Abstract

Even prior to the introduction of RIS criteria, longitudinal clinical data from individuals with incidentally identified T2 lesions suggestive of multiple sclerosis (MS) were described. Healthy individuals who do not exhibit signs of neurological dysfunction commonly have brain MRI studies performed for a reason other than an evaluation for MS that reveal unexpected anomalies highly suggestive of demyelinating plaques given their size, location, and morphology. These healthy subjects lack symptomatology suggestive of MS and fulfill formal criteria for the radiologically isolated syndrome (RIS), a recently described MS subtype that expands upon the phenotype of at-risk individuals for future demyelinating events. A formal description of RIS was first introduced in 2009 by Okuda et al., to define this relevant cohort of individuals who are at risk for future demyelinating events.

In European or North American observational studies, the authors have found that up to 30-45% of patients presenting with a RIS will present clinical progression. The presence of asymptomatic lesions in the cervical cord provides an increased risk of progression, either to a relapsing or to progressive MS.

The consortium studying epidemiology of RIS worldwide (RISC) presented their first retrospective cohort. The 5-year observed conversion rate to the first clinical event was 34%. Of converters within this time period, 9.6% fulfilled criteria for primary progressive MS. In the multivariate model, age, sex (male), and lesions within the cervical or thoracic spinal cord were identified as significant predictors for the development of a first clinical event. In the 10-year update, more than half of the RIS have converted with 4 risk factors at baseline which are young age, CSF positivity, Spinal cord, and infratentorial lesions.

Despite advancements in the characterization of RIS subjects and in our understanding of risk factors for initial symptom development, the natural course of such cases and risk-profiles for a seminal neurological event, from prospectively acquired data, remain unclear. Prospective studies are mandatory to increase our knowledge about these asymptomatic patients. Many experts groups in the USA, Europe, and South America have proposed guidelines to follow the RIS subjects. The recommendation is not to treat off label these subjects as 2 phases 3 studies are ongoing in the USA and Europe with dimethylfumarate and teriflunomide.

Abstract

Even prior to the introduction of RIS criteria, longitudinal clinical data from individuals with incidentally identified T2 lesions suggestive of multiple sclerosis (MS) were described. Healthy individuals who do not exhibit signs of neurological dysfunction commonly have brain MRI studies performed for a reason other than an evaluation for MS that reveal unexpected anomalies highly suggestive of demyelinating plaques given their size, location, and morphology. These healthy subjects lack symptomatology suggestive of MS and fulfill formal criteria for the radiologically isolated syndrome (RIS), a recently described MS subtype that expands upon the phenotype of at-risk individuals for future demyelinating events. A formal description of RIS was first introduced in 2009 by Okuda et al., to define this relevant cohort of individuals who are at risk for future demyelinating events.

In European or North American observational studies, the authors have found that up to 30-45% of patients presenting with a RIS will present clinical progression. The presence of asymptomatic lesions in the cervical cord provides an increased risk of progression, either to a relapsing or to progressive MS.

The consortium studying epidemiology of RIS worldwide (RISC) presented their first retrospective cohort. The 5-year observed conversion rate to the first clinical event was 34%. Of converters within this time period, 9.6% fulfilled criteria for primary progressive MS. In the multivariate model, age, sex (male), and lesions within the cervical or thoracic spinal cord were identified as significant predictors for the development of a first clinical event. In the 10-year update, more than half of the RIS have converted with 4 risk factors at baseline which are young age, CSF positivity, Spinal cord, and infratentorial lesions.

Despite advancements in the characterization of RIS subjects and in our understanding of risk factors for initial symptom development, the natural course of such cases and risk-profiles for a seminal neurological event, from prospectively acquired data, remain unclear. Prospective studies are mandatory to increase our knowledge about these asymptomatic patients. Many experts groups in the USA, Europe, and South America have proposed guidelines to follow the RIS subjects. The recommendation is not to treat off label these subjects as 2 phases 3 studies are ongoing in the USA and Europe with dimethylfumarate and teriflunomide.

Abstract

Even prior to the introduction of RIS criteria, longitudinal clinical data from individuals with incidentally identified T2 lesions suggestive of multiple sclerosis (MS) were described. Healthy individuals who do not exhibit signs of neurological dysfunction commonly have brain MRI studies performed for a reason other than an evaluation for MS that reveal unexpected anomalies highly suggestive of demyelinating plaques given their size, location, and morphology. These healthy subjects lack symptomatology suggestive of MS and fulfill formal criteria for the radiologically isolated syndrome (RIS), a recently described MS subtype that expands upon the phenotype of at-risk individuals for future demyelinating events. A formal description of RIS was first introduced in 2009 by Okuda et al., to define this relevant cohort of individuals who are at risk for future demyelinating events.

