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Observational Study
. 2024 Aug 1;81(8):814-823.
doi: 10.1001/jamaneurol.2024.1961.

Acute Clinical Events Identified as Relapses With Stable Magnetic Resonance Imaging in Multiple Sclerosis

Antoine Gavoille  1   2   3 , Fabien Rollot  4   5 , Romain Casey  4   5 , Anne Kerbrat  6 , Emmanuelle Le Page  6 , Kevin Bigaut  7 , Guillaume Mathey  8 , Laure Michel  6 , Jonathan Ciron  9   10 , Aurelie Ruet  11   12 , Elisabeth Maillart  13 , Pierre Labauge  14   15 , Hélène Zephir  16 , Caroline Papeix  17 , Gilles Defer  18 , Christine Lebrun-Frenay  19 , Thibault Moreau  20 , Eric Berger  21 , Bruno Stankoff  22 , Pierre Clavelou  23   24 , Eric Thouvenot  24   25 , Olivier Heinzlef  26 , Jean Pelletier  27 , Abdullatif Al-Khedr  28 , Olivier Casez  29   30 , Bertrand Bourre  31 , Philippe Cabre  32 , Abir Wahab  33 , Laurent Magy  34 , Jean-Philippe Camdessanché  35 , Inès Doghri  36 , Solène Moulin  37 , Haifa Ben-Nasr  38 , Céline Labeyrie  39 , Karolina Hankiewicz  40 , Jean-Philippe Neau  41 , Corinne Pottier  42 , Chantal Nifle  43 , Eric Manchon  44 , Bertrand Lapergue  45 , Sandrine Wiertlewski  46 , Jérôme De Sèze  7 , Sandra Vukusic  1   4   5   47 , David Axel Laplaud  46 ; OFSEP Investigators
Collaborators, Affiliations
Observational Study

Acute Clinical Events Identified as Relapses With Stable Magnetic Resonance Imaging in Multiple Sclerosis

Antoine Gavoille et al. JAMA Neurol. .

Abstract

Importance: Understanding the association between clinically defined relapses and radiological activity in multiple sclerosis (MS) is essential for patient treatment and therapeutic development.

Objective: To investigate clinical events identified as relapses but not associated with new T2 lesions or gadolinium-enhanced T1 lesions on brain and spinal cord magnetic resonance imaging (MRI).

Design, setting, and participants: This multicenter observational cohort study was conducted between January 2015 and June 2023. Data were extracted on June 8, 2023, from the French MS registry. All clinical events reported as relapses in patients with relapsing-remitting MS were included if brain and spinal cord MRI was performed within 12 and 24 months before the event, respectively, and 50 days thereafter with gadolinium injection.

Exposures: Events were classified as relapses with active MRI (RAM) if a new T2 lesion or gadolinium-enhanced T1 lesion appeared on brain or spinal cord MRI or as acute clinical events with stable MRI (ACES) otherwise.

Main outcomes and measures: Factors associated with ACES were investigated; patients with ACES and RAM were compared regarding Expanded Disability Status Scale (EDSS) course, relapse rate, confirmed disability accrual (CDA), relapse-associated worsening (RAW), progression independent of relapse activity (PIRA), and transition to secondary progressive (SP) MS, and ACES and RAM rates under each disease-modifying therapy (DMT) were estimated.

Results: Among 31 885 clinical events, 637 in 608 patients (493 [77.4%] female; mean [SD] age, 35.8 [10.7] years) were included. ACES accounted for 166 (26.1%) events and were more likely in patients receiving highly effective DMTs, those with longer disease duration (odds ratio [OR], 1.04; 95% CI, 1.01-1.07), or those presenting with fatigue (OR, 2.14; 95% CI, 1.15-3.96). ACES were associated with significant EDSS score increases, lower than those found for RAM. Before the index event, patients with ACES experienced significantly higher rates of relapse (relative rate [RR], 1.21; 95% CI, 1.01-1.46), CDA (hazard ratio [HR], 1.54; 95% CI, 1.13-2.11), and RAW (HR, 1.72; 95% CI, 1.20-2.45). Patients with ACES were at significantly greater risk of SP transition (HR, 2.58; 95% CI, 1.02-6.51). Although RAM rate decreased with DMTs according to their expected efficacy, ACES rate was stable across DMTs.

