State-of-the-art review on AL amyloidosis in Western Countries: Epidemiology, health economics, risk assessment and therapeutic management of a rare disease.

Amyloidosis is the term to define a broad array of rare protein misfolding syndromes. Among them, light chain (AL) amyloidosis is the most common, affecting roughly 10 people per million/year. The core purpose of the present literature review is to shed light on the academic and clinical knowledge on the condition, encompassing its i) epidemiology, ii) economic burden, and iii) quality of life consequences. The areas of interest are Europe and North America. Literature search was primarily performed on Embase® and finally integrated with additional, deemed eligible, sources. Pre-defined PICOS criteria were employed for the inclusion and exclusion processes. A total of 64 studies were comprehensively included in the current literature review as compliant with the inclusion criteria. The results were presented according to the outcomes of interest and eventually triangulated and compared to available literature studies. A broad picture on the main aspects of AL amyloidosis is delivered.

Incidence rate of hospitalization and mortality in the first year following initial diagnosis of cardiac amyloidosis in the US claims databases.

OBJECTIVE: This study aimed to determine rates of hospitalization and in-hospital mortality in the first year following amyloidosis diagnosis with cardiac involvement using observational databases. METHODS: Three administrative claims databases, IBM MarketScan® Commercial Claims and Encounters (CCAE), IBM MarketScan® Multi-State Medicare Database (MDCR), and Optum's de-identified Clinformatics® Data Mart Database (Optum) were analyzed. Adults ≥18 years old, with a diagnosis of amyloidosis and evidence of cardiac involvement (i.e. heart failure, heart block, or cardiomyopathy) but no hepatic/renal failure prior to amyloidosis diagnosis were included for analysis. The primary analyses identified patients between 01-01-2010 and 31-12-2017 period. We calculated the rates of hospitalization and in-hospital mortality within 1 year after the initial diagnosis of amyloidosis. A sensitivity analysis was conducted for patients identified in Optum database during 2004-2011 period, which provided additional mortality information. RESULTS: A total of 419, 654, and 922 patients from CCAE, MDCR, and Optum were identified during 2010-2017 period, with mean age of 55.6, 77.8, and 74.2 years, respectively. Within 1 year following initial amyloidosis diagnosis, incidence rates (95% confidence interval [CI]) of hospitalization were 78.4 (66.3, 90.4), 78.6 (69.2, 87.9), and 61.2 (54.4, 68.0) per 100 person-years, rates of in-hospital mortality were 16.5 (11.8, 21.3), 8.4 (5.7, 11.0), and 17.7 (14.5, 21.0) per 100 person-years, in CCAE, MDCR, and Optum, respectively. The mortality rate from the sensitivity analysis among patients identified in Optum 2004-2011 period was higher compared with Optum 2010-2017 period. CONCLUSIONS: The results from this study indicate that amyloidosis with cardiac involvement is a condition with high rates of hospitalization and mortality in the first year after initial diagnosis. Future studies are needed to further evaluate the outcomes within the subtypes of amyloidosis and understand the risk factors associated with poor prognoses.

Impact of Arrhythmias on Hospitalizations in Patients With Cardiac Amyloidosis.

Cardiac involvement in amyloidosis is associated with a poor prognosis. Data on the burden of arrhythmias in patients with cardiac amyloidosis (CA) during hospitalization are lacking. We identified the burden of arrhythmias using the National Inpatient Sample (NIS) database from January 2016 to December 2017. We compared patient characteristics, outcomes, and hospitalization costs between CA patients with and without documented arrhythmias. Out of 5,585 hospital admissions for CA, 2,020 (36.1%) had concurrent arrhythmias. Propensity-score matching for age, sex, income, and co-morbidities was performed with 1,405 CA patients with arrhythmias and 1,405 patients without. The primary outcome of all-cause mortality was significantly higher in CA patients with arrhythmia than without(13.9% vs 5.3%, p-value <0.001). Atrial fibrillation (AF) was the most common (72.2%) arrhythmia in CA patients with concurrent arrhythmia. The secondary outcomes of AF-related mortality (11.95% vs 9.16%, p-value = 0.02) and acute and acute on chronic as heart failure (HF) exacerbation (32.38% vs 24.91%, p-value <0.0001) were significantly higher in CA and concurrent arrhythmia compared with CA patients without. The total length of hospital stay (6[3 to 12] vs 5[3 to 10], p-value <0.001) and cost of hospitalization were ($ 15,086[7,813 to 30,373] vs $ 12,219[6,865 to 23,997], p-value = 0.001) were significantly greater among CA with arrhythmia compared with those without. These data suggest that the presence of arrhythmias in CA patients during hospital admission is associated with a poorer prognosis and may reflect patients with a higher risk of HF exacerbation and mortality.

