[Skip to Content]
[Skip to Content Landing]

Changes in the Risk of Reaching Multiple Sclerosis Disability Milestones In Recent DecadesA Nationwide Population-Based Cohort Study in Sweden

Educational Objective
To investigate whether the risk of reaching disability milestones in multiple sclerosis changed over the last decade in Sweden.
1 Credit CME
Key Points

Question  Has the risk of reaching disability milestones in multiple sclerosis changed over the last decade?

Findings  In this nationwide population-based cohort study of 7331 patients with multiple sclerosis diagnosed between 1995 and 2010, a significant 3% decrease per calendar year of diagnosis for the risk of sustained Expanded Disability Status Scale score (EDSS) 3.0, a significant 6% decrease for the risk of EDSS 4.0, and a significant 7% decrease for the risk of EDSS 6.0 among patients with relapsing-onset multiple sclerosis was found.

Meaning  The risk of reaching disability milestones decreased significantly over the last decade in patients with relapsing-onset multiple sclerosis in Sweden.

Abstract

Importance  Clinicians’ experience and findings from recent natural history studies suggest that multiple sclerosis (MS) may now be running a more slowly progressing course than before.

Objective  To investigate whether the risk of reaching MS disability milestones has changed over the last decade in Sweden.

Design, Setting, and Participants  A nationwide population-based retrospective cohort study. By April 2017, 12 512 patients with available information on demographics, MS phenotype, and date of MS onset and diagnosis were registered in the Swedish MS Registry of which 7331 patients with at least 2 recorded Expanded Disability Status Scale scores (EDSS) and diagnosed between January 1995 and December 2010 were included. No further exclusion criteria were applied. Patients were followed up until December 2016 with a median duration follow-up of 8.5 (interquartile range, 4.7-13.8) years. Statistical analysis began in April 2017.

Main Outcomes and Measures  Patients were followed up from MS onset date to the date of sustained EDSS 3.0, 4.0, and 6.0. To handle interval-censored observations, a Weibull model was fit, and the change in the risk of EDSS 3.0, 4.0, and 6.0 over calendar years was estimated and hazard ratios (HRs) with corresponding CIs were calculated.

Results  Of 7331 patients, 5196 (70.9%) were women, and the mean (SD) age at diagnosis was 38.3 (11.7) years. Adjusting for sex, number of clinic visits, diagnostic delay, and onset age, a 3% decrease per calendar year of diagnosis for the risk of sustained EDSS 3.0 (HR, 0.97; 95% CI, 0.96-0.97), a 6% decrease for the risk of EDSS 4.0 (HR, 0.94; 95% CI, 0.93-0.95), and a 7% decrease for the risk of EDSS 6.0 (HR, 0.93; 95% CI, 0.91-0.94) among patients with relapsing-onset MS was found. The trends were not significant for patients with progressive-onset MS (EDSS 3.0: HR, 1.01; 95% CI, 0.98-1.03; EDSS 4.0: HR, 1.00; 95% CI, 0.98-1.02; EDSS 6.0: HR, 1.00; 95% CI, 0.98-1.02).

Conclusions and Relevance  Risk of reaching major disability milestones has significantly decreased over the last decade in patients with relapsing-onset MS in Sweden. Several factors could potentially be responsible for this observation. However, given that no change was seen in disability accrual of patients with progressive-onset MS and the absence of efficacious treatment option in this group, increased use of more efficacious disease-modifying treatments could be a possible driver of this change.

Sign in to take quiz and track your certificates

Buy This Activity

JN Learning™ is the home for CME and MOC from the JAMA Network. Search by specialty or US state and earn AMA PRA Category 1 CME Credit™ from articles, audio, Clinical Challenges and more. Learn more about CME/MOC

Article Information

Corresponding author: Jan Hillert, MD, PhD, Department of Clinical Neuroscience, Karolinska Institutet, Widerströmska huset, Tomtebodavägen 18, 171 77 Solna, Stockholm, Sweden (jan.hillert@ki.se).

Accepted for Publication: December 18, 2018.

Published Online: March 18, 2019. doi:10.1001/jamaneurol.2019.0330

Author Contributions: Drs Beiki and Manouchehrinia had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Manouchehrinia and Hillert contributed equally as co–last author.

