2019 10 Clinical perspectives on MS disease progression ...HEOR • Sick leave/pension • Income/earnings/benefits • Cost of illness Pharmacoepidemiology • Safety & Effectiveness:

Clinical perspectives on MS disease progression Jan Hillert

Karolinska Institutet and University Hospital

NP‐SE‐NA‐0038

10 2019

Disclosures I

• Dr Hillert received a honorarium from Celgene AB to prepare and give this presentation

• Dr Hillert received honoraria for serving on advisory boards for Biogen and Sanofi-Genzyme and speaker’s fees from Biogen, Novartis, Merck, Bayer-Schering, Teva and Sanofi-Genzyme. He has served as P.I. for projects sponsored by, or received unrestricted research support from, Biogen, Merck, TEVA, Novartis and Sanofi-Genzyme. His MS research is funded by the Swedish Research Council and the Swedish Brain foundation.

Disclosure II I want you to report to the Finnish MS registry!

Progression of MS in the era ofdisease modifying treatments

Manouchehrinia et al, Multiple Sclerosis, 2017

• Slower progression than in all previous cohorts

Born in 1980

Female

Onset in 2005

First EDSS 2.0

EDSS in 2006

46

7

27

52

43

169

Prediction of secondary progression: a nomogram

https://aliman.shinyapps.io/SPMSnom/

SMSreg: A decision support tooland a scientific resource

The SMSreg patient cohort

2019-12-10 Jan Hillert 7

N= EDSS Attacks DMT episodes

DMT now

Follow‐up yrs MRI CSF MSIS‐29 SDMT EQ5D

All 19,754 117,223 30,314 34,741 10,739 11,2 57,966 17,57 44,752 61,197 30,827

RRMS 11,564 71,247 20,423 24,698 8,985 8,7 45,041 9,771 36,745 50,49 26,166

SPMS 5,578 36,478 8,87 8,202 1,242 18,3 9,932 5,778 6,017 8,952 3,606

PPMS 1,695 6,638 316 948 236 11,4 1,652 1,431 629 607 507

8,870

EDSS and MS courseIn a national registry

Discovery Clinical Public data‐bases



Swedish MS Registry• N=20,000 (18,000 active)• Demographics• Diagnostics• MRI (#lesions)• Attacks• EDSS• MSIS‐29• SDMT• EQ5D• Disease modifying treatment

Discovery Clinical Public data‐bases

N= 12,000/11,000 Questionnaire on exp.DNA/Genomics

• GWAS• Exome seq• GWSeq

Serum/Plasma• Proteomics• Viral serologies• NfL

RNAseqNAbs

Board of Health & research• Comorbidities• Health care consumption• Prescribed drugs• Pregnancy outcomesStatistics Sweden• Income/Earnings• EducationHealth Insurance Sweden• Sickness absence• Disability pensio n• Compensations

The Person Numbere.g.19551021‐0296

N= EDSS Attacks DMT episodes

DMT now

Follow‐up yrs MRI CSF MSIS‐29 SDMT EQ5D

All 19,754 117,223 30,314 34,741 10,739 11,2 57,966 17,57 44,752 61,197 30,827

RRMS 11,564 71,247 20,423 24,698 8,985 8,7 45,041 9,771 36,745 50,49 26,166

SPMS 5,578 36,478 8,87 8,202 1,242 18,3 9,932 5,778 6,017 8,952 3,606

PPMS 1,695 6,638 316 948 236 11,4 1,652 1,431 629 607 507

The Swedish MS Registry:Research projects

HEOR• Sick leave/pension• Income/earnings/benefits• Cost of illness

Pharmacoepidemiology• Safety & Effectiveness:

– IMSE (since 2006)– COMBAT-MS (PCORI 8.3 MUSD)

• PASS (BMSD): Merck, Roche• Pragmatic trial: RIFUND• Long term effects of DMDs• Comparative effectiveness

