The treatment of multiple sclerosis is evolving rapidly with 11 classes of disease-modifying therapies (DMTs). This article provides an overview of a new classification system for DMTs and treatment ...paradigm for using these DMTs effectively and safely.
A summary of research into the use of more active approaches to early and effective treatment of multiple sclerosis with defined treatment targets of no evident disease activity (NEDA). New insights are discussed that is allowing the field to begin to tackle more advanced multiple sclerosis, including people with multiple sclerosis using wheelchairs. However, the need to modify expectations of what can be achieved in more advanced multiple sclerosis are discussed; in particular, the focus on neuronal systems with reserve capacity, for example, upper limb, bulbar and visual function.
The review describes a new more active way of managing multiple sclerosis and concludes with a call to action in solving the problem of slow adoption of innovations and the global problem of untreated, or undertreated, multiple sclerosis.
In this randomized trial involving patients with multiple sclerosis, BG-12 (dimethyl fumarate) reduced clinical relapses, disability progression, and MRI lesions. BG-12 treatment resulted in reduced ...lymphocyte counts and elevated liver aminotransferase levels.
Oral BG-12 (dimethyl fumarate) is being investigated for the treatment of multiple sclerosis. Inflammation and oxidative stress are central pathologic factors in multiple sclerosis.
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Immune cell activation and infiltration into the central nervous system are thought to result in widespread cellular damage, potentially owing to the dysregulated production and release of reactive oxygen and nitrogen species, such as hydrogen peroxide and peroxynitrite, and proinflammatory stimuli.
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This combination of toxic factors ultimately results in demyelination and neurodegeneration, causing disease activity and progression of disability.
BG-12 has been shown to have beneficial effects in preclinical models of neuroinflammation, neurodegeneration, and toxic . . .
Background:
Epstein–Barr virus (EBV) infection is thought to play a central role in the development of multiple sclerosis (MS). If causal, it represents a target for interventions to reduce MS risk.
...Objective:
To examine the evidence for interaction between EBV and other risk factors, and explore mechanisms via which EBV infection may influence MS risk.
Methods:
Pubmed was searched using the terms ‘multiple sclerosis’ AND ‘Epstein Barr virus’, ‘multiple sclerosis’ AND EBV, ‘clinically isolated syndrome’ AND ‘Epstein Barr virus’ and ‘clinically isolated syndrome’ AND EBV. All abstracts were reviewed for possible inclusion.
Results:
A total of 262 full-text papers were reviewed. There was evidence of interaction on the additive scale between anti-EBV antibody titre and HLA genotype (attributable proportion due to interaction (AP) = 0.48, p < 1 × 10−4). Previous infectious mononucleosis (IM) was associated with increased odds ratio (OR) of MS in HLA-DRB1*1501 positive but not HLA-DRB1*1501 negative persons. Smoking was associated with a greater risk of MS in those with high anti-EBV antibodies (OR = 2.76) but not low anti-EBV antibodies (OR = 1.16). No interaction between EBV and risk factors was found on a multiplicative scale.
Conclusion:
EBV appears to interact with at least some established MS risk factors. The mechanism via which EBV influences MS risk remains unknown.
Summary Multiple sclerosis (MS) is a common, complex neurological disease. The precise aetiology of MS is not yet known, although epidemiological data indicate that both genetic and environmental ...factors are important. The evidence that the environment acts long before MS becomes clinically evident is well established and suggests the existence of a prodromal phase for the disease. The increasing incidence of MS emphasises the need for strategies to prevent this chronic disorder, and the possibility of a prodrome indicates a window of opportunity to potentially reverse early disease processes before clinical disease becomes evident. Studying a prodrome requires techniques other than clinical observation such as monitoring endophenotypes that result from associated risk factors. However, our current knowledge of causal pathways and endophenotypes in MS is limited. Identifying and studying individuals with a high risk of developing the disease provides a powerful opportunity to understand the MS causal cascade and is highly relevant to strategies that are aimed at preventing this debilitating disease.
