Association Between Serum Neurofilament Light Chain Levels and Long-term Disease Course Among Patients With Multiple Sclerosis Followed up for 12 Years

Cantó, Ester; Barro, Christian; Zhao, Chao; Caillier, Stacy J.; Michalak, Zuzanna; Bove, Riley; Tomic, Davorka; Santaniello, Adam; Häring, Dieter A.; Hollenbach, Jill A.; Henry, Roland G.; Cree, Bruce A.C.; Kappos, Ludwig; Leppert, David; Hauser, Stephen L.; Benkert, Pascal; Oksenberg, Jorge R.; Kuhle, Jens

doi:10.1001/jamaneurol.2019.2137

Cited by 155 publications

(187 citation statements)

References 42 publications

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“…Both serum and CSF NfL levels have been consistently associated with long-term brain atrophy. 33,34 Of note, this effect size is similar to the percentage of variance explained for the associations between CHIT1 and disease activity measures in our work. In contrast, serum and CSF NfL levels measured at 6 to 8 years of disease duration were not associated or were at most weakly associated with future relapse activity, EDSS worsening, or lesions in 2 recent large-scale studies.…”

Section: Discussionsupporting

confidence: 86%

“…In contrast, serum and CSF NfL levels measured at 6 to 8 years of disease duration were not associated or were at most weakly associated with future relapse activity, EDSS worsening, or lesions in 2 recent large-scale studies. 33,34 Similarly, we did not detect an association between NfL levels at diagnosis and any primary outcome, and associations between CHIT1 and disease activity outcomes were importantly independent of NfL. A combination of biomarkers will likely be indicated to capture the different disease processes in MS.…”

Section: Discussionmentioning

confidence: 69%

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CHIT1 at Diagnosis Reflects Long‐Term Multiple Sclerosis Disease Activity

Oldoni

Smets

Mallants

et al. 2020

Annals of Neurology

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Objective Evidence for a role of microglia in the pathogenesis of multiple sclerosis (MS) is growing. We investigated association of microglial markers at time of diagnostic lumbar puncture (LP) with different aspects of disease activity (relapses, disability, magnetic resonance imaging parameters) up to 6 years later in a cohort of 143 patients. Methods In cerebrospinal fluid (CSF), we measured 3 macrophage and microglia‐related proteins, chitotriosidase (CHIT1), chitinase‐3–like protein 1 (CHI3L1 or YKL‐40), and soluble triggering receptor expressed on myeloid cells 2 (sTREM2), as well as a marker of neuronal damage, neurofilament light chain (NfL), using enzyme‐linked immunosorbent assay and electrochemiluminescence. We investigated the same microglia‐related markers in publicly available RNA expression data from postmortem brain tissue. Results CHIT1 levels at diagnostic LP correlated with 2 aspects of long‐term disease activity after correction for multiple testing. First, CHIT1 increased with reduced tissue integrity in lesions at a median 3 years later (p = 9.6E‐04). Second, CHIT1 reflected disease severity at a median 5 years later (p = 1.2E‐04). Together with known clinical covariates, CHIT1 levels explained 12% and 27% of variance in these 2 measures, respectively, and were able to distinguish slow and fast disability progression (area under the curve = 85%). CHIT1 was the best discriminator of chronic active versus chronic inactive lesions and the only marker correlated with NfL (r = 0.3, p = 0.0019). Associations with disease activity were, however, independent of NfL. Interpretation CHIT1 CSF levels measured during the diagnostic LP reflect microglial activation early on in MS and can be considered a valuable prognostic biomarker for future disease activity. ANN NEUROL 2020;87:633–645

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 69%

CHIT1 at Diagnosis Reflects Long‐Term Multiple Sclerosis Disease Activity

Oldoni

Smets

Mallants

et al. 2020

Annals of Neurology

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“…13,14 Importantly, as shown by recent studies, pNfL concentrations at diagnosis also predict important longterm outcomes, such as brain atrophy and risk to achieve clinical disability milestones. 15,26 Whereas our data reveal differences in pNfL dynamics across the studied DMTs, we cannot rule out that differences had been achieved with a more complete model for the PS, even if our additional adjustments did not lead to major changes in the estimates. Notably, however, we did not have access to sufficiently precise MRI data, which are known to affect pNfL.…”

