The Two Sides of Siponimod: Evidence for Brain and Immune Mechanisms in Multiple Sclerosis.

Siponimod is a selective sphingosine 1-phosphate receptor subtype 1 (S1P1) and 5 (S1P5) modulator approved in the United States and the European Union as an oral treatment for adults with relapsing forms of multiple sclerosis (RMS), including active secondary progressive multiple sclerosis (SPMS). Preclinical and clinical studies provide support for a dual mechanism of action of siponimod, targeting peripherally mediated inflammation and exerting direct central effects. As an S1P1 receptor modulator, siponimod reduces lymphocyte egress from lymph nodes, thus inhibiting their migration from the periphery to the central nervous system. As a result of its peripheral immunomodulatory effects, siponimod reduces both magnetic resonance imaging (MRI) lesion (gadolinium-enhancing and new/enlarging T2 hyperintense) and relapse activity compared with placebo. Independent of these effects, siponimod can penetrate the blood-brain barrier and, by binding to S1P1 and S1P5 receptors on a variety of brain cells, including astrocytes, oligodendrocytes, neurons, and microglia, exert effects to modulate neural inflammation and neurodegeneration. Clinical data in patients with SPMS have shown that, compared with placebo, siponimod treatment is associated with reductions in levels of neurofilament light chain (a marker of neuroaxonal damage) and thalamic and cortical gray matter atrophy, with smaller reductions in MRI magnetization transfer ratio and reduced confirmed disability progression. This review examines the preclinical and clinical data supporting the dual mechanism of action of siponimod in RMS

Cognitive phenotypes predict response to restorative cognitive rehabilitation in multiple sclerosis

Background: Cognitive phenotyping may be useful for predicting rehabilitation response in multiple sclerosis. Objective: To evaluate the association between cognitive phenotype(s) and response to restorative cognitive rehabilitation (RRCR). Methods: In a post hoc retrospective analysis of the RRCR study including 51 multiple sclerosis patients, we evaluated both impairment within specific cognitive domains as well as overall global impairment severity to investigate their relationship to improvement following rehabilitation. Results: Greater improvement in executive function was predicted by impairment within this domain as well as by having fewer impaired cognitive domains overall. Similar results were observed for visuospatial memory. Conclusions: Patients most likely to benefit from restorative cognitive rehabilitation may exhibit impairment within the domain of interest yet lower cognitive burden overall

Quantifying disease pathology and predicting disease progression in multiple sclerosis with only clinical routine T2-FLAIR MRI

Background: Although quantitative measures from research-quality MRI provide a means to study multiple sclerosis (MS) pathology in vivo, these metrics are often unavailable in legacy clinical datasets. Objective: To determine how well an automatically-generated quantitative snapshot of brain pathology, measured only on clinical routine T2-FLAIR MRI, can substitute for more conventional measures on research MRI in terms of capturing multi-factorial disease pathology and providing similar clinical relevance. Methods: MRI with both research-quality sequences and conventional clinical T2-FLAIR was acquired for 172 MS patients at baseline, and neurologic disability was assessed at baseline and five-years later. Five measures (thalamus volume, lateral ventricle volume, medulla oblongata volume, lesion volume, and network efficiency) for quantifying disparate aspects of neuropathology from low-resolution T2-FLAIR were applied to predict standard research-quality MRI measures. They were compared in regard to association with future neurologic disability and disease progression over five years. Results: The combination of the five T2-FLAIR measures explained most of the variance in standard research-quality MRI. T2-FLAIR measures were associated with neurologic disability and cognitive function five-years later (R2 = 0.279, p < 0.001; R2 = 0.382, p < 0.001), similar to standard research-quality MRI (R2 = 0.279, p < 0.001; R2 = 0.366, p < 0.001). They also similarly predicted disability progression over five years (%-correctly-classified = 69.8, p = 0.034), compared to standard research-quality MRI (%-correctly-classified = 72.4%, p = 0.022) in relapsing-remitting MS. Conclusion: A set of five T2-FLAIR-only measures can substitute for standard research-quality MRI, especially in relapsing-remitting MS. When only clinical T2-FLAIR is available, it can be used to obtain substantially more quantitative information about brain pathology and disability than is currently standard practice

