Regression Of Amyloid Deposits Research Articles

A novel knock-in mouse model of cryopyrin-associated periodic syndromes with development of amyloidosis: Therapeutic efficacy of proton pump inhibitors

Cryopyrin-associated periodic syndromes (CAPS) are a group of autoinflammatory diseases linked to gain-of-function mutations in the NOD-like receptor family, pyrin domain containing 3 (NLRP3) gene, which cause uncontrolled IL-1β secretion. Proton pump inhibitors (PPIs), which are commonly used as inhibitors of gastric acid production, also have anti-inflammatory properties, protect mice from sepsis, and prevent IL-1β secretion by monocytes from patients with CAPS. We sought to develop a novel Nlrp3 knock-in (KI) mouse model of CAPS to study amyloidosis, a severe CAPS complication, and test novel therapeutic approaches. We generated KI mice by engineering the N475K mutation, which is associated with the CAPS phenotype, into the mouse Nlrp3 gene. KI and wild-type mice received PPIs or PBS intraperitoneally and were analyzed for survival, inflammation, cytokine secretion, and amyloidosis development. Mutant Nlrp3 KI mice displayed features that recapitulate the immunologic and clinical phenotype of CAPS. They showed systemic inflammation with high levels of serum proinflammatory cytokines, inflammatory infiltrates in various organs, and amyloid deposits in the spleen, liver, and kidneys. Toll-like receptor stimulated macrophages from KI mice secreted high levels of IL-1β, IL-18, and IL-1α but low amounts of IL-1 receptor antagonist. Treatment of KI mice with PPIs had a clear clinical effect, showing a reduction in inflammatory manifestations, regression of amyloid deposits, and normalization of proinflammatory and anti-inflammatory cytokine production by macrophages. Nlrp3 KI mice displayed a CAPS phenotype with many characteristics of autoinflammation, including amyloidosis. The therapeutic effectiveness of PPIs associated with a lack of toxicity indicates that these drugs could represent relevant adjuvants to the anti-IL-1 drugs in patients with CAPS and other IL-1-driven diseases.

AB0320 Biologics Treatment Makes Poor Regression of Renal Amyloid Deposition despite Almost Removal from Gastric Mucosa in Amyloid A Amyloidosis Patients with Rheumatoid Arthritis

BackgroundReactive amyloid A (AA) amyloidosis is a serious and life-threatening systemic complication of rheumatoid arthritis (RA). Several biologics therapy reportedly regress gastric amyloid deposition in amyloid A (AA) amyloidosis patients...

Fibroblasts endocytose and degrade transthyretin aggregates in transthyretin-related amyloidosis

Transthyretin (TTR)-related amyloidosis is a fatal disorder characterized by systemic extracellular deposition of TTR amyloid fibrils. Mutations in the TTR gene cause an autosomal dominant form of the disease—familial amyloidotic polyneuropathy (FAP). Wild-type (WT) TTR can also form amyloid fibrils in elderly patients with senile systemic amyloidosis. Regression of amyloid deposits in FAP patients who undergo liver transplantation to remove the main source of mutant TTR suggests the existence of mechanisms for the clearance of TTR deposits from the extracellular matrix (ECM), but the precise mechanisms are largely unknown. Because fibroblasts are abundant, playing a central role in the maintenance of the ECM and because the skin is one of the major sites of soluble TTR catabolism, in the present study, we analyzed their role in clearance of TTR aggregates. In vitro studies with a fibroblast cell line revealed that fibroblasts endocytosed and degraded aggregated TTR. Subcutaneous injection of soluble and aggregated TTR into WT mice showed internalization and clearance over time by both fibroblasts and macrophages. Immunohistochemical studies of skin biopsies from V30M patients, asymptomatic carriers, recipients of domino FAP livers as well as transgenic mice for human V30M showed intracellular TTR immunoreactivity in fibroblasts and macrophages that increased with clinical status and with age in transgenic mice. Overall, the present in vitro and in vivo data show that fibroblasts endocytose and degrade TTR aggregates. The function or dysfunction of TTR clearance by fibroblasts may have important implications for the development, progression, and regression of TTR deposition in the ECM.

Steady turnover of amyloid fibril proteins in gastric mucosa after liver transplantation in familial amyloid polyneuropathy

Introduction: Our previous study demonstrated marked regression of amyloid deposits in abdominal fat tissues of familial amyloid polyneuropathy (FAP) patients treated with liver transplantation (LT). To determine whether similar changes in deposited amyloid can also occur in other organs, we examined gastric mucosal amyloid before and after LT in FAP patients with ATTRV30M.Methods: We histopathologically and biochemically investigated gastric mucosal amyloid before and after LT in six FAP patients with ATTRV30M.The amounts of amyloid deposits in biopsied gastric mucosa were determined by microscopy, and the proportion of wild-type transthyretin (TTR) in extracted amyloid fibril proteins was assayed by liquid chromatography-ion trap mass spectrometry. Similar examinations were also performed in 21 untreated FAP patients and 13 transplanted patients with ATTRV30M.Results: The amount of deposited amyloid was not markedly different before and after LT in six patients. However, the composition ratios of wild-type TTR in gastric mucosal amyloid increased markedly from 20.0% ± 11.4% before LT to 43.2% ± 13.8% after LT. In addition, the ratio of wild-type TTR in all transplanted patients was significantly higher than that in untransplanted patients (72.7% ± 25.5%, 23.8% ± 14.3%, respectively).Conclusions: Our results showed that the components of amyloid fibril proteins in gastric mucosa of transplanted FAP patients are different from those in untreated patients: a significant portion of preexisting ATTRV30M-derived amyloid seemed to be replaced by wild-type TTR-derived amyloid postoperatively, indicating that continuous turnover of amyloid deposits can occur in all organs in transplanted FAP patients. It was also confirmed that wild-type TTR plays an important role in the pathogenesis of postoperative amyloid deposition in transplanted FAP patients.

A case with rheumatoid arthritis and systemic reactive AA amyloidosis showing rapid regression of amyloid deposition on gastroduodenal mucosa after a combined therapy of corticosteroid and etanercept

Systemic reactive amyloid A (AA) amyloidosis is one of the critical complications associated with rheumatoid arthritis (RA). Recently, there are several useful reports of anti-tumor necrosis factor therapy for RA-related systemic reactive AA amyloidosis patients. However, the time-kinetic transition between effective anti-inflammatory therapies and regression of AA amyloid deposits remains uncertain. Here, we report a RA patient with systemic reactive AA amyloidosis who was successfully treated with prednisolone and etanercept, showing marked regression of gastroduodenal mucosal amyloid deposits within only 4months. This is the first case report of RA-related systemic reactive AA amyloidosis histopathologically demonstrating rapid regression of amyloid deposits on gastroduodenal mucosa after adequate suppression of the underlying inflammatory condition.

A case of AA amyloidosis associated with rheumatoid arthritis effectively treated with Infliximab

We report the case of a 55-year-old Japanese woman with reactive AA amyloidosis associated with rheumatoid arthritis, in which inflammatory disease was completely suppressed with infliximab. Nephrotic syndrome was observed and renal biopsy specimens revealed amyloidosis deposits. Treatment with infliximab normalized the serum amyloid A (SAA) protein level, and subsequently nephritic syndrome disappeared and her creatinine clearance improved. Serial gastrointestinal biopsy specimens showed marked lasting regression of amyloid deposits. Thus treatment with infliximab represents an important therapeutic strategy for AA amyloidosis associated with RA.

Efficacy and Safety of Bortezomib in Systemic AL Amyloidosis - A Preliminary Report.

The prognosis for patients with AL amyloidosis (AL) who have relapsed following conventional treatment or stem cell transplantation has been little studied. Bortezomib (VelcadeTM) potently inhibits the 26S proteosome and has lately been shown to produce useful remissions in ~35–50% patients with relapsed myeloma. Multiple organ impairment in AL is associated with much greater treatment related toxicity than seen with similar regimes in myeloma. Concerns have been voiced regarding the use of bortezomib in AL since ubiquinitin-proteosome inhibition might conceivably influence the intracellular degradation of abnormal amyloidogenic proteins. No clinical studies of bortezomib in AL have yet been reported. We report 18 patients with AL amyloidosis who received bortezomib and were serially evaluated at the UK National Amyloidosis Centre. Median age was 59 yrs (42–73) and bortezomib was given as either 1 or 1.3 mg/m2/dose as a bolus intravenous injection twice weekly for 2 weeks (days 1, 4, 8, and 11) followed by a 10-day rest period. Nine (50%) received dexamethasone in addition. All patients had evidence of progressive amyloidosis and had relapsed or become refractory to their previous line of treatment; all had previously received thalidomide, either with dexamethasone or cyclophosphamide and dexamethasone. The median number of previous lines of treatment was 3 (range 1–6), number of organs involved by amyloid was 2 (1–4) including the heart in 10 (55%) and end stage renal failure in 4 (22%). The median ECOG performance status was 2. The median follow-up since treatment was 10 months and since diagnosis was 31 months. The median number of bortezomib cycles given was 3 (1–6) with a median dose of 1.3 mg/m2/dose. Haematologic response was classified as the worst of conventional (paraprotein) response using EMBT criteria and serum free light chain response using the following criteria: complete response (CR) - sustained normalisation of clonal FLC isotype and ratio; partial response (PR) - sustained ≥50% reduction in pre-treatment clonal isotype. A haematologic response occurred in 14 (77%) patients, comprising CR in 3 (16%) and PR in 11 (61%). Improvement in amyloidotic organ function occurred in 5 (27%) patients, and regression of amyloid deposits was demonstrated by serial SAP scintigraphy in 2 (11%) cases. There was no evidence of progressive amyloidosis in any of the patients who achieved haematologic PR or CR. The median duration of haematologic response was 5.7 months (95% CI 2–9), and Kaplan Meier estimated median survival of the cohort from treatment was 22 months. Toxicity occurred in 11 (61%) patients, which was ≥grade 3 or necessitated cessation of treatment in 7 (36%). Adverse effects included: peripheral neuropathy (grade 1 or 2 only) in 4 (22%) cases; fluid retention in 3 (16%); thrombocytopenia in 2 (11%); myoclonus, herpes zoster, diarrhoea, hypotension, fatigue and chest infection in 1 (5%) case each. Peripheral neuropathy reversed completely in 3 patients, and there were no treatment related deaths. These preliminary results suggest that bortezomib may be efficacious in a substantial proportion patients with relapsed or refractory AL amyloidosis with an acceptable tolerability and safety profile. Haematologic response translated into improvement in amyloidotic organ function in 27% of the patients, but durability of the responses was relatively short. Bortezomib merits further study as treatment for AL amyloidosis, along with the hope that combination with other agents may improve the durability of response.

Localized Castleman’s disease associated with systemic AA amyloidosis. Regression of amyloid deposits after tumor removal

Localized Castleman’s disease associated with systemic AA amyloidosis. Regression of amyloid deposits after tumor removal

Serum amyloid P component scintigraphy for diagnosis and monitoring amyloidosis.

Serum amyloid P component is a normal plasma protein and a universal non-fibrillar constituent of amyloid deposits. Radiolabelled serum amyloid P component scintigraphy is a non-invasive and quantitative method for imaging amyloid deposits, which produces diagnostic images in most patients with systemic amyloidosis, and can be used repeatedly to monitor the course of the disease. The scintigraphy technique and biopsy histology are complementary, providing a detailed microscopic analysis and a quantitative whole body survey respectively. Clinically useful observations provided by the imaging method include different organ distributions of amyloid in different types of the disease, demonstration of amyloid in anatomic sites not available for biopsy, and evidence for rapid progression and sometimes regression of amyloid deposits with different rates in different organs. Labelled serum amyloid P component studies thus make a unique contribution to the diagnosis and management of individual patients with systemic amyloidosis, and to systematic studies of existing and novel therapies. The technique is available routinely for all known or suspected cases of amyloidosis in the NHS National Amyloidosis Centre at the Royal Free Hospital, but it has not been developed commercially.

Studies with Radiolabelled Serum Amyloid P Component Provide Evidence for Turnover and Regression of Amyloid Deposits In Vivo

1. Quantitative scintigraphic and turnover studies, utilizing the specific binding affinity of serum amyloid P component for amyloid fibrils, have been developed as a tool for evaluating amyloid deposits in vivo. 2. Serial studies in over 300 patients have shown characteristic, diagnostic tissue distributions of amyloid in different types of amyloidosis. There is generally a poor correlation between quantity of amyloid and associated organ dysfunction. 3. Contrary to previous expectations, regression of amyloid has been demonstrated systematically for the first time: AA, AL and variant transthyretin-associated amyloid deposits often regress rapidly, and sometimes completely, if the supply of fibril protein precursors is substantially reduced.

Resolution of renal amyloidosis

A patient with renal amyloidosis and the nephrotic syndrome consequent to extensive infected burns demonstrated both clinical resolution of the nephrotic syndrome and morphologic regression of the renal amyloid deposits over a six year period. The regression of the amyloid deposits was associated with several changes in the glomerular capillary wall resulting in a double capillary wall contour. This case indicates that deposits of amyloid in the kidney may regress and suggests a sequence of events in this resolution.