IMPORTANCE: Accumulation of disability in multiple sclerosis may occur as relapse-associated worsening (RAW) or steady progression independent of relapse activity (PIRA), with PIRA regarded as a ...feature of primary and secondary progressive multiple sclerosis. OBJECTIVE: To investigate the contributions of relapse-associated worsening vs relapse-independent progression to overall confirmed disability accumulation (CDA) and assess respective baseline prognostic factors and outcomes of 2 treatments. DESIGN, SETTING, AND PARTICIPANTS: Analyses occurred from July 2015 to February 2020 on pooled data from the intention-to-treat population of 2 identical, phase 3, multicenter, double-blind, double-dummy, parallel-group randomized clinical trials (OPERA I and II) conducted between August 2011 and April 2015. In the trials, patients with relapsing multiple sclerosis (RMS), diagnosed using the 2010 revised McDonald criteria, were randomized from 307 trial sites in 56 countries; resulting data were analyzed in the pooled data set. INTERVENTIONS: Participants were randomized 1:1 to receive 600 mg of ocrelizumab by intravenous infusion every 24 weeks or subcutaneous interferon β-1a 3 times a week at a dose of 44 μg throughout a 96-week treatment period. MAIN OUTCOMES AND MEASURES: Confirmed disability accumulation was defined by an increase in 1 or more of 3 measures (Expanded Disability Status Scale, timed 25-ft walk, or 9-hole peg test), confirmed after 3 or 6 months, and classified per temporal association with confirmed clinical relapses (PIRA or RAW). RESULTS: In the pooled OPERA I and II population (1656 of 2096 eligible participants), baseline demographics and disease characteristics were similar for patients randomized to interferon β-1a vs ocrelizumab (mean SD age, 37.2 9.2 vs 37.1 9.2 years; 552 66.6% vs 541 women 65.4%). After 96 weeks, 12-week composite CDA had occurred in 223 (29.6% by Kaplan-Meier estimate) randomized to interferon β-1a and 167 (21.1%) randomized to ocrelizumab; 24-week composite CDA had occurred in 170 (22.7%) taking interferon β-1a and 129 (16.2%) taking ocrelizumab. The PIRA events were the main contributors to 12-week and 24-week composite CDA after 96 weeks in patients treated with interferon β-1a (174 of 223 78.0% and 137 of 170 80.6%, respectively) and ocrelizumab (147 of 167 88.0% and 115 of 129 89.1%, respectively); a minority had CDA explained by RAW events (69 of 390 17.7% and 52 of 299 17.4%, respectively). Very few patients with composite CDA experienced both RAW and PIRA events (17 of 390 4.4% for 12-week and 15 of 299 5.0% for 24-week composite CDA). Ocrelizumab (vs interferon β-1a) was associated with reduced risk of composite CDA (hazard ratio HR, 0.67) and confirmed PIRA (HR, 0.78) and RAW (HR, 0.47) events. CONCLUSIONS AND RELEVANCE: Most disability accumulation in RMS is not associated with overt relapses. This indicates an underlying progression in this typical RMS population and challenges the current clinical distinction of relapsing and progressive forms of multiple sclerosis. Ocrelizumab was superior to interferon β-1a in preventing both RAW and PIRA. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: OPERA I (NCT01247324) and OPERA II (NCT01412333).
Background:
In the 2-year CLARITY study, cladribine tablets significantly improved clinical and magnetic resonance imaging (MRI) outcomes (vs placebo) in patients with relapsing–remitting multiple ...sclerosis (MS).
Objective:
To assess the safety and efficacy of cladribine treatment in a 2-year Extension study.
Methods:
In this 2-year Extension study, placebo recipients from CLARITY received cladribine 3.5 mg/kg; cladribine recipients were re-randomized 2:1 to cladribine 3.5 mg/kg or placebo, with blind maintained.
Results:
A total of 806 patients were assigned to treatment. Adverse event rates were generally similar between groups, but lymphopenia Grade ⩾ 3 rates were higher with cladribine than placebo (Grade 4 lymphopenia occurred infrequently). In patients receiving cladribine 3.5 mg/kg in CLARITY and experiencing lymphopenia Grade ⩾ 3 in the Extension, >90% of those treated with cladribine 3.5 mg/kg and all treated with placebo in the Extension, recovered to Grade 0–1 by study end. Cladribine treatment in CLARITY produced efficacy improvements that were maintained in patients treated with placebo in the Extension; in patients treated with cladribine 3.5 mg/kg in CLARITY, approximately 75% remained relapse-free when given placebo during the Extension.
Conclusion:
Cladribine tablets treatment for 2 years followed by 2 years’ placebo treatment produced durable clinical benefits similar to 4 years of cladribine treatment with a low risk of severe lymphopenia or clinical worsening. No clinical improvement in efficacy was apparent following further treatment with cladribine tablets after the initial 2-year treatment period in this trial setting.
Patients with primary progressive MS who received the anti-CD20+ humanized antibody ocrelizumab were less likely to have clinical deterioration that was sustained for 12 weeks than those who received ...placebo. The drug was associated with decreased lesion activity on MRI.
Primary progressive multiple sclerosis accounts for 10 to 15% of the overall population with multiple sclerosis.
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The course of this disease differs from those of relapsing–remitting and secondary progressive forms of multiple sclerosis in that progression consists mainly of gradual worsening of neurologic disability from symptom onset, although relapses may occur.
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Phase 3 trials in primary progressive multiple sclerosis have been unsuccessful,
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and no disease-modifying treatments have been approved.
B cells contribute to the pathogenesis of multiple sclerosis, including the primary progressive form.
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Although the mechanisms of tissue injury in multiple sclerosis are uncertain, B cells may influence pathogenesis . . .
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