Amyloidosis Foundation

Abstract Background Introduction of disease-specific medication has revolutionized the management of transthyretin associated cardiomyopathy (ATTR-CM). However, dedicated trials included different patient populations, primary endpoints, and follow-up periods, rendering study comparison challenging. Purpose This systematic review and meta-analysis aimed to harmonize data from all phase-3 placebo-controlled drug trials in ATTR-CM to inform on the magnitude and timing of treatment efficacy of ATTR-specific medication. Methods We searched PubMed and Embase for trials published up to February 23rd, 2025. Efficacy outcomes included all-cause death, cardiovascular (CV-)events, change in 6-minute walk distance (6-MWD), NT-proBNP levels and Kansas-City Cardiomyopathy-Questionnaire-Overall-Score (KCCQ-OS). Outcome metrics were pooled across trials. Results We included data from four identified trials (ATTR-ACT, ATTRibute, APOLLO-B, HELIOS-B) and 2,086 patients. Baseline risk profiles and death rates of the respective placebo groups differed substantially between trials. At 12-months, ATTR-specific medication showed a trend toward less decline in 6-MWD (least squares mean [LSM] difference: 12.9 meters; 95%-CI -4.1 to 29.8) and was associated with a significantly blunted decline in KCCQ-OS (LSM difference: 4.7points; 95%CI 2.3-7.0) and NT-proBNP (geometric mean fold ratio: 0.80; 95%CI 0.74-0.85) compared to placebo. These effects were consolidated with continued treatment. Over the maximum follow-up period and at 30-months, respectively, ATTR-specific medication reduced the risk for all-cause mortality by 28% (HR 0.72; 95%CI 0.59-0.87) and for CV-events by 42% (OR 0.58; 95%CI 0.47-0.73). Conclusions ATTR-specific medication exhibits early salutary effects on blood biomarkers, functional capacity and quality of life. These effects translate into reductions in CV-events and all-cause mortality after continued treatment.Baseline characteristics and KM-curves Forest plots for outcomes.

IntroductionHealthcare systems were reorganised in 2020 to manage the COVID-19 pandemic. Despite their urgent status, hospital admissions for acute heart failure (AHF) were reported to decline from 9% to 66% worldwide between 2020 and 2021, with divergent findings regarding in-hospital mortality. This study aimed to investigate in detail the evolution of AHF hospitalisations and in-hospital mortality in France from 2013 to 2024.MethodsBased on the 2.9 million AHF hospitalisations recorded in France from 2013 to 2024, yearly numbers of hospitalisations and deaths expected in years 2020–2024 were estimated using a Poisson regression model, with 2013–2019 as the reference period. The differences between observed and expected event counts in the years 2020–2024 were used to quantify the disruptions that occurred since the emergence of the pandemic.ResultsA total deficit of −222 913 (−223 908 to −221 926) (mean (95% CI)) AHF hospitalisations was estimated for the years 2020–2024, corresponding to a 16.1% decrease compared with pre-pandemic trends. The yearly reduction in AHF hospitalisations worsened over time, from −39 268 (–39 685 to –38 847) fewer cases in 2020 to –55 521 (–55 984 to −55 051) in 2024. Between 2020 and 2024, 7794 (7557 to 8028) excess in-hospital deaths were estimated, corresponding to an 8.4% excess compared with pre-pandemic trends. From 2021 to 2024, this excess ranged from 9.6% to 16% for females compared with 7.1% to 11.1% for males.ConclusionsThe apparent long-lasting changes in the management of patients with AHF in France observed since the COVID-19 pandemic emergence, particularly among females, suggest further research for better understanding the sustained observed disruptions.

