High Levels of Cerebrospinal Fluid Kappa Free Light Chains Relate to IgM Intrathecal Synthesis and Might Have Prognostic Implications in Relapsing Multiple Sclerosis

Abstract

Cerebrospinal kappa free light chain (KFLC)-index is a marker of intrathecal immunoglobulin synthesis that aids in the diagnosis of multiple sclerosis (MS). However, little evidence exists on its prognostic role. Our aim is to analyze the relationship between KFLC-index and other MS biomarkers and to explore its prognostic role. This is a monocentric observational study in a cohort of 52 people with relapsing MS (pwRMS) performed on prospectively acquired clinical data and with retrospective evaluation of biomarkers. We measured KFLC-index, immunoglobulin intrathecal synthesis, cerebrospinal fluid (CSF) chitinase 3-like 1 (CHI3L1), and neurofilament light protein (NFL) and reviewed MRI to detect leptomeningeal contrast enhancement (LMCE). We compared time to Expanded Disability Status Scale (EDSS) 3 and to initiation of high-efficacy disease-modifying therapies (heDMTs) by multivariate Cox regression analysis. Median KFLC-index correlated with IgG/IgM indexes (p < 0.0001/p < 0.05) and IgG-oligoclonal bands (OCGBs) (p < 0.001). Patients with IgM-oligoclonal bands (OCMBs) had a higher KFLC-index (p = 0.049). KFLC-index was higher in patients with LMCE (p = 0.008) and correlated with CHI3L1 (p = 0.007), but disease activity had no effect on its value. Bivariate and multivariate analyses confirmed KFLC-index > 58 as an independent risk factor for reaching an EDSS of 3 (hazard ratio (HR) = 12.4; 95% CI = 1.1-147; p = 0.047) and for the need of treatment with heDMTs (HR = 3.0; 95% CI = 1.2-7.1; p = 0.0013). To conclude, our data suggest a potential prognostic role of the KFLC-index during the MS course.

Keywords: CHI3L1; ectopic lymphoid follicles; high-efficacy disease-modifying therapies; oligoclonal band; prognostic factor.

Figure 1

Association of KFLC-index with other diagnostic and prognostic MS biomarkers. (A) Correlation between KFLC-index and IgG index. (B) KFLC-index was significantly increased in the presence of OCGBs with respect to patients without intrathecal immunoglobulin synthesis. KFLC-index tended to be higher in the presence of both OCGBs and OCMBs but did not correlate with concurrence of clinical relapse (C) or presence of GEL (D). (E) KFLC-index did not correlate with CSF NFL but did weakly with CSF CHI3L1 and IgM index [(F, G), respectively]. (H) Patients with LMCE had higher median values of KFLC-index. Kappa index, kappa free light chain (KFLC) index; OCB, oligoclonal band; GEL, gadolinium-enhanced lesions; NFL, neurofilament light chain protein; CSF, cerebrospinal fluid; CHI3L1, chitinase 3-like 1; LMCE, leptomeningeal contrast enhancement; MS, multiple sclerosis. n.s., not significant.

Figure 2

Bivariate and multivariate regression models for predicting the risk of reaching EDSS score of 3 and of treatment escalation. (A) Kaplan–Meier survival analysis showing the probability for reaching an EDSS of 3 stratified by KFLC-index value of 58. (B) Forest plot of multivariate analysis for the same disability endpoint adjusted for sex, baseline age, and baseline EDSS. (C) Kaplan–Meier survival analysis showing the probability for treatment escalation to heDMT stratified by KFLC-index value of 58. (D) Forest plot of multivariate analysis for the same disability endpoint adjusted for sex, baseline age, and baseline EDSS. KFLC-index, kappa free light chain index; EDSS, expanded disability severity score; heDMT, high-efficacy disease-modifying therapy.