Scoping review of clinical decision support systems for multiple sclerosis management: Leveraging information technology and massive health data.

BACKGROUND AND PURPOSE: Multiple sclerosis (MS) is a complex autoimmune disease of the central nervous system, with numerous therapeutic options, but a lack of biomarkers to support a mechanistic approach to precision medicine. A computational approach to precision medicine could proceed from clinical decision support systems (CDSSs). They are digital tools aiming to empower physicians through the clinical applications of information technology and massive data. However, the process of their clinical development is still maturing; we aimed to review it in the field of MS. METHODS: For this scoping review, we screened systematically the PubMed database. We identified 24 articles reporting 14 CDSS projects and compared their technical and software development aspects. RESULTS: The projects position themselves in various contexts of usage with various algorithmic approaches: expert systems, CDSSs based on similar patients' data visualization, and model-based CDSSs implementing mathematical predictive models. So far, no project has completed its clinical development up to certification for clinical use with global release. Some CDSSs have been replaced at subsequent project iterations. The most advanced projects did not necessarily report every step of clinical development in a dedicated article (proof of concept, offline validation, refined prototype, live clinical evaluation, comparative prospective evaluation). They seek different software distribution options to integrate into health care: internal usage, "peer-to-peer," and marketing distribution. CONCLUSIONS: This review illustrates the potential of clinical applications of information technology and massive data to support MS management and helps clarify the roadmap for future projects as a multidisciplinary and multistep process.

Long-term clinical outcomes in patients with CIS treated with interferon beta-1b: results from the 15-year follow up of the BENEFIT trial.

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.

High-Efficacy Therapy Discontinuation vs Continuation in Patients 50 Years and Older With Nonactive MS.

Importance: A recent randomized clinical trial concluded that discontinuing medium-efficacy therapy might be a reasonable option for older patients with nonactive multiple sclerosis (MS), but there is a lack of data on discontinuing high-efficacy therapy (HET). In younger patients, the discontinuation of natalizumab and fingolimod is associated with a risk of rebound of disease activity. Objective: To determine whether discontinuing HET in patients 50 years and older with nonactive MS is associated with an increased risk of relapse compared with continuing HET. Design, Setting, and Participants: This observational cohort study used data from 38 referral centers from the French MS registry (Observatoire Français de la Sclérose en Plaques [OFSEP] database). Among 84704 patients in the database, data were extracted for 1857 patients 50 years and older with relapsing-remitting MS treated by HET and with no relapse or magnetic resonance imaging activity for at least 2 years. After verification of the medical records, 1620 patients were classified as having discontinued HET or having remained taking treatment and were matched 1:1 using a dynamic propensity score (including age, sex, disease phenotype, disability, treatment of interest, and time since last inflammatory activity). Patients were included from February 2008 to November 2021, with a mean (SD) follow-up of 5.1 (2.9) years. Data were extracted in June 2022. Exposures: Natalizumab, fingolimod, rituximab, and ocrelizumab. Main Outcomes and Measures: Time to first relapse. Results: Of 1620 included patients, 1175 (72.5%) were female, and the mean (SD) age was 54.7 (4.8) years. Among the 1452 in the HET continuation group and 168 in the HET discontinuation group, 154 patients in each group were matched using propensity scores (mean [SD] age, 57.7 [5.5] years; mean [SD] delay since the last inflammatory activity, 5.6 [3.8] years; mean [SD] follow-up duration after propensity score matching, 2.5 [2.1] years). Time to first relapse was significantly reduced in the HET discontinuation group compared with the HET continuation group (hazard ratio, 4.1; 95% CI, 2.0-8.5; P < .001) but differed between HETs, with a hazard ratio of 7.2 (95% CI, 2.1-24.5; P = .001) for natalizumab, 4.5 (95% CI, 1.3-15.5; P = .02) for fingolimod, and 1.1 (95% CI, 0.3-4.8; P = .85) for anti-CD20 therapy. Conclusion and Relevance: As in younger patients, in patients 50 years and older with nonactive MS, the risk of relapse increased significantly after stopping HETs that impact immune cell trafficking (natalizumab and fingolimod). There was no significant increase in risk after stopping HETs that deplete B-cells (anti-CD20 therapy). This result may inform decisions about stopping HETs in clinical practice.

