Individual Prognostication of Disease Activity and Disability Worsening in Multiple Sclerosis With Retinal Layer Thickness z Scores

Ting-Yi Lin¹, Seyedamirhosein Motamedi¹, Susanna Asseyer¹, Claudia Chien¹, Shiv Saidha¹, Peter A Calabresi¹, Kathryn C Fitzgerald¹, Sara Samadzadeh¹, Pablo Villoslada¹, Sara Llufriu¹, Ari J Green¹, Jana Lizrova Preiningerova¹, Axel Petzold¹, Letizia Leocani¹, Elena Garcia-Martin¹, Celia Oreja-Guevara¹, Olivier Outteryck¹, Patrick Vermersch¹, Laura J Balcer¹, Rachel Kenney¹, Philipp Albrecht¹, Orhan Aktas¹, Fiona Costello¹, Jette Frederiksen¹, Antonio Uccelli¹, Maria Cellerino¹, Elliot M Frohman¹, Teresa C Frohman¹, Judith Bellmann-Strobl¹, Tanja Schmitz-Hübsch¹, Klemens Ruprecht¹, Alexander U Brandt¹, Hanna G Zimmermann¹, Friedemann Paul¹

Affiliations

Affiliation

¹ From the Charité - Universitätsmedizin Berlin (T.-Y.L., S.M., S.A., C.C., S. Samadzadeh, J.B.-S., T.S.-H., A.U.B., H.G.Z., F.P.); Experimental and Clinical Research Center (T.-Y.L., S.M., S.A., C.C., S. Samadzadeh, J.B.-S., T.S.-H., A.U.B., H.G.Z., F.P.), a cooperation between the Max Delbrück Center for Molecular Medicine in the Helmholtz Association and Charité - Universitätsmedizin Berlin; Max-Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) (T.-Y.L., S.M., S.A., C.C., S. Samadzadeh, J.B.-S., T.S.-H., A.U.B., H.G.Z., F.P.); Neuroscience Clinical Research Center (S.M., S.A., C.C., J.B.-S., T.S.-H., H.G.Z., F.P.); Department of Psychiatry and Psychotherapy (C.C.), Charité - Universitätsmedizin Berlin, Germany; Department of Neurology (S. Saidha, P.A.C., K.C.F.); Department of Epidemiology (K.C.F.), Johns Hopkins Bloomberg School of Public Health, Baltimore, MD; Department of Regional Health Research and Molecular Medicine (S. Samadzadeh), University of Southern Denmark, Odense; Department of Neurology (S. Samadzadeh), Slagelse Hospital, Denmark; Department of Neurology (P. Villoslada), Hospital Del Mar - Pompeu Fabra University; Neuroimmunology and Multiple Sclerosis Unit (S.L.), Hospital Clinic Barcelona and IDIBAPS, Barcelona, Spain; Department of Neurology (A.J.G.), University of California San Francisco; Department of Neurology (J.L.P.), Charles University in Prague, Czech Republic; Moorfield's Eye Hospital (A.P.), The National Hospital for Neurology and Neurosurgery, Queen Square Institute of Neurology, University College London, United Kingdom; Neuro-ophthalmology Expert Center (A.P.), Amsterdam UMC, Netherlands; Experimental Neurophysiology Unit (L.L.), Institute of Experimental Neurology (INSPE), San Raffaele Scientific Institute; Vita-Salute San Raffaele University (L.L.), Milan, Italy; Miguel Servet University Hospital (E.G.-M.), Zaragoza; Department of Neurology (C.O.-G.), Hospital Clínico Universitario San Carlos, Madrid, Spain; Department of Neurology (O.O., P. Vermersch); Department of Neuroradiology (O.O., P. Vermersch), Centre Hospitalier Universitaire de Lille, France; Departments of Neurology (L.J.B., R.K.), Population Health and Ophthalmology, NYU Grossman School of Medicine, NY; Department of Neurology (P.A., O.A.), Heinrich-Heine-University, Düsseldorf, Germany; Departments of Clinical Neurosciences and Surgery Cumming School of Medicine (F.C.), University of Calgary, Alberta, Canada; Clinic of Optic Neuritis and Clinic of Multiple Sclerosis (J.F.), Department of Neurology, Rigshospitalet - Glostrup, Denmark; Department of Neurosciences (A.U., M.C.), Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Italy; Laboratory of Neuroimmunology (E.M.F., T.C.F.), Professor Lawrence Steinman, Stanford University School of Medicine, Palo Alto, CA; Department of Neurology (K.R., F.P.), Charité - Universitätsmedizin Berlin; and Einstein Center Digital Future (H.G.Z.), Berlin, Germany.

