Primary Data on ATTR-Amyloidosis Prevalence Among Elderly Patients With Left Ventricular Hypertrophy in Russia.

AIM: To estimate the prevalence of amyloid cardiomyopathy (CM) caused by transthyretin amyloidosis (ATTR) and immunoglobulin light chain (AL) amyloidosis among patients aged >65 years with interventricular septal (IVS) hypertrophy of ≥14 mm. MATERIAL AND METHODS: From January through August 2023, 60 patients (mean age 7.2±7.3 years, 34 (56.67%) men) were enrolled. Patients meeting the inclusion criteria underwent an echocardiographic study with determining the myocardial longitudinal strain, myocardial scintigraphy with 99mTc-pyrfotech, myocardial single-photon emission computed tomography, measurement of N-terminal fragment of brain natriuretic peptide and troponin I, and the immunochemical study of serum and urine proteins with measurement of free light chains. In the presence of grades 2 and 3 radiopharmaceutical uptake according to scintigraphy, a molecular genetic study was performed for differential diagnosis of wild-type transthyretin amyloidosis (wtATTR) and hereditary/variant (hATTR) ATTR-CM. RESULTS: According to data of myocardial scintigraphy with 99mTc-pyrfotech, grade 3 uptake in the absence of monoclonal secretion was detected in 5 (8.3%) cases and grade 2 radiotracer uptake in the absence of monoclonal secretion was detected in 6 (10%) patients. Myeloma complicated by AL amyloidosis and primary AL amyloidosis were found in 5 (8.3%) patients. CONCLUSION: Among patients aged ≥65 years with IVS hypertrophy ≥14 mm, amyloid CM was detected in 20% of cases (12 patients), including 5 cases (8.3%) of AL amyloidosis and 7 cases (11.7%) of ATTR amyloidosis.

Epidemiology and clinical outcomes of light-chain amyloidosis in Sweden: A nationwide population-based study.

OBJECTIVES: This study evaluated data from six Swedish national registries to fill current evidence gaps on the epidemiology, clinical burden, and overall survival (OS) associated with light-chain (AL) amyloidosis. METHODS: Patients newly diagnosed with AL amyloidosis were identified using six linked Swedish nationwide population-based registers. For each case, individuals from the general population were selected and matched with a maximum ratio of 1:5 based on age, sex, calendar year, and county. RESULTS: 846 patients newly diagnosed with AL amyloidosis and 4227 demographically matched individuals were identified. From 2011 to 2019, annual AL amyloidosis incidence increased from 10.5 to 15.1 cases per million. At baseline, patients with AL amyloidosis had a significantly higher disease burden including higher rates of cardiac and renal failure relative to the comparison group. Among patients with AL amyloidosis, 21.5% had incident heart failure and 17.1% had incident renal failure after initial diagnosis. Median OS for patients with AL amyloidosis was 56 months versus not reached in the matched general population comparison group. CONCLUSION: The incidence of newly diagnosed AL amyloidosis in Sweden increased over time with AL amyloidosis being associated with a higher risk of cardiac/renal failure and all-cause mortality compared with the general population.

Cardiac Amyloidosis: Overlooked, Underappreciated, and Treatable.

Cardiac amyloidosis (CA) is an infiltrative and restrictive cardiomyopathy that leads to heart failure, reduced quality of life, and death. The disease has two main subtypes, transthyretin cardiac amyloidosis (ATTR-CA) and immunoglobulin light chain cardiac amyloidosis (AL-CA), characterized by the nature of the infiltrating protein. ATTR-CA is further subdivided into wild-type (ATTRwt-CA) and variant (ATTRv-CA) based on the presence or absence of a mutation in the transthyretin gene. CA is significantly underdiagnosed and increasingly recognized as a cause of heart failure with preserved ejection fraction. Advances in diagnosis that employ nuclear scintigraphy to diagnose ATTR-CA without a biopsy and the emergence of effective treatments, including transthyretin stabilizers and silencers, have changed the landscape of this field and render early and accurate diagnosis critical. This review summarizes the epidemiology, pathophysiology, diagnosis, prognosis, and management of CA with an emphasis on the significance of recent developments and suggested future directions.

Prevalence of plasma cell and lymphoproliferative disorders among blood relatives of patients with light chain amyloidosis.