Transthyretin amyloid deposits in lumbar spinal stenosis and assessment of signs of systemic amyloidosis.

BACKGROUND: Wild-type transthyretin (ATTRwt) amyloidosis is the most common systemic amyloidosis in Western countries and manifests mainly as progressive restrictive cardiomyopathy. OBJECTIVE: To study the prevalence of ATTR deposits in ligament tissue in patients undergoing surgery for lumbar spinal stenosis and to assess whether these deposits are associated with cardiac amyloidosis. MATERIALS AND METHODS: A total of 250 patients, aged 50-89 (57% women), none with known cardiovascular disease, were included. Ligaments were investigated microscopically for amyloid. ATTR type was determined by immunohistochemistry and fibril type by Western blot. The amount of amyloid was graded 0-4. All patients with grade 3-4 ATTR deposits were offered cardiac investigation including ECG, cardiac ultrasound, plasma NT-proBNP and cardiac magnetic resonance (CMR), including modern tissue characterization. RESULTS: Amyloid was identified in 221 of the samples (88.4%). ATTR appeared in 93 samples (37%) of whom 42 (17 women and 25 men) were graded 3-4; all had fibril type A (mixture of full-length TTR and fragmented TTR). Twenty-nine of 42 patients with grade 3-4 ATTR deposits accepted cardiovascular investigations; none of them had definite signs of cardiac amyloidosis, but five men had a history of carpal tunnel syndrome. CONCLUSIONS: The prevalence of ATTR deposits in ligamentum flavum in patients with lumbar spinal stenosis was high but not associated with manifest ATTR cardiac amyloidosis. However, the findings of fibril type A, the prevalence of previous carpal tunnel syndrome and ATTR amyloid in surrounding adipose and vascular tissue indicate that amyloid deposits in ligamentum flavum may be an early manifestation of systemic ATTR disease.

Reproducibility and Repeatability of Assessment of Myocardial Light Chain Amyloidosis Burden Using 18F-Florbetapir PET/CT.

BACKGROUND: 18F-florbetapir PET is emerging as an excellent quantitative tool to quantify cardiac light chain (AL) amyloidosis burden. The primary aim of this study was to determine interobserver reproducibility and intraobserver repeatability, defined per the recommendations of the Quantitative Imaging Biomarker Alliance technical performance group, of PET 18F-florbetapir retention index (RI) in patients with cardiac AL amyloidosis. METHODS: The study cohort comprised 37 subjects with systemic AL amyloidosis enrolled in the prospective study: Molecular Imaging of Primary Amyloid Cardiomyopathy (clinical trials.gov NCT: 02641145). Using 10 mCi of 18F-florbetapir, a 60-minute dynamic cardiac scan was acquired. Global and segmental left ventricular estimates of retention index (RI) of 18F-florbetapir were calculated (Carimas 2.9 software, Turku, Finland). RI was analyzed twice, at least 24 hours apart, by two independent observers. Intraobserver repeatability and interobserver reproducibility were evaluated using Bland-Altman plots and scatter plots with fitted linear regression curves. RESULTS: All reproducibility (interobserver, r = 0.98) and repeatability (intraobserver, R=0.99 for each observer) measures of 18F-florbetapir RI are excellent. On the Bland-Altman plots, the agreement limits for global 18F-florbetapir RI were high and ranged for reproducibility (interobserver) from - 9.3 to + 9.4% (Fig. 1), and for repeatability (observer 1 from - 10.8 to + 10.7% and from - 9.2 to + 11.4%, for observer 2). CONCLUSIONS: The present study showed excellent interobserver reproducibility and intraobserver repeatability of 18F-florbetapir PET retention index in patients with cardiac AL amyloidosis.

Epidemiology of Cardiac Amyloidosis-Associated Heart Failure Hospitalizations Among Fee-for-Service Medicare Beneficiaries in the United States.