A validation study for remote testing of cognitive function in multiple sclerosis

ObjectivesDetermine the validity and reliability of a remote, technician-guided cognitive assessment for multiple sclerosis (MS), incorporating the Symbol Digit Modalities Test (SDMT) and the California Verbal Learning Test, Second Edition (CVLT-II).MethodsIn 100 patients, we compared conventional in-person testing to remote, web-assisted assessments, and in 36 patients, we assessed test-retest reliability using two equivalent, alternative forms.ResultsIn-person and remote-administered SDMT (r = 0.85) and CVLT-II (r = 0.71) results were very similar. Reliability was adequate and alternative forms of SDMT (r = 0.92) and CVLT-II (r = 0.81) produced similar results.ConclusionsFindings indicate remote assessment can provide valid, reliable measures of cognitive function in MS

Quantification of Global Cerebral Atrophy in Multiple Sclerosis from 3T MRI Using SPM: The Role of Misclassification Errors

Purpose We tested the validity of a freely available segmentation pipeline to measure compartmental brain volumes from 3T MRI in patients with multiple sclerosis (MS). Our primary focus was methodological to explore the effect of segmentation corrections on the clinical relevance of the output metrics. Methods: Three-dimensional T1-weighted images were acquired to compare 61 MS patients to 30 age- and gender-matched normal controls (NC). We also tested the within patient MRI relationship to disability (eg, expanded disability status scale [EDSS] score) and cognition. Statistical parametric mapping v. 8 (SPM8)-derived gray matter (GMF), white matter (WMF), and total brain parenchyma fractions (BPF) were derived before and after correcting errors from T1 hypointense MS lesions and/or ineffective deep GM contouring. Results: MS patients had lower GMF and BPF as compared to NC (P<.05). Cognitively impaired patients had lower BPF than cognitively preserved patients (P<.05). BPF was related to EDSS; BPF and GMF were related to disease duration (all P<.05). Errors caused bias in GMFs and WMFs but had no discernable influence on BPFs or any MRI-clinical associations. Conclusions: We report the validity of a segmentation pipeline for the detection of MS-related brain atrophy with 3T MRI. Longitudinal studies are warranted to extend these results

Long-term efficacy and safety of siponimod in patients with secondary progressive multiple sclerosis: Analysis of EXPAND core and extension data up to &gt;5 years.

BackgroundSiponimod significantly reduced the risk of confirmed disability progression (CDP), worsening in cognitive processing speed (CPS), relapses, and magnetic resonance imaging (MRI) measures of brain atrophy and inflammation versus placebo in secondary progressive multiple sclerosis (SPMS) patients in the Phase 3 EXPAND study.ObjectiveThe aim of this study was to assess long-term efficacy and safety of siponimod 2 mg/day from the EXPAND study including the extension part, up to &gt; 5 years.MethodsIn the open-label extension part, participants receiving placebo during the core part were switched to siponimod (placebo-siponimod group) and those on siponimod continued the same treatment (continuous siponimod group).ResultsContinuous siponimod reduced the risk of 6-month CDP by 22% (hazard ratio (HR) (95% confidence interval (CI)): 0.78 (0.66-0.92) p = 0.0026) and 6-month confirmed worsening in CPS by 23% (HR (95% CI): 0.77 (0.65-0.92) p = 0.0047) versus the placebo-siponimod group. Sustained efficacy on annualized relapse rate, total and regional brain atrophy, and inflammatory disease activity was also observed. No new, unexpected safety signals for siponimod were identified over the long term.ConclusionThe sustained efficacy and consistent long-term safety profile of siponimod up to &gt; 5 years support its clinical utility for long-term treatment of SPMS. Benefits in the continuous siponimod versus placebo-siponimod group highlight the significance of earlier treatment initiation.Trial registration numberNCT01665144