Impact of automatic tools for detecting new lesions on therapeutic strategies offered to patients with MS by neurologists.

BACKGROUND: Automatic tools for detecting new lesions in patients with MS between two MRI scans are now available to clinicians. They have been assessed from the radiologist's point of view, but their impact on the therapeutic strategies that neurologists offer their patients has not yet been documented. OBJECTIVES: To compare neurologist's decisions according to whether a lesion detection support system had been used and describe variability between neurologists on decision-making for the same clinical cases. METHODS: We submitted 28 clinical cases associated with pairs of MRI images and radiological reports (produced by the same radiologist without vs. with the help of a system to detect new lesions) to 10 neurologists who regularly follow patients with MS. They examined each clinical case twice (without vs. with support system) in two sessions several weeks apart, and their patient management decisions were recorded. RESULTS: There was considerable variability between neurologists on decision-making (both with and without support system). When the support system had been used, neurologists more often made changes to patient management (75 % vs. 68 % of cases, p = 0.01) and spent significantly less time analyzing the clinical cases (249 s vs. 216 s, p == 3.10-4). CONCLUSION: The use of a lesion detection support system has an impact not only on radiologists' reports, but also on neurologists' subsequent decision-making. This observation constitutes another strong argument for promoting the wider use of such systems in clinical routine. However, despite their use, there is still considerable variability in decision-making across neurologists, which should encourage us to refine the guidelines.

Escalation Versus Induction/High-Efficacy Treatment Strategies for Relapsing Multiple Sclerosis: Which is Best for Patients?

After more than 2 decades of recommending an escalating strategy for the treatment of most patients with multiple sclerosis, there has recently been considerable interest in the use of high-efficacy therapies in the early stage of the disease. Early intervention with induction/high-efficacy disease-modifying therapy may have the best risk-benefit profile for patients with relapsing-remitting multiple sclerosis who are young and have active disease, numerous focal T2 lesions on spinal and brain magnetic resonance imaging, and no irreversible disability. Although we have no curative treatment, at least seven classes of high-efficacy drugs are available, with two main strategies. The first strategy involves the use of high-efficacy drugs (e.g., natalizumab, sphingosine 1-phosphate receptor modulators, or anti-CD20 drugs) to achieve sustained immunosuppression. These can be used as a first-line therapy in many countries. The second strategy entails the use of one of the induction drugs (short-term use of mitoxantrone, alemtuzumab, cladribine, or autologous hematopoietic stem cell transplant) that are mainly recommended as a second-line or third-line treatment in patients with very active or aggressive multiple sclerosis disease. Early sustained immunosuppression exposes patients to heightened risks of infection and cancer proportionate to cumulative exposure, and induction drugs expose patients to similar risks during the initial post-treatment period, although these risks decrease over time. Their initial potential safety risks should now be revisited, taking account of long-term data and some major changes in their regimens: natalizumab with the long-term monitoring of John Cunningham virus; use of monthly courses of mitoxantrone with maximum cumulative doses of 36-72 mg/m2, followed by a safer disease-modifying drug; cladribine with only 2-weekly treatment courses required in years 1 and 2 and no systematic treatment for the following 2 years; alemtuzumab, whose safety and clinical impacts have now been documented for more than 6 years after the last infusion; and autologous haematopoietic stem cell transplant, which dramatically reduces transplantation-related mortality with a new regimen and guidelines. Escalation and induction/high-efficacy treatments need rigorous magnetic resonance imaging monitoring. Monitoring over the first few years, using the MAGNIMS score or American Academy of Neurology guidelines, considerably improves prediction accuracy and facilitates the selection of patients with relapsing-remitting multiple sclerosis requiring aggressive treatment.

A plain language summary on assessing the long-term effectiveness of cladribine tablets in people living with relapsing multiple sclerosis: The CLASSIC-MS study.

