Early clinical markers of aggressive multiple sclerosis

Abstract

Patients with the ‘aggressive’ form of multiple sclerosis accrue disability at an accelerated rate, typically reaching Expanded Disability Status Score (EDSS) ≥ 6 within 10 years of symptom onset. Several clinicodemographic factors have been associated with aggressive multiple sclerosis, but less research has focused on clinical markers that are present in the first year of disease. The development of early predictive models of aggressive multiple sclerosis is essential to optimize treatment in this multiple sclerosis subtype. We evaluated whether patients who will develop aggressive multiple sclerosis can be identified based on early clinical markers. We then replicated this analysis in an independent cohort. Patient data were obtained from the MSBase observational study. Inclusion criteria were (i) first recorded disability score (EDSS) within 12 months of symptom onset; (ii) at least two recorded EDSS scores; and (iii) at least 10 years of observation time, based on time of last recorded EDSS score. Patients were classified as having ‘aggressive multiple sclerosis’ if all of the following criteria were met: (i) EDSS ≥ 6 reached within 10 years of symptom onset; (ii) EDSS ≥ 6 confirmed and sustained over ≥6 months; and (iii) EDSS ≥ 6 sustained until the end of follow-up. Clinical predictors included patient variables (sex, age at onset, baseline EDSS, disease duration at first visit) and recorded relapses in the first 12 months since disease onset (count, pyramidal signs, bowel-bladder symptoms, cerebellar signs, incomplete relapse recovery, steroid administration, hospitalization). Predictors were evaluated using Bayesian model averaging. Independent validation was performed using data from the Swedish Multiple Sclerosis Registry. Of the 2403 patients identified, 145 were classified as having aggressive multiple sclerosis (6%). Bayesian model averaging identified three statistical predictors: age > 35 at symptom onset, EDSS ≥ 3 in the first year, and the presence of pyramidal signs in the first year. This model significantly predicted aggressive multiple sclerosis [area under the curve (AUC) = 0.80, 95% confidence intervals (CIs): 0.75, 0.84, positive predictive value = 0.15, negative predictive value = 0.98]. The presence of all three signs was strongly predictive, with 32% of such patients meeting aggressive disease criteria. The absence of all three signs was associated with a 1.4% risk. Of the 556 eligible patients in the Swedish Multiple Sclerosis Registry cohort, 34 (6%) met criteria for aggressive multiple sclerosis. The combination of all three signs was also predictive in this cohort (AUC = 0.75, 95% CIs: 0.66, 0.84, positive predictive value = 0.15, negative predictive value = 0.97). Taken together, these findings suggest that older age at symptom onset, greater disability during the first year, and pyramidal signs in the first year are early indicators of aggressive multiple sclerosis.

Aggressive multiple sclerosis: a matter of measurement and timing

“…We read with great interest the recently published work of Malpas et al (2020) in which the authors identified clinical markers of patients with aggressive multiple sclerosis in a cohort of relapsing remitting multiple sclerosis (RRMS) patients with 10 years of follow-up. The authors followed the definition a confirmed Expanded Disability Status Scale (EDSS) score ≥6.0 within 10 years of disease onset, which was initially applied by Tintore et al (2019) to a cohort of patients with clinically isolated syndrome.…”

“…(2019) , Spelman et al (2020) , Gholipour et al (2011) , Menon et al . (2017) , Tintore et al (2019) and Malpas et al (2020) (10 years) were presented depending on the disease duration from symptom onset. Additionally, the proportion of early retired patients in the first 5 years is given.…”

“…We have therefore carried out further analyses of GMSR data, comparing the results for different published aggressive multiple sclerosis or highly active multiple sclerosis definitions ( Gholipour et al , 2011 ; Freedman and Rush, 2016 ; Menon et al , 2017 ; Díaz et al , 2019 ; Tintore et al , 2019 ; Malpas et al , 2020 ; Spelman et al , 2020 ). These definitions vary, in part considerably, regarding the parameters to be evaluated (in addition to EDSS, also relapses, MRI data, therapy response and the follow-up time needed):…”

“… Tintore et al (2019) / Malpas et al (2020) : confirmed EDSS ≥ 6.0 within 10 years of symptom onset; and RRMS: as a study inclusion criterion, not part of the aggressive multiple sclerosis definition.…”

“…Second, there is a need for long-term results that validate which patients have a high degree of disability or malignant course, e.g. measured by EDSS, as in Tintore et al (2019) and Malpas et al (2020) . Third, it is necessary to continuously assess the severity of the disease (highly active multiple sclerosis).…”