Amyloidosis Patients Research Articles

Clinical clues for suspecting wild-type transthyretin cardiac amyloidosis in patients with monoclonal gammopathy of undetermined significance: a case report

BackgroundMyeloproliferative disorders, including monoclonal gammopathy of undetermined significance (MGUS), are often associated with amyloid light-chain (AL)-type cardiac amyloidosis (CA) but occasionally with wild-type transthyretin (ATTR) CA. In recent years, ATTR amyloidosis has attracted necessity for its reliable diagnosis with the addition of new treatments. Usually, both wild-type ATTR CA and AL-type CA present with marked cardiac hypertrophy, but renal dysfunction is milder in wild-type ATTR amyloidosis than in AL-type amyloidosis. Peripheral neurologic and autonomic symptoms such as numbness and dysesthesia are moderately present in AL-type amyloidosis, but less so in wild-type ATTR amyloidosis. Furthermore, the prognosis of ATTR-type amyloidosis is better than that of AL-type amyloidosis.Case presentationA 72-year-old man with cardiac hypertrophy presented with New York Heart Association functional class III dyspnea and leg edema. He had no history of carpal tunnel syndrome. An electrocardiogram showed atrial fibrillation and low voltage. The N-terminal pro-B-type natriuretic peptide level was 3310 pg/mL, and troponin T was elevated to 0.073 ng/mL. However, the glomerular filtration rate was only slightly decreased at 69.0 mL/min/1.73 m2. The serum free light-chain assay revealed a significant increase in the kappa chain, with positive results in Bence Jones proteins and serum immunoelectrophoresis. Bone marrow examination confirmed the diagnosis of monoclonal gammopathy of undetermined significance (MGUS). AL-type amyloidosis associated with a myeloproliferative disorder was suspected, and the prognosis was initially predicted to be poor, classified as Mayo stage IV. Contrary to this prognosis, the patient showed a slow progression of heart failure. Further imaging modalities and cardiac tissue findings confirmed the diagnosis as transthyretin type amyloidosis, and a favorable prognosis was established with the use of tafamidis.ConclusionsMGUS occasionally coexists with wild-type ATTR CA. Scant autonomic symptoms, mild renal dysfunction, and slow progression of heart failure might be clues that the CA associated with the myeloproliferative disease is wild-type ATTR amyloidosis.

Long-term outcomes after cardiac transplantation in AL amyloidosis.

7572 Background: Systemic AL amyloidosis can lead to progressive multi-organ dysfunction including advanced heart failure which may require orthotopic heart transplantation (OHT). Hematologic outcomes of AL amyloidosis post-OHT are not well described. Methods: We report outcomes for patients with AL amyloidosis with cardiac involvement post-OHT from Nov 2008 - Jun 2023 at Vanderbilt University Medical Center. Hematologic response was graded per the ISA guidelines. Results: Fourteen pts underwent OHT of whom 13 had lambda light chain disease. Three (21%) pts had isolated AL amyloidosis (AL) without myeloma (MM), while 11 (79%) also had MM: 6 with bone marrow plasma cells (BMPCs) 10-19% (AL-PCMM-10) and 5 with BMPC ≥20% (AL-PCMM-20). One each with AL-PCMM-10 and AL-PCMM-20 had lytic lesions (AL-CRAB). Median age at OHT was 55.5 yrs (range 37-74). Median time from diagnosis to OHT was 18 mo (range 3-62). Five (35%) pts had biopsy-proven extracardiac amyloid involvement. Median difference in serum free light chains at first evaluation was 70 mg/dL (range 9-289). Three pts were Mayo 2012 stage II, 4 stage III, and 7 stage IV. Four pts had t(11;14) and 1 had 1q gain. Ten (71%) pts received triplet therapy (VCd or VRd) and 3 (21%) received quadruplet therapy (Dara-VCd or Isa-VCd) pre-OHT. Six (43%) pts had autologous stem cell transplantation (ASCT); 1 pre-OHT and 5 post-OHT. Of ASCT pts, 1 pt achieved CHR, 1 VGPR, 2 PR, and 1 had PD pre-ASCT. Pre-OHT, 4 pts achieved CHR, 6 VGPR, 3 PR, and 1 had PD. Eleven pts (79%) received maintenance therapy post-OHT (5 proteosome inhibitors, 6 anti-CD38). At last follow-up, 8 pts were in CHR, 3 in VGPR, 1 in PR, and 2 had PD. Four (29%) pts died post-OHT: 2 from AL recurrence (1 each with AL and AL-PCMM-10), 1 from cardiac allograft vasculopathy (AL-CRAB), and 1 from renal failure (AL-CRAB). Three (21%) pts had hematologic relapse 5, 21 and 48 mo post-OHT, and of those, 2 had recurrent cardiac amyloid in graft 37 and 71 mo post-OHT. Of those with hematologic relapse, 2 had AL-PCMM-10 and 1 had AL. One pt had post-transplant lymphoproliferative disorder 126 mo post-OHT, requiring treatment. Median follow-up and survival of the cohort post-OHT was 2.25 yrs (range 0.5-13.8). Conclusions: In this single-center analysis of pts undergoing OHT for cardiac AL amyloidosis, we demonstrate feasibility of excellent long-term outcomes, in predominantly high-risk AL pts where majority harbored high-risk disease with MM overlap, either by AL-CRAB or AL-BMPC. Induction alone led to ≥VGPR response in 10 (71%) pts pre-OHT and further therapy deepened this to 11 (79%) pts. Both AL-CRAB pts died during follow-up, highlighting the overall poor prognosis in this specific subgroup. In our cohort, non-relapse related mortality was seen in only 2 (14%) pts, demonstrating acceptable post-OHT risk and overall ability to achieve far improved outcomes in the high-risk cardiac AL amyloidosis patient population that otherwise suffers from rapid and universal mortality.

Timing and co-occurrence of symptoms prior to a diagnosis of light chain (AL) amyloidosis

It is well-established that most patients with systemic light chain (AL) amyloidosis have multi-organ involvement and are often diagnosed after a lag period of increasing symptoms. We leverage electronic health record (EHR) data from the TriNetX research network to describe the incidence, timing, and co-occurrence of precursor conditions of interests in a cohort of AL amyloidosis patients identified between October 2015-December 2020. Nineteen precursor diagnoses of interest representing features of AL amyloidosis were identified using ICD codes up to 36 months prior to AL amyloidosis diagnosis. Among 1,401 patients with at least 36 months of EHR data prior to AL amyloidosis diagnosis, 46% were females, 16% were non-Hispanic Black, and 6% were Hispanic. The median age was 71 (range, 21–91) years. The median number of precursor diagnoses was 5 with dyspnea and fatigue being the most prevalent. The time from the first occurrence of a precursor to AL diagnosis ranged from 3.2 to 21.4 months. Analyses of pairwise co-occurrence of specific diagnoses indicated a high association (Cole’s coefficient >0.6) among the examined precursor diagnoses. These findings provide novel information about the timing and co-occurrence of key precursor conditions and could be used to develop algorithms for early identification of AL amyloidosis.

Identification of isoaspartate-modified transthyretin as potential target for selective immunotherapy of transthyretin amyloidosis

Background Numerous studies suggest a progressive accumulation of post-translationally modified peptides within amyloid fibrils, including isoaspartate (isoD) modifications. Here, we generated and characterised novel monoclonal antibodies targeting isoD-modified transthyretin (TTR). The antibodies were used to investigate the presence of isoD-modified TTR in deposits from transthyretin amyloidosis patients and to mediate antibody-dependent phagocytosis of TTR fibrils. Methods Monoclonal antibodies were generated by immunisation of mice using an isoD-modified peptide and subsequent hybridoma generation. The antibodies were characterised in terms of affinity and specificity to isoD-modified TTR using surface plasmon resonance, transmission electron microscopy and immunohistochemical staining of human cardiac tissue. The potential to elicit antibody-dependent phagocytosis of TTR fibrils was assessed using THP-1 cells. Results We developed two mouse monoclonal antibodies, 2F2 and 4D4, with high nanomolar affinity for isoD-modified TTR and strong selectivity over the unmodified epitope. Both antibodies show presence of isoD-modified TTR in human cardiac tissue, but not in freshly purified recombinant TTR, suggesting isoD modification only present in aged fibrillar deposits. Likewise, the antibodies only facilitated phagocytosis of TTR fibrils and not TTR monomers by THP-1 cells. Conclusions These antibodies label aged, non-native TTR deposits, leaving native TTR unattended and thereby potentially enabling new therapeutic approaches.

