Kappa free light chains is a valid tool in the diagnostics of MS: A large multicenter study

Leurs, Cyra E.; Twaalfhoven, Harry; Lissenberg‐Witte, Birgit I.; Pesch, Vincent Van; Dujmović, Irena; Drulović, Jelena; Castellazzi, Massimiliano; Bellini, Tiziana; Pugliatti, Maura; Kuhle, Jens; Villar, Luisa María; Álvarez‐Cermeño, José C.; Álvarez‐Lafuente, Roberto; Hegen, Harald; Deisenhammer, Florian; Walchhofer, Lisa-Maria; Thouvenot, Éric; Comabella, Manuel; Montalbán, Xavier; Vécsei, László; Rajda, Cecília; Galimberti, Daniela; Scarpini, Elio; Altıntaş, Ayşe; Rejdak, Konrad; Frederiksen, Jette Lautrup; Pihl-Jensen, Gorm; Jensen, Poul Erik; Khalil, Michael; Voortman, Margarete; Fazekas, Franz; Sáiz, Albert; Puma, Delón La; Vercammen, Martine; Vanopdenbosch, Ludo; Uitdehaag, Bernard M. J.; Killestein, Joep; Bridel, Claire; Teunissen, Charlotte E.

doi:10.1177/1352458519845844

Cited by 66 publications

(84 citation statements)

References 36 publications

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“…Indeed, kappa index values >5.8 were present in one quarter of OCB-negative patients with MS and 98% of OCB-positive MS controls. An additional qualitative analysis, based on literature-derived [5,24] threshold values (5.9 and 6.6), confirmed our data with 24% and 22% of OCB-negative patients with MS, respectively, having kappa index values above these thresholds.…”

Section: Discussionsupporting

confidence: 85%

“… established a cut‐off value of 5.9 in a study on 438 patients and Leurs et al. calculated a cut‐off value of 6.6 in a very recent multicentre study on 745 patients.…”

Section: Discussionmentioning

confidence: 99%

“…5.8, is within this range and is very similar to that found in the two largest studies on this topic. Presslauer et al [5] established a cut-off value of 5.9 in a study on 438 patients and Leurs et al [24] calculated a cut-off value of 6.6 in a very recent multicentre study on 745 patients.…”

Section: Discussionmentioning

confidence: 99%

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Cerebrospinal fluid kappa and lambda free light chains in oligoclonal band‐negative patients with suspected multiple sclerosis

Ferraro

Trovati

Bedin

et al. 2019

Euro J of Neurology

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Background and purpose Cerebrospinal fluid (CSF) kappa free light chains (FLCs) may be a more sensitive marker of intrathecal immunoglobulin (Ig)G synthesis compared with oligoclonal bands (OCBs). Our aim was to retrospectively determine the additional value of the kappa and lambda index (CSF FLC/serum FLC)/(CSF albumin/serum albumin) in predicting a multiple sclerosis (MS) diagnosis in a group of OCB‐negative patients with suspected MS. Methods The CSF and serum kappa and lambda FLCs were tested using the Freelite kit (serum) and Freelite Mx (CSF) assay (The Binding Site Group, Bimingham, UK) in 391 OCB‐negative patients with suspected/possible MS and in 54 OCB‐positive patients with MS. Results The CSF kappa FLC levels were below the detection limit (0.27 mg/L) in 61% of patients. Using quantitative data, we found the best kappa index cut‐off value for the prediction of MS to be 5.8. A kappa index ≥5.8 was present in 25% of OCB‐negative MS (23/92) and in 98% of OCB‐positive patients with MS. Using a qualitative approach and a kappa index cut‐off of 5.9, based on literature data, we likewise found that 24% of OCB‐negative patients with MS had a kappa index ≥5.9, compared with 5.4% of OCB‐negative patients without MS (P < 0.001). No reliable data could be obtained for the lambda index; lambda FLCs were below the detection limit (0.68 mg/L) in 90% of CSF samples. Conclusions The kappa index could contribute to the identification of OCB‐negative patients with a high probability of an MS diagnosis. Using more sensitive techniques might even improve the diagnostic performance of the kappa index and better define the role of the lambda index.

