NFL and CXCL13 may reveal disease activity in clinically and radiologically stable MS

Novakova, Lenka; Axelsson, Markus; Malmeström, Clas; Zetterberg, Henrik; Blennow, Kaj; Svenningsson, Anders; Lycke, Jan

doi:10.1016/j.msard.2020.102463

Cited by 22 publications

(37 citation statements)

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“…We confirmed that high NFL levels are good predictors of patients not fulfilling NEDA-3. 10 In line with the results of a previous study, 31 other measures of disease activity. We found, however, that a significant proportion of patients with ON had normal cNFL levels at diagnosis and no evidence of ongoing disease activity on MRI.…”

Section: Discussionsupporting

confidence: 85%

Exploring CSF neurofilament light as a biomarker for MS in clinical practice; a retrospective registry-based study

et al. 2021

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Background: Neurofilament light (NFL) has been increasingly recognized for prognostic and therapeutic decisions. Objective: To validate the utility of cerebrospinal fluid NFL (cNFL) as a biomarker in clinical practice of relapsing-remitting multiple sclerosis (RRMS). Methods: RRMS patients ( n = 757) who had cNFL analyzed as part of the diagnostic work-up in a single academic multiple sclerosis (MS) center, 2001–2018, were retrospectively identified. cNFL concentrations were determined with two different immunoassays and the ratio of means between them was used for normalization. Results: RRMS with relapse had 4.4 times higher median cNFL concentration (1134 [interquartile range (IQR) 499–2744] ng/L) than those without relapse (264 [125–537] ng/L, p < 0.001) and patients with gadolinium-enhancing lesions had 3.3 times higher median NFL (1414 [606.8–3210] ng/L) than those without (426 [IQR 221–851] ng/L, p < 0.001). The sensitivity and specificity of cNFL to detect disease activity was 75% and 98.5%, respectively. High cNFL at MS onset predicted progression to Expanded Disability Status Scale (EDSS) ⩾ 3 ( p < 0.001, hazard ratios (HR) = 1.89, 95% CI = 1.44–2.65) and conversion to secondary progressive MS (SPMS, p = 0.001, HR = 2.5, 95% CI = 1.4–4.2). Conclusions: cNFL is a robust and reliable biomarker of disease activity, treatment response, and prediction of disability and conversion from RRMS to SPMS. Our data suggest that cNFL should be included in the assessment of patients at MS-onset.

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Section: Discussionsupporting

confidence: 85%

Exploring CSF neurofilament light as a biomarker for MS in clinical practice; a retrospective registry-based study

et al. 2021

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“…Patients with high sNfL had numerically accelerated brain volume loss in the preceding and following year. If our findings will be supported in future research, 15 sNfL may also qualify as an indirect marker of contemporary neurodegeneration that is not captured by the present NEDA-3 concept. Compared to direct assessment of brain volume loss by MRI volumetric methods, as conceptualized in the NEDA-4, 7 an sNfL monitoring may offer an advantage of higher accuracy and precision, detection of changes in entire neuroaxis, greater potential for standardization, and lower financial burden.…”

Section: Discussionmentioning

confidence: 67%

“…An increasing number of studies has established sNfL as marker of disease activity, drug response, and prediction of the disease course, both on clinical and MRI grounds. 9 –19 However, the practical value of sNfL as a monitoring tool for clinical practice has been less studied. 13 –20…”

Section: Introductionmentioning

confidence: 99%

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Measurement of neurofilaments improves stratification of future disease activity in early multiple sclerosis

et al. 2021

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Background: The added value of neurofilament light chain levels in serum (sNfL) to the concept of no evidence of disease activity-3 (NEDA-3) has not yet been investigated in detail. Objective: To assess whether combination of sNfL with NEDA-3 status improves identification of patients at higher risk of disease activity during the following year. Methods: We analyzed 369 blood samples from 155 early relapsing-remitting MS patients on interferon beta-1a. We compared disease activity, including the rate of brain volume loss in subgroups defined by NEDA-3 status and high or low sNfL (> 90th or < 90th percentile). Results: In patients with disease activity (EDA-3), those with higher sNFL had higher odds of EDA-3 in the following year than those with low sNFL (86.5% vs 57.9%; OR = 4.25, 95% CI: [2.02, 8.95]; p = 0.0001) and greater whole brain volume loss during the following year (β = −0.36%; 95% CI = [−0.60, −0.13]; p = 0.002). Accordingly, NEDA-3 patients with high sNfL showed numerically higher disease activity (EDA-3) in the following year compared with those with low sNfL (57.1% vs 31.1%). Conclusion: sNfL improves the ability to identify patients at higher risk of future disease activity, beyond their NEDA-3 status. Measurement of sNfL may assist clinicians in decision-making by providing more sensitive prognostic information.

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“…Analysis of CSF cytokines has also demonstrated an increase in CXCL13 in patients with PPMS compared to healthy control ( 90 ). Additionally, in patients with PPMS, CSF CXCL13 was found to correlate with CSF B and T cell levels ( 91 ) and higher amounts of CXCL13 were found in patients with disease activity compared to those without ( 92 ). Overall, these data suggest a possible pathogenic role for B cells in PPMS via LT-α and CXCL13, which may be mitigated by anti-CD20 therapies.…”

Section: Mechanism Of Action Of B Cell Mediated Disease Progression In Ppmsmentioning

confidence: 99%

The Role of B Cells in Primary Progressive Multiple Sclerosis

et al. 2021

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The success of ocrelizumab in reducing confirmed disability accumulation in primary progressive multiple sclerosis (PPMS) via CD20-targeted depletion implicates B cells as causal agents in the pathogenesis of PPMS. This review explores the possible mechanisms by which B cells contribute to disease progression in PPMS, specifically exploring cytokine production, antigen presentation, and antibody synthesis. B cells may contribute to disease progression in PPMS through cytokine production, specifically GM-CSF and IL-6, which can drive naïve T-cell differentiation into pro-inflammatory Th1/Th17 cells. B cell production of the cytokine LT-α may induce follicular dendritic cell production of CXCL13 and lead indirectly to T and B cell infiltration into the CNS. In contrast, production of IL-10 by B cells likely induces an anti-inflammatory effect that may play a role in reducing neuroinflammation in PPMS. Therefore, reduced production of IL-10 may contribute to disease worsening. B cells are also capable of potent antigen presentation and may induce pro-inflammatory T-cell differentiation via cognate interactions. B cells may also contribute to disease activity via antibody synthesis, although it's unlikely the benefit of ocrelizumab in PPMS occurs via antibody decrement. Finally, various B cell subsets likely promulgate pro- or anti-inflammatory effects in MS.

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NFL and CXCL13 may reveal disease activity in clinically and radiologically stable MS

Cited by 22 publications

References 35 publications

Exploring CSF neurofilament light as a biomarker for MS in clinical practice; a retrospective registry-based study

Exploring CSF neurofilament light as a biomarker for MS in clinical practice; a retrospective registry-based study

Measurement of neurofilaments improves stratification of future disease activity in early multiple sclerosis

The Role of B Cells in Primary Progressive Multiple Sclerosis

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