Section: Discussionmentioning

confidence: 71%

Blood neurofilament light levels segregate treatment effects in multiple sclerosis

et al. 2020

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ObjectiveTo determine factors (including the role of specific disease modulatory treatments [DMTs]) associated with (1) baseline, (2) on-treatment, and (3) change (from treatment start to on-treatment assessment) in plasma neurofilament light chain (pNfL) concentrations in relapsing-remitting multiple sclerosis (RRMS).MethodsData including blood samples analyses and long-term clinical follow-up information for 1,261 Swedish patients with RRMS starting novel DMTs were analyzed using linear regressions to model pNfL and changes in pNfL concentrations as a function of clinical variables and DMTs (alemtuzumab, dimethyl fumarate, fingolimod, natalizumab, rituximab, and teriflunomide).ResultsThe baseline pNfL concentration was positively associated with relapse rate, Expanded Disability Status Scale score, Age-Related MS Severity Score, and MS Impact Score (MSIS-29), and negatively associated with Symbol Digit Modalities Test performance and the number of previously used DMTs. All analyses, which used inverse propensity score weighting to correct for differences in baseline factors at DMT start, highlighted that both the reduction in pNfL concentration from baseline to on-treatment measurement and the on-treatment pNfL level differed across DMTs. Patients starting alemtuzumab displayed the highest reduction in pNfL concentration and lowest on-treatment pNfL concentrations, while those starting teriflunomide had the smallest decrease and highest on-treatment levels, but also starting from lower values. Both on-treatment pNfL and decrease in pNfL concentrations were highly dependent on baseline concentrations.ConclusionChoice of DMT in RRMS is significantly associated with degree of reduction in pNfL, which supports a role for pNfL as a drug response marker.

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“…Recently, the UCSF-Epic cohort reported that at the 5-year follow-up, those treated with highly effective therapies experienced greater decreases in serum NFL compared with those on platform therapies, with a significant interaction found between NFL and EDSS. 61 This biomarker may also have utility in clinic as an adjunct to conventional MRI and may even have prognostic value at disease onset. However, further standardization and refinement of serum neurofilament testing is necessary before neurofilament can enter routine clinical use.…”

Section: The Reported Safety Profiles Of Some Highly Effective Agentsmentioning

confidence: 99%

An argument for broad use of high efficacy treatments in early multiple sclerosis

Stankiewicz

Weiner

2020

Neurol Neuroimmunol Neuroinflamm

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Two different treatment paradigms are most often used in multiple sclerosis (MS). An escalation or induction approach is considered when treating a patient early in the disease course. An escalator prioritizes safety, whereas an inducer would favor efficacy. Our understanding of MS pathophysiology has evolved with novel in vivo and in vitro observations. The treatment landscape has also shifted significantly with the approval of over 10 new medications over the past decade alone. Here, we re-examine the treatment approach in light of these recent developments. We believe that recent work suggests that early prediction of the disease course is fraught, the amount of damage to the brain that MS causes is underappreciated, and its impact on patient function oftentimes is underestimated. These concerns, coupled with the recent availability of agents that allow a better therapeutic effect without compromising safety, lead us to believe that initiating higher efficacy treatments early is the best way to achieve the best possible long-term outcomes for people with MS. Multiple sclerosis following collection(s):This article, along with others on similar topics, appears in the Permissions & Licensing http://nn.neurology.org/misc/about.xhtml#permissions its entirety can be found online at: Information about reproducing this article in parts (figures,tables) or in Reprints http://nn.neurology.org/misc/addir.xhtml#reprintsus Information about ordering reprints can be found online: Academy of Neurology.. All rights reserved. Online

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Association Between Serum Neurofilament Light Chain Levels and Long-term Disease Course Among Patients With Multiple Sclerosis Followed up for 12 Years

Cited by 155 publications

References 42 publications

CHIT1 at Diagnosis Reflects Long‐Term Multiple Sclerosis Disease Activity

CHIT1 at Diagnosis Reflects Long‐Term Multiple Sclerosis Disease Activity

Blood neurofilament light levels segregate treatment effects in multiple sclerosis

An argument for broad use of high efficacy treatments in early multiple sclerosis

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