Translational epidemiology• Multiple MS• NABINMS

Epidemiology• Genetic epidemiology• Prevalences/incidence• Trends• Environmental risks

Natural Course• Progression• Courses• Heterogeneity• Course by novel outcomes

Co‐morbidities• Autoimmunity• Psychiatry

”Real World Evidence”

”The Poverty of Epidemiology” Perspectives in Biology and Medicine, Petr Skrabanek, 1992

”Higher prevalence of epidemiologists than ofproblems that epidemiology can solve”

”Any combination of exposure and disease, regardless of biologicalimplausibility, is fair game for calculating relative risks…”

Epidemiology has improvedsince 1992

‐ Larger materials‐ Population‐base for representativtity‐ Statistical approaches to compensate for bias‐ All available/known confounders corrected for

Disease progression in MS

• Ways to assess progression– Physical disability– Cognition– Socioeconomic outcomes

• What affects MS progression?– Life-style – e.g. smoking– Co-morbidities – e.g. depression– Disease modifying treatment

• Trends in MS progression



• Slower progression than in all previous cohorts: Change or completeness of coverage?

p < 0.0001

0.00

0.25

0.50

0.75

1.00

0 20 40 60 80Time

Sur

viva

l pro

babi

lity

Strata Adult-onset Paediatric-onset

9420 9420 6591 1183 8468 425 79 0 0Paediatric-onsetAdult-onset

0 20 40 60 80Time

Stra

ta Number at risk

Survival curve of time from birth (a) and MS onset (b) to EDSS 4 in POMS versus AOMS.

a)

p < 0.0001

0.00

0.25

0.50

0.75

1.00

0 10 20 30 40Time

Sur

viva

l pro

babi

lity

Strata Adult-onset Paediatric-onset

9420 5162 1643 338 19468 295 123 42 5Paediatric-onsetAdult-onset

0 10 20 30 40Time

Stra

ta Number at risk

b)

40

50

60

20 30 40 50

Age

SD

MT Adult-onset

Pediatric-onset

Mean SDMT score of POMS and AOMS by age at time of SDMT testing.

Cost of illness increases with EDSS





Importance of smoking cessation

N= 332/118, retrospective design,

Quitters reach SPMS at age 55Continuers reach SPMS at age 48

Ramanujam et al. JAMA Neurol, 2015, 72:117-23

Depression and bipolar disorderincrease the risk of MS progression

Stefanie Binzer; Kyla McKay; Philip Brenner; Jan Hillert; Ali Manouchehrinia,ECTRIMS 2018

The Swedish MS registry

The Swedish national patient registry

The Swedish national prescribed drug registry

Depression and bipolar disorderincrease the risk of MS progression: EDSS 6

10th of October 2018 Stefanie Binzer 22

Patients with ICD code for depression showed a 2.1 times(95%CI:1.46‐2.77) increased risk

Patients exposed to SSRIs had a 2.2 times (95%CI:1.69‐2.94) increased risk

SB1

Dia 22

SB1 Stefanie Binzer; 16.9.2018

Early introduction of MS DMTsreduces the risk of progression: EDSS

<1 year: EDSS 4 at age 55>3 years: EDSS 4 at age 45

Risk of reaching EDSS 4, n= 639 , 8.25 years follow-up

Kavaliunas et al, 2017, Multiple Sclerosis Journal

Impact of early treatment on long term disability accumulation in relapsing remitting multiple sclerosis patients

Since 2014: The Big MS Data network

Participants:Italian MS Registry (M Trojano), Swedish MS Registry (J Hillert),

Danish MS Registry, (M Magyari ), OFSEP of France (S Vukusic), MSBase (H Butzkueven)

New opportunities on large pooled data sets

To lead and develop MS research on real world data Standards Methodology Community

Registry Established Number of centres

Estimated number of patients

Danish MS Registry 1948 22 25,000

Swedish MS Registry 2000 64 19,800

OFSEP (France) 1980 51,0000Italian MS Database Network

2001 26 48,500

MSBase 2001 210 58,000

Early introduction of MS DMTsreduces the risk of progression: Pension

Journal of neurology 2018 265;3 701-707

Importance of early initiation of 1st DMT: Loss of salary (to be published)








• Slower progression than in all previous cohorts: Change or completeness of coverage?