Reduced heart failure hospitalizations and improved quality of life in cardiac amyloidosis patients undergoing atrial fibrillation ablation

Abstract Background Cardiac amyloidosis (CA) has been associated with an increased risk of atrial arrhythmias and development and worsening of heart failure due to infiltration of the amyloid protein in the atrial wall. Few data exist regarding prognosis, symptoms, and quality of life after catheter ablation of atrial fibrillation in this category of patients. Objective The study evaluates the outcome of hospitalization for heart failure and quality of life in cardiac amyloidosis patients with atrial fibrillation after catheter ablation. Methods This is a study including 102 consecutive patients from two different centers with an established diagnosis of amyloidosis ATTR that underwent their first AF catheter ablation for persistent AF. They underwent pulmonary vein (PV) isolation + isolation of left atrial posterior wall and superior vena cava. Additionally, extrapulmonary triggers were identified and ablated. Post procedure, patients were followed up routinely with ECG during office visits, 7-day Holter monitor and event recorders during the first year followed by biannual checkups during the remaining part of the follow-up period. Quality of life (QoL) was measured using The Minnesota Living Heart Failure Questionnaire (MLHFQ) before Catheter ablation and after 18 months follow up; QoL was compared with T-test. Results 102 patients (mean age 72 ± 6) were included in the study. After 18 months follow up, 72 patients (70.6%) remained arrhythmia-free without antiarrhythmic drugs (Group 1), whereas 30 patients (29.4%) experienced recurrence (Group 2). In Group 1, 9 patients were hospitalized for heart failure, in contrast to 18 patients in Group 2, indicating a higher rate of heart failure hospitalizations associated with arrhythmia recurrence (p=0.02). The Quality of life in group 1 was 62 ±12 points before ablation and 63±16 points at 18 months follow up (p=0.17) while in group 2 was 68±16 points before ablation and 86±12 points at 18 months follow up (p<0.001). Conclusion Catheter ablation for AF in patients with cardiac amyloidosis is associated with reduced hospitalizations for heart failure, along with improvement in QoL.

Prevalence of non pulmonary vein triggers and pulmonary pressure change in atrial fibrillation ablation for cardiac amyloidosis patients

Abstract Background Cardiac amyloidosis (CA) has been associated with an increased risk of atrial arrhythmias and high risk to develop pulmonary hypertension due to infiltration of the amyloid protein in the atrial wall. Though non-PV triggers are commonly seen in left atrium, they are also seen in the right side of the heart, so identifying them at the time of ablation is essential. Objective The study evaluates the prevalence of non-PV triggers during catheter ablation in atrial fibrillation (AF) patients affected by cardiac amyloidosis and how restoration of sinus rhythm affects pulmonary pressures. Methods This is a study including 74 consecutive patients with an established diagnosis of amyloidosis ATTR diagnosed with cardiac MRI or myocardial biopsy that underwent their first AF catheter ablation. All have a transthoracic echocardiogram before ablation. They underwent pulmonary vein (PV) isolation + isolation of left atrial posterior wall and superior vena cava. Additionally, extrapulmonary triggers, which are defined as ectopic triggers originating from sites other than PVs including left atrial appendage (LAA), coronary sinus (CS), interatrial septum, crista terminalis, mitral valve anulus were identified. Post procedure, patients were followed up routinely with ECG during office visits, echocardiogram, 7-day Holter monitor and event recorders during the first year followed by biannual checkups during the remaining part of the follow-up period. Student’s t-test was used to compare pulmonary pressure between the groups. Results Isoproterenol-challenge revealed non-PV triggers in 51 (68.9%) patients. These triggers were mostly mapped to LAA (39, 52.7%), CS (30, 40,5%), and crista terminalis (35, 47.3%). Besides, ectopic beats were seen originating from inter-atrial septum (19, 25.6%), mitral valve annulus (10, 13.5%). More than one trigger was found in (68%) patients. At 1-year after the ablation, 65 (87.8%) were arrhythmia-free off antiarrhythmic drugs. Moreover, in patients who maintained sinus rhythm post-ablation, there was either a non progression or a reduction in pulmonary pressures (PAPm before ablation: 44.8 ± 8.9 mmHg vs PAPm after ablation 45.1 ± 11.1 mmHg, P value =0.87). Conversely, those experiencing arrhythmic recurrences demonstrated an increase in pulmonary pressures (PAPm before ablation: 41.9 ± 7.7 mmHg vs PAPm after ablation 47.8 ± 10.2 mmHg, P value =0.019). Fig.1 Conclusion Our findings suggest that non-PV triggers are highly prevalent in cardiac amyloidosis AF patients including a high rate crista terminalis firing. Notably, restoration of sinus rhythm post-ablation was linked to stable or reduced pulmonary arterial pressures, whereas patients with arrhythmic recurrences experienced a significant increase.

#2282 Outcomes of renal amyloidosis: 8 years experience of tertiary center

Abstract Background and Aims Amyloidosis is a disease caused by the extracellular deposition of amyloid material that leads to organ dysfunction. Renal involvement is frequent and is characterized by amyloid fibrils pathologic deposition in glomeruli, vessels and interstitium. The most common presentation is nephrotic-range proteinuria or nephrotic syndrome and can progress to end stage kidney disease (ESKD). Prognosis is usually poor, especially with cardiac and severe renal involvement that requires renal replacement therapy. The goal of this study was to analyse the outcomes of patients with amyloidosis followed at the nephrology clinic in our centre. Method Descriptive analysis of all confirmed amyloid patients, followed by the Nephrology department from January 2015 to June 2023. Results We identified 49 patients with a mean age of 64 ± 16 years [18-88], mainly Caucasian (n = 47, 82%) and male (n = 28, 57%). The majority of patients were diagnosed through renal biopsy (26, 53%). The most common amyloid type was AL (n = 18, 38%), followed by ATTR (n = 16, 33%) and AA (n = 12, 25%). In 3 patients the amyloid type couldn't be characterized. Renal presentation was mostly as CKD 28/49 (57%), 15/49 (30.6%) as nephrotic syndrome and 6/49 (12%) patients as AKI. At presentation, almost half of the patients (24/49, 49%) had nephrotic-range proteinuria, with a mean proteinuria of 6.72 ± 6.12 g/d [0.103-19.8] and mean sCr was 2.6 ± 3.1 mg/dl [0.5-18.9]. AL amyloidosis had an almost equal distribution between lambda (9/18, 50%) and kappa chain (8/18, 44%, one unknown). Extrarenal involvement was frequent, mainly cardiac (12/18, 67%). Also 12/18 (67%) patients needed dialysis after a mean of 9 ± 15 months post-diagnosis, 16/18 (89%) received treatment and mortality was 61%, in mean 16 ± 17 months post-diagnosis, mainly due to disease progression. AA amyloidosis was secondary to chronic infection in 7/12 (58%), 3/12 (25%) autoimmune diseases and in 2/12 (17%) unknown. Extrarenal involvement was less frequent, also mainly cardiac (3/12, 25%). 7/12 (58%) patients needed dialysis after a mean of 97 ± 117 months post-diagnosis and mortality was 58%, in mean 46 ± 66 months post-diagnosis, mainly due to acute infection. Two patients were diagnosed already on dialysis. Regarding ATTR amyloidosis, all patients had a positive genetic test, extrarenal involvement was very frequent (13/16, 81%), mostly cardiac and peripheric nervous system. No patients required dialysis during follow-up, and one patient died of unknown cause. Conclusion In our cohort, renal AL and AA amyloidosis had poor prognosis, with a high progression to ESKD and very significant mortality, irrespective of treatment. Conversely, ATTR amyloidosis patients had lower progression to dialysis and death, probably as a consequence of disease-modifying therapies instituted in recent years.

Serum monoclonal immunoglobulin light-chain detection differs between immunofixation electrophoresis methods in patients with AL amyloidosis.

Serum immunofixation electrophoresis (IFE) is often performed for screening monoclonal proteins (M proteins) in immunoglobulin light-chain amyloidosis (AL amyloidosis). However, the performance of serum IFE for detecting M protein in AL amyloidosis patients is often insufficient. In this study, we examined the detection rate of serum M protein in newly diagnosed AL amyloidosis patients and analyzed differences in M protein detection between IFE methods. Among 60 patients newly diagnosed with AL amyloidosis, 22 had undetectable serum M protein by IFE with the Epalyzer2 system. Samples with undetectable M protein had significantly lower involved serum-free light-chain (iFLC) and a smaller difference between involved and uninvolved serum-free light-chain (dFLC) values than samples with IFE-detectable monoclonal light chains. When samples that tested negative for M protein by the Epalyzer2 system were retested by IFE with the HYDRASYS 2 system, 50% had IFE-detectable monoclonal light chains. The IFE system and reagents used may affect serum monoclonal immunoglobulin light-chain detection in AL amyloidosis patients, especially those with low iFLC or low dFLC samples. More attention should be paid to the performance of IFE systems, since it may affect the diagnostic and therapeutic evaluation of AL amyloidosis patients.

Screening for cardiac amyloidosis in patients with tenosynovial red flags: A collaboration between family medicine and cardiology

BackgroundAmyloid deposition in tenosynovial structures precedes cardiac involvement up to 20 years. Therefore, a cardiological screening in patients with a history of tenosynovial manifestations of cardiac amyloidosis (CA) could lead to an increased number of early diagnoses. MethodsPatients with tenosynovial manifestations of CA (carpal tunnel syndrome, atraumatic biceps tendon rupture, lumbar spinal stenosis) have been identified by general practitioners and evaluated in a Referral Center for CA. Patients with a high suspicion of CA underwent the CA diagnostic pathway. ResultsAmong 50 General Practitioners (GP) contacted, 10 (20%) agreed to participate in the study for a total of 5615 patients ≥60 years. One hundred forty-five patients met the inclusion criteria, 2 of them already had a diagnosis of CA, and 57 agreed to undergo a cardiological evaluation (electrocardiography, echocardiography, NTproBNP assay). The median age was 73 [67–80] years and 31 (54%) were women. Eight patients were suggested to start the CA diagnostic pathway, five of them underwent a complete diagnostic evaluation for CA, three refused to complete the diagnostic exams and no new diagnoses were made. ConclusionA screening program for CA in patients with tenosynovial manifestations identified by general practitioners is feasible, but may not yield a high rate of new diagnosis. In this study, we identified two patients who already had a diagnosis of CA, and among patients at high risk for CA, 37% refused to complete the diagnostic pathway. Increased awareness of CA among patients might increase participation and diagnostic yield in screening studies. Further validation of this protocol is needed to evaluate its diagnostic performance.

Clinical characteristics of patients with high extracellular volume fraction evaluated by cardiac computed tomography for coronary artery evaluation.

This study aims to evaluate the distribution of extracellular volume fraction detected via computed tomography, clinical characteristics of high extracellular volume fraction detected via computed tomography, and the rate of incidental detection of cardiac amyloidosis in patients undergoing cardiac computed tomography for coronary artery evaluation. This study included 874 consecutive patients (mean age, 74.4 ± 7.1 years; men, 65%), comprising men aged ≥60 years and women aged ≥70 years, who had undergone cardiac computed tomography between January 2020 and September 2022. The mean extracellular volume fraction detected via computed tomography was 29.7 ± 5.2%, and 108 patients (12.4%) had an extracellular volume fraction detected via computed tomography of ≥35%. Older age (75.9 ± 8.2 years vs. 74.2 ± 6.9 years; P = 0.042), male sex (75.9% vs. 63.0%; P = 0.007), impaired left ventricular ejection fraction, increased high-sensitivity cardiac troponin T and B-type natriuretic peptide levels, and increased left ventricular thickness showed significant associations with an extracellular volume fraction detected via computed tomography of ≥35%. Cardiac amyloidosis was diagnosed incidentally in 15 patients based on an increase in extracellular volume fraction detected via computed tomography. The prevalence of cardiac amyloidosis was 1.7% (15/874) and 14.3% (15/105) in the entire study population and in patients with an extracellular volume fraction detected via computed tomography of ≥35%, respectively. An increase in the extracellular volume fraction detected via computed tomography was suggestive of cardiac amyloidosis. Elevated extracellular volume fraction detected via computed tomography, associated with elevated cardiac biomarker levels and myocardial structural changes, may lead to the incidental diagnosis of cardiac amyloidosis.

A Simple Frailty Score Predicts Survival and Early Mortality in Systemic AL Amyloidosis.

Systemic AL amyloidosis is a challenging disease for which many patients are considered frail in daily clinical practice. However, no study has so far addressed frailty and its impact on the outcome of these patients. We built a simple score to predict mortality based on three frailty-associated variables: age, ECOG performance status (<2 vs. ≥2) and NT-proBNP (<8500 vs. ≥8500 ng/L). Four-hundred and sixteen consecutive newly diagnosed patients diagnosed at ten sites from the Spanish Myeloma Group were eligible for the study. The score was developed in a derivation cohort from a referral center, and it was externally validated in a multicenter cohort. Multivariate analysis showed that the three variables were independent predictors of survival. The score was able to discriminate four groups of patients in terms of overall survival and early mortality in both cohorts. Comorbidity was also analyzed with the Charlson comorbidity index, but it did not reach statistical significance in the model. A nomogram was created to easily estimate the mortality risk of each patient at each time point. This score is a simple, robust, and efficient approach to dynamically assess frailty-dependent mortality both at diagnosis and throughout follow-up. The optimal treatment for frail AL amyloidosis patients remains to be determined but we suggest that the estimation of frailty-associated risk could complement current staging systems, adding value in clinical decision-making in this complex scenario.

Immune Therapies in AL Amyloidosis-A Glimpse to the Future.

Light-chain (AL) amyloidosis is a rare plasma cell disorder characterized by the deposition of misfolded immunoglobulin light chains in target organs, leading to multi-organ dysfunction. Treatment approaches have historically mirrored but lagged behind those of multiple myeloma (MM). Recent advancements in MM immunotherapy are gradually being evaluated and adopted in AL amyloidosis. This review explores the current state of immunotherapeutic strategies in AL amyloidosis, including monoclonal antibodies, antibody-drug conjugates, bispecific antibodies, and chimeric antigen receptor T-cell therapy. We discuss the unique challenges and prospects of these therapies in AL amyloidosis, including the exposure of frail AL amyloidosis patients to immune-mediated toxicities such as cytokine release syndrome (CRS) and immune effector-cell-associated neurotoxicity syndrome (ICANS), as well as their efficacy in promoting rapid and deep hematologic responses. Furthermore, we highlight the need for international initiatives and compassionate programs to provide access to these promising therapies and address critical unmet needs in AL amyloidosis management. Finally, we discuss future directions, including optimizing treatment sequencing and mitigating toxicities, to improve outcomes for AL amyloidosis patients.

Coronavirus Disease 2019 Outcomes in Amyloid A Protein Amyloidosis Secondary to Rheumatic Conditions and Signs of Post- Coronavirus Disease 2019 Proteinuria Progression.

We aimed to investigate coronavirus diease 2019 (COVID-19) outcomes in patients with amyloid A protein (AA) amyloidosis secondary to rheumatic diseases and discuss factors associated with disease course. A retrospective cohort was formed from adult patients with a diagnosis of AA amyloidosis. In patients with a positive severe acute respiratory syndrome coronavirus 2 polymerase chain reaction (PCR) test, rates of hospitalization, intensive care unit admission and mortality due to COVID-19 were collected from medical records. Data regarding to demographics, comorbidities, laboratory tests, medical treatments, adherence to previous treatments during COVID-19 and treatment administered for COVID-19 were collected from hospital databases and patient reviews. In 96 patients with AA amyloidosis, 16 had COVID-19 with a positive PCR. Ten (62.5%) patients were hospitalized, 2 (12.5%) were admitted to ICU, 1 (6.25%) was died. Hospitalized patients tended to be older. Comorbidities seemed to be more frequent in hospitalized patients. None of the patients had rapid progression to end-stage renal disease post-COVID-19. Seven patients had pre-COVID-19 and post-COVID-19 proteinuria levels. Three had notable increase in proteinuria after COVID-19 in 2 of which amyloidosis treatment was revised accordingly. Despite high rates of hospitalization in AA amyloidosis patients, mortality was observed only in 1 patient. Progression of proteinuria requiring treatment adjustment may be an issue in these patients. Cite this article as: Güven SC, Erden A, Küçük H, et al. Coronavirus disease 2019 outcomes in amyloid A protein amyloidosis secondary to rheumatic conditions and signs of post-coronavirus disease 2019 proteinuria progression. Eur J Rheumatol. Published online April 4, 2024. DOI:10.5152/eurjrheum.2024.23050.

Systemic Juvenile idiopathic arthritis in child complicated by amyloidosis with secondary nephrotic syndrome

A 7 years old girl diagnosed as case of juvenile idiopathic arthritis since the age of 1.5 years, generalized onset with systemic presentation is complicated by secondary nephrotic syndrome. Renal biopsy showing amyloidosis. Patient has severe disease course being complicated by sever flare ups of disease symptoms and body swelling. Since onset of disease patient got NSAIDs, methotrexate, steroids, anti TNF inhibitors with no or partial response. After diagnosis with secondary nephrotic syndrome due to secondary amyloidosis patient is started on intravenous tocilizumab. There is improvement of patient symptoms.

The prognostic value of artificial intelligence to predict cardiac amyloidosis in patients with severe aortic stenosis undergoing transcatheter aortic valve replacement.

Cardiac amyloidosis (CA) is common in patients with severe aortic stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR). Cardiac amyloidosis has poor outcomes, and its assessment in all TAVR patients is costly and challenging. Electrocardiogram (ECG) artificial intelligence (AI) algorithms that screen for CA may be useful to identify at-risk patients. In this retrospective analysis of our institutional National Cardiovascular Disease Registry (NCDR)-TAVR database, patients undergoing TAVR between January 2012 and December 2018 were included. Pre-TAVR CA probability was analysed by an ECG AI predictive model, with >50% risk defined as high probability for CA. Univariable and propensity score covariate adjustment analyses using Cox regression were performed to compare clinical outcomes between patients with high CA probability vs. those with low probability at 1-year follow-up after TAVR. Of 1426 patients who underwent TAVR (mean age 81.0 ± 8.5 years, 57.6% male), 349 (24.4%) had high CA probability on pre-procedure ECG. Only 17 (1.2%) had a clinical diagnosis of CA. After multivariable adjustment, high probability of CA by ECG AI algorithm was significantly associated with increased all-cause mortality [hazard ratio (HR) 1.40, 95% confidence interval (CI) 1.01-1.96, P = 0.046] and higher rates of major adverse cardiovascular events (transient ischaemic attack (TIA)/stroke, myocardial infarction, and heart failure hospitalizations] (HR 1.36, 95% CI 1.01-1.82, P = 0.041), driven primarily by heart failure hospitalizations (HR 1.58, 95% CI 1.13-2.20, P = 0.008) at 1-year follow-up. There were no significant differences in TIA/stroke or myocardial infarction. Artificial intelligence applied to pre-TAVR ECGs identifies a subgroup at higher risk of clinical events. These targeted patients may benefit from further diagnostic evaluation for CA.

Longitudinal analysis of serum neurofilament light chain levels as marker for neuronal damage in hereditary transthyretin amyloidosis

Objective To evaluate serum neurofilament light chain (sNfL) as biomarker of disease onset, progression and treatment effect in hereditary transthyretin (ATTRv) amyloidosis patients and TTR variant (TTRv) carriers. Methods sNfL levels were assessed longitudinally in persistently asymptomatic TTRv carriers (N = 12), persistently asymptomatic ATTRv amyloidosis patients (defined as asymptomatic patients but with amyloid detectable in subcutaneous abdominal fat tissue) (N = 8), in TTRv carriers who developed polyneuropathy (N = 7) and in ATTRv amyloidosis patients with polyneuropathy on treatment (TTR-stabiliser (N = 20) or TTR-silencer (N = 18)). Polyneuropathy was confirmed by nerve conduction studies or quantitative sensory testing. sNfL was analysed using a single-molecule array assay. Results sNfL increased over 2 years in persistently asymptomatic ATTRv amyloidosis patients, but did not change in persistently asymptomatic TTRv carriers. In all TTRv carriers who developed polyneuropathy, sNfL increased from 8.4 to 49.8 pg/mL before the onset of symptoms and before polyneuropathy could be confirmed neurophysiologically. In symptomatic ATTRv amyloidosis patients on a TTR-stabiliser, sNfL remained stable over 2 years. In patients on a TTR-silencer, sNfL decreased after 1 year of treatment. Conclusion sNfL is a biomarker of early neuronal damage in ATTRv amyloidosis already before the onset of polyneuropathy. Current data support the use of sNfL in screening asymptomatic TTRv carriers and in monitoring of disease progression and treatment effect.

Prognostic mortality factors in advanced light chain cardiac amyloidosis: A prospective cohort study.

Predicting mortality in severe AL cardiac amyloidosis is challenging due to elevated biomarker levels and limited thresholds for stratifying severe cardiac damage. This prospective, observational, cohort study included de novo, confirmed cardiac AL amyloidosis patients at the Henri Mondor National Reference Centre. The goal was to identify predictors of mortality to enhance prognostic stratification and improve informed decision-making regarding therapy. Over the 12-year study period, among the 233 patients included, 133 were NYHA III-IV and 179 Mayo 2004 III. The independent predictors for mortality identified were hsTnT, NT-proBNP, cardiac output, and conjugated bilirubin. A novel prognostic, conditional stratification, Mondor amyloidosis cardiac staging (MACS) was developed with biomarker cut-off values for Stage 1: hsTnT≤107ng/L and NT-proBNP≤3867ng/L (n=77; 33%); for stage 2 NT-proBNP>3867ng/L (n=72; 30%). For stage 3, if troponin >107ng/L, regardless of NT-proBNP then CB 4μmol/L, was added (n=41; 17.5%) and stage 4: CB>4μmol/L (n=43; 18.5%). The median overall survival was 8months 95% CI [2-24]. At 1year, 102 (44%) patients died and the Kaplan-Meier median survival with MACS Stage 1 was not reached, while stage 2 was 15.2months (95% CI [11-18]) and stage 3, 6.6months (95% CI [1-13]). Notably, among European stage II patients, 17.1%, n=8 were MACS stage 3 and European stage IIIb 21.4% (n=23) were MACS stage 4. Importantly, among European stage IIIb patients 42.2% (n=29) were classified MACS stage 4 and 12.5% n=9 were only MACS stage 2. The Mondor prognostic staging system, including conjugate bilirubin may significantly improve prognostic stratification for patients with severe cardiac amyloidosis.

Prevalence of transthyretin cardiac amyloidosis in patients with high-degree AV block

ObjectiveTransthyretin amyloid cardiomyopathy (ATTR-CM) is an infiltrative cardiac disorder caused by deposition of wild type or mutated transthyretin. As ATTR-CM is associated with conduction disease, we sought to determine its...

Chinese collaborative study of survival analysis in 980 patients with AL amyloidosis

AbstractBackgroundThe prognosis of patients with light‐chain amyloidosis (AL) has improved markedly in the past decade in China; whether the current staging systems are suitable to predict the overall survival (OS) of the patients remains undetermined.MethodsBased on 980 biopsy‐proved AL patients with 5‐year follow‐up from China Registration Network for Light‐chain Amyloidosis, we evaluated the efficacy of existing staging systems and developed a new stratification model. This involved analyzing parameters such as N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) thresholds and estimated glomerular filtration rate (eGFR).ResultsWe found that 30% patients were classified as stage I, 25% as stage II, 26% as stage III, and 19% as stage IV disease using the Mayo 2012 staging system, with varying median OS values. However, the observed median OS values were notably higher than previously reported. By incorporating NT‐proBNP thresholds and eGFR values, we developed a four‐stage score system. With this new model, 41.6% patients were reclassified to stage I, 34.3% to stage II, 17.8% to stage III, and 6.3% to stage IV disease, with adjusted median OS values.ConclusionThe new stratification model exhibited improved consistency compared to traditional staging systems. It effectively identified patients with the best and worst prognoses, even among those receiving comprehensive treatment. Specifically, NT‐proBNP levels exceeding 9000 pg/mL combined with an eGFR less than 60 mL/min/1.73 m2 proved superior in prognosticating patient outcomes. Overall, the median OS of AL amyloidosis patients in China has significantly improved, underscoring the need for tailored prognostic models in clinical practice.

Gait abnormalities in older adults with transthyretin cardiac amyloidosis

Background Transthyretin cardiac amyloidosis (ATTR cardiac amyloidosis) is caused by variant (ATTRv) or wild type (ATTRwt) transthyretin. While gait abnormalities have been studied in younger patients with ATTRv amyloidosis, research on gait in older adults with ATTR cardiac amyloidosis is lacking. Given ATTR cardiac amyloidosis’ association with neuropathy and orthopedic manifestations, we explore the gait in this population. Methods Twenty-eight older male ATTR cardiac amyloidosis patients and 11 healthy older male controls walked overground with and without a dual cognitive task. Gait parameters: stride width, length, velocity and stance time percentage were measured using an instrumented mat. ATTR amyloidosis patients were further categorized based on clinical and functional assessments. Results We found significant gait differences between ATTR cardiac amyloidosis patients and healthy controls; patients had more variable, slower, narrower and shorter strides, with their feet spending more time in contact with the ground as opposed to in swing. However, the observed gait differences did not correlate with clinical and functional measures of ATTR cardiac amyloidosis severity. Conclusions Our results suggest that gait analysis could be a complementary tool for characterizing ATTR cardiac amyloidosis patients and may inform clinical care as it relates to falls, management of anticoagulation, and functional independence.