Ранняя интенсивная терапия в сравнении со стратегией эскалации во франко-карибской группе склероза.

INTRODUCTION

Multiple Sclerosis (MS), the most common demyelinating disease of the central nervous system (CNS), predominantly affects young women, and ranks as a leading cause of disability in young adults. Its incidence and prevalence steadily rise [ 1 ]. The disease etiology is multifactorial [ 2 ], influenced by genetic and environmental factors [ 3 , 4 ], with significant implications for the EBV virus [ 5 , 6 ]. Typically, MS begins as a relapsing–remitting (RR) form before progressing to secondary progressive (SP) MS, while some cases exhibit primary progressive (PP) MS from the onset [ 7 ].

Multiple Sclerosis is also becoming more common in the French Caribbean, whereas it was almost non‐existent before the 1990s [ 8 ]. There has been a notable epidemiological shift with an increasing prevalence and incidence of MS. This rise is partly attributed to the underdiagnosis of MS before the late 1990s, which improved with the advent of MRI technology. However, various other factors have contributed to this trend, such as the association with different models of the Human Leukocyte Antigen (HLA) system [ 9 ], migration from the French West Indian population to mainland France, a decrease in sun exposure, and enhanced hygiene associated with the eradication of intestinal helminthiases [ 8 , 10 , 11 ]. Indeed, other genetic, epigenetic, and environmental factors are yet to be discovered to fully explain the specific presentation of the disease in this geographic region. In addition, in Afro‐American people, the disease seems more severe and aggressive, with higher levels of disease‐related disability [ 12 , 13 , 14 ]. In this specific population, the reasons are undoubtedly multifactorial, including genetic, environmental, and immunological factors and inequality of medical care [ 15 , 16 , 17 , 18 ]. Also, subjects of African descent appeared less responsive to Interferon‐Beta therapies [ 19 , 20 ]. In the French Afro‐Caribbean population, the disease takes the same aggressive trajectory (in our experience). However, disparities in healthcare access are much less present in the French West Indies because social security covers patients suffering from MS at 100%.

Historically, treatment‐naïve RRMS patients typically underwent an escalation approach from moderate‐efficacy (ME) to high‐efficacy (HE) disease‐modifying therapies (DMTs) for more aggressive or resistant disease. Although some patients with highly active diseases benefited from initial HE‐DMTs, these therapies entail complex safety profiles and require closer monitoring. Recently, Early Intensive Therapy (EIT), using HE‐DMTs upfront during the inflammatory phase [ 21 , 22 , 23 ], has shown promising results in reducing long‐term disability [ 24 , 25 ]. However, data on this approach in populations of African descent remain limited. Here, we aim to compare the efficacy and safety of EIT versus Escalation strategies in the French West Indies RRMS population, predominantly of African descent.

MATERIALS AND METHODS

Patients and study design

All patients listed in the European Database for Multiple Sclerosis (EDMUS) database at the MS Reference Center of the University Hospital of Martinique from February 2000 (first use of EIT in our cohort with Mitoxantrone) to June 2023, meeting the latest international diagnostic criteria for RRMS according to McDonald 2017 [ 26 ] were included. The EDMUS database is a comprehensive European registry that collects standardized clinical and treatment data on multiple sclerosis patients, facilitating large‐scale research and longitudinal analysis. Patients required neurological follow‐ups for at least two consecutive years. Although there are no official ethnic statistics because collecting ethnic origin is prohibited by French law, a large majority of patients are of Black African descent (>90%) [ 27 ].

We categorized patients into two groups based on treatment strategy: Escalation or EIT. Escalation group patients received ME‐DMTs such as Interferon‐beta IA/IB, Dimethyl Fumarate, Glatiramer acetate, or Teriflunomide. EIT group patients received HE‐DMTs (as first‐line treatment), such as Mitoxantrone, Natalizumab, Fingolimod, Ocrelizumab, or Rituximab. We classified Fingolimod as a high‐efficacy treatment, aligning with authors who differentiate it from Dimethyl Fumarate based on the European Medicines Agency classification (EMA/CHMP/771815/2011 Rev. 2, 2015) of second‐line therapies [ 22 , 23 ].

