Serum Amyloid P Component Scintigraphy Research Articles

Tracking multi-organ treatment response in systemic AL amyloidosis with cardiac magnetic resonance derived extracellular volume mapping

Abstract Funding Acknowledgements Type of funding sources: None. Background Systemic light-chain (AL) amyloidosis commonly involves the liver, spleen and heart. Cardiac magnetic resonance (CMR) with extracellular volume (ECV) mapping has demonstrated accuracy in measuring cardiac, hepatic and splenic amyloid infiltration. Purpose We sought to: (1) assess the association between baseline multi-organ ECVs and prognosis (2) assess the multi-organ response to treatment using ECV mapping, and (3) assess the association between multi-organ treatment response and prognosis. Methods We identified 351 patients with a confirmed diagnosis of systemic AL amyloidosis who underwent baseline serum amyloid P component (SAP) scintigraphy and CMR at diagnosis, of which 171 had follow-up imaging. We also recruited 20 healthy volunteers who underwent CMR with ECV mapping, without corresponding SAP scintigraphy, to allow calculation of the ECV normal ranges. Results At diagnosis, ECV mapping demonstrated that 304(86.7%) had cardiac involvement, 114(32.5%) significant hepatic involvement and 147(41.9%) significant splenic involvement. Baseline myocardial and liver ECV independently predict mortality (myocardial: HR=1.05,95CI%[1.03–1.07],P<0.001; liver: HR=1.03,95%CI[1.01–1.05],P<0.001). Liver and spleen ECV correlated with amyloid load assessed by SAP scintigraphy (R=0.751,P<0.001; R=0.765,P<0.001, respectively). Serial multi-organ ECV measurements accurately tracked treatment response as validated against serial SAP scintigraphy (the current reference standard). Multi-organ ECV regression was observed as early as 6-months in patients with a good haematological response (liver=15%, spleen=15%, heart=5%). The remaining patients with a good haematological response had stable liver and spleen ECVs, but 20% had cardiac progression. By 12-months more patients with a good haematological response demonstrated cardiac regression (liver=30%, spleen=36%, heart=32%), and this trend was maintained at 24-months. Multi-variable analysis adjusting for haematological response, change in myocardial, liver and spleen ECV demonstrated that haematological response, change in myocardial ECV (HR=1.11, 95%CI[1.02–1.19], P=0.011) and liver ECV (HR=1.06, 95%CI[1.01–1.11], P=0.015) remained independent predictors of prognosis at 6-months. Conclusions Multi-organ ECV quantification accurately tracks treatment response, and demonstrates different rates of organ regression, with the liver and spleen regressing more rapidly than the heart. A good haematological response alone is likely to induce visceral organ stabilisation/regression, but may not be sufficient to induce myocardial stabilisation/regression. Liver and myocardial ECV at diagnosis and changes in ECV at 6-months independently predict mortality. ECV mapping offers a comprehensive multi-organ assessment of treatment response and accurate prognostication.

Tracking Multiorgan Treatment Response in Systemic AL-Amyloidosis With Cardiac Magnetic Resonance Derived Extracellular Volume Mapping

BackgroundSystemic light chain amyloidosis is a multisystem disorder that commonly involves the heart, liver, and spleen. Cardiac magnetic resonance with extracellular volume (ECV) mapping provides a surrogate measure of the myocardial, liver, and spleen amyloid burden. ObjectivesThe purpose of this study was to assess multiorgan response to treatment using ECV mapping, and assess the association between multiorgan treatment response and prognosis. MethodsThe authors identified 351 patients who underwent baseline serum amyloid-P-component (SAP) scintigraphy and cardiac magnetic resonance at diagnosis, of which 171 had follow-up imaging. ResultsAt diagnosis, ECV mapping demonstrated that 304 (87%) had cardiac involvement, 114 (33%) significant hepatic involvement, and 147 (42%) significant splenic involvement. Baseline myocardial and liver ECV independently predict mortality (myocardial HR: 1.03 [95% CI: 1.01-1.06]; P = 0.009; liver HR: 1.03; [95% CI: 1.01-1.05]; P = 0.001). Liver and spleen ECV correlated with amyloid load assessed by SAP scintigraphy (R = 0.751; P < 0.001; R = 0.765; P < 0.001, respectively). Serial measurements demonstrated ECV correctly identified changes in liver and spleen amyloid load derived from SAP scintigraphy in 85% and 82% of cases, respectively. At 6 months, more patients with a good hematologic response had liver (30%) and spleen (36%) ECV regression than myocardial regression (5%). By 12 months, more patients with a good response demonstrated myocardial regression (heart 32%, liver 30%, spleen 36%). Myocardial regression was associated with reduced median N-terminal pro-brain natriuretic peptide (P < 0.001), and liver regression with reduced median alkaline phosphatase (P = 0.001). Changes in myocardial and liver ECV, 6 months after initiating chemotherapy, independently predict mortality (myocardial HR: 1.11 [95% CI: 1.02-1.20]; P = 0.011; liver HR: 1.07 [95% CI: 1.01-1.13]; P = 0.014). ConclusionsMultiorgan ECV quantification accurately tracks treatment response and demonstrates different rates of organ regression, with the liver and spleen regressing more rapidly than the heart. Baseline myocardial and liver ECV and changes at 6 months independently predict mortality, even after adjusting for traditional predictors of prognosis.