WHAT IS THIS SUMMARY ABOUT?: Previous studies have shown that people living with multiple sclerosis (MS) treated with cladribine tablets have fewer relapses (where new symptoms occur or existing symptoms get worse for 24 hours or more) and delayed disability progression (slowing down of the disease getting worse). The CLASSIC-MS study looked at the long-term effectiveness of treatment with cladribine tablets in people living with MS who had taken part in the original CLARITY and CLARITY Extension clinical studies. WHAT WERE THE RESULTS?: Results showed that people treated with cladribine tablets maintained their mobility (the ability to move freely) for longer and experienced other positive effects long after their treatment ended, including being less likely to need further treatment for their MS. WHAT DO THE RESULTS MEAN?: The results obtained from CLASSIC-MS show that the benefits of taking cladribine tablets carry on even when patients stop taking the treatment.

Long-term follow-up of patients with relapsing multiple sclerosis from the CLARITY/CLARITY Extension cohort of CLASSIC-MS: An ambispective study.

BACKGROUND: CLASSIC-MS evaluated the long-term efficacy of cladribine tablets in patients with relapsing multiple sclerosis. OBJECTIVE: Report long-term mobility and disability beyond treatment courses received in CLARITY/CLARITY Extension. METHODS: This analysis represents CLASSIC-MS patients who participated in CLARITY with/without participation in CLARITY Extension, and received ⩾1 course of cladribine tablets or placebo (N = 435). Primary objective includes evaluation of long-term mobility (no wheelchair use in the 3 months prior to first visit in CLASSIC-MS and not bedridden at any time since last parent study dose (LPSD), i.e. Expanded Disability Status Scale (EDSS) score <7). Secondary objective includes long-term disability status (no use of an ambulatory device (EDSS < 6) at any time since LPSD). RESULTS: At CLASSIC-MS baseline, mean ± standard deviation EDSS score was 3.9 ± 2.1 and the median time since LPSD was 10.9 (range = 9.3-14.9) years. Cladribine tablets-exposed population: 90.6% (N = 394), including 160 patients who received a cumulative dose of 3.5 mg/kg over 2 years. Patients not using a wheelchair and not bedridden: exposed, 90.0%; unexposed, 77.8%. Patients with no use of an ambulatory device: exposed, 81.2%; unexposed, 75.6%. CONCLUSION: With a median 10.9 years' follow-up after CLARITY/CLARITY Extension, findings suggest the sustained long-term mobility and disability benefits of cladribine tablets.

Switching from natalizumab administration at the day hospital to administration at home. A 1 year prospective study of patient experience and quality of life in 30 consecutive patients with multiple sclerosis (TYSAD-35).

BACKGROUND: In the context of the COVID-19 pandemic, French health authorities allowed the home administration of natalizumab by a healthcare-at-home service. We evaluated the patients' perception of care quality following the transition from day-hospital to home natalizumab administration. METHODS: Thirty relapsing-remitting multiple sclerosis (MS) patients treated with natalizumab were prospectively evaluated for one year after changing onto a home treatment procedure, using MusiCare, the first MS-specific questionnaire to evaluate patient experience and MusiQol. A numerical rating scale score for satisfaction and a dedicated questionnaire concerning patient experience were completed after each infusion. The primary endpoint was the mean difference in MusiCare score between baseline and 12 months. RESULTS: From June 2020 to November 2021, 306 infusions were performed at home. Three patients withdrew from the study (one lost to follow-up and two preferred to return at the day hospital). No worsening of patient experience or quality of life was observed. The mean scores of the Musicare dimensions were higher at 12 months than at baseline, significantly for the "relationship with healthcare professionals" (p = 0.0203). The MusiQol global score remained stable but the coping and friendship dimensions were significantly better at M12 than at baseline (p = 0.0491 and p = 0.0478, respectively). The satisfaction questionnaire highlighted some pain during the infusions (21.8%) and contradictions between healthcare professionals (17.2%). The mean score for satisfaction with care was 9.1/10. No safety concerns were identified. CONCLUSION: The positive experience of patients with home natalizumab administration provides an important opportunity to improve the quality of patient care.

Discontinuation of second- versus first-line disease-modifying treatment in middle-aged patients with multiple sclerosis.

