Intrathecal kappa free light chain synthesis is associated with worse prognosis in relapsing–remitting multiple sclerosis

Abstract

Background While kappa free light chain (KFLC) index has become a useful diagnostic biomarker in multiple sclerosis (MS), its prognostic properties are less explored. B cells play a crucial role in MS pathogenesis, but the impact from increased intrathecal production of immunoglobulins and KFLC remains to be determined. Recently, it has become evident that insidious worsening is not confined to progressive MS but is also common in relapsing–remitting MS (RRMS), a feature known as progression independent of relapse activity (PIRA). Methods We retrospectively identified 131 patients with clinically isolated syndrome or early RRMS who had determined KFLC index as part of their diagnostic workup. Demographic and clinical data were extracted from the Swedish MS registry. Associations of baseline KFLC index with evidence of disease activity (EDA) and PIRA were investigated in multivariable cox proportional hazards regression models. Results KFLC index was significantly higher in PIRA (median 148.5, interquartile range [IQR] 106.9–253.5) compared with non-PIRA (78.26, IQR 28.93–186.5, p = 0.009). In a multivariable cox regression model adjusted for confounders, KFLC index emerged as an independent risk factor for PIRA (adjusted hazard ratio [aHR] 1.005, 95% confidence interval [CI] 1.002–1.008, p = 0.002). Dichotomized by the cut-off value KFLC index > 100, patients with KFLC index > 100 had an almost fourfold increase in the risk for developing PIRA. KFLC index was also predictive of evidence of disease activity during follow-up. Conclusions Our data indicate that high KFLC index at baseline is predictive of PIRA, EDA-3, and overall worse prognosis in MS.

Disability patterns in multiple sclerosis: a meta-analysis on PIRA and RAW in the real world context

“…The selected studies were conducted in Germany [17],[19],[21],[22],[24], Italy [18],[25]–[27], Switzerland (k = 4) [13],[15],[23],[30], Austria [14], Poland [20], Spain [29], Sweden [28], USA [13], International Registry [16]. Two articles reported composite PIRA based on a combination of EDSS score with either the 25-FWT and 9-HPT [22] or the symbol digit modalities test (SDMT) [14].…”

“…There was a relevant inconsistency in the definition of CDA across different studies, especially for PIRA. For the baseline score, a fixed (k = 11) [14]–[16],[18],[20],[21],[25]–[27],[29],[30] or roving (k = 9) [13],[17],[19],[22]–[24],[28] reference EDSS could be adopted. Regarding the event score, the stepwise clinically significant increase required for CDA was consistently ≥1.5 steps for a reference EDSS = 0 in all but one [17] of the included studies.…”

“…Regarding the event score, the stepwise clinically significant increase required for CDA was consistently ≥1.5 steps for a reference EDSS = 0 in all but one [17] of the included studies. An increase of ≥1.0 step was required for a reference EDSS of 1.0 to either 5.0 (k = 5) [21],[24],[26],[28],[29] or 5.5 (k = 14) [13]–[16],[18]–[20],[22],[23],[25],[27],[30]; accordingly, an increase of ≥0.5 step was required for a reference EDSS of either ≥5.5 or ≥6.0, respectively. Only one study adopted a different definition for CDA, requiring a ≥1.0 step-increase for a reference EDSS ≤3.0 and ≥0.5 step increase for a reference EDSS ≥3.5 [17].…”

“…We found that PIRA events accounted for 71.0% (95% CIs 70.3 to 71.7%) of all CDA events. Furthermore, 27.9% (95% CIs 26.4 to 29.5%) of relapses resulted in RAW events, as estimated on 11 articles [14],[15],[17],[19],[20],[22]–[24],[27],[28],[30] reporting data on the overall number of patients who relapsed during the observation period. There was no association between PIRA and RAW event rates ( p = 0.210); however, RAW were almost completely suppressed, while PIRA accounted for about 82% of all CDA events, in cohorts including only patient under high-efficacy DMTs [17],[19],[23],[27] ( FIG.…”

Prospective multicenter validation of a new laboratory workflow integrating the free light chains kappa quotient in CSF analysis-Protocol of the ORCAS study

“…The most important aspect of this study is the prospective, multicenter and consecutive study design compared to many other FLCκ biomarker studies. Many study results are based on retrospective biobank samples with corresponding limitations regarding their application in routine clinical practice (11)(12)(13)(14). Although most studies on FLCκ have been applied to samples from MS patients (3,6,(8)(9)14), FLCκ are not a specific biomarker for MS but indicate general intrathecal Ig synthesis (13).…”