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The sphingosine 1-phosphate (S1P) signalling pathways have important and diverse functions. S1P receptors (S1PRs) have been proposed as a therapeutic target for various diseases due to their involvement in regulation of lymphocyte trafficking, brain and cardiac function, vascular permeability, and vascular and bronchial tone. S1PR modulators were first developed to prevent rejection by the immune system following renal transplantation, but the only currently approved indication is multiple sclerosis. The primary mechanism of action of S1PR modulators in multiple sclerosis is through binding S1PR subtype 1 on lymphocytes resulting in internalisation of the receptor and loss of responsiveness to the S1P gradient that drives lymphocyte egress from lymph nodes. The reduction in circulating lymphocytes presumably limits inflammatory cell migration into the CNS. Four S1PR modulators (fingolimod, siponimod, ozanimod, and ponesimod) have regulatory approval for multiple sclerosis. Preclinical evidence and ongoing and completed clinical trials support development of S1PR modulators for other therapeutic indications.

Introduction La qualite de vie (HRQoL) des patients SEP est inferieure a la population generale. Optimiser le traitement suppose comprendre les variations de HRQoL apres initiation du traitement de fond. Objectifs Evaluer les variations notees dans Neuro-QoL apres initiation du traitement par natalizumab et comparer les variations des modules du Neuro-QoL sous natalizumab et ocrelizumab, une autre therapie hautement efficace. Patients et methodes Les T-scores des 12 modules Neuro-QoL etaient recueillis lors des visites de routine MS PATHS. Les scores Neuro-QoL des visites apres initiation du natalizumab ont ete compares avec les scores de base de Neuro-QoL pour calculer le taux annualise de variation et la probabilite de variation cliniquement significative (≥ 5 points). Des comparaisons etaient menees avec des patients traites par ocrelizumab apres ponderation et ajustement des scores de propension pour les co-traitements, l’annee et l’interaction medicament-annee. Resultats Les patients traites par natalizumab (n = 164) ont montre une amelioration significative sur 8/12 domaines. Les domaines avec une proportion de patients avec une amelioration de ≥ 5 points sont : troubles du sommeil, anxiete, perte de controle emotionnel et comportemental. Les taux d’amelioration annualises etaient superieurs sous natalizumab (n = 144) que sous ocrelizumab (n = 502) concernant les domaines : bien-etre (p = 0,02), troubles du sommeil (p = 0,003) et satisfaction a l’egard des roles et activites sociaux (p = 0,03). Discussion Le traitement par natalizumab a ete associe a des ameliorations significatives dans la plupart des domaines Neuro-QoL. Ces ameliorations etaient superieures chez les patients presentant un handicap initial, ce qui etaye la pertinence clinique de ces resultats. L’ampleur de ces ameliorations depassant celle d’un autre traitement efficace (ocrelizumab), il est peu probable qu’elles soient principalement dues a un biais d’anticipation. Conclusion Le natalizumab peut deboucher sur des ameliorations cliniquement significatives dans des aspects de la sante mentale et sociale telles qu’evaluees par Neuro-QoL.

Background Objective and longitudinal measurements of disability in patients with multiple sclerosis (MS) are desired in order to monitor disease status and response to disease-modifying and symptomatic therapies. Technology-enabled comprehensive assessment of MS patients, including neuroperformance tests (NPTs), patient-reported outcome measures (PROMs), and MRI, is incorporated into clinical care at our center. The relationships of each NPT with PROMs and MRI measures in a real-world setting are incompletely studied, particularly in larger datasets. Objectives To demonstrate the utility of comprehensive neurological assessment and determine the association between NPTs, PROMs, and quantitative MRI measures in a large MS clinical cohort. Methods NPTs (processing speed [PST], contrast sensitivity [CST], manual dexterity [MDT], and walking speed [WST]) and physical disability-related PROMs (Quality of Life in Neurological Disorders [Neuro-QoL], Patient Determined Disease Steps [PDDS], and Patient-Reported Outcomes Measurement Information System Global-10 [PROMIS-10] physical) were collected as part of routine clinical care. Fully-automated MRI analysis calculated T2-lesion volume (T2LV), whole brain fraction (WBF), thalamic volume (TV), and cervical spinal cord cross-sectional area (CA) for brain MRIs completed within 3 months of a clinic visit during which NPTs and PROMs were assessed. Spearman's rank correlation coefficients evaluated the cross-sectional associations of NPTs with PROMs and MRI measures. Linear regression was utilized to determine which combination of clinical characteristics, patient demographics, MRI measures, and PROMs best cross-sectionally explained each NPT result. Results 997 unique patients (age 47.7 ± 11.4 years, 71.8% female) who underwent assessments over a 2-year period were included. Correlations among NPTs and PROMs were moderate. PST correlations were strongest for Neuro-QoL upper extremity (NQ-UE) (Spearman's rho = 0.43) and lower extremity (NQ-LE) (0.47). CST correlations were strongest for NQ-UE (0.33), NQ-LE (0.36), and PDDS (-0.31). MDT correlations were strongest for NQ-UE (-0.53), NQ-LE (-0.54), and PDDS (0.53). WST correlations were strongest for PDDS (0.64) and NQ-LE (-0.65). NPTs also had moderate correlations with MRI metrics, the strongest of which were observed with PST (with T2LV (-0.44) and WBF (0.49)). Spearman's rho for other NPT-MRI correlations ranged from 0.23 to 0.36. Linear regression identified age, disease duration, PROMIS-10 physical, NQ-UE, NQ-LE, T2LV and WBF as significant cross-sectional explanatory variables for PST (adjusted R2=0.46). For CST, significant variables included age and NQ-LE (adjusted R2 = 0.30). For MDT, significant variables included PDDS, PROMIS-10 physical, NQ-UE, NQ-LE, T2LV, and WBF (adjusted R2=0.37). For WST, significant variables included sex, PDDS, NQ-LE, T2LV, and CA (adjusted R2=0.39). Conclusions Impaired performance on NPTs correlated with worse physical disability-related PROMs and MRI disease severity, but the strongest cross-sectional explanatory variables for each NPT component varied. This study supports the use of comprehensive, objective quantification of MS status in clinical and research settings. Future longitudinal analyses can determine predictors of treatment response and disability worsening.

• Alemtuzumab has been associated with stroke and cervicocephalic dissections. • Monitoring blood pressure is currently recommended by the EMA. • Monitoring blood pressure is not useful in predicting these rare side effects.