BACKGROUND AND PURPOSE: There has been scant research on the consequences of discontinuing second-line disease-modifying treatment (DMT) in middle-aged patients with multiple sclerosis (MS). The objective was therefore to examine the occurrence of focal inflammatory activity after the discontinuation of second versus first-line DMT in patients over 45 years. METHODS: Patients who had been treated for at least 6 months with second (natalizumab, fingolimod, anti CD20) or first-line DMT and who stopped their DMT were retrospectively included. Kaplan-Meier survival curves were used to study the occurrence of relapse and MRI activity according to the type of DMT stopped. Proportional hazard Cox models were calculated to identify factors associated with focal inflammatory activity. The annualized relapse rate was calculated under treatment and for every 3 months after DMT discontinuation. RESULTS: We included 232 patients (median age: 52.8 years), 49 of whom stopped second-line DMT. The probability of having a relapse within the year following discontinuation was 6% for first-line DMT, 9% for fingolimod and 43% for natalizumab. In multivariate analysis, the probability of relapse after DMT discontinuation was significantly increased with natalizumab compared to first-line DMT (HR = 3.24; 95% CI [1.52; 6.90]). A peak of relapse was observed at 0-3 months after stopping natalizumab or fingolimod. CONCLUSION: Our study suggests that the risk of inflammatory activity is greater after discontinuation of natalizumab compared to other DMT even in middle-aged patients. As for younger patients, natalizumab discontinuation should only be considered if there is an adequate substitution of a different therapy. .

Multiple sclerosis clinical decision support system based on projection to reference datasets.

OBJECTIVE: Multiple sclerosis (MS) is a multifactorial disease with increasingly complicated management. Our objective is to use on-demand computational power to address the challenges of dynamically managing MS. METHODS: A phase 3 clinical trial data (NCT00906399) were used to contextualize the medication efficacy of peg-interferon beta-1a vs placebo on patients with relapsing-remitting MS (RRMS). Using a set of reference patients (PORs), selected based on adequate features similar to those of an individual patient, we visualize disease activity by measuring the percentage of relapses, accumulation of new T2 lesions on MRI, and worsening EDSS during the clinical trial. RESULTS: We developed MS Vista, a functional prototype of clinical decision support system (CDSS), with a user-centered design and distributed infrastructure. MS Vista shows the medication efficacy of peginterferon beta-1a versus placebo for each individual patient with RRMS. In addition, MS Vista initiated the integration of a longitudinal magnetic resonance imaging (MRI) viewer and interactive dual physician-patient data display to facilitate communication. INTERPRETATION: The pioneer use of PORs for each individual patient enables personalized analytics sustaining the dialog between neurologists, patients and caregivers with quantified evidence.

Disease Reactivation After Cessation of Disease-Modifying Therapy in Patients With Relapsing-Remitting Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: To evaluate the rate of return of disease activity after cessation of multiple sclerosis (MS) disease-modifying therapy. METHODS: This was a retrospective cohort study from 2 large observational MS registries: MSBase and OFSEP. Patients with relapsing-remitting MS who had ceased a disease-modifying therapy and were followed up for the subsequent 12 months were included in the analysis. The primary study outcome was annualized relapse rate in the 12 months after disease-modifying therapy discontinuation stratified by patients who did, and did not, commence a subsequent therapy. The secondary endpoint was the predictors of first relapse and disability accumulation after treatment discontinuation. RESULTS: A total of 14,213 patients, with 18,029 eligible treatment discontinuation epochs, were identified for 7 therapies. Annualized rates of relapse (ARRs) started to increase 2 months after natalizumab cessation (month 2-4 ARR 0.47, 95% CI 0.43-0.51). Commencement of a subsequent therapy within 2-4 months reduced the magnitude of disease reactivation (mean ARR difference: 0.15, 0.08-0.22). After discontinuation of fingolimod, rates of relapse increased overall (month 1-2 ARR: 0.80, 0.70-0.89) and stabilized faster in patients who started a new therapy within 1-2 months (mean ARR difference: 0.14, -0.01 to 0.29). The magnitude of disease reactivation for other therapies was low but reduced further by commencement of another treatment 1-10 months after treatment discontinuation. Predictors of relapse were a higher relapse rate in the year before cessation, female sex, younger age, and higher EDSS score. Commencement of a subsequent therapy reduced both the risk of relapse (HR 0.76, 95% CI 0.72-0.81) and disability accumulation (0.73, 0.65-0.80). DISCUSSION: The rate of disease reactivation after treatment cessation differs among MS treatments, with the peaks of relapse activity ranging from 1 to 10 months in untreated cohorts that discontinued different therapies. These results suggest that untreated intervals should be minimized after stopping antitrafficking therapies (natalizumab and fingolimod). CLASSIFICATION OF EVIDENCE: This study provides Class III that disease reactivation occurs within months of discontinuation of MS disease-modifying therapies. The risk of disease activity is reduced by commencement of a subsequent therapy.

