Earliest MS: What Do We Know? RMMSC Education Summit May 12,2018. John R. Corboy, MD

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1 Earliest MS: What Do We Know? RMMSC Education Summit May 12,2018 John R. Corboy, MD

2 JRC has received grant support from PCORI, NMSS, Novartis, Biogen, and Med-Day. He receives compensation as the editor of Neurology: Clinical Practice

3 Goal of MS Therapy Life-Long Brain/Spine Health 3

4 Potential Approaches to MS Avoid developing it, ie find cause and stop it Alter immune system function As with presently available disease modifying therapies (DMTs) Protect nerves from degeneration Enhance normal repair in CNS Replace damaged cells in CNS Good behaviors Avoid and treat Co-Morbidities, eg hypertension, diabetes Exercise, no smoking, good diet, maintain good BMI

5 Natural Progression of MS Relapsing forms Subclinical Monosymptomatic Initial demyelinating event Relapsing-Remitting Clinically definite MS Secondary Progressive Relapse Increasing disability Time Gd = gadolinium. Level of disability Accumulated MRI lesion burden Acute (new and Gd+) MRI activity Cognitive dysfunction Brain volume Relapses

6 Natural Progression of MS Relapsing forms Subclinical Monosymptomatic Initial demyelinating event Relapsing-Remitting Clinically definite MS Secondary Progressive Relapse Increasing disability Time Gd = gadolinium. Level of disability Accumulated MRI lesion burden Acute (new and Gd+) MRI activity Cognitive dysfunction Brain volume Relapses

7 MS Prodrome Preclinical MS Decreased activity levels Decreased cognitive function Increased depression and anxiety Increased use of healthcare resources MRI lesions consistent with MS Radiologically Isolated Syndrome MRI brain volume loss

8 Figure 2 Relative physical activity by time of multiple sclerosis (MS) symptoms or diagnosis From the Nurses Health Study 2016 American Academy of Neurology Kirsten S. Dorans et al. Neurology 2016;87: US

9 At least 2SD below control mean RIS v MS RIS/MS v HC Mean Age = 40 for all groups. RIS/MS all fulfilled Barkhof MRI criteria. 16/26 RIS participants were 2+ SD lower than mean age-and sex-matched controls on 1 or more of 13 tests. Lebrun et al Cognitive function in radiologically isolated syndrome. MSJ 16(8):

10 Figure 2 School performance as a marker of cognitive decline prior to diagnosis of multiple sclerosis. Sinay V, Perez Akly M, Zanga G, Ciardi C, Racosta JM. Mult Scler Jun;21(7): doi: / Epub 2014 Oct 24. PMID: Argentina

11 Preclinical disease activity in multiple sclerosis: A prospective study of cognitive performance prior to first symptom Association between low cognitive scores at conscription in men aged 18 or 19 years and the risk of developing multiple sclerosis (MS) in the following years, reflecting the risk of developing MS in the years following the conscription examination with cognitive testing comparing those scoring >1 standard deviation below the controls mean to the remaining individuals. CI = confidence interval; RR = relative risk. Norway Cortese etal. Preclinical disease activity in multiple sclerosis: A prospective study of cognitive performance prior to first symptom.annals of Neurology Volume 80, Issue 4, pages , 28 SEP 2016 DOI: /ana

12 Figure 2 The index date refers to the first demyelinating event, defined as the first demyelinating diseaserelated code recorded by a physician. Health-care use before a first demyelinating event suggestive of a multiple sclerosis prodrome: a matched cohort study. Wijnands JMA, Kingwell E, Zhu F, Zhao Y, Högg T, Stadnyk K, Ekuma O, Lu X, Evans C, Fisk JD, Marrie RA, Tremlett H. Lancet Neurol Jun;16(6): doi: /S (17) Epub 2017 Apr 20. PMID: Canada

13 Representative images of the healthy relatives of patients with MS fulfilling Okuda criteria for radiologically isolated syndrome (RIS) (A) fulfilling modified Okuda criteria for RIS in which the dissemination in space on MR imaging was evaluated by use of Swanton Criteria, (B), or presenting with dirty-appearing white matter (C). 68 asymptomatic relatives of MS patients vs 82 controls with no Fam Hx, mean 39yo Smoking related to presence of any WM abnormalities Obesity related to 9 WM lesions and RIS by Swanton criteria T. Gabelic et al. AJNR Am J Neuroradiol 2014;35: by American Society of Neuroradiology

14 Brain Atrophy in Radiologically Isolated Syndromes Journal of Neuroimaging Volume 25, Issue 1, pages 68-71, 13 OCT 2014 DOI: /jon

15 Brain Atrophy in Radiologically Isolated Syndromes Journal of Neuroimaging Volume 25, Issue 1, pages 68-71, 13 OCT 2014 DOI: /jon

16 RIS=24 HC=14 71% had Cord lesions Minimal microstructural differences v Controls Brain Volume smaller Comparisons of quantitative spinal cord MRI measures and brain atrophy in RIS vs. healthy controls (adjusted for age and sex)(a) FA cord, (B) MTR code, (C) cross-sectional area of the cord, and (D) brain parenchymal fraction. *Boxplots depict median, interquartile range, and upper and lower fences of each MRI index. Asterisks represent outliers. FA = fractional anisotropy; MTR = magnetization transfer ratio; RIS = radiologically isolated syndrome. Alcaide-Leon et al Neurol Neuroimmunol Neuroinflamm Mar; 5(2): e436. Published online 2018 Jan 17. doi: /NXI

17 Prior suggestive symptoms in one-third of patients consulting for a "first" demyelinating event. O Gout et al. J Neurol Neurosurg Psychiatry 2011;82: France 2011 by BMJ Publishing Group Ltd

18 Radiologically Isolated Syndrome Asymptomatic patients with classic MS findings on MRI. Will they go on to develop MS? 1/3 will develop clinical MS over 2-5 yrs. 91% develop radiographic dissemination over 6-30 months 42% - MRI for Headache 194/300 (64.7%) with + OCBs vs ONTT 30% at 5 years relapse 51% relapse if 3+ brain MRI lesions Lebrun et al, Arch Neurol 2009; Okuda et al, PLoS ONE 2014

19 N=451 Radiologically Isolated Syndrome Means: F/U= 4.4 y Age=37.2y 34% convert Of converters 9.6%>PPMS Time to a first clinical event by (A) + spinal cord lesions, (B) age at first MRI suggestive of demyelinating disease, (C) sex, and (D) stratified based on the presence of 0, 1, 2, or 3 risk factors. Okuda DT, Siva A, Kantarci O, Inglese M, Katz I, et al. (2014) Radiologically Isolated Syndrome: 5-Year Risk for an Initial Clinical Event. PLoS ONE 9(3): e90509.

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21 Smoking Obesity Vitamin D Levels Development of MS Risk Factors Epstein-Barr Virus Infection >200 Genes Especially HLA DRB1*1501 Are there other markers of risk of MS? Especially for those with some pre-clinical or early clinical signs?

22 Chitinase 3-like 1 in Spinal Fluid Elevated Levels in Chronic Inflammation -? Biomarker in MS? Figure 1. CSF CHI3L1 concentrations (ng/ml) at different stages of multiple sclerosis compared to controls. SC: symptomatic controls; RIS: radiologically isolated syndrome; CIS: clinically isolated syndrome; RRMS: relapsing-remitting multiple sclerosis. Bars are median ± interquartile range. The p-values were determined by Mann Whitney U test. Bonferroni method was used to correct for multiple comparisons. Published in: Eric Thouvenot; Geoffrey Hinsinger; Christophe Demattei; Ugur Uygunoglu; Giovanni Castelnovo; Sophie Pittion-Vouyovitch; Darin Okuda; Orhun Kantarci; Daniel Pelletier; Sylvain Lehmann; Philippe Marin; Aksel Siva; Christine Lebrun; Mult Scler Ahead of Print DOI: / Copyright 2018 SAGE Publications

23 From: Chitinase 3-like 1: prognostic biomarker in clinically isolated syndromes Brain. 2015;138(4): doi: /brain/awv017. Canto et al. 813 CIS patients at 15 European Centers with mean and median f/u times of 5.4 and 4.6 years respectively. Mean f/u was 6.4 and 4.2 years in converters and non-converters, respectively.

24 Multivariable CHI3L NfL 1.02 OB Age 1.00 T 2 lesions 0.39 Sex 3.15 Treatment 0.73 HR RIS-CIS pvalue HR RIS-MS pvalue ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) For CHI3L1, hazard ratio (HR) indicates the increase in risk for every 100 ng/ml increment. For NfL, hazard ratio indicates the increase in risk for every 50 ng/l increment. OB = presence of IgG oligoclonal bands. Age refers to age at RIS diagnosis. T 2 lesions = the number of brain T 2 lesions recoded into 9 lesions (reference category) and 10 lesions. Sex: females group were taken as reference category; conversion to multiple sclerosis was not calculated for this variable as none of the male patients converted to the disease. Treatment refers to whether patients received immunomodulatory treatment between the RIS diagnosis and the date of conversion to CIS or multiple sclerosis for converters, and during follow-up time for non-converters. Statistically significant values are highlighted in bold. Matute-Blanch et el 2018: Brain Apr 1;141(4): doi: /brain/awy total RIS patients studied.

25 Time to CIS or MS High v Low CHI3L1 (cutoff 170ng/mL) All in CSF High v Low NfL (cutoff 619ng/L) Pos v Neg OCBs (not defined as to number of OCBs) From: Neurofilament light chain and oligoclonal bands are prognostic biomarkers in radiologically isolated syndrome. Matute-Blanch et al. Brain. 2018;141(4): doi: /brain/awy021

26 FIGURE 1. NfL levels in the 2 CIS groups. Results adjusted for CIS topography and diseasemodifying treatment. CDMS = clinically definite multiple sclerosis; CIS = clinically isolated syndrome; NfL = neurofilament light chain. Arrambide etal. Neurology Sep 13; 87(11): doi: /WNL Determined levels of neurofascin, semaphorin 3A, fetuin A, glial fibrillary acidic protein, and neurofilament light (NfL) and heavy chains; 68 CIS patients from Barcelona cohort.

27 FIGURE 2. Scatterplots showing the correlations between NfL levels and brain volume changesthe graphs represent the raw data. The correlation coefficients and p values correspond to the partial correlations adjusted for age and baseline gadoliniumenhancing lesions. (A) BPF change at 1 year. (B) PBVC at 1 year. (C) BPF change at 5 years. (D) PBVC at 5 years. BPF = brain parenchymal fraction; NfL = neurofilament light chain; PBVC = percentage brain volume change.

28 Serum neurofilament light chain (NfL) concentrations across the three investigated groups (FC, fast converters to clinically definite multiple sclerosis (CDMS); NC, non-converters to CDMS; HC, healthy controls) by BMJ Publishing Group Ltd Giulio Disanto et al. J Neurol Neurosurg Psychiatry 2016;87:

29 (A) Serum neurofilament light chain (NfL) levels across T2 lesion categories; (B) serum NfL levels in patients with and without gadolinium-enhancing MRI lesions (Gd+); (C) serum NfL levels across expanded disability status scale (EDSS) categories; (D) serum NfL levels in patients with and without oligoclonal bands (OCB). Serum NfL levels correlate with T2 Lesions, Gad+ Lesions, and EDSS in 100 International CIS patients, but not with Presence of OCBs 2016 by BMJ Publishing Group Ltd Giulio Disanto et al. J Neurol Neurosurg Psychiatry 2016;87:

30 IL-6 Pro-Inflam And IL-10 Anti-Inflam in B Cells Those who convert early express less IL-10 Guerrier et al, Neurol Neuroimmunol Neuroinflamm Mar; 5(2): e431. Published online 2017 Dec 22. doi: /NXI RIS(12)/CIS(46)/MS(31): NO effect of IL10/IL6 changes in long-term conversion to MS

31 RISk factors in Early MS RISE MS Genetic (>200) and environmental (EBV, smoking, obesity, Vitamin D) risk factors First Degree Relatives with fold The study 300 asymptomatic FDRs of MS patients, risk of MS Environmental screen; blood (EBV, Vit D, HLA, SNP, immunological and neuronal damage/nfl markers); activity monitor Brief screening MRI, brain and C spine Compare those with vs those without MRI c/w MS Similar to GEMS (Genes and Environment in MS)

32 Genes and Environment in MS Asymptomatic First Degree Relatives of MS Patients 65 women stratified into High(40) and Low(25) risk based on prior known risks MRI, Exam, OCT, cognitive tests; X= 37 years Outcomes: High v Low Risk Women had Impaired vibratory sensation on exam No differences in Cognitive or OCT measures 5/65 had MRIs fulfill dissemination in space 14 (22%) had at least 40% of T2-weighted brain lesions with a perivenous appearance

33 From: Assessment of Early Evidence of Multiple Sclerosis in a Prospective Study of Asymptomatic High-Risk Family Members. Xia et al. JAMA Neurol. 2017;74(3): doi: /jamaneurol Neuroimaging and Clinical Evaluation of the Neurologically Asymptomatic Women From the Genes and Environment in Multiple Sclerosis (GEMS) Study Cohort of First-Degree Family Members Date of download: 5/7/2018 Copyright 2017 American Medical Association. All rights reserved.

34 What is the Importance of RISEMS? Early recognition >? Treat before symptoms Treatment with Dimethyl Fumarate (Tecfidera) vs Pb in RIS now underway If we create a risk algorithm Identify modifiable risk factors Create monitoring algorithm If we ID and follow participants long-term Determine factors associated with severe vs benign MS > alter treatment regimens accordingly

35 Thank You for Your Attention!