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      Profiling individual clinical responses by high-frequency serum neurofilament assessment in MS

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          Abstract

          Objective

          To evaluate individual neurofilament light chain (NfL) variation over the time of disease course and the potential of NfL measurement to predict treatment response in patients with MS.

          Methods

          We investigated 15 patients with MS after immune reconstitution treatment with alemtuzumab (ATZ). Monthly serum NfL (sNFL) measurements were correlated with Expanded Disability Status Scale (EDSS), MRI, and relapse activity over an observational period of up to 102 months.

          Results

          Before ATZ, sNfL was significantly increased in correlation with previous relapse/MRI activity. After ATZ, sNfL decreased quickly within the first 6 months. In patients classified as NEDA-3, sNfL declined and persisted at an individual low steady-state level of <8 pg/mL. During follow-up, 34 sNfL peaks with a >20 fold increase could be detected, which were associated with clinical or MRI disease activity. Even patient-reported relapse-suspicious symptoms, which have not been confirmed because relapses were accompanied by sNfL, increase, proposing sNfL assessment as a marker for relapse activity. sNfL started to increase earliest 5 months before, peaked at clinical onset, and recovered within 4–5 months. sNfL presented at higher levels in active patients requiring ATZ retreatment compared with responder patients. During 2 documented pregnancies, sNfL was at a low level, whereas a postpartum transient sNfL increase was seen without any signs of activity.

          Conclusions

          This study applied a long-term high-frequency sNfL assessment in an ATZ-treated cohort, allowing a holistic profiling on the individual level and highlighted that sNfL can eminently complement the individual clinical and MRI monitoring in clinical practice.

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          Most cited references20

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          Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial.

          Jeffrey A Cohen, Alasdair J Coles, Douglas L Arnold … (2012)
          The anti-CD52 monoclonal antibody alemtuzumab reduced disease activity in a phase 2 trial of previously untreated patients with relapsing-remitting multiple sclerosis. We aimed to assess efficacy and safety of first-line alemtuzumab compared with interferon beta 1a in a phase 3 trial. In our 2 year, rater-masked, randomised controlled phase 3 trial, we enrolled adults aged 18-50 years with previously untreated relapsing-remitting multiple sclerosis. Eligible participants were randomly allocated in a 2:1 ratio by an interactive voice response system, stratified by site, to receive intravenous alemtuzumab 12 mg per day or subcutaneous interferon beta 1a 44 μg. Interferon beta 1a was given three-times per week and alemtuzumab was given once per day for 5 days at baseline and once per day for 3 days at 12 months. Coprimary endpoints were relapse rate and time to 6 month sustained accumulation of disability in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00530348. 187 (96%) of 195 patients randomly allocated interferon beta 1a and 376 (97%) of 386 patients randomly allocated alemtuzumab were included in the primary analyses. 75 (40%) patients in the interferon beta 1a group relapsed (122 events) compared with 82 (22%) patients in the alemtuzumab group (119 events; rate ratio 0·45 [95% CI 0·32-0·63]; p<0.0001), corresponding to a 54·9% improvement with alemtuzumab. Based on Kaplan-Meier estimates, 59% of patients in the interferon beta 1a group were relapse-free at 2 years compared with 78% of patients in the alemtuzumab group (p<0·0001). 20 (11%) of patients in the interferon beta 1a group had sustained accumulation of disability compared with 30 (8%) in the alemtuzumab group (hazard ratio 0·70 [95% CI 0·40-1·23]; p=0·22). 338 (90%) of patients in the alemtuzumab group had infusion-associated reactions; 12 (3%) of which were regarded as serious. Infections, predominantly of mild or moderate severity, occurred in 253 (67%) patients treated with alemtuzumab versus 85 (45%) patients treated with interferon beta 1a. 62 (16%) patients treated with alemtuzumab had herpes infections (predominantly cutaneous) compared with three (2%) patients treated with interferon beta 1a. By 24 months, 68 (18%) patients in the alemtuzumab group had thyroid-associated adverse events compared with 12 (6%) in the interferon beta 1a group, and three (1%) had immune thrombocytopenia compared with none in the interferon beta 1a group. Two patients in the alemtuzumab group developed thyroid papillary carcinoma. Alemtuzumab's consistent safety profile and benefit in terms of reductions of relapse support its use for patients with previously untreated relapsing-remitting multiple sclerosis; however, benefit in terms of disability endpoints noted in previous trials was not observed here. Genzyme (Sanofi) and Bayer Schering Pharma. Copyright © 2012 Elsevier Ltd. All rights reserved.
          Article 0 comments Cited 390 times – based on 0 reviews     Review now
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            Optimizing treatment success in multiple sclerosis

