Minocycline treatment in clinically isolated syndrome and serum NfL, GFAP, and metalloproteinase levels

Carlos Camara-Lemarroy, Luanne Metz, Jens Kuhle, David Leppert, Eline Willemse, David Kb Li, Anthony Traboulsee, Jamie Greenfield, Graziela Cerchiaro, Claudia Silva, V Wee Yong, Carlos Camara-Lemarroy, Luanne Metz, Jens Kuhle, David Leppert, Eline Willemse, David Kb Li, Anthony Traboulsee, Jamie Greenfield, Graziela Cerchiaro, Claudia Silva, V Wee Yong

Abstract

Background: In the trial of Minocycline in Clinically Isolated Syndrome (MinoCIS), minocycline significantly reduced the risk of conversion to clinically definite multiple sclerosis (CDMS). Neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) are emerging biomarkers in MS, and minocycline modulates matrix metalloproteinases (MMPs).

Objective: To assess the value of blood NfL and GFAP as a biomarker of baseline and future disease activity and its utility to monitor treatment response in minocycline-treated patients with clinically isolated syndrome (CIS).

Methods: We measured NfL, GFAP, and MMPs in blood samples from 96 patients with CIS from the MinoCIS study and compared biomarkers with clinical and radiologic characteristics and outcome.

Results: At baseline, NfL levels correlated with T2 lesion load and number of gadolinium-enhancing lesions. Baseline NfL levels predicted conversion into CDMS at month 6. GFAP levels at baseline were correlated with T2 lesion volume. Minocycline treatment significantly increased NfL levels at 3 months but not at 6 months, and decreased GFAP levels at month 6. Minocycline decreased MMP-7 concentrations at month 1.

Discussion: Blood NfL levels are associated with measures of disease activity in CIS and have prognostic value. Minocycline increased NfL levels at month 3, but reduced GFAP and MMP-7 levels.

Trial registration: ClinicalTrials.gov NCT00666887.

Keywords: CIS; GFAP; MMPs; Multiple sclerosis; NfL; minocycline.

Conflict of interest statement

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: E.W., C.S., G.C., J.G. and L.M. report no conflict of interest related to this manuscript. C.C.-L. received consulting fees from EMD Serono. J.K. received speaker fees, research support, travel support, and served on advisory boards by the Progressive MS Alliance, Swiss MS Society, Swiss National Research Foundation (320030_189140/1), University of Basel, Biogen, Celgene, Merck, Novartis, Octave Bioscience, Roche, and Sanofi. D.L. is Chief Medical Officer of GeNeuro. D.K.B.L. has received research funding from the Multiple Sclerosis Society of Canada. He is Emeritus Director of the UBC MS/MRI Research Group that has been contracted to perform central analysis of MRI scans for therapeutic trials with Roche and Sanofi-Genzyme. The UBC MS/MRI Research Group has also received grant support for investigator-initiated studies from Genzyme, Novartis, and Roche. He has been a consultant to Vertex Pharmaceuticals and Genzyme, served on the Scientific Advisory Board for Celgene and the PML-MS Steering Committee for Biogen. He has given lectures, supported by non-restricted education grants from Academy of Health Care Learning, Consortium of MS Centers and Sanofi-Genzyme. A. Traboulsee has received research funding from MS Society of Canada, Roche, and Sanofi-Genzyme; received honoraria or travel support from Consortium of MS Centers, Biogen, Teva, Roche, Merck/EMD Serono, and Sanofi-Genzyme. W.Y. has received honoraria from Biogen, EMD Serono, Novartis, Roche, and Sanofi-Genzyme. He is the recipient of unrestricted educational grants from Biogen, EMD Serono, Novartis, Roche, Sanofi-Genzyme, and Teva to support educational activities of the Alberta MS Network, which he directs.