Patients with progressive forms (SPMS or PPMS) or other CNS inflammatory pathologies (e.g., NMOSD) were excluded. Additionally, patients who initiated DMT before February 2000 received ME‐DMT for less than 2 years or discontinued ME‐DMT for over 6 months. Those who did not complete at least 6 months of the HE‐DMT EIT protocol, based on the standard recommendations and dosages for these medications, were excluded (According to French recommendations from the ANSM ( National Agency for the Safety of Medicines and Health Products ) Summary of Product Characteristics).

Outcomes and severity factors

The primary outcome was the irreversible reaching of Expanded Disability Status Scale (EDSS) scores 3, 6, and 8 between DMT initiation and the last follow‐up. We used the EDMUS Impairment Scale‐Disability Status Scale (EIS‐DSS) for our statistical analysis. This scale evaluates irreversible changes in the EDSS score from the previous visit and is expressed in whole numbers (from 0 to 10). Although the EIS‐DSS is related to the EDSS, it provides a specific measure of disability progression within the EDMUS framework. This paper uses the term “EDSS” for simplicity, even though it refers to the broader scale for assessing disability. At the same time, the EIS‐DSS is a distinct measure within the EDMUS database focusing on irreversible disability changes. In the EDMUS database, irreversible EDSS is defined as a level of disability that remains constant or worsens over a 6‐month to 1‐year period, reflecting persistent impairment with no improvement in the EDSS score [ 28 ]. Secondary outcomes included changes in EDSS scores, identification of risk factors for EDSS attainment (3,6,8), and safety data based on severe adverse effects from the EDMUS database (severe infections, autoimmune, cardiovascular, neurological, psychiatric, allergic, endocrinological pathologies, cancers). Population characteristics such as sex, age at first inflammatory events (R1), R1 typology, recovery from R1, time between first two relapses (R1–R2), R1 ‐DMT initiation time, initial EDSS score, and annualized relapse rate pre‐DMT (ARR, defined by the number of relapses before treatment/time before starting treatment) were analyzed as potential severity factors.

Statistical analysis

Quantitative variables were summarized as median with interquartile range (IQR), and categorical data were expressed as numbers and frequencies. Comparison of patient characteristics was carried out using appropriate statistical tests (Pearson's χ
2 , Fisher's exact test, or Wilcoxon rank sum test). We performed a survival analysis considering the irreversible reaching of EDSS scores 3, 6, or 8 after the start of treatment as a criterion for the occurrence of an event. This analysis allowed the modeling of Kaplan–Meier curves with individualization of the two therapeutic strategies, which were compared using the log‐rank test. Patients who had already reached irreversible EDSS 3 (or higher) at the time of treatment initiation were excluded from the analysis of survival curves for EDSS 3, and those who had reached irreversible EDSS 6 (or higher) were excluded from the analysis of survival curves for EDSS 3 and 6. The Cox model was performed to estimate crudes and adjusted Hazard Ratio (HR) and their 95% confidence intervals. The adjustment parameters in multivariate analysis were retained in case of a significant result at 10% ( p  < 0.10). Apart from the adjustment, for all analyses, the significance threshold was set at 5% ( p  < 0.05). Analyses were performed using R 4.2.1 software and RStudio 2022.07.1 (R Core Team (2022). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. URL https://www.R‐project.org/ ).

Standard protocol approvals, registrations, and patient consent

From 1993, MS patients were prospectively reported in the EDMUS created at the Hospices Civils de Lyon in 1976. Since 1990, EDMUS has operated on a European scale, cataloging cases of MS and related disorders. All patients gave written informed consent, and the national ethical authority approved data collection (Commission Nationale de l'Informatique et des Libertés; CNIL; registration number 914066v2).

RESULTS

General characteristics

A total of 195 patients were enrolled (Figure  1 ), with characteristics outlined in Table  1 . Thirty‐three percent ( n  = 66; 33.8%) received EIT, while 66.2% ( n  = 129) initiated an Escalation strategy. The cohort exhibited a marked female predominance (77.9%) and predominantly hailed from Caribbean descent (85%). Initial attacks were predominantly monosymptomatic (79%), with spinal cord involvement in 56.4% and posterior fossa lesions in 36.4%. Incomplete clinical recovery from R1 was observed in 40% of cases. The median time between the first two relapses was 15 months overall, significantly shorter in the EIT group compared to the Escalation group (9 months vs. 23 months, p  < 0.001).

