In the absence of new lesions on T2 and T1-weighted magnetic resonance imaging (MRI), acute clinical events in patients with multiple sclerosis (MS) are associated with significantly higher risks of relapse-associated worsening (RAW) and transition to secondary progressive (SP) MS, according to new research.
In a multicenter observational cohort study, recently published in JAMA Neurology, approximately one-fourth of relapses in multiple sclerosis (MS) were not associated with new T2 lesions or gadolinium-enhanced T1 lesions on brain and spinal cord MRI, being classified as acute clinical events with stable MRI (ACES). These results underscore the significance of comprehensive brain and spinal cord MRI for classifying clinical events that could influence therapeutic decisions and considerations for randomized clinical trial design.1
(Editor’s note: This article has been adapted with permission from its original publication on our sister publication NeurologyLive.)
Among 31,885 clinical events reported, 637 events among 608 patients with MS (women, n = 493; mean age, 35.8 years [SD, 10.7]) were included in the analysis. Findings showed that ACES represented 166 (26.1 percent) events and were observed the most in patients who received highly effective disease-modifying therapies (DMTs), had a longer disease duration (odds ratio [OR], 1.04; 95% CI, 1.01-1.07), or presented with fatigue (OR, 2.14; 95% CI, 1.15-3.96). Notably, ACES were associated with significant increases in the Expanded Disability Status Scale (EDSS) score, lower than those reported for relapses with active MRI (RAM).
“We propose several hypotheses that could explain ACES, classified as active or inactive. In active hypotheses, the clinical event might be related to an inflammatory attack of the central nervous system and therefore qualified as relapse, but without new T2 lesions nor gadolinium-enhanced T1 lesions,” wrote senior author David-Axel Laplaud, M.D., Ph.D, head of the neurology department at the Nantes University Hospital in France, and colleagues.1
“In inactive hypotheses, symptoms in ACES might be unrelated to MS inflammatory activity but rather to pseudo relapses with less obvious triggers, to a subjective worsening of MS symptoms linked to another condition, to another neurological condition mimicking a relapse, or might be an early sign of neurodegenerative processes in patients with exhausted compensatory mechanisms.”
Conducting the study between January 2015 and June 2023, investigators gathered data for the study from a French MS registry called Observatoire Français de la Sclérose en Plaques on June 8, 2023.2 All clinical events reported as relapses were used if brain and spinal cord MRI were performed in 12 and 24 months prior to the event, respectively, and 50 days afterwards with gadolinium injection. Researchers classified events as RAM if a new T2 lesion or gadolinium-enhanced T1 lesion showed on brain or spinal cord MRI or as ACES otherwise and investigated factors associated with ACES.
(Editor’s note: For related content, see “Study of Ofatumumab for Multiple Sclerosis Shows ‘Profoundly Suppressed MRI Lesion Activity’,” “FDA Clears Magnetic Resonance Spectroscopy Platform for Non-Invasive Assessment of Brain Chemistry” and “Emerging AI Software for Brain MRI Gets FDA Nod.”)
Prior to the index event, researchers observed that patients with ACES reported significantly higher rates of relapse (relative rate [RR], 1.21; 95% CI, 1.01-1.46), confirmed disability accrual (hazard ratio [HR], 1.54; 95% CI, 1.13-2.11), and RAW (HR, 1.72; 95% CI, 1.20-2.45). In another finding presented in the study, patients with ACES had a significantly higher risk of secondary progressive transition (HR, 2.58; 95% CI, 1.02-6.51). Authors also noted that despite a reduction in RAM rate with DMTs based on expected efficacy, the ACES rate was stable across DMTs.
Three Key Takeaways
1. Lack of MRI evidence in significant number of multiple sclerosis relapses. Approximately 26% of MS relapses occur without new MRI lesions, classified as ACES, highlighting the importance of thorough MRI evaluations.
2. Common contributing factors to ACES. ACES were more common in patients with longer disease duration, those on highly effective DMTs, and those presenting with fatigue.
3. Higher rates of relapse, worsening and secondary progressive MS. The study authors noted that patients with MS and ACES had hazard ratios of 1.72 and 2.58 for relapse-associated worsening (RAW) and transition to secondary progressive MS, respectively.
“The implications of our findings are important for the design of randomized clinical trials and real-life practice. In randomized clinical trials, it is crucial to better determine the target of the therapies tested: if DMTs primarily aim to reduce the rate of relapses with radiological activity, it becomes imperative to validate each clinical relapse with a comprehensive brain and spinal cord MRI; this could also enhance the statistical power of future trials,” noted Laplaud and colleagues.1 “In real-life practice, it may be necessary to investigate radiological activity with a brain and spinal cord MRI when a patient presents with a clinical event to classify it as RAM, which would require a DMT change, or ACES, for which the therapeutic decision is less clear.”
In regard to limitations of the present study, the researchers noted that MRI exams were conducted in routine practice without central review. Also, only clinical events recognized as relapses by the clinicians were reported in the French database. Therefore, clinical events noted in practices that might have differed among experts and centers would be absent. Furthermore, the predicted annualized rates of ACES and RAM for each DMT were computed in a selected population without correction for indication bias. Accordingly, the authors noted that these findings should not be interpreted as reliable measures of DMT effectiveness.
References
1. Gavoille A, Rollot F, Casey R, et al. Acute clinical events identified as relapses with stable magnetic resonance imaging in multiple sclerosis. JAMA Neurol. 2024;81(8):814-823. doi:10.1001/jamaneurol.2024.1961
2. Vukusic S, Casey R, Rollot F, et al. Observatoire Français de la Sclérose en Plaques (OFSEP): a unique multimodal nationwide MS registry in France. Mult Scler. 2020;26(1):118-122.
