Долгосрочное управление и последовательность терапии для пациентов с повторным множественным склерозом во Франции: исследование вигнета.

Key Summary Points

Why carry out this study?

Prescribing decisions for relapsing multiple sclerosis (RMS) are complex, and patient management strategies become heterogeneous over time as physicians seek an individualized approach. We studied prescribing decisions of neurologists in the management of relapsing multiple sclerosis in France using patient vignettes that resembled the evolution over time of commonly encountered presentations of RMS.
What was learned from this study?

A shift towards earlier use of high-efficacy disease-modifying treatments (DMTs) is occurring, particularly for DMT-naïve patients with high MS disease activity, although some practitioners still consider therapeutic escalation even for highly active RMS. The study also emphasizes the increasing importance given to tolerability in long-term therapeutic decision-making. More guidance on the sequencing of DMTs during long-term MS care may be warranted

Introduction

Relapsing multiple sclerosis (RMS) is often diagnosed early in life, and most with this condition require long-term treatment (decades), including with a disease-modifying therapy (DMT) [ 1 , 2 ]. Real-world data confirm that most patients will receive treatment with more than one DMT during the course of their MS [ 3 , 4 ]. Treatment switches may occur for a range of reasons, including lack of efficacy (continuing or returning MS disease activity), safety/tolerability issues, or less commonly due to factors relating to impact of a particular drug regimen on the patient’s preferences or lifestyle, e.g. related to the frequency or route of administration of the DMT, or where the patient desires to start a family [ 2 , 5 , 6 ]. Accordingly, the administration of DMT for RMS is a complex and dynamic process that occurs over a number of years, with changes to treatment occurring as necessary to (ideally) optimize short- and long-term treatment outcomes according to the unique individual needs of the person with RMS.

Guidelines for the management of RMS provide a broad framework for the delivery of DMT-based care. However, the number of high-efficacy DMTs for the management of RMS has increased greatly in recent years, which complicates management decisions relating to the choice of a given DMT at a given stage of the patient’s MS journey, and also the optimal order in which they should be used (sequencing) over the patient’s lifetime. Accordingly, guidelines are not able to provide precise recommendations on the evolution of therapy over time; indeed, such a restrictive approach would be essentially incompatible with their goal of promoting individualized patient care [ 1 ]. It is therefore of interest to study the approach of physicians treating people with MS, with regard to which DMTs they would prescribe, when they would switch a DMT, and the reasons behind these decisions. We studied the long-term therapeutic sequence preferences according to predefined patient profiles in French practice, in order to identify the principal criteria that influenced their DMT-prescribing decisions.

This study was based on hypothetical case vignettes. No new clinical studies were performed by the authors and no patient-specific efficacy or safety data were reported. Therefore, institutional review board (IRB)/ethics approval was not required.

Methods

Study Objectives

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

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).

Table 1 Overview of case vignettes Case 1 ( n  = 80 a ) Case 2 ( n  = 81 a ) Case 3 ( n  = 72 a ) Case 4 ( n  = 61 a ) Case 5 ( n  = 67 a ) Case 6 ( n  = 64 a ) RMS current status Active/poorly controlled b Highly active, poorly controlled b Highly active, poorly controlled b Active, well controlled b Active, poorly controlled b Highly active, well controlled b Previous DMT? No No No DMF (5 years) Interferon (5 y), teriflunomide (4 y) Anti-CD20 (5 y) Gender Female Female Male Male Female Female Age (y) 24 31 39 37 42 35 Comorbidities? Family history of breast cancer None Obesity, uveitis Smoker, hypertension Depression None EDSS 0 1 1 1 2 1 RMS duration c 6 months 4 months 0 y 5 y 10 y 5 y Recent clinical findings Headaches, NORB ON Distal paraesthesia, NORB None Arm weakness and hypoesthesia None Recent MRI activity 2 supratentorial Gd+ lesions in last 6 months 10 cerebral, 1 medullary lesion at presentation, OCB 7 cerebral T2 lesions (1 Gd+) None d 3 supratentorial lesions None e JCV status Negative Positive Negative Negative Positive Positive Reason for first visit in this study MS disease activity MS disease activity MS disease activity Gastrointestinal side-effects MS disease activity recurrent vaginosis + hypogamma-globulinemia Relationship status In a relationship Married Single Single Divorced Married, 3 children Desires pregnancy? Yes (within 5 y) Yes (within 2 y) N/A f N/A f No No DMF dimethyl fumarate, DMT disease-modifying therapy, EDSS Kurtzke Expanded Disability Status Scale, Gd + gadolinium-enhancing, JCV John Cunningham Virus, NORB retrobulbar optic neuritis, OCB oligoclonal bands, ON optic neuritis, RMS relapsing multiple sclerosis, y years a Number presenting at Visit 1 b At time of first visit (see text for discussion of disease activity) c Since diagnosis; originally presented with d Right facial numbness with gait imbalance and cerebral lesions e Double vision and left internuclear ophthalmoplegia; 15 cerebral T2 lesions (6 Gd+) and 2 cervical spinal lesions f For female cases only

