Anti-alpha-glucose-based glycan IgM antibodies predict relapse activity in multiple sclerosis after the first neurological event

Abstract

Background: There is no specific serum-based biomarker for the diagnosis or prognosis of relapsing-remitting multiple sclerosis (RRMS).

Objective: We investigated whether levels of IgM antibodies to Glc(alpha1,4)Glc(alpha) (GAGA4) or to a panel of four glucose-based glycans could differentiate MS from other neurological diseases (OND) or predict risk of early relapse following first presentation (FP) of RRMS.

Methods: Retrospective analysis of 440 sera samples of three cohorts: A) FP-RRMS (n = 44), OND (n = 44); B) FP-RRMS (n = 167), OND (n = 85); and C) FP (n = 100). Anti-GAGA4 IgM levels were measured by enzyme immunoassay in cohort-A and cohort-B. Cohort-C IgM antibodies to glucose-based glycan panel were measured by immunofluorescence.

Results: FP-RRMS had higher levels of anti-GAGA4 IgM than OND patients (cohort-A, P = 0.01; cohort-B, P = 0.0001). Sensitivity and specificity were 27% and 97% for cohort-A; and 26% and 90% for cohort-B, respectively. In cohort-C, 58 patients experienced early relapse (<24 months), 31 had late relapse (> or =24 months), and 11 did not experience second attack during follow-up. Kaplan-Meier curves demonstrated decrease in time to next relapse for patients positive for the antibody panel (P = 0.02, log rank).

Conclusions: Serum anti-GAGA4 IgM discerns FP-RRMS patients from OND patients. Higher levels of serum anti-alpha-glucose IgM in FP patients predict imminent early relapse.

Figure 1

Glycan array format: A – Glass slide patterned with Teflon mask creating 7 clusters of microwells, 32 wells in each cluster. B – An adhesive silicon superstructure attached to the slide defines wells for manual application of multiple serum samples per slide. C – Antigens and controls lay out in each gasket well.

Figure 2

Distribution of anti-GAGA4 IgM levels in cohort-A [FP (n = 44) and OND (n = 44) patients]. Lines indicate SD ± mean. Crossing line indicates cutoff for defining antibody status. P-value (Mann–Whitney U) is FP group versus OND.

Figure 3

Distribution of anti-GAGA4 IgM levels in cohort-B [FP patients (n = 167), and OND (n = 85)]. Lines indicate SD ± mean. Crossing line indicates cutoff value for antibody status. P-value (Mann-Whitney U) is FP group versus OND.

Figure 4

Time to CDMS, Kaplan–Meier, survival plot for cohort-C. FP patients positive for ≥1 (anti-GAGA4, -GAGA2, -GAGA3, or -GAGA6 IgM) versus patients negative for all markers. Cutoff values were 4.0, 4.5, 4.5, and 4.3 for anti-GAGA2, -GAGA3, -GAGA4, and -GAGA6 IgM, respectively. P-values determined by log rank test. With Bonferroni correction only P-values below 0.0125 are considered significant.