Long-Term Management and Therapeutic Sequencing for Patients with Relapsing Multiple Sclerosis in France: A Vignette Study

This was a randomized clinical vignette survey, based on fictional but realistic clinical scenarios, established with the support of a clinical scientific committee of neurologists experienced in the management of MS in France. The objectives of the study were to describe the long-term therapeutic management of RMS by specialist physicians in France and to quantify their responses to different therapeutic challenges as a patient’s RMS progresses and evolves over time.

The case vignettes comprised a range of six realistic, fictional clinical cases which differed in terms of the level of MS disease activity, prior MS treatment (if any), comorbidities, demographic details and lifestyle aspirations. Three patients were naïve to DMT and had active or highly active MS, and three had switched from a platform or high-efficacy DMT. The case vignettes were constructed as clinical cases that the scientific steering committee considered, on the basis of their own clinical experience, to be sufficiently detailed to enable the physician to visualise the patient. All patient cases included a brief description of each patient's sociodemographic data, followed by clinical, aetiological, historical, and therapeutic information.

Table 1 summarises the principal features of these cases as presented during the first visit. All cases were relatively young (24–42 y), with relatively minor signs of disability (EDSS 0–2). Cases 1–3 were DMT-naïve, following a new or recent diagnosis of RMS. Two of these were considered qualitatively to have “highly active” MS, based on clinical and radiologic presentations, while the other had a less severe presentation and was considered to have “active” RMS. These definitions of MS disease activity were applied arbitrarily by the Scientific Committee, as there is no consensus definition of active versus highly active RMS (see Discussion). The highly active cases in our study had > 2 recent MRI lesions at presentation (Cases 2 and 3) or were already receiving a high-efficacy DMT (Case 6).

All three DMT-naïve cases presented with a need to control their MS disease activity. The other three cases had already received one DMT [Cases 4 (platform therapy) and 6 (anti-CD20)] or two DMTs (Case 5, two platform therapies). Cases 4 and 6 had well-controlled MS disease activity and presented with potentially treatment-limiting side-effects, while Case 5 presented with breakthrough MS disease activity (Table 1). Three cases (2, 5 and 6) tested positive for John Cunningham Virus (JCV+), which is consistent with observations that about half of the general RMS population in France are JCV+ in real-life clinical practice [7]. Two of the four female cases had short-to-medium plans to become pregnant.

This non-interventional, multicentre study was conducted in France from April to June 2024. The methodology involved presenting the case vignettes to the participating physicians: a questionnaire explored the physicians’ therapeutic decisions for each case. Participating physicians contributed to the study anonymously and voluntarily, without compensation. The participating physicians first completed a socio-demographic questionnaire which collected information about their clinical practice, including type and region of practice, their age, and their experience in managing MS. Each participating physician then reviewed four randomly selected cases, which the scientific steering committee considered to be a reasonable maximum workload. They then completed a questionnaire for each via a chatbot—a conversational agent enabling text-based interactions. The chatbot was designed and managed by FAST4 (Montpellier, France), a Clinical Research Organization, on behalf of the study sponsor, Merck Santé S.A.S., Lyon, France, an affiliate of Merck KGaA. Each case vignette was presented the same number of times. Case reviews required approximately 15 min of the physicians’ time, during which they indicated their preference for their choice of subsequent DMT.

Treatment choices were platform therapies, anti-trafficking agents (S1P modulators, natalizumab), anti-CD20 agents, or immune reconstitution therapy (effectively restricted to cladribine tablets [CladT]: mitoxantrone and autologous hematopoietic stem cell transplantation [aHSCT] could be categorized under “other” treatment options, while alemtuzumab is not reimbursed in France and is therefore rarely used [8]). Physicians provided reasons for their decisions, selected from a pre-prepared list devised by the Steering Committee.

