Predictors of initiating high-efficacy vs. platform therapies as first-line disease-modifying treatment in multiple sclerosis

ORIGINAL RESEARCH article

Front. Neurol., 29 January 2026 – Sec. Multiple Sclerosis and Neuroimmunology

Volume 17 – 2026 | https://doi.org/10.3389/fneur.2026.1738815

Abstract

Background: 

The therapeutic landscape of multiple sclerosis (MS) is rapidly evolving, with increasing emphasis on early initiation of high-efficacy disease-modifying therapies (heDMTs). However, real-world data on predictors of first-line heDMT use and its outcomes remain scarce in the Middle East.

Objectives: 

To identify demographic and clinical factors influencing the choice of first-line heDMT vs. platform therapy in relapsing-remitting MS (RRMS) and to evaluate whether initial treatment class impacts disability outcomes and treatment persistence.

Methods: 

We conducted a retrospective cohort study of 826 RRMS patients treated at a tertiary center in Saudi Arabia between 2016 and 2024. Predictors of initiating heDMT were identified using multivariable logistic regression. Disability status (EDSS category) was analyzed using ordinal logistic regression. Treatment persistence and causes of discontinuation were examined using Kaplan–Meier survival analysis, Cox proportional hazards modeling, and Fine–Gray competing-risks regression.

Results: 

Of 826 patients, 330 (40%) received heDMTs as first-line therapy. Initiation in the later treatment era (2019–2024) strongly predicted heDMT use compared with the early treatment era (2008–2013; OR = 48.8; p < 0.001), as did cerebellar symptom onset (OR = 2.51; p = 0.025). Age, sex, and comorbidities were not significant predictors. Starting on a heDMT did not translate into higher or lower disability levels compared with platform therapies (OR = 1.08; p = 0.767). However, patients initiating heDMTs demonstrated superior treatment persistence (12-month persistence: 91.7 vs. 83.4%; p < 0.0001) and a markedly lower risk of discontinuation (HR = 0.41; p < 0.001). Competing-risks analysis showed that heDMT users were significantly less likely to discontinue due to inefficacy or adverse events, but more likely to stop for other reasons, such as pregnancy, preference, or supply issues.

Conclusions: 

First-line use of heDMTs in Saudi Arabia has increased substantially over recent years, particularly among patients with cerebellar onset. While disability outcomes were similar between treatment groups, initiating heDMTs conferred clear advantages in persistence and tolerability. These findings reinforce the paradigm shift toward early intensive MS management and highlight the need for broader access and guideline-driven implementation of heDMTs in the region.

Introduction

Multiple sclerosis (MS) is a chronic immune-mediated demyelinating disease of the central nervous system and the most common cause of neurological disability in young adults worldwide (1). Its burden is rising in the Middle East; in Saudi Arabia, the prevalence of MS has increased to an estimated ~62 per 100,000 population (2). The introduction of disease-modifying therapies (DMTs) over the past three decades has revolutionized MS management by reducing relapse rates and slowing the progression of disability in relapsing forms of the disease (1).

Despite these therapeutic advances, the optimal strategy for initial DMT selection remains a subject of debate (3). Traditionally, MS has been managed with a stepwise “escalation” approach in which patients are started on platform therapies and switched to a more potent agent only if disease activity persists. In recent years, however, accumulating evidence has prompted a paradigm shift toward early use of high-efficacy disease-modifying therapies (heDMTs) as first-line treatment in appropriate patients, consistent with the “hit early, hit hard” strategy (4). Several highly effective monoclonal antibody and oral agents (e.g., natalizumab, ocrelizumab, alemtuzumab, cladribine, and sphingosine-1-phosphate receptor modulators) have demonstrated superior suppression of relapses and new lesions compared to platform therapies, albeit with increased risks and monitoring requirements (4). The rationale for an “induction” or early intensive approach is supported by emerging data showing that initiating heDMTs at disease onset can improve long-term outcomes. For example, a recent meta-analysis of seven studies found that over a 5-year horizon, patients started on early intensive therapy had ~30% lower risk of disability worsening (measured by confirmed Expanded Disability Status Scale (EDSS) progression) than those managed with an escalation strategy (5). Likewise, an observational cohort reported that initial treatment with heDMTs (such as fingolimod, natalizumab, or alemtuzumab) was associated with a significantly reduced risk of conversion to secondary progressive MS compared to starting on interferon or glatiramer acetate (6).

Nevertheless, real-world practice shows considerable variation in the uptake of heDMTs as first-line therapy. Clinicians must balance the greater efficacy of heDMTs against their potential adverse effects, costs, and patient-specific factors. Recent evidence indicates that the decision to start a patient on heDMT is influenced by both clinical and demographic factors. For example, one large retrospective study found that only about one in four newly treated MS patients in the United States initially received a heDMT, and those who did were more likely to be male and to have early signs of aggressive disease (such as impaired ambulation or other disability requiring symptomatic treatments) (7). In contrast, patients presenting with primarily sensory or visual symptoms were significantly less likely to be started on a heDMT (7). These patterns suggest that physicians often reserve first-line heDMT for cases perceived as high-risk, while adopting a more cautious approach in patients with ostensibly milder disease.

In Saudi Arabia, data on MS treatment patterns and the determinants of initial therapy choice remain limited (1). There is some concern that the early use of heDMTs may be underutilized in our setting (8), possibly reflecting differences in practice preferences, resource availability, or risk aversion. Understanding how and why clinicians decide to employ heDMTs as first-line treatment in the local context is important, especially since early intensive treatment has been linked to improved patient outcomes (8). Another practical consideration is treatment persistence: heDMTs can offer durable disease control but may be discontinued due to safety/tolerability issues, whereas platform therapies might be switched early because of inadequate efficacy. Real-world studies have shown that roughly one-third of DMT discontinuations are due to adverse events and another third is due to lack of efficacy, and that after 10 years, over 80% of patients started on interferon or glatiramer acetate have switched therapies compared to only ~20% of those treated with alemtuzumab (9). These findings highlight the need to evaluate how initial DMT choice impacts long-term adherence and disease stabilization.

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