P949

References 1. Fox RJ, Cohen JA. Multiple sclerosis. http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/neurology/multiple_sclerosis/. Accessed August 19, 2019. 2. Bermel R, et al. Neurology. 2017;88(16)(suppl):P1.372. 3. Bermel R, et al. Neurology. 2017;88(16)(suppl):P1.369. 4. Tsang A, et al. Presented at: 27th Annual Meeting of the The International Society for Magnetic Resonance in Medicine; May 11–16, 2019; Montreal, QC, Canada. 5. Fartaria MJ, et al. Neuroimage Clin. 2019;23:101938. 6. Rhodes JK, et al. Adv Ther. 2019;36(7):1741-1755. 7. Disanto G, et al; Swiss Multiple Sclerosis Cohort Study Group. Ann Neurol. 2017;81:857-870.

Disclosures: AR: advisory boards for Bayer, Biogen, Icometrix, Novartis, Olea Medical, Sanofi-Genzyme, and SyntheticMR; speaker fees from Bayer, Biogen, Bracco, Merck Serono, Novartis, Roche, Sanofi-Genzyme, and Teva; RDP, YLei, MLB, CdM, SM, TP, CMS, AT, JRW, RAR, and EF: employees of and hold stock/stock options in Biogen; RAB: consultant for Biogen, Genzyme, Genentech, and Novartis; research support from Biogen, Genentech, and Novartis; rights to intellectual property underlying the Multiple Sclerosis Performance Test, currently licensed to Biogen and Qr8 Health; TLSB: research support from Avid Radiopharmaceuticals (Eli Lilly); speaker bureau for Biogen; Investigator for Biogen, Jaansen, Lilly, and Roche; ALB: consulting fees/honoraria from Biogen, Genzyme, Mallinckrodt, Medtronic, Novartis, and Teva; CP: consulting fees from Biogen and Disarm; grants from Biogen and Annexon; RC-J, MJF, TH, and TK: employees of Siemens Healthcare AG; CMH: speaker/consulting fees from Biogen, EMD Serono, Genentech, Genzyme, and Novartis; research support paid to her institution by Biogen and Patient-Centered Outcomes Research Institute; MHH: funding from Biogen (contract with her employer, the University of Rochester); II: funding from Biogen (contract with her employer, Johns Hopkins University); Principal Investigator on a research grant from Siemens paid to Johns Hopkins; consulting fees from Alexion; SEJ: speaker fees from Monteris and Siemens; HHK: research grants/speaker honoraria/travel expenses from and advisory boards for Biogen, Ixico, Novartis, Pfizer, Sanofi-Genzyme, and Teva; LK: consulting fees from Biogen, EMD Serono, Novartis, Pfizer (data safety monitoring board), PK Law, Projects in Knowledge, and Teva Neuroscience; royalty payments from AbbVie and Grifols; research grant support from Biogen, Department of Defense, Lourie Foundation, National Institutes of Health, National Multiple Sclerosis Society, Novartis, and Teva Neuroscience; YLiu: nothing to disclose; XM: speaker fees/travel expenses from and advisory boards for Actelion, Almirall, Bayer, Biogen, Celgene, Genzyme, Merck, Novartis, Oryzon, Roche, Sanofi-Genzyme, and Teva; EMM: research support from and Biogen and Genzyme; free medication for a clinical trial from Teva; Principal Investigator for Biogen and Sun; royalties for editorial duties from UpToDate; RN: consulting fees/honoraria from Acorda, Alkermes, Bayer, Biogen, EMD Serono, Genentech, Genzyme, Novartis, and Teva; DO: research support from Genentech, Genzyme, National Institutes of Health, National Multiple Sclerosis Society, Patient-Centered Outcomes Research Institute, and Race to Erase MS Foundation; consulting fees from Biogen, Genentech-Roche, Genzyme, and Merck; MS: nothing to disclose; BT: advisory boards for Bayer, Biogen, CSL Behring, Genzyme, Grifols, Novartis, and UCB; speaker fees from Bayer, Biogen, CSL Behring, Genzyme, Grifols, Novartis, and Octapharma; consulting fees from Bayer, Biogen, CSL Behring, Genzyme, Grifols, Novartis, and UCB; research support from Biogen and Novartis; MTintore: consulting/speaker fees from Almirall, Bayer, Biogen, Genzyme, Merck Serono, Novartis, Roche, Sanofi, and Teva; coeditor of Multiple Sclerosis Journal – Experimental, Translational and Clinical; MTivarus: funding from Biogen (contract with her employer, University of Rochester); TZ: speaker fees/travel expenses from and advisory boards for clinical trials for Almirall, Bayer, Biogen, Celgene, Merck Serono, Novartis, Roche, Sanofi-Genzyme, and Teva; YZ: nothing to disclose. Acknowledgments MS PATHS is sponsored by Biogen (Cambridge, MA, USA). Editorial support for the preparation of this poster was provided by Excel Scientific Solutions (Fairfield, CT, USA): funding was provided by Biogen.

A Quantitative View of MS Disease Course

Rovira A,1 Perea RD,2 Lei Y,2 Bermel RA,3 Benzinger TLS,4 Blefari ML,2 Boster AL,5 Calabresi P,6 Corredor-Jerez R,7 de Moor C,2 Fartaria MJ,7 Hersh CM,8 Huelnhagen T,7 Hyland MH,9 Izbudak I,6 Jones SE,3 Kitzler HH,10 Kober T,7 Krupp L,11

Lui YW,11 Makaretz S,2 Montalban X,1,12 Mowry EM,6 Naismith R,4 Ontaneda D,3 Plavina T,2 Schulze M,13 Singh CM,2 Tackenberg B,13 Tintore M,1 Tivarus ME,9 Tsang A,2 Ziemssen T,1 Zhuang Y,2,9 Williams JR,2 Rudick RA,2 Fisher E2

1Vall d’Hebron University Hospital, Barcelona, Spain; 2Biogen, Cambridge, MA, USA; 3Cleveland Clinic, Cleveland, OH, USA; 4Washington University in St. Louis, St. Louis, MO, USA; 5OhioHealth, Columbus, OH, USA; 6Johns Hopkins University, Baltimore, MD, USA; 7Advanced Clinical Imaging Technology, Siemens Healthcare AG, Lausanne, Switzerland; 8Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV, USA; 9University of Rochester Medical Center, Rochester, NY, USA; 10Center of Clinical Neuroscience, University Clinic Carl Gustav Carus, Technical University of Dresden, Dresden, Germany; 11NYU Langone Health, New York, NY, USA; 12Division of Neurology, St. Michael’s Hospital, University of Toronto, Toronto, ON, Canada; 13University Hospital of

Giessen and Marburg, Marburg, Germany

• A commonly used diagram to describe the disease course of multiple sclerosis (MS) shows how various measurements of disease activity and progression change over time1 (Figure 1).

• Based on current knowledge of MS, the curves of the diagram are derived hypothetically and some portions are not well established or understood, particularly in the later stage of disease where fewer data are available.

• To derive an updated integrated view of MS disease course, and to determine the best-fit temporal patterns for measures of brain volume and overall burden of disease, using quantitative metrics from a large heterogeneous population of patients from the Multiple Sclerosis Partners Advancing Technology for Health Solutions (MS PATHS) network.2

• Metrics routinely collected in MS PATHS were mapped to each of the disease activity and progression curves shown in Figure 1. The specific MS PATHS metrics used are listed in Table 1.

Data Collection • All data were derived from MS PATHS participants (Table 1).• Two standardized magnetic resonance imaging (MRI) acquisition sequences (3D FLAIR and

3D T1 on Siemens 3T scanners) were incorporated into routine MS imaging protocols at all 10 participating health care institutions.3

• A software prototype (MS PATHS Image Evaluation [MSPie])4-5 was developed and used for automated calculation of brain parenchymal fraction (BPF), total T2 lesion volume (T2LV), and new T2 lesion counts.

• The Multiple Sclerosis Performance Test,6 an iPad-based assessment device, was used for standardized patient reports (disease duration, relapse, Patient Determined Disease Steps [PDDS]).

• Serum was collected as part of an MS PATHS biobanking substudy and analyzed by SIMOA NF-light® Advantage Kit assay to measure serum neurofilament light chain (sNfL).7

INTRODUCTION

OBJECTIVES

METHODS

RESULTS

• Standardization of MRI acquisition and analysis enables high-quality MRI-based metrics and systematic learning from routine patient care.

• Data from a large heterogeneous outpatient population allow estimation of change for radiological, biomarker, and clinical parameters over the full MS disease course.

• Although this approach has some limitations (e.g., cross-sectional analyses, lack of data from severely disabled patients), these real-world data show strong linearity observed for various measures of disease progression, suggesting that MS neither stabilizes nor accelerates in later stages, unlike some hypothetical diagrams of disease evolution.

• While pathogenic mechanisms may change over the course of MS, the data suggest that MRI and clinical measures steadily worsen over time.

CONCLUSIONS

35th Congress of the European Committee for Treatment & Research in Multiple Sclerosis ECTRIMS (2019) I September 11–13, 2019 I Stockholm, Sweden

Disease Characteristic on Diagram in Figure 1

Corresponding MS PATHS Measure MS PATHS Data Source

Disease duration Time since MS diagnosis MSPT – MyHealth Questionnaire

Brain volume BPF MSPie

Disease burden Total T2LV MSPie

MRI activity New T2 lesion count MSPie

Clinical disability PDDS MSPT – MyHealth Questionnaire

Relapses (superimposed on disability curve) Self-reported relapses in prior year MSPT – MyHealth Questionnaire

NA (new MS biomarker) sNfL 888MS002 biobanking substudy

BPF = brain parenchymal fraction; MRI = magnetic resonance imaging; MS = multiple sclerosis; MSPie = MS PATHS Image Evaluation; NA = not available; PDDS = Patient Determined Disease Steps; sNfL = serum neurofilament light chain; T2LV = T2 lesion volume

Table 1. Corresponding MS PATHS Measurements for Disease Course Diagram

Characteristic n Mean (SD) Median (Range)Age, y 6454 45.8 (11.9) 46 (14–84)Disease duration, y 6263 11.5 (9.0) 9 (0–68)Female 4773 (67%) – –Disease subtype

Relapsing MS 4116 (58%) – –Progressive-relapsing MS 498 (7%) – –Progressive MS (secondary or primary) 1480 (20%) – –

Currently receiving DMT 4962 (69%) – –PDDS 6449 1.87 (2.04) 1 (0–8)No. of relapses in prior year 6402 0.87 (1.06) 0 (0–3)BPF 7113 0.850 (0.026) 0.855 (0.709–0.900)T2LV, mL 7113 12.6 (12.2) 8.2 (0.8–115.6)New T2 lesion count 2602 2.8 (5.1) 1 (0–66)SNfL, pg/mL 1238 13.2 (14.6) 10.1 (1.2–262.2) BPF = brain parenchymal fraction; DMT = disease-modifying therapy; MS = multiple sclerosis; PDDS = Patient Determined Disease Steps; sNfL = serum neurofilament light chain; T2LV = T2 lesion volume

Table 2. Patient Characteristics

MS Disease DurationMeasure 0–5 y

n = 27696–10 y

n = 229411–15 yn = 1670

16–20 yn = 1317

21–25 yn = 671

26–30 yn = 374

31+n = 353

Mean (SD) age,y 39.8 (10.8) n=2769

42.6 (10.7) n=2294

47.1 (10.1) n=1670

50.5 (9.2) n=1317

52.5 (9.0) n=671

56.9 (7.7) n=374

60.2 (7.6) n=353

Mean (SD) PDDS 1.2 (1.6) n=2695

1.6 (1.8) n=2228

1.9 (2.1) n=1638

2.4 (2.2) n=1288

2.7 (2.4) n=653

3.0 (2.3) n=365

3.3 (2.3) n=347

Mean (SD) no. of relapses in prior year

0.96 (1.05) n=2741

0.79 (1.01) n=2269

0.80 (1.03) n=1652

0.73 (1.00) n=1295

0.72 (1.05) n=658

0.81 (1.03) n=366

0.72 (0.96) n=345

Mean (SD) BPF 0.862 (0.018) n=2750

0.856 (0.021) n=2273

0.847 (0.024) n=1654

0.841 (0.025) n=1305

0.834 (0.026) n=667

0.826 (0.029) n=373

0.821 (0.035) n=349

Mean (SD) T2LV, mL 8.3 (8.3) n=2750

10.4 (10.8) n=2273

13.4 (11.4) n=1654

15.5 (13.0) n=1305

18.2 (13.1) n=667

19.7 (14.6) n=373

23.0 (17.7) n=349

Mean (SD) new T2 lesion count

1.7 (3.0) n=918

2.0 (5.0) n=872

1.9 (4.6) n=586

1.7 (2.7) n=489

1.9 (4.1) n=251

1.9 (3.4) n=108

2.0 (2.3) n=118

Median sNfL (IQR, 25–75), pg/mL

8.95 (5.68) n=393

8.54 (5.21) n=357

9.69 (7.14) n=181

12.0 (7.45) n=187

11.1 (6.25) n=88

13.9 (10.00) n=38

14.8 (11.12) n=43

BPF = brain parenchymal fraction; DMT = disease-modifying therapy; IQR = interquartile range; MS = multiple sclerosis; PDDS = Patient Determined Disease Steps; sNfL = serum neurofilament light chain; T2LV = T2 lesion volume

Table 3. Evolution of Quantitative Measures of MS by Disease Duration

Figure 1. Typical Disease Course for Relapse-Onset MS Showing 1 Variation on the Shapes of the Curves1

MRI = magnetic resonance imaging; MS = multiple sclerosis

Figure 2. Updated MS Disease Course Diagram Derived From Real-world Data Collected in MS PATHSa

BPF = brain parenchymal fraction; PDDS = Patient Determined Disease Steps; sNfL = serum neurofilament light chain; T2LV = T2 lesion volumeaThe clinical disability curve (green) was depicted as the mean PDDS superimposed with the mean number of relapses as 1-point spikes, representing the frequency of clinical disease activity within each epoch. The frequency of new T2 lesions (blue arrows) was represented in the same manner. The strong linearity in the curves is particularly evident for brain volume (BPF, red) and total burden of disease (T2LV, gold). NfL, BPF, and PDDS were not adjusted for age or comorbidities, although these measures are known to be affected by factors beyond the multiple sclerosis disease process. Note: n values are different for each measure (see Table 3 below for details).

