The OFSEP-HD cohort

The OFSEP-HD cohort is nested in the OFSEP cohort. Patient enrolment started on 10 July 2018 and ended on 11 September 2020 in 25 French MS centres. Individuals were eligible if they had (1) a diagnosis of MS according to the most recent criteria at entry into the HD cohort,24 (2) were ≥15 years old at inclusion, (3) had an MS diagnosis after the study start or, if MS onset occurred before the study start, had at least one visit every 2 years after follow-up in an MS centre with prospective OFSEP data collection; (4) had an irreversible Expanded Disability Status Scale (EDSS) score ≤7.0 (permanent use of a wheelchair) at inclusion in the study and (5) signed a written consent form. The criterion 3 for MS onset date allowed for mixing incident and prevalent cases, accelerating recruitment while benefiting from quality data collected during the OFSEP cohort follow-up, extending the possibility to fund the follow-up of included patients over time and increasing the probability to observe landmarks. Non-inclusion criteria were an inability to answer questionnaires and pregnancy at the time of inclusion (figure 1).

With a sample size of 2842 patients, a factor with a HR of 1.2 could be detected if the event rate was 30%, and one with a HR of 1.6 could be detected if the event rate was 5% (power=0.8; α risk=0.05; SD=0.5).25 We acknowledge that our power calculation does not account for multiple testing, as do other cohorts with many exploratory objectives.

This protocol is registered at ClinicalTrials.gov: NCT03603457.

The OFSEP cohort

The French OFSEP cohort is a nationwide systematic longitudinal study of individuals with MS followed in MS centres with more than 70 000 patient records collected in June 2018. The first objective was to provide a unique source of information on MS epidemiology, with a particular focus on pharmacoepidemiology of recently introduced DMTs. Since 2011, the centres have collected data with a standardised form as well as a minimal set of mandatory clinical data.23 They collect, organise and maintain the clinical database by using the MS-specific EDMUS software.26 In 2015, the OFSEP MRI working group published recommendations on the sequences to be used for regular brain and spinal cord MRI acquisitions of patients with MS,27 28 and standardised acquisition protocols have been disseminated. Pseudonymised MRI data are transferred to a centralised imaging resource centre, the Shanoir platform (http://shanoir.org). Moreover, biological samples are collected for a subsample of OFSEP patients and stored in a biobank.29

Multisource data collection

During the inclusion visit in OFSEP-HD, historical clinical data were collected from medical records if they were incomplete from the OFSEP database, including oligoclonal bands and IgG index from cerebrospinal fluid at diagnosis. The OFSEP-HD follow-up visits are annual, with a time window of ±2 months around the anniversary inclusion date. In case of detection of recent disease activity (see landmarks paragraph below), a new baseline assessment at this key step of the disease (rebaseline) will be done, which will lead to restarting the annual follow-up (figure 2). The rebaseline process is allowed only once for a patient.

Four main landmarks are considered, corresponding to four strategic times in the MS evolution: (1) the first visit when the diagnosis of MS is set; (2) the first visit when the diagnosis of progression (primary or secondary) is set; (3) any visit with recent disease activity, defined by the occurrence of a relapse and/or MRI activity detected with gadolinium enhancement in the past 3 months (or gadolinium-enhanced lesion in the 3 months after an annual visit) and (4) any visit with absence of disease activity in the past 5 years.

