THAOS – The Transthyretin Amyloidosis Outcomes Survey: initial report on clinical manifestations in patients with hereditary and wild-type transthyretin amyloidosis

Abstract

Background:

Transthyretin (TTR) amyloidosis is a rare, life-threatening, systemic, autosomal dominant condition occurring in adults, with two main forms: hereditary (associated with TTR gene mutations) and wild-type. Studies indicate considerable heterogeneity in disease presentation, with predominantly polyneuropathic, predominantly cardiac, or mixed phenotypes.

Methods:

THAOS – the Transthyretin Amyloidosis Outcomes Survey – is the first global, multicenter, longitudinal, observational survey that collects data on the natural history of TTR amyloidosis (ClinicalTrials.gov: NCT00628745). This paper presents data on signs and symptoms, neurological and cardiac assessments, biomarkers and quality of life in the patients enrolled in THAOS from its inception in December 2007 to September 2011.

Results:

At the time of this analysis, data were available from 611 symptomatic patients with hereditary TTR amyloidosis, 67 symptomatic patients with wild-type TTR amyloidosis, and 274 currently asymptomatic individuals with a TTR mutation. Nineteen countries were participating in the registry. The largest patient groups came from Portugal (n = 453), the USA (n = 129), Italy (n = 70), and Japan (n = 68). Predominant symptom presentation in patients with hereditary TTR amyloidosis differed according to the underlying disease-causing mutation (polyneuropathy for Val30Met, cardiomyopathy for Val122Ile and Leu111Met, and mixed for Glu89Gln). However, each mutation was associated with clear multisystem involvement. Similarly, although cardiomyopathy was predominant in patients with wild-type TTR amyloidosis, many also showed symptoms consistent with neuropathy. Quality of life in patients with hereditary TTR amyloidosis, but not asymptomatic carriers of disease-causing mutations, was severely impaired relative to that of the age-matched general US population.

Conclusions:

This preliminary analysis highlights the considerable phenotypic heterogeneity for neurological and cardiac manifestations in patients with hereditary and wild-type TTR amyloidosis and the necessity of providing multidisciplinary care. THAOS registry data will help better characterize the diverse presentation and course of TTR amyloidosis worldwide and aid in improving and standardizing diagnosis and treatment.

Trial registration: ClinicalTrials.gov identifier: NCT00628745.

Key words::

• Amyloidosis
• Familial amyloidotic polyneuropathy
• Polyneuropathy
• Quality of life
• Senile systemic amyloidosis
• THAOS
• Transthyretin

Transparency

Declaration of funding

Data for this manuscript are derived from the THAOS registry (NCT00628745), which is sponsored by Pfizer Inc.

Declaration of financial/other relationships

T.C. has received support from FoldRx Pharmaceuticals, which was acquired by Pfizer Inc. in October 2010, for scientific meeting expenses (travel, accommodation, and registration). Her institution has received support from Pfizer Inc. M.S.M. has received support from FoldRx Pharmaceuticals, which was acquired by Pfizer Inc. in October 2010, as a clinical investigator and for scientific meeting expenses. His institution has received grant support from Pfizer Inc. O.B.S. has acted as a consultant for the following pharmaceutical companies: FoldRx Pharmaceuticals (Boston USA), Pfizer Inc. (New York, USA), Alnylam (Boston, USA) and Isis (Carlsbad, USA). CMRO Peer Reviewers on this manuscript have no relevant financial relationships to disclose.

Acknowledgments

The authors acknowledge the following investigators who contributed data to THAOS that are included in this analysis: Marcia Waddington-Cruz (Rio de Janeiro, Brazil), Sanjiv Shah (Chicago, IL, USA), Josep Campistol (Spain), Dianna Quan (Aurora, CO, USA), Isabel Conceicao (Lisbon, Portugal), Daniel P Judge (Baltimore, MD, USA), Edward J Cupler (Portland, OR, USA), Ronald Witteles (Stanford, CA, USA), Stephen Gottlieb (Baltimore, MA, USA), Shu-ichi Ikeda (Matsumoto, Japan), Theodoros Kyriakides (Nicosia, Cyprus), Wilson H Tang (Cleveland, OH, USA), Rodney Falk (Boston, MA, USA), Henning Mølgaard (Arhus, Denmark), Jeffrey Ralph (San Francisco, CA, USA), Savitri Fedson (Chicago, IL, USA), Annabel K Wang (Orange, CA, USA), Srinivas Murali (Pittsburgh, PA, USA), Horacio Kaufmann (New York, NY, USA), Pedro Trigo (Buenos Aires, Argentina), Sasa Zivkovic (Pittsburgh, PA, USA), Menachem Sadeh (Holon, Israel), Giuseppe Vita (Messina, Italy), Claudio Rapezzi (Bologna, Italy), Yukio Ando (Kumamoto, Japan), Violaine Planté-Bordeneuve (Créteil, France) and Arnt V Kristen (Heidelberg, Germany).

The authors thank THAOS programmer John Sanocki for providing the data. Mr. Sanocki is an employee of Pfizer Inc. The authors also acknowledge Rolf Gunnarsson, MD, PhD, and Donna Grogan, MD, for assisting with data compilation. At the time of manuscript development, Rolf Gunnarsson, MD, PhD, was a full-time employee of Advendo AB who is a paid consultant to FoldRx Pharmaceuticals, which was acquired by Pfizer Inc in October 2010. At the time of manuscript development, Donna Grogan, MD, was a full-time employee of FoldRx Pharmaceuticals, which was acquired by Pfizer Inc in October 2010. Harriet Crofts, PhD, of Oxford PharmaGenesis Ltd provided medical writing support during the preparation of the manuscript in the form of editorial work and collating/implementing comments from the authors. Oxford PharmaGenesis Ltd, was funded by Advendo AB. Advendo AB was contracted by FoldRx Pharmaceuticals, a wholly owned subsidiary of Pfizer Inc., to provide medical writing support for this manuscript. John Clinton Earnheart, PhD, of Scientific Strategy Partners, also provided editorial assistance with support from Pfizer Inc. Kin Cheung, PhD, provided statistical assistance, also with support from Pfizer Inc.