Innovations In Clinical Neuroscience

HOTTOP Multiple Sclerosis DEC 2017

A peer-reviewed, evidence-based journal for clinicians in the field of neuroscience

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R E V I E W 18 Hot Topics in Multiple Sclerosis [December 2017] meet its primary endpoint in PPMS 4 (Table 1). In the following section, we try to summarize the most promising treatments in PPMS. Ocrelizumab. The immunomodulatory agent "Ocrelizumab" is a humanized monoclonal anti-CD20 antibody. It attacks different epitopes on pre-B cells and memory B, rendering it better tolerable and possibly more effective than Rituximab. 77 Ocrelizumab acts mainly against antigen-presenting and cytokine-releasing B cells, not stem cells or plasma cells. 68 The resulting B cell depletion is mediated either through compliments, cytotoxic CD8+, or induced apoptosis. 78 Ocrelizumab is the first drug ever to show efficacy in slowing the disease progression in a Phase 3 clinical trial with patients with PPMS. 79 In the double- blinded, placebo-controlled study "ORATORIO" with 732 patients with PPMS, ocrelizumab reduced time to onset of 12-week confirmed disability progression risk by 24 percent (p=0.0321) compared with placebo. Timed 25-foot walk improved after 120 weeks (p=0.04). Biotin. Vitamin B7-biotin activates acetylCoA carboxylase, a potentially rate-limiting enzyme in myelin synthesis and subsequently might help induce remyelination. 80 Indeed, a pilot study with 23 patients with SPMS and PPMS reported improvement in clinical, radiological, or electrophysiological parameters in 91.3 percent of the patients receiving high dose (100– 300mg) biotin. 80 Very recently, the results of the Phase 3 MS-SPI study with its extension phase were published revealing that the primary endpoint "reversal of disability" was met in 13.2 percent of the study population (progressive MS) at Month 12. Secondary endpoints like slowing of the EDSS progression were also met with acceptable tolerability and side effects profile 3 making biotin the first remyelinating agent to possibly enter the market. Laquinimod. Laquinimod is an orally available carboxamide derivative with multimodal mechanism of action rendering it both anti-inflammatory and neuroprotective; 81 laquinimod reduces inflammatory cells in the brain (Th1 and Th17), shifts the cytokines into anti-inflammatory profile, promotes monocytes/macrophage maturation into regulatory subtypes, and modulates the dendritic cells reducing their ability to induce the CD4+ cells. 82 The unexpected discrepancy between the modest effect on relapse rates and the unprecedented reduction of disease progression in clinical studies suggests a novel neuroprotective effect of laquinimod. Indeed, laquinimod increases brain- derived neuroprotective factor 83 and inhibit the inflammatory response of astrocytes and microglia leading to reduction of the axonal damage. 84 Simvastatin. In the MS-STAT study, 80mg/day simvastatin was reported to cut the annualized brain atrophy rates in patients with SPMS by almost the half in a placebo-controlled randomized clinical trial. 85 Simvastatin exhibits its immunomodulatory action by impacting the Th1 and Th17 as well as by modulation the dendritic cells. 86,87 EBV-directed therapies. Adoptive immunotherapy with autologous T cells expanded in vitro with AdE1-LMPpoly increased survival in patients with the EBV-associated carcinoma. 88 Pender et al. applied the same approach in one patient with SPMS with EDSS score of 8.0, leading to clinical and radiological improvement without serious side effects, 89 a novel approach targets a mechanism provoking the autoimmune response in MS itself not the immune system generally. 23 Furthermore, vaccination of seronegative individuals with recombinant gp350 may be considered as a novel "primary FIGURE 2. Different risk factors and their effect on the clinical phenotype in multiple sclerosis (MS). The pathological process in MS occurs in genetically susceptible individuals after in presence of the Epstein–Barr virus (EBV) infection and predisposing intestinal microbiome (see below). Initially, the pathological process does not lead to clinical manifestations, but radiological changes may be present [radiologically isolated syndrome (RIS)]. The presence of vitamin D deficiency will exacerbate the inflammatory changes, leading to appearance of the first relapse [clinically isolated syndrome (CIS)], which is usually followed by complete recovery. Fluctuation in vitamin D levels and eventually other unknown factors will lead to appearance of further relapses and starting of relapsing remitting multiple sclerosis (RRMS). Another slowly inflammatory triggered neurodegenerative process takes place in the background and exhibits its clinical manifestation only after exceeding an age threshold. One possible explanation for the age threshold is known changes in the host defense to EBV infection. Other factors like age-dependent local iron precipitation may play a role.

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