Kappa free light chains could predict early disease course in multiple sclerosis

doi:10.1016/j.msard.2019.02.001

Multiple Sclerosis and Related Disorders

Volume 30, May 2019, Pages 81-84

https://doi.org/10.1016/j.msard.2019.02.001 Get rights and content

Highlights

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Our study suggested kappa free light chains (KFLC) as a quantitative marker to predict early disability in multiple sclerosis (MS).
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KFLC resulted a significant predictor for disability over time and early treatment in MS.
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KFLC were not associated to known MS prognostic markers such as gender, age at onset, and enhancing lesions.
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KFLC are easy-detectable and quantitative, but not a substitute for OB.

Abstract

Background

Cerebrospinal fluid (CSF) kappa free light chains (KFLC) have been suggested as quantitative alternative to oligoclonal bands (OB) in multiple sclerosis (MS) diagnosis. Despite OB have been associated to poor disease prognosis, little is known on KFLC in predicting MS early progression. Our aim is to evaluate the prognostic value of KFLC in a cohort of Italian MS patients.

Methods

100 patients (64 females) underwent CSF analysis during their diagnostic MS work-up. We collected clinical/paraclinical features (gender, age at onset, clinical course, early MS treatments (within 1 year), gadolinium-enhancing (Gd+) lesions), calculated K index (ratio CSF-serum KFLC and albumin), and MS severity score (MSSS) at last follow up (minimum 1 year). Statistical analysis included Mann-Whitney descriptive analysis, Spearman correlation for independent samples, and linear regression for significant predictors.

Results

K index resulted a significant predictor for disability over time being higher in patients who developed greater MSSS. Accordingly, K index was also significantly increased in patients undergoing early versus delayed treatment (N = 50/100, p = 0.046). A similar role in predicting MS disability was confirmed for age at onset. No other factors were retained in our regression model. Of note, K index was not associated to known MS prognostic markers such as gender, age at onset, and Gd+ lesions (N = 31/96).

Conclusion

Our study suggests KFLC as a CSF quantitative marker to predict early disability in MS (despite not being a substitute for OB).

Introduction

Multiple sclerosis (MS) course presents a high variability among individuals ranging from a minimal disability over time to a rapid and severe progression (Tutuncu et al., 2013). Disease-modifying treatments (DMTs) with a different risk to benefit ratios impact on disease history, and the possibility of predicting early MS course is crucial. Many clinical and radiological factors at MS diagnosis have been related to MS prognosis, such as gender, age of onset, disability, number of relapses, magnetic resonance imaging (MRI) measures (Swanton et al., 2014, Wattjes et al., 2015). A similar role has been proposed for cerebrospinal fluid (CSF) biomarkers: notably the presence of oligoclonal IgG bands (OB) has been introduced in the 2017 McDonald criteria for dissemination in time (Thompson et al., 2018). Although OB have been related to clinical isolated syndromes (CIS) conversion to MS (Dobson et al., 2013), a role in predicting progression is still debated (Becker et al., 2015) especially if unrelated to clinical and radiological data (Moroso et al., 2015). Several authors considered not only the presence, but also the number of OB (Avasarala et al., 2001) as a marker for MS prognosis. Moreover, not only the presence of IgG but also of IgM OB at the time of diagnosis has been related to a worse outcome (Mandrioli et al., 2008). However, OB remain a mainly qualitative measure of intrathecal synthesis whose result could be also influenced by operator interpretation (Gastaldi et al., 2017). CSF immunoglobulin free light chains (FLC) have been suggested as quantitative alternative to OB in MS diagnosis (Crespi et al., 2017). CSF-serum ratio of kappa FLC corrected for albumin ratio (Presslauer et al., 2016) has been demonstrated as a valid and rather-independent tool alternative to OB detection in CIS and MS patients. Despite OB were associated to poor disease prognosis, little is known on FLC in predicting MS early progression (Rathbone et al., 2018) and could probably not be related to lesion load (Voortman et al., 2017). Our aim was to evaluate the prognostic value of KFLC in a cohort of Italian MS patients who underwent lumbar puncture in their diagnostic MS work-up.

Section snippets

Methods

We recruited 100 patients (64 females) who underwent lumbar puncture (LP) in their diagnostic MS work-up including who: 1) had a CSF study at the time of their MS work up including OB and FLC measures. 2) had a diagnosis of CIS or MS according to McDonald 2017. 3) had a minimum follow up from LP of 1 year. Control population included 97 neurological non-inflammatory diseases excluding lympho-proliferative disorders.

Demographic and clinical variables at diagnosis were recorded: gender, age at

Results

Baseline features are summarized in Table 1. Median age at onset was 34.4 years (SD ± 10.7). MS course at diagnosis was: 2 radiological isolated syndromes (RIS), 9 CIS, 84 relapsing-remitting (RR) MS, and 5 progressive (PR) MS. Median time from onset to last follow up was 3.9 years (±5.0).

