It is unknown whether the currently known risk factors of multiple sclerosis reflect the etiology of progressive-onset multiple sclerosis (POMS) as observational studies rarely included analysis by type of onset. We designed a case-control study to examine associations between environmental factors and POMS and compared effect sizes to relapse-onset MS (ROMS), which will offer insights into the etiology of POMS and potentially contribute to prevention and intervention practice. This study utilizes data from the Primary Progressive Multiple Sclerosis (PPMS) Study and the Australian Multi-center Study of Environment and Immune Function (the AusImmune Study). This report outlines the conduct of the PPMS Study, whether the POMS sample is representative, and the planned analysis methods. The study includes 155 POMS, 204 ROMS, and 558 controls. The distributions of the POMS were largely similar to Australian POMS patients in the MSBase Study, with 54.8% female, 85.8% POMS born before 1970, mean age of onset of 41.44 ± 8.38 years old, and 67.1% living between 28.9 and 39.4° S. The POMS were representative of the Australian POMS population. There are some differences between POMS and ROMS/controls (mean age at interview: POMS 55 years vs. controls 40 years; sex: POMS 53% female vs. controls 78% female; location of residence: 14.3% of POMS at a latitude ≤ 28.9°S vs. 32.8% in controls), which will be taken into account in the analysis. We discuss the methodological issues considered in the study design, including prevalence-incidence bias, cohort effects, interview bias and recall bias, and present strategies to account for it. Associations between exposures of interest and POMS/ROMS will be presented in subsequent publications.

Aarhus University Hospital Aarhus Denmark

AHEPA University Hospital Thessaloniki Greece

Al Zahra Hospital Isfahan Iran

American University of Beirut Medical Center Beirut Lebanon

Amiri Hospital Sharq Kuwait

Austin Health Melbourne Australia

Bombay Hospital Institute of Medical Sciences Mumbai India

Central Clinical School Monash University Melbourne Australia

Centro Hospitalar Universitario de Sao Joao Porto Portugal

Charles University Prague and General University Hospital Prague Czech Republic

CHUM and Universite de Montreal Montreal Canada

CSSS Saint Jérôme Saint Jerome Canada

Department of Medical and Surgical Sciences and Advanced Technologies GF Ingrassia Catania Italy

Department of Medicine CORe University of Melbourne Melbourne Australia

Department of Medicine School of Clinical Sciences Monash University Melbourne Australia

Department of Medicine The University of Melbourne Melbourne Australia

Department of Neurology and Koc University Research Center for Translational Medicine Koc University School of Medicine Istanbul Turkey

Department of Neurology LR 18SP03 Clinical Investigation Centre Neurosciences and Mental Health University Hospital Razi Manouba Tunis Tunisia

Department of Neurology Neroimmunology Centre Royal Melbourne Hospital Melbourne Australia

Dipartimento di Scienze Biomediche e Neuromotorie Università di Bologna Bologna Italy

Dokuz Eylul University Konak Izmir Turkey

Faculty of Health Sciences University Fernando Pessoa Porto Portugal

Faculty of Medicine of Tunis University of Tunis El Manar 1007 Tunis Tunisia

Florey Institute for Neuroscience The University of Melbourne Melbourne VIC Australia

Florey Institute for Neuroscience University of Melbourne Melbourne VIC Australia

Golestan University of Medical Sciences Gogan Iran

Groene Hart Ziekenhuis Gouda Netherlands

Hacettepe University Ankara Turkey

Hospital Clinic de Barcelona Barcelona Spain

Hospital Clinico San Carlos Madrid Spain

Hospital General Universitario de Alicante Alicante Spain

Hospital Germans Trias i Pujol Badalona Spain

Hospital Universitario Donostia and IIS Biodonostia San Sebastián Spain

Hospital Universitario Virgen Macarena Seville Spain

Hunter Medical Research Institute University of Newcastle Callaghan Australia

IRCCS Istituto delle Scienze Neurologiche di Bologna Bologna Italy

Isfahan University of Medical Sciences Isfahan Iran

King Fahad Specialist Hospital Dammam Khobar Saudi Arabia

Melbourne School of Population and Global Health Neuroepidemiology Unit The University of Melbourne Melbourne VIC Australia

Menzies Institute of Medical Research University of Tasmania 17 Liverpool Street Hobart TAS 7000 Australia

Monash Medical Centre Melbourne Australia

Monash University Melbourne Australia

Nemocnice Jihlava Jihlava Czech Republic

Neuro Rive Sud Quebec Canada

Neuroscience Section Department of Applied Clinical Sciences and Biotechnology University of L'Aquila Via Vetoio 1 L'Aquila Italy

