Blood neurofilament light levels segregate treatment effects in multiple sclerosis

Abstract

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.

Serum neurofilament light chain

“… 37 Most of our patients though were currently treated with DMTs known to effectively reduce disease progression and blood NfL levels. 35 , 38 We found cognitive performance (especially in the domains of attention and information processing, as well as verbal and visuospatial learning and memory) instead to be correlated with MRI variables, with much stronger effect sizes than relations between sNfL and cognition or between sNfL and MRI (table e-1, links.lww.com/NXI/A311 ). Measures such as lesion load and atrophy of brain structures reflect accumulated damage over time and therefore might constitute better predictors of functional outcomes, which are assessed in the absence of acute disease activity.…”

“…37 Most of our patients though were currently treated with DMTs known to effectively reduce disease progression and blood NfL levels. 35,38 We found cognitive performance (especially in the domains of attention and information processing, as well as verbal and visuospatial learning and memory) instead to be correlated with MRI variables, with much stronger effect sizes than relations between sNfL and cognition or between sNfL and MRI (table e-1, links. lww.com/NXI/A311).…”

“…19 Visuospatial learning and memory were indeed defined within 1 cognitive cluster along with information processing speed, both being frequently and severely affected in the course of the disease and thus constituting sensitive domains for cognitive screening, particularly in SPMS. 33,34 Other studies correspondingly observed information processing speed to be linked with NfL derived from plasma, 35 CSF, 17,18 and serum. 36 Despite approaching a medium effect size, this association did not reach significance in our sample though.…”

Mitigating alemtuzumab-associated autoimmunity in MS

“…Recent evidence has demonstrated that an emerging biomarker for assessing tissue damage in the CNS of patients with MS, the neurofilament light chain, is reduced most markedly following the administration of alemtuzumab when compared with other disease-modifying therapies and that such levels remain reduced to the greatest magnitude over time. 44 …”

Neurofilament light chain in demyelinating conditions of the central nervous system: a promising biomarker

“…In particular, the largest reduction in NfL values was noted on treatment with alemtuzumab and the lowest on teriflunomide, while reduced NfL levels similar to that observed under treatment with alemtuzumab were noted under dimethyl fumarate, fingolimod, and natalizumab. However, groups were not homogeneous for characteristics influencing NfL levels, including age, disease duration, and disease severity, potentially resulting in an indication bias, which the authors tried to overcome with statistical adjustments for baseline characteristics [57] .…”