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Section: Discussionsupporting

confidence: 85%

“… established a cut‐off value of 5.9 in a study on 438 patients and Leurs et al. calculated a cut‐off value of 6.6 in a very recent multicentre study on 745 patients.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Cerebrospinal fluid kappa and lambda free light chains in oligoclonal band‐negative patients with suspected multiple sclerosis

Ferraro

Trovati

Bedin

et al. 2019

Euro J of Neurology

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“…We compared four different methods to assess an intrathecal synthesis of KFLC in order to help standardize this promising biomarker for the diagnosis of MS. Although measurement of KFLC is easy to perform, it has not yet found its way into clinical routine [9,17]. One of the reasons might be the disagreement about the "correct" cut-off for the KFLC index, which is used to determine the intrathecal produced KFLC fraction [9,17].…”

Section: Discussionmentioning

confidence: 99%

“…Although measurement of KFLC is easy to perform, it has not yet found its way into clinical routine [9,17]. One of the reasons might be the disagreement about the "correct" cut-off for the KFLC index, which is used to determine the intrathecal produced KFLC fraction [9,17]. In addition to the inconsistent use of KFLC index cut-off values, a CSF/serum index reflects the non-linear relationship between blood-derived molecules of different size only inaccurate [1].…”

Section: Discussionmentioning

confidence: 99%

Reiber’s Diagram for Kappa Free Light Chains: The New Standard for Assessing Intrathecal Synthesis?

et al. 2019

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Oligoclonal bands are the gold standard for determination of an intrathecal immunoglobulin G synthesis and were recently included in the McDonald criteria of 2017 to diagnose relapsing multiple sclerosis (MS) as a substitute for dissemination in time. Intrathecally produced kappa free light chains (KFLC) are a novel promising biomarker with similar characteristics and the advantage for automated determination. However, different approaches exist to determine the intrathecal KFLC fraction. The most common method is to calculate the CSF/serum KFLC quotient with reference to the albumin CSF/serum quotient (QKappa/QAlb) the so-called KFLC index. Recently, Reiber developed a theoretically and empirically founded hyperbolic function similar to his traditional hyperbolic function for the immunoglobulins A, G, M. Our study included a total of 168 patients with either MS according to the McDonald criteria of 2017, clinically isolated syndrome (CIS) with conversion to MS during follow-up, or stable CIS. Positive oligoclonal bands were compared with the KFLC index, Reiber’s KFLC diagram, Presslauer’s KFLC exponential curve, and Senel’s linear curve for KFLC. Reiber’s diagram detected an intrathecal production of KFLC in 98/100 patients with MS, only one patient fewer than oligoclonal bands positivity (99/100). By using the KFLC index ≥ 5.9, Presslauer’s KFLC exponential function, and Senel’s linear curve two more patients would not have been identified (96/100). For the group of patients who converted from CIS to MS similar results were obtained for both the oligoclonal bands and the Reiber graph (21/24, 88%). The KFLC index ≥ 5.9, Presslauer’s method, and Senel’s linear function each identified two patients fewer (19/24, 79%). In patients with stable CIS, 11/44 patients (25%) displayed oligoclonal bands in contrast to 9/44 patients (20%) with elevated KFLC by using Reiber’s diagram and Presslauer’s method, 8/44 patients (18%) with elevated KFLC as detected by Senel’s linear function, and 7/44 patients (16%) with KFLC index ≥ 5.9. In conclusion, Reiber’s KFLC diagram shows a great diagnostic performance to detect an intrathecal KFLC production in patients with MS.

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Stereotyped B‐cell responses are linked to IgG constant region polymorphisms in multiple sclerosis

et al. 2022

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Clonally related B cells infiltrate the brain, meninges, and cerebrospinal fluid of MS patients, but the mechanisms driving the B-cell response and shaping the immunoglobulin repertoires remain unclear. Here, we used single-cell full-length RNA-seq and BCR reconstruction to simultaneously assess the phenotypes, isotypes, constant region polymorphisms, and the paired heavy-and light-chain repertoires in intrathecal B cells. We detected extensive clonal connections between the memory B cell and antibody-secreting cell (ASC) compartments and observed clonally related cells of different isotypes including IgM/IgG1, IgG1/IgA1, IgG1/IgG2, and IgM/IgA1. There was a strong dominance of the G1m1 allotype constant region polymorphisms in ASCs, but not in memory B cells. Tightly linked to the G1m1 allotype, we found a preferential pairing of the immunoglobulin heavy-chain variable (IGHV)4 gene family with the κ variable (IGKV)1 gene family. The IGHV4-39 gene was most used and showed the highest frequency of pairing with IGKV1-5 and IGKV1(D)-33. These results link IgG constant region polymorphisms to stereotyped B-cell responses in MS and indicate that the intrathecal B-cell response in these patients could be directed against structurally similar epitopes.

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Kappa free light chains is a valid tool in the diagnostics of MS: A large multicenter study

Cited by 66 publications

References 36 publications

Cerebrospinal fluid kappa and lambda free light chains in oligoclonal band‐negative patients with suspected multiple sclerosis

Cerebrospinal fluid kappa and lambda free light chains in oligoclonal band‐negative patients with suspected multiple sclerosis

Reiber’s Diagram for Kappa Free Light Chains: The New Standard for Assessing Intrathecal Synthesis?

Stereotyped B‐cell responses are linked to IgG constant region polymorphisms in multiple sclerosis

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