Multiple Sclerosis anno 2017: Handvatten voor de bedrijfsarts. Joep Killestein, neuroloog VUmc

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1 Multiple Sclerosis anno 2017: Handvatten voor de bedrijfsarts Joep Killestein, neuroloog VUmc

2 Disclosures J. Killestein has accepted speaker and consulting fees from Merck-Serono, Biogen, Roche, Teva, Genzyme and Novartis. VU Medical Center has received financial support for research activities from Bayer Schering Pharma, Biogen, GlaxoSmithKline, Merck Serono, Novartis, Roche and Teva.

3 Inhoud Klinische verschijnselen, diagnose en beloop Behandeling Arbeidsparticipatie en MS

4 MULTIPLE SCLEROSE (MS) Begin meestal tussen 20 e en 40 e levensjaar Twee tot 4 keer meer vrouwen dan mannen 1 op 1000 Nederlanders Ruim Nederlanders met MS

5 MULTIPLE SCLEROSE MS Ziekte van hersenen en ruggenmerg Sterk uiteenlopende klachten Uiteenlopend klinisch beloop

6 Neuritis optica wazig zien gestoorde kleurwaarneming scotoom pijnlijke oogbewegingen

7 Dubbelzien en nystagmus Internucleaire ophthalmoplegie Adductie ipsilaterale oog beperkt Abductie contralaterale oog: nystagmus

8 Tractus corticospinalis, piramidebaan Demyelinisatie corticospinale banen spierzwakte ledematen verstoring van fijne motoriek Onbehandeld 25% rolstoelgebonden 15 jaar na ontstaan klachten na 30 jaar 50%

9 Stoornissen van de sensibiliteit Tintelingen Doofheid Pijn (trigeminus neuralgie) Thermosensitiviteit

10 Stoornissen van de blaas Verlies descenderende banen neurogene blaas (reflexmatig) tevens minder goede samenwerking blaassfincter en blaas

11 Moeheid Veel voorkomende klacht Vaak grote impact Ernst moeheid niet altijd gecorreleerd aan ernst MS Oorzaak onbekend

12 Percentage of MS Patients Impaired Cognitive Impairment Visual Memory 60 Immediate Delayed Processing Speed 50 Verbal Memory Visuospatial perception Immediate Delayed Speed of working memory Concept formation 20 Fluency 10 0 COWAT=Controlled Oral Word Association Test; JLO=Judgment of Line Orientation Test; CVLT -II=California Verbal Learning Test. second edition; TL=Total Learning; DR=Delayed Recovery; BVMT-R =Brief Visuospatial Memory Test; PASAT=Paced Auditory Serial Addition Test; SDMT=Symbol Digit Modalities Test; DKEFS=Delis-Kaplan Executive Function System; CS=Correct Score; DS=Description Score. Adapted from Benedict RH et al. J Int Neuropsychol Soc. 2006;12: TYS-CH-0270 Biogen Confidential and Proprietary 12

13 People with MS (%) Fatigue, Walking Ability, and Other Physical Impairments Fatigue Losing Balance Trouble Walking Inability to Walk Abnormal Sensations Muscle Spasms Pain Tremors Other Physical Effects Other Do Not Nonphysical Experience Effects Any Negative Effects Adapted from Larocca NG et al. Patient. 2011;4: TYS-CH-0270 Biogen Confidential and Proprietary 13

14 MS Has a Broad Range of Negative Effects on the Lives of Patients with MS Cognition 1 Vision 2 Depression 3 Fatigue 6,7 Quality of life 8 Bladder/bowel control 4 Sexual function 4 Employment 9,10 Healthcare costs 10 Relationship status 11 Walking ability 5 Mortality Benedict RH et al. J Int Neuropsychol Soc. 2006;12: ; 2. Jasse L et al. Mult Scler. 2013;19: ; 3. Feinstein A. Mult Scler. 2011;17: ; 4. Hawker KS, Frohman EM. Curr Treat Options Neurol. 2001;3: ; 5. LaRocca NG et al. Patient. 2011;4: ; 6. Krupp L. Mult Scler. 2006;12: ; 7. Krupp LB et al. Arch Neurol.1988;45: ; 8. Berg J et al. Eur J Health Econ. 2006;7:S75-S85; 9. Pfleger CC et al. Mult Scler. 2010;16: ; 10. Kobelt G. J Neurol Neurosurg Psychiatry. 2006;77: ; 11. Pfleger CC et al. Mult Scler. 2010;16: ; 12. Torkildsen NG et al. Mult Scler. 2008;14: TYS-CH-0270 Biogen Confidential and Proprietary 14

15 De diagnose neurol examination lumbar puncture blood tests MS evoked potential MR imaging

16 Dissociatie in tijd en plaats Optic neuritis paraparesis diplopia RRMS

17 Beloopsvormen RRMS SPMS PPMS 10%

18 Periventriculair en infratentorieel

19 Etiologie MS Genetic predisposition Infectious agent Environmental factors abnormal immune response MS

20 Epidemiologie

21 Inflammatie en demyelinisatie van het CZS Cannella B, et al. Ann Neurol. 1995;37: ; von Andrian UH, et al. N Engl J Med. 2003;348:68-72.

22 Key Components of Pathophysiology Inflammation Demyelination Axonal Loss Trapp BD et al. Curr Opin Neurol. 1999;12: ; Trapp BD et al. J Neuroimmunol. 1999;98:49-56; Trapp BD et al. Neuroscientist. 1999;5:48. TYS-CH-0270 Biogen Confidential and Proprietary 22

23 Clinical and MRI Disease Activity Throughout the Course of MS RIS CIS RRMS SPMS Cerebral Volume Relapses and Disability MRI Lesion Load MRI Activity RIS=radiologically isolated syndrome; RRMS=relapsing-remitting MS; SPMS=secondary progressive MS. Trapp BD et al. Neuroscientist. 1999;5: TYS-CH-0270 Biogen Confidential and Proprietary 23

24 Targets for MS Drugs

25 Natalizumab: effectiviteit

26 Efficacy (Relapse rate / MRI) Efficacy vs safety and tolerability Nata Mito Alem IFN GA DMF Teri Fingo Risks (safety and tolerability)

27 MS Markt NL in volume t/m 12/16 Source: TEVA

28 Treatment for MS: development and marketed Interferons Antiproliferative agents Other Peg IFNb (BIIB017) Azathioprine Teriflunomide Pixantrone Vaccine (tolerization) BIIB033 Idebenone Rebif ATX-MS-1467 PI2301 RTL1000 Extavia Cladribine Phase I Phase II Phase III Marketed Avonex Betaferon Novantrone Copaxone generics x2 LV Copaxone Copaxone Ocrelizumab Belimumab Campath Cytolytic mabs Firategrast BAF312 Fingolimod Tysabri Laquinimod Ofatumumab CS-0777 BG12 Sativex Ampyra IPX-056 LY Lymphocyte trafficking ONO-4641 ACT RPI-78M Nerispirdine ELND-002 AIN457 AZD5904 Daclizumab GRC4039 CCX-140 NI-0801 Immune regulation Symptomatic Tx = Oral = Injectable

29 Disability Early Treatment Has the Potential to Slow the Course of MS Early Therapy Is Important to Delay the Accumulation of Irreversible Neurologic Damage and Consequent Disability Window of opportunity Later treatment Natural course of MS Treatment at diagnosis Later treatment Early treatment Disease onset Time Adapted from Miller JR. J Manag Care Pharm. 2004;10(suppl S-b):S4-S11. TYS-CH-0270 Biogen Confidential and Proprietary 29

30 Introduction of RRMS Therapies in the EU Outcome Measures Goals of Therapy The Goal of Therapy in MS Has Evolved as Treatment Options Have Increased Address Symptoms Slow Disease Progression Stop Disease Progression Repair EDSS Relapse rate MRI lesion activity 3 (T1, T2, Gd+) 1996 MSFC NEDA Sustained improvement SC IFNβ-1b 1995 IM IFNβ-1a 1997 SC IFNβ-1a 1998 Natalizumab GA Fingolimod 2010 Mitoxantrone 2000 Alemtuzumab Teriflunomide 2013 MSFC=Multiple Sclerosis Functional Composite; IM=intramuscular; SC=subcutaneous; GA=glatiramer acetate; DMF=dimethyl fumarate. 1. Kurtzke J. Neurology. 1983;33: ; 2. The IFNB Multiple Sclerosis Study Group. Neurology. 1993;43: ; 3. Miller DH et al. Ann Neurol. 1996;39:6-16; 4. Miller DM et al. Arch Neurol. 2000;57: ; 5. Havrdová E et al. Lancet Neurol. 2009;8: ; 6. Phillips J et al. Mult Scler. 2011;17: ? DMF Peginterferon Beta-1a 2014 TYS-CH-0270 Biogen Confidential and Proprietary 30