In European or North American observational studies, the authors have found that up to 30-45% of patients presenting with a RIS will present clinical progression. The presence of asymptomatic lesions in the cervical cord provides an increased risk of progression, either to a relapsing or to progressive MS.

The consortium studying epidemiology of RIS worldwide (RISC) presented their first retrospective cohort. The 5-year observed conversion rate to the first clinical event was 34%. Of converters within this time period, 9.6% fulfilled criteria for primary progressive MS. In the multivariate model, age, sex (male), and lesions within the cervical or thoracic spinal cord were identified as significant predictors for the development of a first clinical event. In the 10-year update, more than half of the RIS have converted with 4 risk factors at baseline which are young age, CSF positivity, Spinal cord, and infratentorial lesions.

Despite advancements in the characterization of RIS subjects and in our understanding of risk factors for initial symptom development, the natural course of such cases and risk-profiles for a seminal neurological event, from prospectively acquired data, remain unclear. Prospective studies are mandatory to increase our knowledge about these asymptomatic patients. Many experts groups in the USA, Europe, and South America have proposed guidelines to follow the RIS subjects. The recommendation is not to treat off label these subjects as 2 phases 3 studies are ongoing in the USA and Europe with dimethylfumarate and teriflunomide.

Background

Radiologically isolated syndrome (RIS) is defined by the incidental finding of MRI lesions suggestive of multiple sclerosis in subjects with a normal neurological examination. Some studies suggested that the use of wearables could unveil infra-clinical differences between RIS subjects and healthy controls (HC).

Objectives

To demonstrate that digital biomarkers collected by a smartphone application can distinguish healthy controls (HC) from subjects with radiologically isolated syndrome (RIS).

Methods

We created a mobile app called MS Screen Test (MSST) that contains:

- Finger tapping speed test: during this task, we measure the mean tapping speed for the dominant hand and the non dominant hand

- Level test: the subject is asked to tilt the phone to move a ball inside a target, then maintain it inside the target for 10 seconds. We measure the required time to bring the ball to the target, then the proportion of time during which the ball is maintained inside the target

- Low contrast vision (LCV) test: letters with varying contrast randomly appearing on the screen. The subject has to tap on the screen each time a letter is seen. The number of good answers is collected

- Cognition test: letters or digits randomly appear on the screen. The subject has to tap on the screen only if a letter is seen. The mean tap latency in milliseconds is collected as well as bad answers

A cohort of HC and RIS subjects were evaluated to compare performances on MSST.

Results

60 HC and 16 RIS subjects were prospectively included (F/M 3.15, mean age 41.6 yrs)

Compared to HC, RIS subjects had a lower tapping speed on both dominant (5.6 Hz vs 6.5 Hz, p=0.001) and non dominant hand (5.1 Hz vs 5.6 Hz, p=0.04), fewer detected letters on the LCV test (10 vs 13, p=0.001) and a higher latency of response on the cognitive test (731 ms vs 599 ms, p<0.0001).

On the level test, the time during which the ball was maintained is the target was shorter for RIS subjects (3 sec vs 4.9 sec, p=0.05).

Conclusions

Our study confirms that digital biomarkers collected by a smartphone can unveil differences between HC and subjects at a presymptomatic stage of MS.

It would be relevant to evaluate whether those biomarkers could predict the risk of conversion to multiple sclerosis, as well as to evaluate their potential predictive value in early diagnosed MS patients

Background

Therapeutic options are growing for active RRMS patients, however, few prospective studies are available to compare the efficacy of those treatments. Best Escalation Strategy in MS (BEST MS) started in France in 2013 when natalizumab (NTZ) and fingolimod (FTY) were the two most employed second-line therapies in active RRMS.

Objectives

To compare the efficacy between natalizumab (NTZ) and fingolimod (FTY) in active relapsing-remitting multiple sclerosis (RRMS).

Methods

BEST-MS is a French prospective multicentric study.

Patients with active RRMS (defined as at least 1 relapse in the last 12 months on a well-conducted 1^st line treatment with at least 9 T2 hyperintensities on MRI, OR at least 2 relapses in the last 12 months with evidence of active disease on MRI for naïve patients) were enrolled to be treated either with NTZ or FTY. Treatments choice was at the discretion of the physician.

Relapses, EDSS and brain MRI were collected at baseline and at 12 months.

