Clinical Use of κ Free Light Chains Index as a Screening Test for Multiple Sclerosis

Luisa Agnello, PhD; Bruna Lo Sasso, PhD; Giuseppe Salemi, MD; Patrizia Altavilla, BS; Emanuela Maria Pappalardo, BS; Rosalia Caldarella, BS; Francesco Meli, BS; Concetta Scazzone, BS; Giulia Bivona, MD; Marcello Ciaccio, MD, PhD

Disclosures

Lab Med. 2020;51(4):402-407. 

In This Article

Discussion

OCB detection is the criterion standard for CSF analysis in MS diagnosis because it reflects the intratechal Ig synthesis with high sensitivity. However, there is ongoing research into easily measurable biomarkers that could be used as first-line tests to stratify patients at a higher probability of MS who should be tested with a confirmatory assay such as OCB. Accordingly, κFLC stands out among MS biomarkers. Intratechal FLC production is an early phenomenon in MS.[15] Some evidence suggested a diagnostic role for quantitative κFLC evaluation in MS.[16,17] Although κFLC can be measured by a rapid and automatized method, it has lower specificity than OCB detection.[18,19] Thus, it could be used as a screening tool to identify patients at higher probability of having MS, which would limit unnecessary OCB evaluation. Indeed, κFLCi should be regarded as an indicator of intratechal inflammation that results from several neuroinflammatory pathways.[20,21]

In this study, we tested the accuracy of κFLCi as a screening test for MS and OCB as a confirmatory test in cases of positive results. Accordingly, we propose a diagnostic algorithm for MS diagnosis based on the initial evaluation of κFLC index followed by OCB detection. This approach could have several advantages, such as a reduced turnaround time and lower costs, limiting the number of OCB analyses. In such a study, we would avoid 20% of OCB detection by applying the proposed algorithm. However, the current study was performed with a small sample size. Thus, we advocate for a larger study, to confirm our results and to support the diagnostic usefulness of applying the proposed algorithm.

Our ROC analysis results revealed an ideal κFLCi cutoff of 4.3 for distinguishing patients with MS from those with other NDs, with sensitivity of 94.8%. However, we also tested the use of a cutoff value of 2.9 to improve sensitivity (97.4%). Our results are in accordance with those reported by Valencia-Vera et al,[17] which proposed an algorithm based on the initial determination of κFLCi followed by OCB detection in cases selected according to κFLCi values. Moreover, the authors identified an optimal κFLCi cutoff value of 2.9 to distinguish MS from other neurological diseases but with lower sensitivity than the value found in our study (83.7% vs 97.4%) Pressaleur and colleagues[22] found that a κFLCi cutoff value of 5.9 was associated with sensitivity of 93% for detecting MS. Recently, Emersic et al[19] reported an optimal cutoff value for κFLCi of 5.3, with sensitivity of 96%. Right now, there is no consensus on the best κFLCi cutoff values for the diagnosis of MS,[17,23,24] so we advocate for international standardization.

There is heated debate regarding whether the measurement of κFLC could be used as an alternative test to or in combination with OCB detection for MS diagnosis.[25,26] Crespi et al[27] estimated the costs of a different diagnostic approach for MS based on the application of κFLCi by itself or combination with OCB detection. In particular, they considered 4 scenarios: OCB detection only, κFLC index only, κFLC index and OCB detection in all patients, and κFLC index followed by OCB detection for all patients testing positive for MS. The authors concluded that the sequential use of κFLC and OCB detection should be preferred.

Based on reports in the present literature, κFLC represents a reliable, easy-to-perform quantitative method to assess intratechal IgG synthesis. Together with OCB detection, it could support the diagnosis of MS, especially when clinical examination finding and imaging findings are inconclusive.

It should be considered that κFLC measurement is affected by certain analytical concerns, such as potential overestimation of κFLC levels due to the presence of polymeric FLC that can arise from the aggregation of oligomeric complexes.[28] This observation, together with the results of our study, supports the combined sequential use of κFLC and OCB. Nevertheless, the approach of using κFLCi as a screening test is suboptimal due to the presence of a low percentage of false-negative results. We consider it noteworthy that in our study findings, only 1 patient with MS tested negative for κFLCi and OCB, the latter of which represents the criterion standard for MS diagnosis. Thus, biochemical analysis should be always interpreted in relation to clinical context. Also, if a high suspicion of MS still exists in presence of a negative κFLCi result, further evaluation with clinical/imaging tests is recommended.

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