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Musculoskeletal Manifestations in Patients with ATTR Amyloidosis: Evidence from Real-World Analyses and Clinical Trials
Mazen A Hanna, MD1, Chafic Karam, MD2, Simon Gibbs, MBBS, FRACP, FRCPA3, Robert L Gottlieb, MD, PhD, FACC, FAST, FIDSA4, Shaun Bender, PhD5, Colleen Moffitt, PharmD, MS5, Catherine Summers, PhD, MS5, Emre Aldinc, MD5, Kelley Capocelli, MD5 and Brian M Drachman, MD6, (1)Cleveland Clinic, Cleveland, OH, (2)University of Pennsylvania, Philadelphia, PA, (3)Box Hill Hospital, Melbourne, VIC, Australia, (4)Center for Advanced Heart and Lung Disease, Baylor University Medical Center, Dallas, TX, (5)Alnylam Pharmaceuticals, Cambridge, MA, (6)Penn Presbyterian Medical Center, Philadelphia, PA

Introduction: Transthyretin-mediated (ATTR) amyloidosis is a progressive, debilitating, and fatal disease caused by amyloid deposition, including early deposition in musculoskeletal (MSK) tissues in addition to the heart and nerves. There are two types of ATTR amyloidosis: hereditary (ATTRv) and wild-type (ATTRwt). Diagnosis can be delayed due to the heterogeneous nature of ATTR amyloidosis, although MSK manifestations including carpal tunnel syndrome (CTS), spinal stenosis (SS), and trigger finger (TF), may precede diagnosis by several years. Increased recognition of MSK manifestations associated with ATTR amyloidosis would allow surgeons to play an active role in patient referral, which may be critical for early diagnosis and treatment.

Materials & Methods: Medical/surgical histories of patients with ATTR amyloidosis from seven Alnylam-sponsored clinical trials, a patient survey, or the patisiran Expanded Access Protocol (EAP) for cardiomyopathy (NCT05505838) were analyzed for prevalence of MSK manifestations (CTS, SS, TF).

Results: Medical/surgical histories were evaluated from 1010 patients from Alnylam-sponsored trials (24–85 years at enrollment; 72% ATTRv), 47 respondents to a patient survey (42‒82 years at diagnosis; 43% ATTRv), and 172 patients participating in the EAP (41–85 years at enrollment; 6% ATTRv). Mean age was 7‒9 years higher in patients with ATTRwt amyloidosis vs ATTRv amyloidosis. Of patients enrolled in Alnylam-sponsored trials, 39% had history of CTS and/or CT decompression, 8% had SS, and 3% had TF. Prevalence was higher in the patient survey and EAP populations, where 45% and 67%, respectively, had prior bilateral CTS, 26% and 42% had SS, and 28% and 34% had TF. MSK manifestations were more prevalent in patients with ATTRwt amyloidosis vs ATTRv amyloidosis in the Alnylam-sponsored trials (CTS and/or CT decompression [ATTRwt vs ATTRv]: 53% vs 33%; SS, 13% vs 6%; TF, 5% vs 2%) and patient survey (bilateral CTS: 56% vs 30%; SS, 33% vs 15%; TF, 33% vs 20%). In the EAP, 87% of patients with ATTR amyloidosis had a history of ≥1 MSK manifestation at baseline, 34% had 2, and 7% had 4 manifestations. Only 12% reported no history of MSK manifestations.

Conclusions: These data represent the first comprehensive analysis exploring prevalence of MSK manifestations in patients with ATTR amyloidosis across randomized clinical trials and real-world studies. Understanding the epidemiology of MSK manifestations in ATTR amyloidosis may support recognition of these symptoms among surgeons, supporting early diagnosis and improved disease management. Surgeons should consider taking biopsies to detect amyloid deposition in at-risk patients during relevant surgical procedures.

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