Background Cardiac amyloidosis is a substantially underdiagnosed disease, and contemporary estimates of the epidemiology of amyloidosis are lacking. This study aims to determine the incidence and prevalence of cardiac amyloidosis among Medicare beneficiaries from 2000 to 2012. Methods and Results Medicare beneficiaries were counted in the prevalence cohort in each year they had (1) ≥1 principal or secondary International Classification of Diseases, Ninth Revision code for amyloidosis and (2) ≥1 principal or secondary International Classification of Diseases, Ninth Revision code for heart failure or cardiomyopathy within 2 years after the systemic amyloidosis code. A beneficiary was counted in the incidence cohort only during the first year in which they met criteria. Primary outcomes included the prevalence and incidence of hospitalizations for cardiac amyloidosis. There were 4746 incident cases of cardiac amyloidosis in 2012 and 15 737 prevalent cases in 2012. There was also a significant increase in the prevalence rate (8 to 17 per 100 000 person-years) and incidence rate (18 to 55 per 100 000 person-years) from 2000 to 2012, most notable after 2006. Incidence and prevalence increased substantially more among men, the elderly, and in blacks. Conclusions The incidence and prevalence rates of cardiac amyloidosis are higher than previously thought. The incidence and prevalence rates of cardiac amyloidosis among hospitalized patients have increased since 2000, particularly among specific patient subgroups and after 2006, suggesting improved amyloidosis awareness and higher diagnostic rates with noninvasive imaging. In light of these trends, cardiac amyloidosis should be considered during the initial work up of patients ≥65 years old hospitalized with heart failure.

Disease burden of systemic light-chain amyloidosis: a systematic literature review.

INTRODUCTION: A systematic literature review on systemic light chain (AL) amyloidosis was conducted in order to understand the disease burden, and identify unmet medical needs and knowledge gaps. METHODS: MEDLINE, Embase and Cochrane databases were searched for English language studies published in the last 10 years using search terms that focused on the clinical, economic, and patient-reported outcome (PRO) aspects of AL amyloidosis. There was a low yield of articles in the economic and PRO categories and additional searches were conducted in clinical conference proceedings, and using Google and Google Scholar. After review, there were 65 articles included for data extraction. RESULTS: AL amyloidosis is a rare disorder without any FDA or EMA approved indications for drug therapy. Using off-label therapies, there is a high rate, 42-64%, of non-response or progression, and an associated high mortality. Toxicities during therapy are common with estimates of up to 30-40% of patients experiencing severity of grade 3 or higher. Patients with AL amyloidosis report severe psychological distress, anxiety and clinical depression. CONCLUSIONS: There is a deficiency in the literature on the economic costs associated with AL amyloidosis, and information on costs has been derived from studies that examined multiple myeloma or other disease or treatment components common to AL amyloidosis.

Incidence rate of amyloidosis in patients from a medical care program in Buenos Aires, Argentina: a prospective cohort.

BACKGROUND: There are limited data concerning the incidence density (ID) of ATTRwt, AL and AA amyloidosis in the Argentinean population. Our aim was to estimate the ID of ATTRwt, AL and AA amyloidosis at the Hospital Italiano Medical Care Program in Buenos Aires, Argentina. METHODS: Population was all members of a hospital-based health maintenance organization who were affiliated since January 2006 to December 2014. Each person was followed contributing time at risk since January 2006 or enrollment date to the final date. Incident cases of amyloidosis were captured from the institutional registry of amyloidosis. Incidence rate was calculated with 95% confidence intervals. RESULTS: During the nine-year study period, there were 15 patients with ATTRwt, 12 with AL and 2 with AA amyloidosis for 1 105 152 person-years of follow-up. The crude ID of ATTRwt amyloidosis was 13.5 (95%CI 8.1-22.4), that of AL amyloidosis 11 (95%CI: 6-19) and that of AA amyloidosis 1.8 (95%CI: 0.5-7.2) per 1 000 000 person-years. The highest ID was found in men (31.7 for ATTRwt, 15.9 for AL and 2.27 for AA amyloidosis per 1 000 000 person-years). The ID adjusted to the population of the city of Buenos Aires was 6.46 (95%CI: 3.17-9.74) for ATTRwt, 6.13 (95%CI: 2.57-9.7) for AL and 1.21 (95%CI: 0.56 to 2.99) for AA amyloidosis. CONCLUSIONS: This is the first paper to report the incidence density of ATTRwt, AL and AA amyloidosis in Latin America. Our results are consistent with other studies from other regions. Although systemic amyloidosis is a rare disease, it is a major health problem because of its morbi-mortality.

Management of systemic AL amyloidosis: recommendations of the Myeloma Foundation of Australia Medical and Scientific Advisory Group.