Abstract Background/Introduction Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive myocardial disease that leads to repeated cardiovascular hospitalisations and death within 3 to 10 years if left untreated. A progressive rise in NT-proBNP (>30% and >300 pg/mL) can be a prognostic marker of disease progression and is associated with an increased risk of mortality in people with ATTR-CM. In addition, the 6-minute walk distance (6MWD) test is a tool for evaluating functional capacity and is associated with prognosis in patients with ATTR-CM. Although targeted therapies have shown clinical efficacy, thresholds for clinically meaningful improvements from baseline in ATTR-CM remain unclear. Acoramidis, an oral transthyretin (TTR) stabiliser that achieves near-complete (≥90%) TTR stabilisation, is approved in the US and Europe for the treatment of ATTR-CM. In the phase 3 randomised controlled study ATTRibute-CM, acoramidis demonstrated significant efficacy on the primary endpoint of all-cause mortality, cardiovascular-related hospitalization, change from baseline (CFB) in NT-proBNP, and CFB in 6MWD (p<0.0001). Purpose We assessed the capacity for acoramidis to achieve clinically meaningful improvements from baseline through 30 months in NT-proBNP and 6MWD in participants with ATTR-CM from the phase 3 ATTRibute-CM study. Methods Randomised participants in the ATTRibute-CM study received acoramidis or placebo (2:1) for 30 months. Clinically meaningful improvements from baseline for NT-proBNP were adopted as the inverse of those used to denote progression (reduction of >30% with a minimum decrease of >300 pg/mL) and defined improvement in 6MWD as an increase of >30 m. The proportion of participants who met clinically meaningful improvement in NT-proBNP and/or 6MWD were evaluated at month 30. Participants with missing assessments at month 30 were categorised as worsened. Univariate logistic regression with treatment group as an independent variable was performed to compute the odds ratio (OR) for response. Results A total of 611 participants were analysed in the modified intention-to-treat population (acoramidis: 409; placebo: 202). Participant baseline characteristics were comparable between groups. A total of 106 (25.9%) participants in the acoramidis group showed improvement in at least one parameter compared with 19 (9.4%) in the placebo group (Table 1; OR 3.4, 95% CI 2.0–5.7, p<0.0001). Among those meeting both improvement criteria, 12 (2.9%) were in the acoramidis group compared with two (1.0%) in the placebo group (Table 2; OR 3.0, 95% CI 0.7–13.6, p<0.1502). Conclusion(s) Acoramidis treatment resulted in clinically meaningful improvements from baseline in NT-proBNP and/or 6MWD across 30 months in >25% of patients with ATTR-CM, a finding inconsistent with the natural history of this progressive disease. Further studies are needed to understand patient characteristics and factors that influence these improvements on acoramidis.

Background/Objectives: Carpal tunnel syndrome (CTS) may signal extracardiac amyloid deposition years before transthyretin cardiac amyloidosis (ATTR-CA). This study investigated potential alterations of wrist tissue T1 values in ATTR-CA patients. Methods: Patients with ATTR-CA and healthy volunteers underwent 1.5T wrist MRI using a gradient echo sequence. Manual contouring of the transverse carpal ligament (TCL), median nerve (MN), sheaths of the flexor carpi tendons (SFCT), subcutaneous fat (SCF), muscle of the thenar eminence (MTE), and global wrist (GCW) was performed by two readers. Native T1 values were compared between groups. Results: Thirty-six patients with ATTR-CA (mean age, 78 ± 9 years; 32 men) and 69 volunteers (43 ± 14 years; 24 men) were evaluated. Mean native T1 values of TCL, MN, SFCT, SCF, and GCW were significantly lower in patients than in volunteers (p < 0.005 for all). Multivariable regression adjusted for age and sex confirmed these associations. SCF T1 was significantly lower in patients with CTS symptoms (885 [762–1080] ms) than in asymptomatic patients (1041 [949–1267] ms, p = 0.04). The highest area under the curve (AUC) for detecting CA was obtained for SFCT (AUC = 0.85; 95% CI 0.77–0.93). Conclusions: Patients with transthyretin cardiac amyloidosis show a significant reduction in the native T1 of wrist tissues compared with controls. These preliminary findings suggest that wrist T1 mapping may serve as a non-invasive marker of peripheral amyloid involvement, but require further validation in larger, age-matched, histologically validated studies.

Monoclonal gammopathy of renal significance (MGRS) defines disorders characterized by direct or indirect kidney injury caused by a monoclonal immunoglobulin produced by a B cell or plasma cell clone that does not meet current hematologic criteria for therapy. There are numerous MGRS-associated kidney diseases and these can result in the development of end stage kidney disease. As recurrence has been reported for all MGRS-associated kidney diseases, the current paradigm states that the underlying hematologic condition should be treated, and a complete or very good partial response should be obtained before kidney transplantation can be performed. However, based on a critical analysis of recent literature, we suggest that decisions regarding kidney transplantation in MGRS patients should be individualized considering the type of MGRS-associated kidney disease, patient age and comorbidity, underlying hematologic disorder, the risk to develop a hematological malignancy, presence and risk of extrarenal complications, estimated waiting time, the availability of a living kidney donor, availability of effective treatment and previous hematological treatment and response.

Wild-type transthyretin (ATTRwt) amyloidosis typically presents with restrictive cardiomyopathy. Kidney involvement is exceedingly rare. We report to our knowledge the first antemortem diagnosis of ATTRwt amyloidosis with kidney vasculature deposition in a patient presenting with progressive kidney failure. Notably, technetium-99m pyrophosphate scintigraphy showed no myocardial uptake. This case expands the known spectrum of organ involvement in ATTRwt amyloidosis and underscores the need to consider extracardiac manifestations in its diagnosis.

