ECTRIMS 2019

• 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.
• 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.

• To derive an updated integrated view of MS disease course, and to determine the bestfit 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

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.

• 7113 unique patients had MRI metrics from ≥ 1 timepoint 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.
• 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)

• 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.

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.