Risk Factors and Time to Clinical Symptoms of Multiple Sclerosis Among Patients With Radiologically Isolated Syndrome
Authors: Christine Lebrun-Frénay, Fabien Rollot, Lydiane Mondot, Helene Zephir, Celine Louapre, Emmanuelle Le Page, Françoise Durand-Dubief, Pierre Labauge, Caroline Bensa, Eric Thouvenot, David Laplaud, Jerome de Seze, Jonathan Ciron, Bertrand Bourre, Philippe Cabre, Olivier Casez, Aurélie Ruet, Guillaume Mathey, Eric Berger, Thibault Moreau, Abdulatif Al Khedr, Nathalie Derache, Pierre Clavelou, Anne-Marie Guennoc, Alain Créange, Jean-Philippe Neau, Ayman Tourbah, Jean-Philippe Camdessanché, Adil Maarouf, Celine Callier, Patrick Vermersch, Orhun Kantarci, Aksel Siva, Christina Azevedo, Naila Makhani, Mikael Cohen, Daniel Pelletier, Darin Okuda, Sandra Vukusic, Orhun Kantarci, Aksel Siva, Daniel Pelletier, Darin Okuda, Christina Azevedo, Naila Makhani, Fatai Radji, Nathalie Morel, Deborah Grosset-Jeannin, Aurelian Ungureanu, Latine Boyer, Laurent Suchet, Zyad Elias, Christine Lebrun-Frénay, Mikael Cohen, Lydiane Mondot, Eric Thouvenot, Jonathan Ciron, Françoise Durand-Dubief, Bruno Brochet, Aurélie Ruet, Jean-Christophe Ouallet, Gilles Defer, Pierre Branger, Nathalie Derache, Pierre Clavelou, Frédéric Taithe, Adullatif Alkhedr, Agnès Fromont, Thibault Moreau, Ayman Tourbah, Olivier Casez, Eric Berger, Helene Zephir, Olivier Outteryck, Patrick Vermersch, Patrick Hautecoeur, Geraldine Androdias, Iuliana Ionescu, Jean Pelletier, Bertrand Audoin, Adil Maarouf, Xavier Ayrignac, Clarisse Carra-Dalliere, Pierre Labauge, Marc Debouverie, Guillaume Mathey, Philippe Cabre, David Laplaud, Sandrine Wiertlevski, Saskia Bresch, Giovanni Castelnovo, Caroline Papeix, Celine Louapre, Elisabeth Maillart, Catherine Lubetzki, Bruno Stankoff, Bertrand Fontaine, Claire Giannesini, Olivier Heinzleff, Alain Créange, Bertrand Bourre, Olivier Gout, Antoine Guegen, Caroline Bensa, Emmanuelle Le Page, Laure Michel, Laurent Magy, Jerome De Seze, Nicolas Collongues, Emmanuelle Leray, Anne Marie Guennoc, Damien Biotti, Jean-Philippe Camdessanché, Thomas De Broucker, Sabrina Sehaki, Nathalie Devys-Meyer, Mathieu Bereau, Chrystelle Cappe, Katy-Kim Kounkou, Emilie Dumont, Edwige Lescieux, Alexia Protin, Maty Diop Kane, Julie Boucher, Julie Petit, Irène Tabellah Kasonde, Aymeric De Vilmarrest, Marie Nicol, Muriel Malbezin, Javier Olaiz, Claire Rigaud-Bully, Romain Casey, Fabien Rollot, Irena Vukusic, Nadine Debard, François Cotton, Amalle Abdelalli, Bernadette Di Lelio, Frédéric Pinna, Francis Guillemin, Amandine Ziegler, Céline Callier, Karima Zehrouni, Jérôme Hodel, Abir Wahab, Mickaël Zedet, Ombeline Fagniez, Clémence Laage, Corinne Pottier, Iuliana Slesari, Mathilde Sampaio, Jean-Philippe Neau, Emilie Rabois, Cédric Castex, Benjamin Hebant, Maxime Guillaume, Christine Vimont, Romain Muraz, Damien Le Port, Carole Henry, Carole Berthe, Noellie Freitas, Vincent Visneux, Melanie Forestier, Stéphane Beltran, Géraldine Meunier, Jérôme Servan, Fernando Pico, Virginie Chatagner
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Younger age, oligoclonal bands, and infratentorial and spinal cord lesions are factors associated with an increased 10-year risk of clinical conversion from radiologically isolated syndrome (RIS) to multiple sclerosis (MS). Whether disease-modifying therapy is beneficial for individuals with RIS is currently unknown. <h3>Objectives</h3> To evaluate the 2-year risk of a clinical event (onset of clinical symptoms of MS) prospectively, identify factors associated with developing an early clinical event, and simulate the sample size needed for a phase III clinical trial of individuals with RIS meeting 2009 RIS criteria. <h3>Design, Setting, and Participants</h3> This cohort study used data on prospectively followed-up individuals with RIS identified at 1 of 26 tertiary centers for MS care in France that collect data for the Observatoire Français de la Sclérose en Plaques database. Participants were aged 10 to 80 years with 2 or more magnetic resonance imaging (MRI) scans after study entry and an index scan after 2000. All diagnoses were validated by an expert group, whose review included a double centralized MRI reading. Data were analyzed from July 2020 to January 2021. <h3>Exposure</h3> Diagnosis of RIS. <h3>Main Outcomes and Measures</h3> Risk of clinical event and associated covariates at index scan were analyzed among all individuals with RIS. Time to the first clinical event was compared by covariates, and sample size estimates were modeled based on identified risk factors. <h3>Results</h3> Among 372 individuals with RIS (mean [SD] age at index MRI scan, 38.6 [12.1] years), 354 individuals were included in the analysis (264 [74.6%] women). A clinical event was identified among 49 patients (13.8%) within 2 years, which was associated with an estimated risk of conversion of 19.2% (95% CI, 14.1%-24.0%). In multivariate analysis, age younger than 37 years (hazard ratio [HR], 4.04 [95% CI, 2.00-8.15];<i>P</i> &lt; .001), spinal cord lesions (HR, 5.11 [95% CI, 1.99-13.13];<i>P</i> = .001), and gadolinium-enhancing lesions on index scan (HR, 2.09 [95% CI, 1.13-3.87];<i>P</i> = .02) were independently associated with an increased risk of conversion to MS. Having 2 factors at the time of the index MRI scan was associated with a risk of 27.9% (95% CI, 13.5%-39.9%) of a seminal event within 2 years, increasing to 90.9% (95% CI, 41.1%-98.6%) for individuals with all 3 factors (3 risk factors vs none: HR, 23.34 [95% CI, 9.08-59.96];<i>P</i> &lt; .001). Overall, with 80% power to detect an effect size of 60% within 24 months, a total of 160 individuals with RIS were needed assuming an event rate of 20%. <h3>Conclusions and Relevance</h3> This study found that age younger than age 37 years, spinal cord involvement, and gadolinium-enhancing lesions on index MRI scan were associated with earlier clinical disease and relevant to the number of enrolled patients needed to detect a potential treatment effect.