            Tjalf Ziemssen, Tobias Derfuss, Nicola De Stefano … (2015)
            Despite important advances in the treatment of multiple sclerosis (MS) over recent years, the introduction of several disease-modifying therapies (DMTs), the burden of progressive disability and premature mortality associated with the condition remains substantial. This burden, together with the high healthcare and societal costs associated with MS, creates a compelling case for early treatment optimization with highly efficacious therapies. Often, patients receive several first-line therapies, while more recent and in part more effective treatments are still being introduced only after these have failed. However, with the availability of highly efficacious therapies, a novel treatment strategy has emerged, where the aim is to achieve no evidence of disease activity (NEDA). Achieving NEDA necessitates regular monitoring of relapses, disability and functionality. However, there is only a poor correlation between conventional magnetic resonance imaging measures like T2 hyperintense lesion burden and the level of clinical disability. Hence, MRI-based measures of brain atrophy have emerged in recent years potentially reflecting the magnitude of MS-related neuroaxonal damage. Currently available DMTs differ markedly in their effects on brain atrophy: some, such as fingolimod, have been shown to significantly slow brain volume loss, compared to placebo, whereas others have shown either no, inconsistent, or delayed effects. In addition to regular monitoring, treatment optimization also requires early intervention with efficacious therapies, because accumulating evidence shows that effective intervention during a limited period early in the course of MS is critical for maintaining neurological function and preventing subsequent disability. Together, the advent of new MS therapies and evolving management strategies offer exciting new opportunities to optimize treatment outcomes.
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              Plasma neurofilament light chain levels in patients with MS switching from injectable therapies to fingolimod

              Fredrik Piehl, Ingrid Kockum, Mohsen Khademi … (2018)
              Neurofilament light chain (NFL) is a cerebrospinal fluid (CSF) marker of neuroaxonal damage in multiple sclerosis (MS). To determine the correlation of NFL in CSF and serum/plasma, and in plasma after switching from injectable MS therapies to fingolimod. A first cohort consisted of MS patients ( n = 39) and neurological disease controls ( n = 27) where CSF and plasma/serum had been collected for diagnostic purposes. A second cohort ( n = 243) consisted of patients from a post-marketing study of fingolimod. NFL was determined with Single Molecule Array (Simoa™) technology (detection threshold 1.95 pg/mL). Mean NFL pg/mL (standard deviation ( SD)) was 341 (267) and 1475 (2358) in CSF and 8.2 (3.58) and 17.0 (16.94) in serum from controls and MS, respectively. CSF/serum and plasma/serum levels were highly correlated ( n = 66, rho = 0.672, p < 0.0001 and n = 16, rho = 0.684, p = 0.009, respectively). In patients starting fingolimod ( n = 243), mean NFL pg/mL ( SD) in plasma was reduced between baseline (20.4 (10.7)) and at 12 months (13.5 (7.3), p < 3 × 10 −6 ), and levels remained stable at 24 months (13.2 (6.2)). NFL in serum and CSF are highly correlated and plasma NFL levels decrease after switching to highly effective MS therapy. Blood NFL measurement can be considered as a biomarker for MS therapy response.
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                Author and article information

                Contributors
                Katja Akgün:
                Comment :

                Scientific Advisory Boards:

                1. (1) Advisory Board from Roche(2) Advisory Board from Sanofi

                Gifts:

                1. NONE

                Funding for Travel or Speaker Honoraria:

                1. (1) Speaker Honoraria from Biogen idec and Merck. (2) Travel honoraria from Novartis.