At the inclusion and annual OFSEP-HD follow-up visits, the following multisource data are collected. First, the investigators oversee the collection of sociodemographic data, geographic residence, geographic area of origin, neurological episodes, EDSS, DMTs (date of onset and stopping, reasons for stopping), serious adverse events (OFSEP minimal report form), standardised brain and whenever possible spinal cord MRI results following OFSEP recommendations for MRI acquisitions,27 28 and additional clinical evaluation with Time 25-Foot Walk, 9-Hole Peg Test30 and Computerised Speed Cognitive Test.31 They also collect brain MRI results obtained in one of the labelled centres using the OFSEP acquisition protocols in a 3-month period before or after the inclusion visit and in a 2-month period before or after the follow-up visit. This time window is necessary to not undermine the routine follow-up of the patient, but special attention will be paid to organise the MRI examinations as close as possible to the visits. Biological samples (blood, serum) were collected at inclusion for constitution of a biobank29 and to dose (1) biomarkers (neurofilament light chain (NFL), Tau, Glial fibrillar acidic protein (GFAP), ubiquitin C terminal hydrolase L1) with Simoa Human Neurology 4-Plex assay and every 2 years with 2-Plex (NFL, GFAP) of Quanterix, which detects subpicogram levels of biomarkers, a very sensitive (limit of 0.32 pg/mL) and reproducible (coefficient of variation in the 10% range) method, (2) vitamin D with mass spectrometry, which is very sensitive and reproducible and (3) genetic ancestry. When necessary, we will use a part of the historical OFSEP biological collection. Establishing such a biological collection will allow to assess other markers (eg, EBV status) and help validate new serum biomarkers of MS in the future (eg, other neuronal or glial markers, cholesterol, oxidative stress, cytokine profile, auto-antibodies) as well as persistent organic pollutants possibly involved in the progression of MS.

Second, patient self-reporting questionnaires will be used to assess PROs (see below).

Third, the OFSEP-HD cohort will be linked to the French Système national des données de santé (SNDS) claims database registering all data for reimbursed health prescriptions and hospital stays covered by the national health insurance system.2 32 Sick leave and disability status/pension will be obtained from the SNDS as will use of healthcare (specific to and apart from MS), and geographic location with related socioeconomic variables and access to care.

Clinical outcomes

These refer to physical disability commonly assessed with the EDSS33 and other parameters, such as activity and progression, as defined in the 2013 Lublin clinical classification.34 Clinical evaluations will be completed with more specific measures of physical and cognitive disability:

Disability is defined as irreversible when the assignment to a given score has been reached and persists for at least 6 months, excluding any transient worsening of disability related to relapses.36

MRI outcomes

These data represent surrogate markers of disease activity and progression. MRI annual acquisitions will conform to OFSEP recommendations for MRI standardised acquisitions in France.27 28 Because raw acquisitions will be available (3D FLAIR, 3D T1, diffusion images), many MRI measures will be assessable, in particular:

Patient-reported outcomes

These include the following questionnaires:

Combined outcomes

By considering both clinical and MRI data, combined outcomes allow for stratifying patients into active and progressive groups as defined by the last Lublin classification,34 in activity defined on clinical and/or MRI features and progression on clinical features only:

Potential prognostic factors

Factors with a potential prognostic value will be studied in two different sets. First, specific attention will be paid to sociodemographic and clinical determinants and biomarkers of the progression of disability. Such characteristics include age, sex, level of education, occupation, residency, initial relapse, clinical MS form (primary progressive, relapsing remitting and secondary progressive), past and current disease activity, DMTs and comorbidities including health behaviours (smoking, alcohol, body mass index, etc). Comorbidities are assessed using the Functional Comorbidity Index47 and the Charlson Comorbidity Index adapted for claims databases.48 To enrich prognostic models with potential predictors of disease evolution, questionnaires will be annually proposed.

Second, high efficacy classes of DMT and switches as well as off-label prescriptions are available since disease onset. Nine DMTs are currently available for relapsing remitting MS and secondary progressive MS with activity. These drugs include interferons, glatiramer acetate, teriflunomide, sphingosine 1-phosphate receptor modulators, fumarates, cladribine and five types of monoclonal antibodies.8 49