PMID: 38941572
PMCID: PMC11214150
DOI: 10.1212/NXI.0000000000200269

Individual Prognostication of Disease Activity and Disability Worsening in Multiple Sclerosis With Retinal Layer Thickness z Scores

Ting-Yi Lin et al. Neurol Neuroimmunol Neuroinflamm. 2024 Sep.

. 2024 Sep;11(5):e200269.

doi: 10.1212/NXI.0000000000200269. Epub 2024 Jun 28.

Authors

Affiliation

¹ From the Charité - Universitätsmedizin Berlin (T.-Y.L., S.M., S.A., C.C., S. Samadzadeh, J.B.-S., T.S.-H., A.U.B., H.G.Z., F.P.); Experimental and Clinical Research Center (T.-Y.L., S.M., S.A., C.C., S. Samadzadeh, J.B.-S., T.S.-H., A.U.B., H.G.Z., F.P.), a cooperation between the Max Delbrück Center for Molecular Medicine in the Helmholtz Association and Charité - Universitätsmedizin Berlin; Max-Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) (T.-Y.L., S.M., S.A., C.C., S. Samadzadeh, J.B.-S., T.S.-H., A.U.B., H.G.Z., F.P.); Neuroscience Clinical Research Center (S.M., S.A., C.C., J.B.-S., T.S.-H., H.G.Z., F.P.); Department of Psychiatry and Psychotherapy (C.C.), Charité - Universitätsmedizin Berlin, Germany; Department of Neurology (S. Saidha, P.A.C., K.C.F.); Department of Epidemiology (K.C.F.), Johns Hopkins Bloomberg School of Public Health, Baltimore, MD; Department of Regional Health Research and Molecular Medicine (S. Samadzadeh), University of Southern Denmark, Odense; Department of Neurology (S. Samadzadeh), Slagelse Hospital, Denmark; Department of Neurology (P. Villoslada), Hospital Del Mar - Pompeu Fabra University; Neuroimmunology and Multiple Sclerosis Unit (S.L.), Hospital Clinic Barcelona and IDIBAPS, Barcelona, Spain; Department of Neurology (A.J.G.), University of California San Francisco; Department of Neurology (J.L.P.), Charles University in Prague, Czech Republic; Moorfield's Eye Hospital (A.P.), The National Hospital for Neurology and Neurosurgery, Queen Square Institute of Neurology, University College London, United Kingdom; Neuro-ophthalmology Expert Center (A.P.), Amsterdam UMC, Netherlands; Experimental Neurophysiology Unit (L.L.), Institute of Experimental Neurology (INSPE), San Raffaele Scientific Institute; Vita-Salute San Raffaele University (L.L.), Milan, Italy; Miguel Servet University Hospital (E.G.-M.), Zaragoza; Department of Neurology (C.O.-G.), Hospital Clínico Universitario San Carlos, Madrid, Spain; Department of Neurology (O.O., P. Vermersch); Department of Neuroradiology (O.O., P. Vermersch), Centre Hospitalier Universitaire de Lille, France; Departments of Neurology (L.J.B., R.K.), Population Health and Ophthalmology, NYU Grossman School of Medicine, NY; Department of Neurology (P.A., O.A.), Heinrich-Heine-University, Düsseldorf, Germany; Departments of Clinical Neurosciences and Surgery Cumming School of Medicine (F.C.), University of Calgary, Alberta, Canada; Clinic of Optic Neuritis and Clinic of Multiple Sclerosis (J.F.), Department of Neurology, Rigshospitalet - Glostrup, Denmark; Department of Neurosciences (A.U., M.C.), Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Italy; Laboratory of Neuroimmunology (E.M.F., T.C.F.), Professor Lawrence Steinman, Stanford University School of Medicine, Palo Alto, CA; Department of Neurology (K.R., F.P.), Charité - Universitätsmedizin Berlin; and Einstein Center Digital Future (H.G.Z.), Berlin, Germany.

