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• W2885356711 abstract "In immunoglobulin light chain (AL) amyloidosis an indolent, malignant plasma cell clone produces monoclonal proteins that misfold and deposit systemically as amyloid causing life-threatening organ dysfunction. Diagnostic delays of up to a year or more are common even in patients that progress to AL from known asymptomatic plasma cell dyscrasias such as monoclonal gammopathy of undetermined significance (MGUS). Early recognition is important, especially in patients with advanced cardiac involvement, of which more than half still die within 6 months from diagnosis, despite advances in therapy. Immunoenrichment followed by MALDI-TOF MS—a method termed MASS-FIX—has been developed and validated at our institution as a sensitive, specific, cost-effective and efficient method to detect and type monoclonal light chains in plasma cell disorders.1 Monoclonal light chains (LCs) in AL amyloidosis, especially kappa restricted ones, were initially shown to display unusual patterns that included proteins with higher molecular mass and the presence of additional, high mass peaks.1 Prior work from our group that included deglycosylation experiments2 and confirmation with high resolution, high mass measurement accuracy LC-mass spectrometry (MS) has shown that these patterns are consistent with N-glycosylated forms of the monoclonal LCs and that these were 5 times more common in patients with AL amyloidosis compared to other PCD, and 13 times more common in kappa restricted patients. However, it was not known if these glycosylated forms are present during the MGUS phase or if they arise closer to diagnosis of AL amyloidosis. Here, we show that these glycosylated LCs are present years before the diagnosis of AL amyloidosis and should be used clinically for monitoring patients with presumably asymptomatic plasma cell disorders who are at risk for AL amyloidosis. Patients were included in this study the following criteria were met: (a) A diagnosis of MGUS or smoldering multiple myeloma (SMM) predating the diagnosis of AL amyloidosis; and (b) a stored serum or plasma sample was available at the time of each of their diagnoses. All patient samples were obtained with approval from the Mayo Clinic Institutional Review Board. The diagnosis of AL amyloidosis was made between April 1982 and June 2013 and was predicated on the presence of Congophilic deposits that demonstrate apple-green birefringence under polarized light. Amyloid typing was performed by immunohistochemistry or MS. In the cases where amyloid typing was not available, the clinical history of patients was carefully reviewed retaining only those cases with a presentation typical for AL amyloidosis. Two cases diagnosed with AL amyloidosis that included patients ages 89 and 90 years old, with indolent cardiac involvement were excluded, because their clinical picture could possibly be more consistent with transthyretin amyloidosis. Since patients did not always have a bone marrow biopsy at diagnosis an accurate distinction between SMM and MGUS could not always be made and these patients were considered together. Immuno-enrichment was performed as previously described in Ref. [3]. The samples were analyzed by MALDI-TOF MS (Microflex Bruker, LT). The spectra were acquired in the range of 9000-3200 mass/charge (m/z) in positive ion mode using sum of 500 laser shots. The spectra for each immuno-enrichment (IgG, IgA, and IgM and κ and λ) were overlaid and analyzed visually in both [M + H] + 1 and [M + H] + 2 LC range using an in-house developed standalone viewer and flexAnalysis software. The mass spectrum acquired for each patient was placed into 1 of 2 categories (glycosylated or not) by 4 independent reviewers (TK, AD, DLM, SD) based on patterns that have been previously described in.1, 2 Statistical analyses was carried out using JMP 12 (SAS Institute Inc., Cary, NC) statistical software. The Fischer exact test was used to compare categorical variables and the Wilcoxon Rank Sum/Kruskal Wallis for continuous variables. A P value of < .05 was considered statistically significant. The baseline characteristics of the 70 patients that were included are shown in the Table 1. Patterns consistent with glycosylation were detected in the serum from the time of the amyloidosis diagnosis in 11 patients (16%) of which 6 were kappa (29% of kappa cases) and 5 lambda (10% of lambda cases). In all of these cases the glycosylated form was noted in the MGUS/SMM sample. Patients with glycosylated LCs were more likely to be female (Table 1, P = .03). No difference in the incidence of cardiac or renal involvement was noted between the glycosylated or non-glycosylated groups. No other differences were noted in the baseline characteristics (Table 1) between the 2 groups. No differences were noted in the baseline characteristics when considering patients that had or did not have amyloid typing separately. In this study, we confirm that 16% of patients with AL amyloidosis have glycosylated LCs and demonstrate that in all cases these glycosylated forms are present years before the diagnosis of AL and can be used clinically to identify patients at risk for developing AL. We have previously reported4 that the respective odds ratios for a diagnosis of AL over another PCD if a glycosylated LC is found by MASS-FIX is 12.7 for kappa and 2.20 for lambda. A variety of post-translational modifications including glycosylation have been described in AL amyloidosis patients5 and glycosylation can be considered a post-translational modification that increases the risk of kappa LCs to form amyloid fibrils.5 Glycosylation appeared to be more common in female patients. The mechanism underlying this is unclear, although pregnancy is temporarily associated with higher levels of glycosylated polyclonal immunoglobulins, suggesting that hormonal differences might play a role.6 This report, further illustrates the clinical utility of MASS-FIX, which, in addition to detecting monoclonal proteins can easily identify glycated forms and resolve monoclonal antibody interference. In conclusion, we have shown that glycosylated monoclonal proteins are present years before the diagnosis of AL amyloidosis. This finding, taken together with our previous report of glycosylation and higher risk for AL amyloidosis, reinforce the importance of identifying glycosylation in patients with presumptive asymptomatic PCD. When identified, patients with glycosylated LCs should be followed more closely since they are at a higher risk to progress into AL compared with patients without glycosylated forms. All authors read and approved the final version of the article. Conception and design: TK, SD, DM, AD. Provision of study materials of patients: TK, DLM, SD, SK, DB, BM, BA, PM, GM, MR-A, RAK, AD. Collected and assembled data, performed experiments: TK, DLM, SD, SK, DB, BM, BA, PM, GM, MR-A, RAK, AD. Data analysis and interpretation: TK, SD, DM, AD Writing of article: TK, DLM, SD, SK, DB, BM, BA, PM, GM, MR-A, RAK, AD. Final approval of article: TK, DLM, SD, SK, DB, BM, BA, PM, GM, MR-A, RAK, AD. DLM and SD have a financial interest in the MASS-FIX technology used in this study." @default.
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• W2885356711 date "2018-09-21" @default.
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• W2885356711 title "MASS-FIX may allow identification of patients at risk for light chain amyloidosis before the onset of symptoms" @default.
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• W2885356711 doi "https://doi.org/10.1002/ajh.25244" @default.
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