High levels of kappa free light chain synthesis predict cognitive decline in relapsing-remitting multiple sclerosis.

Background: Evolving evidence suggests that measurement of cerebrospinal fluid (CSF) kappa free light chain (KFLC) synthesis has high diagnostic sensitivity and specificity for multiple sclerosis (MS), but its prognostic ability is less investigated. The usefulness of KFLC in predicting cognitive impairment (CI) is still unknown. Methods: In a monocentric longitudinal retrospecitve cohort study, KFLC-index ([CSF KFLC/serum KFLC]/[CSF albumin/serum albumin]) measured by latex-enhanced immunonephelometry was prospectively determined as part of the diagnostic workup in patients with early relapsing-remitting MS (RRMS, n=77). The ability of KFLC-index to predict information processing speed (IPS) worsening as assessed with the symbol digit modalities test (SDMT) was investigated in univariable and multivariable models. Results: In patients with KFLC-index>100 (n=31), 11 subjects (35.5%) showed reduced SDMT scores by ≥8 points at follow-up (mean follow-up time 7.3 ± 2.6 years), compared with their baseline scores (p=0.01). Baseline KFLC-index>100 was strongly associated with a higher hazard of SDMT score reduction at follow-up (adjusted hazard ratio 10.5, 95% confidence interval 2.2-50.8, p=0.003; median time to SDMT reduction 7 years). Conclusion: Intrathecal KFLC synthesis has become an attractive diagnostic tool for MS. We show for the first time that in a real-world setting of early RRMS, KFLC-index predicted cognitive decline. Whether this predictive ability of KFLC-index also concerns other cognitive domains than IPS, warrants further investigations.

Increased intrathecal neurofilament light and immunoglobulin M predict severe disability in relapsing-remitting multiple sclerosis.

Background: Emerging evidence supports that determination of intrathecal immunoglobulin M (IgM) synthesis (ITMS) and neurofilament light (NfL) concentration in cerebrospinal fluid (CSF) may be clinically useful as disease severity biomarkers in relapsing-remitting multiple sclerosis (RRMS). Methods: Monocentric observational longitudinal cohort study in which prospectively collected data were retrospectively retrieved. Included were patients with RRMS (n=457) who had a diagnostic investigation including analysis of ITMS and CSF neurofilament light (cNfL). ITMS was calculated with the linear index formula, the intrathecal fraction of IgM according to Reiber (IgMIF), and by qualitative determination of oligoclonal IgM bands (OCMB). Univariable and multivariable models were performed to predict Evidence of Disease Activity-3 (EDA-3) status within 24 months from onset, and the risk of Expanded Disability Status Score (EDSS) ≥3 and ≥6. Results: All investigated methods to calculate ITMS significantly predicted evidence of disease activity (EDA-3) within 24 months. IgMIF>0% showed the strongest association with EDA-3 status (adjusted hazard ratio [aHR] 3.7, 95%CI 2.7-5, p<0.001). Combining IgM-index>0.1 or OCMB with increased cNfL were strong predictors of EDSS≥3 (for cNfL + /IgM-index + : aHR 4.6, 95%CI 2.6-8.2, p<0.001) and EDSS≥6 (aHR 8.2, 95%CI 2.3-30, p<0.001). Conclusions: In a real-world setting, ITMS was a useful biomarker in early RRMS to predict disabling MS and its prognostic value was even stronger in combination with cNfL. Our data suggest that determination of ITMS and cNfL should be included in the diagnostic work-up of RRMS for prognostic purposes and in decisions of disease-modifying therapy.

Kappa free light chain index as a diagnostic biomarker in multiple sclerosis: A real-world investigation.

Kappa free light chain (KFLC) index, a measure for intrathecal production of free kappa chains, has been increasingly recognized for its diagnostic potential in multiple sclerosis (MS) as a quantitative alternative to IgG oligoclonal bands (OCBs). Our objective was to investigate the sensitivity, specificity, and overall diagnostic accuracy of KFLC index in MS. KFLC index was prospectively determined as part of the diagnostic workup in patients with suspected MS (n = 327) between May 2013 and February 2020. Patients with clinically isolated syndrome (CIS), radiologically isolated syndrome (RIS), and MS had markedly higher KFLC index (44.6, IQR 16-128) compared with subjects with other neuro-inflammatory disorders (ONID) and symptomatic controls (SC) (2.19, IQR 1.68-2.98, p < 0.001). KFLC index had a sensitivity of 0.93 (95% CI 0.88-0.95) and specificity of 0.87 (95% CI 0.8-0.92) to discriminate CIS/RIS/MS from ONID and SC (AUC 0.94, 95% CI 0.91-0.97, p < 0.001). KFLC index and intrathecal fraction (IF) KFLC had similar accuracies to detect MS. Treatment with disease-modifying therapy (DMT) did not influence the level of KFLC index and it was not affected by demographic factors or associated with degenerative or inflammatory biomarkers in cerebrospinal fluid (CSF). KFLC index in MS diagnostics has methodological advantages compared to OCB and is independent to subjective interpretation. Moreover, it is an attractive diagnostic tool since the diagnostic specificity and sensitivity of KFLC index are similar with that of OCBs and KFLCIF and better than for IgG index. We show that KFLC index was influenced neither by DMT nor by demographic factors or other inflammatory or degenerative processes in MS as determined by biomarkers in CSF.