CI, confidence interval; DMD, disease-modifying drug; EDSS, Expanded Disability Status Scale; HR, hazard ratio; POMS, progressive-onset MS; ROMS, relapsing-onset MSBeiki O et al. JAMA Neurol 2019;76:665–71

• 7331 patients from the Swedish MS registry, diagnosed between 1995 and 2010, were followed from the date of MS onset to the date of first sustained EDSS 3.0, 4.0 and 6.0

• After adjusting for confounding factors, a reduction in the risk of reaching EDSS milestones in patients with ROMS was found

– e.g. a patient diagnosed in 2010 has a 14% lower risk of reaching EDSS 3.0 than a patient diagnosed in 2005

– No significant effect was observed in patients with POMS

• This trend may be due to the increased use of DMDs over time, or to earlier diagnosis and treatment of MS

HR (95% CI) for reaching EDSS milestones per calendar year of diagnosis

EDSS 3.0

EDSS 4.0

EDSS 6.0

0,90 0,95 1,00 1,05

Reduced risk Increased riskROMS POMS

Figure developed using data from Beiki O et al. JAMA Neurol 2019;76:665–71

Hazard ratio

30

MS cost of illness decreased from 2006–2012 due to lower indirect costs

SEK, Swedish kronaGyllensten H et al. Mult Scler 2018;24:520–8 31

Without MS

2006

MS patients Without MS MS patients Without MS MS patients

2009 2012

0

50,000

100,000

150,000

200,000

Aver

age

cost

s (S

EK

)

Figure from Gyllensten H et al. Comparing costs of illness of multiple sclerosis in three different years: a population-based study. Multiple Sclerosis 24(4), pp.

520–8. Copyright © 2018 by the Authors. Reprinted by permission of SAGE Publications, Ltd

€1 ≈ 10 SEK

Prescribed drugsOutpatient healthcare useInpatient healthcare useSick leaveDisability pension





Conclusions

• Several outcomes may be used to show MS progression– Disability– Cognitive performance– Quality of life– Socioeconomic outcomes

• MS long term outcomes may be influenced by– Life style– Co-mobidities– MS disease modifying treatments

• Times they are a’changing for persons with MS!

Real world evidence in MS is an expanding research area

Big MS Data Network is a collaborative effort between five

MS registries which wasinitiated in 2014 with financial

support from Biogen

The participants are the national registries of Denmark, France, Italy and Sweden and

the international databasenetwork MSBase

Remember:I want you to report to the Finnish MS registry!

Thank you toHillert group• Anna Glaser• Ali Manouchehrinia• Ryan Ramanujam• Andrius Kavaliunas• Tim Spelman• Sahl Bedri• Omid Beiki• Virginia Karrenbauer• Katharina Fink

Swedish MS/Neuro regsitry• Leszek Stawiarz• Karin Lycke• Lillemor Bergström• Jenny Link

Karolinska MS network• Tomas Olsson• Lars Alfredsson• Kristina Alexanderson• Ingrid Kockum• Anna Fogdell-Hahn

Big MS Data• H. Butzkueven• Maria Trojano• Sandra Vukusic• Melinda Magyari

Helen TremlettStephen SawcerTomas Kalincik

Nordic MS Genetics groupIMSGC

Biogen - Rob HydeNovartisGenzyme

Thanks to all Swedish MS patients participating in the Swedish MS registry!

Documents

2019 10 Clinical perspectives on MS disease progression ...HEOR • Sick leave/pension • Income/earnings/benefits • Cost of illness Pharmacoepidemiology • Safety & Effectiveness: