The recent approval of three drugs for the treatment of amyloid transthyretin (ATTR) amyloidosis, both hereditary and wild-type, has opened a new era in the care of these diseases. ATTR amyloidosis ...is embedded in its pathophysiology, and the drugs target critical steps of the amyloid cascade. In addition to liver transplant, which removes the pathogenic variants, the introduction of gene silencers has allowed the suppression of both wild type and mutant transthyretin (TTR), thus extending the potential therapeutic range to wild-type cardiac amyloidosis. The kinetic stabilisation of TTR using small molecules has proved to be clinically effective both for amyloid neuropathy and cardiomyopathy. Gene silencers and kinetic stabilizers were recently approved on the basis of the outcome of phase III trials; however, comparative trials have not been performed, making it difficult to draw recommendations. Indications for liver transplantation have narrowed considerably. Here, guidelines for therapy are proposed based on expert consensus, acknowledging that the several drugs currently undergoing clinical trials will probably change in the near future the therapeutic armamentarium and, consequently, the therapeutic strategy. Indications for monitoring disease progression and drug efficacy are also provided for the management of these complexes, but now very treatable, diseases.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Purpose
To review the management of gastrointestinal symptoms in patients with hereditary transthyretin amyloidosis, discussing diagnostic evaluations, assessment of disease progression and ...therapeutic strategies that could be implemented in routine practice.
Methods
Literature review. Key search terms included “gastrointestinal symptoms”, “autonomic neuropathy”, “hereditary transthyretin amyloidosis” and “familial amyloid polyneuropathy”.
Results
Gastrointestinal disturbances are a common and serious manifestation of hereditary transthyretin amyloidosis, with significant effects on patients' quality of life and demonstrating a strong association with mortality. Gastrointestinal involvement is more often subclinical in the early stages of the disease, although in some patients gastric and/or bowel abnormalities may be the inaugural symptoms. In both cases, under-recognition, delayed investigation and suboptimal treatment frequently occur. A clear understanding of the mechanisms underlying gastrointestinal dysfunction in hereditary transthyretin amyloidosis is still lacking, but similar to diabetic enteropathy, multiple pathophysiological alterations seem to play a role.
Conclusions
Early detection and treatment of gastrointestinal disturbances is key to the successful treatment of this devastating disease. Gastroenterologists play a valuable role in both the diagnosis and the timely management of gastrointestinal symptoms in hereditary transthyretin amyloidosis and should, therefore, be part of a multidisciplinary and comprehensive approach to this disorder.
Transthyretin amyloidosis is a progressive and eventually fatal disease primarily characterized by sensory, motor, and autonomic neuropathy and/or cardiomyopathy. Given its phenotypic ...unpredictability and variability, transthyretin amyloidosis can be difficult to recognize and manage. Misdiagnosis is common, and patients may wait several years before accurate diagnosis, risking additional significant irreversible deterioration. This article aims to help physicians better understand transthyretin amyloidosis--and, specifically, familial amyloidotic polyneuropathy--so they can recognize and manage the disease more easily and discuss it with their patients. We provide guidance on making a definitive diagnosis, explain methods for disease staging and evaluation of disease progression, and discuss symptom mitigation and treatment strategies, including liver transplant and several pharmacotherapies that have shown promise in clinical trials.
These recommendations highlight recent experience in genetic counselling for the severe autosomal-dominant, late-onset transthyretin familial amyloid polyneuropathy (TTR-FAP) disease, and present a ...structured approach towards identification and monitoring of asymptomatic carriers of the mutated gene.
The effectiveness of current treatment options is still limited in patients with TTR-FAP beyond stage I. Diagnosis in the early stages of TTR-FAP is essential to prevent or delay the progression of disease. Existing legal and cultural issues differ among countries within Europe. Experts of the European Network for TTR-FAP (ATTReuNET) concluded that genetic counselling for diagnosed individuals and at-risk family members is mostly beneficial and should be carried out with care by trained professionals. Systematic and regular monitoring of an asymptomatic carrier is necessary to detect early signs of TTR-FAP and maximize the effectiveness of treatment. This includes five areas of assessment: history/clinical examination, sensorimotor function, autonomic dysfunction, cardiac function, and renal function. At least two related symptoms and positive biopsy findings are required to confirm diagnosis of TTR-FAP.
Early detection of TTR-FAP is essential to improve the prognosis of TTR-FAP. ATTReuNET recommends genetic counselling and routine monitoring for asymptomatic carriers of TTR-FAP.
The combination of oral melphalan and dexamethasone is considered standard therapy for patients with light-chain amyloidosis ineligible for autologous stem cell transplantation. However, previous ...trials reported different rates of response and survival, mainly because of the different proportions of high-risk patients. In the present study, including a total of 259 subjects, we treated 119 patients with full-dose melphalan and dexamethasone (dexamethasone 40 mg days 1-4), and 140 patients with advanced cardiac disease with an attenuated dexamethasone schedule (20 mg). Hematologic response rates were 76% in the full-dose group and 51% in the patients receiving the attenuated schedule; the corresponding complete response rates were 31% and 12%, respectively. The median survival was 7.4 years in the full-dose group and 20 months in the attenuated-dose group. Use of high-dose dexamethasone, amino-terminal pro-natriuretic peptide type-B >1800 ng/L, a difference between involved and uninvolved free light chains of >180 mg/L, troponin I >0.07 ng/mL, and response to therapy were independent prognostic determinants. In relapsed/refractory subjects bortezomib combinations granted high hematologic response rates (79% and 63%, respectively), proving the most effective rescue treatment after melphalan and dexamethasone. In summary, melphalan plus dexamethasone was highly effective with minimal toxicity, confirming its central role in the treatment of AL amyloidosis. Future randomized trials will clarify whether bortezomib is best used in frontline combination with melphalan and dexamethasone or as rescue treatment.
To evaluate the response to treatment of autoinflammatory diseases from an international registry and an up-to-date literature review.
The response to treatment was studied in a web-based registry in ...which clinical information on anonymised patients with autoinflammatory diseases was collected retrospectively as part of the Eurofever initiative. Participating hospitals included paediatric rheumatology centres of the Paediatric Rheumatology International Trial Organisation network and adult centres with a specific interest in autoinflammatory diseases. The following diseases were included: familial Mediterranean fever (FMF), cryopyrin-associated periodic syndromes (CAPS), tumour necrosis factor (TNF)-receptor associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), pyogenic arthritis pustulosis acne (PAPA) syndrome, deficiency of interleukin-1 receptor antagonist (DIRA), NLRP12-related periodic fever and periodic fever aphthosis pharyngitis adenitis (PFAPA) syndrome. Cases were independently validated by experts for each disease. A literature search regarding treatment of the abovementioned diseases was also performed using Medline and Embase.
22 months from the beginning of the enrolment, complete information on 496 validated patients was available. Data from the registry in combination with evidence from the literature confirmed that colchicine is the treatment of choice for FMF and IL-1 blockade for DIRA and CAPS. Corticosteroids on demand probably represent a valid therapeutic strategy for PFAPA, but also for MKD and TRAPS. Patients with poorly controlled MKD, TRAPS, PAPA or FMF may benefit from IL-1 blockade; anti-TNF treatment may represent a possible valuable alternative.
In the absence of high-grade evidence, these results could serve as a basis for therapeutic guidelines and to identify candidate drugs for future therapeutic trials.
Considering the important advances in treating specific types of systemic amyloidoses, unequivocal typing of amyloid deposits is now essential. Subcutaneous abdominal fat aspiration is the easiest, ...most common diagnostic procedure. We developed a novel, automated approach, based on Multidimensional Protein Identification Technology, for typing amyloidosis. Fat aspirates were obtained from patients with the most common systemic amyloidoses (ALλ, ALκ, transthyretin, and reactive amyloidosis), with Congo red score more than or equal to 3+, and nonaffected controls. Peptides from extracted and digested proteins were analyzed by Multidimensional Protein Identification Technology. On semiquantitative differential analysis (patients vs controls) of mass spectrometry data, specific proteins up-represented in patients were identified and used as deposit biomarkers. An algorithm was developed to classify patients according to type and abundance of amyloidogenic proteins in samples; in all cases, proteomic characterization was concordant with fibril identification by immunoelectron microscopy and consistent with clinical presentation. Our approach allows reliable amyloid classification using readily available fat aspirates.
Cerebral amyloid angiopathy (CAA), one of the main types of cerebral small vessel disease, is a major cause of spontaneous intracerebral haemorrhage and an important contributor to cognitive decline ...in elderly patients. Despite the number of experimental in vitro studies and animal models, the pathophysiology of CAA is still largely unknown. Although several pathogenic mechanisms including an unbalance between production and clearance of amyloid beta (Aβ) protein as well as 'the prion hypothesis' have been invoked as possible disease triggers, they do not explain completely the disease pathogenesis. This incomplete disease knowledge limits the implementation of treatments able to prevent or halt the clinical progression. The continuous increase of CAA patients makes imperative the development of suitable experimental in vitro or animal models to identify disease biomarkers and new pharmacological treatments that could be administered in the early disease stages to prevent irreversible changes and disease progression.
Abstract
Background
Monogenic autoinflammatory diseases are caused by pathogenic variants in genes that regulate innate immune responses, and are characterized by sterile systemic inflammatory ...episodes. Since symptoms can overlap within this rapidly expanding disease category, accurate genetic diagnosis is of the utmost importance to initiate early inflammation-targeted treatment and prevent clinically significant or life-threatening complications. Initial recommendations for the genetic diagnosis of autoinflammatory diseases were limited to a gene-by-gene diagnosis strategy based on the Sanger method, and restricted to the 4 prototypic recurrent fevers (MEFV, MVK, TNFRSF1A, and NLRP3 genes). The development of best practices guidelines integrating critical recent discoveries has become essential.
Methods
The preparatory steps included 2 online surveys and pathogenicity annotation of newly recommended genes. The current guidelines were drafted by European Molecular Genetics Quality Network members, then discussed by a panel of experts of the International Society for Systemic Autoinflammatory Diseases during a consensus meeting.
Results
In these guidelines, we combine the diagnostic strength of next-generation sequencing and recommendations to 4 more recently identified genes (ADA2, NOD2, PSTPIP1, and TNFAIP3), nonclassical pathogenic genetic alterations, and atypical phenotypes. We present a referral-based decision tree for test scope and method (Sanger versus next-generation sequencing) and recommend on complementary explorations for mosaicism, copy-number variants, and gene dose. A genotype table based on the 5-category variant pathogenicity classification provides the clinical significance of prototypic genotypes per gene and disease.
Conclusions
These guidelines will orient and assist geneticists and health practitioners in providing up-to-date and appropriate diagnosis to their patients.
ABSTRACT
Introduction
Hereditary transthyretin (hATTR) amyloidosis is a progressive, degenerative disease, with peripheral neuropathy, cardiomyopathy, and other clinical manifestations. In this study ...we examine the impact of hATTR amyloidosis on quality of life (QOL).
Methods
Neuropathy‐specific QOL, measured with the Norfolk QOL‐Diabetic Neuropathy questionnaire, was compared between patients with hATTR amyloidosis and patients with type 2 diabetes, whereas generic QOL, measured with the 36‐item Short Form Health Survey version 2 (SF‐36v2), was compared between patients with hATTR amyloidosis, the general population, and patients with chronic diseases.
Results
Neuropathy‐specific QOL for patients with hATTR amyloidosis was nearly equivalent to that of patients with type 2 diabetes with diabetic neuropathy accompanied by a history of ulceration, gangrene, or amputation. Generic QOL was worse than that seen in the general population, with physical functioning worse than that for patients with multiple sclerosis and congestive heart failure.
Discussion
Patients with hATTR amyloidosis show significant burden on QOL, particularly in physical functioning. Muscle Nerve 60: 169–175, 2019
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