Dejan Milosavljevic

Elevated levels of kappa free light chains in CSF support the diagnosis of multiple sclerosis

BackgroundNumerous studies have demonstrated elevated kappa free light chains (KFLCs) in CSF of multiple sclerosis (MS) patients. However, so far only small cohorts have been examined, and generally only through qualitative KFLCs analysis. Using a recently developed free light chain (FLC) immunoassay, it is now possible to quantitatively measure KFLCs by automated nephelometry. Our objective was to determine the extent to which KFLC levels in CSF correlated with the diagnosis of MS and CISSMS (clinically isolated syndrome suggestive of MS) compared to oligoclonal banding (OCB) and the immunoglobulin G (IgG) index.MethodsCSF and serum samples from 438 unselected patients, including a MS group of 70 patients (41 MS, 29 CISSMS), were analysed using nephelometry and isoelectric focusing. We then retrospectively correlated results with patients’ diagnoses.ResultsOf the MS group (n = 70), 67 patients had elevated KFLCs using the KFLC index (≥ 5.9), 64 patients showed OCB and 56 patients presented with an elevated IgG index (≥ 0.6). Sensitivities were 0.96 for the KFLC index, 0.91 for OCB and 0.80 for the IgG index. The specificity of the KFLC index for the MS group (0.86) was lower than that of OCB (0.92) but distinctly higher compared to the IgG index (0.77).ConclusionIn this study, an elevated KFLC-index represented the most sensitive and specific quantitative diagnostic parameter for MS. As it is measured by automated, routinely available laboratory methods, KFLC quantitation can provide a rapid and reproduceable indication of intrathecal immunological processes supporting current MS diagnostic criteria.

Validation of kappa free light chains as a diagnostic biomarker in multiple sclerosis and clinically isolated syndrome: A multicenter study

Background: Kappa free light chains (KFLCs) have been proposed as a diagnostic biomarker in patients with clinically isolated syndrome (CIS) and multiple sclerosis (MS). Objective: The objective of this paper is to validate the diagnostic accuracy of intrathecal KFLC synthesis in a multicenter study. Methods: KFLCs were measured by nephelometry under blinded conditions in cerebrospinal fluid (CSF) and serum sample pairs of patients with CIS (n = 60), MS (n = 60) and other neurological diseases (n = 60) from four different MS centers. The upper normal limit for intrathecal KFLC concentrations depending on blood-CSF barrier function was previously calculated in a cohort of 420 control patients. Results: Diagnostic sensitivity of intrathecal KFLC synthesis, IgG synthesis according to Reiber, IgG index and oligoclonal bands (OCBs) was 95%, 72%, 73% and 93% in patients with MS and 82%, 47%, 43% and 72% in patients with CIS. Specificity of intrathecal KFLC synthesis was 95% and 98% for all other measures. Conclusion: These findings further support the diagnostic value of intrathecal KFLC synthesis in CIS and MS patients and demonstrate a valid, easier and rater-independent alternative to OCB detection.

Kappa Free Light Chains: Diagnostic and Prognostic Relevance in MS and CIS

Background Quantification of kappa free light chains (KFLC) in cerebrospinal fluid shows high diagnostic sensitivity in multiple sclerosis and clinically isolated syndrome patients. However, a clearly defined threshold value is still missing and a possible prognostic value of the KFLC levels in these patients remains undefined. Methods Results of KFLC quantification in 420 controls were used to set an upper limit of normal KFLC concentration in CSF under different blood-CSF-barrier conditions. Additionally, KFLC values of MS and CIS patients were assessed and results were evaluated with reference to the patients corresponding disease courses. Results The calculated upper limit of normal KFLC-concentration covers 98% of these control patients. Using this cut-off, plasma cell activity in CSF can be detected in 97% of MS patients and in 97% of CIS patients. However, there is no evidence that the extent of KFLC elevation provides prognostic value in MS and CIS patients in this study. Conclusion KFLC determination should become a first line screen in the diagnostic algorithms of MS and CIS. The extent of elevation of intrathecal KFLC has no prognostic value on the disease course in MS and CIS patients.

Suppression of the noninvolved pair of the myeloma isotype correlates with poor survival in newly diagnosed and relapsed/refractory patients with myeloma.

