BACKGROUND: Serum neurofilament light (sNfL) chain levels, a sensitive measure of disease activity in multiple sclerosis (MS), are increasingly considered for individual therapy optimization yet without consensus on their use for clinical application. OBJECTIVE: We here propose treatment decision algorithms incorporating sNfL levels to adapt disease-modifying therapies (DMTs). METHODS: We conducted a modified Delphi study to reach consensus on algorithms using sNfL within typical clinical scenarios. sNfL levels were defined as "high" (>90th percentile) vs "normal" (<80th percentile), based on normative values of control persons. In three rounds, 10 international and 18 Swiss MS experts, and 3 patient consultants rated their agreement on treatment algorithms. Consensus thresholds were defined as moderate (50%-79%), broad (80%-94%), strong (≥95%), and full (100%). RESULTS: The Delphi provided 9 escalation algorithms (e.g. initiating treatment based on high sNfL), 11 horizontal switch (e.g. switching natalizumab to another high-efficacy DMT based on high sNfL), and 3 de-escalation (e.g. stopping DMT or extending intervals in B-cell depleting therapies). CONCLUSION: The consensus reached on typical clinical scenarios provides the basis for using sNfL to inform treatment decisions in a randomized pragmatic trial, an important step to gather robust evidence for using sNfL to inform personalized treatment decisions in clinical practice.

• Keywords
• Delphi study, de-escalation, escalation, personalized treatment strategies, serum neurofilament light chain,
• MeSH
• Algorithms * MeSH
• Delphi Technique MeSH
• Adult MeSH
• Immunologic Factors * therapeutic use   MeSH
• Precision Medicine * methods   MeSH
• Clinical Decision-Making * methods   MeSH
• Consensus MeSH
• Middle Aged MeSH
• Humans MeSH
• Neurofilament Proteins * blood   MeSH
• Multiple Sclerosis * blood   drug therapy   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Immunologic Factors * MeSH
• neurofilament protein L MeSH Browser
• Neurofilament Proteins * MeSH

Multiple sclerosis (MS) is characterized by a progressive worsening of disability over time. As many regulatory-cleared disease-modifying treatments aiming to slow down this progression are now available, a clear need has arisen for a personalized and data-driven approach to treatment optimization in order to more efficiently slow down disease progression and eventually, progressive disability worsening. This strongly depends on the availability of biomarkers that can detect and differentiate between the different forms of disease worsening, and on predictive models to estimate the disease trajectory for each patient under certain treatment conditions. To this end, we here describe a multicenter, retrospective, observational study, aimed at setting up a harmonized database to allow the development, training, optimization, and validation of such novel biomarkers and AI-based decision models. Additionally, the data will be used to develop the tools required to better monitor this progression and to generate further insights on disease worsening and progression, patient prognosis, treatment decisions and responses, and patient profiles of patients with MS.

• Keywords
• AI model, biomarker, clinical trial, data, disease worsening, multiple sclerosis, observational study, real-world data,
• Publication type
• Journal Article MeSH

BACKGROUND AND OBJECTIVES: Early treatment of multiple sclerosis (MS) reduces disease activity and the risk of long-term disease progression. Effectiveness of ocrelizumab is established in relapsing MS (RMS); however, data in early RMS are lacking. We evaluated the 4-year effectiveness and safety of ocrelizumab as a first-line therapy in treatment-naive patients with recently diagnosed relapsing-remitting MS (RRMS). METHODS: ENSEMBLE was a prospective, 4-year, international, multicenter, single-arm, open-label, phase IIIb study. Patients were treatment naive, aged 18-55 years, had early-stage RRMS with a disease duration ≤3 years, Expanded Disability Status Scale (EDSS) score ≤3.5, and ≥1 clinically reported relapse(s) or ≥1 signs of brain inflammatory activity on MRI in the prior 12 months. Patients received IV ocrelizumab 600 mg every 24 weeks. Effectiveness endpoints over 192 weeks were proportion of patients with no evidence of disease activity (NEDA-3; defined as absence of relapses, 24-week confirmed disability progression [CDP], and MRI measures, with prespecified MRI rebaselining at week 8), 24-week/48-week CDP and 24-week confirmed disability improvement, annualized relapse rate (ARR), mean change in EDSS score from baseline, and safety. Cognitive status, patient-reported outcomes, and serum neurofilament light chain (NfL) were assessed. Descriptive analysis was performed on the intention-to-treat population. RESULTS: Baseline characteristics (N = 678) were consistent with early-stage RRMS (n = 539 patients, 64.6% female, age 40 years and younger; median age: 31.0 years; duration since: MS symptom onset 0.78 years, RRMS diagnosis 0.24 years; mean baseline EDSS score [SD] 1.71 [0.95]). At week 192, most of the patients had NEDA-3 (n = 394/593, 66.4%), 85.0% had no MRI activity, 90.9% had no relapses, and 81.8% had no 24-week CDP over the study duration. Adjusted ARR at week 192 was low (0.020, 95% CI 0.015-0.027). NfL levels were reduced to and remained within the healthy donor range, by week 48 and week 192, respectively. No new or unexpected safety signals were observed. DISCUSSION: Disease activity based on clinical and MRI measures was absent in most of the patients treated with ocrelizumab over 4 years in the ENSEMBLE study. Safety was consistent with the known profile of ocrelizumab. Although this single-arm study was limited by lack of a parallel group for comparison of outcome measures, the positive benefit-risk profile observed may provide confidence to adopt ocrelizumab as a first-line treatment in newly diagnosed patients with early RMS. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that adult patients with early-stage MS who were treatment naive maintained low disease activity (NEDA-3) over 4 years with ocrelizumab treatment; no new safety signals were detected. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier NCT03085810; first submitted March 16, 2017; first patient enrolled: March 27, 2017; available at clinicaltrials.gov/ct2/show/NCT03085810.

