Amyloidosis Research and Treatment Center

Pavia, Italy

Amyloidosis Research and Treatment Center

Pavia, Italy
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Palladini G.,Amyloidosis Research and Treatment Center | Palladini G.,University of Pavia | Milani P.,Amyloidosis Research and Treatment Center | Milani P.,University of Pavia | And 10 more authors.
Blood | Year: 2017

Immunomodulatory drugs are active agents in light-chain (AL) amyloidosis. However, previous studies could not show a survival advantage for patients with AL amyloidosis responding to salvage treatment with pomalidomide. In this phase 2 trial,weassessed the safety and efficacy of pomalidomide and dexamethasone (PDex) in patients with AL amyloidosis who were previously exposed to bortezomib, alkylators, and other immunomodulatory drugs. Twenty-eight patients were enrolled. Three patients received pomalidomide 2 mg/d with no dose-limiting toxicity. The remaining patients received 4mg/d. Pomalidomide was administered continuously and dexamethasone was given once per week at a dose of 20 or 40 mg. Fifteen patients experienced grade 3 to 4 adverse events; the most common were fluid retention and infection. Hematologic response was observed in 68% of patients (very good partial response or complete response in 29%), as well as improved survival. Median timetoresponsewas1month.PDexisarapidly active regimen and improves survival in responding, heavily pretreated patients with AL amyloidosis. © 2017 by The American Society of Hematology.


Ando Y.,Kumamoto University | Coelho T.,Hospital Of Santo Antonio | Berk J.L.,Boston University | Cruz M.W.,Federal University of Rio de Janeiro | And 7 more authors.
Orphanet Journal of Rare Diseases | Year: 2013

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. © 2013 Ando et al; licensee BioMed Central Ltd.


Palladini G.,Amyloidosis Research and Treatment Center | Palladini G.,University of Pavia | Hegenbart U.,University of Heidelberg | Milani P.,Amyloidosis Research and Treatment Center | And 13 more authors.
Blood | Year: 2014

The kidney is involved in 70% of patients with immunoglobulin light-chain (AL) amyloidosis, but little is known on progression or reversibility of renal involvement, and criteria for renal response have never been validated. Newly diagnosed patients from the Pavia (n = 461, testing cohort) and Heidelberg (n = 271, validation cohort) centers were included. Proteinuria >5 g/24h and estimated glomerular filtration rate (eGFR) <50 mL/min predicted progression to dialysis best. Proteinuria below and eGFR above the thresholds indicated low risk (0 and 4% at 3 years in the testing and validation cohorts, respectively). High proteinuria and low eGFR indicated high risk (60% and 85% at 3 years). At 6 months, a ≥25% eGFR decrease predicted poor renal survival in both cohorts and was adopted as criterion for renal progression. A decrease in proteinuria by ≥30% or below 0.5 g/24 h without renal progression was the criterion for renal response, being associated with longer renal survival in the testing and validation populations. Hematologic very good partial or complete remission at 6 months improved renal outcome in both populations. We identified and validated a staging system for renal involvement and criteria for early assessment of renal response and progression in AL amyloidosis that should be used in clinical practice and trial design. © 2014 by The American Society of Hematology.


Palladini G.,Amyloidosis Research and Treatment Center | Palladini G.,University of Pavia | Merlini G.,Amyloidosis Research and Treatment Center | Merlini G.,University of Pavia
European Journal of Internal Medicine | Year: 2013

Systemic amyloidoses are rare, complex diseases caused by misfolding of autologous proteins. Although these diseases are fatal, effective treatments exist that can alter their natural history, provided that they are started before irreversible organ damage has occurred. The cornerstones of the management of systemic amyloidoses are early diagnosis, accurate typing, appropriate risk-adapted therapy, tight follow-up, and effective supportive treatment. Internists play a key role in suspecting the disease, thus allowing early diagnosis, starting the diagnostic workup and selecting patients that should be referred to specialized centers, judiciously titrating supportive measures, and following patients throughout the course of the disease. Here we review the pathogenesis, diagnosis and treatment of the most common forms of systemic amyloidoses. © 2013 European Federation of Internal Medicine.


Obici L.,Amyloidosis Research and Treatment Center | Merlini G.,Amyloidosis Research and Treatment Center | Merlini G.,University of Pavia
Expert Opinion on Investigational Drugs | Year: 2014

Introduction: Transthyretin (TTR)-related hereditary amyloidosis is an adult-onset, dominantly inherited, systemic neurodegenerative disease endemic in some populations. Stabilization of the native structure of TTR by small-molecule ligands has recently proved effective in slowing neurological progression. Two drugs, tafamidis and diflunisal, are now available for most patients, particularly in the early stage of the disease. However, this disorder remains life threatening with several unmet needs. There are great expectations for a number of novel agents undergoing investigation.Areas covered: The authors review the current investigational drugs for the treatment of TTR amyloidosis according to the different steps of the fibrillogenesis process they target. Innovative approaches include suppression of TTR secretion, prevention of TTR misfolding by stronger stabilizers identified through structure-based design and high-throughput screening methodologies as well as the redirection of pathogenic aggregates toward nontoxic species and reabsorption of deposits through amyloid disrupters and immunotherapy.Expert opinion: Suppression of TTR synthesis by antisense oligonucleotides and small-interfering RNA is presently one of the most promising therapeutic approaches. However, well-designed clinical trials are required to establish their safety and efficacy compared with liver transplantation, tafamidis and diflunisal. With a longer time frame, it may be possible to develop combination therapies that target multiple steps of the aggregation process that could provide the best long-life effective treatments for this devastating disease. © 2014 Informa UK, Ltd.


Brambilla F.,CNR Institute of Neuroscience | Lavatelli F.,Amyloidosis Research and Treatment Center | Merlini G.,Amyloidosis Research and Treatment Center | Merlini G.,University of Pavia | Mauri P.,CNR Institute of Neuroscience
Proteomics - Clinical Applications | Year: 2013

Amyloidoses are characterized by deposition of misfolded proteins as β-pleated sheet fibrils in organs. Despite the similar morphologic appearance of fibrils, at least 28 different proteins have been identified as causative agents of amyloidosis in humans, 14 of which responsible for systemic forms. Correct identification of the amyloidogenic proteins in each patient is crucial for clinical management, in order to avoid misdiagnosis, inappropriate treatment, and to assess the prognosis. Amyloidosis, being essentially a protein deposition disorder, is an attractive venue for the application of proteomics methodologies; among the different possible analytic goals, the most important is the unequivocal diagnosis and typing of the amyloid deposits. Amyloidosis typing has been traditionally based on a multidisciplinary approach, requiring detailed clinical evaluation and immunohistochemical studies together with biochemical and genetic tests. However, drawbacks of immunohistochemistry-based techniques have driven the search for alternative methods for direct amyloid typing. In particular, MS-based proteomics, recently introduced in the clinical practice with or without the previous 2DE separation of proteins, has revolutionized amyloid typing. This review provides a description of current proteomics methods for the identification of the amyloidogenic proteins, with special attention to the most innovative MS-based techniques. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Obici L.,Amyloidosis Research and Treatment Center | Merlini G.,Amyloidosis Research and Treatment Center | Merlini G.,University of Pavia
Swiss Medical Weekly | Year: 2012

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.


Rowczenio D.M.,University College London | Noor I.,University College London | Gillmore J.D.,University College London | Lachmann H.J.,University College London | And 6 more authors.
Human Mutation | Year: 2014

Hereditary systemic amyloidosis comprises a group of rare monogenic diseases inherited in an autosomal dominant fashion. It is associated with mutations in genes encoding eight different proteins, including transthyretin, apolipoprotein AI, apolipoprotein AII, lysozyme, fibrinogen A α-chain, cystatin C, gelsolin and beta-2-microglobulin. With support from the EU FP6 EURAMY project we have designed an online registry of genes and mutations in hereditary amyloidosis including their associated clinical phenotypes, with a view to having a single free online portal for the collection and distribution of this information. Users can search the registry by either mutation, phenotype or authors who have published or submitted mutations. It provides a submission form for reporting newly identified mutations. We also wanted to introduce nomenclature which complies with recommendations set out by Human Genome Variation Society and HUGO Gene Nomenclature Committee for description of new and known genetic variants. We hope this registry would be a useful and convenient tool for the medical and scientific community. © 2014 WILEY-LISS, INC.


Obici L.,Amyloidosis Research and Treatment Center | Merlini G.,Amyloidosis Research and Treatment Center | Merlini G.,University of Pavia
Autoimmunity Reviews | Year: 2012

AA amyloidosis may still dramatically impact on the outcome of patients with autoinflammatory diseases, particularly when diagnosis is delayed. Clinicians should maintain a high level of attention to identify early this severe complication. Initial signs mostly reflect kidney damage, with proteinuria, with or without renal failure, being the more frequent presenting feature. If SAA levels are not rapidly normalized, progression toward end-stage kidney disease and dialysis invariably occurs. Over time, multiple organ failure, including heart, autonomic and adrenal insufficiency usually complicates the disease course. Limited tools are still available to predict the occurrence of AA, therefore close monitoring of at risk patients is required to detect promptly the "early red flags" through periodic search for preclinical amyloid deposits and regular assessment of proteinuria and SAA concentration. Effective control of the underlying inflammatory process may halt disease progression and even reverse damage. Anti-cytokine agents are becoming the mainstay of therapy to prevent and treat AA, including patients with FMF that do not respond or do not tolerate adequate colchicine dosages. Renal transplantation can be considered in selected patients progressing to end-stage kidney disease. Novel treatments are under development, targeting key molecular events in the fibrillogenesis process. © 2012 Elsevier B.V.


Mollee P.,Princess Alexandra Hospital | Mollee P.,University of Queensland | Merlini G.,Amyloidosis Research and Treatment Center | Merlini G.,University of Pavia
Clinical Chemistry and Laboratory Medicine | Year: 2016

The disease causing agent in systemic AL amyloidosis is a monoclonal immunoglobulin free light chain, or fragments thereof, circulating in the blood. It is not surprising, therefore, that measurement of serum free light chains plays a central role in the management of this disorder. In this paper, we review the utility of the serum free light chain assay in the investigation, prognostication and monitoring of AL amyloidosis. Data on the two currently available commercial assays is compared and some practical applications of the assay's use are presented. While there are limitations, it is clear that the availability of the free light chain assay in the laboratory is a major advance and plays an essential role in the management of patients with AL amyloidosis. © 2016 by De Gruyter 2016.

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