Damiano Marastoni1, Chiara Eccher1, Daniela Anni1, Alessio Signori2, Federica Virla1, Ermanna Turano1, Stefano Ziccardi1, Giulia Zanetti1, Anna Fratucello3, Maria Pia Sormani2, Massimiliano Calabrese1
1Dept. of Neurosciences, Biomedicine and Movement, University of Verona, 2Department of Health Sciences - Section of Biostatistics, University of Genoa, 3Clinical Research Unit, Azienda Ospedaliera Universitaria di Verona
Objective:
To investigate effect of Cladribine on cerebrospinal fluid (CSF) inflammatory proteomic profile, cortical lesions (CLs) and positive RIM lesions (PRLs) in patients with relapsing-remitting MS (RRMS).
Background:
Cladribine is an oral drug capable to cross the blood-brain barrier and licensed for treatment of relapsing MS. Its efficacy on intrathecal inflammatory markers and MRI markers of chronic compartmentalized inflammation remains unclear.
Design/Methods:
Forty-two patients with RRMS were enrolled in a prospective 2-year study and treated with Cladribine. All patients underwent a lumbar puncture before treatment initiation and after two-years, a clinical evaluation every 6 months and a 3TMRI every year. CSF levels of 69 inflammatory markers were assessed by multiplex immune assay. White matter lesion number and volume, CLs and volume, PRLs number were evaluated. NEDA-3 was defined by no relapses, MRI activity and 6-months confirmed disability progression, defined as an increase of ≥1 point in EDSS.
Results:
Thirty-nine patients completed the study. Baseline median EDSS was 2(0-5), disease duration was 2.4±4.3 years. After two years, 19 (48.7%) patients retained the NEDA status. Cladribine reduced most of CSF markers. After correction for multiple comparisons, a reduction of TNF (p=0.047), TNFR1 (p=0.039), Pentraxin3 (p=0.002) and CCL22 (p=0.017) and a almost significant reduction of CCL21, CXCL5, IFNgamma, BAFF, CD163, Chitinase 3like1 were detected. On the contrary, CXCL12, OPN, sTNFR2 didn’t decrease after treatment. The decrease in markers was more pronounced in those patients that reached NEDA status. The down-regulation of TWEAK and CXCL13 correlated with EDSS change (r=0.34,p=0.034 and r=0.32,p=0.043, respectively). No patients accumulated new CLs neither a significant increase in PRLs was observed.
Conclusions:
Cladribine showed efficacy in reducing intrathecal inflammatory markers, corroborating an effect on intrathecal compartmentalized inflammation which was also suggested by the absence of CLs and PRLs accumulation.
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