Cardiac Magnetic Resonance-Derived Extracellular Volume Mapping for the Quantification of Hepatic and Splenic Amyloid.

Systemic amyloidosis is characterized by amyloid deposition that can involve virtually any organ. Splenic and hepatic amyloidosis occurs in certain types, in some patients but not others, and may influence prognosis and treatment. SAP (serum amyloid P component) scintigraphy is uniquely able to identify and quantify amyloid in the liver and spleen, thus informing clinical management, but it is only available in 2 centers globally. The aims of this study were to examine the potential for extracellular volume (ECV) mapping performed during routine cardiac magnetic resonance to: (1) detect amyloid in the liver and spleen and (2) estimate amyloid load in these sites using SAP scintigraphy as the reference standard. Five hundred thirty-three patients referred to the National Amyloidosis Centre, London, between 2015 and 2017 with suspected systemic amyloidosis who underwent SAP scintigraphy and cardiac magnetic resonance with T1 mapping were studied. The diagnostic performance of ECV to detect splenic and hepatic amyloidosis was high for both organs (liver: area under the curve, -0.917 [95% CI, 0.880-0.954]; liver ECV cutoff, 0.395; sensitivity, 90.7%; specificity, 77.7%; P<0.001; spleen: area under the curve, -0.944 [95% CI, 0.925-0.964]; spleen ECV cutoff, 0.385; sensitivity, 93.6%; specificity, 87.5%; P<0.001). There was good correlation between liver and spleen ECV and amyloid load assessed by SAP scintigraphy (r=0.504, P<0.001; r=0.693, P<0.001, respectively). There was high interobserver agreement for both the liver and spleen (ECV liver intraclass correlation coefficient, 0.991 [95% CI, 0.984-0.995]; P<0.001; ECV spleen intraclass correlation coefficient, 0.995 [95% CI, 0.991-0.997]; P<0.001) with little bias across a wide range of ECV values. Our study demonstrates that ECV measurements obtained during routine cardiac magnetic resonance scans in patients with suspected amyloidosis can identify and measure the magnitude of amyloid infiltration in the liver and spleen, providing important clues to amyloid type and offering a noninvasive measure of visceral amyloid burden that can help guide and track treatment.

The Pentraxins 1975-2018: Serendipity, Diagnostics and Drugs.

The phylogenetically ancient, pentraxin family of plasma proteins, comprises C-reactive protein (CRP) and serum amyloid P component (SAP) in humans and the homologous proteins in other species. They are composed of five, identical, non-covalently associated protomers arranged with cyclic pentameric symmetry in a disc-like configuration. Each protomer has a calcium dependent site that mediates the particular specific ligand binding responsible for all the rigorously established functional properties of these proteins. No genetic deficiency of either human CRP or SAP has been reported, nor even any sequence polymorphism in the proteins themselves. Although their actual functions in humans are therefore unknown, gene deletion studies in mice demonstrate that both proteins can contribute to innate immunity. CRP is the classical human acute phase protein, routinely measured in clinical practice worldwide to monitor disease activity. Human SAP, which is not an acute phase protein, is a universal constituent of all human amyloid deposits as a result of its avid specific binding to amyloid fibrils of all types. SAP thereby contributes to amyloid formation and persistence in vivo. Whole body radiolabelled SAP scintigraphy safely and non-invasively localizes and quantifies systemic amyloid deposits, and has transformed understanding of the natural history of amyloidosis and its response to treatment. Human SAP is also a therapeutic target, both in amyloidosis and Alzheimer's disease. Our drug, miridesap, depletes SAP from the blood and the brain and is currently being tested in the DESPIAD clinical trial in Alzheimer's disease. Meanwhile, the obligate therapeutic partnership of miridesap, to deplete circulating SAP, and dezamizumab, a humanized monoclonal anti-SAP antibody that targets residual SAP in amyloid deposits, produces unprecedented removal of amyloid from the tissues and improves organ function. Human CRP binds to dead and damaged cells in vivo and activates complement and this can exacerbate pre-existing tissue damage. The adverse effects of CRP are completely abrogated by compounds that block its binding to autologous ligands and we are developing CRP inhibitor drugs. The present personal and critical perspective on the pentraxins reports, for the first time, the key role of serendipity in our work since 1975. (345 words)