Disease modifying therapies and disease activity during pregnancy and postpartum in a contemporary cohort of relapsing Multiple Sclerosis patients.

BACKGROUND: In Multiple Sclerosis (MS) women, therapeutic management for pregnancy planning and during pregnancy still represents a challenge regarding timing of disease-modifying therapies (DMT) stop, risk of disease reactivation and potential fetal toxicity. The objective of this study was to describe disease activity during pregnancy and postpartum depending on treatment status before conception in women with MS. METHODS: 339 MS patients who have achieved a pregnancy between 2007 and 2017 were included. Women were classified according to their exposure to DMT in the 18 months period prior to pregnancy (untreated / first- / second/third-line treatment). RESULTS: 122 women were not exposed to DMT prior to conception, whereas 147 were exposed to first-line DMT and 70 to second/third line DMT (73% to natalizumab and 23% to fingolimod) before conception. In the first-line group, the ARR decreased from 0.39 during the year before conception to 0.21 during pregnancy, whereas it increased in the second/third-line group from 0.59 to 0.78. 47.1% of the second/third-line group faced at least one relapse during pregnancy and the time from conception to first relapse was significantly shorter in this group (p < 10-4). The risk of relapse during pregnancy and postpartum was associated with occurrence of pre-conception relapses and second/third line DMT exposure before pregnancy. CONCLUSION: Careful consideration should be given to natalizumab and fingolimod exposed patients before conception as they are at higher risk of reactivation of MS during pregnancy.

Severity of COVID19 infection among patients with multiple sclerosis treated with interferon-ß.

BACKGROUND: Interferon-ß, a disease-modifying therapy (DMT) for MS, may be associated with less severe COVID-19 in people with MS. RESULTS: Among 5,568 patients (83.4% confirmed COVID-19), interferon-treated patients had lower risk of severe COVID-19 compared to untreated, but not to glatiramer-acetate, dimethyl-fumarate, or pooled other DMTs. CONCLUSIONS: In comparison to other DMTs, we did not find evidence of protective effects of interferon-ß on the severity of COVID-19, though compared to the untreated, the course of COVID19 was milder among those on interferon-ß. This study does not support the use of interferon-ß as a treatment to reduce COVID-19 severity in MS.

Updated Results of the COVID-19 in MS Global Data Sharing Initiative: Anti-CD20 and Other Risk Factors Associated With COVID-19 Severity.

BACKGROUND AND OBJECTIVES: Certain demographic and clinical characteristics, including the use of some disease-modifying therapies (DMTs), are associated with severe acute respiratory syndrome coronavirus 2 infection severity in people with multiple sclerosis (MS). Comprehensive exploration of these relationships in large international samples is needed. METHODS: Clinician-reported demographic/clinical data from 27 countries were aggregated into a data set of 5,648 patients with suspected/confirmed coronavirus disease 2019 (COVID-19). COVID-19 severity outcomes (hospitalization, admission to intensive care unit [ICU], requiring artificial ventilation, and death) were assessed using multilevel mixed-effects ordered probit and logistic regression, adjusted for age, sex, disability, and MS phenotype. DMTs were individually compared with glatiramer acetate, and anti-CD20 DMTs with pooled other DMTs and with natalizumab. RESULTS: Of 5,648 patients, 922 (16.6%) with suspected and 4,646 (83.4%) with confirmed COVID-19 were included. Male sex, older age, progressive MS, and higher disability were associated with more severe COVID-19. Compared with glatiramer acetate, ocrelizumab and rituximab were associated with higher probabilities of hospitalization (4% [95% CI 1-7] and 7% [95% CI 4-11]), ICU/artificial ventilation (2% [95% CI 0-4] and 4% [95% CI 2-6]), and death (1% [95% CI 0-2] and 2% [95% CI 1-4]) (predicted marginal effects). Untreated patients had 5% (95% CI 2-8), 3% (95% CI 1-5), and 1% (95% CI 0-3) higher probabilities of the 3 respective levels of COVID-19 severity than glatiramer acetate. Compared with pooled other DMTs and with natalizumab, the associations of ocrelizumab and rituximab with COVID-19 severity were also more pronounced. All associations persisted/enhanced on restriction to confirmed COVID-19. DISCUSSION: Analyzing the largest international real-world data set of people with MS with suspected/confirmed COVID-19 confirms that the use of anti-CD20 medication (both ocrelizumab and rituximab), as well as male sex, older age, progressive MS, and higher disability are associated with more severe course of COVID-19.