Overview of case vignettes

DMF dimethyl fumarate, DMT disease-modifying therapy, EDSS Kurtzke Expanded Disability Status Scale, Gd + gadolinium-enhancing, JCV John Cunningham Virus, NORB retrobulbar optic neuritis, OCB oligoclonal bands, ON optic neuritis, RMS relapsing multiple sclerosis, y years

a Number presenting at Visit 1

b At time of first visit (see text for discussion of disease activity)

c Since diagnosis; originally presented with

d Right facial numbness with gait imbalance and cerebral lesions

e Double vision and left internuclear ophthalmoplegia; 15 cerebral T2 lesions (6 Gd+) and 2 cervical spinal lesions

f For female cases only

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.

Chatbot Interviews with Physicians

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.

Table 2 Disruptive events that influenced management decisions for Visits 2 and 3 Treatment Event (applicability to specific cases, where applicable) Time after initiation Weighting a % Platform therapies MS disease activity: left-sided numbness; left upper limb hypoesthesia; 7 new brain lesions (incl. 3 Gd+); no spinal cord lesions 2–4 y 80 Adherence issue: fatigue, repeated missed doses of the treatment 3–4 y 20 CladT MS disease activity: new periventricular supratentorial FLAIR lesion (no clinical activity, fatigue or cognitive issues) 3 y 50 MS disease activity: 1 relapse (impaired balance/coordination); 2 new T1 Gd+ brainstem lesions  > 5 y 35 Tolerability issue: shingles— occurred only at Visit 2 15 months 15 S1P modulator MS disease activity: lower limb weakness in the lower limbs, followed 4 month later by significant right lower limb numbness and sphincter dysfunction. Periventricular and juxtacortical white matter lesions (incl. 1 T1 Gd+ lesion) and 1 thoracic lesion 4–5 y 50 Desire for pregnancy: within the next 2 y 10 y (Case 1), 5 y (Case 2) 15 Adherence issue: fatigue and repeated forgetfulness regarding daily medication  > 3 y 20 Tolerability issue: HPV positive (smear test, no dysplasia)—occurred between Visits 2 and 3  > 5 y 15 Anti-CD20 Tolerability issue: hypogammaglobulinemia and admission for respiratory tract infection— occurred only at Visit 2  > 5 y 60 Tolerability issue: hypogammaglobulinemia recurrent urinary tract infections— occurred only at Visit 2  > 5 y 40 MS disease activity: mild right-hand weakness in the and fatigue + 2 new T1 brain lesions (1 of which Gd+)— occurred only at Visit 3  > 8 y 100 Natalizumab MS disease activity: 3 new T2 lesions over the past 3 y (no clinical findings)  > 8 y 20 Tolerability issue: JCV seroconversion (index > 3)— occurred between Visits 2 and 3 for Cases 1, 3, and 5  > 4 y 20 Other issue: change in lifestyle incompatible with monthly hospital visits  > 5 y 60 CladT cladribine tablets, Gd + gadolinium-enhancing, HPV human papilloma virus, JCV John Cunningham Virus, y years a The probability of a disruptive event occurring before the next Visit (see Online Supplementary Table 1 for more details of disruptive events)

Disruptive events that influenced management decisions for Visits 2 and 3

CladT cladribine tablets, Gd + gadolinium-enhancing, HPV human papilloma virus, JCV John Cunningham Virus, y years

a The probability of a disruptive event occurring before the next Visit (see Online Supplementary Table 1 for more details of disruptive events)

Information Recorded

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).

Data analysis and Statistical Considerations

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%.

Ethics

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.

Results

Participating Physicians

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).

Table 3 Details of participating physicians ( n  = 111) Number of cases evaluated n (%) of neurologists 1 case 5 (4.5%) 2 cases 2 (1.8%) 4 cases 104 (93.7%) Age categories of neurologists (years)  25–40 40 (36.0%)  41–50 29 (26.1%)  51–60 28 (25.2%)  61–70 10 (9.0%)  > 70 4 (3.6%) Region of practice  Auvergne–Rhône–Alpes 19 (17.1%)  Burgundy–Franche–Comté 5 (4.5%)  Brittany 1 (0.9%)  Centre–Val de Loire 7 (6.3%)  Grand Est 6 (5.4%)  Hauts–de–France 21 (18.9%)  Normandy 13 (11.7%)  New Aquitaine 8 (7.2%)  Occitanie 15 (13.5%)  Pays de la Loire 3 (2.7%)  Provence–Alpes–Côte d'Azur 4 (3.6%)  Île–de–France 9 (8.1%) Type of practice  Mixed 10 (9%)  MS specialist centres a 18 (16.2%)  University hospital b only 18 (16.2%)  General hospital c only 45 (40.5%)  Private only 20 (18%) Number of people with RMS treated/month  0–5 17 (15.3%)  6–10 24 (21.6%)  11–20 24 (21.6%)  > 20 46 (41.4%) a Centre de ressources et de compétences pour la sclérose en plaques b Centre Hospitalier Universitaire c Centre Hospitalier Général

