Treatment Of Systemic Amyloidosis Research Articles

Kidney Carbuncle in a Patient with Primary Systemic Al-Amyloidosis and Nephortic Syndrome

The diagnosis and treatment of systemic amyloidosis remains a significant clinical problem for physicians of various specialties. Infectious complications and sepsis account for up to 8% of deaths in amyloidosis patients. This clinical case describes the development of an initially asymptomatic monoclonal gammopathy of unclear significance into systemic AL-amyloidosis, which was complicated by the formation of a renal carbuncle after the first cycles of chemotherapy. There was a significant discrepancy between the severity of the patient’s overall clinical state and changes in laboratory parameters. There were no objective factors for the ascending spread of urinary tract infection or hematogenous dissemination from other foci, so a primary bacteremia was assumed.

Progress and challenges in the treatment of cardiac amyloidosis: a review of the literature.

Cardiac amyloidosis is a restrictive cardiomyopathy determined by the accumulation of amyloid, which is represented by misfolded protein fragments in the cardiac extracellular space. The main classification of systemic amyloidosis is determined by the amyloid precursor proteins causing a very heterogeneous disease spectrum, but the main types of amyloidosis involving the heart are light chain (AL) and transthyretin amyloidosis (ATTR). AL, in which the amyloid precursor is represented by misfolded immunoglobulin light chains, can involve almost any system carrying the worst prognosis among amyloidosis patients. This has however dramatically improved in the last few years with the increased usage of the novel therapies such as proteasome inhibitors and haematopoietic cell transplantation, in the case of timely diagnosis and initiation of treatment. The treatment for AL is directed by the haematologist working closely with the cardiologist when there is a significant cardiac involvement. Transthyretin (TTR) is a protein that is produced by the liver and is involved in the transportation of thyroid hormones, especially thyroxine and retinol binding protein. ATTR results from the accumulation of transthyretin amyloid in the extracellular space of different organs and systems, especially the heart and the nervous system. Specific therapies for ATTR act at various levels of TTR, from synthesis to deposition: TTR tetramer stabilization, oligomer aggregation inhibition, genetic therapy, amyloid fibre degradation, antiserum amyloid P antibodies, and antiserum TTR antibodies. Treatment of systemic amyloidosis has dramatically evolved over the last few years in both AL and ATTR, improving disease prognosis. Moreover, recent studies revealed that timely treatment can lead to an improvement in clinical status and in a regression of amyloid myocardial infiltration showed by imaging, especially by cardiac magnetic resonance, in both AL and ATTR. However, treating cardiac amyloidosis is a complex task due to the frequent association between systemic congestion and low blood pressure, thrombo‐embolic and haemorrhagic risk balance, patient frailty, and generally poor prognosis. The aim of this review is to describe the current state of knowledge regarding cardiac amyloidosis therapy in this constantly evolving field, classified as treatment of the cardiac complications of amyloidosis (heart failure, rhythm and conduction disturbances, and thrombo‐embolic risk) and the disease‐modifying therapy.

Challenges in Diagnosis and Treatment of Systemic Amyloidosis: 10 Years of Experience in a Public Brazilian University Center

