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Multicenter Study
. 2023 Apr 1;80(4):397-403.
doi: 10.1001/jamaneurol.2023.0010.

Association of Serum Neurofilament Light Chain Levels at Disease Onset With Disability Worsening in Patients With a First Demyelinating Multiple Sclerosis Event Not Treated With High-Efficacy Drugs

Enric Monreal  1 , José Ignacio Fernández-Velasco  2 , María Isabel García-Sánchez  3 , Susana Sainz de la Maza  1 , Sara Llufriu  4 , Roberto Álvarez-Lafuente  5 , Bonaventura Casanova  6 , Manuel Comabella  7 , Lluís Ramió-Torrentà  8   9   10 , José Enrique Martínez-Rodríguez  11 , Luis Brieva  12 , Albert Saiz  4 , Sara Eichau  13 , José María Cabrera-Maqueda  4 , Noelia Villarrubia  2 , Mercedes Espiño  2 , Francisco Pérez-Miralles  6 , Xavier Montalbán  7 , Mar Tintoré  7 , Ana Quiroga-Varela  8   9   10 , María Inmaculada Domínguez-Mozo  5 , Fernando Rodríguez-Jorge  1 , Juan Luís Chico-García  1 , Daniel Lourido  14 , José Carlos Álvarez-Cermeño  1 , Jaime Masjuan  1 , Lucienne Costa-Frossard  1 , Luisa María Villar  2
Affiliations
Multicenter Study

Association of Serum Neurofilament Light Chain Levels at Disease Onset With Disability Worsening in Patients With a First Demyelinating Multiple Sclerosis Event Not Treated With High-Efficacy Drugs

Enric Monreal et al. JAMA Neurol. .

Abstract

Importance: The value of serum neurofilament light chain (sNfL) levels for predicting long-term disability in patients with multiple sclerosis (MS) remains controversial.

Objective: To assess whether high sNfL values are associated with disability worsening in patients who underwent their first demyelinating MS event.

Design, setting, and participants: This multicenter cohort study included patients who underwent their first demyelinating event suggestive of MS at Hospital Universitario Ramón y Cajal (development cohort; June 1, 1994, to September 31, 2021, with follow-up until August 31, 2022) and 8 Spanish hospitals (validation cohort; October 1, 1995, to August 4, 2020, with follow-up until August 16, 2022).

Exposures: Clinical evaluations at least every 6 months.

Main outcomes and measures: The main outcomes were 6-month confirmed disability worsening (CDW) and an Expanded Disability Status Scale (EDSS) score of 3. Levels of sNfL were measured in blood samples obtained within 12 months after disease onset using a single molecule array kit. The cutoffs used were sNfL level of 10 pg/mL and a standardized score (z score) of 1.5. Multivariable Cox proportional hazards regression models were used to evaluate outcomes.

Results: Of the 578 patients included in the study, 327 were in the development cohort (median age at sNfL analysis, 34.1 years [IQR, 27.2-42.7 years]; 226 female [69.1%]) and 251 patients were in the validation cohort (median age at sNfL analysis, 33.3 years [IQR, 27.4-41.5 years]; 184 female [73.3%]). The median follow-up was 7.10 years (IQR, 4.18-10.0 years). Levels of sNfL greater than 10 pg/mL were independently associated with higher risk of 6-month CDW and an EDSS of 3 in the development cohort (6-month CDW: hazard ratio [HR], 2.39; 95% CI, 1.39-4.12; P = .002; EDSS of 3: HR, 4.12; 95% CI, 2.18-7.77; P < .001) and the validation cohort (6-month CDW: HR, 1.61; 95% CI, 1.07-2.42; P = .02; EDSS of 3: HR, 2.03; 95% CI, 1.23-3.33; P = .005). Highly effective disease-modifying treatments were associated with lower risks of 6-month CDW and an EDSS of 3 in patients with high baseline sNfL values.

Conclusions and relevance: This cohort study found that high sNfL values obtained within the first year of disease were associated with long-term disability worsening in MS, suggesting that sNfL level measurement may help identify optimal candidates for highly effective disease-modifying treatments.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Monreal reported receiving research grants, travel support, or honoraria for speaking engagements from Biogen, Sanofi, Merck, Novartis, Almirall, Roche, Bristol Myers Squibb, and Janssen outside the submitted work. Dr Sainz de la Maza reported receiving personal fees from Almirall, Bristol Myers Squibb, and Teva outside the submitted work and receiving compensation for lectures or travel expenses from Merck Serono, Biogen, Sanofi Genzyme, Roche, Janssen, and Novartis. Dr Llufriu reported receiving compensation for consulting services and speaker honoraria from Biogen Idec, Novartis, Teva, Genzyme, Sanofi Genzyme, and Merck. Dr Álvarez-Lafuente reported receiving nonfinancial support for meeting attendance from Biogen, Novartis, and Sanofi Genzyme outside the submitted work. Dr Casanova reported receiving compensation for consulting services and speaker honoraria from Sanofi Genzyme, Roche, Bristol Myers Squibb, Janssen, and Novartis. Dr Ramió-Torrentà reported receiving personal fees from Roche, Janssen, and Bristol Myers Squibb outside the submitted work and receiving compensation for consulting services and speaking honoraria from Biogen, Merck, Novartis, Bayer, Sanofi Genzyme, Teva Pharmaceutical Industries Ltd, Almirall, and Mylan. Dr Martínez-Rodríguez reported participating as a principal investigator in pharmaceutical company-sponsored clinical trials for Novartis, Roche, Merck Serono, Actelion, and Celgene and receiving personal fees for consulting services and lectures from Novartis, Biogen Idec, Sanofi, and Merck Serono. Dr Brieva reported receiving support for research projects from the Neuroimmunology and Multiple Sclerosis Unit, Department of Neurology, Doctor Josep Trueta University Hospital, and receiving speaker and consultancy fees and travel expenses for attending conferences from Bayer, Biogen, Roche, Merck, Novartis, Almirall, and Sanofi. Dr Saiz reported receiving compensation for consulting services and speaker honoraria from Bayer Schering, Merck, Biogen Idec, Sanofi-Aventis, Teva, Novartis, Roche, Janssen, and Horizon Therapeutics. Dr Eichau reported receiving personal fees from Novartis, Biogen, Merck, Roche, Sanofi, Bristol Myers Squibb, and Janssen outside the submitted work and receiving speaker honoraria and fees for consulting from Biogen Idec, Novartis, Merck, Bayer, Sanofi Genzyme, Roche, and Teva. Dr Cabrera-Maqueda reported receiving speaking honoraria from Sanofi and personal fees from Bristol Myers Squibb outside the submitted work. Dr Pérez-Miralles reported receiving speaking honoraria from Almirall, Biogen, Sanofi Genzyme, Mylan, Novartis, Roche, Sanofi-Aventis, Teva, and Merck Serono; receiving compensation for serving on scientific advisory boards for Roche and Sanofi-Aventis; and being a member of the steering committee for Roche outside the submitted work. Dr Montalbán reported receiving speaking honoraria from Actelion, Alexion, Bayer, Biogen, Bristol Myers Squibb/Celgene, EMD Serono, Exemed, Genzyme, Hoffmann-La Roche, Immunic, Janssen Pharmaceuticals, MedDay, Merck, Mylan, Multiple Sclerosis International Federation, NervGen, Novartis, Sandoz, Sanofi Genzyme, Teva Pharmaceutical, and TG Therapeutics; receiving travel expenses for scientific meeting participation from the National Multiple Sclerosis Society; and being a member of clinical trials of a steering committee or participating on advisory boards of clinical trials in the past 3 years with Biogen, Hoffmann-La Roche, Sanofi Genzyme, Merck, Novartis, and Teva Pharmaceutical outside the submitted work. Dr Tintoré reported receiving personal fees for consulting services and speaking honoraria from Almirall, Bayer Schering Pharma, Biogen Idec, Genzyme, Janssen, Merck Serono, Viatris, Novartis, Roche, Sanofi-Aventis, Vela Bio, and Teva Pharmaceutical and grants from the Carlos III Health Institute, the Genzyme Charitable Foundation, Fundación Salud 2000, Biogen Idec, Novartis, and Biogen Idec during the conduct of the study; receiving personal fees from Almirall, Bayer Schering Pharma, Biogen Idec, Genzyme, Janssen, Merck Serono, Viatris, Novartis, Roche, Sanofi-Aventis, Vela Bio, and Teva Pharmaceutical and grants from the Carlos III Health Institute, Biogen Idec, and Novartis outside the submitted work; and serving as the 2015 to 2021 coeditor of the Multiple Sclerosis Journal–Experimental, Translational and Clinical and 2022 president of the European Committee for Treatment and Research in Multiple Sclerosis. Dr Rodríguez-Jorge reported receiving personal fees from Sanofi outside the submitted work and receiving speaker honoraria from Biogen Idec and Sanofi. Dr Álvarez-Cermeño reported receiving other fees from the Biogen board membership, the Merck Serono board membership, Bayer Healthcare, Sanofi, and Roche for lectures; receiving grants from Novartis; and receiving nonfinancial support from Teva outside the submitted work. Dr Costa-Frossard reported receiving speaker fees and travel support and/or serving on advisory boards for Biogen, Sanofi, Merck, Bayer, Novartis, Roche, Teva, Celgene, Ipsen, Biopas, Bristol Myers Squibb, Janssen, and Almirall. Dr Villar reported receiving grants and personal fees from Merck, Roche, Sanofi Genzyme, Bristol Myers Squibb, Celgene, Biogen, and Novartis outside the submitted work. No other disclosures were reported.

Figures

Figure.
Figure.. Kaplan-Meier Curves of Risk of 6-Month Confirmed Disability Worsening (CDW) and an Expanded Disability Status Scale Score (EDSS) of 3 by Serum Neurofilament Light Chain (sNfL) Levels Stratified by Highly Effective Disease-Modifying Treatment (HE-DMT) Use
The stratification of patients was made according to HE-DMT use before each outcome (6-month CDW and EDSS of 3).
See this image and copyright information in PMC

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