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.

中文翻译：

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非地方性遗传性转甲状腺素蛋白淀粉样变性伴多发性神经病的真实世界结果：20 年德国单一转诊中心经验

摘要

背景

遗传性转甲状腺素蛋白淀粉样变性是由TTR基因的致病性变异引起的，除了心脏和其他器官功能障碍外，通常还表现为快速进展的感觉运动和自主神经多发性神经病 (ATTRv-PN)，导致严重残疾。虽然大多数前瞻性研究都集中在地方性 ATTRv-PN 上，但关于非地方性、主要是迟发性 ATTRv-PN 的真实数据是有限的。

方法

这项回顾性研究调查了 1999 年 11 月至 2020 年 7 月期间在海德堡大学医院淀粉样变性中心接受治疗的 ATTRv-PN 患者。分析了 tafamidis 治疗的临床症状、生存率、预后因素和疗效。使用 Coutinho ATTRv-PN 分期和周围神经病变残疾 (PND) 评分评估神经系统结果。

结果

在具有遗传性TTR变异的 346 名受试者中，168 名患者有症状的 ATTRv-PN，并鉴定了 32 种不同的 TTR 变异。其中，81.6% 为晚发型 ATTRv-PN。在 4.1 ± 2.8 年的平均随访期内，40.5% 的患者死亡。基线血浆脑钠肽 N 末端激素原 (NT-proBNP) ≥900 ng/l（HR 3.259 [1.421–7.476]；p  = 0.005）是多变量分析中死亡率的主要预测因子。64 名患者接受了 tafamidis 治疗，并接受了定期随访检查。在 ATTRv-PN 1 期早期开始治疗时，tafamidis 的治疗益处更加明显（PND 评分 II 与 I；HR 2.718 [1.258–5.873]；p  = .011）。

结论

在非地方性、多为迟发性 ATTRv-PN 中，通过 NT-proBNP 评估的心脏受累是总生存期的有力预测指标。长期使用 tafamidis 治疗是安全有效的。治疗开始时的神经系统疾病严重程度是 tafamidis 上 ATTRv-PN 进展的主要预测因素。