Pelt and Hasselt University Hasselt Belgium

Royal Brisbane and Women's Hospital Brisbane Australia

Royal Victoria Hospital Belfast UK

S Maria delle Croci Hospital AUSL Romagna Ravenna Italy

School for Mental Health and Neuroscience Maastricht University Maastricht The Netherlands

School of Medicine and Dentistry Griffith University Brisbane QLD Australia

South Eastern HSC Trust Belfast UK

St Vincent's University Hospital Dublin Ireland

The Alfred Hospital Melbourne Australia

Universitary Hospital Ghent Ghent Belgium

University College Dublin Dublin Ireland

University G d'Annunzio Chieti Italy

University Hospital Center Zagreb Zagreb Croatia

University of Florence Florence Italy

University of Queensland Brisbane Australia

University of Zagreb School of Medicine Zagreb Croatia

UOS Sclerosi Multipla AOU Policlinico G Rodloico San Marco University of Catania Catania Italy

Zuyderland Medical Center Sittard Geleen The Netherlands

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Campbell JA, Simpson S, Jr, Ahmad H, Taylor BV, van der Mei I, Palmer AJ. Change in multiple sclerosis prevalence over time in Australia 2010–2017 utilising disease-modifying therapy prescription data. Mult Scler. 2019 doi: 10.1177/1352458519861270. PubMed DOI

Lublin FD, Reingold SC, Cohen JA, Cutter GR, Sorensen PS, Thompson AJ, Wolinsky JS, Balcer LJ, Banwell B, Barkhof F, Bebo B, Calabresi PA, Clanet M, Comi G, Fox RJ, Freedman MS, Goodman AD, Inglese M, Kappos L, Kieseier BC, Lincoln JA, Lubetzki C, Miller AE, Montalban X, O'Connor PW, Petkau J, Pozzilli C, Rudick RA, Sormani MP, Stuve O, Waubant E, Polman CH. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology. 2014;83:278–286. doi: 10.1212/wnl.0000000000000560. PubMed DOI PMC

Antel J, Antel S, Caramanos Z, Arnold DL, Kuhlmann T. Primary progressive multiple sclerosis: part of the MS disease spectrum or separate disease entity? Acta Neuropathol. 2012;123:627–638. doi: 10.1007/s00401-012-0953-0. PubMed DOI

Lassmann H. Relapsing–remitting and primary progressive MS have the same cause (s)–the neuropathologist’s view: 1. Mult Scler J. 2013;19:266–267. doi: 10.1177/1352458512474091. PubMed DOI

Kalincik T, Vivek V, Jokubaitis V, Lechner-Scott J, Trojano M, Izquierdo G, Lugaresi A, Grand’Maison F, Hupperts R, Oreja-Guevara C. Sex as a determinant of relapse incidence and progressive course of multiple sclerosis. Brain. 2013;136:3609–3617. doi: 10.1093/brain/awt281. PubMed DOI

Tao CR, Simpson S, van der Mei I, Blizzard L, Havrdova E, Horakova D, Shaygannejad V, Lugaresi A, Izquierdo G, Trojano M, Duquette P, Girard M, Grand'Maison F, Grammond P, Alroughani R, Terzi M, Oreja-Guevara C, Sajedi SA, Iuliano G, Sola P, Lechner-Scott J, Van Pesch V, Pucci E, Bergamaschi R, Barnett M, Ramo C, Singhal B, Spitaleri DLA, Slee M, Verheul F, Bolanos RF, Amato MP, Cristiano E, Granella F, Hodgkinson S, Fiol M, Gray O, McCombe P, Saladino ML, Menoyo JLS, Shuey N, Vucic S, Shaw C, Deri N, Arruda WO, Butzkueven H, Spelman T, Taylor BV, Group MS Higher latitude is significantly associated with an earlier age of disease onset in multiple sclerosis. J Neurol Neurosur Ps. 2016;87:1343–1349. doi: 10.1136/jnnp-2016-314013. PubMed DOI

Taylor BV, Lucas RM, Dear K, Kilpatrick TJ, Pender MP, van der Mei IA, Chapman C, Coulthard A, Dwyer T, McMichael AJ, Valery PC, Williams D, Ponsonby AL. Latitudinal variation in incidence and type of first central nervous system demyelinating events. Mult Scler. 2010;16:398–405. doi: 10.1177/1352458509359724. PubMed DOI

Taylor BV, Pearson JF, Clarke G, Mason DF, Abernethy DA, Willoughby E, Sabel C. MS prevalence in New Zealand, an ethnically and latitudinally diverse country. Mult Scler. 2010;16:1422–1431. doi: 10.1177/1352458510379614. PubMed DOI