Disease reactivation after fingolimod cessation in Multiple Sclerosis patients with pregnancy desire: A retrospective study.

Reactivation of Multiple Sclerosis (MS) activity has been described after fingolimod cessation. Because of its contra indication during pregnancy, switch towards lower efficacy treatments are frequent in MS patients with childbearing desire but expose them to a risk of disease reactivation. In this retrospective study including 44 women with MS, a significant increase of the median annualized relapse rate was found in the year following fingolimod discontinuation compared to the period before (p < 0.0001), and 57% of women experienced at least one relapse. When considering to start fingolimod, particular attention should be paid to women with a short-term pregnancy desire.

COPP-MS: COrticosteroids during the Post-Partum in relapsing Multiple Sclerosis patients.

BACKGROUND: No specific treatment has demonstrated its effectiveness to prevent post-partum relapses for multiple sclerosis (MS) women. OBJECTIVE: To assess the effectiveness of preventive high-dose corticosteroids in the post-partum period by comparing two strategies: (1) no preventive treatment and (2) standardized preventive treatment. METHODS: We selected five French Multiple Sclerosis centers using the same post-partum strategy for their patients-either high-dose steroids (treating centers TC) or no treatment (non-treating centers NTC). We included relapsing-remitting multiple sclerosis women who delivered between January 2007 and January 2017. Our primary outcomes were the time from delivery to first relapse, EDSS progression and MRI activity between patients of treating centers and non-treating centers, after propensity-score weighting. RESULTS: 350 patients were included (116 from treating centers, 234 from non-treating centers). For both groups, the annualized relapse rate decreased during pregnancy (0.28 in treating centers and 0.34 in non-treating centers during the third trimester) and increased during the first post-partum trimester (0.45 and 0.69, respectively) with 11% and 14% (NS) of patients facing at least one relapse, respectively. Our primary outcomes were not statistically different between both groups. CONCLUSION: This study provides class III evidence that systematic high-dose corticosteroids are not associated with a reduced inflammatory activity during the post-partum period in multiple sclerosis patients.

Disability Progression in Multiple Sclerosis Patients using Early First-line Treatments.

BACKGROUND: Therapeutic management of relapsing-remitting multiple sclerosis (RRMS) has evolved towards early treatment. The objective was to assess the impact of early treatment initiation on disability progression among RRMS first-line treated patients. METHODS: This study included all incident RRMS cases starting interferon or glatiramer acetate for the first time from 1996/01/01 to 2012/31/12 (N=5,279) from ten MS expert OFSEP centers (Observatoire Français de la Sclérose en Plaques). The delay from treatment start to attain an irreversible Expanded Disability Status Scale score of 3.0 were compared between "Early" group (N= 1,882; treated within 12 months following MS clinical onset) and "Later" group using propensity score weighted Kaplan-Meier methods, overall and stratified by age. RESULTS: Overall, the restricted mean time before reaching EDSS 3.0 (RMST) from treatment start was 11 years and two months for patients treated within the year following MS clinical onset and 10 years and seven months for patients treated later. Thus, early treated patients gained 7 months (95% CI: [4-11] months) in the time to reach EDSS 3.0 compared to patients treated later (treatment start delayed by 28 months). The difference in RMST was respectively six months (95% CI: [1-10] months) and 14 months (95% CI: [4-24] months) in the "≤40 years" age group and in the ">40 years" age group, in favour of early group. . CONCLUSIONS: Early treatment initiation resulted in a significant reduction of disability progression among patients with RRMS, and also among older patients.

