Real-world outcomes in non-endemic hereditary transthyretin amyloidosis with polyneuropathy: a 20-year German single-referral centre experience

Abstract

Background

Hereditary transthyretin amyloidosis is caused by pathogenic variants in the TTR gene and typically manifests, alongside cardiac and other organ dysfunctions, with a rapidly progressive sensorimotor and autonomic polyneuropathy (ATTRv-PN) leading to severe disability. While most prospective studies have focussed on endemic ATTRv-PN, real-world data on non-endemic, mostly late-onset ATTRv-PN are limited.

Methods

This retrospective study investigated ATTRv-PN patients treated at the Amyloidosis Centre of Heidelberg University Hospital between November 1999 and July 2020. Clinical symptoms, survival, prognostic factors and efficacy of treatment with tafamidis were analysed. Neurologic outcome was assessed using the Coutinho ATTRv-PN stages, and the Peripheral Neuropathy Disability (PND) score.

Results

Of 346 subjects with genetic TTR variants, 168 patients had symptomatic ATTRv-PN with 32 different TTR variants identified. Of these, 81.6% had the late-onset type of ATTRv-PN. Within a mean follow-up period of 4.1 ± 2.8 years, 40.5% of patients died. Baseline plasma N-terminal prohormone of brain natriuretic peptide (NT-proBNP) ≥900 ng/l (HR 3.259 [1.421–7.476]; p = .005) was the main predictor of mortality in multivariable analysis. 64 patients were treated with tafamidis and presented for regular follow-up examinations. The therapeutic benefit of tafamidis was more pronounced when treatment was started early in ATTRv-PN stage 1 (PND scores II vs. I; HR 2.718 [1.258–5.873]; p = .011).

Conclusions

In non-endemic, mostly late-onset ATTRv-PN, cardiac involvement assessed by NT-proBNP is a strong prognosticator for overall survival. Long-term treatment with tafamidis is safe and efficacious. Neurologic disease severity at the start of treatment is the main predictor for ATTRv-PN progression on tafamidis.

Keywords:

• Hereditary transthyretin (ATTRv) amyloidosis
• polyneuropathy
• progression
• survival
• tafamidis

Acknowledgements

The authors wish to thank all participants of this study.

Disclosure statement

E. Hund reports advisory board and speaker honoraria and financial support for conference attendance from Akcea Therapeutics, Alnylam Pharmaceuticals, and Pfizer, outside this work.

J. C. Purrucker reports consultation fees and travel expenses from Abbott, Akcea Therapeutics, Boehringer Ingelheim, Daiichi Sankyo, and Pfizer, outside this work.

C. Kimmich reports speaker honoraria from Pfizer.

F. aus dem Siepen reports advisory board and speaker honoraria from Akcea Therapeutics, Alnylam Pharmaceuticals and Pfizer, outside this work.

S. Hein reports research support from Alnylam Therapeutics and Pfizer, and travel expenses from Novartis and Pfizer, outside this work.

A. V. Kristen reports research support, consultant fees, and speaker honoraria from Akcea Therapeutics, Alnylam Pharmaceuticals, and Pfizer, outside this work.

K. Hinderhofer reports travel grants from Pfizer.

J. Kollmer reports a research grant, personal fees, and lecture honoraria from Alnylam Pharmaceuticals, advisory board honoraria from Akcea Therapeutics, financial support for conference attendance, and lecture honoraria from Pfizer, and the Olympia Morata stipend grant from the Medical Faculty of the University of Heidelberg, outside this work.

U. Hegenbart reports travel grants from Janssen, Prothena, and Pfizer, advisory board honoraria from Pfizer and Prothena, honoraria from Janssen, Pfizer, Alnylam Pharmaceuticals, and Akcea Therapeutics, and financial support for the Amyloidosis Registry from Prothena, and Janssen, outside this work.

M. Weiler reports advisory board and speaker honoraria and financial support for conference attendances from Akcea Therapeutics, Alnylam Pharmaceuticals, Biogen, and Pfizer, and advisory board and consultant honoraria from Hoffmann-La Roche, outside this work.

The other authors report no disclosures relevant to this work.