Systemic amyloidosis Wechalekar, Ashutosh D, Dr; Gillmore, Julian D, FRCP; Hawkins, Philip N, FMedSci
The Lancet (British edition),
06/2016, Letnik:
387, Številka:
10038
Journal Article
Recenzirano
Summary Tissue deposition of protein fibrils causes a group of rare diseases called systemic amyloidoses. This Seminar focuses on changes in their epidemiology, the current approach to diagnosis, and ...advances in treatment. Systemic light chain (AL) amyloidosis is the most common of these conditions, but wild-type transthyretin cardiac amyloidosis (ATTRwt) is increasingly being diagnosed. Typing of amyloid fibrils, a critical determinant of therapy, has improved with the wide availability of laser capture and mass spectrometry from fixed histological tissue sections. Specific and accurate evaluation of cardiac amyloidosis is now possible using cardiac magnetic resonance imaging and cardiac repurposing of bone scintigraphy tracers. Survival in AL amyloidosis has improved markedly as novel chemotherapy agents have become available, but challenges remain in advanced disease. Early diagnosis, a key to better outcomes, still remains elusive. Broadening the amyloid-specific therapeutic landscape to include RNA inhibitors, fibril formation stabilisers and inhibitors, and immunotherapeutic targeting of amyloid deposits holds promise to transform outcomes in systemic amyloidoses.
Hereditary transthyretin amyloidosis is caused by the deposition of misfolded transthyretin proteins in peripheral nerves and other tissues. This phase 3 trial tested patisiran, a small interfering ...RNA targeting transthyretin messenger RNA, to treat the disease.
Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease, but many rheumatologists are not well acquainted with its management. The objective of this report is to ...produce evidence-based recommendations to guide rheumatologists and other health professionals in the treatment and follow-up of patients with FMF. A multidisciplinary panel, including rheumatologists, internists, paediatricians, a nurse, a methodologist and a patient representative, was assembled. Panellists came from the Eastern Mediterranean area, Europe and North America. A preliminary systematic literature search on the pharmacological treatment of FMF was performed following which the expert group convened to define aims, scope and users of the guidelines and established the need for additional reviews on controversial topics. In a second meeting, recommendations were discussed and refined in light of available evidence. Finally, agreement with the recommendations was obtained from a larger group of experts through a Delphi survey. The level of evidence (LoE) and grade of recommendation (GR) were then incorporated. The final document comprises 18 recommendations, each presented with its degree of agreement (0–10), LoE, GR and rationale. The degree of agreement was greater than 7/10 in all instances. The more controversial statements were those related to follow-up and dose change, for which supporting evidence is limited. A set of widely accepted recommendations for the treatment and monitoring of FMF is presented, supported by the best available evidence and expert opinion. It is believed that these recommendations will be useful in guiding physicians in the care of patients with FMF.
Nonbiopsy Diagnosis of Cardiac Transthyretin Amyloidosis Gillmore, Julian D; Maurer, Mathew S; Falk, Rodney H ...
Circulation (New York, N.Y.),
2016-June-14, 2016-Jun-14, 2016-06-14, 20160614, Letnik:
133, Številka:
24
Journal Article
Recenzirano
Odprti dostop
BACKGROUND—Cardiac transthyretin (ATTR) amyloidosis is a progressive and fatal cardiomyopathy for which several promising therapies are in development. The diagnosis is frequently delayed or missed ...because of the limited specificity of echocardiography and the traditional requirement for histological confirmation. It has long been recognized that technetium-labeled bone scintigraphy tracers can localize to myocardial amyloid deposits, and use of this imaging modality for the diagnosis of cardiac ATTR amyloidosis has lately been revisited. We conducted a multicenter study to ascertain the diagnostic value of bone scintigraphy in this disease.
METHODS AND RESULTS—Results of bone scintigraphy and biochemical investigations were analyzed from 1217 patients with suspected cardiac amyloidosis referred for evaluation in specialist centers. Of 857 patients with histologically proven amyloid (374 with endomyocardial biopsies) and 360 patients subsequently confirmed to have nonamyloid cardiomyopathies, myocardial radiotracer uptake on bone scintigraphy was >99% sensitive and 86% specific for cardiac ATTR amyloid, with false positives almost exclusively from uptake in patients with cardiac AL amyloidosis. Importantly, the combined findings of grade 2 or 3 myocardial radiotracer uptake on bone scintigraphy and the absence of a monoclonal protein in serum or urine had a specificity and positive predictive value for cardiac ATTR amyloidosis of 100% (positive predictive value confidence interval, 98.0–100).
