Workshop B: Optimizing diagnosis and patient care in ATTR

Current standards of care for patients with ATTR cardiomyopathy

Bouke P.C. Hazenberg UMC Groningen

The Netherlands

UMCG UMC Groningen – & Clinical Guard Disclosures

Financial support

 From Alnylam as clinical consultant

 From Pfizer as clinical consultant

 As external scientific advisor GSK

UMCG UMC Groningen – Rheumatology & Clinical Immunology Guard ATTR : a systemic disease

 ATTRv

 Autosomal dominant hereditary disease

 Clinical manifestations:

 Polyneuropathy, autonomic neuropathy, CTS

 Cardiomyopathy

 Ocular: vitreous opacities, retinal vascular abnormalities

 Leptomeningeal/cerebrovascular deposition

 ATTRwt

 Men>women, >60jr

 Clinical manifestations:

 Cardiomyopathy

 CTS, lumbar spinal stenosis

 Tendon ruptures, soft tissue and joint deposition

 Lung and kidney involvement

UMCGUMCG UMC Groningen – Rheumatology & Clinical Immunology Guard Case 1, Mrs. A.

 Progressive failure: NYHA III (walk 25 meters, edema, ascites)

 Echo: wall thickness 15 mm

 Rectal : amyloid, but unable to type using immunohistochemistry

 NT-proBNP 2347 (N<125), TnT 21 (N,15)

 No FLCs, no M-protein, and bone marrow: no clonal plasma cells

 Gene analysis: no TTR mutation

UMCGUMCG UMC Groningen – Rheumatology & Clinical Immunology Guard HMDP-Bone scan: cardiac uptake grade 1 SAP scan: liver and spleen uptake

 What amyloid type do you consider?  What would you investigate?

UMCGUMCG UMC Groningen – Rheumatology & Clinical Immunology Guard Types of amyloidosis with cardiomyopathy

Note added: Gelsolin (AGel) can cause conduction problems

Dubrey and Comenzo. Q J Med 2012; 105:617-31

UMCGUMCG UMC Groningen – Rheumatology & Clinical Immunology Guard Bone scan in Apo A-I en Apo A-II amyloidosis

Bone scan 99mTc-DPD or 99mTC-PYP positive (grade 1-3):

 ApoA-I Q172P variant1  ApoA-I Leu174Ser variant2   ApoA-II Stop78Arg variant3

1. Vonberg et al, Amyloid 2015; 22:252-3 2. Quarta, et al. Amyloid 2013: 20:48-51 Conclusion Case 1: 3. Yazaki, et al. Kidney Int 2003; 64:11-6 4. Hazenberg, et al. Laryngoscope 2009; 119:608-15 Uncle hoarse voice, known with amyloidosis Gene panel: ApoA-I Leu178Pro variant4

UMCGUMCG UMC Groningen – Rheumatology & Clinical Immunology Guard Case 2, Mr. A.

 Black man

 Cardiac failure NYHA II

 NT-proBNP 4400, TnT 160, creat 90

 Echo wall thickness 15 mm, MRI late gadolinium enhancement

 Fat aspirate: amyloid (2+)

 M-protein IgG-kappa, BJ kappa, FLC kappa

 Bone marrow: small kappa-positive plasma cell clone

 What would you investigate?

UMCGUMCG UMC Groningen – Rheumatology & Clinical Immunology Guard Case 2, Mr. A.

HMDP-Bone scan: cardiac uptake grade 3 SAP scan: little liver uptake

UMCG UMC Groningen – Rheumatology & Clinical Immunology Guard ATTR amyloidose

Gillmore, et al. UMCGUMCG UMC Groningen – Rheumatology & Clinical Immunology Circulation 2016; 133:2404-12 Guard Case 2, Mr. A.

 Gene panel: TTR Val122Ile mutation present

 Fat aspirate: Amyloid TTR +, kappa negative

 Endomyocardial biopsy: TTR +, kappa non-specific

 Liver biopsy: no amyloid

 Conclusion: ATTRv (Val122Ile) amyloidosis

However …

UMCGUMCG UMC Groningen – Rheumatology & Clinical Immunology Guard Congo red Anti-TTR Anti-lambda sample Y sample X Extremely rare1

Two types of amyloid in a single heart:

ATTR and AL-lambda

1. Mahmood, et al. Blood 2014; 124:3025-7

UMCGUMCG UMC Groningen – Rheumatology & Clinical Immunology Guard Key learnings and recommendations

 Both ATTRv and ATTRwt amyloidosis are systemic diseases

 AL and ATTR amyloidosis are the main causes of amyloid cardiomyopathy, but do not overlook rarer

types, such as AA, AFib, AANF, AApoAI, and AApoAII

 A negative bone scan does not exclude amyloid cardiomyopathy. If serious doubt: consider a biopsy

 A positive bone scan is not specific for ATTR type: consider first AL, then rarer: AApoAI and AApoAII

 M-protein, serum free light chains, urine BJ, gene panel amyloidosis, bone scan and endomyocardial

biopsy are essential elements for detecting and typing of

UMCGUMCG UMC Groningen – Rheumatology & Clinical Immunology Guard www.amyloid.nl

UMCG UMC Groningen – Rheumatology & Clinical Immunology Guard