Dr. Hegen and coauthors performed a systematic review and meta-analysis to evaluate whether the κ-FLC index has similar diagnostic value in identifying patients with clinically isolated syndrome (CIS) or MS compared with oligoclonal bands and to determine the κ-FLC index cutoff (Hegen H, et al. Mult Scler. 2023;29[2]:169–181). Thirty-two κ-FLC studies were included in their meta-analysis.
They found that the diagnostic sensitivity and specificity for the κ-FLC index ranged from 52 percent to 100 percent (weighted average: 88 percent) and 69 percent to 100 percent (weighted average: 89 percent), respectively. For oligoclonal banding, sensitivity ranged from 37 percent to 100 percent (weighted average: 85 percent) and specificity from 74 percent to 100 percent (weighted average: 92 percent).
“The sensitivity is quite comparable,” Dr. Hegen said, as is the specificity.
Because of heterogeneity among the studies, he and his coauthors performed a power analysis for a bivariate mixed model to ensure a valid interpretation for not statistically significant differences. “We could show with a quite high statistical power of 99 percent—by including more than 3,300 CIS/MS patients and more than 5,800 controls—that there’s basically no difference in the diagnostic value, in the diagnostic sensitivity and specificity, between kappa free light chain index and oligoclonal bands to identify MS patients and to discriminate them from other neurological diseases,” Dr. Hegen said.
To differentiate CIS/MS patients from controls, a discriminatory cutoff for the κ-FLC index was determined to be 6.1.
Many of the studies in the meta-analysis were confined to patients with relapsing-remitting MS, which affects 85 percent of patients, he said. “So we were also interested in the other 15 percent of MS patients with a primary progressive disease course.” They conducted a multicenter study in which 174 patients with primary progressive MS were recruited from 11 MS centers in seven countries. Using a cutoff of 6.1, the κ-FLC index was positive in 161 patients (93 percent). Oligoclonal bands were positive in 153 patients (88 percent) (Hegen H, et al. Front Immunol. 2023;14:1327947).
In the same study, they also looked at the agreement between positive and negative κ-FLC index (using the 6.1 cutoff) and positive and negative oligoclonal bands, “and the agreement was quite good at 90 percent,” Dr. Hegen said. When they allowed a site-specific cutoff for the κ-FLC index to define positivity and negativity (each site’s cutoff was slightly different), the agreement with oligoclonal bands was also good, at 89 percent, and confirmed by other studies.
“The reason for this good agreement in some range independent of the cutoff is that most of the MS patients are clearly positive, with kappa free light chain index values of 20, 30, up to 100 or even higher, and the controls are clearly below the cutoff of 6.1,” Dr. Hegen said. “So we have a good discrimination between patients and controls” (Arrambide G, et al. Brain. 2022;145[11]:3931–3942).
Kappa free light chain is also a robust biomarker, he said. “We have in CSF diagnostics, in up to 20 percent of cases, the issue of a dramatic lumbar puncture,” with blood contamination of the CSF. “And we know that in a case of blood contamination, we can have false-positive results, especially for IgA and IgM,” he said. “But this is not the case for the kappa free light chains. So the intrathecal kappa free light chain synthesis is largely independent of blood contamination of CSF” (Hannich MJ, et al. Cells. 2021;10[3]:616).
In addition, CSF κ-FLC concentration is not directly affected by renal function. “We know there is a correlation between decreased renal function and serum kappa free light chains,” Dr. Hegen said, “and when we look at CSF levels, there is also a correlation between decreased renal function and high CSF kappa free light chains on the first view.”
He and colleagues hypothesized a causality: The decreased renal function has an impact on serum κ-FLC levels, and those levels influence the amount of CSF κ-FLC levels on the physiological conditions.