Patient selection flowchart. EDMUS, European Database for Multiple Sclerosis; EIT, Early Intensive Therapy; HE‐DMT, High‐efficacy disease‐modifying therapy; ME‐DMT, Moderate‐efficacy disease‐modifying therapy; MS, multiple sclerosis; NMOSD, neuromyelitis optica spectrum disorder; PPMS, primary progressive multiple sclerosis; RRMS, relapsing–remitting multiple sclerosis; SPMS, Secondary progressive multiple sclerosis.

TABLE 1 Clinical characteristics of patients according to the therapeutic strategy. Overall N  = 195 EIT N  = 66 Escalation N  = 129
p ‐value Female, n (%) 152 (77.9%) 54 (81.8%) 98 (76.0%) 0.351 Geographic Origin, n (%) Martinique 123 (63.1%) 43 (65.2%) 80 (62.0%) 0.012 Guadeloupe 37 (19.0%) 16 (24.2%) 21 (16.3%) Guyane 2 (1.0%) 0 (0.0%) 2 (1.5%) Other Caribbean Country 3 (1.5%) 3 (4.5%) 0 (0.0%) Mainland France 23 (11.8%) 3 (4.5%) 20 (15.5%) Others 7 (3.6%) 1 (1.5%) 6 (4.7%) Age at first relapse (years), median (IQR) 31 (24, 39) 28 (23, 37) 32 (24, 40) 0.168 Polysymptomatic first relapse, n (%) 41 (21.0%) 18 (27.3%) 23 (17.8%) 0.126 Optic Neuritis, n (%) 40 (20.5%) 14 (21.2%) 26 (20.2%) 0.863 Spinal Cord, n (%) 110 (56.4%) 39 (59.1%) 71 (55.0%) 0.589 Brainstem, n (%) 71 (36.4%) 27 (40.9%) 44 (34.1%) 0.350 Brain, n (%) 28 (14.4%) 11 (16.7%) 17 (13.2%) 0.511 Incomplete recovery after first relapse, n (%) 78 (40.0%) 21 (31.8%) 57 (44.2%) 0.095 Time between the first two relapses (months), median (IQR) 15 (6, 39) 9 (3, 26) 23 (10, 46) <0.001 Abbreviations: EIT, Early Intensive Therapy; IQR, interquartile range; MS, multiple sclerosis.

Clinical characteristics of patients according to the therapeutic strategy.

Abbreviations: EIT, Early Intensive Therapy; IQR, interquartile range; MS, multiple sclerosis.

The treatments administered to patients are summarized in Table  2 . Following the onset of R1, the initial treatment was initiated after a median delay of 14 months, which was comparable between the two subgroups (12 months for the EIT group, 16 months for the Escalation group, p  = 0.121). However, patients in the EIT group were generally younger at treatment initiation (median = 31 years) compared to the Escalation group (median = 38 years, p  = 0.016). In the EIT group, the main treatments included natalizumab (39.4%), mitoxantrone (28.8%), and fingolimod (27.3%), while the Escalation group predominantly received various forms of interferon‐beta (72.9%).

