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. 2021 Oct 1;4(10):e2128271.
doi: 10.1001/jamanetworkopen.2021.28271.

Risk Factors and Time to Clinical Symptoms of Multiple Sclerosis Among Patients With Radiologically Isolated Syndrome

Christine Lebrun-Frénay  1 , Fabien Rollot  2   3   4 , Lydiane Mondot  1 , Helene Zephir  5 , Celine Louapre  6 , Emmanuelle Le Page  7 , Françoise Durand-Dubief  8 , Pierre Labauge  9   10 , Caroline Bensa  11 , Eric Thouvenot  12 , David Laplaud  13 , Jerome de Seze  14 , Jonathan Ciron  15 , Bertrand Bourre  16 , Philippe Cabre  17 , Olivier Casez  18 , Aurélie Ruet  19 , Guillaume Mathey  20 , Eric Berger  21 , Thibault Moreau  22 , Abdulatif Al Khedr  23 , Nathalie Derache  24 , Pierre Clavelou  25 , Anne-Marie Guennoc  26 , Alain Créange  27 , Jean-Philippe Neau  28 , Ayman Tourbah  29 , Jean-Philippe Camdessanché  30 , Adil Maarouf  31 , Celine Callier  1 , Patrick Vermersch  5 , Orhun Kantarci  32 , Aksel Siva  33 , Christina Azevedo  34 , Naila Makhani  35 , Mikael Cohen  1 , Daniel Pelletier  34 , Darin Okuda  36 , Sandra Vukusic  4   8 ; RISC, SFSEP, and OFSEP Investigators
Collaborators, Affiliations

Risk Factors and Time to Clinical Symptoms of Multiple Sclerosis Among Patients With Radiologically Isolated Syndrome

Christine Lebrun-Frénay et al. JAMA Netw Open. .

Abstract

Importance: 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.

Objectives: 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.

Design, setting, and participants: 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.

Exposure: Diagnosis of RIS.

Main outcomes and measures: 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.

Results: 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]; P < .001), spinal cord lesions (HR, 5.11 [95% CI, 1.99-13.13]; P = .001), and gadolinium-enhancing lesions on index scan (HR, 2.09 [95% CI, 1.13-3.87]; P = .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]; P < .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%.