Findings to date

A cohort of 2842 individuals has been recruited from July 2018 to September 2020. Their characteristics are described in online supplemental table S1). They are 73.4% women, with mean (SD) age at inclusion 42.7 (11.6) years. Their mean age at onset was 31.7 (10.2) years and median disease duration was 8.8 (4.3–15.7) years. At inclusion, the mean EDSS was 2.4 (1.9) and the course of MS was a unique episode in 14.4%, relapsing remitting in 67.7%, secondary progressive in 11.9% and primary progressive in 6.0%. The mean annual relapse rate was 0.98 (0.80–1.19). The disease-modifying treatment received was highly effective therapy in 50.3%, moderately effective therapy in 30.7%, while 6.4% were naive of DMT and 12.5% had no current treatment. Landmarks at inclusion were documented by an MS diagnosis for less than 6 months in 4.4%, MS progression in the past 12 months in 1.2%, relapse or MRI activity in the past 3 months in 25,5% (with 369 missing values) and remission (NEDA 3) in the past 5 years in 10.7% (with 34 missing values).

We compared the characteristics of 2847 included and 16 239 non-included individuals among 19 806 eligible MS individuals, according to inclusion criteria, attending the 25 centres over the period. The data are presented in online supplemental table S2 and show that among eligible MS individuals, those included have less MRI activity in the past 3 months, an MS diagnosis for more than 6 months, a moderate EDSS and receive more highly effective therapy, with a significant heterogeneity of recruitment across MS centres.

A comparison of their characteristics at inclusion showed that individuals with missing data on clinical outcomes (22.4%), PROs (13.5%) and landmarks (19.2%) were older, with MS onset or MS diagnosed at older age, had slightly lower education, more progressive phenotype, higher EDSS score, and received less active treatment than those without missing data (online supplemental tables S3–S5).

Statistical analysis strategy

Several prognostic models will be developed and validated. The model development will be based on a training cohort consisting of a random selection of two-thirds of the centres. The above list of prognostic factors (ie, first, sociodemographic, clinical, imaging, biological variables and comorbidities and second, treatments and the four landmarks) will be considered as three blocks. The prognostic factors will be considered to achieve dynamic predictions50 of the following times to events: reaching irreversible EDSS scores of 4, 6 and 7; first relapse; disease progression; MRI outcomes; PROs (QoL), social consequences and combined outcomes of clinical and MRI data reflecting activity and disease progression.

To consider the longitudinal predictors up to the landmark time, we will adapt the methodology proposed by Devaux et al.51

According to data from the remaining one-third of centres in the external validation cohort, we will use several metrics to appraise the predictive capacities of the models. We will randomise centres and not individuals for learning and validation, because the latter strategy would have been considered as internal validation, questioning the generalisation of the results.52

In a stratified medicine perspective, we aim to develop stratified algorithms for medical decision-making for maximising the number of years without disease progression and with the best QoL, this last dimension depending on both the disease activity and the treatment adverse events. The knowledge gained will allow for a clear picture of the history of MS in the 2010–2020s and the various determinants of outcomes. This landmark approach will identify some prognostic factors that play a permanent role and others to be considered at some stages of the disease course for more appropriate decision-making for care, regardless of treatment. We will study the potential of the new classification of disease activity and progression to modify the prognostic classification of cases initially developed using the classical progressive relapse secondary progressive classification.

Economic analysis plan

Two types of economic analysis will be conducted: (1) a cost-of-illness analysis for identifying the current cost burden to society, together with the identification of the main cost drivers and (2) a cost-effectiveness analysis for exploring the efficiency of recent DMT treatments, namely biotherapies, compared with standard treatments. The effectiveness of new treatments for previously defined outcomes will be assessed after controlling for the prognostic information determined above.

We expect the findings of this research from the OFSEP-HD cohort to have an impact on MS diagnosed adult, with limited disability progression and preserved ambulatory ability, whatever the disease duration, potentially eligible to DMT, and followed in a French expert centre, so representing a large proportion of French MS ambulatory people.

Collaboration

Scientific collaboration based on data sharing with other teams in the scientific community will be open and encouraged, in line with the funding body policy. Any scientific project will be examined by the OFSEP scientific committee, also in consideration of technical feasibility and full respect of general data protection rules.