• MeSH
• Adult MeSH
• Antibodies, Monoclonal, Humanized * therapeutic use   adverse effects   administration & dosage   MeSH
• Immunologic Factors * therapeutic use   adverse effects   administration & dosage   MeSH
• Middle Aged MeSH
• Humans MeSH
• Magnetic Resonance Imaging MeSH
• Adolescent MeSH
• Young Adult MeSH
• Disability Evaluation MeSH
• Disease Progression MeSH
• Prospective Studies MeSH
• Multiple Sclerosis, Relapsing-Remitting * drug therapy   diagnostic imaging   MeSH
• Treatment Outcome MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase III MeSH
• Multicenter Study MeSH
• Names of Substances
• Antibodies, Monoclonal, Humanized * MeSH
• Immunologic Factors * MeSH
• ocrelizumab MeSH Browser

BACKGROUND: Alemtuzumab (ALEM) is a humanised monoclonal antibody that depletes circulating lymphocytes by selectively targeting CD52, which is expressed in high levels on T- and B-lymphocytes. This depletion is followed by lymphocyte repopulation and a cytokine expression shift towards a lesser inflammatory profile, both of which may contribute to prolonged efficacy. National recommendations for enrolling and treating multiple sclerosis (MS) patients with ALEM have been established. However, there are no recommendations in place for the treatment of MS reactivation after the ALEM treatment. OBJECTIVES: To evaluate the effectiveness and safety of the use of ALEM and to analyse subsequent disease-modifying treatments (DMTs). A multidimensional prediction model was developed to make a patient-specific prognosis regarding the response to ALEM. DESIGN: A multicentre, prospective, non-controlled, non-interventional, observational cohort study. METHODS: Relapsing multiple sclerosis patients (RMSp) who received ⩾1 dose of ALEM were enrolled. In each treatment year, the following baseline and prospective data were collected: age, MS history, number, type and duration of previous disease-modifying treatment (PDMT), relapse rate (REL), expanded disability status scale (EDSS), magnetic resonance imaging and serious adverse events (AE). In cases of reactivation of MS, all data about the subsequent DMT were collected. RESULTS: A total of 142 RMSp from 10 MS Slovak Centres fulfilled the inclusion criteria. The average age was 35 years (standard error 8.56). The overall average EDSS was 3.87 (1.46) when ALEM was started. The average duration of PDMT was 6.0 (4.04) years, and the median number of PDMTs was 3 (0-5), while the patients were mostly treated with 2 or 3 DMTs (>65.00%). Post-ALEM treatment was needed in 39 cases (27.46%). The most frequent post-ALEM treatment indicated was ocrelizumab, followed by natalizumab (NAT), siponimod and cladribine. The ocrelizumab and NAT treatment bring little benefit to patients. Siponimod showed less EDSS increase in contrast to ocrelizumab and NAT. Another repopulation therapy, cladribine, may also be an effective option. Statistically significant predictors for the expected EDSS are age (p-value <0.0001), number of ALEM cycles (0.0066), high number of PDMT (0.0459) and the occurrence of relapses (<0.0001). There was no statistically significant effect on the patient's gender (0.6038), duration of disease-modifying treatment before alemtuzumab (0.4466), or the occurrence of AE (0.6668). CONCLUSION: The study confirms the positive effect of ALEM on clinical and radiological outcomes. We need more data from long-term sequencing studies.