008 Demonstration of cardiac AL amyloidosis regression after succesful chemotherapy. a CMR study

Background Cardiac involvement in immunoglobulin light chain (AL) amyloidosis is the major determinant of survival; Cardiac response to chemotherapy is conventionally assessed by serum brain natriuretic peptide (NT-proBNP) and echocardiography, but neither quantify amyloid burden. The aim of this study was to evaluate cardiac AL amyloid serially using cardiovascular MR (CMR) including extracellular volume measurement (ECV), which is the site of the amyloid deposits. Methods 31 patients with cardiac AL amyloidosis who had chemotherapy were studied serially using ECG, echocardiography, 123I-labelled serum amyloid P component (SAP) scintigraphy, NT-proBNP measurements and CMR with T1 mapping and ECV measurements (mean interval 20±11 months). Nineteen patients achieved a complete or very good partial haematological response (CR n=10; VGPR n=9). Twelve patients attained a partial response (PR) or no response (NR). Results At follow-up (mean 20±11 months), the amyloid burden had decreased substantially in 6 of the 10 (60%) attaining a CR, 6 of the 9 (67%) in VGPR and 1 of the 8 (13%) in PR. Changes in the ECV consistent with regression of amyloid were concordant with the changes in native T1, reduction in amyloid volume and in 5 patients with changes in late gadolinium enhancement pattern (figure 1). Overall there was significant reduction in NT-proBNP concentration, LV mass, left atrial area and improvement in diastolic function in patients whose amyloid burden decreased. Regression of cardiac amyloid by CMR correlated with regression of amyloid in other organs measured by SAP scintigraphy.

Dose-Dependent Progressive Immunotherapeutic Clearance of Systemic Amyloid Deposits By Repeated Doses of Antibody to Serum Amyloid P Component (SAP)

In systemic amyloidosis, disease is caused by the extracellular accumulation of amyloid fibrils which do not elicit the normally efficient mechanisms of clearance of interstitial debris, and which progressively disrupt tissue architecture and function. Diagnosis is often late, with advanced organ dysfunction and major morbidity. The condition is usually fatal despite organ support and efforts to reduce production of the fibril precursor protein. In the most common type, AL, caused by monoclonal gammopathy, treatment with cytotoxic chemotherapy can slow or arrest amyloid deposition in some patients, and amyloid deposits may sometimes slowly regress but about 20% of patients still die within 6 months of diagnosis. No specific interventions exist for many of the rarer forms of systemic amyloidosis. Directly targeted measures are required to specifically remove amyloid deposits in order to preserve and possibly restore organ function. We have identified the normal plasma protein, serum amyloid P component (SAP), as a therapeutic target for this purpose.SAP binds to amyloid fibrils of all types and is thus always present in human amyloid deposits. Acute administration of (R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC), swiftly depletes circulating SAP but leaves some SAP in amyloid deposits as an amyloid-specific antigen target. In patients with systemic AL, AA and AApoAI amyloidosis, we have lately reported that, following depletion of circulating SAP by CPHPC, a single dose of humanized monoclonal anti-SAP antibody substantially reduced the amyloid load, especially from the liver (D.B. Richards et al, New England Journal of Medicine, July 15, 2015; DOI: 10.1056/NEJMoa1504942). Here we show that repeated administration of the obligate therapeutic partnership of CPHPC with appropriate doses of anti-SAP antibody, progressively removed amyloid from the liver and other organs, including the kidney.Up to three antibody doses were given at intervals to patients, mostly with AL or AFib amyloidosis, in this second part of a phase I dose-ascending study. Treatments were generally well tolerated. Infusion reactions were largely mitigated by hydrocortisone and antihistamine premedication. Pharmacodynamic responses were associated with an early transient inflammatory cytokine response and increased CRP and SAA production, followed by substantial depletion of plasma C3 and a less marked fall in C4 and CH50. Pharmacodynamic responses were sometimes associated with self-limiting cutaneous rashes, especially in subjects without hepatic amyloidosis. Reduced amyloid load was demonstrated by radiolabelled SAP scintigraphy (liver, spleen, kidneys), extracellular volume measurement by equilibrium MRI (liver, spleen) and liver stiffness determined by transient elastography. Amyloid removal was not associated with detectable additional organ dysfunction. Abnormal liver function tests improved following clearance of hepatic amyloid. Renal parameters were stable but follow up is still too short to ascertain long term renal effects.In the preclinical mouse model, amyloid clearance mediated by anti-SAP antibody requires complement and macrophages and is effected by multinucleated giant cells. Consistent with this mechanism, the extent of amyloid clearance in patients depended on the dose of anti-SAP antibody in relation to the whole body amyloid load. In patients with hepatic and splenic amyloid, the anti-SAP antibody rapidly disappeared from the circulation, consistent with its easy access to these organs via their sinusoidal endothelium. Liver and spleen amyloid were cleared first but, after major reduction of liver and spleen load, renal amyloid was cleared by subsequent antibody doses.These preliminary observations demonstrate that progressive amyloid removal can probably be achieved in all types of systemic amyloidosis by repeated courses of CPHPC and anti-SAP antibody. A phase II study is now planned.This program is funded by GlaxoSmithKline. [Display omitted] DisclosuresPepys:Pentraxin Therapeutics Ltd: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; UK NIHR: Research Funding; UK MRC: Research Funding. Cookson:GlaxoSmithKline: Employment, Equity Ownership. Barton:GlaxoSmithKline: Employment, Equity Ownership. Berges:GlaxoSmithKline: Employment, Equity Ownership. Moon:GlaxoSmithKline: Consultancy, Research Funding. Richards:GlaxoSmithKline: Employment, Equity Ownership.