TABLE 2 Treatment characteristics of patients according to the therapeutic strategy. Overall N  = 195 EIT N  = 66 Escalation N  = 129
p ‐value Age at first therapy (years), median (IQR) 35 (27, 43) 31 (24, 40) 38 (28, 43) 0.016 Time to first therapy (months), median (IQR) 14 (5, 62) 12 (4, 49) 16 (6, 73) 0.121 If EIT, first HE‐DMT, n (%) Fingolimod 18 (27.3%) 18 (27.3%) N/A Natalizumab 26 (39.4%) 26 (39.4%) N/A Mitoxantrone 19 (28.8%) 19 (28.8%) N/A Ocrelizumab 2 (3.0%) 2 (3.0%) N/A Rituximab 1 (1.5%) 1 (1.5%) N/A If Escalation, first ME‐DMT, n (%) Interferon‐Beta‐IA SC 27 (20.9%) N/A 27 (20.9%) Interferon‐Beta‐IA IM 41 (31.8%) N/A 41 (31.8%) Dimethyl Fumarate 3 (2.3%) N/A 3 (2.3%) Glatiramer Acetate 10 (7.8%) N/A 10 (7.8%) Teriflunomide 22 (17.1%) N/A 22 (17.1%) Interferon‐Beta‐IB SC 26 (20.2%) N/A 26 (20.2%) If Escalation, switch or short interruption < 6 months of first ME‐DMT, n (%) 39 (30.2%) N/A 39 (30.2%) If Escalation, time to HE‐DMT (years), median (IQR) 4 (3, 8) N/A 4 (3, 8) If Escalation, type of HE‐DMT, n (%) Fingolimod 25 (34.2%) N/A 25 (34.2%) Natalizumab 33 (45.2%) N/A 33 (45.2%) Mitoxantrone 6 (8.2%) N/A 6 (8.2%) Ocrelizumab 4 (5.5%) N/A 4 (5.5%) Rituximab 2 (2.7%) N/A 2 (2.7%) Cyclophosphamide 2 (2.7%) N/A 2 (2.7%) Ofatumumab 1 (1.4%) N/A 1 (1.4%) No switch to HE‐DMT, n (%) 56 (43.4%) N/A 56 (43.4%) Number of relapses at first therapy, median (IQR) 2 (1, 3) 2 (2, 3) 2 (1, 3) 0.036 Abbreviations: EIT, Early Intensive Therapy; HE‐DMT, high‐efficacy disease‐modifying therapy; IM, intramuscular; IQR, interquartile range; ME‐DMT, moderate‐efficacy disease‐modifying therapy, N/A, not applicable; SC, subcutaneous.

Treatment characteristics of patients according to the therapeutic strategy.

Abbreviations: EIT, Early Intensive Therapy; HE‐DMT, high‐efficacy disease‐modifying therapy; IM, intramuscular; IQR, interquartile range; ME‐DMT, moderate‐efficacy disease‐modifying therapy, N/A, not applicable; SC, subcutaneous.

Evolution of EDSS score under treatment

The median follow‐up duration was 6 years for the EIT group and 9 years for the Escalation group ( p  < 0.001). Survival curve analysis revealed a slower irreversible progression to EDSS 3 with the EIT strategy compared to the Escalation strategy (median survival 13.5 years versus 9.8 years, p  = 0.024) (Figure  2 ). After a median follow‐up of 8 years, EIT showed 89.5% without irreversible EDSS 3 versus 63.8% on Escalation (Figure  2 ). There were no significant differences between the two strategies regarding irreversible progression to EDSS 6 ( p  = 0.33) (Figure  3a ) and EDSS 8 ( p  = 0.98) (Figure  3b ). Table  3 displays the evolution of EDSS scores among treated patients. The median baseline EDSS score was significantly different between the two groups (3 in EIT vs. 2 in Escalation, p  < 0.001). During treatment follow‐up, after excluding patients who had already reached specific irreversible EDSS stages (3, 6, 8), the EIT group showed a lower rate of irreversible progression: 15.9% reached EDSS 3 compared to 47.4% in the Escalation group; similar trends were observed for EDSS 6 and 8 (see Table  3 ). Figure  4 illustrates the variation in median EDSS score from treatment initiation to the last consultation, showing a significant difference between the EIT and Escalation groups (0 (IQR −2‐1) vs. +2 (IQR 0–3), respectively, p  < 0.001).

Survival analysis demonstrating the probability of reaching irreversible EDSS 3. EDSS, Expanded Disability Status Scale; EIT, Early Intensive Therapy.

Survival analysis demonstrating the probability of reaching irreversible EDSS 6 (a), and EDSS 8 (b). EDSS, Expanded Disability Status Scale; EIT, Early Intensive Therapy.

