CSF levels of Chitinase3like1 correlate with early response to cladribine in multiple sclerosis

Damiano Marastoni; Matteo Foschi; Chiara Eccher; Francesco Crescenzo; Valentina Mazziotti; Agnese Tamanti; Albulena Bajrami; Valentina Camera; Stefano Ziccardi; Maddalena Guandalini; Francesca Bosello; Daniela Anni; Federica Virla; Ermanna Turano; Michele Romoli; Raffaella Mariotti; Francesca Benedetta Pizzini; Bruno Bonetti; Massimiliano Calabrese

doi:10.3389/fimmu.2024.1343892

CSF levels of Chitinase3like1 correlate with early response to cladribine in multiple sclerosis

Front Immunol. 2024 Feb 9:15:1343892. doi: 10.3389/fimmu.2024.1343892. eCollection 2024.

Authors

Damiano Marastoni^#¹, Matteo Foschi^#^{2

3}, Chiara Eccher^#¹, Francesco Crescenzo⁴, Valentina Mazziotti¹, Agnese Tamanti¹, Albulena Bajrami¹, Valentina Camera¹, Stefano Ziccardi¹, Maddalena Guandalini¹, Francesca Bosello⁵, Daniela Anni¹, Federica Virla^{1

6}, Ermanna Turano^{1

6}, Michele Romoli⁷, Raffaella Mariotti⁶, Francesca Benedetta Pizzini⁸, Bruno Bonetti⁹, Massimiliano Calabrese¹

Affiliations

¹ Neurology B, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.
² Neurology Unit, Department of Neuroscience, Multiple Sclerosis Center, S. Maria delle Croci Hospital, AUSL, Romagna, Ravenna, Italy.
³ Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy.
⁴ Neurology Unit, "Mater Salutis" Hospital, Scaligera AULSS 9, Verona, Italy.
⁵ Eye Clinic, Department of Surgery, Dentistry, Maternity, and Infant, University of Verona, Verona, Italy.
⁶ Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.
⁷ Neurology and Stroke Unit, Ospedale "Bufalini", Cesena, Italy.
⁸ Radiology and Neuroradiology Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.
⁹ Neurology A, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.

^# Contributed equally.

Abstract

Background: Cladribine has been introduced as a high-efficacy drug for treating relapsing-remitting multiple sclerosis (RRMS). Initial cohort studies showed early disease activity in the first year after drug initiation. Biomarkers that can predict early disease activity are needed.

Aim: To estimate cerebrospinal fluid (CSF) markers of clinical and radiological responses after initiation of cladribine.

Methods: Forty-two RRMS patients (30F/12M) treated with cladribine were included in a longitudinal prospective study. All patients underwent a CSF examination at treatment initiation, clinical follow-up including Expanded Disability Status Scale (EDSS) assessment, and a 3T MRI scan after 6,12 and 24 months, including the evaluation of white matter (WM) and cortical lesions (CLs). CSF levels of 67 inflammatory markers were assessed with immune-assay multiplex techniques. The 'no evidence of disease activity' (NEDA-3) status was assessed after two years and defined by no relapses, no disability worsening measured by EDSS and no MRI activity, including CLs.

Results: Three patients were lost at follow-up. At the end of follow-up, 19 (48%) patients remained free from disease activity. IFNgamma, Chitinase3like1, IL32, Osteopontin, IL12(p40), IL34, IL28A, sTNFR2, IL20 and CCL2 showed the best association with disease activity. When added in a multivariate regression model including age, sex, and baseline EDSS, Chitinase 3 like1 (p = 0.049) significantly increased in those patients with disease activity. Finally, ROC analysis with Chitinase3like1 added to a model with EDSS, sex, age previous relapses, WM lesion number, CLs, number of Gad enhancing lesions and spinal cord lesions provided an AUC of 0.76 (95%CI 0.60-0.91).

Conclusions: CSF Chitinase 3 like1 might provide prognostic information for predicting disease activity in the first years after initiation of cladribine. The drug's effect on chronic macrophage and microglia activation deserves further evaluation.

Keywords: biomarkers; chemokines; cladribine; cytokines; disease activity; relapsing multiple sclerosis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Chitinase-3-Like Protein 1* / cerebrospinal fluid
Cladribine* / therapeutic use
Humans
Multiple Sclerosis, Relapsing-Remitting* / diagnostic imaging
Multiple Sclerosis, Relapsing-Remitting* / drug therapy
Prospective Studies

Substances

Cladribine
CHI3L1 protein, human
Chitinase-3-Like Protein 1

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This research was supported by grant MS700568_0091 from Merck Serono S.p.A, Italy, an affiliate of Merck KGaA (CrossRef Funder ID: 10.13039/100009945). MC was supported by the GR-2013-02-355322 grant from the Italian Ministry of Health. Work supported by #NEXTGENERATIONEU (NGEU) and funded by the Ministry of University and Research (MUR), National Recovery and Resilience Plan (NRRP), project MNESYS (PE0000006) – A Multiscale integrated approach to the study of the nervous system in health and disease (DN. 1553 11.10.2022).