Systemic Amyloidosis (SA) results from tissue deposition of insoluble protein fibrils leading to organ dysfunction. Considering the scarcity of data from Latin America, a retrospective study was conducted by reviewing medical records of patients with biopsy proven SA diagnosed from 2009 to 2018 at a public tertiary center to assess clinical, laboratory and therapeutic features. Confirmed SA subtype was established if causative protein was identified on tissue biopsies by immunohistochemistry (IHC), indirect immunofluorescence (IIF), mass spectrometry (MS) or in the presence of pathogenic gene mutation related to SA. Probable cases were classified as light chain SA (AL) if evidence of monoclonal gammopathy (MG), transthyretin SA (ATTR) if moderate/strong cardiac uptake in 99mTc-pyrophosphate scintigraphy (99mTc-PYP), classical neurological symptoms with familial history or previous liver transplant from a donor with hereditary ATTR (hATTR), and secondary SA (AA) in the context of underlying chronic inflammatory disease. Inconclusive cases had ≥2 concomitant features suggestive of different subtypes. Primary endpoint was overall survival (OS). From 198 cases revised, 110 met the eligibility criteria. Median age was 60 years, 56% were male. Before diagnosis 53% were seen by ≥3 physicians: 65% general practitioners, 45% nephrologists, 42% cardiologists. Median time from onset of symptoms to diagnosis was 11.3 months. In 79% of patients ECOG was ≤2. Clinical presentations were: 54% renal disorders, 43% heart disease, 36% consumptive syndrome, 26% gastrointestinal symptoms, 25% neuropathy, 19% fatigue, 12% skin lesions, 9% hepatic disorders. The mean number of biopsies performed per patient was 2.3 and 60% had a method to subtype amyloid on biopsy: 67% IIF, 36% IHC and MS in 1 case. Mean number of affected organs was 2.6 (19% 1 organ, 38% 2 and 43% ≥ 3). Main organs were: 75% heart, 55% kidney, 43% soft tissue, 37% peripheral nervous system. Dialysis patients were 12%. Positive familial history was seen in 7% and 17% were tested for genetic mutations: 63% for transthyretin, 21% fibrinogen, 5% lysozyme, 16% MEFV gene. MG screening was assessed in 97% of patients, amyloid protein A in 4 and 99m Tc-PYP performed in 11. SA subtypes were confirmed in 32% of patients, probable in 59% and inconclusive in 9%. Frequency of subtypes were 68% AL, 12% ATTR, 6% AA, 4% fibrinogen amyloidosis (AFib), 1% lysozyme amyloidosis (ALys). Most of AL were λ (75%) and 34% had coexisting multiple myeloma. Standard Mayo Clinic Staging (MCS) was evaluated in 56% (59% stage III, 31% II, 10% I). Stage III were assessed by European staging (32% IIIa, 48% IIIb, 20% IIIc). Revised MCS was available in 21% (25% each I to IV). Renal staging showed 81% stages I/II, 19% stage III. Among ATTR patients 1 was wild type and 69% had mutation in TTR gene: 44% V30M, 33% V122I, 11% G89L. In 11% genetic data were not assessed. Mutated ATTR was presumed in 2 domino liver transplant recipients from hATTR donors. Inflammatory diseases in AA were: 43% Familial Mediterranean Fever (FMF), rheumatoid arthritis, vasculitis, immunoglobulin G4-related disease, combined polymyositis/primary biliary cholangitis (14% each). Treatments in AL were: 81% chemotherapy (CT) (54% melphalan, 18% thalidomide, 10% bortezomib), 12% stem cell transplant, 12% supportive measures (SM), 4% doxycycline, 1 kidney transplantation. Responses were available in 40 cases: 30% PR, 13% VGPR, 18% CR, 25% no response, 15% progression. ATTR was treated with: 31% liver transplantation, 54% SM, 8% tafamidis, 8% doxycycline. AA related to FMF treatments were anti-IL1 and colchicine and other AA received immunosuppressive therapy for underlying diseases. ALys was treated with SM. CT was given to 1 AFib patient before proper diagnosis, the others received SM. Inconclusive cases were managed 90% with SM, 1 received empirical CT. Median follow-up time of survivors was 66.3 months. At 5 years, estimated OS was 33%. Median OS in AL and non-AL were 18 and 74.4 months respectively (p < 0.001). In conclusion, the broad clinical spectrum of SA and the complex diagnostic approach lead to late diagnoses in advanced stages. Medical awareness of the disease, early suspicion, establishment of reference centers, better diagnostic tools, multidisciplinary team, a SA registry and access to disease-modifying drugs may result in early diagnosis and prompt intervention, improving outcomes in Brazil and Latin America. Disclosures No relevant conflicts of interest to declare.

Effect of glyoxal and 1-methylisatin on stress-induced fibrillation of Hen Egg White Lysozyme: Insight into the anti-amyloidogenic property of the compounds with possible therapeutic implications

Systemic amyloidosis is a hereditary disorder that mostly arises as a result of specific point mutations to the wild type gene of lysozyme, forming mutant lysozyme variants leading to aggregation of the protein. The small monomeric protein Hen Egg White Lysozyme (HEWL) is a structural homolog of Human Lysozyme and is widely used as a model protein to investigate protein aggregation. In the present study, we have investigated the effect of 1-methylisatin, an indole derivative and glyoxal, a reactive dicarbonyl compound, on stress-induced aggregation of HEWL. Interaction of the compounds with HEWL induced changes in structure and surface hydrophobicity of the protein as evident from CD spectroscopy, tryptophan fluorescence and ANS binding studies. Additional experiments (Thioflavin T fluorescence, AFM imaging and DLS studies) demonstrate that stress induces amyloid-like fibrillation of HEWL, however, prior modification of the protein with glyoxal or 1-methylisatin significantly reduces its susceptibility to aggregation. High resolution mass spectrometric analysis indicated that 1-methylisatin primarily complexes with the protein in the form of a dimer. On the other hand, glyoxal-mediated modification of the protein induces formation of glycated adducts (carboxymethyllysine, hydroimidazolone). The results highlight possible clinical implications of the compounds in treatment of systemic amyloidosis and protein conformational disorder.

Клинические рекомендации по диагностике и лечению системного амилоидоза

Клинические рекомендации по диагностике и лечению системного амилоидоза

Detergent properties as the basis of the dimexide therapeutic effect in AA-amyloidosis infectious nature (clinical case analysis)

The article discusses the current possibilities of postinfectious AA-amyloidosis treatment with dimexide on the example of clinical observation, discribes in detail the problem of functional amyloid and debates the prospects of the principle of amyloid resorption in the treatment of systemic amyloidosis. The history of the use of dimexide in medical practice is given, thenecessary dataon the pharmacology of dimexide are presented.

Systemic Amyloidosis: a Contemporary Overview.

Amyloidosis constitutes a large spectrum of diseases characterized by an extracellular deposition of a fibrillar aggregate, generating insoluble and toxic amasses that may be deposited in tissues in bundles with an abnormal cross-β-sheet conformation, known as amyloid. Amyloidmay lead to a cell damage and an impairment of organ function. Several different proteins are recognized as able to produce amyloid fibrils with a different tissue tropism related to the molecular structure. The deposition of amyloid may occur as a consequence of the presence of an abnormal protein, caused by high plasma levels of a normal protein, or as a result of the aging process along with some environmental factors. Although amyloidosis is rare, amyloid deposits play a role in several conditions as degenerative diseases. Thus, the development of antiamyloid curative treatments may be a rational approach to treat neurodegenerative conditions like Alzheimer's disease in the future. Nowadays, novel treatment options are currently refined through controlled trials, as new drug targets and different therapeutic approaches have been identified and validated through modern advances in basic research. Fibril formation stabilizers, proteasome inhibitors, and immunotherapy revealed promising results in improving the outcomes of patients with systemic amyloidosis, and these novel algorithms will be effectively combined with current treatments based on chemotherapeutic regimens. The aim of this review is to provide an update ondiagnosis and treatment for systemic amyloidosis.

Molecular basis of the inhibition and disaggregation of thermally-induced amyloid fibrils of human serum albumin by an anti-Parkinson's drug, benserazide hydrochloride

This study summarises the results of multifactorial analysis of the inhibition/destabilization of human serum albumin (HSA) amyloid fibrils by an anti-Parkinson's drug, benserazide hydrochloride (BH). Different biophysical techniques have been utilized for this purpose. Rayleigh light scattering (RLS) and dynamic light scattering (DLS) confirmed the formation of aggregates, that were identified as amyloid fibrils by the thioflavin T (ThT) and Congo Red (CR) fluorescent dye binding assays. Formation of amyloid fibrils and their inhibition/disaggregation was further characterized by transmission electron microscopy (TEM). The cytoprotective role of BH was examined by cytotoxicity assay performed on the SH-SY5Y neuronal cells. The deviation from linearity in the Stern Volmer plot indicated the presence of static and dynamic quenching of the HSA intrinsic fluorescence by BH. The value of Kd obtained by Scatchard plot was 4.5 × 10−4 M. The changes in the Trp microenvironment caused by the BH binding were further characterized by the synchronous fluorescence spectroscopy. Circular dichroism (CD) and differential scanning calorimetry (DSC) indicated increased HSA stability when bound to BH. Multiple binding sites in human serum albumin (HSA) for BH were found by binding and docking analysis, which revealed the involvement of hydrophobic and hydrogen bonding in the HSA-BH complex formation. Further, the negativity of the binding free energy suggested the spontaneity of the BH-HSA interaction. Overall, our study indicated that BH can serve as an efficient inhibitor/destabilizer of amyloid fibrils and the possible mechanism of this efficiency includes stabilization of HSA in the presence of BH. Therefore, BH can be used in treatment of systemic amyloidoses, since this drug cannot cross blood brain barrier (BBB).

Doksycyklina w terapii amyloidozy układowej z zajęciem serca

The leading strategy in the management of systemic amyloidosis is currently focused on reducing the production of amyloid precursor proteins. This approach is based on the use of chemotherapy in light chain amyloidosis (AL amyloidosis) or liver transplantation, or attempts to suppress transthyretin gene expression (TTR) in patients with transthyretin amyloidosis (ATTR). Recently, however, therapies have been increasingly developed to reduce the formation of amyloid deposits from circulating precursors or to eliminate already formed amyloid deposits. This approach includes, in particular, the chronic use of doxycycline, a well-known bacteriostatic antibiotic from the tetracycline group. In preclinical studies it was shown that the anti-amyloidogenic potential of doxycycline in AL amyloidosis depends on interference in the process of amyloidogenesis and the destruction of amyloid deposits. Clinical retrospective studies indicate that doxycycline used with standard chemotherapy improves prognosis in patients with AL amyloidosis with heart involvement, which is the most unfavorable prognostic group, while maintaining a favorable safety profile of therapy. In contrast, in ATTR, doxycycline appears to stabilize the clinical course of the disease. In this paper, we review literature on the role of doxycycline therapy in the treatment of systemic amyloidosis.

A specific nanobody prevents amyloidogenesis of D76N \u03b22-microglobulin in vitro and modifies its tissue distribution in vivo

Systemic amyloidosis is caused by misfolding and aggregation of globular proteins in vivo for which effective treatments are urgently needed. Inhibition of protein self-aggregation represents an attractive therapeutic strategy. Studies on the amyloidogenic variant of β2-microglobulin, D76N, causing hereditary systemic amyloidosis, have become particularly relevant since fibrils are formed in vitro in physiologically relevant conditions. Here we compare the potency of two previously described inhibitors of wild type β2-microglobulin fibrillogenesis, doxycycline and single domain antibodies (nanobodies). The β2-microglobulin -binding nanobody, Nb24, more potently inhibits D76N β2-microglobulin fibrillogenesis than doxycycline with complete abrogation of fibril formation. In β2-microglobulin knock out mice, the D76N β2-microglobulin/ Nb24 pre-formed complex, is cleared from the circulation at the same rate as the uncomplexed protein; however, the analysis of tissue distribution reveals that the interaction with the antibody reduces the concentration of the variant protein in the heart but does not modify the tissue distribution of wild type β2-microglobulin. These findings strongly support the potential therapeutic use of this antibody in the treatment of systemic amyloidosis.

Menadione Suppresses Amyloid Fibrillogenesis and Cytotoxicity: Implication in the Treatment of Systemic Amyloidosis

Background: The amassing of β- sheet rich amyloid fibrils is complex, multistep process which is allied with cellular toxicity in number of human protein misfolding diseases including Parkinson's, Alzheimer's and systemic amyloidosis.Methodology: In vitro aggregation of lysozyme was induced by incubation for 3 days at 60 degrees C and monitored by ThT binding assay, Congo red binding, ANS binding circular dichroism and electron microscopy.Results: Menadione inhibits the fibrillogenesis of lysozyme by directly binding to lysozyme and preventing their conversion to toxic aggregates and modulates amyloid cytotoxicity against human neuroblastoma cell line (SH-SY5Y) which confirmed the anti-amyloidogenic behaviour of menadione. Importantly, it was found that menadione remodel preformed amyloids to less toxic amorphous aggregates with less cross beta sheet content. The inhibition is likely due to attractive intermolecular interactions (hydrogen bonding) between menadione and lysozyme.Conclusions: In the present study, anti-amyloidogenic effect of menadione was evaluated on aggregation behaviour of human lysozyme which is responsible for systemic amyloidosis. These finding may provide new therapeutic approach to prevent systemic amyloidosis.

Systemic amyloidosis as a cause of cerebral thrombo-embolic stroke: A case report

Systemic amyloidosis is a rare clinical disorder and can lead to single organ or fatal multiple organ failure, heart and kidneys are the most affected organs. Currently, there are no relevant guidelines and recommendations about the treatment of systemic amyloidosis. Ischemic stroke is an uncommon complication of systemic amyloidosis and patients with systemic amyloidosis may carry a worse prognosis. We report a case of cerebral thrombo-embolism in a 40-year-old woman due to indicated systemic amyloidosis, she received intravenous rt-PA thrombolytic therapy in hyperacute phase of ischemic stroke and this case proved that intravenous rt-PA thrombolysis therapy may be an effective treatment for acute cerebral thrombo-embolic stroke patients with systemic amyloidosis.

Pathophysiology and treatment of systemic amyloidosis

Amyloid is an abnormal extracellular fibrillar protein deposit in the tissues. In humans, more than 25 different proteins can adopt a fibrillar conformation in vivo that results in the pathognomonic tinctorial property of amyloid (that is, green birefringence when an affected tissue specimen is stained with Congo red dye and viewed by microscopy under cross-polarized light). Amyloid deposition is associated with disturbance of organ function and causes a wide variety of clinical syndromes that are classified according to the respective fibril protein precursor. Systemic amyloidosis, in which amyloid deposits are widespread and typically accumulate gradually, continues to be fatal and is responsible for about one in 1,500 deaths per year in the UK. Advances in our understanding of the pathogenesis of systemic amyloidosis have resulted in the identification of new therapeutic targets, and several drugs with novel mechanisms of action are currently under development. Meanwhile, an increased awareness of amyloidosis coupled with enhancements to existing diagnostic techniques and therapeutic strategies have already resulted in better outcomes for patients with the disease.

Pathogenesis, diagnosis and treatment of systemic amyloidosis.

Amyloidosis is a disorder of protein folding in which normally soluble proteins are deposited as abnormal, insoluble fibrils that disrupt tissue structure and cause disease. Although about 20 different unrelated proteins can form amyloid fibrils in vivo, all such fibrils share a common cross-beta core structure. Some natural wild-type proteins are inherently amyloidogenic, form fibrils and cause amyloidosis in old age or if present for long periods at abnormally high concentration. Other amyloidogenic proteins are acquired or inherited variants, containing amino-acid substitutions that render them unstable so that they populate partly unfolded states under physiological conditions, and these intermediates then aggregate in the stable amyloid fold. In addition to the fibrils, amyloid deposits always contain the non-fibrillar pentraxin plasma protein, serum amyloid P component (SAP), because it undergoes specific calcium-dependent binding to amyloid fibrils. SAP contributes to amyloidogenesis, probably by stabilizing amyloid fibrils and retarding their clearance. Radiolabelled SAP is an extremely useful, safe, specific, non-invasive, quantitative tracer for scintigraphic imaging of systemic amyloid deposits. Its use has demonstrated that elimination of the supply of amyloid fibril precursor proteins leads to regression of amyloid deposits with clinical benefit. Current treatment of amyloidosis comprises careful maintenance of impaired organ function, replacement of end-stage organ failure by dialysis or transplantation, and vigorous efforts to control underlying conditions responsible for production of fibril precursors. New approaches under development include drugs for stabilization of the native fold of precursor proteins, inhibition of fibrillogenesis, reversion of the amyloid to the native fold, and dissociation of SAP to accelerate amyloid fibril clearance in vivo.

全身性アミロイドーシスに対するｄｉｍｅｔｈｙｌ ｓｕｌｆｏｘｉｄｅ，血しょう交換併用療法の検討

全身性アミロイドーシスに対するdimethyl sulfoxide (DMSO), 血漿交換併用療法の有用性を明らかにする目的で, 11例の全身性アミロイドーシスを対象に, 併用療法群と従来の通常の治療群において, その臨床経過や予後等を比較検討した. DMSO, 血漿交換併用療法は原発性アミロイドーシス1例, 続発性アミロイドーシス3例の計4例に施行され, 血漿交換は血中アミロイド蛋白の存在様式が多彩であること, また未知のamyloidogenic factorsの関与などを考慮し, 原則として単一膜分離法にて施行した. また血漿交換施行前日にはDMSO 5-10mlを経皮的に投与した. 治療開始時すでに多くの症例でアミロイド蛋白の広範囲な沈着がみられたため, 併用療法群と通常の治療群との間には, その生存率や生存期間に全く有意な差が認められず, 併用療法群4例中3例は入院後1年以内に死亡, 11例全体の死亡率も64%と高率であった. しかし併用療法を行った2症例において, 一時的ではあるが, 自他覚症状の改善や腎機能悪化の軽減がみられたことから, 本療法を早期に開始することにより, 全身性アミロイドーシスの予後が改善される可能性が示唆された.

Treatment of systemic amyloidosis by dialysis.Trial of the beta 2-M removal by the direct blood adsorption therapy.

Treatment of systemic amyloidosis by dialysis.Trial of the beta 2-M removal by the direct blood adsorption therapy.