TABLE 3 Disability characteristics of patients according to the therapeutic strategy. Overall N  = 195 EIT N  = 66 Escalation N  = 129
p ‐value Follow‐up since first therapy (years), median (IQR) 8 (4, 12) 6 (4, 9) 9 (5, 14) <0.001 EDSS score at baseline, median (IQR) 2 (1, 3) 3 (2, 5) 2 (1, 3) <0.001 Patients who had reached EDSS 3, n (%) Under treatment 61 (31.3%) 7 (10.6%) 54 (41.9%) <0.001 At onset 37 (19.0%) 22 (33.3%) 15 (11.6%) Not reached 97 (49.7%) 37 (56.1%) 60 (46.5%) Patients who had reached EDSS 3 during follow‐up
a
, n (%) 61/158 (38.6%) 7/44 (15.9%) 54/114 (47.4%) <0.001 Patients who had reached EDSS 6, n (%) Under treatment 26 (13.3%) 4 (6.1%) 22 (17.1%) <0.001 At onset 8 (4.1%) 7 (10.6%) 1 (0.8%) Not reached 161 (82.6%) 55 (83.3%) 106 (82.2%) Patients who had reached EDSS 6 during follow‐up
b
, n (%) 26/187 (13.9%) 4/59 (6.8%) 22/128 (17.2%) 0.056 Patients who had reached EDSS 8, n (%) Under treatment 10 (5.1%) 2 (3.0%) 8 (6.2%) 0.499 Not reached 185 (94.9%) 64 (97.0%) 121 (93.8%) Abbreviations: EDSS, Expanded Disability Status Scale; EIT, Early Intensive Therapy; IQR, Interquartile range.
a
Patients with an EDSS 3 before initiating either therapeutic strategy were excluded from the analysis.
b
Patients with an EDSS 6 before initiating either therapeutic strategy were excluded from the analysis.

Disability characteristics of patients according to the therapeutic strategy.

Abbreviations: EDSS, Expanded Disability Status Scale; EIT, Early Intensive Therapy; IQR, Interquartile range.

Patients with an EDSS 3 before initiating either therapeutic strategy were excluded from the analysis.

Patients with an EDSS 6 before initiating either therapeutic strategy were excluded from the analysis.

EDSS variation under treatment. EDSS, Expanded Disability Status Scale; EIT, Early Intensive Therapy.

Determinants of irreversible reaching of EDSS 3

The risk factors for the irreversible reaching of EDSS 3 are reported in Table  4 . In univariate analysis, we identified that the choice of Escalation strategy (HR 2.42, 95% CI [1.09–5.34], p  = 0.029), age at first relapse (HR 1.04, 95% CI [1.01–1.06], p  = 0.004), and incomplete symptom recovery (HR 1.69, 95% CI [1.02–2.77], p  = 0.040) were associated with an increased risk of irreversible reaching of EDSS 3. In multivariate analysis, after adjustment for therapeutic strategy, sex, age, complete symptom recovery, and the time interval between onset of symptoms (R1) and treatment initiation, only two factors were identified as significant: age at first relapse (HR 1.04, 95% CI [1.01–1.07], p  = 0.006) and the time interval between onset of symptoms (R1) and treatment initiation (HR 1.00, 95% CI [1.00–1.01], p  = 0.007).

TABLE 4 Factors influencing the median duration from the initiation of therapy to the onset of irreversible EDSS 3. Crudes HR Adjusted HR HR 95% CI
p ‐value HR 95% CI
p ‐value Therapeutic Strategy (Escalation) 2.42 1.09, 5.34 0.029 1.90 0.85, 4.26 0.118 Sex (female) 0.81 0.44, 1.47 0.491 0.78 0.42, 1.46 0.437 Age at first relapse 1.04 1.01, 1.06 0.004 1.04 1.01, 1.07 0.006 Typology of first relapse (monosymptomatic) 0.77 0.40, 1.48 0.427 Time between the first two relapses (months) 1.00 0.99, 1.00 0.247 Incomplete recovery after first relapse 1.69 1.02, 2.77 0.040 1.56 0.91, 2.70 0.106 Time to first therapy 1.00 1.00, 1.01 0.075 1.00 1.00, 1.01 0.007 EDSS score at first therapy ≥3 0.49 0.18, 1.34 0.164 ARR before treatment 0.57 0.25, 1.28 0.171 Abbreviations: ARR, Annual Relapse Rate; EDSS, Expanded Disability Status Scale.

Factors influencing the median duration from the initiation of therapy to the onset of irreversible EDSS 3.

Abbreviations: ARR, Annual Relapse Rate; EDSS, Expanded Disability Status Scale.

Cumulative effect of risk factors

The study of the cumulative risk factors for reaching irreversible EDSS 3 is reported in Table  S1 (EIT strategy) and Table  S2 (Escalation strategy). We defined seven risk factors commonly found in the literature and adapted them to our study: male sex, age > 30 years, polysymptomatic nature of the first relapse (R1), initial involvement of the spinal cord or posterior fossa, incomplete recovery from R1, R1‐R2 interval <15 months. By employing various strategies for combining risk factors, none emerged as statistically significant.