Details of participating physicians ( n  = 111)

a Centre de ressources et de compétences pour la sclérose en plaques

b Centre Hospitalier Universitaire

c Centre Hospitalier Général

Heterogeneous Management Decisions in Response to Evolving Clinical Cases

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.

Sankey diagram for management decisions at successive visits for cases with active MS disease at Visit 1 (Cases 1, 4 and 5; n  = 208). The initial treatment (left-hand column) is based on the how the hypothetical patient was managed immediately before the first case review by participating physicians and column 2 shows the management decisions of the participating physicians after reviewing the cases. Columns 3 and 4 reflect later management decisions following subsequent presentations with or without disruptive events (see text)

Sankey diagram for management decisions at successive visits for cases with highly active MS disease at Visit 1 (Cases 2, 3 and 6; n  = 217). The initial treatment (left-hand column) is based on the how the hypothetical patient was managed immediately before the first case review by participating physicians and column 2 shows the management decisions of the participating physicians after reviewing the cases. Columns 3 and 4 reflect later management decisions following subsequent presentations with or without disruptive events (see text)

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.

Drivers of Sequencing Decisions

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.

Discussion

This was the first study to use vignettes to study treatment sequences in people with RMS. The case vignette methodology that we used is a well-described and validated approach to investigate aspects of clinical practice, which is useful for engaging a relatively large population of participants in a time-effective manner [ 9 – 12 ]. While this methodology has been used to evaluate the consistency and quality of clinical decision-making, our intention was to investigate the range of responses of physicians to a given clinical scenario; comparing these decisions to guideline recommendations, etc. is beyond the scope of our study.

The responses of the participating physicians to the cases were heterogeneous, although some themes could be discerned. Only 39% of recommendations for patients with active MS in Case 1 were for platform therapies, which is a lower proportion compared with published real-world datasets, which typically show > 50% of populations with MS receiving platform agents [ 13 , 14 ]. A lateral switch to an alternative platform therapy, or to agents with higher efficacy (S1P inhibitor or CladT), was the most common choice for cases encountering side-effects on DMF, reflecting a somewhat cautious approach compared with going directly to a true high-efficacy DMT. Escalation was usually preferred where only moderate disease activity occurred after long-term treatment with a platform DMT (Case 5), which we believe is in line with standard clinical practice. Side-effects on anti-CD20 prompted a switch to CladT for about half the population (Case 6), although JCV+ status largely precluded the use of natalizumab here. It is arguable that use of CladT before anti-CD20 may have been a reasonable option, as this approach can delay the need for a DMT that acts via continuous immunosuppression, such as anti-CD20, which highlights the issue of balancing the immediate need of the patient with the need to plan longer-term treatment sequencing [ 8 ]. In general, seropositivity for JCV almost always prevented prescription of natalizumab and usually prompted a switch to anti-CD20. Slightly more than half of people with MS demonstrated seropositivity for JCV in an international survey [ 15 ], which is consistent with the 3/6 cases being JCV+ at baseline, and 20% of cases who received natalizumab becoming JCV+ as a result of a disruptive event (see Table  2 ).

A high proportion of cases received CladT as their first DMT following participating physicians’ reviews of DMT-naïve cases (19%, 30% and 35% of reviews of Cases 3, 2 and 1, respectively, resulted in prescription of CladT). Two of our case vignettes featured women who aimed to become pregnant, and the potential for a prolonged period free of continuous DMT following a therapeutic response of CladT can provide an opportunity for this [ 16 ]. Similar considerations may explain the relatively high usage of natalizumab in Case 1, as most experts consider that this DMT is safe during the early part of a pregnancy (as well as the low use of S1P inhibitors, which are not) [ 16 – 18 ].

There was also some indication in our data that participating physicians may have been more ready to prescribe a higher-efficacy DMT for younger cases, which is consistent with recent real-word evidence [ 19 ]. These findings are consistent with recent research which has highlighted the potential benefits of earlier intervention with a DMT to optimise long-term outcomes in people with RMS [ 20 – 22 ]. This approach appears to be reflected increasingly in real-world clinical practice [ 23 ]. On the other hand, as shown by the literature [ 24 ] and the opinion of the authors, the participating physicians prescribed a platform DMT for about 1 in 5 cases of untreated highly active RMS at initial presentation. This indicates some reluctance to prescribe these agents, possibly influenced by the post-COVID context (especially for anti-CD20 agents, where physicians may be concerned about immunosuppression associated with high-efficacy DMTs) [ 24 ] or concerns about high-efficacy therapies for women desiring pregnancy.

