Wild-type transthyretin cardiac amyloidosis: When is a rare disease no longer a rare disease?

In this issue of JNC, Cuscaden and colleagues report the prevalence of cardiac uptake (a hallmark of cardiac amyloidosis) in patients undergoing routine {99m}^Tc-HMDP (hydroxymethylene diphosphonate) and {99m}^Tc-MDP (methylene diphosphonate) scintigraphy, suggesting a high prevalence of the disease increasing with age.

Confirming the Diagnosis of Amyloidosis

Amyloidosis is a general term for diseases characterised by the deposition of insoluble amyloid fibrils in organs or tissues, leading to organ dysfunction and, in many cases, death. Amyloid fibrils are derived from soluble precursor proteins, with the number of known amyloidogenic proteins increasing over time. The identity of the precursor protein often predicts the disease phenotype, although many of the amyloidoses have overlapping clinical features. Most patients with amyloidosis will require biopsy of an involved organ or tissue to confirm the diagnosis. Cardiac transthyretin amyloidosis, however, may be diagnosed without a biopsy provided stringent criteria are met. Where amyloid is confirmed histologically, the identity of the amyloidogenic protein must be determined, given several of the amyloidoses have disease-specific therapies. Laser capture microdissection and tandem mass spectrometry, LCM-MS, has revolutionised amyloid subtyping, being able to identify the amyloidogenic protein more reliably than antibody-based methods such as immunohistochemistry. Here we summarise the biopsy approach to amyloidosis, as well as the non-biopsy diagnosis of cardiac transthyretin amyloidosis. Proteomic and antibody-based methods for amyloid subtyping are reviewed. Finally, an algorithm for confirming the diagnosis of amyloidosis is presented

Systemic Amyloidosis due to Low-Grade Lymphoma

Lymphoma-related amyloidosis is a rare entity. Systemic AL amyloidosis is generally caused by an underlying plasma cell clone in the bone marrow with an intact monoclonal immunoglobulin G (IgG) or IgA protein. The rarity of the lymphoma-related amyloidosis makes the generation of data in randomized trials and the determination of the optimal treatment almost impossible. Therefore, treatment recommendations discussed here are based on either retrospective or small prospective trials of single centers

Recent guidelines for high-dose chemotherapy and autologous stem cell transplant for systemic AL amyloidosis: a practitioner's perspective

INTRODUCTION: High-dose melphalan followed by autologous stem cell transplant (ASCT) has been transformative in treating AL amyloidosis since the early nineties. Recently, the European Hematology Association (EHA) and International Society of Amyloidosis (ISA) have developed a combined guideline for the management of patients undergoing an ASCT for AL amyloidosis. AREAS COVERED: In this practitioner's perspective, we review the guideline, focusing on 6 major areas and offer practical advice for its application. We provide a perspective on the optimal use of ASCT and its potential application in the future. EXPERT OPINION: The EHA-ISA guideline comprehensively outlines the practicalities of performing an ASCT in AL amyloidosis. The critical aspect is careful patient selection. Vigilant fluid balance assessments are crucial as associated complications are common and dangerous. The role of ASCT is changing with improving hematological responses associated with novel agents. Evidence is limited for the use of ASCT in patients who achieve a complete hematological response (CR). Therefore, ASCT should be considered for those who only achieve a very good partial response (VGPR)/partial response (PR) and fulfil the strict selection criteria. Future research identifying the cohort who would benefit most from ASCT in the era of novel therapies is warranted

AL Amyloidosis for Cardiologists: Awareness, Diagnosis, and Future Prospects: JACC: CardioOncology State-of-the-Art Review

Amyloid light chain (AL) amyloidosis is a rare, debilitating, often fatal disease. Symptoms of cardiomyopathy are common presenting features, and patients often are referred to cardiologists. Cardiac amyloid infiltration is the leading predictor of death. However, the variable presentation and perceived rarity of the disease frequently lead to delay in suspecting amyloidosis as a cause of heart failure, leading to misdiagnoses and a marked delay in diagnosis, with devastating consequences for the patient. A median time from symptom onset to correct diagnosis of about 2 years is often too long when median survival from diagnosis for patients with AL amyloidosis and cardiomyopathy is 4 months to 2 years. The authors highlight the challenges to diagnosis, identify gaps in the current knowledge, and summarize novel treatments on the horizon to raise awareness about the critical need for early recognition of symptoms and diagnosis of AL amyloidosis aimed at accelerating treatment and improving outcomes for patients

Systemic amyloidosis in England: an epidemiological study.

Epidemiological studies of systemic amyloidosis are scarce and the burden of disease in England has not previously been estimated. In 1999, the National Health Service commissioned the National Amyloidosis Centre (NAC) to provide a national clinical service for all patients with amyloidosis. Data for all individuals referred to the NAC is held on a comprehensive central database, and these were compared with English death certificate data for amyloidosis from 2000 to 2008, obtained from the Office of National Statistics. Amyloidosis was stated on death certificates of 2543 individuals, representing 0·58/1000 recorded deaths. During the same period, 1143 amyloidosis patients followed at the NAC died, 903 (79%) of whom had amyloidosis recorded on their death certificates. The estimated minimum incidence of systemic amyloidosis in the English population in 2008, based on new referrals to the NAC, was 0·4/100 000 population. The incidence peaked at age 60-79 years. Systemic AL amyloidosis was the most common type with an estimated minimum incidence of 0·3/100 000 population. Although there are various limitations to this study, the available data suggest the incidence of systemic amyloidosis in England exceeds 0·8/100 000 of the population

Immune checkpoints in rheumatoid arthritis: progress and promise

Rheumatoid arthritis (RA) is one of the most prevalent autoimmune inflammatory conditions, and while the mechanisms driving pathogenesis are yet to be completely elucidated, self-reactive T cells and immune checkpoint pathways have a clear role. In this review, we provide an overview of the importance of checkpoint pathways in the T cell response and describe the involvement of these in RA development and progression. We discuss the relationship between immune checkpoint therapy in cancer and autoimmune adverse events, draw parallels with the involvement of immune checkpoints in RA pathobiology, summarise emerging research into some of the lesser-known pathways, and the potential of targeting checkpoint-related pathways in future treatment approaches to RA management