Evaluation of CHIT1 and SERPINA3 as Candidate Cerebrospinal Fluid Biomarkers of Progressive Biology in Multiple Sclerosis
Amit Bar-Or1, Jeffrey Gelfand2, Chinaza Agbim3, H.-Christian von Büdingen4, Briana Cameron3, Ann Herman3, Xiaoming Jia3, Akshaya Ramesh3, Ryan Winger3, Jenny Jiang3, Christopher Harp3, Anne Cross5
1University of Pennsylvania, 2University of California, San Francisco, 3Genentech, Inc., 4F. Hoffmann-La Roche Ltd, 5Washington University School of Medicine
Objective:

To quantitatively confirm associations between chitotriosidase-1 (CHIT1) or serpin family A member 3 (SERPINA3) and measures of multiple sclerosis (MS) progressive biology and quantitatively assess ocrelizumab treatment effect on cerebrospinal fluid (CSF) levels of these biomarkers.

Background:
Biomarkers distinguishing nonrelapsing progressive disease biology from relapsing biology in MS are lacking. Previously, CSF proteomics via data-independent acquisition mass spectrometry identified CHIT1 (activated myeloid cells) and SERPINA3 (reactive astrocytes) as candidate markers putatively reflecting MS progressive biology by associating with slowly expanding lesions (SELs).
Design/Methods:

CHIT1 and SERPINA3 were measured in CSF from healthy individuals (n=30) and people with relapsing MS (pwRMS; n=79) or with primary progressive MS (pwPPMS; n=22) from the Ocrelizumab Biomarker Outcome Evaluation (OBOE) study (NCT02688985) via enzyme-linked immunosorbent assay. Baseline associations with clinical and magnetic resonance imaging measures were analyzed using Spearman-correlation analysis. Comparisons between pre- vs post-treatment levels were performed using the paired Wilcoxon test.

Results:

CHIT1 levels were elevated in pwRMS and pwPPMS, while SERPINA3 levels were elevated only in pwPPMS, vs healthy individuals (all, P<0.05). CHIT1 levels correlated with measures of acute disease activity (T1 gadolinium-enhancing lesions, R=0.33; CSF neurofilament light chain levels, R=0.58) and progressive biology (SEL volume, R=0.38). SERPINA3 levels correlated with progressive biology (SEL volume, R=0.39; CSF glial fibrillary acidic protein levels, R=0.44) (all, P<0.001). Ocrelizumab treatment reduced levels of CHIT1 in pwRMS (median change, −41% [interquartile range {IQR}, −59% to −21%]) and pwPPMS (IQR, −27% [−42% to −17%]) at Week 52 (all, P<0.01). CSF SERPINA3 levels were unaltered following ocrelizumab treatment.

Conclusions:

We provide confirmatory evidence for CHIT1 and SERPINA3 as candidate biomarkers of progressive biology in MS. CHIT1 levels were elevated in both pwRMS and pwPPMS and were reduced following ocrelizumab treatment, highlighting CHIT1’s potential role as a treatment response marker of microglial activity in acute and progressive disease.

10.1212/WNL.0000000000210408
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