Concept and design: Beiki, Manouchehrinia, Hillert.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Beiki, Manouchehrinia.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: All authors.

Obtained funding: Hillert.

Supervision: Hillert.

Conflict of Interest Disclosures: Dr Beiki has received salary for epidemiological consultation for pharmaceutical companies from Cognizant Technology Solutions. Dr Hillert has received honoraria for serving on advisory boards for Biogen, Sanofi Genzyme, and Novartis, speaker’s fees from Biogen, Novartis, Merck Serono, Bayer Schering, Teva Pharmaceutical Industries, and Sanofi Genzyme; and has served as principal investigator for projects or has received unrestricted research support from Biogen Idec, Merck Serono, Teva Pharmaceutical Industries, Sanofi Genzyme, and Bayer Schering. No other disclosures were reported.

Funding/Support: This research was funded by the Swedish Research Council and the Swedish Brain Foundation.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

References
1.
Steinvorth  SM, Rover  C, Schneider  S, Nicholas  R, Straube  S, Friede  T.  Explaining temporal trends in annualised relapse rates in placebo groups of randomised controlled trials in relapsing multiple sclerosis: systematic review and meta-regression.  Mult Scler. 2013;19(12):1580-1586. doi:10.1177/1352458513481009Google Scholar
2.
Röver  C, Nicholas  R, Straube  S, Friede  T.  Changing EDSS progression in placebo cohorts in relapsing MS: a systematic review and meta-regression.  PLoS One. 2015;10(9):e0137052. doi:10.1371/journal.pone.0137052PubMedGoogle Scholar
3.
Tremlett  H, Zhao  Y, Rieckmann  P, Hutchinson  M.  New perspectives in the natural history of multiple sclerosis.  Neurology. 2010;74(24):2004-2015. doi:10.1212/WNL.0b013e3181e3973fPubMedGoogle Scholar
4.
Weinshenker  BG, Bass  B, Rice  GP,  et al.  The natural history of multiple sclerosis: a geographically based study: I: clinical course and disability.  Brain. 1989;112(pt 1):133-146. doi:10.1093/brain/112.1.133PubMedGoogle Scholar
5.
Runmarker  B, Andersen  O.  Prognostic factors in a multiple sclerosis incidence cohort with twenty-five years of follow-up.  Brain. 1993;116(pt 1):117-134. doi:10.1093/brain/116.1.117PubMedGoogle Scholar
6.
Confavreux  C, Vukusic  S, Moreau  T, Adeleine  P.  Relapses and progression of disability in multiple sclerosis.  N Engl J Med. 2000;343(20):1430-1438. doi:10.1056/NEJM200011163432001PubMedGoogle Scholar
7.
Pittock  SJ, Mayr  WT, McClelland  RL,  et al.  Change in MS-related disability in a population-based cohort: a 10-year follow-up study.  Neurology. 2004;62(1):51-59. doi:10.1212/01.WNL.0000101724.93433.00PubMedGoogle Scholar
8.
Tremlett  H, Paty  D, Devonshire  V.  Disability progression in multiple sclerosis is slower than previously reported.  Neurology. 2006;66(2):172-177. doi:10.1212/01.wnl.0000194259.90286.fePubMedGoogle Scholar
9.
Brown  M, Andreou  P, Kirby  S, Murray  J. EDSS natural history atlas: MS disability progression in Nova Scotia 1979-2004. Presented at: ECTRIMS Conference; September 17-20, 2008; Montreal, Quebec, Canada.
10.
Kister  I, Chamot  E, Cutter  G,  et al; MSBase Investigators.  Increasing age at disability milestones among MS patients in the MSBase Registry.  J Neurol Sci. 2012;318(1-2):94-99. doi:10.1016/j.jns.2012.03.017PubMedGoogle Scholar
11.
Shirani  A, Zhao  Y, Kingwell  E, Rieckmann  P, Tremlett  H.  Temporal trends of disability progression in multiple sclerosis: findings from British Columbia, Canada (1975-2009).  Mult Scler. 2012;18(4):442-450. doi:10.1177/1352458511422097Google Scholar