Miller DH, Leary SM. Primary-progressive multiple sclerosis. Lancet Neurol. 2007;6:903–912. doi: 10.1016/S1474-4422(07)70243-0. PubMed DOI

McKay KA, Kwan V, Duggan T, Tremlett H. Risk factors associated with the onset of relapsing-remitting and primary progressive multiple sclerosis: a systematic review. BioMed Res Int. 2015;2015:817238. doi: 10.1155/2015/817238. PubMed DOI PMC

van der Mei I, Lucas RM, Taylor BV, Valery PC, Dwyer T, Kilpatrick TJ, Pender MP, Williams D, Chapman C, Otahal P, Ponsonby AL. Population attributable fractions and joint effects of key risk factors for multiple sclerosis. Mult Scler. 2016;22:461–469. doi: 10.1177/1352458515594040. PubMed DOI

Montalban X, Hauser SL, Kappos L, Arnold DL, Bar-Or A, Comi G, de Seze J, Giovannoni G, Hartung HP, Hemmer B, Lublin F, Rammohan KW, Selmaj K, Traboulsee A, Sauter A, Masterman D, Fontoura P, Belachew S, Garren H, Mairon N, Chin P, Wolinsky JS, Investigators OC. Ocrelizumab versus placebo in primary progressive multiple sclerosis. N Engl J Med. 2017;376:209–220. doi: 10.1056/NEJMoa1606468. PubMed DOI

Wolinsky JS, Arnold DL, Brochet B, Hartung H-P, Montalban X, Naismith RT, Manfrini M, Overell J, Koendgen H, Sauter A, Bennett I, Hubeaux S, Kappos L, Hauser SL. Long-term follow-up from the ORATORIO trial of ocrelizumab for primary progressive multiple sclerosis: a post-hoc analysis from the ongoing open-label extension of the randomised, placebo-controlled, phase 3 trial. Lancet Neurol. 2020;19:998–1009. doi: 10.1016/S1474-4422(20)30342-2. PubMed DOI

Rezaeimanesh N, Moghadasi AN, Sahraian MA, Eskandarieh S. Dietary risk factors of primary progressive multiple sclerosis: a population-based case-control study. Mult Scler Relat Disord. 2021;56:103233. doi: 10.1016/j.msard.2021.103233. PubMed DOI

Alsharie AM, Rafiee F, Rezaeimanesh N, Moghadasi AN, Sahraian MA, Eskandarieh S. Stressful life events and the risk of primary progressive multiple sclerosis: a population-based case-control study. Mult Scler Relat Disord. 2021;51:102937. doi: 10.1016/j.msard.2021.102937. PubMed DOI

Tremlett H, Marrie RA. The multiple sclerosis prodrome: emerging evidence, challenges, and opportunities. Mult Scler J. 2021;27:6–12. doi: 10.1177/1352458520914844. PubMed DOI

Lucas RM, Ponsonby AL, Dear K, Taylor BV, Dwyer T, McMichael AJ, Valery P, van der Mei I, Williams D, Pender MP, Chapman C, Coulthard A, Kilpatrick T. Associations between silicone skin cast score, cumulative sun exposure, and other factors in the Ausimmune study: a multicenter Australian study. Cancer Epidemiol Biomarkers Prev. 2009;18:2887–2894. doi: 10.1158/1055-9965.EPI-09-0191. PubMed DOI

Lucas RM, Ponsonby AL, Dear K, Valery PC, Pender MP, Taylor BV, Kilpatrick TJ, Dwyer T, Coulthard A, Chapman C, van der Mei I, Williams D, McMichael AJ. Sun exposure and vitamin D are independent risk factors for CNS demyelination. Neurology. 2011;76:540–548. doi: 10.1212/WNL.0b013e31820af93d. PubMed DOI

Hughes AM, Lucas RM, McMichael AJ, Dwyer T, Pender MP, van der Mei I, Taylor BV, Valery P, Chapman C, Coulthard A, Dear K, Kilpatrick TJ, Williams D, Ponsonby AL. Early-life hygiene-related factors affect risk of central nervous system demyelination and asthma differentially. Clin Exp Immunol. 2013;172:466–474. doi: 10.1111/cei.12077. PubMed DOI PMC

Valery PC, Lucas RM, Williams DB, Pender MP, Chapman C, Coulthard A, Dear K, Dwyer T, Kilpatrick TJ, McMichael AJ, van der Mei I, Taylor BV, Ponsonby AL. Occupational exposure and risk of central nervous system demyelination. Am J Epidemiol. 2013;177:954–961. doi: 10.1093/aje/kws361. PubMed DOI

