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

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

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, p0.1 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

No increase of serum neurofilament light in relapsing-remitting multiple sclerosis patients switching from standard to extended-interval dosing of natalizumab

BACKGROUND: Accumulating evidence supports the efficacy of administering natalizumab (NZ) with extended-interval dosing (EID) in patients with relapsing-remitting multiple sclerosis (RRMS). OBJECTIVES: We switched NZ dosing from 4-week to 6-week intervals in patients with RRMS, and investigated the effect on serum neurofilament light chain (sNfL) concentrations. METHODS: We included two cohorts of patients with RRMS treated with NZ: one received the standard-interval dosing (4 weeks) at baseline, and were switched to 6-week intervals (EID4-6, N = 45). The other cohort received EID (5- or 6-week intervals) both at baseline and during follow-up (EID5/6, N = 25). Serum samples were collected in the EID4-6 cohort at every NZ infusion, for 12 months. The primary outcome was the change in sNfL concentrations after switching to EID. RESULTS: The baseline mean sNfL concentration in the EID4-6 cohort was 10.5 ng/L (standard deviation (SD) = 6.1), and it remained unchanged at 12 months. Moreover, individual sNfL concentrations did not change significantly after extending the NZ dosing intervals. In addition, the EID4-6 and EID5/6 cohorts had similar baseline sNfL concentrations. CONCLUSION: We concluded that extending the NZ dosing interval did not increase axonal damage, as determined with sNfL, in patients with RRMS

Ultrasensitive DNA Immune Repertoire Sequencing Using Unique Molecular Identifiers

BACKGROUND: Immune repertoire sequencing of the T-cell receptor can identify clonotypes that have expanded as a result of antigen recognition or hematological malignancies. However, current sequencing protocols display limitations with nonuniform amplification and polymerase-induced errors during sequencing. Here, we developed a sequencing method that overcame these issues and applied it to gamma delta T cells, a cell type that plays a unique role in immunity, autoimmunity, homeostasis of intestine, skin, adipose tissue, and cancer biology. METHODS: The ultrasensitive immune repertoire sequencing method used PCR-introduced unique molecular identifiers. We constructed a 32-panel assay that captured the full diversity of the recombined T-cell receptor delta loci in gamma delta T cells. The protocol was validated on synthetic reference molecules and blood samples of healthy individuals. RESULTS: The 32-panel assay displayed wide dynamic range, high reproducibility, and analytical sensitivity with single-nucleotide resolution. The method corrected for sequencing-depended quantification bias and polymerase-induced errors and could be applied to both enriched and nonenriched cells. Healthy donors displayed oligoclonal expansion of gamma delta T cells and similar frequencies of clonotypes were detected in both enrichment and nonenriched samples. CONCLUSIONS: Ultrasensitive immune repertoire sequencing strategy enables quantification of individual and specific clonotypes in a background that can be applied to clinical as well as basic application areas. Our approach is simple, flexible, and can easily be implemented in any molecular laboratory.Peer reviewe

Prospective evaluation of entrainment mapping as an adjunct to new-generation high-density activation mapping systems of left atrial tachycardias

BACKGROUND Identification of atrial tachycardia (AT) mechanism remains challenging. OBJECTIVE We sought to investigate the added value of entrainment maneuvers (EM) when using new high-density activation mapping (HDAM) technologies for the identification of complex left ATs. METHODS Thirty-six consecutive complex ATs occurring after ablation of persistent atrial fibrillation were prospectively analyzed. The AT mechanism was diagnosed in 2 steps by 2 experts: (1) based on H DAM only (Coherent module, CARTO, Biosense Webster Inc., Irvine, CA) and (2) with additional analysis from EM. RESULTS EM resulted in atrial fibrillation in 1 patient, who was excluded from the analysis. Ten of 11 single loop macroreentries identified by HDAM were confirmed by EM. Only 4 of 14 double loop macroreentries identified by HDAM wereconfirmed by EM (in 10 patients, EM unmasked passive activation of one of the visual cir- cuits). One sole microreentry circuit identified by HDAM was confirmed by EM. A combination of macro- and microreentry circuits was visualized in 3 ATs using H DAM. However, EM revealed passive activation of the visual macroreentrant loop in 2 of these 3 cases. By using HDAM in 6 of 35 ATs (17%), no univocal mechanism could be identified, whereas EM finally enabled the diagnosis of 5 microreentry circuits and 1 macroreentrant AT. All the diagnoses made from EM in addition to HDAM were confirmed by ablation. CONCLUSION Entrainment maneuvers are still useful during mapping of complex left ATs, mostly to differentiate active from passive macroreentrant loops and to demonstrate microreentry circuits

A five-year observational prospective mono-center study of the efficacy of alemtuzumab in a real-world cohort of patients with multiple sclerosis

