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Research paper
Factors associated with and long-term outcome of benign multiple sclerosis: a nationwide cohort study
  1. Loes Crielaard1,
  2. Andrius Kavaliunas1,
  3. Ryan Ramanujam1,
  4. Tomas Olsson2,
  5. Jan Hillert1,
  6. Pernilla Stridh2,
  7. Ingrid Kockum2,
  8. Ali Manouchehrinia2
  1. 1 Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden
  2. 2 The Karolinska Neuroimmunology & Multiple Sclerosis Centre, Centre for Molecular Medicine, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
  1. Correspondence to Dr Ali Manouchehrinia, Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden; ali.manouchehrinia{at}


Objective Benign multiple sclerosis (BMS) is often defined by the Expanded Disability Status Scale (EDSS) score of ≤3.0 after ≥15 years of disease duration. This classification’s clinical relevance remains unclear as benign patients may suffer other impairments and advance towards a progressive course, prompting our objective to holistically investigate factors associated with BMS and its long-term prognosis.

Methods Benign cases were identified in the Swedish Multiple Sclerosis registry. Baseline clinical data, demographic features and influence of multiple sclerosis (MS) major risk alleles on likelihood of benign course were investigated. Physical disability (EDSS), cognitive function (Symbol Digit Modalities Test; SDMT) and self-reported and socioeconomic differences between benign and non-benign patients were evaluated using generalised estimation equations models.

Results 11222 patients (2420 benign/8802 non-benign) were included. Benign patients were more likely to be female and younger at MS onset, have fewer relapses within the first two and 5 years from onset and fully recover from the first relapse (p<0.001). No association between human leucocyte antigen (HLA) DRB1*15:01 carriership (OR: 0.97, 95% CI: 0.86 to 1.09) or HLA-A*02:01 lacking (OR: 0.99, 95% CI: 0.87 to 1.11) and benign/non-benign was found. Non-benign patients accumulated an extra 0.04 (95% CI 0.03 to 0.04, p<0.001) EDSS score/year, lost an extra 0.3 (95% CI − 0.39 to − 0.18, p<0.001) SDMT score/year and deteriorated faster in self-reported impact and socioeconomic measures (p<0.001).

Conclusion Patients with BMS have a better disease course as they progress more slowly at the group level in all respects. Lack of an association with major genetic risk factors indicates that MS course is most likely influenced by either environmental factor(s) or genetic factors outside the HLA region.

  • multiple sclerosis
  • benign
  • genotype data
  • physical disability
  • cognitive function
  • self-reported impact
  • risk of death
  • Severity

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  • Contributors LC, AM designed the study, analysed and interpreted data, wrote and revised the manuscript. RR, AK, TO interpreted data and revised the manuscript. JH designed the study, interpreted data and revised the manuscript. JH and TO contributed to data collection and data acquisition.

  • Funding The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Biogen provided a courtesy review and feedback on the paper to the authors. The authors had full editorial control of the paper, and provided their final approval of all content.

  • Competing interests LC, RM, AK, AM declare no conflict of interests. TO has received honoraria for lectures and advisory boards from Biogen, Novartis, Genzyme, Merck and TEVA. Unrestricted research grants from Biogen, Novartis and Genzyme. JH received honoraria for serving on advisory boards for Biogen, Sanofi-Genzyme and Novartis and speaker’s fees from Biogen, Merck-Serono, Bayer-Schering, Teva and Sanofi-Genzyme. He has served as P.I. for projects sponsored by, or received unrestricted research support from, Biogen, Merck-Serono, TEVA, Novartis, Sanofi-Genzyme and Bayer-Schering.

  • Patient consent for publication Obtained.

  • Ethics approval The study was approved by the Regional Ethical Review Board of Stockholm.

  • Provenance and peer review Not commissioned; externally peer reviewed.