Although colchicine is the mainstay of familial Mediterranean fever (FMF) treatment, 5-10% of patients are considered to have colchicine resistance (CR). However, there is no globally agreed CR definition or indications for biological disease-modifying anti-rheumatic drugs (bDMARDs). A survey on 'Biologics in Monogenic Autoinflammatory Diseases', part of the 'Clinical Practice Strategies' (CLiPS) initiative, was conducted by a JIR cohort-initiated eCOST network among expert participants worldwide. Our primary aim was to provide a flowchart reflecting the different CR definitions and present data regarding bDMARD indications. The secondary aim was to determine how specific biases influence clinical approaches. We analysed the CliPS according to the experience levels of physicians, country-specific FMF prevalence, countries' gross domestic product, bDMARD availability and reimbursement policies of the countries. A total of 223 responses from 46 countries were included in the study. Almost half of the respondents (73/160, 45.6%) indicated that three to four attacks within the preceding 6 months were necessary for their CR definition. The most frequently used acute-phase reactant was C-reactive protein (157/164, 95.7%). Almost three-fourths of the respondents (74%, n=165) considered that supplementary factors, including complications of FMF, attack severity, elevated activity scores, patient-reported outcome and quality of life scales, influenced their CR definition. We present a novel flowchart describing physicians' general attitudes and unique findings regarding management strategies for colchicine-resistant FMF and shifting trends influenced by epidemiological and socioeconomic factors.

Renal prognosis in light-chain amyloidosis (AL) is determined by categorizing patients into three renal stages at diagnosis and assessing renal response or renal progression following chemotherapy after 6 months. We evaluated, in a test (N=1,935) cohort of patients with renal AL amyloidosis who were followed for a median of 95 months, a modified 4-stage model where Renal Stage 2 was sub-categorized according to preserved (2A) or reduced (2B) estimated glomerular filtration rate (eGFR). A hybrid model for evaluation of renal progression was also introduced, using an eGFR cut-off of 30 mL/min/1.73 m2. These models were compared with existing models; namely those of Palladini and Kastritis, and results were validated in a multicenter cohort (N=438). The risk of progression to renal replacement therapy (RRT) increased progressively across all Renal Stages of the Revised staging model (hazard ratio [HR] =3.25, HR=5.13, HR=10.66 for stages 2A, 2B and 3 respectively vs. stage 1; each P<0.001). Our revised criteria for renal response (HR=0.26, 95% confidence interval [CI]: 0.18-0.38 at 60 months) and renal progression (HR=8.15, 95% CI: 6.1-10.9) were independently predictive of RRT and outperfomed existing criteria at all follow-up time points. Renal progression was independently associated with mortality (HR=1.5, 95% CI: 1.26-1.86; P<0.001). The enhanced performance of these refined renal staging and response models enables timely and appropriate chemotherapy adjustment in patients with renal AL amyloidosis.

e13574 Background: AL (amyloid light chain) amyloidosis is associated with poor prognosis especially if diagnosis occurs with cardiac involvement. Current AL treatments target the plasma cell clone producing the light chains that misfold, aggregate and deposit in various tissues. The multi-organ manifestations of AL amyloidosis require a multidisciplinary care team of hematologist-oncologists, cardiologists, and other healthcare providers (HCPs) for comprehensive, patient-centric management. Since 2022, Amyloidosis Stakeholder Partnerships for Impact, Reach &amp; Equity (ASPIRE), facilitated by Amyloidosis Research Consortium (ARC) has been bringing together biotech and pharmaceutical companies with the shared goal of optimizing amyloidosis patient care. Through this study, ARC-ASPIRE sought to document and share the current best practices and key barriers to patient-centric amyloidosis care at US specialized amyloidosis centers (SACs). A broad range of stakeholders in amyloidosis care – healthcare providers at SACs, patients, referring physicians, and patient advocacy group representatives – were interviewed for this study. This abstract presents findings relevant to the management of patients with AL amyloidosis. Methods: Structured interviews were conducted between December 2023 and February 2024 with 77 amyloidosis stakeholders (physicians, advanced practice providers, registered nurses from 17 SACs, patients, referring physicians, and patient advocacy group representatives), including 12 hematology-oncologists and 8 AL patients. SACs were selected to be representative of current US amyloidosis care, based on geography, amyloidosis patient volume, years since establishment, and types of amyloidosis treated. Results: Three-quarters of participating SACs treat AL patients under a single multidisciplinary amyloidosis program. Multidisciplinary care is facilitated by regular team meetings, dedicated clinic days, and informal communications across specialties. At diagnosis, collaboration between cardiology and hematology-oncology ensures AL patients are accurately diagnosed and promptly treated. Sixty percent of SACs have a centralized intake system, and patients suspected with AL are prioritized to ensure an appointment within 1 week of referral. Key barriers were delayed or missed diagnosis due to low awareness of AL amyloidosis within community oncologists, travel burden to SACs, lack of seamless medical records sharing and telehealth regulations. Conclusions: The best practices outlined in this study serve to educate AL amyloidosis and non-AL amyloidosis HCPs for better multidisciplinary collaboration and early diagnosis. The key barriers identified should be addressed to improve patient care.