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Merlini G.,Amyloidosis Research and Treatment Center
Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program | Year: 2012

Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic plasma cell disorder occurring in 4.2% of adults > 50 years of age, which can progress into symptomatic diseases either through proliferation of the plasma cell clone, giving rise to multiple myeloma and other lymphoplasmacellular neoplasms, or through organ damage caused by the monoclonal protein, as seen in light-chain amyloidosis and related conditions. Differential diagnosis of asymptomatic and symptomatic monoclonal gammopathies is the determinant for starting therapy. The criteria for determining end-organ damage should include markers of organ injury caused by the monoclonal protein. Patient assessment and optimal follow-up are now performed using risk stratification models that should also take into account the risk of developing AL amyloidosis. Patients with low-risk MGUS (approximately 40% of all MGUS patients) need limited assessment and very infrequent follow-up. The ongoing development of novel molecular biomarkers and advanced imaging techniques will improve the identification of high-risk patients who may benefit from early therapeutic intervention through innovative clinical trials.

Ando Y.,Kumamoto University | Coelho T.,Hospital de Santo Antonio | Berk J.L.,Boston University | Cruz M.W.,Federal University of Rio de Janeiro | And 8 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.

The increasing number of effective agents allows rescue therapy of patients with light-chain (AL) amyloidosis refractory to ≥2 previous treatments. Lenalidomide is effective in this disease and its toxicity profile encourages its use in salvage regimens. All the patients with AL amyloidosis refractory to both melphalan and bortezomib referred to our center between July 2007 and July 2009 were treated with the combination of lenalidomide and dexamethasone. Twenty-four consecutive patients were enrolled. Seventy-nine percent were also refractory to thalidomide. Two patients died before evaluation of response, and 50% experienced severe adverse events. Survival was significantly shorter in subjects with troponin I >0.1 ng/mL and in patients diagnosed <18 months before treatment initiation. Hematologic response was observed in 41% of patients and prolonged survival (median 10 months vs. not reached, P = 0.005) independently from troponin I concentration and from pre-treatment disease duration. Salvage therapy beyond second line of treatment can improve survival in AL amyloidosis and lenalidomide plus dexamethasone is a valuable option in this setting.

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.

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.

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