With limited existing data on hereditary factors in light chain (AL) amyloidosis, we conducted a study of patients with plasma cell dyscrasias or lymphoproliferative disorders in their family history. Among 1621 patients, we identified 44 probands (2·7%) with 52 relatives affected. The most common disorders in family members were multiple myeloma (48%) and AL amyloidosis (18%). Light chain isotype was 100% congruent in families with known clonal immunoglobulin for both members. Despite matching light chain isotype, organ involvement varied between members in families with multiple cases of AL amyloidosis. These findings help generate hypotheses about familial influences in AL amyloidosis.

Cardiac amyloidosis-interdisciplinary approach to diagnosis and therapy.

The vast majority of cardiac amyloidosis (CA) cases are caused by light chain (AL) or transthyretin (ATTR) amyloidosis. The latter is divided into hereditary (ATTRv) and wild-type forms (ATTRwt). The incidence of ATTRwt amyloidosis has significantly increased, particularly due to the improved diagnosis of cardiac manifestations, with relevant proportions in patient populations with heart failure (HF) and preserved ejection fraction (HFpEF). Cardiac amyloidosis should be suspected in HF with indicative clinical scenarios/"red flags" with typical signs of CA in echocardiography. Further noninvasive imaging (cardiovascular magnetic resonance imaging, scintigraphy) and specific laboratory diagnostics are important for the diagnosis and typing of CA into the underlying main forms of ATTR and AL amyloidosis. The histopathologic analysis of an endomyocardial biopsy is necessary if noninvasive diagnostic methods do not enable reliable typing of CA. This is crucial for initiating specific therapy. Therapy of HF in CA is largely limited to the use of diuretics in the absence of evidence on the benefit of classic HF therapy with neurohormonal modulators. Innovative therapies have been developed for amyloidosis with improvement in organ protection, prognosis, and quality of life. These include specific cytoreductive therapies for monoclonal light-chain disease in AL amyloidosis and pharmacologic stabilization or inhibition of transthyretin expression in ATTR amyloidosis. Since the CA underlying amyloidosis is a systemic disease also affecting other organ systems, close interdisciplinary cooperation is crucial for rapid and effective diagnosis and therapy.

Haematologic responses and survival do not significantly decrease with subsequent lines of therapy in systemic immunoglobulin light chain amyloidosis: results from an analysis of real-world longitudinal data.

Systemic immunoglobulin light chain amyloidosis (AL) is an incurable disorder, and the natural history is incompletely understood. In this study, we describe its natural history based on an analysis of real-world longitudinal data. All patients seen at the National Amyloidosis Centre, UK, between February 2010 and August 2019 and treated with up-front bortezomib are included. In all, 1 276 patients received the first-line treatment; 259, 85, and 32 patients received second, third, and fourth treatment lines, respectively. Among patients requiring further treatment after the first line, 77·2% started the second line within two years of the first line; 50·5%, 50·6%, 40·1% and 40·6% of patients had achieved at least very good partial response after the first, second, third and fourth treatment lines. Median overall survival (OS) from first, second, third and fourth lines was 45 months, 56 months, 37 months and not reached, respectively (P = 0·109). In summary, although relapses occur in AL amyloidosis, the outcomes and responses do not worsen with each subsequent relapse, making it attractive to design therapeutics with curative intent.

Characterization and prognostic implication of delayed complete response in AL amyloidosis.

INTRODUCTION: Little is known on continued response following completion of therapy in light chain (AL) amyloidosis. METHODS: We studied 373 AL amyloidosis patients who achieved complete response (CR) or very good partial response (VGPR) to first-line therapy. RESULTS: By end of therapy (EOT), 46% of patients achieved a CR and 54% a VGPR. With no further therapy, 17.5% of patients were upstaged from VGPR to CR (delayed CR), with a median of 9 months. Compared with CR and VGPR at EOT, patients with a delayed CR were characterized by higher proportion of t(11;14) and lower rate of trisomies. Autologous stem cell transplant was more frequent in the delayed CR group. Patients with a delayed CR were characterized by minimal residual disease negativity and organ response rates similar to patients with CR at EOT and higher than patients achieving VGPR at EOT. Patients with a delayed CR had a longer PFS/OS compared to patients with CR or VGPR by EOT (median PFS 149 vs 92 vs 52 months, P < .001; 10-year OS 87% vs 71% vs 56%, P < .001). CONCLUSIONS: This study characterizes delayed CR in AL amyloidosis, highlights its prognostic impact which is at least similar to those who achieved CR at EOT, and underlines another aspect of response monitoring.

