CSF inflammatory biomarkers responsive to treatment in progressive multiple sclerosis capture residual inflammation associated with axonal damage

Abstract

Background:

Development of treatments for progressive multiple sclerosis (MS) is challenged by the lack of sensitive and treatment-responsive biomarkers of intrathecal inflammation.

Objective:

To validate the responsiveness of cerebrospinal fluid (CSF) inflammatory biomarkers to treatment with natalizumab and methylprednisolone in progressive MS and to examine the relationship between CSF inflammatory and tissue damage biomarkers.

Methods:

CSF samples from two open-label phase II trials of natalizumab and methylprednisolone in primary and secondary progressive MS. CSF concentrations of 20 inflammatory biomarkers and CSF biomarkers of axonal damage (neurofilament light chain (NFL)) and demyelination were analysed using electrochemiluminescent assay and enzyme-linked immunosorbent assay (ELISA).

Results:

In all, 17 natalizumab- and 23 methylprednisolone-treated patients had paired CSF samples. CSF sCD27 displayed superior standardised response means and highly significant decreases during both natalizumab and methylprednisolone treatment; however, post-treatment levels remained above healthy donor reference levels. Correlation analyses of CSF inflammatory biomarkers and NFL before, during and after treatment demonstrated that CSF sCD27 consistently correlates with NFL.

Conclusion:

These findings validate CSF sCD27 as a responsive and sensitive biomarker of intrathecal inflammation in progressive MS, capturing residual inflammation after treatment. Importantly, CSF sCD27 correlates with NFL, consistent with residual inflammation after anti-inflammatory treatment being associated with axonal damage.

Keywords

Primary progressive multiple sclerosis secondary progressive multiple sclerosis natalizumab methylprednisolone cerebrospinal fluid inflammation axonal damage

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References

Ontaneda

Fox

Chataway

Clinical trials in progressive multiple sclerosis: Lessons learned and future perspectives. Lancet Neurol 2015; 14(2): 208–223.

Kutzelnigg

Lucchinetti

Stadelmann

et al . Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain 2005; 128(Pt 11): 2705–2712.

Lassmann

New concepts on progressive multiple sclerosis. Curr Neurol Neurosci Rep 2007; 7(3): 239–244.

Magliozzi

Howell

Reeves

et al . A gradient of neuronal loss and meningeal inflammation in multiple sclerosis. Ann Neurol 2010; 68(4): 477–493.

Frischer

Bramow

Dal-Bianco

et al . The relation between inflammation and neurodegeneration in multiple sclerosis brains. Brain 2009; 132(Pt 5): 1175–1189.

Androdias

Reynolds

Chanal

et al . Meningeal T cells associate with diffuse axonal loss in multiple sclerosis spinal cords. Ann Neurol 2010; 68(4): 465–476.

Komori

Blake

Greenwood

et al . Cerebrospinal fluid markers reveal intrathecal inflammation in progressive multiple sclerosis. Ann Neurol 2015; 78(1): 3–20.

Romme Christensen

Bornsen

Khademi

et al . CSF inflammation and axonal damage are increased and correlate in progressive multiple sclerosis. Mult Scler 2013; 19: 877–884.

Romme Christensen

Ratzer

Bornsen

et al . Natalizumab in progressive MS: Results of an open-label, phase 2A, proof-of-concept trial. Neurology 2014; 82(17): 1499–1507.

10.

Ratzer

Iversen

Bornsen

et al . Monthly oral methylprednisolone pulse treatment in progressive multiple sclerosis. Mult Scler 2016; 22: 926–934.

11.

Montalban

Hauser

Kappos

et al . Ocrelizumab versus placebo in primary progressive multiple sclerosis. N Engl J Med 2017; 376(3): 209–220.

12.

Kappos

Bar-Or

Cree

et al . Efficacy and safety of siponimod in secondary progressive multiple sclerosis – Results of the placebo controlled, double-blind, Phase III EXPAND study. Mult Scler 2016; 22(3 suppl): 828–883.

13.

Kapoor

Campbell

et al . Effect of natalizumab on disease progression in secondary progressive multiple sclerosis (ASCEND): a phase 3, randomised, double-blind, placebo-controlled trial with an open-label extension. Lancet Neurol 2018; 17(5): 405–415.