The main outcome measure was the proportion of patients reaching No Evidence of Disease Activity (NEDA) at 12 months, defined as the absence of relapses, absence of new T2 lesions, absence of new gadolinium enhancing lesions and a stable EDSS score.

Results

230 patients were included (age: 38.2 yrs, F/M: 3.1, FTY: 117, NTZ: 113). There was no statistical difference between groups regarding baseline characteristics.

Treatment drop out rate was higher in FTY group (22% vs 12%, p<0.0001) and most of thoses cases were related to a lack of efficacy.

At M12, 43% of patients treated with NTZ reached NEDA versus 27% in the FTY group (p=0.04)

NTZ indicated a better efficacy regarding new T2 lesions (0.7 vs 1.4, p=0.01) and gadolinium enhancing lesions (0.03 vs 0.5, p<0.0001).

Relapse rate (ARR) was lower in NTZ group (0.2 vs 0.27, p = 0.04), even if most relapses occurred during the first 4 months of treatment in both groups.

Conclusions

NTZ showed higher efficacy than FTY on MRI in active RRMS patients. ARR was also lower in favor of NTZ, but most relapses occurred early. However, the rate of drop out was higher for patients treated with FTY.

Background

At any time in multiple sclerosis (MS) management, a disease-modifying therapy (DMT) stop, restart or change can occur. In PRO-MSACTIVE (NCT03589105), an open-label, single-arm, phase IV study designed to evaluate the efficacy, safety and impact of ocrelizumab on patient reported outcomes in patients with active relapsing MS (RMS), every patient’s treatment history was gathered.

Objectives

To describe the therapeutic management of French patients with active RMS (relapsing-remitting [RRMS] and secondary progressive [SPMS]), as reported at baseline, prior to the first ocrelizumab infusion (IV OCR).

Methods

PRO-MSACTIVE is being conducted in France (46 active centers) in patients with active RMS, ≥18 years old, naïve or pretreated with DMT. Washout periods between the last DMT taken by the patient and baseline IV OCR were pre-specified. For each patient, all previous DMTs were collected during the screening period, ≤4 weeks prior to baseline.

Results

Treatment history was documented for the 422 enrolled patients: 376 RRMS and 46 SPMS. Most (74.9%) had at least one previous DMT prior to the first IV OCR: 73.9% for RRMS and 82.6% for SPMS patients. The longest therapeutic sequence includes 8 DMTs prior to the first IV OCR. The most frequent previous DMTs were β interferons and assimilated products (IFN-AP) (51.4% all patients, 49.2% RRMS, 69.6% SPMS); selective oral immunosuppressants (30.8% all patients, 30.6% RRMS, 32.6% SPMS; mainly fingolimod); and teriflunomide (24.2% all patients, 24.5% RRMS, 21.7% SPMS). IFN-AP ranked first among the older DMTs (46.5% all patients, 45.0% RRMS, 58.7% SPMS). Mean time (standard deviation, SD) from the oldest DMT to the first IV OCR was 6.55 yrs (5.44) for RRMS patients, and 14.20 yrs (8.46) for SPMS patients. The most recent DMTs prior to IV OCR were fingolimod (22.8% all patients, 23.7% RRMS, 15.2% SPMS); dimethyl fumarate (14.7% all patients, 15.7% RRMS, 6.5% SPMS); teriflunomide (14.5% all patients, 14.6% RRMS, 13.0% SPMS); IFN-AP (14.0% all patients, 14.1% RRMS, 13.0% SPMS); and natalizumab (4.3% all patients, 4.5% RRMS, 2.2% SPMS). Mean time (SD) from the most recent DMT to the first IV OCR was 2.65 yrs (2.12) for RRMS patients and 3.01 yrs (2.85) for SPMS patients.

Conclusions

Treatment history with DMTs prior to the first IV OCR is well characterized in the PRO-MSACTIVE study. These data permit a better understanding of the therapeutic strategies in RMS patients in current medical practice.

Background

Yellow fever vaccine (YFV) is mandatory for travel in areas where yellow fever is endemic, but is not authorized for multiple sclerosis (MS) patients because of the potential risk of post-vaccine relapses. However, this recommendation is only based on a single study including 7 patients.

Objectives

The aim of the study is to assess the risk of worsening in relapsing remitting (RR) MS after YFV.

The primary objective was to compare the risk of relapse, during the 12 months after the YFV between exposed and non-exposed subjects. The secondary objectives were: (i) to assess the time to first relapse after YFV, using Kaplan-Meier curves. Hazard Ratio (HR) was estimated by an adjusted Cox model for EDSS score and for DMT at the time of YFV (ii) to compare the disability progression and the disease form 12 months after YFV, and at the end of the follow-up.