12.
Pittock  SJ, Mayr  WT, McClelland  RL,  et al.  Disability profile of MS did not change over 10 years in a population-based prevalence cohort.  Neurology. 2004;62(4):601-606. doi:10.1212/WNL.62.4.601PubMedGoogle Scholar
13.
Manouchehrinia  A, Beiki  O, Hillert  J.  Clinical course of multiple sclerosis: a nationwide cohort study.  Mult Scler. 2017;23(11):1488-1495. doi:10.1177/1352458516681197Google Scholar
14.
Freilich  J, Manouchehrinia  A, Trusheim  M,  et al.  Characterization of annual disease progression of multiple sclerosis patients: a population-based study.  Mult Scler. 2018;24(6):786-794. doi:10.1177/1352458517706252Google Scholar
15.
Burkill  S, Montgomery  S, Hajiebrahimi  M, Hillert  J, Olsson  T, Bahmanyar  S.  Mortality trends for multiple sclerosis patients in Sweden from 1968 to 2012.  Neurology. 2017;89(6):555-562. doi:10.1212/WNL.0000000000004216PubMedGoogle Scholar
16.
Ahlgren  C, Odén  A, Lycke  J.  High nationwide prevalence of multiple sclerosis in Sweden.  Mult Scler. 2011;17(8):901-908. doi:10.1177/1352458511403794Google Scholar
17.
Ahlgren  C, Odén  A, Lycke  J.  High nationwide incidence of multiple sclerosis in Sweden.  PLoS One. 2014;9(9):e108599. doi:10.1371/journal.pone.0108599PubMedGoogle Scholar
18.
Hillert  J, Stawiarz  L.  The Swedish MS registry: clinical support tool and scientific resource.  Acta Neurol Scand. 2015;132(199):11-19. doi:10.1111/ane.12425PubMedGoogle Scholar
19.
Andersen  O.  From the Gothenburg cohort to the Swedish multiple sclerosis registry.  Acta Neurol Scand Suppl. 2012;(195):13-19. doi:10.1111/ane.12023PubMedGoogle Scholar
20.
Kurtzke  JF.  Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS).  Neurology. 1983;33(11):1444-1452. doi:10.1212/WNL.33.11.1444PubMedGoogle Scholar
21.
Collett  D.  Modelling Survival Data in Medical Research. 3rd ed. Boca Raton, Florida: Chapman and Hall/CRC; 2015.
22.
Kalbfleisch  JD, Prentice  RL.  The Statistical Analysis of Failure Time Data. 2nd ed. Hoboken, New Jersey: Wiley-Interscience; 2002.
23.
Zhang  Z, Sun  J.  Interval censoring.  Stat Methods Med Res. 2010;19(1):53-70. doi:10.1177/0962280209105023PubMedGoogle Scholar
24.
McAlpine  D, Compston  A. McAlpine's Multiple Sclerosis. 4th ed. London, United Kingdom: Churchill Livingstone; 2005.
25.
Kappos  L, Traboulsee  A, Constantinescu  C,  et al.  Long-term subcutaneous interferon beta-1a therapy in patients with relapsing-remitting MS.  Neurology. 2006;67(6):944-953. doi:10.1212/01.wnl.0000237994.95410.cePubMedGoogle Scholar
26.
Ford  C, Goodman  AD, Johnson  K,  et al.  Continuous long-term immunomodulatory therapy in relapsing multiple sclerosis: results from the 15-year analysis of the US prospective open-label study of glatiramer acetate.  Mult Scler. 2010;16(3):342-350. doi:10.1177/1352458509358088Google Scholar
27.
Ebers  G, Traboulsee  A, Langdon  D,  et al. The final results of the interferon beta-1b 16-year long-term follow-up study. https://ora.ox.ac.uk/objects/uuid:4f0c52f2-64a4-486e-a074-a22498bd236b. Accessed February 12, 2019.
28.
Trojano  M, Pellegrini  F, Paolicelli  D,  et al; Italian Multiple Sclerosis Database Network (MSDN) Group.  Real-life impact of early interferon beta therapy in relapsing multiple sclerosis.  Ann Neurol. 2009;66(4):513-520. doi:10.1002/ana.21757PubMedGoogle Scholar
29.
Veugelers  PJ, Fisk  JD, Brown  MG,  et al.  Disease progression among multiple sclerosis patients before and during a disease-modifying drug program: a longitudinal population-based evaluation.  Mult Scler. 2009;15(11):1286-1294. doi:10.1177/1352458509350307PubMedGoogle Scholar