Safety data

The safety data were generally favorable, as shown in Table  S3 . Over the entire follow‐up period, a total of six patients experienced serious adverse events (3.1%), of whom four were treated with Escalation and two with EIT ( p  = 1.00). One case of hepatitis was reported with interferon‐beta‐1B, which turned out to be autoimmune hepatitis after liver biopsy, with no evidence of drug toxicity. Two serious events associated with teriflunomide (severe blood pressure surge, which required several hours of intravenous hypotensive treatment, and a case of mild neuropathy that improved after stopping the treatment) necessitated hospitalization but ultimately resulted in a favorable outcome. In the EIT group, one case of Progressive Multifocal Leukoencephalopathy (PML) was observed in a patient receiving natalizumab, and this patient is still alive. Additionally, two cases of cancer (breast cancer with fingolimod in a patient on EIT strategy and prostate cancer with ocrelizumab in a patient on Escalation strategy) were reported in patients over 50 years old who temporarily discontinued treatment before resuming it. Finally, several cases of minor adverse events occurred with the Escalation strategy, primarily due to poor tolerance of first‐line therapies, resulting in treatment switch or temporary interruption (<6 months) in 30.2% of patients (Table  2 ).

DISCUSSION

In our study, the EIT strategy demonstrated a slower irreversible progression to EDSS 3 compared to the Escalation strategy, with median survival times of 13.5 years versus 9.8 years, respectively ( p  = 0.024), over a median follow‐up of 8 years. After a median follow‐up of 8 years, 89.5% of EIT patients had not reached irreversible EDSS 3 compared to 63.8% in the Escalation group. While the Escalation strategy was associated with a two‐point increase in EDSS during follow‐up, the EIT strategy either stabilized or reduced EDSS, with 56.1% of EIT patients maintaining an EDSS <3. Univariate analysis identified Escalation strategy, age at first attack, and incomplete symptom regression as risk factors for irreversible EDSS 3. In multivariate analysis, only an older age at first relapse (HR 1.04) and a longer time before initiation of treatment (HR 1.0) were significant, but their clinical relevance is limited. Both strategies showed reassuring safety profiles.

Patients who benefited from the EIT strategy took significantly longer to reach irreversible EDSS 3 (13.5 years) than patients in the Escalation strategy (9.8 years), that is, a differential of at least 3.7 years. Furthermore, the difference in follow‐up duration probably underestimates the real beneficial impact of the EIT strategy on the progression of the disability. Indeed, after a median follow‐up of 8 years, the EIT strategy demonstrated that 89.5% of patients had yet to reach irreversible EDSS 3, compared to 63.8% in the Escalation group. We did not find any significant difference in the irreversible reaching of EDSS 6 and 8, which could explain the short follow‐up and the number of patients in these categories. However, in both cases, the shape of the survival curves seemed in favor of the EIT strategy. In our study, we managed left censoring by excluding patients who had already crossed the EDSS 3 or 6 threshold before the study began, ensuring that all included patients were at risk from the start. To address the right censoring, we ensured a minimum follow‐up of 2 years and a median follow‐up of 8 years. Some recent studies have focused on directly comparing the two practices, with, for example, a 25% reduction in the risk of disability progression and reaching an EDSS score of 3 or 4 in a Scandinavian cohort [ 23 ]. A recent French cohort study of pediatric‐onset MS found a reduction in the risk of first relapse with an optimal rate outcome in the first 2 years [ 29 ]. In our study, the change in the EDSS score between the start of treatment and the last follow‐up consultation was significantly different between EIT and Escalation (0 points vs. +2 points). The distribution of EDSS scores changed in the EIT strategy, with an increase in patients with a score between 0 and 3 after treatment. In contrast, this category of patients was reduced by half with the Escalation strategy. A recent Italian study [ 25 ] also found significantly higher mean annual delta‐EDSS values in the Escalation vs. EIT group, and the differences tended to increase with each additional year of follow‐up.

