Background
Early diagnosis of cardiac amyloidosis (CA) is warranted to initiate specific treatment and improve outcome. The amyloid light chain (AL) and inferior wall thickness (IWT) scores have been ...proposed to assess patients referred by haematologists or with unexplained left ventricular (LV) hypertrophy, respectively. These scores are composed of 4 or 5 variables, respectively, including strain data.
Methods
Based on 2 variables common to the AL and IWT scores, we defined a simple score named AMYLoidosis Index (AMYLI) as the product of relative wall thickness (RWT) and E/e′ ratio, and assessed its diagnostic performance.
Results
In the original cohort (n = 251), CA was ultimately diagnosed in 111 patients (44%). The 2.22 value was selected as rule‐out cut‐off (negative likelihood ratio LR− 0.0). In the haematology subset, AL CA was diagnosed in 32 patients (48%), with 2.36 as rule‐out cut‐off (LR− 0.0). In the hypertrophy subset, ATTR CA was diagnosed in 79 patients (43%), with 2.22 as the best rule‐out cut‐off (LR− 0.0). In the validation cohort (n = 691), the same cut‐offs proved effective: indeed, there were no patients with CA in the whole population or in the haematology or hypertrophy subsets scoring < 2.22, <2.36 or < 2.22, respectively.
Conclusions
The AMYLI score (RWT*E/e′) may have a role as an initial screening tool for CA. A < 2.22 value excludes the diagnosis in patients undergoing a diagnostic screening for CA, while a < 2.36 and a < 2.22 value may be better considered in the subsets with suspected cardiac AL amyloidosis or unexplained hypertrophy, respectively.
Summary
With improving outcomes in amyloid light‐chain (AL) amyloidosis, there is a need to study novel agents in this setting. We report outcomes of 40 patients with relapsed AL amyloidosis treated ...with ixazomib + lenalidomide + dexamethasone (IRd). Haematological responses were assessed on an intention‐to‐treat basis at three months: complete response (CR) – 8 (20·5%), very good partial response (VGPR) – 8 (20·5%), partial response (PR) – 7 (17·9%) and no response (NR) – 16 (41·0%). One patient had missing data. Six patients subsequently improved response. Best responses were: CR – 10 (25·6%), VGPR – 8 (20·5%), PR – 7 (17·9%), NR – 14 (35·9%). Cardiac and renal organ responses occurred in 5·6% and 13·3% respectively. Median progession‐free survival (PFS) was 17·0 months (95% CI 7·3–20·7 months), improving to 28·8 months (95% CI 20·6–37·0 months) in those achieving CR/VGPR. Median overall survival was 29·1 months (95% CI 24–33 months). Serious adverse events were seen in 14 (35·0%) patients inclusive of 15 admissions due to: infection (6/15, 40·0%), fluid overload (5/15, 33·3%), cardiac arrhythmia (2/15, 13·3%), renal dysfunction (1/15, 6·6%) and anaemia (1/15, 6·6%). In summary, IRd is an oral treatment option with a manageable toxicity profile leading to deep responses in 47% of patients with relapsed AL amyloidosis.
Aims
Transthyretin amyloid cardiomyopathy (ATTR‐CM) is often assumed to be associated with wild‐type TTR genotype (ATTRwt) in elderly patients (aged ≥70), some of whom are not offered genetic ...testing. We sought to estimate the prevalence, clinical characteristics and prognostic implications of transthyretin (TTR) variants among elderly patients diagnosed with ATTR‐CM.
Methods and results
Data from consecutive patients over 70 years of age diagnosed with ATTR‐CM at the UK National Amyloidosis Centre between January 2010 and August 2022 were retrospectively evaluated. All patients underwent clinical evaluation, biochemical tests, echocardiography and TTR genotyping. The study outcome was all‐cause mortality. The study population consisted of 2029 patients with ATTR‐CM (median age 79 years at diagnosis, 13.5% females, 80.4% Caucasian). Variant ATTR‐CM (ATTRv‐CM) was diagnosed in 20.7% (n = 421) of the study population of whom 327 (77.7%) carried V122I, 47 (11.2%) T60A, 16 (3.8%) V30M and 31 (7.3%) other pathogenic TTR variants. During a median (range) follow‐up of 29 (12–48) months, ATTRv‐CM was associated with increased all‐cause mortality compared to ATTRwt‐CM, with the poorest survival observed in V122I‐associated ATTRv‐CM (p < 0.001). Univariable and multivariable logistic regression analyses in those with ATTR‐CM showed younger age at diagnosis (odds ratio OR 0.85 per year, p < 0.001), female sex (OR 2.73, p < 0.001), Afro‐Caribbean ethnicity (OR 65.5, p < 0.001), atrial fibrillation (OR 0.65, p = 0.015), ischaemic heart disease (OR 0.54, p = 0.007), peripheral polyneuropathy (OR 5.70, p < 0.001) and orthostatic hypotension (OR 6.29, p < 0.001) to be independently associated with ATTRv‐CM.
Conclusion
Up to 20.7% of elderly patients with ATTR‐CM have a pathogenic TTR variant. These findings support routine sequencing of the TTR gene in all patients with ATTR‐CM regardless of age.
Summary
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.
Transthyretin amyloidosis (ATTR) is caused by deposition of either wild‐type (ATTRwt) or variant (ATTRm) transthyretin. ATTRwt presents with restrictive cardiomyopathy, while ATTRm displays a range ...of organ involvement. This retrospective analysis includes all patients referred to a single UK center in the last 25 years for clinical and laboratory assessment of known or suspected amyloidosis who underwent TTR gene sequencing. A total of 4459 patients were included in this study; 37% had final diagnosis of ATTR amyloidosis; 27% light chain amyloidosis; 0.7% other types of amyloidosis; 21.3% had no amyloid and 14% had no data. TTR variants were found in 770 (17%) cases; the most prevalent were p.V142I, p.T80A, and p.V50M identified in 42, 25, and 16%, respectively. The median age at referral in each group was: 76 (range 47–93), 66 (40–81), and 45 years (21–86), respectively. Overall 42 rare or novel variants were identified. Forty‐two percent patients with ATTRm died at a median age of 73 years (33–89) with a median survival from diagnosis of 50 months. ATTRwt was the final diagnosis in 20% of patients undergoing genetic testing. Our findings of TTR variants in 17% of screened patients highlight the need for routine genetic testing in the evaluation of suspected ATTR amyloidosis.
This review reports genetic testing results for 4459 patients with known or suspected amyloidosis who underwent TTR gene sequencing over the last 25 years in the UK single centre. 37% had final diagnosis of ATTR amyloidosis; 27% light chain amyloidosis; 0.7% other types of amyloidosis; 21.3% had no amyloid and 14% had no data. 45 different TTR variants were found in 770 (17%) cases; most prevalent were p.V142I, p.T80A, and p.V50M identified in 42%, 25% and 16% respectively.
Abstract
Aims
To perform evaluation of widely embraced bone scintigraphy-based non-biopsy diagnostic criteria (NBDC) for ATTR amyloid cardiomyopathy (ATTR-CM) in clinical practice, and to refine ...serum free light chain (sFLC) ratio cut-offs that reliably exclude monoclonal gammopathy (MG) in chronic kidney disease.
Methods and results
A multi-national retrospective study of 3354 patients with suspected or histologically proven cardiac amyloidosis (CA) referred to specialist centres from 2015 to 2021; evaluations included radionuclide bone scintigraphy, serum and urine immunofixation, sFLC assay, eGFR measurement and echocardiography. Seventy-nine percent (1636/2080) of patients with Perugini grade 2 or 3 radionuclide scans fulfilled NBDC for ATTR-CM through absence of a serum or urine monoclonal protein on immunofixation together with a sFLC ratio falling within revised cut-offs incorporating eGFR; 403 of these patients had amyloid on biopsy, all of which were ATTR type, and their survival was comparable to non-biopsied ATTR-CM patients (p = 0.10). Grade 0 radionuclide scans were present in 1091 patients, of whom 284 (26%) had CA, confirmed as AL type (AL-CA) in 276 (97%) and as ATTR-CM in only one case with an extremely rare TTR variant. Among 183 patients with grade 1 radionuclide scans, 122 had MG of whom 106 (87%) had AL-CA; 60/61 (98%) without MG had ATTR-CM.
Conclusion
The NBDC for ATTR-CM are highly specific 97% (95% CI 0.91-0.99) in clinical setting, and diagnostic performance was further refined here using new cut-offs for sFLC ratio in patients with CKD. A grade 0 radionuclide scan all but excludes ATTR-CM but occurs in most patients with AL-CA. Grade 1 scans in patients with CA and no MG are strongly suggestive of early ATTR-type, but require urgent histologic corroboration.
Structured Graphical Abstract
Structured Graphical Abstract
A real-world analysis of 3354 patients referred to specialist centres with suspected or proven cardiac amyloidosis showed that the non-biopsy diagnostic criteria for ATTR-CM remain highly specific with inclusion of refined cut-offs for sFLC ratio in CKD, as long as the diagnostic algorithm is carefully adhered to and technical considerations are met. Legend: AL, light chain amyloidosis; ATTR, transthyretin amyloidosis; ATTR-CM, transthyretin amyloid cardiomyopathy; CA, cardiac amyloidosis; IFE, immunofixation electrophoresis; CA, cardiac amyloidosis; CMR, cardiac magnetic resonance; NBDC, non-biopsy diagnostic criteria; eGFR, estimated glomerular filtration rate; MG, monoclonal gammopathy; sFLC, serum free light chains; TTR, transthyretin.
Aims
Transthyretin amyloid cardiomyopathy (ATTR‐CM) is predominantly diagnosed in men. The few available studies suggest affected women have a more favourable cardiac phenotype. We aimed to ...characterize sex differences among consecutive patients with non‐hereditary and two prevalent forms of hereditary (h)ATTR‐CM diagnosed over a 20‐year period.
Methods and results
Analysis of deep phenotyping at presentation, changes on serial echocardiography and overall prognosis were evaluated. In total, 1732 consecutive patients were studied, comprising: 1095 with wild‐type (wt)ATTR‐CM; 206 with T60A‐hATTR‐CM; and 431 with V122I‐hATTR‐CM. Female prevalence was greater in T60A‐hATTR‐CM (29.6%) and V122I‐hATTR‐CM (27.8%) compared to wtATTR‐CM (6%). At presentation, females were 3.3 years older than males (wtATTR‐CM: 81.9 vs. 77.8 years; T60A‐hATTR‐CM: 68.7 vs. 65.1 years; V122I‐hATTR‐CM: 77.1 vs. 74.9 years). Body size significantly influenced measures of disease severity; when indexed, overall structural and functional phenotype was similar between sexes, the few significant differences suggested a mildly worse phenotype in females. No significant differences were observed in both disease progression on serial echocardiography and mortality across the overall population (p = 0.459) and when divided by genotype (wtATTR‐CM: p = 0.730; T60A‐hATTR‐CM: p = 0.161; V122I‐hATTR‐CM: p = 0.056).
Conclusion
This study of a well‐characterized large cohort of ATTR‐CM patients did not demonstrate overall differences between sexes in either clinical phenotype, when indexed, or with respect to disease progression and prognosis. Non‐indexed wall thickness measurements may have contributed to both under‐representation and delays in diagnosis for affected females and highlights the potential role of utilizing indexed echocardiographic parameters for a more accurate assessment of patients at diagnosis and for disease prognostication.
Deep echocardiographic phenotyping of 1732 patients with ATTR‐CM found no differences in the clinical phenotype between males and females when taking body size into account, with no differences in disease progression on serial imaging and no difference in mortality. Current clinical practice adopts the use of non‐indexed wall thickness measurements, which may have contributed to females being under‐represented, presenting later than males and often with a mildly worse phenotype.
Summary
Renal risk stratification in systemic immunoglobulin light‐chain (AL) amyloidosis is according to estimated glomerular filtration rate (eGFR) and urinary protein creatinine ratio (uPCR), the ...latter attributed to glomerular dysfunction, with proximal tubular dysfunction (PTD) little studied. Urinary retinol binding protein 4 (uRBP), a low molecular weight tubular protein and highly sensitive marker of PTD, was prospectively measured in 285 newly diagnosed, untreated patients with systemic AL amyloidosis between August 2017 to August 2018. At diagnosis, the uRBP/creatinine ratio (uRBPCR) correlated with serum creatinine (r = 0·618, P < 0·0001), uPCR (r = 0·422, P < 0·0001) as well as both fractional excretion of phosphate and urate (r = 0·563, P < 0·0001). Log uRBPCR at diagnosis was a strong independent predictor of end‐stage renal disease {hazard ratio HR 2·65, 95% confidence interval (CI) 1·06–6·64; P = 0·038}, particularly in patients with an eGFR >30 ml/min/1.73 m2 HR 4·11, (95% CI 1·45–11·65); P = 0·008 and those who failed to achieve a deep haematological response to chemotherapy within 3 months of diagnosis HR 6·72, (95% CI 1·83–24·74); P = 0·004, and also predicted renal progression HR 1·91, (95% CI 1·18–3·07); P = 0·008. Elevated uRBPCR indicates PTD and predicts renal outcomes independently of eGFR, uPCR and clonal response in systemic AL amyloidosis. The role of uRBPCR as a novel prognostic biomarker merits further study, particularly in monoclonal gammopathies of renal significance.
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