                Editorial Boards:

                1. NONE

                Patents:

                1. NONE

                Publishing Royalties:

                1. NONE

                Employment, Commercial Entity:

                1. NONE

                Consultancies:

                1. NONE

                Speakers' Bureaus:

                1. NONE

                Other Activities:

                1. NONE

                Clinical Procedures or Imaging Studies:

                1. NONE

                Research Support, Commercial Entities:

                1. NONE

                Research Support, Government Entities:

                1. NONE

                Research Support, Academic Entities:

                1. NONE

                Research Support, Foundations and Societies:

                1. NONE

                Stock/Stock Options/Board of Directors Compensation:

                1. NONE

                License Fee Payments, Technology or Inventions:

                1. NONE

                Royalty Payments, Technology or Inventions:

                1. NONE

                Stock/Stock Options, Research Sponsor:

                1. NONE

                Stock/Stock Options, Medical Equipment & Materials:

                1. NONE

                Legal Proceedings:

                1. NONE

                Nicole Kretschmann:
                Comment :

                Scientific Advisory Boards:

                1. NONE

                Gifts:

                1. NONE

                Funding for Travel or Speaker Honoraria:

                1. NONE

                Editorial Boards:

                1. NONE

                Patents:

                1. NONE

                Publishing Royalties:

                1. NONE

                Employment, Commercial Entity:

                1. NONE

                Consultancies:

                1. NONE

                Speakers' Bureaus:

                1. NONE

                Other Activities:

                1. NONE

                Clinical Procedures or Imaging Studies:

                1. NONE

                Research Support, Commercial Entities:

                1. NONE

                Research Support, Government Entities:

                1. NONE

                Research Support, Academic Entities:

                1. NONE

                Research Support, Foundations and Societies:

                1. NONE

                Stock/Stock Options/Board of Directors Compensation:

                1. NONE

                License Fee Payments, Technology or Inventions:

                1. NONE

                Royalty Payments, Technology or Inventions:

                1. NONE

                Stock/Stock Options, Research Sponsor:

                1. NONE

                Stock/Stock Options, Medical Equipment & Materials:

                1. NONE

                Legal Proceedings:

                1. NONE

                Rocco Haase:
                Comment :

                Scientific Advisory Boards:

                1. NONE

                Gifts:

                1. NONE

                Funding for travel or speaker honoraria:

                1. Travel grants from TEVA and Celgene.

                Editorial Boards:

                1. NONE

                Patents:

                1. NONE

                Publishing Royalties:

                1. NONE

                Employment, Commercial Entity:

                1. NONE

                Consultancies:

                1. NONE

                Speakers' Bureaus:

                1. Speaker fee from Sanofi.

                Other Activities:

                1. NONE

                Clinical Procedures or Imaging Studies:

                1. NONE

                Research Support, Commercial Entities:

                1. NONE

                Research Support, Government Entities:

                1. NONE

                Research Support, Academic Entities:

                1. NONE

                Research Support, Foundations and Societies:

                1. NONE

                Stock/Stock Options/Board of Directors Compensation:

                1. NONE

                License Fee Payments, Technology or Inventions:

                1. NONE

                Royalty Payments, Technology or Inventions:

                1. NONE

                Stock/Stock Options, Research Sponsor:

                1. NONE

                Stock/Stock Options, Medical Equipment & Materials:

                1. NONE

                Legal Proceedings:

                1. NONE

                Undine Proschmann:
                Comment :

                Scientific Advisory Boards:

                1. NONE

                Gifts:

                1. NONE

                Funding for travel or speaker honoraria:

