The modern era of multiple sclerosis (MS) treatment began 25 years ago, with the approval of IFNβ and glatiramer acetate for the treatment of relapsing-remitting MS. Ten years later, the first monoclonal antibody, natalizumab, was approved, followed by a third important landmark with the introduction of oral medications, initially fingolimod and then teriflunomide, dimethyl fumarate and cladribine. Concomitantly, new monoclonal antibodies (alemtuzumab and ocrelizumab) have been developed and approved. The modern era of MS therapy reached primary progressive MS in 2018, with the approval of ocrelizumab. We have also learned the importance of starting treatment early and the importance of clinical and MRI monitoring to assess treatment response and safety. Treatment decisions should account for disease phenotype, prognostic factors, comorbidities, the desire for pregnancy and the patient's preferences in terms of acceptable risk. The development of treatment for MS during the past 25 years is a fantastic success of translational medicine.

Treatment of multiple sclerosis — success from bench to bedside

Lysophospholipids are a class of bioactive lipid molecules that produce their effects through various G protein-coupled receptors (GPCRs). Sphingosine 1-phosphate (S1P) is perhaps the most studied lysophospholipid and has a role in a wide range of physiological and pathophysiological events, via signalling through five distinct GPCR subtypes, S1PR1 to S1PR5. Previous and continuing investigation of the S1P pathway has led to the approval of three S1PR modulators, fingolimod, siponimod and ozanimod, as medicines for patients with multiple sclerosis (MS), as well as the identification of new S1PR modulators currently in clinical development, including ponesimod and etrasimod. S1PR modulators have complex effects on S1PRs, in some cases acting both as traditional agonists as well as agonists that produce functional antagonism. S1PR subtype specificity influences their downstream effects, including aspects of their benefit:risk profile. Some S1PR modulators are prodrugs, which require metabolic modification such as phosphorylation via sphingosine kinases, resulting in different pharmacokinetics and bioavailability, contrasting with others that are direct modulators of the receptors. The complex interplay of these characteristics dictates the clinical profile of S1PR modulators. This review focuses on the S1P pathway, the characteristics and S1PR binding profiles of S1PR modulators, the mechanisms of action of S1PR modulators with regard to immune cell trafficking and neuroprotection in MS, together with a summary of the clinical effectiveness of the S1PR modulators that are approved or in late-stage development for patients with MS. Sphingosine 1-phosphate receptor modulator therapy for multiple sclerosis: differential downstream receptor signalling and clinical profile effects (MP4 65540 kb).

/pdf/sphingosine-1-phosphate-receptor-modulator-therapy-for-58ybqgrsw6.pdf

Sphingosine 1-phosphate Receptor Modulator Therapy for Multiple Sclerosis: Differential Downstream Receptor Signalling and Clinical Profile Effects

This review will examine the current evidence that genetic and/or epigenetic variation may influence the multiple sclerosis (MS) clinical course, phenotype, and measures of MS severity including disability progression and relapse rate. There is little evidence that MS clinical phenotype is under significant genetic control. There is increasing evidence that there may be genetic determinants of the rate of disability progression. However, studies that can analyse disability progression and take into account all the confounding variables such as treatment, clinical characteristics, and environmental factors are by necessity longitudinal, relatively small, and generally of short duration, and thus do not lend themselves to the assessment of hundreds of thousands of genetic variables obtained from GWAS. Despite this, there is recent evidence to support the association of genetic loci with relapse rate. Recent progress suggests that genetic variations could be associated with disease severity, but not MS clinical phenotype, but these findings are not definitive and await replication. Pooling of study results, application of other genomic techniques including epigenomics, and analysis of biomarkers of progression could functionally validate putative severity markers.

Genotype and Phenotype in Multiple Sclerosis-Potential for Disease Course Prediction?

CEM has been funded throughout his PhD by MedImmune, The Jean Shanks Foundation and the James Baird Fund. The work here has also been funded by the British Trust for the Myelin Project and the UK MS Society.

Research in RJMF’s laboratory is supported by a core support grant from the Wellcome Trust and MRC to the Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute.

CNS remyelination and the gut microbiota

Die fruhzeitige, individualisierte Therapie der schubformig-remittierenden Multiplen Sklerose (RRMS) kann die Prognose der Patienten verandern. Wird eine Eskalationstherapie notwendig, steht heute eine ganze Reihe von Therapeutika zur Auswahl. Dabei stellt sich die Frage nach der individuell besten Strategie.

Immunsuppression bei schubförmig-remittierender Multipler Sklerose

The effect of disease-modifying treatments on conversion to secondary progressive multiple sclerosis

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The effect of disease-modifying treatments on conversion to secondary progressive multiple sclerosis