• Keywords
• alemtuzumab, long-term efficacy, long-term safety, multiple sclerosis, post-alemtuzumab treatment, real-world data,
• Publication type
• Journal Article MeSH

Multiple sclerosis (MS) is a devastating immune-mediated disorder of the central nervous system resulting in progressive disability accumulation. As there is no cure available yet for MS, the primary therapeutic objective is to reduce relapses and to slow down disability progression as early as possible during the disease to maintain and/or improve health-related quality of life. However, optimizing treatment for people with MS (pwMS) is complex and challenging due to the many factors involved and in particular, the high degree of clinical and sub-clinical heterogeneity in disease progression among pwMS. In this paper, we discuss these many different challenges complicating treatment optimization for pwMS as well as how a shift towards a more pro-active, data-driven and personalized medicine approach could potentially improve patient outcomes for pwMS. We describe how the 'Clinical Impact through AI-assisted MS Care' (CLAIMS) project serves as a recent example of how to realize such a shift towards personalized treatment optimization for pwMS through the development of a platform that offers a holistic view of all relevant patient data and biomarkers, and then using this data to enable AI-supported prognostic modelling.

• Keywords
• AI, data, diagnosis, disease progression, multiple sclerosis, personalized medicine, prognosis,
• MeSH
• Biomarkers MeSH
• Precision Medicine * methods   trends   MeSH
• Quality of Life MeSH
• Humans MeSH
• Prognosis MeSH
• Disease Progression MeSH
• Multiple Sclerosis * therapy   immunology   MeSH
• Artificial Intelligence * trends   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Biomarkers MeSH

Multiple sclerosis (MS) treatment intervention with immunomodulating therapy at early disease stage improves short term clinical outcomes. The objective of this study is to describe the long-term outcomes and healthcare utilization of patients with clinically isolated syndrome (CIS) included in the Betaferon®/Betaseron® in Newly Emerging MS for Initial Treatment (BENEFIT) randomized, parallel group trial. In BENEFIT patients were assigned to "early" IFNB-1b treatment or placebo ("delayed" treatment). After 2 years or conversion to clinically definite multiple sclerosis (CDMS), all patients were offered IFNB-1b and were reassessed 15 years later. Of 468 patients, 261 (55.8%) were enrolled into BENEFIT 15 (161 [55.1%] from the early, 100 [56.8%] from the delayed treatment arm). In the full BENEFIT analysis set, risk of conversion to CDMS remained lower in the early treatment group ( - 30.5%; hazard ratio 0.695 [95% CI, 0.547-0.883]; p = 0.0029) with a 15.7% lower risk of relapse than in the delayed treatment group (p = 0.1008). Overall, 25 patients (9.6%; 9.9% early, 9.0% delayed) converted to secondary progressive multiple sclerosis. Disability remained low and stable with no significant difference between groups in Expanded Disability Status Scale score or MRI metrics. Paced Auditory Serial Addition Task-3 scores were better in the early treatment group (p = 0.0036 for treatment effect over 15 years). 66.3% of patients were still employed at Year 15 versus 74.7% at baseline. In conclusion, results 15 years from initial randomization support long-term benefits of early treatment with IFNB-1b.

• Keywords
• Clinically isolated syndrome, Immunotherapy, Interferon beta-1b, Multiple sclerosis,
• MeSH
• Demyelinating Diseases drug therapy   MeSH
• Adult MeSH
• Double-Blind Method MeSH
• Interferon beta-1b * therapeutic use   pharmacology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Follow-Up Studies MeSH
• Disease Progression MeSH
• Multiple Sclerosis * drug therapy   MeSH
• Treatment Outcome MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Randomized Controlled Trial MeSH
• Names of Substances
• Interferon beta-1b * MeSH

This review addresses current changes in the approach to treating patients with multiple sclerosis (MS). The widely practiced approach of utilizing agents with lower treatment efficacy (LETA) at onset with subsequent escalation has been challenged by new data suggesting that MS patients derive greater benefit when therapy is initiated with high-efficacy treatment agents (HETA). Several recent studies compared treatment efficacy and safety of early administration of HETA versus LETA. The results of randomized, double blind, phase III studies with LETA as a control arm and population-based larger and longer studies using propensity scoring, marginal structural modeling and weighted cumulative exposure analysis support the benefit of early treatment with HETA. Patients initiating their treatment with HETA, regardless of prognostic factors and MRI burden at baseline, showed significantly lower annualized relapse rate (ARR) and reduced disability progression in follow-up periods of up to 10-15 years. Moreover, the safety profile of recently approved HETA ameliorates concerns about off-target effects associated with a number of earlier high-efficacy drugs. Patient perception has also changed with an increasing preference for medication profiles that both improve symptoms and prevent disease progression. Accumulating data from randomized studies and the results of large population-based studies demonstrating short-term and longer-term patient benefits support the view that HETA should be more widely used. The adoption of early treatment with HETA capitalizes on a window of opportunity for anti-inflammatory drugs to maximally impact disease pathology and heralds a sea change in clinical practice toward pro-active management and away from a philosophy routed in generating clinical benefit as a consequence of treatment failure.