Conclusions and relevance: The findings in this study introduce the concept of ACES in MS, which accounted for one-fourth of clinical events identified as relapses.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Le Page reported consulting or lectures and invitations for national and international congresses from Biogen, Merck, Teva Pharmaceuticals, Sanofi-Genzyme, Novartis Alexion; research support from Teva Pharmaceuticals and Biogen; academic research grants from PHRC and LFSEP, and a travel grant from ARSEP Foundation. Dr Ciron reported consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Novartis, Merck Serono, Sanofi-Genzyme, Roche, Alexion, and Horizon Therapeutics. Dr Ruet reported honoraria for meeting speaking from Merck Serono, Alexion, Horizon Therapeutics, and Sanofi-Genzyme as well as support for traveling from Biogen, Novartis, and Merck Serono; her institution received research grants from Biogen, Roche, Sanofi-Genzyme, and Bristol Myers Squibb. Dr Maillart reporting consulting and lecturing fees from Alexion, Biogen, Horizon, Janssen, Merck Serono, Novartis, Roche, Sandoz, Sanofi-Genzyme, and Teva Pharmaceuticals and research support from Biogen. Dr Labauge reported consulting and lecturing fees, travel grants, and unconditional research support from Biogen, Sanofi-Genzyme, Novartis, Merck Serono, Roche, and Teva Pharmaceuticals. Dr Zephir reported consulting or lectures and invitations for national and international congresses from Biogen, Merck Serono, Teva Pharmaceuticals, Sanofi-Genzyme, Novartis, and Bayer as well as research support from Teva Pharmaceuticals and Roche and academic research grants from Académie de Médecine, LFSEP, FHU Imminent, and ARSEP Foundation. Dr Defer reported consulting and lecturing fees from Biogen, Novartis, Sanofi-Genzyme, Merck Serono, Roche, and Teva Pharmaceuticals and funding for travel from Merck Serono, Biogen, Sanofi-Genzyme, Novartis, and Teva Pharmaceuticals; Dr Defer’s institution received research support from Merck Serono, Biogen, Sanofi-Genzyme, and Novartis. Dr Moreau reported fees for serving as scientific advisor from Biogen, MedDay, Novartis, and Sanofi-Genzyme. Dr Berger reported honoraria and consulting fees from Novartis, Sanofi-Genzyme, Biogen, Roche, and Teva Pharmaceuticals. Dr Stankoff reported consulting and lecturing fees from Biogen, Merck Serono, Novartis, and Janssen and unconditional research support from Merck Serono, and Roche. Dr Clavelou reported consulting and lecturing fees, travel grants, and unconditional research support from Biogen, Janssen, MedDay, Merck Serono, Novartis, Roche, Sanofi-Genzyme, and Teva Pharmaceuticals. Dr Thouvenot reported consulting and lecturing fees, travel grants, or unconditional research support from Actelion, Biogen, Janssen, Merck Serono, Novartis, Roche, and Sanofi-Genzyme. Dr Heinzlef reported consulting and lecturing fees from Bayer Schering, Merck Serono, Teva Pharmaceuticals, Sanofi-Genzyme, Novartis, Almirall, and Biogen; travel grants from Novartis, Teva Pharmaceuticals, Sanofi-Genzyme, Merck Serono, and Biogen; and research support from Roche, Merck Serono, and Novartis. Dr Casez reported consulting or lecturing fees and travelling or congress support from Biogen, Roche, Merck Serono, Novartis, Janssen, and Sanofi-Genzyme. Dr Bourre reported serving on scientific advisory boards for Alexion, Bristol Myers Squibb, Biogen, Sanofi-Genzyme, Janssen, Merck Serono, Horizon, Novartis, Roche, and Sandoz and received funding for travel and honoraria from Alexion, Merck Serono, Novartis, Sanofi-Genzyme, Roche, and Janssen. Dr Wahab reported giving expert testimony for Roche and receiving travel grants from Biogen. Dr Camdessanche reported consulting and lecturing fees from Akcea, Alexion, Alnylam, argenx, Biogen, Bristol Myers Squibb, CSL Behring, Sanofi-Genzyme, Grifols, Laboratoire Français des Biotechnologies, Merck Serono, Natus, Novartis, Pfizer, Pharmalliance, UCB Pharma, Teva Pharmaceuticals, and SNF Floerger and travel grants from Akcea, Alexion, Alnylam, argenx, Biogen, CSL Behring, Sanofi-Genzyme, Grifols, Laboratoire Français des Biotechnologies, Merck Serono, Natus, Novartis, Pfizer, Teva Pharmaceuticals, and SNF Floerger. Dr Ben-Nasr reported honoraria and consulting fees from Novartis, Sanofi-Genzyme, and Roche; research support from Biogen and Novartis; and travel grants from Sanofi-Genzyme, Novartis, and Roche. Dr Neau reported support from Merck Serono, Biogen, Novartis, Teva Pharmaceuticals, Roche, and Alexion. Dr Wiertlewski reported consulting fees, speaker fees, honoraria for RESEP Pays de Loire from Alexion, Biogen, Janssen-Cilag, Merck Serono, Novartis, Roche, and Sanofi-Genzyme. Dr De Seze reported consulting and lecturing fees, travel grants, and unconditional research support from Biogen, Sanofi-Genzyme, Novartis, Roche, Sanofi Aventis, and Teva Pharmaceuticals. Dr Sandra Vukusic reported lecturing fees, travel grants, and research support from Biogen, Bristol Myers Squibb–Celgene, Janssen, Merck Serono, Novartis, Roche, Sandoz, and Sanofi-Genzyme. Dr Laplaud reported serving on scientific advisory boards for Alexion, Bristol Myers Squibb, Roche, Sanofi-Genzyme, Novartis, Merck Serono, Janssen, and Biogen; received conference travel support and/or speaker honoraria from Alexion, Novartis, Biogen, Roche, Sanofi-Genzyme, Bristol Myers Squibb, and Merck Serono; and received research support from Fondation ARSEP, Fondation EDMUS, and Agence Nationale de la Recherche. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Comparison of Patients With Acute Clinical Events With Stable MRI (ACES) and Relapses With Active MRI (RAM)
The mean change in Expanded Disability Status Scale (EDSS) score in each time period relative to the index event is predicted from the EDSS mixed-effects linear model for a mean patient. Relapse and confirmed disability accrual (CDA), relapse-associated worsening (RAW), and progression independent of relapse activity (PIRA) rates are unadjusted observed values. Cumulative incidence curves of transition to secondary progressive (SP) disease were obtained using the Kaplan-Meier method. Whiskers represent 95% CIs. MRI indicates magnetic resonance imaging.
Figure 2.
Figure 2.. Estimated Annualized Rate of Relapses With Active MRI (RAM) and Acute Clinical Events With Stable MRI (ACES) Under Each Disease-Modifying Therapy (DMT)
Horizontal dashed lines indicate overall mean rate. Whiskers indicate 95% CIs. MRI indicates magnetic resonance imaging.
See this image and copyright information in PMC

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