30.
Kister  I, Chamot  E, Bacon  JH, Cutter  G, Herbert  J; New York State Multiple Sclerosis Consortium.  Trend for decreasing Multiple Sclerosis Severity Scores (MSSS) with increasing calendar year of enrollment into the New York State Multiple Sclerosis Consortium.  Mult Scler. 2011;17(6):725-733. doi:10.1177/1352458510396269Google Scholar
31.
Odell  PM, Anderson  KM, D’Agostino  RB.  Maximum likelihood estimation for interval-censored data using a Weibull-based accelerated failure time model.  Biometrics. 1992;48(3):951-959. doi:10.2307/2532360PubMedGoogle Scholar
32.
Coria  VH, Maximov  S, Rivas-Dávalos  F, Melchor-Hernández  CL.  Perturbative method for maximum likelihood estimation of the Weibull distribution parameters.  Springerplus. 2016;5(1):1802. doi:10.1186/s40064-016-3500-yPubMedGoogle Scholar
33.
Westerlind  H, Stawiarz  L, Fink  K, Hillert  J, Manouchehrinia  A. A significant decrease in diagnosis of primary progressive multiple sclerosis: a cohort study.  Mult Scler. 2016;22(8):1071-1079. doi:10.1177/1352458516643394Google Scholar
34.
D'Hooghe  MB, Nagels  G, Bissay  V, De Keyser  J.  Modifiable factors influencing relapses and disability in multiple sclerosis.  Mult Scler. 2010;16(7):773-785. doi:10.1177/1352458510367721Google Scholar
35.
Zivadinov  R, Zorzon  M, Weinstock-Guttman  B,  et al.  Epstein-Barr virus is associated with grey matter atrophy in multiple sclerosis.  J Neurol Neurosurg Psychiatry. 2009;80(6):620-625. doi:10.1136/jnnp.2008.154906PubMedGoogle Scholar
36.
Ginde  AA, Liu  MC, Camargo  CA  Jr.  Demographic differences and trends of vitamin D insufficiency in the US population, 1988-2004.  Arch Intern Med. 2009;169(6):626-632. doi:10.1001/archinternmed.2008.604PubMedGoogle Scholar
37.
Gyllensten  H, Wiberg  M, Alexanderson  K, Friberg  E, Hillert  J, Tinghög  P.  Comparing costs of illness of multiple sclerosis in three different years: a population-based study.  Mult Scler. 2018;24(4):520-528. doi:10.1177/1352458517702549Google Scholar
38.
Hobart  J, Freeman  J, Thompson  A.  Kurtzke scales revisited: the application of psychometric methods to clinical intuition.  Brain. 2000;123(Pt 5):1027-1040. doi:10.1093/brain/123.5.1027PubMedGoogle Scholar
39.
Kragt  JJ, Nielsen  JM, van der Linden  FA, Polman  CH, Uitdehaag  BM.  Disease progression in multiple sclerosis: combining physicians' and patients' perspectives?  Mult Scler. 2011;17(2):234-240. doi:10.1177/1352458510385505Google Scholar
40.
Ontaneda  D, Cohen  JA.  EDSS improvement: recovery of function or noise?  Mult Scler. 2012;18(11):1520-1521. doi:10.1177/1352458512441689Google Scholar
41.
Ebers  GC, Heigenhauser  L, Daumer  M, Lederer  C, Noseworthy  JH.  Disability as an outcome in MS clinical trials.  Neurology. 2008;71(9):624-631. doi:10.1212/01.wnl.0000313034.46883.16PubMedGoogle Scholar
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
jn-learning_Modal_LoginSubscribe_Purchase
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
jn-learning_Modal_LoginSubscribe_Purchase
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right

Name Your Search

Save Search
With a personal account, you can:
  • Track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
jn-learning_Modal_SaveSearch_NoAccess_Purchase

Lookup An Activity

or

My Saved Searches

You currently have no searches saved.

With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
Topics
State Requirements