Heavy light chain (HLC) assays allow precise measurement of the monoclonal and of the noninvolved polyclonal immunoglobulins of the same isotype as the M‐protein (e.g., monoclonal IgAκ and polyclonal IgAλ in case of an IgAκ myeloma), which was not possible before. The noninvolved polyclonal immunoglobulin is termed ‘HLC‐matched pair’. We investigated the impact of the suppression of the HLC‐matched pair on outcome in 203 patients with multiple myeloma, a phenomenon that likely reflects the hosts attempt to control the myeloma clone. Severe (>50%) HLC‐matched pair suppression was identified in 54.5% of the 156 newly diagnosed patients and was associated with significantly shorter survival (45.4 vs. 71.9 months, P = 0.019). This correlation was statistically significant in IgG patients (46.4 vs. 105.1 months, P = 0.017), but not in patients with IgA myelomas (32.9 vs. 54.1 months, P = 0.498). At best response, HLC‐matched pair suppression improved only in patients with ≥VGPR, indicating partial or complete humoral immune reconstitution during remission in those with excellent response. Severe HLC‐matched pair suppression retained its prognostic impact also during follow‐up after first response. In the 47 pretreated patients with relapsed/refractory disease, a similar correlation between severe HLC suppression and survival was noted (22.8 vs. not reached, P = 0.028). Suppression of the polyclonal immunoglobulins of the other isotypes than the myeloma protein correlated neither with HLC‐matched pair suppression, nor with outcome. Multivariate analysis identified severe HLC‐matched pair suppression as independent risk factor for shorter survival, highlighting the impact of isotype specific immune dysregulation on outcome in multiple myeloma. Am. J. Hematol. 91:295–301, 2016.

Suppression of the non‐involved pair of the myeloma isotype (HLC‐matched pair) correlates with poor survival in newly diagnosed and relapsed/refractory patients with myeloma

Heavy light chain (HLC) assays allow precise measurement of the monoclonal and of the noninvolved polyclonal immunoglobulins of the same isotype as the M‐protein (e.g., monoclonal IgAκ and polyclonal IgAλ in case of an IgAκ myeloma), which was not possible before. The noninvolved polyclonal immunoglobulin is termed ‘HLC‐matched pair’. We investigated the impact of the suppression of the HLC‐matched pair on outcome in 203 patients with multiple myeloma, a phenomenon that likely reflects the hosts attempt to control the myeloma clone. Severe (>50%) HLC‐matched pair suppression was identified in 54.5% of the 156 newly diagnosed patients and was associated with significantly shorter survival (45.4 vs. 71.9 months, P = 0.019). This correlation was statistically significant in IgG patients (46.4 vs. 105.1 months, P = 0.017), but not in patients with IgA myelomas (32.9 vs. 54.1 months, P = 0.498). At best response, HLC‐matched pair suppression improved only in patients with ≥VGPR, indicating partial or complete humoral immune reconstitution during remission in those with excellent response. Severe HLC‐matched pair suppression retained its prognostic impact also during follow‐up after first response. In the 47 pretreated patients with relapsed/refractory disease, a similar correlation between severe HLC suppression and survival was noted (22.8 vs. not reached, P = 0.028). Suppression of the polyclonal immunoglobulins of the other isotypes than the myeloma protein correlated neither with HLC‐matched pair suppression, nor with outcome. Multivariate analysis identified severe HLC‐matched pair suppression as independent risk factor for shorter survival, highlighting the impact of isotype specific immune dysregulation on outcome in multiple myeloma. Am. J. Hematol. 91:295–301, 2016.

Cerebrospinal fluid free light chains as diagnostic biomarker in neuroborreliosis

Abstract Background: Free light chains (FLC) have been proposed as diagnostic biomarker in patients with inflammatory central nervous system diseases. The objective of this study was to investigate the diagnostic utility of intrathecal κ- and λ-FLC synthesis in patients with neuroborreliosis. Methods: κ- and λ-FLC were measured by nephelometry under blinded conditions in cerebrospinal fluid (CSF) and serum sample pairs of 34 patients with neuroborreliosis and compared to a cohort of 420 control patients. κ-FLC index was calculated as [CSF κ-FLC/serum κ-FLC]/[CSF albumin/serum albumin], and λ-FLC index in analogy. Results: κ-FLC and λ-FLC index were significantly elevated in patients with neuroborreliosis compared to the control group. At a specificity level of 95%, κ-FLC and λ-FLC index showed a diagnostic sensitivity of 88.2% and 100%. In comparison, IgM and IgG synthesis according to Reiber formula, IgG index >0.7 and OCB status reached a sensitivity of 83.9%, 44.1%, 58.8% and 64.7%. Conclusion: These findings support the diagnostic value of intrathecal FLC synthesis in neuroborreliosis patients and demonstrate a valid, easy and rater-independent alternative for the detection of an intrathecal immunoglobulin production.