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Title: Early clinical markers of aggressive multiple sclerosis.
Austin 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;Sidhom, Youssef;Gouider, Riadh;Spitaleri, Daniele;Soysal, Aysun;Petersen, Thor;Verheul, Freek;Karabudak, Rana;Turkoglu, Recai;Ramo-Tello, Cristina;Terzi, Murat;Cristiano, Edgardo;Slee, Mark;McCombe, Pamela;Macdonell, Richard A L ;Fragoso, Yara;Olascoaga, Javier;Altintas, Ayse;Olsson, Tomas;Butzkueven, Helmut;Hillert, Jan;Kalincik, Tomas
Affiliation: Université Catholique de Louvain, Brussels, Belgium
Department of Biomedical and Neuromotor Science, University of Bologna, Bologna, Italy
IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy
Cliniques Universitaires Saint-Luc, Brussels, Belgium
CORe Unit, Department of Medicine, University of Melbourne, Melbourne, Australia
Centre for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden
Flinders University, Adelaide, Australia
Royal Brisbane and Women's Hospital, Brisbane, Australia
University of Queensland, Brisbane, Australia
Department of Neurology, Box Hill Hospital, Monash University, Melbourne, Australia
Department of Neurology, The Alfred Hospital, Melbourne, Australia
Central Clinical School, Monash University, Melbourne, Australia
Austin Health, Heidelberg, Victoria, Australia
Department of Neurology, Royal Melbourne Hospital, Melbourne, Australia
Department of Neuroscience, Azienda Ospedaliera Universitaria, Modena, Italy
Department of Biomedical, Metabolic and Neurosciences, University of Modena and Reggio Emilia, Modena, Italy
Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University in Prague and General University Hospital, Prague, Czech Republic
Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari, Bari, Italy
Hospital Universitario Virgen Macarena, Sevilla, Spain
IRCCS Mondino Foundation, Pavia, Italy
Department of Neuroscience, Azienda Ospedaliera Universitaria, Modena, Italy
CHUM and Universite de Montreal, Montreal, Canada
CISSS de Chaudière-Appalaches, Levis, Canada
Neuro Rive-Sud, Quebec, Canada
Dokuz Eylul University, Konak/Izmir, Turkey
Department of Medicine and Surgery, University of Parma, Parma, Italy
Zuyderland Ziekenhuis, Sittard, The Netherlands
UOC Neurologia, Azienda Sanitaria Unica Regionale Marche - AV3, Macerata, Italy
KTU Medical Faculty Farabi Hospital, Trabzon, Turkey
Department of Neurology, Razi Hospital, Manouba, Tunisia
Department of Neurology, Razi Hospital, LR 18SP03, Clinical Investigation Center Neurosciences and Mental Health, Faculty of Medicine University Tunis El Manar, Tunis, Tunisia
Azienda Ospedaliera di Rilievo Nazionale San Giuseppe Moscati Avellino, Avellino, Italy
Bakirkoy Education and Research Hospital for Psychiatric and Neurological Diseases, Istanbul, Turkey
Kommunehospitalet, Arhus C, Denmark
Groene Hart Ziekenhuis, Gouda, The Netherlands
Hacettepe University, Ankara, Turkey
Haydarpasa Numune Training and Research Hospital, Istanbul, Turkey
Hospital Germans Trias i Pujol, Badalona, Spain
Medical Faculty, 19 Mayis University, Samsun, Turkey
Hospital Italiano, Buenos Aires, Argentina
Universidade Metropolitana de Santos, Santos, Brazil
Instituto de Investigación Sanitaria Biodonostia, Hospital Universitario Donostia, San Sebastián, Spain
Koc University, School of Medicine, Department of Neurology, Istanbul, Turkey
Department of Clinical Neuroscience, Karolinska Institutet, Sweden
Issue Date: 9-May-2020 2020-05-09
Publication information: Brain : a journal of neurology 2020; online first: 9 May
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.
DOI: 10.1093/brain/awaa081
Journal: Brain : a journal of neurology
PubMed URL: 32386427
Type: Journal Article
Subjects: aggressive disease
multiple sclerosis
precision medicine
Appears in Collections:Journal articles

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