eprintid: 10146221 rev_number: 10 eprint_status: archive userid: 699 dir: disk0/10/14/62/21 datestamp: 2022-04-04 11:10:24 lastmod: 2022-08-17 06:10:25 status_changed: 2022-04-04 11:10:24 type: article metadata_visibility: show sword_depositor: 699 creators_name: Benkert, P creators_name: Meier, S creators_name: Schaedelin, S creators_name: Manouchehrinia, A creators_name: Yaldizli, Ö creators_name: Maceski, A creators_name: Oechtering, J creators_name: Achtnichts, L creators_name: Conen, D creators_name: Derfuss, T creators_name: Lalive, PH creators_name: Mueller, C creators_name: Müller, S creators_name: Naegelin, Y creators_name: Oksenberg, JR creators_name: Pot, C creators_name: Salmen, A creators_name: Willemse, E creators_name: Kockum, I creators_name: Blennow, K creators_name: Zetterberg, H creators_name: Gobbi, C creators_name: Kappos, L creators_name: Wiendl, H creators_name: Berger, K creators_name: Sormani, MP creators_name: Granziera, C creators_name: Piehl, F creators_name: Leppert, D creators_name: Kuhle, J creators_name: Aeschbacher, S creators_name: Barakovic, M creators_name: Buser, A creators_name: Chan, A creators_name: Disanto, G creators_name: D'Souza, M creators_name: Du Pasquier, R creators_name: Findling, O creators_name: Galbusera, R creators_name: Hrusovsky, K creators_name: Khalil, M creators_name: Lorscheider, J creators_name: Mathias, A creators_name: Orleth, A creators_name: Radue, EW creators_name: Rahmanzadeh, R creators_name: Sinnecker, T creators_name: Subramaniam, S creators_name: Vehoff, J creators_name: Wellmann, S creators_name: Wuerfel, J creators_name: Zecca, C title: Serum neurofilament light chain for individual prognostication of disease activity in people with multiple sclerosis: a retrospective modelling and validation study ispublished: pub divisions: C07 divisions: F86 divisions: B02 divisions: UCL divisions: D07 keywords: Science & Technology, Life Sciences & Biomedicine, Clinical Neurology, Neurosciences & Neurology, DISABILITY note: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. abstract: Background: Serum neurofilament light chain (sNfL) is a biomarker of neuronal damage that is used not only to monitor disease activity and response to drugs and to prognosticate disease course in people with multiple sclerosis on the group level. The absence of representative reference values to correct for physiological age-dependent increases in sNfL has limited the diagnostic use of this biomarker at an individual level. We aimed to assess the applicability of sNfL for identification of people at risk for future disease activity by establishing a reference database to derive reference values corrected for age and body-mass index (BMI). Furthermore, we used the reference database to test the suitability of sNfL as an endpoint for group-level comparison of effectiveness across disease-modifying therapies. Methods: For derivation of a reference database of sNfL values, a control group was created, comprising participants with no evidence of CNS disease taking part in four cohort studies in Europe and North America. We modelled the distribution of sNfL concentrations in function of physiological age-related increase and BMI-dependent modulation, to derive percentile and Z score values from this reference database, via a generalised additive model for location, scale, and shape. We tested the reference database in participants with multiple sclerosis in the Swiss Multiple Sclerosis Cohort (SMSC). We compared the association of sNfL Z scores with clinical and MRI characteristics recorded longitudinally to ascertain their respective disease prognostic capacity. We validated these findings in an independent sample of individuals with multiple sclerosis who were followed up in the Swedish Multiple Sclerosis registry. Findings: We obtained 10 133 blood samples from 5390 people (median samples per patient 1 [IQR 1–2] in the control group). In the control group, sNfL concentrations rose exponentially with age and at a steeper increased rate after approximately 50 years of age. We obtained 7769 samples from 1313 people (median samples per person 6·0 [IQR 3·0–8·0]). In people with multiple sclerosis from the SMSC, sNfL percentiles and Z scores indicated a gradually increased risk for future acute (eg, relapse and lesion formation) and chronic (disability worsening) disease activity. A sNfL Z score above 1·5 was associated with an increased risk of future clinical or MRI disease activity in all people with multiple sclerosis (odds ratio 3·15, 95% CI 2·35–4·23; p<0·0001) and in people considered stable with no evidence of disease activity (2·66, 1·08–6·55; p=0·034). Increased Z scores outperformed absolute raw sNfL cutoff values for diagnostic accuracy. At the group level, the longitudinal course of sNfL Z score values in people with multiple sclerosis from the SMSC decreased to those seen in the control group with use of monoclonal antibodies (ie, alemtuzumab, natalizumab, ocrelizumab, and rituximab) and, to a lesser extent, oral therapies (ie, dimethyl fumarate, fingolimod, siponimod, and teriflunomide). However, longitudinal sNfL Z scores remained elevated with platform compounds (interferons and glatiramer acetate; p<0·0001 for the interaction term between treatment category and treatment duration). Results were fully supported in the validation cohort (n=4341) from the Swedish Multiple Sclerosis registry. Interpretation: The use of sNfL percentiles and Z scores allows for identification of individual people with multiple sclerosis at risk for a detrimental disease course and suboptimal therapy response beyond clinical and MRI measures, specifically in people with disease activity-free status. Additionally, sNfL might be used as an endpoint for comparing effectiveness across drug classes in pragmatic trials. Funding: Swiss National Science Foundation, Progressive Multiple Sclerosis Alliance, Biogen, Celgene, Novartis, Roche. date: 2022-03-01 date_type: published publisher: ELSEVIER SCIENCE INC official_url: https://doi.org/10.1016/S1474-4422(22)00009-6 oa_status: green full_text_type: other language: eng primo: open primo_central: open_green verified: verified_manual elements_id: 1942468 doi: 10.1016/S1474-4422(22)00009-6 medium: Print pii: S1474-4422(22)00009-6 lyricists_name: Zetterberg, Henrik lyricists_id: HZETT94 actors_name: Zetterberg, Henrik actors_name: Harriot, Anne-Marie actors_id: HZETT94 actors_id: AHARA72 actors_role: owner actors_role: impersonator funding_acknowledgements: [Swiss National Science Foundation]; [Progressive Multiple Sclerosis Alliance]; [Biogen]; [Celgene]; [Novartis]; [Roche] full_text_status: public publication: The Lancet Neurology volume: 21 number: 3 pagerange: 246-257 event_location: England issn: 1474-4422 citation: Benkert, P; Meier, S; Schaedelin, S; Manouchehrinia, A; Yaldizli, Ö; Maceski, A; Oechtering, J; ... Zecca, C; + view all <#> Benkert, P; Meier, S; Schaedelin, S; Manouchehrinia, A; Yaldizli, Ö; Maceski, A; Oechtering, J; Achtnichts, L; Conen, D; Derfuss, T; Lalive, PH; Mueller, C; Müller, S; Naegelin, Y; Oksenberg, JR; Pot, C; Salmen, A; Willemse, E; Kockum, I; Blennow, K; Zetterberg, H; Gobbi, C; Kappos, L; Wiendl, H; Berger, K; Sormani, MP; Granziera, C; Piehl, F; Leppert, D; Kuhle, J; Aeschbacher, S; Barakovic, M; Buser, A; Chan, A; Disanto, G; D'Souza, M; Du Pasquier, R; Findling, O; Galbusera, R; Hrusovsky, K; Khalil, M; Lorscheider, J; Mathias, A; Orleth, A; Radue, EW; Rahmanzadeh, R; Sinnecker, T; Subramaniam, S; Vehoff, J; Wellmann, S; Wuerfel, J; Zecca, C; - view fewer <#> (2022) Serum neurofilament light chain for individual prognostication of disease activity in people with multiple sclerosis: a retrospective modelling and validation study. The Lancet Neurology , 21 (3) pp. 246-257. 10.1016/S1474-4422(22)00009-6 <https://doi.org/10.1016/S1474-4422%2822%2900009-6>. Green open access document_url: https://discovery-pp.ucl.ac.uk/id/eprint/10146221/1/Zetterberg_Benkert%20%281%29.pdf