Patient outcomes in light chain (AL) amyloidosis: The clock is ticking from symptoms to diagnosis.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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 diagnosed <6 months from initial symptoms (52.3%, n = 102). In contrast, time to diagnosis from symptom onset was >6 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, and >12 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). CONCLUSION: These results support the importance of early diagnosis for patients with AL amyloidosis.

Pattern of renal amyloidosis in South Africa.

BACKGROUND: Kidney disease is a serious manifestation of systemic amyloidosis and a major cause of morbidity and mortality. Tuberculosis (TB) occurs up to 27 times more commonly in human immunodeficiency virus (HIV) infected patients and is also an important cause of renal amyloid; there are however no reports of renal amyloidosis in South Africa in the HIV era. METHODS: This was a retrospective record review of cases of amyloidosis diagnosed on renal biopsies at our tertiary referral hospital between January 1985 and December 2016. RESULTS: Forty-six cases of amyloidosis were identified over the study period. The calculated biopsy prevalence was 1.38 per 100 non-transplant renal biopsies (95% Confidence Interval 1.02-1.86). AL amyloidosis was identified in 26 (57%) cases and AA in 20 (43%). The median age at presentation was 51 years and 52% of cases were female. Patients with AA amyloidosis were significantly younger compared to their AL counterparts (age 42 years vs. 58 years, p = < 0.001) and were all significantly non-white. The main clinical presentation was nephrotic syndrome (85%) and 52% of cases also had a serum creatinine value of greater than 120 µmol/L. Of the 20 cases of AA amyloidosis, 12 (60%) were associated with tuberculosis. HIV infection was noted in only two (10%) of the 20 AA cases. Median survival after diagnosis was 2 months. CONCLUSION: Amyloidosis is a rare cause of kidney disease and typically presents with nephrotic syndrome. A similar number of AA and AL types were observed, and outcomes are worse in cases of AA amyloid. While TB remains the major underlying disease in this type, HIV infection was infrequent in cases of AA renal amyloidosis.

AL amyloidosis in the Chilean public health system: a pending debt. Multicenter study of the Chilean Monoclonal Gammopathies Cooperative Group.

BACKGROUND: Immunoglobulin light chain (AL) amyloidosis is a rare and underdiagnosed entity. AIM: To characterize patients with AL amyloidosis in Chilean public health centers. MATERIAL AND METHODS: We conducted a retrospective, multicenter study. Public centers of the Chilean Monoclonal Gammopathies Cooperative Group were asked to search for patients with AL amyloidosis in their databases. Epidemiological, clinical and laboratory characteristics were evaluated. RESULTS: Forty-two patients aged 22 to 84 years were found. Twenty four percent had localized AL amyloidosis; 64% had a lambda light chain clone; 47% were associated with multiple myeloma and 9% with non-Hodgkin lymphoma. The most commonly involved organ was the kidney (76%). Serum free light chains were measured in 31% and an echocardiogram was performed in 74% of patients. Seventeen percent of patients received only palliative care, 17% were treated with bortezomib, 21% with thalidomide, and 40% with melphalan. No patient was transplanted. The mean overall survival (OS) of the group was 19 months. The 5-year OS was 28%. CONCLUSIONS: It is important to obtain these realistic, national data to initiate strategies to improve early diagnosis and proper management of this disease.

Intratubular amyloid in light chain cast nephropathy is a risk factor for systemic light chain amyloidosis.

Light chain cast nephropathy is the most common form of kidney disease in patients with multiple myeloma. Light chain casts may occasionally show amyloid staining properties, that is, green birefringence after Congo red staining. The frequency and clinical significance of this intratubular amyloid are poorly understood. Here, we retrospectively assessed the clinicopathological features of 60 patients with histologically proven light chain cast nephropathy with a specific emphasis on intratubular amyloid, especially, its association with extrarenal systemic light chain amyloidosis. We found intratubular amyloid in 17 cases (17/60, 28%) and it was more frequent in patients with λ light chain gammopathy (13/17 in the 'intratubular amyloid' group vs 19/43 in the 'no intratubular amyloid' group, P=0.02). Pathological examination of extrarenal specimens showed that intratubular amyloid was significantly associated with the occurrence of systemic light chain amyloidosis (5/13 in the 'intratubular amyloid' group vs 0/30 in the 'no intratubular amyloid' group, P=0.001). Our results indicate that first, intratubular amyloid is not a rare finding in kidney biopsies of patients with light chain cast nephropathy, and, second, it reflects an amyloidogenic capacity of light chains that can manifest as systemic light chain amyloidosis. Thus, intratubular amyloid should be systematically screened for in kidney biopsies from patients with light chain cast nephropathy and, if detected, should prompt a work-up for associated systemic light chain amyloidosis.