CONCLUSIONS—Bone scintigraphy enables the diagnosis of cardiac ATTR amyloidosis to be made reliably without the need for histology in patients who do not have a monoclonal gammopathy. We propose noninvasive diagnostic criteria for cardiac ATTR amyloidosis that are applicable to the majority of patients with this disease.
BACKGROUND:Transthyretin amyloidosis cardiomyopathy (ATTR-CM) is an increasingly recognized cause of heart failure in older individuals. We sought to characterize the natural history of ATTR-CM and ...compare outcomes and quality of life among patients with acquired and hereditary forms of the disease.
METHODS:We studied 711 patients with wild-type ATTR-CM, 205 with hereditary ATTR-CM associated with the V1221 variant (V122I-hATTR-CM), and 118 with non-V122I-hATTR-CM at the UK National Amyloidosis Center between 2000 and 2017. Patients underwent prospective protocolized evaluations comprising assessment of cardiac parameters, functional status by 6-minute walk test, quality of life according to the Kansas City Cardiomyopathy Questionnaire, and survival. Hospital service usage pre- and postdiagnosis was established using English central health records in a subset of patients.
RESULTS:There was substantial diagnostic delay, with patients using hospital services a median (interquartile range) of 17 (9–27) times during the 3 years before diagnosis, by which time quality of life was poor; diagnosis of wild-type ATTR-CM was delayed >4 years after presentation with cardiac symptoms in 42% of cases. Patients with V122I-hATTR-CM were more impaired functionally (P<0.001) and had worse measures of cardiac disease (P<0.001) at the time of diagnosis, a greater decline in quality of life, and poorer survival (P<0.001) in comparison with the other subgroups.
CONCLUSIONS:ATTR-CM is an inexorably progressive and eventually fatal cardiomyopathy associated with poor quality of life. Diagnosis is often delayed for many years after symptoms develop. Improved awareness and wider use of recently validated diagnostic imaging methods are urgently required for patients to benefit from recent therapeutic developments.
Objectives This study sought to explore the potential role of noncontrast myocardial T1 mapping for detection of cardiac involvement in patients with primary amyloid light-chain (AL) amyloidosis. ...Background Cardiac involvement carries a poor prognosis in systemic AL amyloidosis. Late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) is useful for the detection of cardiac amyloid, but characteristic LGE patterns do not always occur or they appear late in the disease. Noncontrast characterization of amyloidotic myocardium with T1 mapping may improve disease detection. Furthermore, quantitative assessment of myocardial amyloid load would be of great value. Methods Fifty-three AL amyloidosis patients (14 with no cardiac involvement, 11 with possible involvement, and 28 with definite cardiac involvement based on standard biomarker and echocardiographic criteria) underwent CMR (1.5-T) including noncontrast T1 mapping (shortened modified look-locker inversion recovery ShMOLLI sequence) and LGE imaging. These were compared with 36 healthy volunteers and 17 patients with aortic stenosis and a comparable degree of left ventricular hypertrophy as the cardiac amyloid patients. Results Myocardial T1 was significantly elevated in cardiac AL amyloidosis patients (1,140 ± 61 ms) compared to normal subjects (958 ± 20 ms, p < 0.001) and patients with aortic stenosis (979 ± 51 ms, p < 0.001). Myocardial T1 was increased in AL amyloid even when cardiac involvement was uncertain (1,048 ± 48 ms) or thought absent (1,009 ± 31 ms). A noncontrast myocardial T1 cutoff of 1,020 ms yielded 92% accuracy for identifying amyloid patients with possible or definite cardiac involvement. In the AL amyloidosis cohort, there were significant correlations between myocardial T1 time and indices of systolic and diastolic dysfunction. Conclusions Noncontrast T1 mapping has high diagnostic accuracy for detecting cardiac AL amyloidosis, correlates well with markers of systolic and diastolic dysfunction, and is potentially more sensitive for detecting early disease than LGE imaging. Elevated myocardial T1 may represent a direct marker of cardiac amyloid load. Further studies are needed to assess the prognostic significance of T1 elevation.
To identify the criteria for hematologic and cardiac response to treatment in immunoglobulin light chain (AL) amyloidosis based on survival analysis of a large patient population.
We gathered for ...analysis 816 patients with AL amyloidosis from seven referral centers in the European Union and the United States. A different cohort of 374 patients prospectively evaluated at the Pavia Amyloidosis Research and Treatment Center was used for validation. Data was available for all patients before and 3 and/or 6 months after initiation of first-line therapy. The prognostic relevance of different criteria for hematologic and cardiac response was assessed.
There was a strong correlation between the extent of reduction of amyloidogenic free light chains (FLCs) and improvement in survival. This allowed the identification of four levels of response: amyloid complete response (normal FLC ratio and negative serum and urine immunofixation), very good partial response (difference between involved and uninvolved FLCs dFLC < 40 mg/L), partial response (dFLC decrease > 50%), and no response. Cardiac involvement is the major determinant of survival, and changes in cardiac function after therapy can be reliably assessed using the cardiac biomarker N-terminal natriuretic peptide type B (NT-proBNP). Changes in FLC and NT-proBNP predicted survival as early as 3 months after treatment initiation.
This study identifies and validates new criteria for response to first-line treatment in AL amyloidosis, based on their association with survival in large patient populations, and offers surrogate end points for clinical trials.
Diagnostic and therapeutic advances have led to much greater awareness of transthyretin cardiac amyloidosis (ATTR-CA). We aimed to characterize changes in the clinical phenotype of patients diagnosed ...with ATTR-CA over the past 20 years.
This is a retrospective observational cohort study of all patients referred to the National Amyloidosis Centre (2002-2021) in whom ATTR-CA was a differential diagnosis.
We identified 2995 patients referred with suspected ATTR-CA, of whom 1967 had a diagnosis of ATTR-CA confirmed. Analysis by 5-year periods revealed an incremental increase in referrals, with higher proportions of patients having been referred after bone scintigraphy and cardiac magnetic resonance imaging (2% versus 34% versus 51% versus 55%, chi-square
<0.001). This was accompanied by a greater number of ATTR-CA diagnoses, predominantly of the wild-type nonhereditary form, which is now the most commonly diagnosed form of ATTR-CA (0% versus 54% versus 67% versus 66%, chi-square
<0.001). Over time, the median duration of associated symptoms before diagnosis fell from 36 months between 2002 and 2006 to 12 months between 2017 and 2021 (Mann-Whitney
<0.001), and a greater proportion of patients had early-stage disease at diagnosis across the 5-year periods (National Amyloidosis Centre stage 1: 34% versus 42% versus 44% versus 53%, chi-square
<0.001). This was associated with more favorable echocardiographic parameters of structure and function, including lesser interventricular septal thickness (18.0±3.8 mm versus 17.2±2.6 mm versus 16.9±2.3 mm versus 16.6±2.4 mm,
=0.01) and higher left ventricular ejection fraction (46.0%±8.9% versus 46.8%±11.0% versus 47.8%±11.0% versus 49.5%±11.1%,
<0.001). Mortality decreased progressively during the study period (2007-2011 versus 2012-2016: hazard ratio, 1.57 95% CI, 1.31-1.89,
<0.001; and 2012-2016 versus 2017-2021: hazard ratio, 1.89 95% CI, 1.55-2.30,
<0.001). The proportion of patients enrolled into clinical trials and prescribed disease-modifying therapy increased over the 20-year period, but even when censoring at the trial or medication start date, year of diagnosis remained a significant predictor of mortality (2012-2016 versus 2017-2021: hazard ratio, 1.05 95% CI, 1.03-1.07,
<0.001).
There has been a substantial increase in ATTR-CA diagnoses, with more patients being referred after local advanced cardiac imaging. Patients are now more often diagnosed at an earlier stage of the disease, with substantially lower mortality. These changes may have important implications for initiation and outcome of therapy and urgently need to be factored into clinical trial design.
Objectives This study was devised to describe the different cardiac magnetic resonance (CMR) appearances in light chain amyloid (AL) and transthyretin-related amyloidosis (ATTR). Background CMR is ...increasingly used to investigate patients with suspected amyloidosis. Global subendocardial late gadolinium enhancement (LGE) has been reported as typical of AL amyloidosis, whereas different patterns have been noted in ATTR amyloidosis. Methods We performed de novo analyses on original DICOM magnetic resonance imaging in 46 patients with cardiac AL amyloidosis and 51 patients with ATTR type who had been referred to a specialist amyloidosis center between 2007 and 2012 after CMR. Histological examination was performed in all cases, with immunohistochemistry, to confirm systemic amyloidosis. Results Patients' median age was 68 ± 10 years, and 74% were male. Left ventricular mass was markedly increased in ATTR amyloidosis (228 g 202 to 267 g) compared with AL type (167 g 137 to 191 g) (p < 0.001). LGE was detected in all but 1 cardiac amyloidosis patient (AL type) and was substantially more extensive in ATTR compared with AL amyloidosis. Ninety percent of ATTR patients demonstrated transmural LGE compared with 37% of AL patients (p < 0.001). Right ventricular LGE was apparent in all ATTR patients but in only 33 AL patients (72%) (p < 0.001). Despite these findings, survival was significantly better in cardiac ATTR amyloidosis compared with AL type. We derived an LGE scoring system (Query Amyloid Late Enhancement) that independently differentiated ATTR from AL amyloidosis and, when incorporated into a logistic regression model with age and wall thickness, detected ATTR type with 87% sensitivity and 96% specificity. Conclusions Transmural patterns of LGE distinguished ATTR from AL cardiac amyloidosis with high accuracy in this real-world analysis of CMR. Precise diagnosis of cardiac amyloidosis is crucial given the role of chemotherapy in AL type and with novel therapies for ATTR type currently in development.
This study evaluated the prognostic potential of native myocardial T1 in cardiac transthyretin amyloidosis (ATTR) and compared native T1 with extracellular volume (ECV) in terms of diagnostic ...accuracy and prognosis.
ATTR is an increasingly recognized cause of heart failure that has an overlapping clinical phenotype with hypertrophic cardiomyopathy (HCM). Native T1 mapping by cardiac magnetic resonance (CMR) is useful for diagnosis in cardiac amyloidosis but its prognostic potential has never been assessed.
A total of 134 patients with wild-type ATTR (ATTRwt) (122 men; age 76 ± 7 years), 81 patients with hereditary-type ATTR (ATTRm) (60 men; age 69 ± 11 years), 44 patients with HCM (32 men; age 51 ± 13 years), and 12 asymptomatic mutation carriers (4 men; age 47 ± 10 years) were studied. All subjects underwent CMR with T1 mapping and ECV measurement. ATTR patients also underwent 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) scintigraphy.
Native T1 and ECV were elevated in ATTR compared with HCM (p < 0.001) and were both associated with a high diagnostic accuracy (area under the curve AUC: 0.87; 95% confidence interval CI: 0.82 to 0.91) for T1 and an AUC of 0.91 (95% CI: 0.87 to 0.94) for ECV. No significant difference in native T1 and ECV was found between ATTRwt and ATTRm, and ECV correlated well with 99mTc-DPD scintigraphy. During follow-up of a mean of 32 ± 17 months, 55 ATTRwt and 40 ATTRm patients died. Native T1 and ECV predicted death (T1: hazard ratio HR: 1.225 for each 59-ms increase; 95% CI: 1.010 to 1.486; p < 0.05; ECV: HR: 1.155 for each 3% increase; 95% CI: 1.097 to 1.216; p < 0.001), but only ECV remained independently predictive after adjustment for age, N-terminal pro−B-type natriuretic peptide, left ventricular ejection fraction, E/E′, left ventricular mass index, DPD grade, and late gadolinium enhancement.
Native T1 mapping and ECV are good diagnostic techniques for cardiac ATTR that are associated with prognosis. Both parameters correlated with mortality, but only ECV remained independently predictive of prognosis, suggesting that it is a more robust marker in cardiac ATTR.
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