The number of distinct therapeutic sequences selected by our physicians increased markedly as the cases progressed through their disruptive events and associated hypothetical clinic visits. Thus, there was little consistency between physicians on required changes to MS therapeutic management in the face of these events. Nevertheless, some sequences may be more beneficial for long-term patient disease control and management of side-effects. The development of guidelines to support the order of sequencing of DMTs in different clinical scenarios may provide support to practising physicians, to be considered alongside the individual preferences and lifestyle situation of the person with MS. Such an approach has the potential to optimise the management of MS disease activity while preserving the principle of individualized, patient-centred care.

Strengths and Limitations

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.

Conclusions

This study offers valuable insights into the current practices of French neurologists in managing RMS, emphasizing the complexity of therapeutic decisions, the diversity of strategies, and the significance of an individualized approach in treatment management. Overall, our data suggested a willingness among neurologists to treat with higher-efficacy DMTs early in the course of RMS, with platform agents given to only one-quarter of DMT-naïve cases. MS disease activity was the main driver of switches to higher-efficacy DMTs, although an escalation approach was common in response to either moderate MS disease activity or side-effects on platform agents. A desire for pregnancy drove high usage of CladT and natalizumab (especially for JCV– cases). These findings, which require confirmation in additional studies, suggest that the management of RMS in France has shifted in recent years towards a desire to achieve earlier and more effective control of disease activity of people with RMS. Better guidance on the sequencing of DMTs for different scenarios within the overall management of RMS is warranted.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 873 KB)

Acknowledgments

Medical writing and/or editorial assistance

A medical writer (Dr Mike Gwilt, GT Communications) provided editorial support, funded by Merck Serono S.A.S., Lyon, France, an affiliate of Merck KGaA .

Author Contributions

Baptiste Roux, Anais Lecomte, Laura Luciani and Martine Paret conducted the study and contributed to the conception and design of the analysis, as well as interpretation of the data. Patrick Vermersch, Xavier Moisset and Jerome de Seze were members of the scientific committee and contributed to the validation of the study design and data interpretation. All authors contributed to critical review of this manuscript. All authors approved the manuscript for submission to the journal.

Funding

Merck Santé S.A.S., Lyon, France, an affiliate of Merck KGaA (CrossRef Funder ID: 10.13039/100009945) funded and administered the study, editorial support (see below) and the Journal’s Rapid Service Fee. Role of the funding source: Merck Serono S.A.S., Lyon, France, an affiliate of Merck KGaAis the pharmaceutical sponsor for CladT in France. However, there was no preference towards recruitment of physicians known to prescribe this treatment. Moreover, participating physicians were asked to base their decisions only on the therapeutic indications for treatments.

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Declarations

Conflict of interest

Patrick Vermersch received fees for consultancy, advisory board and scientific meetings from Biogen, Sanofi-Genzyme, Novartis, Teva, Merck Serono S.A.S, Lyon, France, an affiliate of Merck KGaA, Roche, Imcyse, AB Science, Janssen, Ad Scientiam and BMS, and research support. from Novartis, Sanofi-Genzyme, Roche and Merck. Xavier Moisset received financial support from Allergan-Abbvie, Aptis Pharma, Biogen, BMS-Celgène, Grünenthal, Lilly, Lundbeck, Teva, Merck Serono S.A.S, Lyon, France, an affiliate of Merck KGaA, Novartis, Orion, Pfizer, Roche, and Sanofi-Genzyme and non-financial support from SOS Oxygène unrelated to the current work. Jérôme de Sèze received fees for consultancy, advisory board and scientific meetings from Novartis, Biogen, Sanofi, Roche, Janssen, Merck Santé S.A.S, Lyon, France, an affiliate of Merck KGaA, Alexion, CSL Behring, Horizon Therapeutics, LFB, Sandoz, and Pfizer. Baptiste Roux and Anais Lecomte are employees of Société Fast4, Montpellier, France. Laura Luciani is an employee of Merck Santé S.A.S, Lyon, France, an affiliate of Merck KGaA. Martine Paret is an employee of Merck Serono S.A.S, Lyon, France, an affiliate of Merck KGaA.

Ethical Approval

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.

Footnotes

Prior publication : Data from this study were presented in a poster at the 32nd meeting of the European Charcot Foundation, Baveno, Italy, 21–23 November 2024.

References

Associated Data

Supplementary Materials

Supplementary file1 (PDF 873 KB)

Data Availability Statement

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.