Within each case vignette, the hypothetical patient visited their physician three times, with each visit prompted by a change in their MS-related or personal status. The progress of the interaction with the chatbot depended on the choices made by the physician at the first visit. Specifically, “disruptive events” were applied to the disease course of the case after the first visit: these related to changes in MS disease activity, tolerability or adherence issues that were relevant to the treatment being received at the time, or (for the female cases) a newly-expressed desire to become pregnant. The likelihood of each disruptive event that prompted visits reflected the likelihood of it occurring in real clinical practice, according to the experience of the Scientific Steering Committee. For example, unacceptable MS disease activity is a common finding in people with MS starting a platform DMT as their first pharmacologic intervention: for cases where the physician selected “platform therapy” for Visit 1, four of five (80%) of these would return for Visit 2 prompted by appearance of MS disease activity to reflect the real-life situation. The remaining 20% of cases reported adherence issues at Visit 2, another common issue with these treatments. Similar choices and subsequent clinical consequences applied at the second visit. The disruptive events and the likelihood of them appearing at each hypothetical visit are described briefly in Table 2 and in more detail in Online Supplementary Table 1.

Physicians recorded whether or not they wished to change the treatment, along with reasons for this, when presented with the evolving scenarios described above. Demographic and practice details of physicians were also recorded (age, region of practice, type of practice, number of people with MS seen each month).

The analysis was performed by a Clinical Research Organisation (FAST4). Data are described using descriptive statistics without formal significance testing. Sankey diagrams were used to depict changes in the use of different treatment strategies over time in two pooled groups of cases, representing “active” or “highly active” MS, as defined by the clinical steering committee (see Discussion).

With regard to a power calculation, It was calculated that 105 physicians assessing a total of 420 case vignettes would allow estimates with a half-width of the 95% confidence interval varying from 3% for a percentage of 10% (or 90%) to 5% for a percentage of 50%.

This study used fictional cases and does not fall within the scope of Articles L.1121–1 and following of the French Public Health Code. Given the nature of the study and the absence of real patient data, the protocol did not require submission to an Institutional Review Board (IRB) or Ethics Committees for approval. Therefore, IRB approval was not required.

All participants were informed of the study objectives during recruitment phase. This communication was integral to ensuring that participants understood the purpose and significance of the study. Also, participants were made aware at this time that the results of the study would be published. Participants agreed to participate by providing verbal consent during the recruitment phase and were informed that they could withdraw from the study at any time without any consequences, ensuring their autonomy and comfort throughout the process. The independence of participants was verified as they completed the questionnaire autonomously on their personal devices, including phones, tablets, or computers, thus ensuring that their responses were not influenced by external factors. The protection of individuals’ data was maintained rigorously in accordance with the guidelines specified in the Information Security and Privacy Policy (ISSP). Detailed information regarding these protocols can be provided upon request.

A total of 425 case vignettes were presented to a total of 111 participating physicians, all practising neurologists (Table 3); 104 (93.7%) of the participating physicians who started the study evaluated all four vignettes. The participating physicians demonstrated a broad distribution of ages with substantial proportions of younger physicians (62% were aged < 50 years); in addition, 73% were public hospital-based (university or general hospitals), 18% were in private practice, and the remaining 9% had a mixed practice. Only 15% reported seeing a fewer than 5 people with MS per month, 62% treated > 10 people with MS each month, and almost half (41%) treated > 20 such patients each month. The geographical distribution of participating physicians was representative of the distribution of neurologists in mainland France (data not shown).

After Visit 1, management decisions were made according to the changes in patients’ status (disruptive events, described above). Figures 1 and 2 show Sankey diagrams for all cases with active MS (Cases 1, 4 and 5) or highly active MS (Cases 2, 3 and 6), respectively.

The majority of the cases with active MS disease (patient journeys based on cases 1, 4 and 5, with 208 cases in total; Table 1) had been receiving platform therapy prior to their first visit in our study (128/208, 62%), with the remaining 80 cases (38%) being naïve to DMT (Fig. 1). The most usual change in treatment after a disruptive event was an escalation strategy involving a switch to a higher-efficacy DMT, likely for active MS disease. Only 27% received a platform DMT after Visit 1 (20% of the prior platform therapy group stayed on this treatment and 39% of those without prior DMT group were started on platform therapy). Only a single case remained on platform therapy after Visit 1 when the disruptive event was MS disease activity, compared with 19% remaining on platform therapy when the disruptive event was side-effects. A low level of switching to platform therapies occurred throughout, up to 5 cases receiving this therapy at any given Visit.

