the SMSC. We aim to evaluate new personalized care strategies that ensure no evidence of disease activity, while achieving

better patient outcomes, fewer adverse events and improved care. By using the procedures and high-quality real-world data collection of the SMSC usual care, MultiSCRIPT avoids almost all burden for participants that traditional clinical trials would require. This innovative approach will make clinical research part of usual care in MS. All RRMS patients in the SMSC for at least a year will be eligible. We expect to include 915 patients. One half of the patients will be randomly allocated to intensive sNfL monitoring every 6 months, plus the established clinical and MRI evaluation used in the SMSC, and the other half will be treated as usual with no added sNfL monitoring. We will consider intensive biomarker monitoring strategy better than usual care if either more patients have no evidence of disease activity, or more patients have a better health-related quality of life. MultiSCRIPT aims to be a continuous learning system. Each comparison of a new personalized strategy is one learning cycle, which ends with a decision whether the strategy is better and should be implemented in usual care, or not. This project is the first cycle. It is designed to lay the foundation for subsequent cycles, in which a new strategy, based on the learnings of this first cycle, will be evaluated. The continuous evaluation in MultiSCRIPT initiates an evolutionary process that systematically develops, improves and personalizes treatment and care of patients living with MS in Switzerland and beyond.

The choroid plexus has been proposed as a modulator of multiple sclerosis (MS)-related inflammation. Our study group recently found that the choroid plexus is larger in MS than healthy controls and patients with migraine.

The aim is to investigate the associations between the choroid plexus volume and MS disease characteristics including clinical and MRI outcomes and serum biomarkers such as neurofilament-light chain (sNfL) and glial fibrillary acidic protein (sGFAP) longitudinally in a large cohort of MS patients. We aim to make use of the data from one of the largest MS cohorts in the world - the Swiss MS cohort (SMSC) study. By time of this application, this database includes high quality clinical data of 1899 MS patients with a median follow-up time of 7 years. There are more than 13'000 documented visits with standardized clinical examinations by Neurostatus-certified treating physicians, more than 8'000 brain MRI scans and more than 300'000 bio-samples of which >3'000 exist as CSF/serum/plasma pairs. This setting provides a unique opportunity to find biomarkers associated with choroid plexus enlargement in MS. Moreover, co-morbidities and treatments of these patients are well-documented. We will use Freesurfer - a standard MRI analysis software - to segment automatically the choroid plexus of the brain lateral ventricles. We will check the outcomes of this analysis manually using 3D Slicer. The associations between choroid plexus volume and clinical parameters (Expanded disability status scale (EDSS) score, disease duration, time since last relapse and disease-modifying therapy), radiological outcomes (T2-weighted lesion number and volume, lateral ventricle volume, gray and white matter volume fraction, brain parenchymal fraction) and body fluid parameters (serum neurofilament light chain, glial fibrillary acidic protein) will be investigated using multivariable linear regression models adjusted for age, sex and total intracranial volume.There are many studies suggesting the specific role of the choroid plexus in MS pathology and clinical studies have found that t he choroid plexus is enlarged in MS compared to healthy individuals. Our study group also found that this might be specific for MS as the choroid plexus was significantly larger in MS than e.g. neuromyelitis optica spectrum disorders. However, it is unknown whether the choroid plexus volume is suitable as an MRI biomarker in MS. If this study shows that the choroid plexus volume is longitudinally associated clinical, MRI and body fluid biomarkers in MS, it might serve as an outcome parameter for future Phase II studies and potentially as a biomarker for treatment monitoring in MS.