Figures

Figure 1.
Figure 1.
Correlation matrix plots of NfL/GFAP (a) and MMP (b) concentrations and clinical/radiological variables. The heatmaps indicate the Spearman r value, where red is a positive correlation and blue is a negative correlation. Associations between baseline NfL and Gad+ lesions (c), T2 lesion volume (d), and GFAP (e). Association between baseline GFAP and T2 lesion volume (f). The dots represent the medians and the error lines represent the IQR. Significance levels for MMPs are corrected with the false discovery rate method. ns: not significant. * 

Figure 2.

Association between outcome and baseline…

Figure 2.

Association between outcome and baseline Gad+ lesions (a), T 2 lesion volume (b),…

Figure 2.
Association between outcome and baseline Gad+ lesions (a), T2 lesion volume (b), NfL (c), and GFAP (d). CDMS: clinically definite MS (outcome); ns: not significant. Points represent the medians and the error lines the IQR. ** 

Figure 3.

Longitudinal dynamics of NfL (a),…

Figure 3.

Longitudinal dynamics of NfL (a), GFAP (b), and MMP-7 (c) concentrations. Statistical tests…

Figure 3.
Longitudinal dynamics of NfL (a), GFAP (b), and MMP-7 (c) concentrations. Statistical tests are the Friedman test with the post hoc Wilcoxon test and Bonferroni correction. The dots represent the medians and error bars IQR. BL: baseline; M1: month 1; M3: month 3; M6: month 6. *
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References
    1. Metz LM. Clinically isolated syndrome and early relapsing multiple sclerosis. Continuum 2019; 25(3): 670–688. - PubMed
    1. Metz LM, Li DKB, Traboulsee AL, et al.. Trial of minocycline in a clinically isolated syndrome of multiple sclerosis. N Engl J Med 2017; 376(22): 2122–2133. - PubMed
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Figure 2.
Figure 2.
Association between outcome and baseline Gad+ lesions (a), T2 lesion volume (b), NfL (c), and GFAP (d). CDMS: clinically definite MS (outcome); ns: not significant. Points represent the medians and the error lines the IQR. ** 

Figure 3.

Longitudinal dynamics of NfL (a),…

Figure 3.

Longitudinal dynamics of NfL (a), GFAP (b), and MMP-7 (c) concentrations. Statistical tests…

Figure 3.
Longitudinal dynamics of NfL (a), GFAP (b), and MMP-7 (c) concentrations. Statistical tests are the Friedman test with the post hoc Wilcoxon test and Bonferroni correction. The dots represent the medians and error bars IQR. BL: baseline; M1: month 1; M3: month 3; M6: month 6. *
Similar articles
References
    1. Metz LM. Clinically isolated syndrome and early relapsing multiple sclerosis. Continuum 2019; 25(3): 670–688. - PubMed
    1. Metz LM, Li DKB, Traboulsee AL, et al.. Trial of minocycline in a clinically isolated syndrome of multiple sclerosis. N Engl J Med 2017; 376(22): 2122–2133. - PubMed
    1. Yong VW, Zabad RK, Agrawal S, et al.. Elevation of matrix metalloproteinases (MMPs) in multiple sclerosis and impact of immunomodulators. J Neurol Sci 2007; 259(1–2): 79–84. - PubMed
    1. Kuhle J, Kropshofer H, Haering DA, et al.. Blood neurofilament light chain as a biomarker of MS disease activity and treatment response. Neurology 2019; 92(10): e1007–e1015. - PMC - PubMed
    1. Kuhle J, Daizadeh N, Benkert P, et al.. Sustained reduction of serum neurofilament light chain over 7 years by alemtuzumab in early relapsing-remitting MS. Mult Scler 2022; 28: 573–582. - PMC - PubMed
Show all 27 references
Publication types
Associated data
Full text links [x]
[x]
Cite
Copy Download .nbib
Format: AMA APA MLA NLM
Figure 3.
Figure 3.
Longitudinal dynamics of NfL (a), GFAP (b), and MMP-7 (c) concentrations. Statistical tests are the Friedman test with the post hoc Wilcoxon test and Bonferroni correction. The dots represent the medians and error bars IQR. BL: baseline; M1: month 1; M3: month 3; M6: month 6. *

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