Overall, 92 patient had intrathecal synthesis, 5 had no or indistinct bands, and 3 had similar bands both in serum and CSF; median number of CSF bands was 13 (range 0–42). Mean K index 68.2 (SD 84.4) and CSF

Discussion

Our data suggest a prognostic role of K index for developing early disability in MS: this quantitative marker of intrathecal synthesis showed a direct correlation with MSSS and could be effective in stratifying the risk among those patients who had classically defined OB. In fact, we also confirmed the correlation of disability and OB that remains an established but qualitative and frequent marker to intrathecal synthesis. Notably, the number of bands or CSF IgG did not relate to MSSS in our

Conclusion

We suggest a prognostic value of intrathecal synthesis using K index in terms of disability over time. This quantitative marker is not a substitute for OB in MS diagnosis, but could help also in differentiating patients with intrathecal synthesis according the risk of severe outcomes.

Acknowledgements

None.

Conflict of interest

Dr. Vecchio received a Merk-Serono fellowship.

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Prognostic value of cerebrospinal fluid biomarkers in multiple sclerosis: The key role of kappa free light chains and a multivariate predictor for disease progression
2024, Multiple Sclerosis and Related Disorders
Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the central nervous system with varying progression rates among individuals. The ability to predict disease progression is crucial for treatment decisions with disease-modifying therapies (DMTs). A few cerebrospinal fluid (CSF) biomarkers have been investigated in relation to disease progression, but few have been effectively translated into clinical practice. The aim of this study was to evaluate the diagnostic and prognostic value of known CSF markers, to compare their sensitivity and specificity, and to develop a prognostic model using a combination of markers to predict disease progression.
This retrospective cohort study included 82 patients with a first episode of inflammatory demyelinating symptoms suggestive of MS between January 2018 and January 2021. Patients underwent diagnostic lumbar puncture and other investigations according to the multiple sclerosis (MS) protocol. They were divided into three groups according to MRI findings, relapse rate and EDSS score. CSF marker concentrations were determined by laser nephelometry and electrochemiluminescence immunoassay.
The results showed that the number of oligoclonal bands could discriminate the progression-free group from the other groups, but had a lower discriminatory power compared to CSF marker concentrations. Among CSF markers, FLC kappa showed the best discriminatory performance. By combining FLC kappa with gender and lesion localization information, a simple predictor of progression-free group membership was proposed. This predictor showed good sensitivity (91 %) and specificity (65 %).
In conclusion, CSF FLC kappa concentration, together with gender and lesion localization, may be a valuable predictor of disease progression in MS patients. This study highlights the potential of using CSF biomarkers for prognostic purposes and offers a simple approach to predicting disease progression.
Free light chains as a reliable biomarker of intrathecal synthesis in the diagnosis of CNS inflammatory diseases
2023, Journal of Neuroimmunology
To address the diagnostic performances of cerebrospinal fluid (CSF) free light chains (FLC) measurements compared to oligoclonal bands (OCB) to support multiple sclerosis (MS) diagnosis.
kFLC index showed the highest diagnostic accuracy to detect MS patients with the highest AUC compared to OCB, IgG index, IF kFLC R, kFLC H, λFLC index and IF λFLC.
FLC indices are biomarkers of intrathecal Immunoglobulin synthesis and central nervous system (CNS) inflammation. kFLC index can discriminate between MS and other CNS inflammatory disorders, while λFLC index is less informative for MS but can play a role to support the diagnosis of other inflammatory CNS disorders.
Biomarkers in multiple sclerosis
2023, Translational Neuroimmunology: Multiple Sclerosis: Volume 8
The search for biomarkers in multiple sclerosis (MS) is a wide area of interest, due to the complexity and unpredictability of the disease: from pathogenesis and disease course further down to treatment options. In the last few decades, the use of cerebrospinal fluid (CSF) biomarkers has become a staple in MS diagnosis, especially after the reintroduction of CSF study in the latest diagnostic criteria. On the other hand, evidence on serum biomarkers is rapidly growing, suggesting their potential future applications in clinical practice, as is the case with serum neurofilaments. In this chapter, we discuss the main biological markers, chosen by their utility in MS prediction, diagnosis, prognosis, disease activity, and treatment management.
K index utility as diagnostic and prognostic biomarker in the assessment of patients with suspected Multiple Sclerosis
2022, Journal of Neuroimmunology
Citation Excerpt :
EDSS at the last follow-up was used to derivate MS Severity Score (MSSS) (Roxburgh et al., 2005). Decision of the expert treating neurologist (who was never aware of FLC values) of introduction of DMT according to the rules of best clinical practice was used as a further surrogate marker of disease severity (Vecchio et al., 2019). Anonymised matched CSF and serum samples of each patient were centrifuged for 10 min at 3000g and 2000 g, respectively, and stored at −20° until analysis, according to standardized methods (Valencia-Vera et al., 2018; Bernardi et al., 2021).