Role of oral examination in newly diagnosed multiple myeloma patients: A safe and simple way to detect light chain amyloidosis.

OBJECTIVE: Up to 30% of multiple myeloma (MM) patients have subclinical amyloid deposits. These patients are under-recognized and are more susceptible to drug toxicity, bleeding and death. Early diagnosis and adjustment of treatment are crucial. Biopsies of oral mucosa might be a potentially useful diagnostic tool. The objective of this study was to assess the prevalence and characteristics at presentation of oral amyloidosis in a large cohort of MM patients. METHODS: The prevalence and characteristics of oral amyloidosis in a large cohort of MM patients who were referred for oral evaluation before and during bisphosphonate therapy were assessed, retrospectively. RESULTS: Among 212 patients analysed, 13 (6%) were diagnosed with concomitant light chain (AL) amyloidosis. In 54% (n = 7), lesions in the oral cavity compatible with amyloid deposition were detected by examination. CONCLUSIONS: The salient feature of this study is the high prevalence of oral manifestations among MM patients with amyloidosis. These results highlight the value of routine oral cavity examination and biopsy as a safe and simple method for detecting light chain amyloidosis.

The treatment of paraprotein-related kidney disease.

PURPOSE OF REVIEW: Myeloma kidney and amyloid light-chain (AL) amyloidosis remain the principal kidney complications of paraproteins. In this review, we update readers to many of the recent advances which have occurred in the care and outcomes for patients with these presentations. RECENT FINDINGS: Myeloma kidney has historically caused a severe acute kidney injury with very poor outcomes. The combination of new diagnostic techniques, enabling a rapid diagnosis and novel chemotherapy agents has transformed these poor outcomes for the better. Two multicentre randomized controlled trials have recently evaluated if the removal of free light chains by high cut-off haemodialysis improves renal outcomes beyond effective chemotherapy alone. Although we await the full articles of these studies to be published, abstracts suggested the studies will have contradictory primary results. In the field of AL amyloidosis, there are now novel criteria for the risk stratification of kidney outcomes which can be used in combination with markers of early kidney response to provide clinicians with powerful tools to guide patient discussions. SUMMARY: Across both AL amyloidosis and myeloma kidney patient outcomes continue to improve. Principally this improvement has been driven by the continuing development of novel chemotherapy agents in this field.

Timing and co-occurrence of symptoms prior to a diagnosis of light chain (AL) amyloidosis.

It is well-established that most patients with systemic light chain (AL) amyloidosis have multi-organ involvement and are often diagnosed after a lag period of increasing symptoms. We leverage electronic health record (EHR) data from the TriNetX research network to describe the incidence, timing, and co-occurrence of precursor conditions of interests in a cohort of AL amyloidosis patients identified between October 2015-December 2020. Nineteen precursor diagnoses of interest representing features of AL amyloidosis were identified using ICD codes up to 36 months prior to AL amyloidosis diagnosis. Among 1,401 patients with at least 36 months of EHR data prior to AL amyloidosis diagnosis, 46% were females, 16% were non-Hispanic Black, and 6% were Hispanic. The median age was 71 (range, 21-91) years. The median number of precursor diagnoses was 5 with dyspnea and fatigue being the most prevalent. The time from the first occurrence of a precursor to AL diagnosis ranged from 3.2 to 21.4 months. Analyses of pairwise co-occurrence of specific diagnoses indicated a high association (Cole's coefficient >0.6) among the examined precursor diagnoses. These findings provide novel information about the timing and co-occurrence of key precursor conditions and could be used to develop algorithms for early identification of AL amyloidosis.

Healthcare resource utilisation and costs associated with AL amyloidosis: a retrospective matched cohort study.