Methods

This is a non-interventional observational retrospective, exposed/non-exposed cohort study, nested in the French national cohort including MS patients. Exposed RR-MS patients received one subcutaneous dose of YFV. Each exposed subject was matched to 3 RR-MS non-exposed to YFV. The matching criteria were: age, sex and annualized relapse rate (ARR) for the year before vaccination. The risk of relapse during the 12 months after the YFV was compared between exposed and non-exposed subjects. The time to first relapse after YFV was assessed using Kaplan Meier curves; Hazard Ratio (HR) was estimated by an adjusted Cox model for EDSS score and for disease modifying therapy at time of YFV. The disability progression 12 months after the YFV was compared between exposed and non-exposed subjects.

Results

128 RR MS according to McDonald Criteria 2017 (32 exposed/96 non-exposed) were included. The ARR the year after YFV did not differ between exposed: 0.233 (0.430) and non-exposed subjects: 0.213 (0.511) (p=0.84). Time to first relapse was not different between the 2 survival curves (adjusted HR, 1.33; 95% CI 0.53-3.30, p=0.54). The disability progression over the year following YFV did not differ between exposed and non-exposed subjects (p=0.83).

Conclusions

YF vaccine, a live attenuated vaccine which is very effective, is required to enter the territory of endemic areas. French and US recommendations for immunization in MS concluded that « There is insufficient data in the literature to conclude on the potential risks related to yellow fever vaccine because studies are either lacking or insufficiently powered ».These results show that YFV doesn’t worsen RR-MS, and suggest that non-immunosuppressed RR-MS patients travelling to endemic areas for professional or personal reasons could be vaccinated against YF.

Background

At any time in multiple sclerosis (MS) management, a disease-modifying therapy (DMT) stop, restart or change can occur. In PRO-MSACTIVE (NCT03589105), an open-label, single-arm, phase IV study designed to evaluate the efficacy, safety and impact of ocrelizumab on patient reported outcomes in patients with active relapsing MS (RMS), every patient’s treatment history was gathered.

Objectives

To describe the therapeutic management of French patients with active RMS (relapsing-remitting [RRMS] and secondary progressive [SPMS]), as reported at baseline, prior to the first ocrelizumab infusion (IV OCR).

Methods

PRO-MSACTIVE is being conducted in France (46 active centers) in patients with active RMS, ≥18 years old, naïve or pretreated with DMT. Washout periods between the last DMT taken by the patient and baseline IV OCR were pre-specified. For each patient, all previous DMTs were collected during the screening period, ≤4 weeks prior to baseline.

Results

Treatment history was documented for the 422 enrolled patients: 376 RRMS and 46 SPMS. Most (74.9%) had at least one previous DMT prior to the first IV OCR: 73.9% for RRMS and 82.6% for SPMS patients. The longest therapeutic sequence includes 8 DMTs prior to the first IV OCR. The most frequent previous DMTs were β interferons and assimilated products (IFN-AP) (51.4% all patients, 49.2% RRMS, 69.6% SPMS); selective oral immunosuppressants (30.8% all patients, 30.6% RRMS, 32.6% SPMS; mainly fingolimod); and teriflunomide (24.2% all patients, 24.5% RRMS, 21.7% SPMS). IFN-AP ranked first among the older DMTs (46.5% all patients, 45.0% RRMS, 58.7% SPMS). Mean time (standard deviation, SD) from the oldest DMT to the first IV OCR was 6.55 yrs (5.44) for RRMS patients, and 14.20 yrs (8.46) for SPMS patients. The most recent DMTs prior to IV OCR were fingolimod (22.8% all patients, 23.7% RRMS, 15.2% SPMS); dimethyl fumarate (14.7% all patients, 15.7% RRMS, 6.5% SPMS); teriflunomide (14.5% all patients, 14.6% RRMS, 13.0% SPMS); IFN-AP (14.0% all patients, 14.1% RRMS, 13.0% SPMS); and natalizumab (4.3% all patients, 4.5% RRMS, 2.2% SPMS). Mean time (SD) from the most recent DMT to the first IV OCR was 2.65 yrs (2.12) for RRMS patients and 3.01 yrs (2.85) for SPMS patients.

Conclusions

Treatment history with DMTs prior to the first IV OCR is well characterized in the PRO-MSACTIVE study. These data permit a better understanding of the therapeutic strategies in RMS patients in current medical practice.