The agenda of the global patient reported outcomes for multiple sclerosis (PROMS) initiative: Progresses and open questions.

On 12 September 2019, the global Patient Reported Outcome for Multiple Sclerosis (PROMS) Initiative was launched at the 35th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). The multi-stakeholder PROMS Initiative is jointly led by the European Charcot Foundation (ECF) and the Multiple Sclerosis International Federation (MSIF), with the Italian Multiple Sclerosis Society (AISM) acting as the lead agency for and on behalf of the global MSIF movement. The initiative has the ambitious mission to (i) maximize the impact of science with and of patient input on the life of people affected by MS, and (ii) to represent a unified view on Patient-Reported Outcomes for MS to people affected by MS, healthcare providers, regulatory agencies and Health Technologies Assessments agencies. Equipped with an innovative participatory governance of an international and interdisciplinary network of different stakeholders, PROMS has the potential to guide future breakthroughs in MS patient-focused research and care. In this paper we present the progresses of the global PROMS Initiative and discuss the open questions that we aim to address.

Comparative Effectiveness of Natalizumab Versus Anti-CD20 in Highly Active Relapsing-Remitting Multiple Sclerosis After Fingolimod Withdrawal.

In France, two therapeutic strategies can be offered after fingolimod (FNG) withdrawal to highly active relapsing-remitting multiple sclerosis (RRMS) patients: natalizumab (NTZ) or anti-CD20. We compared the effectiveness of these two strategies as a switch for FNG within the OFSEP database. The primary endpoint was the time to first relapse. Other outcomes were the relapse rates over 3-month periods, time to worsening the EDSS score, proportion of patients with worsened 24-month MRI, time to treatment discontinuation, and incidence rates of serious adverse events. The dynamics of event rates over time were modeled using multidimensional penalized splines, allowing the possibility to model the effects of covariates in a flexible way, considering non-linearity and interactions. A total of 740 patients were included (337 under anti-CD20 and 403 under NTZ). There was no difference between the two treatments regarding the dynamic of the first occurrence of relapse, with a monthly probability of 5.0% at initiation and 1.0% after 6 months. The rate of EDSS worsening increased in both groups until 6 months and then decreased. No difference in the proportion of patients with new T2 lesions at 24 months was observed. After 18 months of follow-up, a greater risk of NTZ discontinuation was found compared to anti-CD20. This study showed no difference between NTZ and anti-CD20 after the FNG switch regarding the clinical and radiological activity. The effect of these treatments was optimal after 6 months and there was more frequent discontinuation of NTZ after 18 months, probably mainly related to JC virus seroconversions.

Body mass index as a predictor of MS activity and progression among participants in BENEFIT.

BACKGROUND: There is a lack of studies on the association between obesity and conversion from a clinically isolated syndrome (CIS) to multiple sclerosis (MS). OBJECTIVE: The aim of this study was to determine whether obesity predicts disease activity and prognosis in patients with CIS. METHODS: Body mass index (BMI) at baseline was available for 464 patients with CIS in BENEFIT. Obesity was defined as BMI ⩾ 30 kg/m2 and normal weight as 18.5 ⩽ BMI < 25. Patients were followed up for 5 years clinically and by magnetic resonance imaging. Hazard of conversion to clinically definite (CDMS) or to 2001 McDonald criteria (MDMS) MS, annual rate of relapse, sustained progression on Expanded Disability Status Scale (EDSS), change in brain and lesion volume, and development of new brain lesions were evaluated. RESULTS: Obese individuals were 39% more likely to convert to MDMS (95% CI: 1.02-1.91, p = 0.04) and had a 59% (95% CI: 1.01-2.31, p = 0.03) higher rate of relapse than individuals with normal weight. No associations were observed between obesity and conversion to CDMS, sustained progression on EDSS or magnetic resonance imaging (MRI) outcomes, except for a larger reduction of brain volume in obese smokers as compared to normal weight smokers (-0.82%; 95% CI: -1.51 to -0.12, p = 0.02). CONCLUSION: Obesity was associated with faster conversion to MS (MDMS) and a higher relapse rate.