For Doctors in a Hurry
- Researchers investigated whether patients with late-onset multiple sclerosis receive fewer disease-modifying therapies than younger patients with similar disease severity.
- This retrospective cohort study analyzed 36,148 patients from the French MS registry, including 2,308 individuals aged 50 or older at onset.
- Late-onset patients had a lower annual probability of receiving highly effective therapy (24.6% versus 44.4%; odds ratio 0.41; 95% CI 0.36-0.46).
- The researchers concluded that late-onset patients are less likely to initiate treatment and more likely to discontinue therapy without escalating.
- Clinicians must determine if these treatment disparities reflect biological differences or potential undertreatment in patients diagnosed after age 50.
Therapeutic Divergence in Maturing Multiple Sclerosis Populations
The management of relapsing-remitting multiple sclerosis has been altered by a diverse armamentarium of disease-modifying therapies targeting neuroinflammatory pathways to reduce relapse rates [1, 2]. While high-efficacy agents such as ocrelizumab and natalizumab offer substantial protection against disability progression, their use requires careful monitoring for serious adverse events like opportunistic infections [3, 4]. Clinical guidelines advocate for early intervention, but the foundational evidence for these therapies is largely derived from trials in younger cohorts, creating an evidence gap for patients presenting later in life [5, 6]. Consequently, determining when to intensify treatment or consider complete discontinuation as the disease phenotype shifts from inflammatory to more degenerative phases remains a clinical challenge [7]. A new large-scale registry study now quantifies how these decisions are made in real-world practice for patients with late-onset disease.
Registry Analysis of Relapsing-Remitting MS Cohorts
To investigate real-world prescribing patterns, researchers conducted a retrospective cohort study using data from the French MS registry, encompassing patients with a relapsing-remitting disease onset between 1997 and 2023. The study population included 36,148 patients, of whom 26,540 (73.4%) were female, with a mean age of 33.5 years (SD, 9.7). A key subgroup consisted of 2,308 patients (6.4%) who were aged 50 or older at disease onset, defined as late-onset multiple sclerosis (LOMS). The registry's longitudinal data provided a robust median follow-up of 10.8 years (interquartile range, 5.6-17.0), allowing for a detailed analysis of long-term treatment trajectories.
To isolate the effect of age from that of disease progression, the analysis was statistically adjusted for disease severity. The researchers employed a longitudinal logistic model with generalized estimating equations, a statistical method designed to analyze repeated measurements over time while accounting for correlations within individual patient data. They also applied inverse-probability-of-censoring weighting, a technique that statistically corrects for patients who drop out of follow-up, ensuring that the results remain representative of the initial cohort. These methods provided a rigorous comparison of treatment probabilities between the late-onset and adult-onset groups.
Quantifying the Treatment Gap in Older Patients
The study's primary outcome, the annual probability of receiving any disease-modifying therapy (DMT), revealed a significant disparity between age groups after adjusting for disease severity. Patients with LOMS had a lower annual probability of receiving a DMT compared with patients with adult-onset multiple sclerosis (AOMS), at 73.7% versus 83.1% respectively. This corresponds to an odds ratio of 0.57 (95% CI 0.52-0.62), indicating that patients diagnosed at or after age 50 were substantially less likely to be on treatment in any given year. This gap widened considerably when focusing on the most potent medications. The annual probability of receiving a highly effective DMT (HEDMT) was 24.6% in the LOMS group versus 44.4% in the AOMS group, yielding an odds ratio of 0.41 (95% CI 0.36-0.46).
Interestingly, this difference in therapeutic intensity was not due to less diligent monitoring. The investigators found that the frequency of clinical and radiologic follow-up, including annual assessments with the Expanded Disability Status Scale (EDSS) and brain MRI scans, did not differ significantly between the LOMS and AOMS cohorts. This finding suggests the observed treatment gap is not an artifact of reduced clinical surveillance in older patients but rather reflects a fundamental difference in prescribing philosophy, where age at onset appears to be a key factor in clinical decision-making, independent of disease severity or available monitoring data.
Specific Agent Selection and Initiation Rates
The analysis of prescribing patterns for individual agents further illuminated the conservative treatment approach for older patients. The data showed that patients with LOMS were more likely to receive teriflunomide, an oral pyrimidine synthesis inhibitor, than their younger counterparts. Conversely, they were less likely to be prescribed fumarates, sphingosine-1-phosphate receptor (S1PR) modulators, natalizumab, or anti-CD20 monoclonal antibodies. This pattern indicates a clinical preference for a narrower set of therapies and an avoidance of higher-efficacy biologics and certain oral immunomodulators in the LOMS population.
This therapeutic divergence was also reflected in the rate of new treatment starts. The study found that the rate of DMT initiation was lower in patients with LOMS (0.13 initiations per patient-year) compared to the AOMS group (0.17 initiations per patient-year). This lower propensity to initiate therapy, combined with the specific selection of less potent agents, contributes directly to the overall lower treatment prevalence observed in patients diagnosed later in life.
Shifting Strategies from Escalation to Discontinuation
While the overall rates of stopping a DMT were similar between groups (59.7% in LOMS vs. 60.4% in AOMS, excluding pregnancy-related discontinuations), the clinical reasoning behind these decisions differed markedly. The findings point to a distinct shift in long-term management philosophy for older patients. For the LOMS cohort, treatment cessation was more often part of a complete discontinuation strategy (27.9% vs. 22.3%), where the decision was made to stop DMTs altogether.
In contrast, for younger patients, stopping a particular drug was more frequently a prelude to intensifying therapy. Discontinuations in the LOMS group were less often attributed to an escalation strategy, where a patient is switched to a more effective medication, compared to the AOMS group (9.2% vs. 13.8%). Taken together, these results suggest that for patients with comparable disease severity, a later age of onset is associated with a clinical trajectory that favors the withdrawal of immunomodulatory treatment rather than the proactive escalation commonly pursued in younger populations.
References
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2. Melendez-Torres G, Auguste P, Armoiry X, et al. Clinical effectiveness and cost-effectiveness of beta-interferon and glatiramer acetate for treating multiple sclerosis: systematic review and economic evaluation.. Health Technology Assessment. 2017. doi:10.3310/hta21520
3. Śladowska K, Kawalec P, Holko P, Osiecka O. Comparative safety of high-efficacy disease-modifying therapies in relapsing-remitting multiple sclerosis: a systematic review and network meta-analysis.. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. 2022. doi:10.1007/s10072-022-06197-3
4. Kappos L, Traboulsee A, Li DKB, et al. Ocrelizumab exposure in relapsing-remitting multiple sclerosis: 10-year analysis of the phase 2 randomized clinical trial and its extension.. Journal of neurology. 2024. doi:10.1007/s00415-023-11943-4
5. Bayas A, Christ M, Faissner S, et al. Disease-modifying therapies for relapsing/active secondary progressive multiple sclerosis - a review of population-specific evidence from randomized clinical trials.. Therapeutic advances in neurological disorders. 2023. doi:10.1177/17562864221146836
6. Lucchetta RC, Leonart LP, Gonçalves MVM, et al. Reliability in long-term clinical studies of disease-modifying therapies for relapsing-remitting multiple sclerosis: A systematic review.. PloS one. 2020. doi:10.1371/journal.pone.0231722
7. Williams T, Zetterberg H, Chataway J. Neurofilaments in progressive multiple sclerosis: a systematic review.. Journal of neurology. 2021. doi:10.1007/s00415-020-09917-x