Linear Term Quadratic TermPDDS 0.073 (p < 2e-16) –0.00019 (p = 0.615)Relapses –0.014 (p < 2e-08) 0.00054 (p = 0.008)BPF –0.0015 (p < 2e-16) 0.000011 (p= 0.0007)T2LV, mL 0.497 (p < 2e-16) –0.0039 (p < 0.01)New T2 lesion count 0.000014 (p = 0.999) –0.000056 (p = 0.952)Log(sNfL), pg/mL 0.015 (p < 2e-08) –0.00032 (p = 0.155)BPF = brain parenchymal fraction; MS = multiple sclerosis; PDDS = Patient Determined Disease Steps; sNfL = serum neurofilament light chain; T2LV = T2 lesion volume

Table 4. Regression With MS Disease Duration

• 7113 patients had MRI metrics and were included in these analyses. Patient characteristics are listed in Table 2. For patients on disease-modifying therapy, 28% were on injectable, 43% were on oral, and 22% were on infusion medications.

• Summary statistics for the quantitative disease measures grouped by 5-year disease duration epochs are shown in Table 3.

Preclinicalphase

Relapsing-remittingphase

Secondary progressivephase

Brain volume

Clinical disability

Disease burden

MRI activity

20+ years10–15 years? years

0.0

1.0

2.0

3.0

4.0

5.0

6.0

0–5(n = 2769)

6–10(n = 2294)

11–15(n = 1670)

16–20(n = 1317)

21–25(n = 671)

26–30(n = 374)

31+(n = 353)

MS Disease Duration, y

0.80

0.85

0.70

0.75

0

8

16

24

40

48

32

Mea

n P

DD

ST2

LV, m

L

0

8

16

24

32

Mea

n B

PF

Med

ian

sNfL

, pg/

mL

New T2 lesions Disability (PDDS + relapses) T2LV sNfLBPF

Preclinicalphase

Relapsing-remittingphase

Secondary progressivephase

Brain volume

Clinical disability

Disease burden

MRI activity

20+ years10–15 years? years

0.0

1.0

2.0

3.0

4.0

5.0

6.0

0–5(n = 2769)

6–10(n = 2294)

11–15(n = 1670)

16–20(n = 1317)

21–25(n = 671)

26–30(n = 374)

31+(n = 353)

MS Disease Duration, y

0.80

0.85

0.70

0.75

0

8

16

24

40

48

32

Mea

n P

DD

ST2

LV, m

L

0

8

16

24

32

Mea

n B

PF

Med

ian

sNfL

, pg/

mL

New T2 lesions Disability (PDDS + relapses) T2LV sNfLBPF

Statistical Analyses• For patients with quantitative MRI metrics available, data for each measurement were

analyzed to calculate: – Cross-sectional mean/median values for sequential subgroups based on disease duration in 5-year epochs

– Slopes for each measure versus disease duration using linear regression – Tests for quadratic terms to assess linearity over time.

Disease Course Diagram Construction• To construct a diagram similar to Figure 1, PDDS, BPF, T2LV, and sNfL curves were

constructed by plotting the mean (PDDS, BPF, T2LV) or median (sNfL) values at the center value for each 5-year epoch, with disease duration represented as a categorical variable on the x-axis.

• Discrete count measures of disease activity (new T2 lesion counts and relapses) were depicted graphically by multiplying the mean value for each 5-year epoch by 5, and representing the corresponding number of arrows (new T2 lesion counts) or disability spikes evenly spaced within each epoch.

• The height of the relapse spikes was set to a constant value of 1 PDDS point and superimposed on the continuous PDDS curve.

• Different versions of the diagram show the brain volume and T2 disease burden curves as either linear, accelerating, or decelerating over time because the actual temporal patterns are uncertain.

• It is also unknown whether the diagrams represent MS in the current era where most patients are receiving disease-modifying therapies.

• As shown in Figure 2, over 4 decades of MS disease duration: – BPF decreased linearly (slope = –0.17%/year) – PDDS increased linearly (slope = 0.072/year) – T2LV increased linearly (slope = 0.47 mL/year) – For these 3 variables, linear terms (slopes) were highly significant (p < 10-15); whereas quadratic terms were relatively weak or not significant (Table 4).

– Markers of inflammatory activity stayed constant or trended toward decrease over the course of MS:• New T2 lesion count (slope = –0.0004/year; p=0.96) • Relapses (slope = –0.01/year; p < 10-6)

– sNfL increased linearly (slope = 0.17/year; p = 0.0012)