Serum contactin-1 as a biomarker of long-term disease progression in natalizumab-treated multiple sclerosis

Abstract

Background: Natalizumab treatment provides a model for non-inflammation-induced disease progression in multiple sclerosis (MS).

Objective: To study serum contactin-1 (sCNTN1) as a novel biomarker for disease progression in natalizumab-treated relapsing-remitting MS (RRMS) patients.

Methods: Eighty-nine natalizumab-treated RRMS patients with minimum follow-up of 3 years were included. sCNTN1 was analyzed at baseline (before natalizumab initiation), 3, 12, 24 months (M) and last follow-up (median 5.2 years) and compared to 222 healthy controls (HC) and 15 primary progressive MS patients (PPMS). Results were compared between patients with progressive, stable, or improved disability according to EDSS-plus criteria.

Results: Median sCNTN1 levels (ng/mL,) in RRMS (baseline: 10.7, 3M: 9.7, 12M: 10.4, 24M: 10.8; last follow-up: 9.7) were significantly lower compared to HC (12.5; p ⩽ 0.001). It was observed that 48% of patients showed progression during follow-up, 11% improved, and 40% remained stable. sCNTN1 levels were significantly lower in progressors both at baseline and at 12M compared to non-progressors. A 1 ng/mL decrease in baseline sCNTN1 was consistent with an odds ratio of 1.23 (95% confidence interval 1.04-1.45) (p = 0.017) for progression during follow-up.

Conclusion: Lower baseline sCNTN1 concentrations were associated with long-term disability progression during natalizumab treatment, making it a possible blood-based prognostic biomarker for RRMS.

Keywords: Multiple sclerosis; contactin 1; disease activity; disease progression; natalizumab; prediction.

Figure 1.

Serum CNTN1 levels at each timepoint (ng/mL; symbols are placed at the median values and vertical bars indicate interquartile range (IQR)) separated by disability group. Disability categories were defined by EDSS plus (EDSS combined with 9HPT and T25W) criteria as follows: patients with progressive disability (“progressors,” n = 43), patients with “stable” disability (n = 36), or improved (“improvers,” n = 10) disability. Samples were taken at baseline (BL, before natalizumab initiation), after 3 months (3M), 12 months (12M), 24 months (24M), and at last follow-up (last FU). Healthy control (HC) levels (only measured once) are illustrated in between these timepoints for the purpose of clarity of this graph. The asterisks (*) indicate significant differences in sCNTN1 levels found between progressors and non-progressors (stable patients and improvers together).

Figure 2.

Serum CNTN1 levels (ng/mL; symbols are placed at the median values and vertical bars indicate interquartile range (IQR)) in primary progressive MS measured prior to ocrelizumab initiation (BL), prior to the second 300 mg dose (FU1) and prior to the first 600 mg dose (FU2). All levels were significantly lower compared to HC (p = 0.002) and a significant decrease was found between BL and FU1 timepoint (p = 0.011).