Therapeutic Clearance of Amyloid by Antibodies to Serum Amyloid P Component

BackgroundThe amyloid fibril deposits that cause systemic amyloidosis always contain the nonfibrillar normal plasma protein, serum amyloid P component (SAP). The drug (R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC) efficiently depletes SAP from the plasma but leaves some SAP in amyloid deposits that can be specifically targeted by therapeutic IgG anti-SAP antibodies. In murine amyloid A type amyloidosis, the binding of these antibodies to the residual SAP in amyloid deposits activates complement and triggers the rapid clearance of amyloid by macrophage-derived multinucleated giant cells.MethodsWe conducted an open-label, single-dose-escalation, phase 1 trial involving 15 patients with systemic amyloidosis. After first using CPHPC to deplete circulating SAP, we infused a fully humanized monoclonal IgG1 anti-SAP antibody. Patients with clinical evidence of cardiac involvement were not included for safety reasons. Organ function, inflammatory markers, and amyloid load were monitored.ResultsThere were no serious adverse events. Infusion reactions occurred in some of the initial recipients of larger doses of antibody; reactions were reduced by slowing the infusion rate for later patients. At 6 weeks, patients who had received a sufficient dose of antibody in relation to their amyloid load had decreased liver stiffness, as measured with the use of transient elastography. These patients also had improvements in liver function in association with a substantial reduction in hepatic amyloid load, as shown by means of SAP scintigraphy and measurement of extracellular volume by magnetic resonance imaging. A reduction in kidney amyloid load and shrinkage of an amyloid-laden lymph node were also observed.ConclusionsTreatment with CPHPC followed by an anti-SAP antibody safely triggered clearance of amyloid deposits from the liver and some other tissues. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT01777243.)

Risk Of Progression Of Localised Amyloidosis To Systemic Disease In 606 Patients Over 30 Years

Localised AL (light chain) amyloidosis arises due to local formation and deposition of AL amyloid fibrils within a tissue. Little data exists as to the underlying aetiology, biological significance and natural progression of this disease. The primary objective of this study was to evaluate the incidence, clinical course, treatment outcomes and risk of progression to systemic disease. MethodsThis study included all patients with localised amyloidosis assessed at the UK National Amyloidosis centre between 1980 and 2011. Localised amyloidosis was defined as biopsy proven amyloid deposition confined to a single site without any evidence of vital organ involvement (including cardiac, renal, liver, peripheral or autonomic neuropathy) on detailed baseline assessment organ function and no visceral organ uptake on 123I serum amyloid P component (SAP) scintigraphy. Progression to systemic AL was defined as development of new vital organ involvement or dysfunction as by tests of organ function or SAP scintigraphy. Kaplan Meier curves were used to estimate the overall survival (OS); calculated from the start of diagnosis until death or last follow-up. ResultsSix hundred and six patients were diagnosed with localised amyloidosis, accounting for 12% of all newly diagnosed amyloidosis patients during this period at our Centre. The baseline characteristics are given in table 1. The median age was 59.5 years (range 48.8-68.6), 51% were male and median symptom duration was 7 months (range 4-24). All patients had biopsy proven amyloid deposition. Definitive light chain immunostaining for AL kappa or lambda was positive in only 15% while 52% had no immunostaining with antibodies to kappa, lambda, transthyretin or SAA. Three patients had ATTR on bladder biopsy (none with ATTR at other sites) and one with ApoA1 on laryngeal amyloidosis (with ApoA1 Ala164Ser mutation). The sites of localised amyloidosis included: bladder 94 (15%), lung 47 (7.7%), trachea-bronchial 35 (5.7%), larynx/vocal cords - 70 (11.6%), tonsil 4 (0.7%), conjunctiva 12 (2%), orbit 10 (1.7%), lymph nodes 31 (5.1%), GI tract 36 (6%), skin 54 (13.8%) and others. Presenting symptoms depended upon the tissue involved. A serum monoclonal protein was present in 12.5%, with an abnormal kappa/lambda ratio in 13.8%. Therapeutic options for localised disease include surgical procedures (36%), laser therapy (7%), steroids (2%), radiotherapy (2.8% predominantly for amyloidomas/symptom control) and chemotherapy (2.3%; treating amyloid symptoms/disease in 1%, treating co-existing multiple myeloma, lymphoplasmacytic lymphoma and MALT lymphoma in 1.3%). Some patients undergoing surgical procedures had recurrent local amyloid deposition needing repeated procedures. Only one patient out of 606 progressed to systemic AL amyloidosis. This patient presented with mediastinal LN involvement, progressed 5 years following diagnosis, with evidence of new uptake by 123I SAP scintigraphy localised within the spleen and bone marrow infiltration of 10% clonal plasma cells but no abnormal free light chain ratio or presence of a paraprotein. The majority of patients had other co-morbidities with the median age of death 74 years (range 66.5-80). There were no deaths due to progressive amyloidosis. The median follow up was 64 months. The median overall survival (OS) was 69.7 months (range 37.1-130.7) with 2 and 5 year OS 96% and 92% respectively figure 1.Table 1Patient CharacteristicsNumber (%)Male307 (51)Monoclonal M protein76 (12.5)Abnormal kappa139 (22.9)Abnormal lambda93 (15.3)Abnormal kappa/lambda ratio82 (13.5)Median (range)Age59.5 (48.8-68.6) yearsEstimated glomerular filtration rate81 (70-100) mls/minAlkaline phosphatase72 (59-89) U/LAlbumin44 (42-46) g/L24 hour urinary proteinuria0.1 g [Display omitted] ConclusionThe overall survival of localised AL amyloidosis is excellent and strikingly different from systemic AL amyloidosis. Treatment options are primarily directed locally to the amyloid deposit which is adequate in the majority, with less than satisfactory control and numerous procedures required in some patients, especially those with tracheobronchial amyloidosis, leading to a poor quality of life. Progression to systemic disease is an exceptionally rare occurrence even in presence of a detectable M-protein or abnormal light chain ratio. Disclosures:Bridoux:Janssen Cilag: Honoraria; Celgene: Honoraria; Celgene: Research Funding, Research support, Research support Other.

Multiorgan ECV as measured by EQ-MRI in systemic amyloidosis

Background Systemic AL Amyloidosis causes multiorgan dysfunction through interstitial expansion. We measured the extracellular volume fraction (ECV) in the : heart, liver, spleen and skeletal muscle in healthy volunteers and patients with Systemic Amyloidosis to test the hypotheses that (1) tissue ECV is greater in systemic AL Amyloidosis than in health and (2) ECV tracks organ amyloid burden. Methods Healthy volunteers (n=70; 35 male; 35 female; median age 46 years) and patients with systemic AL Amyloidosis (n=56; 36 male; 20 female; median age 62 years), with clinical indications for CMR scanning, additionally underwent multi-organ ECV measurement. Technical details were: gadoteric acid, 0.1mmol/Kg plus infusion, multibreathhold T1 measurement and equilibrium imaging of heart, liver spleen and biceps muscle at 1.5T (Siemens Avanto). Amyloidosis patients also underwent serum amyloid P component (SAP) scintigraphy to score liver and spleen involvement by amyloid. Results ECV of the heart, liver, spleen and muscle was significantly elevated in patients with amyloidosis (0.40, 0.33, 0.42 and 0.12 respectively) compared to healthy controls (0.25, 0.30, 0.34 and 0.09 respectively) (P<0.001). ECV measured in the liver and spleen tracked increasing organ amyloid burden assessed by SAP scintigraphy (P<0.001). In healthy volunteers, ECV varied between different organs, being highest in the spleen and lowest in skeletal muscle. Conclusions The cardiac ECV technique measures cardiac amyloid burden, but can be translated into also in other tissues and organs in the body. Here its use is validated against the gold standard of SAP scanning in the liver and spleen. ECV measurement may represent a key technique for measuring ECV increase in systemic diseases. Funding We receive money from Glaxo Smith Kline for some of our studies.

Sustained pharmacological depletion of serum amyloid P component in patients with systemic amyloidosis

Serum amyloid P component (SAP) is a universal constituent of amyloid deposits and contributes to their formation and/or persistence. We therefore developed CPHPC ((R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexa-noyl]pyrrolidine-2 carboxylic acid), a novel bis(D-proline) drug, to specifically target SAP and report here a first, exploratory, open label proof of principle study in systemic amyloidosis. CPHPC produced sustained, >95% depletion of circulating SAP in all patients and c. 90% reduction in the SAP content of the two amyloidotic organs that became available. There were no significant adverse effects of either SAP depletion or CPHPC itself. No accumulation of amyloid was demonstrable by SAP scintigraphy in any patient on the drug. In hereditary fibrinogen amyloidosis, which is inexorably progressive, proteinuria was reduced in four of five patients receiving CPHPC and renal survival was prolonged compared to a historical control group. These promising clinical observations merit further study.

Risk-Adapted Cyclophosphamide, Thalidomide and Dexamethasone (CTD) for the Treatment of Systemic AL Amyloidosis: Long Term Outcomes among 202 Patients.

Risk-adapted oral regimen of cyclophosphamide, thalidomide, and dexamethasone (CTD) was previously reported by our group to be highly effective in patients with systemic AL amyloidosis. However, the numbers were small with limited long-term follow-up. We now report the use of this regimen in a much larger series of 202 patients with prolonged follow-up. All patients treated with CTD between 2002 – 2008 were identified from the database of the UK National Amyloidosis Centre, London. Organ involvement and response was assessed according to international consensus criteria (Gertz et al, 2005). The course of amyloid deposits was quantified by serial I123 labelled serum amyloid P component (SAP) scintigraphy and has been reported separately. Survival was assessed by the method of Kaplan-Meier and multivariate analysis was by Cox regression. Males accounted for 58% of patients, and the light chain excess was predominately lambda (72%). Renal involvement was seen in 150 patients (75%), cardiac in 95 (47%), hepatic in 36 (15%), peripheral and/or autonomic nerve involvement in 30 (15%), pulmonary in 4 (2%), gastrointestinal tract in 15 (7%), and soft tissue in 56 (28%). Abnormalities in SAP scintigraphy were seen in 170 patients (84%). Median number of organs involved was 2. Full dose CTD was administered to 139 (69%) patients while 63 (31%) received the dose attenuated regimen. 123 (61%) patients received this chemotherapy as first line treatment. The median number of cycles delivered was 5 (range 1–15). A hematologic response occurred in 120 (62%) of 193 evaluable patients. Complete responses (CR) were seen in 49 patients (25%), near complete response (nCR) in 5 (3%) and partial responses (PR) in 66 (34%) cases. 67% of newly diagnosed and 54% of relapsed cases responded. There was no significant difference in the CR rates between newly diagnosed and relapsed cases (29 vs. 27%). Organ responses were observed in 50/120 (42%) patients - renal in 40/87 patients (46%), hepatic in 6/21 (29%), nerve in 2/16 (13%), cardiac in 4/53 (8%), gastrointestinal in 2/8 (25%), and soft tissue involvement in 7/37 (19%). Improvements on SAP scintigraphy were noted in 42 patients (21%) post-treatment. The median follow-up was 20 months (range 1 – 69 months). Median estimated overall survival (OS) from commencement of treatment and from diagnosis was 42 months and 83 months respectively. At 60 months, the median survival has not been reached for patients achieving a CR, 50 months for PR and 33 months for non-responders. There was no significant difference in OS from commencement of treatment if the patient was previously treated or not (41 vs 45 months respectively, p = 0.75). Among 120 responders, 51 patients (43%) relapsed. Median estimated time to clonal relapse (PFS) was 32 months. The PFS was 33 months for patients without prior treatment and 25 months for those treated for relapsed disease (p = 0.69). Toxicity of any grade was reported by 171 (85%) patients and was ≥ grade 3 in 21%. The commonest severe toxicity was fluid retention. Treatment-related mortality was 3%. In conclusion, this large study confirms that risk adapted CTD has comparable efficacy with other reported oral regimes, namely melphalan-dexamethasone, for the treatment of AL amyloidosis. High rates and durable clonal responses were frequently accompanied by organ responses. Treatment related mortality was low. CTD in an effective regimen for the treatment of patients with newly diagnosed AL amyloidosis and those whose clonal dyscrasias have relapsed. It has the advantages of being stem cell sparing and not requiring dose adjustment in cases of advanced renal failure. [Display omitted]

Science and serendipity

Good science demands independent replication of new ideas and results and abandonment of accepted theories in light of more reliable evidence. Failure to comply leads to damaging bad science, as with the falsely claimed association between measles, mumps and rubella vaccination and autism. Progress of good science also often requires serendipity, 'making discoveries by accident and sagacity of things not sought'. Work on the pentraxin proteins, C-reactive protein (CRP) and serum amyloid P component (SAP), and on amyloidosis, has benefited from abundant serendipity, leading to routine clinical use of CRP measurements, the invention of SAP scintigraphy for amyloidosis, the establishment of the NHS National Amyloidosis Centre providing superior patient care, and latterly the invention of a novel pharmacological mechanism for therapeutic depletion of pathogenic proteins. New drugs using this mechanism are in development for amyloidosis and cardiovascular disease and potentially also Alzheimer's disease, type II diabetes and other tissue damaging conditions.

Diagnostic Performance of 123I-Labeled Serum Amyloid P Component Scintigraphy in Patients with Amyloidosis

Purpose To assess the diagnostic accuracy and additional information provided by 123I-labeled serum amyloid P component (SAP) scintigraphy in patients with systemic and localized amyloidosis. Subjects and methods 123I-labeled human SAP was injected intravenously into 20 controls and 189 consecutive patients with histologically proven amyloidosis: of AA type in 60 cases, AL type in 80, hereditary ATTR type in 27, and localized amyloidosis in 22 cases. SAP scintigrams were obtained 24 hours after tracer injection and were analyzed for abnormal patterns of uptake. Sensitivity and specificity were determined, and scintigraphic findings were compared with clinical data. Results Diagnostic sensitivity of SAP scintigraphy for systemic AA, AL, and ATTR amyloidosis was 90%, 90%, and 48% respectively, and specificity was 93%. The distribution of amyloid was less diverse in AA than in AL type. Myocardial uptake was not visualized in any patient. Splenic amyloid was very frequent (80%) in AA and AL type but rarely detected clinically (14%). Abnormal tracer uptake in the liver and kidneys correlated with disturbed liver function and proteinuria, respectively. Bone marrow uptake was specific for AL (21%) and was more frequent in AL kappa than AL lambda. Localized amyloid deposits were not imaged. Conclusion SAP scintigraphy is diagnostic of amyloid in most patients with AA and AL type but fewer with hereditary ATTR type, relating to differing distributions and burdens of amyloid in these disorders. It usually reveals more widespread organ involvement than is identified clinically, and certain distributions of amyloid are characteristic of particular fibril types.

Quantitative high-resolution microradiographic imaging of amyloid deposits in a novel murine model of AA amyloidosis

The mouse model of experimentally induced systemic AA amyloidosis is long established, well validated, and closely analogous to the human form of this disease. However, the induction of amyloid by experimental inflammation is unpredictable, inconsistent, and difficult to modulate. We have previously shown that murine AA amyloid deposits can be imaged using iodine-123 labeled SAP scintigraphy and report here substantial refinements in both the imaging technology and the mouse model itself. In this regard, we have generated a novel prototype of AA amyloid in which mice expressing the human interleukin 6 gene, when given amyloid enhancing factor, develop extensive and progressive systemic AA deposition without an inflammatory stimulus, i.e., a transgenic rapidly inducible amyloid disease (TRIAD) mouse. Additionally, we have constructed high-resolution micro single photon emission computed tomography (SPECT)/computed tomography (CT) instrumentation that provides images revealing the precise anatomic location of amyloid deposits labeled by radioiodinated serum amyloid P component (SAP). Based on reconstructed microSPECT/CT images, as well as autoradiographic, isotope biodistribution, and quantitative histochemical analyses, the 125I-labeled SAP tracer bound specifically to hepatic and splenic amyloid in the TRIAD animals. The ability to discern radiographically the extent of amyloid burden in the TRIAD model provides a unique opportunity to evaluate the therapeutic efficacy of pharmacologic compounds designed to inhibit fibril formation or effect amyloid resolution.

Diagnostic tools for amyloidosis

Demonstration of amyloid deposits in biopsy specimens is the only means of confirming the diagnosis of amyloidosis. In experienced hands, nonsurgical biopsies of the rectal mucosa or, preferably, of the abdominal fat pad or labial salivary glands provide the diagnosis in 80 to 85% of cases. Immunolabeling studies help to determine the histological type of amyloidosis but are not performed routinely in everyday practice. In patients with a family history of amyloidosis, studies of the genome and amyloid protein can identify the protein variants capable of causing systemic amyloidosis. Once the diagnosis of amyloidosis is established, the extent of systemic involvement with amyloid should be evaluated by performing renal and hepatic function tests, a proteinuria assay, and an echocardiogram. Scintigraphy with radiolabeled serum amyloid P (SAP) component is a rapid and specific investigation that provides a map of the amyloid deposits. Deposits are usually seen in the liver and spleen. SAP component scintigraphy can provide support for the diagnosis of amyloidosis in patients with negative histological studies. Tissue retention of radioactivity predicts survival.

Clinical, radiological and serum amyloid P component scintigraphic features of beta2-microglobulin amyloidosis associated with continuous ambulatory peritoneal dialysis.

Beta2-Microglobulin (beta2M) amyloidosis occurs in patients with end-stage renal failure (ESRF) who undergo long-term continuous ambulatory peritoneal dialysis (CAPD), but its prevalence in patients treated exclusively by CAPD is unknown. In addition, its features may differ from those of haemodialysis-associated beta2M amyloidosis because CAPD is more biocompatible. We performed serum amyloid P component (SAP) scintigraphy, a specific technique for imaging amyloid deposits, in 13 consecutive patients with ESRF who had been dialysed for >5 years, at least 80% of the time by CAPD. Clinical and radiological features of beta2M amyloidosis were sought and compared with the results of SAP scintigraphy. SAP scans showed articular amyloid deposits in seven patients, all of whom had evidence of carpal tunnel syndrome and four of whom had arthralgia characteristic of dialysis amyloidosis. Typical radiographic bone cysts were present in only one case who had been dialysed for >17 years. The remaining six patients had no clinical, radiological or scintigraphic evidence of beta2M amyloidosis. The prevalence of beta2M amyloidosis in this study was comparable with that in reported haemodialysis populations. Many of the amyloid deposits demonstrated by SAP scintigraphy were not associated with symptoms, but larger and longer term studies are required to determine whether CAPD favourably influences their clinical expression.

Serum amyloid P component scintigraphy and turnover studies for diagnosis and quantitative monitoring of AA amyloidosis in juvenile rheumatoid arthritis.

To evaluate aspects of the natural history of AA amyloidosis complicating juvenile rheumatoid arthritis (JRA), and its response to therapy with chlorambucil. Scintigraphy and 7-day turnover studies were performed in JRA patients with histologically proven (n = 35) or clinically suspected (n = 30) AA amyloidosis, following intravenous injection of 123I and 125I-labeled serum amyloid P component (SAP). Prospective monitoring studies were performed over 2-3 years in 20 patients with amyloidosis. All but 2 amyloidosis patients were treated with chlorambucil. Positive scanning results were obtained in all patients in whom imaging was performed within 12 years of positive biopsy findings of amyloid and in 5 patients with clinically suspected amyloidosis. Negative scanning results with normal SAP metabolism, indicating regression of amyloid, were obtained in 4 patients whose amyloidosis had been in full clinical remission for more than 12 years. Prospective monitoring studies in patients whose JRA-associated inflammatory activity was in remission demonstrated regression of amyloid in 8 patients and no substantial changes in 8 others; however, in 4 further patients with active inflammation, there was accumulation of amyloid. There was a very poor correlation between the amount of amyloid present at a particular site and the resultant organ dysfunction. Radiolabeled SAP scintigraphy and turnover studies are useful complementary tools in the diagnosis, screening, and quantitative monitoring of type AA amyloidosis in JRA. The amyloid deposits may progress and/or regress at different rates in different anatomic sites over short periods.

Place de la scintigraphie à la SAP marquée à l'iode 123 dans le diagnostic et le bilan d'extension de l'amylose: expérience à partir de 23 malades avec amylose AA et AL

123-I-labeled serum amyloid P component (SAP) scintigraphy was performed in 23 patients with proved amyloidosis and in 10 normal subjects. We conclude that SAP scintigraphy would be helpful to evaluate organ involvement, not only in patients with biopsy-proven amyloidosis, but mainly when a strong suspicion of amyloidosis is found in spire of repeated negative biopsy.