14.

Blennow

Fredman

Wallin

et al . Protein analysis in cerebrospinal fluid. II. Reference values derived from healthy individuals 18–88 years of age. Eur Neurol 1993; 33(2): 129–133.

15.

Norman

Wyrwich

Patrick

DL.

The mathematical relationship among different forms of responsiveness coefficients. Qual Life Res 2007; 16(5): 815–822.

16.

Storey

Tibshirani

Statistical significance for genomewide studies. Proc Natl Acad Sci U S A 2003; 100(16): 9440–9445.

17.

Mondria

Lamers

te Boekhorst

et al . Bone-marrow transplantation fails to halt intrathecal lymphocyte activation in multiple sclerosis. J Neurol Neurosurg Psychiatry 2008; 79(9): 1013–1015.

18.

Komori

Lin

Cortese

et al . Insufficient disease inhibition by intrathecal rituximab in progressive multiple sclerosis. Ann Clin Transl Neurol 2016; 3(3): 166–179.

19.

Buechler

Ritter

Orso

et al . Regulation of scavenger receptor CD163 expression in human monocytes and macrophages by pro- and antiinflammatory stimuli. J Leukoc Biol 2000; 67(1): 97–103.

20.

Vogel

Glim

Stavenuiter

et al . Human macrophage polarization in vitro: Maturation and activation methods compared. Immunobiology 2014; 219(9): 695–703.

21.

Natrajan

Komori

Kosa

et al . Pioglitazone regulates myelin phagocytosis and multiple sclerosis monocytes. Ann Clin Transl Neurol 2015; 2(12): 1071–1084.

22.

Stilund

Reuschlein

Christensen

et al . Soluble CD163 as a marker of macrophage activity in newly diagnosed patients with multiple sclerosis. PLoS ONE 2014; 9(6): e98588.

23.

Defer

Barre

Ledudal

et al . Methylprednisolone infusion during acute exacerbation of MS: Plasma and CSF concentrations. Eur Neurol 1995; 35(3): 143–148.

24.

Mahad

Callahan

Williams

et al . Modulating CCR2 and CCL2 at the blood-brain barrier: Relevance for multiple sclerosis pathogenesis. Brain 2006; 129(Pt 1): 212–223.

25.

Lundstrom

Hermanrud

Sjostrand

et al . Interferon beta treatment of multiple sclerosis increases serum interleukin-7. Mult Scler 2014; 20(13): 1727–1736.

26.

Khademi

Dring

Gilthorpe

et al . Intense inflammation and nerve damage in early multiple sclerosis subsides at older age: A reflection by cerebrospinal fluid biomarkers. PLoS ONE 2013; 8(5): e63172.

27.

Norgren

Sundstrom

Svenningsson

et al . Neurofilament and glial fibrillary acidic protein in multiple sclerosis. Neurology 2004; 63(9): 1586–1590.

28.

Axelsson

Malmestrom

Gunnarsson

et al . Immunosuppressive therapy reduces axonal damage in progressive multiple sclerosis. Mult Scler 2014; 20(1): 43–50.

29.

Malmestrom

Haghighi

Rosengren

et al . Neurofilament light protein and glial fibrillary acidic protein as biological markers in MS. Neurology 2003; 61(12): 1720–1725.

30.

Ravnborg

Blinkenberg

Sellebjerg

et al . Responsiveness of the Multiple Sclerosis Impairment Scale in comparison with the Expanded Disability Status Scale. Mult Scler 2005; 11(1): 81–84.

31.

Giovannoni

Steiner

Sellebjerg

et al . Sustained disability improvement as assessed by a multicomponent endpoint in secondary progressive multiple sclerosis (SPMS) patients: A post hoc analysis from ASCEND (P5.359). Neurology 2017; 88(16 Supplement). http://n.neurology.org/content/88/16_Supplement/P5.359

32.

Zetterberg

Fluid biomarkers for microglial activation and axonal injury in multiple sclerosis. Acta Neurol Scand 2017; 136(Suppl 201): 15–17.