Fontana, M

Gillmore, J

Hawkins, PN

Patel, RK

English

UCL Discovery

Splenic regression of amyloid on multi-modality imaging in response to treatment with patisiran and diflunisal in hereditary transthyretin amyloidosis Rishi K Patel MBBS BSc (Hons), Marianna Fontana MD PhD, Philip N Hawkins PhD, Julian Gillmore MD PhD  National Amyloidosis Centre, Division of Medicine, University College London, Royal Free Campus, London, UK Address for correspondence: Professor Julian Gillmore, National Amyloidosis Centre, University College London, Royal Free Campus, Rowland Hill Street, London, NW3 2PF, UK E-mail: julian.gillmore@nhs.net, Phone No: +44 2074332816, Fax No: +44 2044332817 Author email addresses: Rishi Patel: rishipatel@nhs.netMarianna Fontana: m.fontana@ucl.ac.ukPhilip Hawkins: p.hawkins@ucl.ac.ukWord Count: 594 (including main text and figure legend)FundingProfessor Fontana is funded from a British heart foundation fellowship FS/18/21/33447. Professor Fontana has a research grant from Pfizer and Eidos.   Disclosures Professor Fontana has done consultancy for Alnylam, Akcea, Eidos, Intellia, Pfizer, and Alexion.  Professor Gillmore is an advisory board member for Alnylam, Akcea, Intellia and Eidos.  Professor Hawkins does consultancy for Alnylam. The remaining authors have nothing to disclose.  Hereditary transthyretin amyloidosis (ATTRv) gives rise to varying patterns of multi-organ amyloid infiltration, characteristically with cardiomyopathic and/or neuropathic phenotypes. Splenic amyloid infiltration is rare but can be visualised by 123I-labelled serum-amyloid-P component (SAP) scintigraphy and cardiac magnetic resonance imaging (CMR).  Novel treatments which target hepatic transthyretin (TTR) production have been shown to improve clinical outcomes but there are no studies showing their direct effect on amyloid burden.  We report the first case of unequivocal splenic amyloid regression using multi-modality imaging in a patient with ATTRv amyloidosis after treatment with the small interfering RNA drug patisiran and the transthyretin-stabilising drug diflunisal. A 32-year-old female presented with paresthesiae and bilateral floaters secondary to vitreous aggregates. Fundoscopic and retinal imaging were consistent with ocular amyloidosis. N-terminal pro B-type natriuretic peptide (NT-proBNP) was 419ng/L.  Early cardiac amyloidosis was demonstrated on CMR and 99mTechnetium 3,3-diphosphon-1,2-propanodicarboxylic acid (99mTc-DPD) scintigraphy was Perugini grade 3 which, accompanied by normal monoclonal protein studies, was diagnostic of ATTR amyloidosis (1).  123I-SAP scintigraphy demonstrated splenic amyloid. Neurological investigations demonstrated axonal peripheral neuropathy and early autonomic neuropathy.  She was confirmed to be heterozygous for a TTR mutation encoding the F33V (p.Phe53Val) variant, previously identified in her father who had died from ATTRv amyloidosis.  She commenced disease-modifying therapy in September 2017 with both patisiran and diflunisal, reporting gradual improvement in her neuropathic symptoms and functional capacity with no drug-related adverse effects.  Figure 1 shows annual SAP and CMR scans performed to assess her disease burden in response to treatment.  The colour maps on CMR represent extra-cellular volume (ECV), a surrogate of amyloid deposition within tissues. Progressive reduction in tracer uptake within the spleen on scintigraphy, and ECV within both the spleen and myocardium on CMR, can be appreciated over a 24-month follow-up period.  NT-proBNP concurrently fell to 102 ng/L.  This is the first report of unequivocal regression of visceral ATTR amyloid deposits in the absence of liver transplantation, following combination therapy with patisiran and diflunisal.  123I-labelled SAP scintigraphy is used to quantify amyloid burden in visceral organs including the spleen but does not quantify amyloid in the heart or nerves.  In this regard, CMR imaging allows cardiac amyloid deposition to be accurately quantified through measurement of myocardial ECV (2).  Measurement of extra-cardiac amyloid burden by ECV on CMR and by SAP scintigraphy have been shown to be strongly correlated in AL amyloidosis (3).  In ATTRv, treatment with liver transplantation has been superseded by drugs such as patisiran, which reduces circulating TTR concentration by up to 90% (4).  One study has demonstrated cardiac regression through a reduction in CMR-derived ECV in patients with ATTRv following 12 months of patisiran (5).  Since splenic amyloid is unusual in ATTR amyloidosis, SAP scintigraphy is of limited value to monitor amyloid turnover.  However, this rare ATTRv amyloidosis-causing F33V (p.Phe53Val) TTR variant with splenic amyloid deposits, trackable by serial SAP scintigraphy and corroborated by measurement of ECV using CMR, provides the first unequivocal evidence of splenic amyloid regression accompanying cardiac regression and clinical benefit following medical therapy. References 1.  Gillmore JD, Maurer MS, Falk RH, et al. Nonbiopsy Diagnosis of Cardiac Transthyretin Amyloidosis. Circulation. 2016 Jun 14;133(24):2404–12. 2.  Martinez-Naharro A, Kotecha T, Norrington K, et al. Native T1 and Extracellular Volume in Transthyretin Amyloidosis. JACC Cardiovasc Imaging. 2019;12(5):810–9. 3.  Martinez-Naharro A, Abdel-Gadir A, Treibel TA, et al. CMR-Verified Regression of Cardiac AL Amyloid After Chemotherapy. JACC Cardiovasc Imaging. 2018 Jan 1;11(1):152–4. 4.  Suhr OB, Coelho T, Buades J, et al. Efficacy and safety of patisiran for familial amyloidotic polyneuropathy: a phase II multi-dose study. Orphanet J Rare Dis. 2015 Sep 4;10:109. 5.  Fontana M, Martinez-Naharro A, Chacko L, et al. Reduction in CMR Derived Extracellular Volume With Patisiran Indicates Cardiac Amyloid Regression. JACC Cardiovasc Imaging. 2021 Jan;14(1):189–99. 

Splenic regression of amyloid on multi-modality imaging in response to treatment with patisiran and diflunisal in hereditary transthyretin amyloidosis

https://discovery.ucl.ac.uk/10127351/8/Hawkins_Splenic%20Regression_Amyloid%20Letter_R1.pdf

Splenic regression of amyloid on multi-modality imaging in response to treatment with patisiran and diflunisal in hereditary transthyretin amyloidosis

Abstract

Similar works

Full text

Available Versions

UCL Discovery