The aim of the present study is to evaluate the composite role of k index in the initial assessment of Multiple Sclerosis (MS) patients and to select useful cut-offs exportable in clinical practice. We analysed CSF/serum samples of 140 patients and followed-up the CIS/MS subgroup for 7 years. Our results suggest κ index as a quantitative diagnostic and prognostic biomarker in MS, significantly associated to baseline lesion load and to successive clinical course. We propose k index ≥106 as a prognostic cut-off to select patients at major risk of relapse, potentially influencing initial therapeutic decisions.
Mono/polyclonal free light chains as challenging biomarkers for immunological abnormalities
2022, Advances in Clinical Chemistry
Citation Excerpt :
Increased FLC indices were shown to correctly identified patients with high conversion risk to multiple sclerosis and predicted time of conversion from CIS [122]. Some have suggested that the FLC index may represent a reliable marker of humoral immune response to facilitate treatment [123]. Technically, the FLC index provides a rapid, robust and quantitative approach that is automated in most clinical laboratories thus providing excellent inter-facility correlation [118] at low cost (vs OCB) [115].
Free light chain (FLC) kappa (k) and lambda (λ) consist of low molecular weight proteins produced in excess during immunoglobulin synthesis and secreted into the circulation. In patients with normal renal function, over 99% of FLCs are filtered and reabsorbed. Thus, the presence of FLCs in the serum is directly related to plasma cell activity and the balance between production and renal clearance. FLCs are bioactive molecules that may exist as monoclonal (m) and polyclonal (p) FLCs. These have been detected in several body fluids and may be key indicators of ongoing damage and/or illness. International guidelines now recommend mFLC for screening, diagnosis and monitoring multiple myeloma and other plasma cell dyscrasias. In current clinical practice, FLCs in urine indicate cast nephropathy and other renal injury, whereas their presence in cerebrospinal fluid is important for identifying central nervous system inflammatory diseases such as multiple sclerosis. Increased pFLCs have also been detected in various conditions characterized by B cell activation, i.e., chronic inflammation, autoimmune disease and HCV infection. Monitoring the coronavirus (COVID-19) pandemic by analysis of salivary FLCs presents a significant opportunity in clinical immunology worthy of scientific pursuit.
Cerebrospinal Tau levels as a predictor of early disability in multiple sclerosis
2021, Multiple Sclerosis and Related Disorders
Axonal loss is an important feature of Multiple Sclerosis (MS), being strongly related to irreversible disability accumulation. Nonetheless, the exact mechanisms underlying axonal loss remain unclear. Cerebrospinal fluid (CSF) levels of Tau and Beta-amyloid (Abeta) currently represent diagnostic biomarkers in other neurodegenerative diseases. In MS, studies on CSF Tau and Abeta provided preliminary informations on disease prognosis, but results have not yet been replicated.
We investigated whether CSF Tau and Abeta levels could predict early disability accumulation in MS patients. 100 patients underwent CSF analysis during their diagnostic work-up. Demographic, clinical, radiological features and CSF were collected at baseline. MS severity score (MSSS) and age-related MSSS (ARMSS) were calculated at last follow-up. We performed Mann–Whitney test, Spearman's coefficient, and multiple regression analysis for significant predictors of disability based on CSF Abeta and Tau levels, gender, age at diagnosis and MRI characteristics at baseline.
Baseline CSF Tau levels moderately correlated with MSSS (r=0.372 p=0.0001) and weakly with ARMSS (r=0.237 p=0.0176) after a mean two years follow-up. Predictors of early disability evaluated with MSSS and ARMSS were CSF Tau (Beta:0.258 p=0.009 and Beta:0.252 p=0.01) and spinal cord involvement (Beta:0.196 p=0.029 and Beta:0.240 p=0.008); as well as age at MS diagnosis (Beta:0.286 p=0.001) for MSSS, and high brain lesion load (Beta:0.207 p=0.02) for ARMSS.
CSF Tau levels at diagnosis possibly has a predictive value along with MRI features and age at diagnosis. We hypothesize that Tau levels may express chronic axonal damage, possibly contributing to early MS disability.

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View full text

Kappa free light chains could predict early disease course in multiple sclerosis

Highlights

Abstract

Background

Methods

Results

Conclusion

Introduction

Section snippets

Methods

Results

Discussion

Conclusion

Acknowledgements

Conflict of interest

Lancet

J. Neurol. Sci.

Mult. Scler. Relat. Disord.

Handb. Clin. Neurol.

Lancet Neurol.

Clin. Chim. Acta.

Oligoclonal band number as a marker for prognosis in multiple sclerosis.

Arch. Neurol.

No prognostic value of routine cerebrospinal fluid biomarkers in a population-based cohort of 407 multiple sclerosis patients.

BMC Neurol.

Combined use of kappa free light chain index and isolectrofocusing of cerebro-spinal fluid in diagnosing multiple sclerosis: performance and costs.

Clin. Lab.

Cerebrospinal fluid oligoclonal bands in multiple sclerosis and clinically isolated syndromes: a meta-analysis of prevalence, prognosis and effect of latitude.

J. Neurol. Neurosurg. Psychiatry

Intrathecal oligoclonal bands synthesis in multiple sclerosis: is it always a prognostic factor?

J. Neurol.

Cerebrospinal fluid analysis and the determination of oligoclonal bands.

Neurol. Sci.