Abstract
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. 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. 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. Diagnosis of RIS. 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. 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%. 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.
Highlights
Since the 1980s, preclinical multiple sclerosis (MS) was identified as brain magnetic resonance imaging (MRI) findings consistent with central nervous system (CNS) demyelination incidentally discovered among individuals without symptoms.[1,2,3,4,5] In 2009, criteria for radiologically isolated syndrome (RIS) were defined to enhance the characterization of patients.[3]
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%
Having 2 factors at the time of the index MRI scan was associated with a risk of 27.9% of a seminal event within 2 years, increasing to 90.9% for individuals with all 3 factors (3 risk factors vs none: hazard ratio (HR), 23.34 [95% CI, 9.08-59.96]; P < .001)
Summary
Since the 1980s, preclinical multiple sclerosis (MS) was identified as brain magnetic resonance imaging (MRI) findings consistent with central nervous system (CNS) demyelination incidentally discovered among individuals without symptoms.[1,2,3,4,5] In 2009, criteria for radiologically isolated syndrome (RIS) were defined to enhance the characterization of patients.[3]. An analysis of sizeable multicenter retrospective data collected by the RIS Consortium (RISC) found that younger age, male sex, and the presence of spinal cord lesions were associated with 5-year-risk of conversion to a first clinical demyelinating event, suggesting the importance of intramedullary lesions on clinical evolution.[11,12] After 10 years, age and spinal cord lesions were still associated with increased risk, as were oligoclonal bands (OCBs) in cerebrospinal fluid (CSF) and infratentorial lesions on the index scan[13] and occurrences of gadolinium-enhancing lesions on followup MRIs. An analysis of sizeable multicenter retrospective data collected by the RIS Consortium (RISC) found that younger age, male sex, and the presence of spinal cord lesions were associated with 5-year-risk of conversion to a first clinical demyelinating event, suggesting the importance of intramedullary lesions on clinical evolution.[11,12] After 10 years, age and spinal cord lesions were still associated with increased risk, as were oligoclonal bands (OCBs) in cerebrospinal fluid (CSF) and infratentorial lesions on the index scan[13] and occurrences of gadolinium-enhancing lesions on followup MRIs Despite this homology with MS, the association of early treatment with decreased conversion to MS is unknown. We evaluated the 2-year risk of a first clinical event suggestive of MS and estimated sample sizes needed for 24-month prospective clinical trials based on the primary outcome of a first clinical event and critical risk factors that may enrich cohorts studied
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