• Keywords
• Escalation therapy, High-efficacy drugs, Multiple sclerosis, Safety,
• MeSH
• Pharmaceutical Preparations MeSH
• Humans MeSH
• Randomized Controlled Trials as Topic MeSH
• Multiple Sclerosis, Relapsing-Remitting * drug therapy   MeSH
• Multiple Sclerosis * diagnostic imaging   drug therapy   MeSH
• Treatment Outcome MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Pharmaceutical Preparations MeSH

Disease-modifying therapies for relapsing multiple sclerosis reduce relapse rates by suppressing peripheral immune cells but have limited efficacy in progressive forms of the disease where cells in the central nervous system play a critical role. To our knowledge, alemtuzumab, fumarates (dimethyl, diroximel, and monomethyl), glatiramer acetates, interferons, mitoxantrone, natalizumab, ocrelizumab, ofatumumab, and teriflunomide are either limited to the periphery or insufficiently studied to confirm direct central nervous system effects in participants with multiple sclerosis. In contrast, cladribine and sphingosine 1-phosphate receptor modulators (fingolimod, ozanimod, ponesimod, and siponimod) are central nervous system-penetrant and could have beneficial direct central nervous system properties.

• Keywords
• central nervous system, cladribine, fingolimod hydrochloride, multiple sclerosis, ozanimod, ponesimod, siponimod, sphingosine 1 phosphate receptor modulators,
• MeSH
• Immunosuppressive Agents MeSH
• Cladribine MeSH
• Humans MeSH
• Central Nervous System Diseases * MeSH
• Multiple Sclerosis, Relapsing-Remitting * MeSH
• Multiple Sclerosis * drug therapy   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Names of Substances
• Immunosuppressive Agents MeSH
• Cladribine MeSH

INTRODUCTION: Prescribing guidance for disease-modifying treatment (DMT) in multiple sclerosis (MS) is centred on a clinical diagnosis of relapsing-remitting MS (RRMS). DMT prescription guidelines and monitoring vary across countries. Standardising the approach to diagnosis of disease course, for example, assigning RRMS or secondary progressive MS (SPMS) diagnoses, allows examination of the impact of health system characteristics on the stated clinical diagnosis and treatment access. METHODS: We analysed registry data from six cohorts in five countries (Czech Republic, Denmark, Germany, Sweden and United Kingdom) on patients with an initial diagnosis of RRMS. We standardised our approach utilising a pre-existing algorithm (DecisionTree, DT) to determine patient diagnoses of RRMS or secondary progressive MS (SPMS). We identified five global drivers of DMT prescribing: Provision, Availability, Funding, Monitoring and Audit, data were analysed against these concepts using meta-analysis and univariate meta-regression. RESULTS: In 64,235 patients, we found variations in DMT use between countries, with higher usage in RRMS and lower usage in SPMS, with correspondingly lower usage in the UK compared to other registers. Factors such as female gender (p = 0.041), increasing disability via Expanded Disability Status Scale (EDSS) score (p = 0.004), and the presence of monitoring (p = 0.029) in SPMS influenced the likelihood of receiving DMTs. Standardising the diagnosis revealed differences in reclassification rates from clinical RRMS to DT-SPMS, with Sweden having the lowest rate Sweden (Sweden 0.009, range: Denmark 0.103 - UK portal 0.311). Those with higher EDSS at index (p < 0.03) and female gender (p < 0.049) were more likely to be reclassified from RRMS to DT-SPMS. The study also explored the impact of diagnosis on DMT usage in clinical SPMS, finding that the prescribing environment and auditing practices affected access to treatment. DISCUSSION: This highlights the importance of a healthcare system's approach to verifying the clinical label of MS course in facilitating appropriate prescribing, with some flexibility allowed in uncertain cases to ensure continued access to treatment.

• Keywords
• big data, clinical audit, decision tree, disease registers, international collaboration, multiple sclerosis,
• Publication type
• Journal Article MeSH

Early intervention with high-efficacy disease-modifying therapy (HE DMT) may be the best strategy to delay irreversible neurological damage and progression of multiple sclerosis (MS). In European healthcare systems, however, patient access to HE DMTs in MS is often restricted to later stages of the disease due to restrictions in reimbursement despite broader regulatory labels. Although not every patient should be treated with HE DMTs at the initial stages of the disease, early and unrestricted access to HE DMTs with a positive benefit-risk profile and a reasonable value proposition will provide the freedom of choice for an appropriate treatment based on a shared decision between expert physicians and patients. This will further optimize outcomes and facilitate efficient resource allocation and sustainability in healthcare systems and society.

• Keywords
• Benefit–risk profile, Healthcare system, High-efficacy disease-modifying therapy, Multiple sclerosis, Pharmacoeconomics, Unrestricted access,
• MeSH
• Consensus MeSH
• Humans MeSH
• Multiple Sclerosis * drug therapy   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH