Screening for transthyretin amyloid cardiomyopathy in patients with musculoskeletal symptoms: Red flags in the rheumatology/orthopedics practice setting

Published: Dec 26, 2025

Highlights

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Transthyretin amyloidosis cardiomyopathy progression can be slowed with treatment.
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Musculoskeletal conditions commonly occur in the years preceding cardiomyopathy.
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Presence of these red flags should prompt additional screening for amyloidosis.
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Increased rheumatologist and orthopedic awareness could increase early diagnoses.
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Earlier diagnosis and therefore treatment improves patient prognosis.

Abstract

Musculoskeletal manifestations of transthyretin amyloidosis (ATTR) are common, early in the disease course (usually years before cardiac involvement), and are potentially predictive. They include carpal tunnel syndrome (CTS), trigger finger, atraumatic tears of the brachial biceps tendon or rotator cuff, spinal stenosis, and large joint osteoarthritis. These extra-cardiac ‘red flags’ for ATTR amyloidosis may present individually or in clusters, particularly in older males, several years in advance of signs of ATTR cardiomyopathy (ATTR-CM), such as arrhythmia or heart failure. Deposition of ATTR in the heart leads to severe, often fatal, ATTR-CM that can now be effectively treated. Available treatments slow amyloid fiber deposition but do not allow fiber removal, making early diagnosis and early treatment crucial to improve prognosis. Orthopedists’ and rheumatologists’ knowledge, recognition, and participation in the diagnostic pathway of amyloidosis-related musculoskeletal conditions may help increase suspicion, facilitate early diagnosis, allowing prompt disease-modifying treatment, improving patient outcomes. If surgical intervention is required in patients with these red flags, tissue biopsy at the time of surgery may allow early diagnosis of ATTR deposition, followed by cardiologic screening and/or patient referral to amyloidosis specialty centers if amyloid deposition is evident in biopsy findings. To improve awareness among orthopedic and rheumatology specialists, this narrative review summarizes the published literature on musculoskeletal disorders associated with ATTR amyloidosis, presents relevant diagnostic pathways and indications for histologic examination to facilitate identification of at-risk patients among large numbers of patients, and suggests appropriate follow-up approaches for patients in whom amyloidosis is detected during musculoskeletal surgical procedures.

Introduction

Transthyretin amyloidosis (ATTR) is a major type of systemic amyloidosis resulting from misfolding of transthyretin (TTR) monomers, TTR aggregation into insoluble amyloid fibrils, and extracellular fibril deposition in various tissues and organs [1], [2], [3]. TTR protein misfolding and amyloid fibril deposition in the heart lead to irreversible deterioration of myocardial function, progressing to heart failure and death. Transthyretin amyloidosis cardiomyopathy (ATTR-CM) is increasingly recognized as a cause of heart failure in older patients, with an estimated median survival of approximately 3.5 years without treatment [1]. Grade 2 or 3 myocardial uptake of radiotracer isotope during bone scintigraphy is a valuable, non-invasive tool indicating a diagnosis of ATTR-CM when monoclonal gammopathy is excluded [1]. ATTR amyloidosis exists in two distinct forms that may involve the heart: the hereditary variant (ATTRv) and the age-related wild-type (ATTRwt). Differentiation between these forms requires genotyping [1]. In both forms, the amyloidogenic process begins with the destabilization of the tetrameric structures of TTR into folded monomers, which then transform into amyloid fibrils [1], [4].

Although prognosis is largely centered on myocardial involvement, ATTR amyloidosis is a systemic disorder, also characterized by amyloid deposits in other organs, including musculoskeletal tissues, particularly ligaments, synovia, and joint cartilage [3]. Non-cardiac musculoskeletal manifestations such as carpal tunnel syndrome (CTS) typically appear years in advance of cardiac signs of ATTR amyloidosis [5], [6]. CTS is the most common manifestation, found in up to 87% of patients, and its presentation can precede diagnosis of amyloidosis by up to 12 years [7], [8]. Other musculoskeletal conditions commonly observed early in the disease course should alert rheumatologists and orthopedic surgeons to the possibility of underlying ATTR amyloidosis [3]. The implementation of screening strategies is crucial given that ATTR-CM can now be treated. Early treatment has been demonstrated to significantly improve prognosis, with better cardiac outcomes and longer survival [1], [9]. Rheumatologists and orthopedic surgeons therefore have a key role in the early detection of ATTR amyloidosis and in improving the diagnostic and therapeutic pathway, but their awareness appears suboptimal [10]. This narrative review aims to examine the various musculoskeletal disorders associated with ATTR amyloidosis, to assess the extent to which their recognition by rheumatologists and orthopedic surgeons can promote early diagnosis and treatment of ATTR heart disease, to define the indications for histologic examination in patients at risk of having ATTR-CM, and to propose appropriate follow-up measures for patients in whom amyloidosis is discovered during musculoskeletal surgery.

Authors

Thomas Bardin a 1, Nicolas Bigorre b 1, Eric Hachulla c, Roland Chapurlat d, Marc-Antoine Delbarre e, Laurent Obert f, Jean Sibilia g, Uma Basseville h, Margaux Dubois h, Michel Slama i, Olivier Lairez j, Thibaud Damy k