Early clinical markers of aggressive multiple sclerosis
Authors: Malpas Charles B , Manouchehrinia Ali , Sharmin Sifat , Roos Izanne , Horakova Dana , Havrdova Eva Kubala , Trojano Maria , Izquierdo Guillermo , Eichau Sara , Bergamaschi Roberto , Sola Patrizia , Ferraro Diana , Lugaresi Alessandra , Prat Alexandre , Girard Marc , Duquette Pierre , Grammond Pierre , Grand’Maison Francois , Ozakbas Serkan , Van Pesch Vincent , Granella Franco , Hupperts Raymond , Pucci Eugenio , Boz Cavit , Iuliano Gerardo , Sidhom Youssef , Gouider Riadh , Spitaleri Daniele , Butzkueven Helmut , Soysal Aysun , Petersen Thor , Verheul Freek , Karabudak Rana , Turkoglu Recai , Ramo-Tello Cristina , Terzi Murat , Cristiano Edgardo , Slee Mark , McCombe Pamela , Macdonell Richard , Fragoso Yara , Olascoaga Javier , Altintas Ayse , Olsson Tomas , Hillert Jan , Kalincik Tomas 
Published: July 2019

Patients with the ‘aggressive’ form of MS accrue disability at an accelerated rate, typically reaching EDSS >= 6 within 10 years of symptom onset. Several clinicodemographic factors have been associated with aggressive MS, 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 MS is essential to optimise treatment in this MS subtype. We evaluated whether patients who will develop aggressive MS can be identified based on early clinical markers, and to replicate this analysis in an independent cohort. Patient data were obtained from MSBase. Inclusion criteria were (a) first recorded disability score (EDSS) within 12 months of symptom onset, (b) at least 2 recorded EDSS scores, and (c) at least 10 years of observation time. Patients were classified as having ‘aggressive MS’ if they: (a) reached EDSS >= 6 within 10 years of symptom onset, (b) EDSS >=6 was confirmed and sustained over >=6 months, and (c) EDSS >=6 was 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, hospitalisation). Predictors were evaluated using Bayesian Model Averaging (BMA). Independent validation was performed using data from the Swedish MS Registry. Of the 2,403 patients identified, 145 were classified as having aggressive MS (6%). BMA 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 MS (AUC = .80, 95% CIs = .75, .84). 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 MS Registry cohort, 34 (6%) met criteria for aggressive MS. The combination of all three signs was also predictive in this cohort (AUC = .75, 95% CIs = .66, .84). 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 MS.