BackgroundAlemtuzumab (ALZ) is a pulsed immune reconstitution therapy for multiple sclerosis (MS).ObjectiveTo assess basic characteristics, therapeutic effects, and prognostic biomarkers on clinical and imaging parameters of disease activity for relapsing–remitting MS (RRMS) patients selected for ALZ, in a real-world long-term setting.MethodsFifty-one RRMS patients [female = 31; mean age 36 (standard deviation 7.1) years; median expanded disability status scale (EDSS) 2 (interquartile range (IQR) 1.5)] initiating ALZ treatment, were consecutively included. Patients were assessed at baseline and thereafter annually for 5 years with clinical measures, symbol digit modality test (SDMT), and magnetic resonance imaging (MRI). Concentrations of glial fibrillary acidic protein (GFAP), reflecting astrogliosis, and neurofilament light (NfL), reflecting axonal damage, were measured in cerebrospinal fluid (CSF) and serum samples collected at baseline and after 2 years in CSF, and annually in serum. Control subjects were symptomatic controls (SCs, n = 27), who were examined at baseline and after 5 years without evidence of neurological disease.ResultsWhile the mean annualized relapse rate was significantly reduced from baseline at each year of follow-up, disability was essentially maintained at a median EDSS of 1.5 and IQR between 1.13 and 2.25. New MRI activity was recorded in 26 patients (53%) over 5 years. The proportion of patients who achieved no evidence of disease activity (NEDA-3), 6-months confirmed disability worsening (CDW), and 6-months confirmed disability improvement (CDI) at 5 years were 33, 31, and 31%, respectively. The SDMT score was reduced for patients (p &lt; 0.001), but unchanged for SCs. ALZ treatment did not change GFAP levels, whereas there was a significant decrease for RRMS patients in median CSF and serum NfL levels at follow-up [CSF month 24: 456 pg./mL (IQR 285.4) (p = 0.05); serum month 24: 6.7 pg/mL (IQR 4.7) (p &lt; 0.01); serum month 60: 7.2 pg/mL (IQR 4.7) (p &lt; 0.01)], compared to baseline [CSF: 1014 pg/mL (IQR 2832.5); serum 8.6 pg/mL (IQR 17.4)].ConclusionIn this real-world mono-center population, we observed a progression-free survival of 69%, cumulative NEDA-3 of 33%, and reduced NfL levels, over a five-year follow-up. This confirms ALZ as an effective pulsed immune reconstitution therapy that significantly reduces neuro axonal loss, and therefore has the potential to reduce long-term neurological disability. ALZ did not appear to affect astrogliosis

Система дистанційної освіти та її захист

BACKGROUND: It is currently unknown whether early immunomodulatory treatment in relapsing-remitting MS (RRMS) can delay the transition to secondary progression (SP). OBJECTIVE: To compare the time interval from onset to SP in patients with RRMS between a contemporary cohort, treated with first generation disease modifying drugs (DMDs), and a historical control cohort. METHODS: We included a cohort of contemporary RRMS patients treated with DMDs, obtained from the Swedish National MS Registry (disease onset between 1995-2004, n = 730) and a historical population-based incidence cohort (onset 1950-64, n = 186). We retrospectively analyzed the difference in time to SP, termed the "period effect" within a 12-year survival analysis, using Kaplan-Meier and Cox regression analysis. RESULTS: We found that the "period" affected the entire severity spectrum. After adjusting for onset features, which were weaker in the contemporary material, as well as the therapy initiation time, the DMD-treated patients still exhibited a longer time to SP than the controls (hazard ratios: men, 0.32; women, 0.53). CONCLUSION: Our results showed there was a longer time to SP in the contemporary subjects given DMD. Our analyses suggested that this effect was not solely driven by the inclusion of benign cases, and it was at least partly due to the long-term immunomodulating therapy given

High Interferon-γ Uniquely in Vδ1 T Cells Correlates with Markers of Inflammation and Axonal Damage in Early Multiple Sclerosis

We have identified a population of T lymphocytes in peripheral blood, Vδ1 TCRγδ T lymphocytes, which unexpectedly was uniquely expressing high production of interferon-γ in newly diagnosed, untreated multiple sclerosis (MS) patients. IFN-γ production in this population distinctly correlated to parameters of clinical disease activity, inflammation, and neuronal damage. These Vδ1 T lymphocytes belong to a population of innate T lymphocytes that recognize antigen in the context of CD1d/CD1c and which include reactivity to the myelin glycosphingolipid sulfatide. Importantly, patients treated with natalizumab, blocking leukocyte transmigration to central nervous system, had completely normalized levels of interferon-γ-producing Vδ1 T lymphocytes. A biomarker and early sign of demyelinating disease in MS is much warranted and would help identify immunopathogenesis and prognosis of disease as well as monitor success with adequate treatment. The present study identifies the Vδ1 T lymphocytes as an early marker of MS and a possible link to understanding the disease etiology

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

BackgroundEvolving 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.MethodsIn 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.ResultsIn patients with KFLC-index&gt;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&gt;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).ConclusionIntrathecal 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