Systemic AL amyloidosis is a plasma cell dyscrasia with a characteristic clinical phenotype caused by multi-organ deposition of an amyloidogenic monoclonal protein. This condition poses a unique management challenge due to the complexity of the clinical presentation and the narrow therapeutic window of available therapies. Improved appreciation of the need for risk stratification, standardised use of sensitive laboratory testing for monitoring disease response, vigilant supportive care and the availability of newer agents with more favourable toxicity profiles have contributed to the improvement in treatment-related mortality and overall survival seen over the past decade. Nonetheless, with respect to the optimal management approach, there is a paucity of high-level clinical evidence due to the rarity of the disease, and enrollment in clinical trials is still the preferred approach where available. This review will summarise the Clinical Practice Guidelines on the Management of Systemic Light Chain (AL) Amyloidosis recently prepared by the Medical Scientific Advisory Group of the Myeloma Foundation of Australia. It is hoped that these guidelines will assist clinicians in better understanding and optimising the management of this difficult disease.

Prevalence of amyloid deposition in long standing rheumatoid arthritis in Iranian patients by abdominal subcutaneous fat biopsy and assessment of clinical and laboratory characteristics.

BACKGROUND: The study was aimed at determining the prevalence of secondary amyloidosis in a group of Iranian patients with Rheumatoid Arthritis (RA), and the assessment of its correlation with the clinical and laboratory findings and data. METHOD: A total number of 220 patients (167 female and 53 male) with a minimum five-year history of RA were selected. Congo red staining method was used for staining the specimens obtained by abdominal subcutaneous fat biopsy (ASFB) method. All of the specimens were examined for apple-green birefringence under polarized light microscope. Clinical and laboratory characteristics of the patients were assessed. Chi-square test and unpaired student's t-test were run for intergroup comparisons. RESULTS: Amyloid deposition test yielded positive results in 15 out of the 220 cases (6.8%) examined by the ASFB technique. Thirteen patients were found to have minimal amyloid deposits. Of all the clinically significant cases, 8 (53%) presented with proteinuria, and 7 cases (46.6%) had severe constipation. CONCLUSION: The prevalence of fat amyloid deposits in Iranian patients with RA is low. In up to half of the study group the deposits were subclinical. Follow up studies are required to determine whether this subclinical amyloidosis can develop into full-blown clinically significant amyloidosis.

Amyloidosis and its impact on patients with ESRD.

Patients, like those with ESRD, who have lost the ability to filter excess proteins from their bodies are at risk to develop beta-2-microglobin amyloidosis, also known as dialysis-related amyloidosis (DRA). When the kidneys do not work efficiently, a protein called beta-2-microglobulin can build up in the blood. Eventually, these molecules can form large deposits and potentially damage surrounding tissues. Currently, dialyzer membranes do not effectively remove these large molecules and, as the blood levels become elevated, deposits begin forming in bone, joints, and tendons resulting in pain and/or stiffness. Unfortunately, there is no known cure for DRA, although attempts are being made to develop dialyzer membranes that can more efficiently remove beta-2-microglobulin from the blood. Implications for practice include early diagnosis, patient teaching, optimal pain management and fall risk management.

Macular amyloidosis: an assessment of prevalence, sex, and age.

Macular amyloidosis is a relatively common cutaneous disease in Asia and the Middle East. It is characterized by a reticulated or rippled pattern of pigmentation mostly in the upper back. This study was performed not only to determine the disease sex and age distribution, but also to evaluate its risk factors and the frequency among the dermatology clinic patients. Based on the clinical and random histopathologic findings, 100 macular amyloidosis patients were evaluated in a period of 3 years. Although the sex distribution (9 : 1, female : male ratio) differed dramatically from most of the previous reports, it was consistent with few other series. Eighty one percent of patients were between 21 and 50 years of age. The mean age of the female patients was higher than that of the males (difference of two means was 10.26 years and P = 0.027). Backscatching during bathing probably is not a common practice in Iran, therefore we could not consider this as a risk factor in our study. We found no evidence of any other associated risk factors.

[Natural course of primary skin amyloidosis]. / Evolución natural de la amiloidosis cutánea primitiva.

We reviewed forty medical histories of patients with primitive cutaneous amyloidosis registered in the Unit of Dermatology, Venereology and Allergy of the Ecuadorian Social Security Institute of Guayaquil, who have abandoned the treatment for four or more years, finding a favorable evolution in the 37.5% of patients.