In our study, in univariate analysis, the Escalation strategy was considered a risk factor for irreversible reaching EDSS 3 compared to the EIT strategy (HR 2.42). This result was not replicated in multivariate analysis, possibly explained by the small number of patients in the EIT subgroup ( n  = 66). Data from the literature suggests that disability progression is organized in two phases [ 30 , 31 ]: an early phase, from multiple sclerosis clinical onset to irreversible Disability Status Scale (DSS) 3, and a late phase, from irreversible DSS 3 to irreversible DSS 6 [ 31 ]. The early phase (largely dependent on focal inflammation) appears therapeutically critical to modify the natural history of MS. This early phase is influenced by the tropism of the first relapse, spinal cord, or posterior fossa, mainly represented in our population (56 and 36% of patients, respectively) and is predictive of a higher risk of further attacks and progression to irreversible EDSS 3 [ 32 ]. Moreover, a study in the French West Indian population showed that treatment with Interferon‐Beta was only marginally effective in the Afro‐Caribbean population [ 20 ], but 70% of our patients in the Escalation strategy had this treatment, especially those who started a DMT before the 2010s. This slight effect was also found in the Afro‐American population in a post‐hoc analysis of the EVIDENCE study [ 19 ]. Given these data, all effective therapeutic means should be tried to avoid the transition to irreversible EDSS 3.

The safety profile in both strategies appeared acceptable, with fewer serious adverse events: six cases (3.1%), two in the EIT strategy, and four in the Escalation strategy. For EIT, a case of PML under natalizumab was reported but occurred before the possibility of semi‐annual JC Virus serology testing. In contrast, minor adverse effects were widespread in the Escalation strategy, with nearly 30% of our patients needing to change or suspend their treatment (<6 months). Local infectious risks (mainly arboviral diseases due to dengue or zika virus) were not mentioned as our patients did not experience infections classified as serious adverse events under treatment.

Our study had several limitations. First is its retrospective nature. However, all data were prospectively collected in the EDMUS database. Second, although the study was multicentric, the number of patients in the EIT subgroup was low compared to other recent cohorts. It should be noted that the French Caribbean is a modestly populated territory with a lower prevalence of the disease than in countries with a large population of Caucasian origin. Third, the follow‐up was limited, with a shorter follow‐up in the EIT subgroup than in the Escalation subgroup (because of a more recent adoption of EIT in routine clinical practice), but remained consistent with durations found in the literature [ 21 , 22 , 25 ]. Fourth, Patients in the Escalation group were significantly older at treatment initiation compared to those in the EIT group, which could contribute to worse outcomes in this group. Fifth, although the two groups appeared comparable, this study does not account for indication bias, limiting definitive conclusions on the universal applicability of EIT. Finally, in France, it is not acceptable to classify patients according to their ethnicity. Overall, our patients were overwhelmingly of African ancestry, even those from mainland France having family roots in the Caribbean. Our study also has strengths. This study is grounded on robust data from a leading center, with patients meeting the most recent international diagnostic criteria established in 2017 [ 26 ]. To our knowledge, this is, the first study comparing the two strategies in a population with more severe forms of RRMS than the Caucasian population.

Overall, in our African‐descent population exhibiting more severe forms of MS, the EIT strategy has demonstrated the ability to postpone the irreversible reaching of EDSS 3 by several years compared to Escalation therapy while maintaining a favorable safety profile. These findings suggest the potential for altering the prognosis of French West Indian patients by initiating an EIT strategy as early as possible. Further investigations with extended follow‐up periods will be required to validate this hypothesis while ensuring acceptable long‐term safety profiles.

AUTHOR CONTRIBUTIONS

Thomas David: Data curation; formal analysis; investigation; writing – original draft; conceptualization. Quentin Lobjois: Writing – review and editing; investigation; formal analysis. Benoit Tressières: Methodology; software; data curation; formal analysis. Aissatou Signaté: Writing – review and editing; validation; visualization. Annie Lannuzel: Validation; formal analysis; writing – review and editing; visualization. Philippe Cabre: Conceptualization; methodology; investigation; validation; formal analysis; supervision; writing – review and editing; resources; data curation; visualization. Hugo Chaumont: Conceptualization; methodology; data curation; supervision; formal analysis; validation; visualization; writing – original draft; writing – review and editing.

FUNDING INFORMATION

H. Chaumont and A. Lannuzel were supported by the Network of Centers of Excellence in Neurodegeneration (ANR‐20‐COEN‐0002‐02).

CONFLICT OF INTEREST STATEMENT

The authors report no relevant disclosures.

Supporting information

Table S1:

Table S2:

Table S3: