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Symptomology of AL amyloidosis can be vague, with a broad range of manifestations and potential etiologies. We sought to determine whether time from initial patient-reported symptom onset to diagnosis was associated with survival.The Boston University Amyloidosis Patient Database was queried for patients with AL amyloidosis who presented to the Center for initial evaluation from 2010 to 2015.A total of 324 patients with AL amyloidosis were evaluated for initial evaluation. The median time to diagnosis from initial symptom onset was 7.1 months (range, 0-61). At data cutoff, 60.2% (n = 195) of patients were alive; of those, the majority were diagnosed6 months from initial symptoms (52.3%, n = 102). In contrast, time to diagnosis from symptom onset was6 months in 63.6% (n = 82) of patients who did not survive at the time of data cutoff (P = .0005). Survival analysis of time from diagnosis to death or data cutoff stratified by time from patient-reported symptom onset to diagnosis (6, 6-12, and12 months) showed significant differences among groups (P = .001). Additionally, multivariable regression demonstrated that an increase in time from self-reported symptom onset to diagnosis was significantly associated with an increased risk of death (HR = 1.02, 95% CI = 1.01-1.04, P = .002).These results support the importance of early diagnosis for patients with AL amyloidosis.

AIMS Wild-type transthyretin (ATTRwt) cardiac amyloidosis has emerged as an important cause of heart failure in the elderly. Atrial fibrillation (AF) commonly affects older adults with heart failure and is associated with reduced survival, but its role in ATTRwt is unclear. We sought to explore the clinical impact of AF in ATTRwt. METHODS AND RESULTS Patients with biopsy-proven ATTRwt cardiac amyloidosis (n = 146) were retrospectively identified, and clinical, echocardiographic, and biochemical data were collected. Patients were classified as AF or non-AF and followed for survival for a median of 41.4 ± 27.1 months. Means testing, univariable, and multivariable regression models were employed. A systematic review was performed. AF was observed in 70% (n = 102). Mean age was similar (AF, 75 ± 6 vs. non-AF, 74 ± 5 years, P = 0.22). Anticoagulant treatment of patients with AF was as follows: 78% warfarin, 17% novel anticoagulant, and 6% no anticoagulation. Amiodarone was prescribed to 24%. There were no differences in left ventricular ejection fraction (P = 0.09) or left atrial volume (P = 0.87); however, mean diastolic dysfunction grade was higher in AF (mean 2.7 ± 0.5 vs. 2.4 ± 0.5, P = 0.01). While creatinine (P = 0.52) and B-type natriuretic peptide (P = 0.48) were similar, patients with AF had lower serum transthyretin concentrations (221 ± 51 vs. 250 ± 52 μg/mL, P

Objective To characterize symptoms and signs of AL amyloidosis that may bring patients to the attention of rheumatologists, evaluate Ig VL gene usage in this subgroup of patients, and assess the impact of soft tissue and bone involvement and VL gene usage on survival. Methods Clinical features of soft tissue and bone involvement were assessed in 191 patients with AL amyloidosis. VL gene sequencing was carried out to determine light-chain family, rate of somatic mutation, and evidence of antigen selection. The association of soft tissue and bone involvement with VL gene usage was assessed by logistic regression analysis, and survival time was analyzed using log rank tests and Cox regression models. Results Soft tissue and bone involvement occurred in 42.9% of the patients, and 9.4% had dominant soft tissue and bone involvement. The most common manifestations were submandibular gland enlargement, macroglossia, and carpal tunnel syndrome. Dominant soft tissue and bone involvement was significantly associated with VLκI gene usage. Mutation rate and evidence of antigen selection in the VL genes were not found to be confounding factors, providing evidence against a contribution of autoimmunity in this type of AL amyloidosis. Survival time was initially longer in patients with dominant soft tissue and bone involvement than in patients with other dominant organ involvement; however, this difference diminished over time. Conclusion Amyloid infiltration into soft tissue, joints, periarticular structures, and bones can bring patients with AL amyloidosis to the attention of rheumatologists. Recognition of the presenting symptoms is essential for accurate diagnosis and appropriate treatment, since the long-term outlook for untreated patients with dominant soft tissue and bone involvement is not better than that for patients with other dominant features of AL amyloidosis.

Familial transthyretin amyloidosis (ATTR) is an autosomal dominant disorder associated with a variant form of the plasma carrier protein transthyretin (TTR). Amyloid fibrils consisting of variant TTR, wild-type TTR, and TTR fragments deposit in tissues and organs. The diagnosis of ATTR relies on the identification of pathologic TTR variants in plasma of symptomatic individuals who have biopsy proven amyloid disease. Previously, we have developed a mass spectrometry-based approach, in combination with direct DNA sequence analysis, to fully identify TTR variants. Our methodology uses immunoprecipitation to isolate TTR from serum, and electrospray ionization and matrix-assisted laser desorption/ionization mass spectrometry (MS) peptide mapping to identify TTR variants and posttranslational modifications. Unambiguous identification of the amino acid substitution is performed using tandem MS (MS/MS) analysis and confirmed by direct DNA sequence analysis. The MS and MS/MS analyses also yield information about posttranslational modifications. Using this approach, we have recently identified a novel pathologic TTR variant. This variant has an amino acid substitution (Phe → Cys) at position 33. In addition, like the Cys10 present in the wild type and in this variant, the Cys33 residue was both S-sulfonated and S-thiolated (conjugated to cysteine, cysteinylglycine, and glutathione). These adducts may play a role in the TTR fibrillogenesis.

The transformation of serum proteins into Congo red-sensitive fibrillar material is requisite for the onset and progression of amyloid disease. All the mechanisms which lead to the disease itself have not been elucidated, but our knowledge has increased significantly. It is apparent that in all types of amyloid fibrils, three common features are displayed by the major protein constituents. These are that the fibril protein has (1) a serum precursor, (2) a high degree of anti-parallel beta-sheet conformation and (3) a distinctive ultrastructure on electron microscopy. In the AL and AA forms of amyloidosis, the putative precursors appear to undergo limited degradation to form the protein component of amyloid fibrils. It has been suggested that there may be certain primary structural characteristics inherent in precursor molecules which make them amyloidogenic, thus predisposing them to amyloid fibril formation.33 This would include certain subtypes of immunoglobulin light chains, possibly kappa I and lambda VI, in the AL type of amyloidosis and one of the polymorphic SAA species, SAA2, which has been identified as the predominating isotype found in AA amyloid fibrils.32,33,110 In AH amyloidosis, the mechanism of amyloid fibril formation appears to be simply a concentration phenomenon where elevated concentrations of B2-M are not handled normally and amyloid deposition is the result. Amyloidogenesis in the hereditary form of systemic amyloidosis may involve other factors in addition to the presence of a variant precursor prealbumin as indicated by the delayed onset of the disease. It is evident that the elucidation of the mechanism(s) which governs the onset and progression of the amyloidoses will allow future regulation and treatment of these all too often complex disorders.