31 Toward Composite Outcome Measures in MS: No Evidence of Disease Activity A more widely used definition of NEDA consists of the following features 1 : No Relapses No Disability Progression EDSS Progression + + No MRI Activity No new/enlarging T2 lesions No new Gd+ lesions Achievement of NEDA status in patients receiving a DMT seems to be an ideal goal for therapy 1 Comparing NEDA status across DMTs is problematic for the following reasons 1-3 : All NEDA determinations are based on post hoc analyses The definition of NEDA and individual components may vary from study to study The handling of missing data may be different Patient populations may be different Frequency of data point collection and the study duration may be different DMT=disease-modifying therapy; LOCF=last observation carried forward. 1. Imitola J, Racke MK. JAMA Neurol. 2015;72: ; 2. Stangel M et al. Ther Adv Neurol Disord. 2015;8:3-13; 3. Nixon R et al. Adv Ther. 2014;31: TYS-CH-0270 Biogen Confidential and Proprietary 31

32 MS Has a Broad Range of Negative Effects on the Lives of Patients with MS Quality of life 8 Employment 9,10 Healthcare costs 10 Relationship status 11 Mortality Benedict RH et al. J Int Neuropsychol Soc. 2006;12: ; 2. Jasse L et al. Mult Scler. 2013;19: ; 3. Feinstein A. Mult Scler. 2011;17: ; 4. Hawker KS, Frohman EM. Curr Treat Options Neurol. 2001;3: ; 5. LaRocca NG et al. Patient. 2011;4: ; 6. Krupp L. Mult Scler. 2006;12: ; 7. Krupp LB et al. Arch Neurol.1988;45: ; 8. Berg J et al. Eur J Health Econ. 2006;7:S75-S85; 9. Pfleger CC et al. Mult Scler. 2010;16: ; 10. Kobelt G. J Neurol Neurosurg Psychiatry. 2006;77: ; 11. Pfleger CC et al. Mult Scler. 2010;16: ; 12. Torkildsen NG et al. Mult Scler. 2008;14: TYS-CH-0270 Biogen Confidential and Proprietary 32

33 Utility (EQ-5D: 0=Death; 1=Full Health) Decline in Quality of Life with Increased EDSS Score: QALY 1.00 Best Possible Health Status Utility Assessment Scale (Based on EQ-5D) 0.85 mean utility of normal population mean utility of aging patients with osteoporosis, no fracture mean utility of patients with rheumatoid arthritis at stage mean utility of patients with Parkinson s disease mean utility of patients with MS mean utility of severe 0.00 Worst Possible hemophilia patients with Health Status inhibitors QALY 1 Mean utility in the sample=0.55 Normal population= EDSS Score EDSS=Expanded Disability Status Scale; QALY=quality-adjusted life-year; EQ-5D=EuroQoL-5 Dimension. 1. Adapted from Berg J et al. Eur J Health Econ. 2006;7:S75-S85; 2. Oleksik A et al. J Bone Miner Res. 2000;15: ; 3. Kobelt G et al. Arthritis Rheum. 1999;42: ; 4. Siderowf A et al. Neurology. 2002;59: ; 5. Ekert H et al. Haemophilia. 2001;7: TYS-CH-0270 Biogen Confidential and Proprietary 33

34 Probability Unemployment Probability of Remaining in Active Employment After Onset of MS 1.0 Control Persons MS Patients Time (years) Pfleger CC et al. Mult Scler. 2010;16: TYS-CH-0270 Biogen Confidential and Proprietary 34

