BACKGROUND: To assign a course of secondary progressive multiple sclerosis (MS) (SPMS) may be difficult and the proportion of persons with SPMS varies between reports. An objective method for disease course classification may give a better estimation of the relative proportions of relapsing-remitting MS (RRMS) and SPMS and may identify situations where SPMS is under reported. MATERIALS AND METHODS: Data were obtained for 61,900 MS patients from MS registries in the Czech Republic, Denmark, Germany, Sweden, and the United Kingdom (UK), including date of birth, sex, SP conversion year, visits with an Expanded Disability Status Scale (EDSS) score, MS onset and diagnosis date, relapses, and disease-modifying treatment (DMT) use. We included RRMS or SPMS patients with at least one visit between January 2017 and December 2019 if ≥ 18 years of age. We applied three objective methods: A set of SPMS clinical trial inclusion criteria ("EXPAND criteria") modified for a real-world evidence setting, a modified version of the MSBase algorithm, and a decision tree-based algorithm recently published. RESULTS: The clinically assigned proportion of SPMS varied from 8.7% (Czechia) to 34.3% (UK). Objective classifiers estimated the proportion of SPMS from 15.1% (Germany by the EXPAND criteria) to 58.0% (UK by the decision tree method). Due to different requirements of number of EDSS scores, classifiers varied in the proportion they were able to classify; from 18% (UK by the MSBase algorithm) to 100% (the decision tree algorithm for all registries). Objectively classified SPMS patients were older, converted to SPMS later, had higher EDSS at index date and higher EDSS at conversion. More objectively classified SPMS were on DMTs compared to the clinically assigned. CONCLUSION: SPMS appears to be systematically underdiagnosed in MS registries. Reclassified patients were more commonly on DMTs.

1st Faculty of Medicine and General University Hospital Department of Neurology and Center of Clinical Neuroscience Charles University Prague Prague Czech Republic

Czech National Multiple Sclerosis ReMuS IMPULS Endowment Fund Prague Czech Republic

Danish Multiple Sclerosis Center Copenhagen University Hospital Copenhagen Denmark

Department of Basic Medical Sciences Neurosciences and Sense Organs University of Bari Aldo Moro Bari Italy

Department of Cellular and Molecular Neuroscience Imperial College London London UK

Department of Clinical Neuroscience Center for Molecular Medicine Karolinska Institutet Stockholm Sweden

Department of Clinical Neuroscience Karolinska Institutet Stockholm Sweden

Department of Mathematics Royal Institute of Technology Stockholm Sweden

Department of Neuroscience Central Clinical School Monash University Melbourne Australia

Division of Clinical Neurosciences University Hospital and University of Turku Turku Finland

Hôpital Neurologique Service de Neurologie A the European Database for Multiple Sclerosis Coordinating Center and INSERM U 433 Lyon France

MS Forschungs und Projektentwicklungs gGmbH Hannover Germany

Novartis Pharma AG Basel Switzerland

Swansea University Medical School Swansea UK

The Danish Multiple Sclerosis Registry Copenhagen University Hospital Copenhagen Denmark

Zobrazit více v PubMed

McAlpine D, Compston N, Lumsden C. Course and prognosis of multiple sclerosis. Mult Scler 1955: 135–155.

Wolinsky JS, PROMiSe Study Group. The diagnosis of primary progressive multiple sclerosis. J Neurol Sci 2003; 206: 145–152. PubMed

Lublin FD, Reingold SC. National multiple sclerosis society (USA) advisory committee on clinical trials of new agents in multiple sclerosis*. defining the clinical course of multiple sclerosis: results of an international survey. Neurology 1996; 46: 907–911. PubMed

Lublin FD, Reingold SC, Cohen JA, et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology 2014; 83: 278–286. PubMed PMC

Kutzelnigg A, Lucchinetti CF, Stadelmann C, et al. Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain : A Journal of Neurology 2005; 128: 2705–2712. PubMed

Grothe M, Lotze M, Langner Set al. et al. The role of global and regional gray matter volume decrease in multiple sclerosis. J Neurol 2016; 263: 1137–1145. PubMed

De Stefano N, Matthews PM, Filippi M, et al. Evidence of early cortical atrophy in MS: relevance to white matter changes and disability. Neurology 2003; 60: 1157–1162. PubMed

Lucchinetti CF, Popescu BFG, Bunyan RF, et al. Inflammatory cortical demyelination in early multiple sclerosis. N Engl J Med 2011; 365: 2188–2197. PubMed PMC

Vollmer TL, Nair KV, Williams IMet al. et al. Multiple sclerosis phenotypes as a Continuum: the role of neurologic reserve. Neurology Clinical Practice 2021; 11: 342–351. PubMed PMC

Cree BAC, Arnold DL, Chataway J, et al. Secondary progressive multiple sclerosis: new insights. Neurology 2021; 97: 378–388. PubMed PMC

Kappos L, Bar-Or A, Cree BAC, et al. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study. Lancet (London, England) 2018; 391: 1263–1273. PubMed

Trojano M, Tintoré M, Montalban X, et al. Treatment decisions in multiple sclerosis - insights from real-world observational studies. Nature Reviews Neurology 2017; 13: 105–118. PubMed

Confavreux C, Vukusic S. Natural history of multiple sclerosis: a unifying concept. Brain : A Journal of Neurology 2006; 129: 606–616. PubMed

Lorscheider J, Buzzard K, Jokubaitis V, et al. Defining secondary progressive multiple sclerosis. Brain : A Journal of Neurology 2016; 139: 2395–2405. PubMed

Iaffaldano P, Lucisano G, Patti F, et al. Transition to secondary progression in relapsing-onset multiple sclerosis: definitions and risk factors. Multiple Sclerosis (Houndmills, Basingstoke, England) 2021; 27: 430–438. PubMed

Kopp TI, Bramow S, Illes Z, et al. Application of definitions for conversion to secondary progressive MS in a Danish nationwide population. Mult Scler Relat Disord 2021; 56: 103319. PubMed

Iaffaldano P, Lucisano G, Guerra T, et al. Towards a validated definition of the clinical transition to secondary progressive multiple sclerosis: A study from the Italian MS Register . Multiple sclerosis 2022; 28(14): 2243–2252. PubMed

Ramanujam R, Zhu F, Fink K, et al. Accurate classification of secondary progression in multiple sclerosis using a decision tree. Multiple Sclerosis (Houndmills, Basingstoke, England) 2021; 27(8): 1240–1249. PubMed PMC

Middleton RM, Rodgers WJ, Chataway J, et al. Validating the portal population of the United Kingdom multiple sclerosis register. Mult Scler Relat Disord 2018; 24: 3–10. PubMed

Horakova D, Rockova P, Jircikova J, et al. Initiation of first disease-modifying treatment for multiple sclerosis patients in the Czech republic from 2013 to 2016: data from the national registry ReMuS. Mult Scler Relat Disord 2019; 35: 196–202. PubMed

Ohle L-M, Ellenberger D, Flachenecker P, et al. Chances and challenges of a long-term data repository in multiple sclerosis: 20th birthday of the German MS registry. Sci Rep 2021; 11: 13340–9. PubMed PMC

Magyari M, Joensen H, Laursen Bet al. et al. The Danish multiple sclerosis registry. Brain Behav 2021; 11: e01921. PubMed PMC

Hillert J, Stawiarz L. The Swedish MS registry clinical support tool and scientific resource. Acta Neurol Scand 2015; 132: 11–19. PubMed PMC

Team RC. R: A language and environment for statistical computing. 2013.

Vasanthaprasad V, Khurana V, Vadapalle Set al. et al. Systematic literature review and meta-analysis of the prevalence of secondary progressive multiple sclerosis in the USA, Europe, Canada, Australia, and Brazil . BMC Neurol 2022; 22: 301–320. PubMed PMC

The impact of healthcare systems on the clinical diagnosis and disease-modifying treatment usage in relapse-onset multiple sclerosis: a real-world perspective in five registries across Europe