Of note, most of the highly active MS cases 2, 3 and 6 (total n = 217; Table 1) who entered the study without DMT treatment received a high-efficacy DMT as their first pharmacologic therapy (80%). This was also seen in cases with highly active MS (patient journeys based on cases 2, 3 and 6), where only 13% of previously DMT-naïve patients received a platform therapy after the first visit [anti-CD20 agents were used most commonly here (32%) followed by CladT (25%)]. About half of cases switched from anti-CD20 due to side-effects received CladT after Visit 1 (52%, in Case 6), with 34% remaining on anti-CD20 (2–8% of these patients were switched to another DMT).

Overall, the highest use of CladT occurred after the second visit for active MS (52% of all cases; Fig. 1) and highly active MS (55% of all cases; Fig. 2): this was due to a low rate of switching away from this treatment after the previous visit, together with accumulation of switches from all of the other treatments. Corresponding proportions using anti-CD20 at Visit 2 were 24% for active MS and 34% for highly active MS. Similarly, the majority of cases in either group ended the study (Visit 3) receiving either CladT or and anti-CD20 (41% vs. 35%, respectively for active cases and 45% vs. 26%, respectively, for highly active cases). By the end of the study, 6% of active cases and 10% of highly active cases were receiving “other” treatments, e.g. mitoxantrone or aHSCT.

MS disease activity was the most commonly stated driver of prescribing decisions in most scenarios. This was true for all DMTs at Visit 1 (except for S1P inhibitors, which had only three cases) and for all DMTs at Visits 3 and 5. Family planning was an important consideration for CladT (71% of participating physicians rated this as an important factor influencing the treatment decision). Scenarios where other factors were at least as important than MS disease activity were: Case 2—family planning for CladT (92%) and platform therapies (92%); Case 4—JCV status for natalizumab for Case 4 (100%); Case 5—JCV status for platform therapies (100%); Case 6—age for platform therapies (100%) or JCV status inhibitors for S1P inhibitors (100%), though again, only three or fewer case vignettes were represented for Case 6. All ratings driving treatment decisions by participating physicians are shown in Online Supplementary Table 2.

We recruited a broad selection of participating physicians (all neurologists) who were distributed widely by age, regions of the country and types of institutions. Almost all (94%) of physicians with demographic data completed all the cases. This engagement and diversity was a strength of the study, as it facilitated the identification of real-world clinical practice among different generations of physicians and in a variety of settings within France, which was a key objective of the study. Our survey population was also experienced in MS care on average, as shown by the numbers of patients they see each month. The main limitation of our study is that it is based on hypothetical, rather than real, patients, and it has been shown in a non-RMS setting (decisions on referral to hospital treatment) that physicians’ responses to even realistic case presentations were inconsistent with objective measures of actual clinical practice [25]. Future studies should therefore audit the actual practice of participating physicians. The complexity of our case vignettes was limited by the rapid increase in the number of patient trajectories as the disruptive events directed them towards different care decisions; for practical reasons, we could only consider and evaluate the effect of a limited number of clinical variables. In addition, participating physicians focussed only on clinical indications when choosing a DMT in the face of a disruptive event, without additional barriers or constraints to the use of a particular DMT (beyond a desire for pregnancy and JCV+ status in some cases). Also, our definitions of “active” and highly active” RMS were qualitative and subjective. In practice, no consensus exists for categorizing the severity of MS, although several have been proposed, including two documented MS relapses occurring during the previous year [26.27]. It is important to note here that the participating physicians were responding to the information in the patient profiles themselves, and were not provided with an a priori classification of their MS disease severity. We also focussed only on pharmacologic management with DMTs, without consideration on non-pharmacologic interventions which may improve the quality of life of people with MS [28‐30]. Finally, our analysis should be seen as relevant to those who experience problems on treatment, rather than the general population of people with MS, many of whom do well on their DMT, as we did not include cohorts with no disruptive event, so as to focus only on changes (or absence of changes) in management in response to them.