PMID: 38941572
PMCID: PMC11214150
DOI: 10.1212/NXI.0000000000200269

Abstract

Background and objectives: Retinal optical coherence tomography (OCT) provides promising prognostic imaging biomarkers for future disease activity in multiple sclerosis (MS). However, raw OCT-derived measures have multiple dependencies, supporting the need for establishing reference values adjusted for possible confounders. The purpose of this study was to investigate the capacity for age-adjusted z scores of OCT-derived measures to prognosticate future disease activity and disability worsening in people with MS (PwMS).

Methods: We established age-adjusted OCT reference data using generalized additive models for location, scale, and shape for peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell-inner plexiform layer (GCIP) thicknesses, involving 910 and 423 healthy eyes, respectively. Next, we transformed the retinal layer thickness of PwMS from 3 published studies into age-adjusted z scores (pRNFL-z and GCIP-z) based on the reference data. Finally, we investigated the association of pRNFL-z or GCIP-z as predictors with future confirmed disability worsening (Expanded Disability Status Scale score increase) or disease activity (failing of the no evidence of disease activity [NEDA-3] criteria) as outcomes. Cox proportional hazards models or logistic regression analyses were applied according to the original studies. Optimal cutoffs were identified using the Akaike information criterion as well as location with the log-rank and likelihood-ratio tests.

Results: In the first cohort (n = 863), 172 PwMS (24%) had disability worsening over a median observational period of 2.0 (interquartile range [IQR]:1.0-3.0) years. Low pRNFL-z (≤-2.04) were associated with an increased risk of disability worsening (adjusted hazard ratio (aHR) [95% CI] = 2.08 [1.47-2.95], p = 3.82e^-5). In the second cohort (n = 170), logistic regression analyses revealed that lower pRNFL-z showed a higher likelihood for disability accumulation at the two-year follow-up (reciprocal odds ratio [95% CI] = 1.51[1.06-2.15], p = 0.03). In the third cohort (n = 78), 46 PwMS (59%) did not maintain the NEDA-3 status over a median follow-up of 2.0 (IQR: 1.9-2.1) years. PwMS with low GCIP-z (≤-1.03) had a higher risk of showing disease activity (aHR [95% CI] = 2.14 [1.03-4.43], p = 0.04). Compared with raw values with arbitrary cutoffs, applying the z score approach with optimal cutoffs showed better performance in discrimination and calibration (higher Harrell's concordance index and lower integrated Brier score).

Discussion: In conclusion, our work demonstrated reference cohort-based z scores that account for age, a major driver for disease progression in MS, to be a promising approach for creating OCT-derived measures useable across devices and toward individualized prognostication.

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Conflict of interest statement

T.-Y. Lin has received compensation from ADA Health, unrelated to the presented work; S. Asseyer has received conference grant from Celgene and speaking honoraria from Bayer Healthcare, Roche, and Alexion; C. Chien has received research support from Novartis and Alexion and writing honoraria from the British Society for Immunology, as well as serves as a member of the Standing Committee on Science for the Canadian Institutes of Health Research (CIHR); S. Saidha has received consulting fees from Medical Logix for the development of CME programs in neurology and has served on scientific advisory boards for Biogen, Novartis, Genentech Corporation, TG therapeutics, Clene Pharmaceuticals & ReWind therapeutics. He has performed consulting for Novartis, Genentech Corporation, JuneBrain LLC, Innocare Pharma, Kiniksa pharmaceuticals and Lapix therapeutics. He is the PI of investigator-initiated studies funded by Genentech Corporation, Biogen, and Novartis. He previously received support from the Race to Erase MS foundation. He has received equity compensation for consulting from JuneBrain LLC and Lapix therapeutics. He was also the site investigator of trials sponsored by MedDay Pharmaceuticals, Clene Pharmaceuticals, and is the site investigator of trials sponsored by Novartis, as well as Lapix therapeutics; P.A. Calabresi has received consulting fees from Lilly, Idorsia, and Novartis; and is PI on grants to Johns Hopkins from Genentech and the Myelin repair Foundation; P. Villoslada has received an honorarium from Heidelberg Engineering in 2014, has received unrestricted research grants from Novartis (including for the OCTIMS study), Biogen, Genzyme, and Roche, and has participated in advisory boards for Novartis, Roche, Genzyme, and Biogen; S. Llufriu received compensation for consulting services and speaker honoraria from Biogen Idec, Novartis, Janssen, Merck and Bristol-Myers Squibb, and holds grants from the Instituto de Salud Carlos III; J.L. Preiningerova has received consulting fees and travel grants from Biogen, Novartis, Merck, Genzyme, and Roche and unrestricted research grant from Biogen, all unrelated to the presented work; A. Petzold received speaker honorary from Heidelberg and Roche, consultancy fees from Novartis and is supported by the UK NIHR; L. Leocani received research support from Novartis, Almirall, Biogen, Merck and consultancy or speaker fees from Novartis, Almirall, Biogen, Merck, Janssen-Cilag, Bristol-Myers Squibb, Roche; C. Oreja-Guevara has received honoraria for speaking and serving on advisory boards from Biogen Idec., F. Hoffmann-La Roche Ltd, Sanofi-Genzyme, Merck, Janssen, BMS, Novartis and Teva; O. Outteryck reports grant for research from Novartis and Bayer; grant for research and personal fees from Biogen-Idec, funding for travel from Biogen, Genzyme-Sanofi, Merck-Serono, Novartis and Teva Pharmaceutical Industries, outside the submitted work; L.J. Balcer is editor-in-chief of the Journal of Neuro-Ophthalmology; P. Albrecht received research support and speaker honoraria from Abbvie, Allergan, BMS, Celgene, Ipsen, Merck, Merz, Novartis, Roche and speaker honoraria from Lilly and Teva; O. Aktas reports grants from the German Ministry of Education and Research (BMBF) and the German Research Foundation (DFG); grants and personal fees from Biogen and Novartis; and travel support and personal fees from Alexion, Almirall, MedImmune, Merck Serono, Roche, Sanofi, Viela Bio/Horizon Therapeutics and Zambon; and is a member of the European Reference Network for Rare Eye Diseases (ERN-EYE), co-funded by the Health Program of the European Union under the Framework Partnership Agreement No 739534 'ERN-EYE. J.L. Frederiksen has served on scientific advisory boards for and received funding for travel related to these activities as well as honoraria from Biogen Idec, Merck Serono, Sanofi-Aventis, Teva, Novartis and Almirall, outside the submitted work; M. Cellerino received fees for consultation or public speaking from Roche, Novartis, Genzyme, Teva, Merck, and Zambon; E. Frohman has received speaker and consulting fees from Alexion, Janssen, Genzyme, Biogen, and Novartis; T. Frohman has received consulting fees from Alexion; J. Bellmann-Strobl has received speaking honoraria and travel grants from Bayer Healthcare, and sanofi-aventis/Genzyme, in addition received compensation for serving on a scientific advisory board of Roche, unrelated to the presented work; K. Ruprecht received research support from Novartis, Merck Serono, German Ministry of Education and Research, European Union (821283-2), Stiftung Charité, Guthy-Jackson Charitable Foundation, and Arthur Arnstein Foundation; received travel grants from Guthy-Jackson Charitable Foundation; received speaker's honoraria from Novartis and Virion Serion. K. Ruprecht is a participant in the BIH Clinical Fellow Program funded by Stiftung Charité; A.U. Brandt is cofounder and holds shares of medical technology companies Motognosis GmbH and Nocturne GmbH. He is named as inventor on several patents and patent applications describing methods for retinal image analyses, motor function analysis, multiple sclerosis serum biomarkers and myelination therapies using N-glycosylation modification. He is cofounder of IMSVISUAL. A.U. Brandt is now a full-time employee and holds stocks and stock options of Eli Lilly and Company. His contribution to this work is his own and does not represent a contribution from Eli Lilly; H.G. Zimmermann received research grants and speaking honoraria from Novartis; F. Paul served on the scientific advisory boards of Novartis and MedImmune; received travel funding and/or speaker honoraria from Bayer, Novartis, Biogen, Teva, Sanofi-Aventis/Genzyme, Merck Serono, Alexion, Chugai, MedImmune, and Shire; is an associate editor of Neurology: Neuroimmunology & Neuroinflammation; is an academic editor of PLoS ONE; consulted for Sanofi Genzyme, Biogen, MedImmune, Shire, and Alexion; received research support from Bayer, Novartis, Biogen, Teva, Sanofi-Aventis/Geynzme, Alexion, and Merck Serono; and received research support from the German Research Council, Werth Stiftung of the City of Cologne, German Ministry of Education and Research, Arthur Arnstein Stiftung Berlin, EU FP7 Framework Program, Arthur Arnstein Foundation Berlin, Guthy-Jackson Charitable Foundation, and NMSS. F. Paul is also supported by Deutsche Forschungsgemeinschaft (DFG Exc 257), Bundesministerium für Bildung und Forschung (Competence Network Multiple Sclerosis KKNMS) and the Guthy Jackson Charitable Foundation. P. Villoslada is supported by Instituto de Salud Carlos III, Spain (PI15/00061 and RD012/0060/01). P.A. Calabresi is supported by NIH R01NS082347 and the National Multiple Sclerosis Society. A.J. Green is supported by the National Multiple Sclerosis Society Harry Weaver Neuroscience Scholars programme (JF2151-A-1). J.L. Preiningerova receives institutional support of the hospital research RVO VFN 64165 and Czech Ministry of Education – project Cooperatio LF1. A. Petzold is supported by the Stichting MS Research (Netherlands). L. Leocani is supported by INSPE-Institute of Experimental Neurology, Hospital San Raffaele, and by Merck Serono SA (Geneva, Switzerland). F. Costello has received funding support from the MS Society of Canada. A. Uccelli is also supported by the Ministry of University and Research (MUR), National Recovery and Resilience Plan (NRRP), project MNESYS (PE0000006). The other authors report no relevant disclosures. Go to Neurology.org/NN for full disclosures.

