Kappa Free Light Chain Biomarkers Are Efficient for the Diagnosis of Multiple Sclerosis

Abstract

Background and ObjectivesKappa free light chains (KFLC) seem to efficiently diagnose MS. However, extensive cohort studies are lacking to establish consensus cut-offs, notably to rule out non-MS autoimmune CNS disorders. Our objectives were to (1) determine diagnostic performances of CSF KFLC, KFLC index, and KFLC intrathecal fraction (IF) threshold values that allow us to separate MS from different CNS disorder control populations and compare them with oligoclonal bands' (OCB) performances and (2) to identify independent factors associated with KFLC quantification in MS.MethodsWe conducted a retrospective multicenter study involving 13 French MS centers. Patients were included if they had a noninfectious and nontumoral CNS disorder, eligible data concerning CSF and serum KFLC, albumin, and OCB. Patients were classified into 4 groups according to their diagnosis: MS, clinically isolated syndrome (CIS), other inflammatory CNS disorders (OIND), and noninflammatory CNS disorder controls (NINDC).ResultsOne thousand six hundred twenty-one patients were analyzed (675 MS, 90 CIS, 297 OIND, and 559 NINDC). KFLC index and KFLC IF had similar performances in diagnosing MS from nonselected controls and OIND (p= 0.123 andp= 0.991 for area under the curve [AUC] comparisons) and performed better than CSF KFLC (p< 0.001 for all AUC comparisons). A KFLC index of 8.92 best separated MS/CIS from the entire nonselected control population, with better performances than OCB (p< 0.001 for AUC comparison). A KFLC index of 11.56 best separated MS from OIND, with similar performances than OCB (p= 0.065). In the multivariate analysis model, female gender (p= 0.003), young age (p= 0.013), and evidence of disease activity (p< 0.001) were independent factors associated with high KFLC index values in patients with MS, whereas MS phenotype, immune-modifying treatment use at sampling, and the FLC analyzer type did not influence KFLC index.DiscussionKFLC biomarkers are efficient tools to separate patients with MS from controls, even when compared with other patients with CNS autoimmune disorder. Given these results, we suggest using KFLC index or KFLC IF as a criterion to diagnose MS.Classification of EvidenceThis study provides Class III evidence that KFLC index or IF can be used to differentiate patients with MS from nonselected controls and from patients with other autoimmune CNS disorders.

Cerebrospinal fluid kappa free light chains for the diagnosis of multiple sclerosis: A systematic review and meta-analysis

“…9 Another very recent large multicenter study including more than 1600 patients also reported that κ-FLC index and IF κ-FLC performed slightly better than absolute CSF κ-FLC concentration. 62 Further studies are required to compare the different κ-FLC measures in patients with varying degree of intrathecal B cell activity and varying blood–CSF-barrier function.…”

“…We did not find a statistically significant impact of assay and platform on κ-FLC index, in line with a recent large multicentre study that also did not observe any impact of the platform on κ-FLC index. 62 Using the ratio of the CSF and serum κ-FLC concentration (for calculating the index) might be less prone to laboratory variations. The potentially different susceptibility of κ-FLC index and absolute CSF κ-FLC concentrations to laboratory variation should be further addressed.…”

Biomarkers in autoimmune diseases of the central nervous system

“…The index is obtained by linear modeling to calculate the concentration of KFLC in serum and CSF. The formula of KFLC index is: FLC index = Q FLC/ Q alb with Q FLC = CSF FLC/serum FLC and Q alb = CSF albumin/serum albumin ( 47 ). Similar to CSF KFLC, KFLC index is better than OCB in the diagnosis of MS and differentiation of MS and other inflammatory CNS disorders ( 44 , 47 , 48 ), so KFLC index may replace OCB as a first-line biomarker of MS in clinical practice.…”

“…The formula of KFLC index is: FLC index = Q FLC/ Q alb with Q FLC = CSF FLC/serum FLC and Q alb = CSF albumin/serum albumin ( 47 ). Similar to CSF KFLC, KFLC index is better than OCB in the diagnosis of MS and differentiation of MS and other inflammatory CNS disorders ( 44 , 47 , 48 ), so KFLC index may replace OCB as a first-line biomarker of MS in clinical practice. The early initiation of DMDs in MS is important to slow down progression in disability and cognitive impairment.…”

Cerebrospinal fluid kappa free light chains for the diagnosis of multiple sclerosis: A consensus statement

“…A very recent large multicenter study including more than 1600 patients also reported that κ-FLC index and IF κ-FLC performed slightly better than absolute CSF κ-FLC concentration. 63 Further studies are required to compare the different κ-FLC measures in patients with varying degrees of intrathecal B-cell activity, varying blood-CSF-barrier function and varying serum κ-FLC concentrations, as the impact of grossly elevated serum FLC levels or elevated Q alb has not been sufficiently investigated. This might be of interest also in terms of differential diagnosis, as, for example, NMOSD sometimes shows considerable blood-CSF-barrier dysfunction, 13 which might lead to higher diffusion of κ-FLC from the blood into CSF and possibly to false-positive results if only absolute CSF κ-FLC concentrations are measured.…”