35 Proportion of Patients Aged 65 Years Working (%) Employment Change with EDSS Score Increase Work Capacity by Disability Level* Austria Belgium Germany Italy Netherlands Spain Sweden Switzerland United Kingdom / /9.0 EDSS Score NOTE: The reduced work capacity, particularly at EDSS score compared with EDSS score 4.0, is explained by an increased frequency of relapses in this group and hence a concentration of sick leaves *The proportion of patients employed or on long-term sick leave is calculated as a percentage of patients aged 65 years or younger. Adapted from Kobelt G et al. J Neurol Neurosurg Psychiatry. 2006;77: TYS-CH-0270 Biogen Confidential and Proprietary 35

36 Purchasing Power Parity* ( ) Increasing EDSS Scores and Healthcare Costs 90,000 80,000 AU Austria BE Belgium GE Germany Indirect Costs Informal Care 70,000 60,000 IT Italy NL Netherlands ES Spain SE Sweden Services/Investments Direct Healthcare 50,000 CH Switzerland UK United Kingdom 40,000 30,000 20,000 10,000 0 AU BE GE IT NL ES SE CH UK Mild (EDSS ) AU BE GE IT NL ES SE CH UK Moderate (EDSS ) AU BE GE IT NL ES SE CH UK Severe (EDSS ) *Purchasing Power Parity=total mean annual cost per patient; local currencies were transformed using the gross domestic product purchasing power parity index. Kobelt G et al. J Neurol Neurosurg Psychiatry. 2006;77: TYS-CH-0270 Biogen Confidential and Proprietary 36

37 Probability Divorce and Separation 1.0 Crude Probability of Remaining in a Relationship After Onset of MS* Control Persons MS Patients Time to Event or End of Observation (years) *Life table method; for each MS patient, 20 control persons were drawn by random from the Civil Registration System and matched to the index person by sex and year of birth and being alive at 1 January of the year of disease onset of the corresponding patient (N=36,014); patients with definite or probable MS identified through the nationwide Danish MS Registry with onset from 1980 to 1989 were included in the study and were followed up to 1 January 2004 (n=1804). Pfleger CC et al. Mult Scler. 2010;16: TYS-CH-0270 Biogen Confidential and Proprietary 37

38 Survival (%) Mortality Survival Probability of Norwegian Patients with RRMS (Hordaland County, Western Norway, ) Years After Onset General Population RRMS Population 95% CI Approximate Patient Age (years) CI=confidence interval. Adapted from Torkildsen NG et al. Mult Scler. 2008;14: TYS-CH-0270 Biogen Confidential and Proprietary 38

39 Arbeidsparticipatie Onbehandeld: na 10 jaar 50% zonder werk Verminderde arbeidsparticipatie loopt op tot 80% Toenemend aantal patiënten blijft stabiel op lange termijn en participeert volledig op hoog niveau CBO richtlijn MS 2012

40 Arbeidsparticipatie Ziektespecifieke factoren Functionele beperkingen Ziekteprogressie Cognitie Vermoeidheid Medicatie CBO richtlijn MS 2012

41 Arbeidsparticipatie Werkgerelateerde factoren Opleidingsduur en niveau behoud werk bij lange duur en hoger niveau Type werk en werkomgeving toegang tot werk en reizen naar en van werk CBO richtlijn MS 2012

42 Arbeidsparticipatie Beoordeling belastbaarheid In overleg met behandelaar (neuroloog en revalidatiearts) Houd rekening met exacerbaties (geen uitspraken binnen 3 maanden na relaps) Houd rekening met (toenemend effectieve) medicatie CBO richtlijn MS 2012

43 Arbeidsparticipatie Interventies voor re-integratie of participatie Weinig onderzoek bij MS In algemeen: arbeidsrevalidatie positief effect Te denken valt aan: Optimaliseren zelfvertrouwen bij werk gerelateerde problematiek Training in bespreekbaar maken aanpassingen Realiseren vroege en laagdrempelige start begeleiding Optimaliseren belangrijker dan maximaliseren CBO richtlijn MS 2012

44 Take home MS steeds beter te behandelen Maar blijft grillig en onvoorspelbaar qua beloop Kan enorme impact hebben op kwaliteit van leven Arbeidsparticipatie: analyse belemmerende factoren aanpassingen of begeleiding nodig? samenwerking bedrijfsarts met neuroloog en revalidatiearts Optimaliseren!