We conducted a retrospective population-based, matched cohort study using the National Health Insurance Research Database to estimate healthcare resource utilisation (HRU) and costs in patients with newly diagnosed AL amyloidosis in Taiwan. Cases were matched 10:1 by age, sex, and area of residence to patients without AL amyloidosis (comparators) randomly selected from the database during the same time period. Annual all-cause HRU and costs for 3 years were quantified. AL amyloidosis-attributable costs were obtained by subtracting all-cause HRU costs incurred by comparators from cases. The mean age of all patients was 60.78 years and 59.07% were male. Co-morbidities were more frequent in cases than comparators. By 6 months after diagnosis, 12.1% of cases had died versus 0.9% of comparators. In the first year, cases had 103% more outpatient visits, 177% more emergency room visits, were hospitalised 4-times more frequently, and spent 5.5-times more days in hospital than comparators, and total healthcare costs were > sixfold higher. Costs incurred during the first year after diagnosis accounted for 55% of the 3-year cumulative cost. High HRU costs associated with delayed diagnosis and end-organ damage indicate a need for earlier diagnosis and more effective treatments for AL amyloidosis.

Prevalence, Characteristics, and Impact on Prognosis of Aortic Stenosis in Patients With Cardiac Amyloidosis.

BACKGROUND: Cardiac amyloidosis (CA) is frequently found in older patients with aortic stenosis (AS). However, the prevalence of AS among patients with CA is unknown. The objective was to study the prevalence and prognostic impact of AS among patients with CA. METHODS AND RESULTS: We conducted a retrospective analysis of a prospective registry comprising 976 patients with native aortic valves who were confirmed with wild type transthyretin amyloid (ATTRwt), hereditary variant transthyretin amyloid (ATTRv), or immunoglobulin light-chain (AL) CA. CA patients' echocardiograms were re-analyzed focusing on the aortic valve. Multivariable Cox regression analysis was performed to assess the mortality risk associated with moderate or greater AS in ATTRwt CA. The crude prevalence of AS among patients with CA was 26% in ATTRwt, 8% in ATTRv, and 5% in AL. Compared with population-based controls, all types of CA had higher age- and sex-standardized rate ratios (SRRs) of having any degree of AS (AL: SRR, 2.62; 95% Confidence Interval (CI) [1.09-3.64]; ATTRv: SRR, 3.41; 95%CI [1.64-4.60]; ATTRwt: SRR, 10.8; 95%CI [5.25-14.53]). Compared with hospital controls, only ATTRwt had a higher SRR of having any degree of AS (AL: SRR, 0.97, 95%CI [0.56-1.14]; ATTRv: SRR, 1.27; 95%CI [0.85-1.44]; ATTRwt: SRR, 4.01; 95%CI [2.71-4.54]). Among patients with ATTRwt, moderate or greater AS was not associated with increased all-cause death after multivariable adjustment (hazard ratio, 0.71; 95%CI [0.42-1.19]; P=0.19). CONCLUSIONS: Among patients with CA, ATTRwt but not ATTRv or AL is associated with a higher prevalence of patients with AS compared with hospital controls without CA, even after adjusting for age and sex. In our population, having moderate or greater AS was not associated with a worse outcome in patients with ATTRwt.

Real-world treatment patterns, costs, and outcomes in patients with AL amyloidosis: analysis of the Optum EHR and commercial claims databases.

BACKGROUND: This study characterised real-world treatment patterns, clinical outcomes, and cost-of-illness in patients with light-chain (AL) amyloidosis. METHODS: Data were extracted from the US-based Optum® EHR and Clinformatics® Data Mart (claims) databases (2008-2019) for patients newly diagnosed with AL amyloidosis and who initiated anti-plasma cell therapies. Healthcare resource utilisation (HCRU) and related costs were compared across lines of therapy (LOT). Incidences of cardiac and renal failure were evaluated using the Kaplan-Meier method. RESULTS: About 1347 patients (EHR, n = 776; claims, n = 571) were included. Median age was 68 years; 56.8% were male. At initial diagnosis, 33.1% and 15.1% of patients had cardiac and renal failure, respectively. Most patients received bortezomib-containing treatment in LOT1 (69%); bortezomib-cyclophosphamide-dexamethasone was most common (26%). HCRU was similar across LOTs. Mean per-patient-per-month and per-patient-per-LOT costs were $19,343 and $105,944 for LOT1, $19,183 and $95,793 for LOT2, and $16,611 and $128,446 for LOT3, respectively. Costs were primarily driven by anti-plasma cell therapies, outpatient visits, and hospitalisations. The 5-year cardiac and renal failure rates following initial diagnosis were 64.5% and 39.0%, respectively. CONCLUSION: AL amyloidosis is associated with substantial costs and suboptimal outcomes, highlighting the need for new therapeutic approaches to prevent organ deterioration, and reduce disease burden.