Conclusions and relevance: 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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Lebrun-Frénay reported serving as principal investigator of the Teriflunomide in Radiologically Isolated Syndrome (TERIS) study, on the steering committee for the Arise study, and as co–president of the Observatoire Français de la Sclérose En Plaques (OFSEP) scientific committee. Dr Zephir reported serving as co–president of the OFSEP scientific committee and receiving personal fees from Biogen, Merck, Novartis, Alexion, and Edimark and grants from Roche outside the submitted work. Dr Louapre reported receiving personal fees from Biogen, Roche, Novartis, Teva, Sanofi, and Merck, and grants from Biogen outside the submitted work. Dr Le Page reported receiving personal fees from Biogen, Merck Serono, Teva, Roche, Sanofi, Novartis, and Bristol Myers Squibb outside the submitted work. Dr Laplaud reported receiving personal fees from Biogen, Novartis, Merck, MSD, Bristol Myers Squibb, Sanofi and grants from the Agence Nationale de la Recherche, Aide pour la Recherche sur la Sclérose En Plaques Foundation and European Database for Multiple Sclerosis Foundation outside the submitted work. Dr de Seze reported receiving personal fees from Biogen, Roche, Sanofi, Alexion, Bristol Myers Squibb, Actelion, and Teva outside the submitted work. Dr Ciron reported receiving personal fees from Biogen, Novartis, Merck, Sanofi Genzyme, Roche, Bristol Myers Squibb, and Alexion outside the submitted work. Dr Casez reported receiving personal fees from Biogen, Novartis, Roche, and Sanofi Genzyme and meeting invitations from Merck, Biogen, Novartis, and Roche outside the submitted work. Dr Ruet reported receiving grants from Novartis, Sanofi Genzyme, Roche and personal fees from Novartis, Biogen, Merck, and Roche outside the submitted work. Dr Derache reported receiving personal fees from Biogen, Novartis, Merck, and Roche outside the submitted work. Dr Clavelou reported receiving personal fees from Roche, Merck, Sanofi, and Novartis outside the submitted work. Dr Créange reported receiving travel expenses from MedDay Pharmaceuticals and personal fees from Merck, Novartis, Roche, and Biogen outside the submitted work. Dr Tourbah reported receiving personal fees from MedDay Pharmaceuticals, Novartis, and Hikma Pharmaceuticals and consulting fees from Roche outside the submitted work. Dr Vermersch reported receiving personal fees from Biogen, Novartis, Teva, Imcyse, AB Science, and Bristol Myers Squibb Celgene and grants from Sanofi Genzyme, Roche, and Merck outside the submitted work. Drs Kantarci, Siva, Azevedo, and Pelletier reported serving on the steering committee for the Arise and TERIS studies. Dr Makhani reported receiving a grant from the National Institutes of Health (NIH) National Institute of Neurological Disorders and Stroke (NINDS). Dr Siva reported receiving personal fees from Novartis, Sanofi Genzyme, Roche, and Merck Serono and grants from Istanbul University and the Scientific and Technological Research Council of Turkey outside the submitted work. Dr Azevedo reported receiving personal fees from Biogen, Genentech, Sanofi Genzyme, Novartis, Alexion, and EMD Serono outside the submitted work. Dr Makhani reported receiving grants from the NIH NINDS during the conduct of the study and grants from Charles H Hood Foundation outside the submitted work. Dr Cohen reported receiving personal fees from Biogen, Merck, Novartis, Roche, Alexion, Ad Scientiam, Teva, and Sanofi outside the submitted work. Dr Pelletier reported receiving personal fees from Roche, Novartis, and Sanofi Genzyme outside the submitted work. Dr Okuda reported serving as the principal investigator of the Arise study and on the steering committee for the TERIS study; receiving grants from Biogen; and receiving personal fees from Bristol Myers Squibb Celgene, EMD Serono, Sanofi Genzyme, Novartis, Osmotica Pharmaceuticals, and Viela Bio outside the submitted work. Dr Vukusic reported serving as the scientific coordinator of OFSEP; receiving grants from Biogen, Merck, Novartis, Roche, and Sanofi; receiving personal fees from Biogen, Bristol Myers Squibb Celgene, Merck, Novartis, Roche, and Sanofi; and receiving nonfinancial support from Biogen, Merck, Novartis, Roche, and Sanofi outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Kaplan-Meier Survival Analysis With the End Point of Time to First Acute or Progressive Event Suggestive of Multiple Sclerosis at 2 Years
A, At 2 years, 49 patients (19.2% [95% CI, 14.1%-24.0%]) presented with a clinical event. Shaded area indicates 95% CIs. B, The association of age with risk of a clinical event at 2 years is presented. C, The association of the presence of spinal cord lesions at baseline with risk of a clinical event is presented. D, The association of the presence of gadolinium-enhancing brain lesions at baseline with risk of a clinical event is presented.
Figure 2.
Figure 2.. Stratification for a Clinical Event Suggestive of Multiple Sclerosis by Number of Risk Factors
Among patients with 3 factors, 90.9% (95% CI, 41.1%-98.6%) had a clinical event at 2 years.
Figure 3.
Figure 3.. Sample Size Calculation for a 2-Year Radiologically Isolated Syndrome (RIS) Study Using 2009 RIS Criteria
Overall event rates of 15%, 20%, 30%, and 90% and an SD on the covariate of 0.6 were assumed. Power function from a simulation procedure estimating total sample sizes that would be needed to detect 40% (dark blue), 50% (orange), 60% (brown), and 70% (light blue) effect sizes, assuming a 1-sided α of .05 is presented. A, Estimated power for the entire RIS cohort with 20% cumulative probability of a clinical event at 2 years is presented. B, Patients with RIS and 0 or 1 risk factors, with 15% cumulative probability, are presented. C, Patients with RIS and 2 risk factors, with 30% cumulative probability, are presented. D, Patients with RIS and 3 identified risk factors, with 90% cumulative probability, are presented.
See this image and copyright information in PMC

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