Ponsonby AL, Lucas RM, van der Mei IA, Dear K, Valery PC, Pender MP, Taylor BV, Kilpatrick TJ, Coulthard A, Chapman C, Williams D, McMichael AJ, Dwyer T. Offspring number, pregnancy, and risk of a first clinical demyelinating event: the AusImmune Study. Neurology. 2012;78:867–874. doi: 10.1212/WNL.0b013e31824c4648. PubMed DOI

Lucas RM, Ponsonby AL, Dear K, Valery P, Pender MP, Burrows JM, Burrows SR, Chapman C, Coulthard A, Dwyer DE, Dwyer T, Kilpatrick T, Lay ML, McMichael AJ, Taylor BV, van der Mei IA, Williams D. Current and past Epstein-Barr virus infection in risk of initial CNS demyelination. Neurology. 2011;77:371–379. doi: 10.1212/WNL.0b013e318227062a. PubMed DOI

Black LJ, Baker K, Ponsonby A-L, Ingrid LRM, Pereira G, Chapman C, Coulthard A, Dear K, Dwyer T, Kilpatrick T, Lucas R, McMichael T, Pender MP, Ponsonby A-L, Taylor B, Valery P, Van Der Mei I, Williams D. A higher Mediterranean diet score, including unprocessed red meat, is associated with reduced risk of central nervous system demyelination in a case-control study of Australian adults. J Nutr. 2019;149:1385–1392. doi: 10.1093/jn/nxz089. PubMed DOI

Lucas R, Ponsonby AL, McMichael A, van der Mei I, Chapman C, Coulthard A, Dear K, Dwyer T, Kilpatrick T, Pender M, Taylor B, Valery P, Williams D. Observational analytic studies in multiple sclerosis: controlling bias through study design and conduct. The Australian Multicentre Study of Environment and Immune Function. Mult Scler. 2007;13:827–839. doi: 10.1177/1352458507077174. PubMed DOI

Polman CH, Reingold SC, Edan G, Filippi M, Hartung HP, Kappos L, Lublin FD, Metz LM, McFarland HF, O'Connor PW, Sandberg-Wollheim M, Thompson AJ, Weinshenker BG, Wolinsky JS. Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria”. Ann Neurol. 2005;58:840–846. doi: 10.1002/ana.20703. PubMed DOI

Hou Y, Jia Y, Hou J. Natural course of clinically isolated syndrome: a longitudinal analysis using a Markov model. Sci Rep. 2018 doi: 10.1038/s41598-018-29206-y. PubMed DOI PMC

Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, Fujihara K, Havrdova E, Hutchinson M, Kappos L, Lublin FD, Montalban X, O'Connor P, Sandberg-Wollheim M, Thompson AJ, Waubant E, Weinshenker B, Wolinsky JS. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011;69:292–302. doi: 10.1002/ana.22366. PubMed DOI PMC

van der Mei IA, Ponsonby AL, Dwyer T, Blizzard L, Simmons R, Taylor BV, Butzkueven H, Kilpatrick T. Past exposure to sun, skin phenotype, and risk of multiple sclerosis: case-control study. BMJ. 2003;327:316. doi: 10.1136/bmj.327.7410.316. PubMed DOI PMC

van der Mei IA, Blizzard L, Ponsonby AL, Dwyer T. Validity and reliability of adult recall of past sun exposure in a case-control study of multiple sclerosis. Cancer Epidemiol Biomarkers Prev. 2006;15:1538–1544. doi: 10.1158/1055-9965.EPI-05-0969. PubMed DOI

Butzkueven H, Chapman J, Cristiano E, Grand’Maison F, Hoffmann M, Izquierdo G, Jolley D, Kappos L, Leist T, Pöhlau D, Rivera V, Trojano M, Verheul F, Malkowski JP. MSBase: an international, online registry and platform for collaborative outcomes research in multiple sclerosis. Mult Scler J. 2006;12:769–774. doi: 10.1177/1352458506070775. PubMed DOI

Statistics ABo. Population by age and sex, Regions of Australia. https://www.abs.gov.au/AUSSTATS/abs@.nsf/DetailsPage/3218.02016?OpenDocument.

Zhang Y, Taylor BV, Simpson S, Jr, Blizzard L, van der Mei I. Patient-reported outcomes are worse for progressive-onset multiple sclerosis than relapse-onset multiple sclerosis, particularly early in the disease process. Eur J Neurol. 2018 doi: 10.1111/ene.13786. PubMed DOI