Cerebrospinal fluid immunoglobulin light chain ratios predict disease progression in multiple sclerosis.

ABSTRACT

OBJECTIVE: To determine whether the ratio of cerebrospinal fluid (CSF) immunoglobulin kappa to lambda light chains at time of multiple sclerosis (MS) diagnosis predicts disease progression and whether this was intrinsic to CSF plasmablasts. METHODS: CSF and peripheral blood were obtained from patients undergoing elective diagnostic lumbar puncture and included clinically isolated syndrome (CIS) (n=43), relapsing remitting MS (RRMS; n=50), primary progressive MS (PPMS; n=20) and other neurological disease controls, both inflammatory (ONID; n=23) and non-inflammatory (OND; n=114). CSF samples were assayed for free and immunoglobulin-associated light chains and on B cells and plasmablasts. Clinical follow-up data were collected during a 5-year follow-up period where available. RESULTS: There was an increased median CSF κλ free light chain (FLC) in all MS groups (CIS 18.2, 95% CI 6.8 to 30.3; RRMS 4.4, 95% CI 2.7 to 11.4; PPMS 12.0, 95% CI 3.6 to 37.1) but not controls (OND 1.61, 95% CI 1.4 to 1.9; ONID 1.7, 95% CI 1.3 to 2.2; p<0.001). This ratio predicted Expanded Disability Status Scores (EDSS) progression at 5 years, with a lower median EDSS in the group with high (>10) CSF κλ FLC (0.0, 95% CI 0 to 2.5 vs 2.5, 95% CI 0 to 4, high vs low; p=0.049). CSF κλ FLC correlated with CSF IgG1 κλ (r=0.776; p<0.0001) and was intrinsic to CSF plasmablasts (r=0.65; p=0.026). CONCLUSIONS: These data demonstrate that CSF immunoglobulin κλ ratios, determined at the time of diagnostic lumbar puncture, predict MS disease progression and may therefore be useful prognostic markers for early therapeutic stratification.