Figures

**Figure 1. pRNFL and GCIP Age-Adjusted z Score Reference Curves**
GCIP = combined macular ganglion cell and inner plexiform layer thickness; pRNFL = peripapillary retinal nerve fiber layer thickness.

**Figure 2. Association Between Risk of Disability Accumulation and pRNFL z Scores in PwMS**
Multivariable analyses adjusted for sex, disease duration, and use of disease-modifying therapies at baseline. (A) Multivariable-adjusted hazard ratio for confirmed EDSS score increase to pRNFL age-adjusted z score on a continuous scale. The solid blue line indicates the multivariable-adjusted hazard ratio, with dashed blue lines showing the 95% CIs derived from restricted cubic spline regressions with 3 knots. The solid red line is the reference line for no association at a hazard ratio of 1.0. (B) Optimal pRNFL age-adjusted z score cutoff point for determination of PwMS with a higher risk of disability accumulation. (C) Multivariable-adjusted hazard ratio for confirmed EDSS score increase according to categories of pRNFL age-adjusted z score. EDSS = Expanded Disability Status Scale; pRNFL = peripapillary retinal nerve fiber layer thickness; PwMS = people with multiple sclerosis.

**Figure 3. Association Between Risk of Future Disease Activity and GCIP z Scores in PweMS**
Multivariable analyses adjusted for sex, disease duration, and use of disease-modifying therapies at baseline. (A) Multivariable-adjusted hazard ratio for new disease activity to GCIP age-adjusted z score on a continuous scale. The solid blue line indicates the multivariable-adjusted hazard ratio, with dashed blue lines showing the 95% CIs derived from restricted cubic spline regressions with 3 knots. The solid red line is the reference line for no association at a hazard ratio of 1.0. (B) Optimal GCIP age-adjusted z score cutoff point for determination of PwMS with higher risk of having new disease activity. (C) Multivariable-adjusted hazard ratio for new disease activity according to categories of GCIP age-adjusted z score. GCIP = combined macular ganglion cell and inner plexiform layer thickness; PweMS = people with early multiple sclerosis.

See this image and copyright information in PMC

References

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Individual Prognostication of Disease Activity and Disability Worsening in Multiple Sclerosis With Retinal Layer Thickness z Scores

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Individual Prognostication of Disease Activity and Disability Worsening in Multiple Sclerosis With Retinal Layer Thickness z Scores

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Abstract

Conflict of interest statement

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