                1. (1) ROCHE, Speaker honoraria (2) MERCK, Speaker honoraria (3) TEVA, funding for travel to conference (4) BIOGEN, funding for travel to conference (5) BAYER, funding for travel to conference (6) CELEGENE, funding for travel to conference

                Editorial Boards:

                1. NONE

                Patents:

                1. NONE

                Publishing Royalties:

                1. NONE

                Employment, Commercial Entity:

                1. NONE

                Consultancies:

                1. NONE

                Speakers' Bureaus:

                1. NONE

                Other Activities:

                1. NONE

                Clinical Procedures or Imaging Studies:

                1. NONE

                Research Support, Commercial Entities:

                1. NONE

                Research Support, Government Entities:

                1. NONE

                Research Support, Academic Entities:

                1. NONE

                Research Support, Foundations and Societies:

                1. NONE

                Stock/Stock Options/Board of Directors Compensation:

                1. NONE

                License Fee Payments, Technology or Inventions:

                1. NONE

                Royalty Payments, Technology or Inventions:

                1. NONE

                Stock/Stock Options, Research Sponsor:

                1. NONE

                Stock/Stock Options, Medical Equipment & Materials:

                1. NONE

                Legal Proceedings:

                1. NONE

                Hagen H. Kitzler:
                Comment :

                Scientific Advisory Boards:

                1. (1) Novartis scientific advisory board (2) Ixico scientific advisory board

                Gifts:

                1. NONE

                Funding for travel or speaker honoraria:

                1. (1) Biogen, funding for travel or speaker honoraria (1) Novartis, funding for travel or speaker honoraria (1) Pfizer, speaker honoraria (1) Sanofi-Genzyme, speaker honoraria (1) Teva Pharmaceutical, speaker honoraria

                Editorial Boards:

                1. NONE

                Patents:

                1. NONE

                Publishing Royalties:

                1. NONE

                Employment, Commercial Entity:

                1. NONE

                Consultancies:

                1. (1) Ixico, consultancies

                Speakers' Bureaus:

                1. NONE

                Other activities:

                1. (1) Biogen, MS PATHS network, funding for travel

                Clinical Procedures or Imaging Studies:

                1. NONE

                Research Support, Commercial Entities:

                1. (1) Novartis, research support funding (1) Biogen, MS PATHS network funding

                Research Support, Government Entities:

                1. NONE

                Research Support, Academic Entities:

                1. NONE

                Research Support, Foundations and Societies:

                1. NONE

                Stock/Stock Options/Board of Directors Compensation:

                1. NONE

                License Fee Payments, Technology or Inventions:

                1. NONE

                Royalty Payments, Technology or Inventions:

                1. NONE

                Stock/Stock Options, Research Sponsor:

                1. NONE

                Stock/Stock Options, Medical Equipment & Materials:

                1. NONE

                Legal Proceedings:

                1. NONE

                Heinz Reichmann:
                Comment :

                Scientific Advisory Boards:

                1. Abbott, Cephalon, Novartis, TEVA, Lundbeck, GSK, Boehringer Ingelheim, Schering/Bayer Health Care, UCB/Schwarz Pharma, Desitin, Merck-Serono, Solvay, Zambon

                Gifts:

                1. NONE

                Funding for travel or speaker honoraria:

                1. for advisory board meetings or lectures. Cephalon, Novartis, TEVA, Lundbeck, GSK, Boehringer Ingelheim, Schering/Bayer Health Care, Pfizer, UCB/Schwarz Pharma, Desitin,Solvay.Zambon

                Editorial Boards:

                1. UCB/Schwarz Pharma, GSK

                Patents:

                1. NONE

                Publishing Royalties:

                1. NONE

                Employment, Commercial Entity:

                1. NONE

                Consultancies:

                1. NONE

                Speakers' Bureaus:

                1. NONE

                Other Activities:

                1. NONE

                Clinical Procedures or Imaging Studies:

                1. NONE

                Research Support, Commercial Entities:

                1. NONE

                Research Support, Government Entities:

                1. NONE

                Research Support, Academic Entities:

                1. NONE

                Research Support, Foundations and Societies:

                1. NONE

                Stock/Stock Options/Board of Directors Compensation:

                1. NONE

                License Fee Payments, Technology or Inventions:

                1. NONE

                Royalty Payments, Technology or Inventions:

                1. NONE

                Stock/Stock Options, Research Sponsor:

                1. NONE

                Stock/Stock Options, Medical Equipment & Materials:

                1. NONE

                Legal Proceedings:

                1. NONE

                Tjalf Ziemssen:
                Comment :

                Scientific Advisory Boards:

                1. (1) Bayer Healthcare (2) Biogen Idec (3) Novartis (4) Merck Serono (5) Teva (6) Genzyme (7) Roche (8) Celgene; all commercial

                Gifts:

                1. NONE

                Funding for travel or speaker honoraria:

                1. Speaker honorarium for all commercial entities (1) Bayer Healthcare (2) Biogen Idec (3) Sanofi Genzyme (4) Celgene (5) Roche (6) Novartis (7) Teva (8) Almirall (o) Merck

                Editorial Boards:

                1. (1) BMC Neurology, Section editor, demyelinating disorders, since 2016

                Patents:

                1. NONE

                Publishing Royalties:

                1. NONE

                Employment, Commercial Entity:

                1. NONE

                Consultancies:

                1. NONE

                Speakers' Bureaus:

                1. NONE

                Other Activities:

                1. NONE

                Clinical Procedures or Imaging Studies:

                1. NONE

                Research Support, Commercial Entities:

                1. (1) Biogen Idec (2) Sanofi Genzyme (3) Novartis (4) Teva

                Research Support, Government Entities:

                1. NONE

                Research Support, Academic Entities:

                1. NONE

                Research Support, Foundations and Societies:

                1. NONE

                Stock/Stock Options/Board of Directors Compensation:

                1. NONE

                License Fee Payments, Technology or Inventions:

                1. NONE

                Royalty Payments, Technology or Inventions:

                1. NONE

                Stock/Stock Options, Research Sponsor:

                1. NONE

                Stock/Stock Options, Medical Equipment & Materials:

                1. NONE

                Legal Proceedings:

                1. Expert witness for glatiramer acetate, 2015-2016

                Journal
                Journal ID (nlm-ta): Neurol Neuroimmunol Neuroinflamm
                Journal ID (iso-abbrev): Neurol Neuroimmunol Neuroinflamm
                Journal ID (hwp): nnn
                Journal ID (publisher-id): NEURIMMINFL
                Title: Neurology® Neuroimmunology & Neuroinflammation
                Publisher: Lippincott Williams & Wilkins (Hagerstown, MD )
                ISSN (Electronic): 2332-7812
                Publication date (Electronic): 08 April 2019
                Publication date Collection: May 2019
                Publication date PMC-release: 08 April 2019
                Volume: 6
                Issue: 3
                Electronic Location Identifier: e555
                Affiliations
                From the Center of Clinical Neuroscience (K.A., N.K., R.H., U.P., T.Z.), University Hospital, Dresden, Germany; Department of Neuroradiology (H.H.K.), University Hospital, Dresden, Germany; and Department of Neurology (H.R.), University Hospital, Dresden, Germany.
                Author notes

                Funding information and disclosures are provided at the end of the article. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/NN.

                The Article Processing Charge was funded by the authors.

                Article
                Publisher ID: NEURIMMINFL2018019505
                DOI: 10.1212/NXI.0000000000000555
                PMC ID: 6501638
                PubMed ID: 31119188
                SO-VID: 77e080c7-4810-4bdb-a364-487fd401406c
                Copyright © Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

                History
                Date received : 19 December 2018
                Date accepted : 28 January 2019
                Categories
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                Subject: Article
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