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Meta-Analysis
. 2023 Feb;29(2):169-181.
doi: 10.1177/13524585221134213. Epub 2022 Dec 1.

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

Harald Hegen  1 , Janette Walde  2 , Klaus Berek  1 , Georgina Arrambide  3 , Sharmilee Gnanapavan  4 , Batia Kaplan  5 , Michael Khalil  6 , Ruba Saadeh  7 , Charlotte Teunissen  8 , Hayrettin Tumani  9 , Luisa M Villar  10 , Maria Alice V Willrich  11 , Henrik Zetterberg  12 , Florian Deisenhammer  1
Affiliations
Meta-Analysis

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

Harald Hegen et al. Mult Scler. 2023 Feb.

Abstract

Background: Intrathecal immunoglobulin-G synthesis is a hallmark of multiple sclerosis (MS), which can be detected by oligoclonal IgG bands (OCB) or by κ-free light chains (κ-FLC) in cerebrospinal fluid.

Objective: To perform a systematic review and meta-analysis to evaluate whether κ-FLC index has similar diagnostic value to identify patients with clinically isolated syndrome (CIS) or MS compared to OCB, and to determine κ-FLC index cut-off.

Methods: PubMed was searched for studies that assessed diagnostic sensitivity and specificity of κ-FLC index and OCB to discriminate CIS/MS patients from control subjects. Two reviewers following preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines performed study eligibility assessment and data extraction. Findings from studies were analyzed with bivariate mixed models.

Results: A total of 32 studies were included in the meta-analysis to evaluate diagnostic value of κ-FLC index. Sensitivity and specificity ranged from 52% to 100% (weighted average: 88%) and 69% to 100% (89%) for κ-FLC index and from 37% to 100% (85%) and 74% to 100% (92%) for OCB. Mean difference of sensitivity and specificity between κ-FLC index and OCB was 2 and -4 percentage points. Diagnostic accuracy determined by mixed models revealed no significant difference between κ-FLC index and OCB. A discriminatory cut-off for κ-FLC index was determined at 6.1.

Conclusion: The findings indicate that κ-FLC index has similar diagnostic accuracy in MS as OCB.

Keywords: Cerebrospinal fluid; biomarker; clinically isolated syndrome; diagnosis; index; intrathecal fraction; kappa free light chains; meta-analysis; multiple sclerosis; systematic review.

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Conflict of interest statement

Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: HH has participated in meetings sponsored by, received speaker honoraria or travel funding from Bayer, Biogen, Celgene, Merck, Novartis, Sanofi-Genzyme, Siemens, Teva, and received honoraria for acting as consultant for Biogen, Celgene, Novartis and Teva. GA has received speaking honoraria and compensation for consulting services or participation in advisory boards from Sanofi, Merck, Roche and Horizon Therapeutics; travel funding from Novartis, Roche and ECTRIMS; is the editor for Europe of Multiple Sclerosis Journal—Experimental, Translational and Clinical; and is a member of the International Women in Multiple Sclerosis (iWiMS) network executive committee. KB has participated in meetings sponsored by, received speaking honoraria or travel funding from Roche, Biogen, Sanofi, and Teva. SG has received speaker honoraria and has been a member of scientific boards for Biogen Idec, Genzyme, Novartis, and Merck and received grant funding from Genzyme, Merck and Takeda. MK has received funding for travel and speaker honoraria from Bayer, Novartis, Merck, Biogen Idec and Teva Pharmaceutical Industries Ltd. and serves on scientific advisory boards for Biogen Idec, Merck Serono, Roche, Novartis and Gilead. CT has a collaboration contract with ADx Neurosciences, Quanterix and Eli Lilly, performed contract research or received grants from AC-Immune, Axon Neurosciences, Bioconnect, Biogen, Biorchestra, Brainstorm Therapeutics, Celgene, EIP Pharma, Eisai, Novo Nordisk, PeopleBio, Roche, Toyama, and Vivoryon. She serves on editorial boards of Medidact Neurologie/Springer, Alzheimer Research and Therapy, Neurology: Neuroimmunology & Neuroinflammation, and is editor of a Neuromethods book Springer. Research of CET is supported by the European Commission (Marie Curie International Training Network, grant agreement no. 860197 (MIRIADE), Innovative Medicines Initiatives 3TR (Horizon 2020, grant no. 831434) and JPND (bPRIDE), National MS Society (Progressive MS alliance) and Health Holland, the Dutch Research Council (ZonMW), Alzheimer Drug Discovery Foundation, The Selfridges Group Foundation, Alzheimer Netherlands, Alzheimer Association. CT is recipient of ABOARD, which is a public–private partnership receiving funding from ZonMW (#73305095007) and Health~Holland, Topsector Life Sciences & Health (PPP-allowance; #LSHM20106). ABOARD also receives funding from Edwin Bouw Fonds and Gieskes-Strijbisfonds. HT has participated in meetings sponsored by or received honoraria for acting as an advisor/speaker for Alexion, Bayer, Biogen, Celgene, Fresenius, Genzyme-Sanofi, Janssen, Merck, Novartis, Roche, Siemens and Teva. LMV has served at scientific advisory boards, participated in meetings sponsored by, received speaking honoraria or travel funding or research grants from Roche, Sanofi, Merck, Biogen, Bristol Myers, and Novartis. MAVW has received research grants from The Binding Site, Siemens Healthineers and Sebia Inc, has participated in an advisory board for Myeloma360. HZ has served in scientific advisory boards and/or as a consultant for Abbvie, Alector, Annexon, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Pinteon Therapeutics, Red Abbey Labs, Passage Bio, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave; has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen, and Roche; and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). FD has participated in meetings sponsored by or received honoraria for acting as an advisor/speaker for Alexion, Almirall, Biogen, Celgene, Genzyme-Sanofi, Merck, Novartis Pharma, Roche, and Teva. His institution has received research grants from Biogen and Genzyme Sanofi. He is section editor of the MSARD Journal (Multiple Sclerosis and Related Disorders). JW, BK, and RS have nothing to disclose.

Figures

Figure 1.
Figure 1.
PRISMA flow diagram of study identification, screening, eligibility review, and selection for this systematic review and meta-analysis. PRISMA: preferred reporting items for systematic reviews and meta-analyses; CSF: cerebrospinal fluid; FLC: free light chain; MS: multiple sclerosis.
Figure 2.
Figure 2.
Forest plot of studies comparing the diagnostic accuracy of κ-FLC index and OCB. In the left column, forest plot of sensitivities for the studies included in the meta-analysis are shown for κ-FLC index (above) and OCB (below); in the right column forest plot of specificities for the studies included in the meta-analysis for κ-FLC index (above) and OCB (below) are provided. Confidence intervals are computed at a 95% confidence level. FLC: free light chain; OCB: oligoclonal band.
Figure 3.
Figure 3.
Comparison of the diagnostic accuracy of κ-FLC index with OCB to identify CIS/MS patients Bivariate summary estimates of sensitivity and specificity for κ-FLC index with OCB and the corresponding 95% confidence ellipse around these mean values are shown as well as the original data of the meta-analysis together with the corresponding sROC curves. FLC: free light chain; OCB: oligoclonal band; sROC: summary receiver operating curve; CIS: clinically isolated syndrome; MS: multiple sclerosis.
See this image and copyright information in PMC

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