Hereditary transthyretin (TTR) amyloidosis is a rare, adult-onset, autosomal dominant disease caused by misfolding and extracellular amyloid deposition of variant forms of the circulating transport ...protein transthyretin. Originally described according to the predominant clinical presentation as familial amyloid polyneuropathy (FAP) or familial amyloid cardiomyopathy, it is now called by the name of the amyloidogenic protein. Not merely a nosological exercise, the current classification highlights the systemic nature of a phenotypically heterogeneous but single disease and reflects the likelyunique underlying molecular pathway. Since tafamidis, the first pharmacological therapy for the treatment of hereditary transthyretin amyloid polyneuropathy was approved in Europe in 2011, disease awareness has significantly improved worldwide, with patients increasingly being identified in regions where the disorder was not previously recognized.
Until recently, systemic amyloidoses were regarded as ineluctably disabling and life‐threatening diseases. However, this field has witnessed major advances in the last decade, with significant ...improvements in therapeutic options and in the availability of accurate and non‐invasive diagnostic tools. Outstanding progress includes unprecedented hematological response rates provided by risk‐adapted regimens in light chain (AL) amyloidosis and the approval of innovative pharmacological agents for both hereditary and wild‐type transthyretin amyloidosis (ATTR). Moreover, the incidence of secondary (AA) amyloidosis has continuously reduced, reflecting advances in therapeutics and overall management of several chronic inflammatory diseases. The identification and validation of novel therapeutic targets has grounded on a better knowledge of key molecular events underlying protein misfolding and aggregation and on the increasing availability of diagnostic, prognostic and predictive markers of organ damage and response to treatment. In this review, we focus on these recent advancements and discuss how they are translating into improved outcomes. Neurological involvement dominates the clinical picture in transthyretin and gelsolin inherited amyloidosis and has a significant impact on disease course and management in all patients. Neurologists, therefore, play a major role in improving patients' journey to diagnosis and in providing early access to treatment in order to prevent significant disability and extend survival.
Systemic AA amyloidosis is a long-term complication of several chronic inflammatory disorders, including rheumatoid arthritis, ankylosing spondylitis, autoinflammatory syndromes, Crohn's disease, ...malignancies and conditions predisposing to recurrent infections. Organ damage results from the extracellular deposition of proteolytic fragments of the acute-phase reactant serum amyloid A (SAA) as amyloid fibrils. A sustained high concentration of SAA is the prerequisite for developing AA amyloidosis. However, only a minority of patients with long-standing inflammation actually presents with this complication, pointing to the existence of disease-modifying factors, the best characterised of which being SAA1 genotype. The kidneys, liver and spleen are the main target organs of AA amyloid deposits. In more than 90% of patients proteinuria, nephrotic syndrome and/or renal dysfunction dominate the clinical picture at onset. If not effectively treated, this disease invariably leads to end stage kidney disease and renal replacement therapy, that are still associated with a poor outcome. Although the incidence of AA in rheumatoid arthritis and other chronic arthritides has continuously decreased over the past ten years, thanks to the increasing availability of more effective anti-inflammatory and immunosuppressive therapies, AA remains a life-threatening disease with several areas of uncertainty and unmet needs, deserving continuous efforts at prevention and effective treatment. The deeper understanding of the molecular mechanisms of amyloid formation and regression is now driving the development of novel treatments targeting different steps in the amyloidogenic cascade. These therapies will hopefully improve the quality of life and outcome of these patients in a near future.
Different diagnostic and classification criteria are available for hereditary recurrent fevers (HRF)-familial Mediterranean fever (FMF), tumour necrosis factor receptor-associated periodic fever ...syndrome (TRAPS), mevalonate kinase deficiency (MKD) and cryopyrin-associated periodic syndromes (CAPS)-and for the non-hereditary, periodic fever, aphthosis, pharyngitis and adenitis (PFAPA). We aimed to develop and validate new evidence-based classification criteria for HRF/PFAPA.
Step 1: selection of clinical, laboratory and genetic candidate variables; step 2: classification of 360 random patients from the Eurofever Registry by a panel of 25 clinicians and 8 geneticists blinded to patients' diagnosis (consensus ≥80%); step 3: statistical analysis for the selection of the best candidate classification criteria; step 4: nominal group technique consensus conference with 33 panellists for the discussion and selection of the final classification criteria; step 5: cross-sectional validation of the novel criteria.
The panellists achieved consensus to classify 281 of 360 (78%) patients (32 CAPS, 36 FMF, 56 MKD, 37 PFAPA, 39 TRAPS, 81 undefined recurrent fever). Consensus was reached for two sets of criteria for each HRF, one including genetic and clinical variables, the other with clinical variables only, plus new criteria for PFAPA. The four HRF criteria demonstrated sensitivity of 0.94-1 and specificity of 0.95-1; for PFAPA, criteria sensitivity and specificity were 0.97 and 0.93, respectively. Validation of these criteria in an independent data set of 1018 patients shows a high accuracy (from 0.81 to 0.98).
Eurofever proposes a novel set of validated classification criteria for HRF and PFAPA with high sensitivity and specificity.
Transthyretin amyloid cardiomyopathy (ATTR-CM) is a life-threatening, progressive, infiltrative disease caused by the deposition of transthyretin amyloid fibrils in the heart, and can often be ...overlooked as a common cause of heart failure. Delayed diagnosis due to lack of disease awareness and misdiagnosis results in a poorer prognosis. Early accurate diagnosis is therefore key to improving patient outcomes, particularly in the context of both the recent approval of tafamidis in some countries (including the United States) for the treatment of ATTR-CM, and of other promising therapies under development. With the availability of scintigraphy as an inexpensive, noninvasive diagnostic tool, the rationale to screen for ATTR-CM in high-risk populations of patients is increasingly warranted. Here the authors propose a framework of clinical scenarios in which screening for ATTR-CM is recommended, as well as diagnostic “red flags” that can assist in its diagnosis among the wider population of patients with heart failure.
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•ATTR-CM is a life-threatening, progressive disease that is often underdiagnosed and misdiagnosed.•Certain clinical scenarios have been identified that now warrant screening for ATTR-CM.•Once ATTR-CM is suspected, a definitive diagnosis can usually be achieved noninvasively.•Accurate, early diagnosis of ATTR-CM is key to enabling appropriate patient care.
Early and accurate diagnosis of transthyretin familial amyloid polyneuropathy (TTR-FAP) represents one of the major challenges faced by physicians when caring for patients with idiopathic progressive ...neuropathy. There is little consensus in diagnostic and management approaches across Europe.
The low prevalence of TTR-FAP across Europe and the high variation in both genotype and phenotypic expression of the disease means that recognizing symptoms can be difficult outside of a specialized diagnostic environment. The resulting delay in diagnosis and the possibility of misdiagnosis can misguide clinical decision-making and negatively impact subsequent treatment approaches and outcomes.
This review summarizes the findings from two meetings of the European Network for TTR-FAP (ATTReuNET). This is an emerging group comprising representatives from 10 European countries with expertise in the diagnosis and management of TTR-FAP, including nine National Reference Centres. The current review presents management strategies and a consensus on the gold standard for diagnosis of TTR-FAP as well as a structured approach to ongoing multidisciplinary care for the patient. Greater communication, not just between members of an individual patient's treatment team, but also between regional and national centres of expertise, is the key to the effective management of TTR-FAP.
Transthyretin amyloid cardiomyopathy (ATTR‐CM) is a life‐threatening condition with a heterogeneous clinical presentation. The recent availability of treatment for ATTR‐CM has stimulated increased ...awareness of the disease and patient identification. Stratification of patients with ATTR‐CM is critical for optimal management and treatment; however, monitoring disease progression is challenging and currently lacks best‐practice guidance. In this report, experts with experience in treating amyloidosis and ATTR‐CM developed consensus recommendations for monitoring the course of patients with ATTR‐CM and proposed meaningful thresholds and frequency for specific parameters. A set of 11 measurable features across three separate domains were evaluated: (i) clinical and functional endpoints, (ii) biomarkers and laboratory markers, and (iii) imaging and electrocardiographic parameters. Experts recommended that one marker from each of the three domains provides the minimum requirements for assessing disease progression. Assessment of cardiac disease status should be part of a multiparametric evaluation in which progression, stability or improvement of other involved systems in transthyretin amyloidosis should also be considered. Additional data from placebo arms of clinical trials and future studies assessing ATTR‐CM will help to elucidate, refine and define these and other measurements.
This consensus document from an international expert panel recommends a set of clinically feasible tools for the long‐term monitoring of patients with transthyretin amyloid cardiomyopathy (ATTR‐CM), including meaningful thresholds for defining disease progression and the frequency of measurements. 6MWT, 6‐min walk test; ECG, electrocardiogram; EQ‐5D, EuroQol five dimensions; GLS, global longitudinal strain; HF, heart failure; KCCQ, Kansas City Cardiomyopathy Questionnaire; LV, left ventricular; LVEF, LV, left ventricular ejection fraction; NAC, UK National Amyloidosis Centre; NT‐proBNP, N‐terminal pro‐B‐type natriuretic peptide; NYHA, New York Heart Association; QoL, quality of life.
Accurate diagnosis of systemic amyloidosis is necessary both for assessing the prognosis and for delineating the appropriate treatment. It is based on histologic evidence of amyloid deposits and ...characterization of the amyloidogenic protein. We prospectively evaluated the diagnostic performance of immunoelectron microscopy (IEM) of abdominal fat aspirates from 745 consecutive patients with suspected systemic amyloidoses. All cases were extensively investigated with clinical and laboratory data, with a follow-up of at least 18 months. The 423 (56.8%) cases with confirmed systemic forms were used to estimate the diagnostic performance of IEM. Compared with Congo-red–based light microscopy, IEM was equally sensitive (75% to 80%) but significantly more specific (100% vs 80%; P < .001). In amyloid light-chain (AL) amyloidosis, κ cases were more difficult to diagnose (sensitivity 71%), whereas the analysis of abdominal aspirate was informative in only 40% of patients with transthyretin amyloidosis. We found a high prevalence (20%) of a monoclonal component in patients with non-AL amyloidosis, highlighting the risk of misdiagnosis and the need for unequivocal amyloid typing. Notably, IEM identified correctly the specific form of amyloidosis in >99% of the cases. IEM of abdominal fat aspirates is an effective tool in the routine diagnosis of systemic amyloidoses.
•The first wide, prospective report on the role of IEM in the differential diagnosis of systemic amyloidosis.•IEM allows for the correct characterization of the amyloid protein in virtually all cases and represents a viable alternative to mass spectrometry.
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