Amyloid transthyretin (ATTR) amyloidosis is caused by the systemic deposition of transthyretin molecules, either normal (wild-type ATTR, ATTRwt) or mutated (variant ATTR, ATTRv). ATTR amyloidosis is a progressive disease with a severe impact on patient quality of life (QoL)^1-3. Nonetheless, limited attention has been paid to QoL so far, and no specific tools for QoL assessment in ATTR amyloidosis currently exist³. QoL can be evaluated through patient-reported outcome measures, which are completed by patients, or through scales, which are compiled by clinicians. The scales investigate QoL either directly or indirectly, that is by assessing the degree of functional impairment and limitations imposed by the disease. In a recent review article, we performed a systematic assessment of the measures of QoL evaluated in phase 2 and phase 3 clinical trials on ATTR amyloidosis³. We are grateful to Dr Yarlas from QualityMetric for pointing out that we referred only to the 36-Item Short Form Survey (SF-36) instead of mentioning specifically its second version.

The 36-Item Short Form Health Survey questionnaire (SF-36) is a very popular tool to assess health-related QoL. Indeed, a PubMed search for ‘SF-36 health survey’ on 11 July 2021 yielded 13,715 results. The SF-36 was designed as a generic indicator of health status to be used in population surveys and in studies evaluating health policies. It can also be used as an outcome measure in clinical practice and research. The concept of the SF-36 was devised in the 1970s, and an 18-item scale was developed in 1984, followed by a 20-item form (SF-20) in 1986. The SF-36 was constructed to overcome limitations in the SF-20. Version 1 of the SF-36 was introduced in 1996. Version 2 of the SF-36 changed some dichotomous answers to 5-point scales and slightly altered the wording of several items. The development of the SF-36 is now coordinated by QualityMetric⁴.

As a generic instrument, the SF-36 was designed to be applicable to a wide range of types and severities of conditions. It includes multi-item scales to measure the following 8 dimensions: physical functioning, role limitations due to physical health problems, bodily pain, social functioning, general mental health, role limitations due to emotional problems, vitality, energy or fatigue and general health perceptions. Additionally, a question covers change in health status over the past year.

As for the ‘additional error’ pointed out by Dr Yarlas, the correct reference regarding the polyneuropathy disability (PND) score was the paper by Dyck et al⁵, 2019. The extent of disability in ATTRv amyloidosis has been typically evaluated through the familial amyloidotic polyneuropathy (FAP) staging system and/or the PND scoring system. FAP staging was developed in an endemic area of Portugal⁶ in 1980. FAP stage 1 is defined by unassisted walking, in which patients typically experience mild bilateral neuropathy in the feet and legs; stage 2 is defined by the patient requiring assistance walking with crutches or sticks; stage 3 is defined by the patient becoming wheelchair-bound or bedridden because of severe neuropathy. PND scoring involves a greater separation of disease stages: a score of I indicates sensory disturbance with preserved walking capacity; II indicates difficult, but unassisted walking; IIIa indicates the need of one stick or crutch for walking; IIIb indicates the requirement of 2 sticks or crutches for walking; and IV denotes a patient wheelchair-bound or bedridden⁷. Assessing ATTRv polyneuropathy in this manner can provide a broad indication of the global disease state, but transition from one FAP stage or PND score to another can take up to 5 years⁷. These metrics are then poorly effective to track disease progression over shorter time periods and cannot be proposed as outcome measures in clinical trials, where the Neuropathy Impairment Score (NIS), the NIS-lower limb (NIS-LL; a subset of the NIS) and the NIS+7 (a variation of NIS that includes nerve conduction studies and quantitative sensory and autonomic endpoints) have been used instead ⁵.

Despite the imprecisions carefully highlighted by Dr Yarlas, the main message of our review remains, which is that there are no specific measures to assess QoL in patients with ATTR amyloidosis, not even the SF-36v2^® Health Survey by QualityMetric. The challenge for clinicians, researchers and private companies is to develop such metrics to improve the management of these patients.

淀粉样转甲状腺素蛋白 (ATTR) 淀粉样变性是由转甲状腺素蛋白分子的全身沉积引起的，这些分子可以是正常的（野生型 ATTR，ATTRwt）或突变的（变异的 ATTR，ATTRv）。ATTR 淀粉样变性是一种进行性疾病，严重影响患者的生活质量 (QoL) ^1-3。尽管如此，迄今为止对 QoL 的关注有限，目前尚无针对 ATTR 淀粉样变性的 QoL 评估的特定工具³. 生活质量可以通过由患者完成的患者报告的结果测量来评估，或者通过临床医生编制的量表来评估。这些量表直接或间接地调查生活质量，即通过评估功能障碍的程度和疾病施加的限制。在最近的一篇综述文章中，我们对在 ATTR 淀粉样变性³的 2 期和 3 期临床试验中评估的生活质量指标进行了系统评估。我们感谢来自 QualityMetric 的 Yarlas 博士指出我们只提到了 36 项短表调查 (SF-36)，而不是特别提到它的第二个版本。

包含 36 项的简短健康调查问卷 (SF-36) 是一种非常流行的评估健康相关生活质量的工具。事实上，PubMed 在 2021 年 7 月 11 日对“SF-36 健康调查”的搜索产生了 13,715 个结果。SF-36 被设计为健康状况的通用指标，用于人口调查和评估卫生政策的研究。它也可以用作临床实践和研究中的结果测量。SF-36 的概念是在 1970 年代设计的，1984 年开发了 18 项量表，随后在 1986 年开发了 20 项形式 (SF-20)。SF-36 的构建是为了克服在SF-20。SF-36 的第 1 版于 1996 年推出。SF-36 的第 2 版将一些二分法的答案改为 5 分制，并略微更改了几个项目的措辞。SF-36 的开发现在由 QualityMetric 协调⁴ .

作为通用仪器，SF-36 旨在适用于各种类型和严重程度的条件。它包括多项量表，用于衡量以下 8 个维度：身体机能、因身体健康问题导致的角色限制、身体疼痛、社会功能、一般心理健康、因情绪问题导致的角色限制、活力、精力或疲劳以及一般健康感知. 此外，一个问题涵盖了过去一年中健康状况的变化。

至于 Yarlas 博士指出的“额外错误”，关于多发性神经病残疾 (PND) 评分的正确参考是 Dyck 等人在 2019 年⁵月发表的论文。通常通过家族性淀粉样变性评估 ATTRv 淀粉样变性的残疾程度多发性神经病 (FAP) 分期系统和/或 PND 评分系统。FAP 分期是在葡萄牙的一个流行地区开发的⁶1980 年。FAP 阶段 1 定义为无辅助行走，患者通常会在脚和腿出现轻度双侧神经病变；阶段 2 由需要使用拐杖或拐杖辅助行走的患者定义；第 3 阶段的定义是患者因严重的神经病变而需要坐轮椅或卧床不起。PND 评分涉及更大程度的疾病阶段分离：I 分表示感觉障碍但行走能力保留；II 表示困难但没有辅助的行走；IIIa 表示走路需要一根拐杖或拐杖；IIIb 表示步行需要2根拐杖或拐杖；IV 表示患者坐轮椅或卧床不起⁷. 以这种方式评估 ATTRv 多发性神经病可以提供全球疾病状态的广泛指示，但从一个 FAP 阶段或 PND 评分过渡到另一个可能需要长达 5 年⁷。这些指标在较短的时间内跟踪疾病进展的效果很差，并且不能作为临床试验中的结果指标，其中神经病变损伤评分（NIS）、NIS 下肢（NIS-LL；NIS 的一个子集）而 NIS+7（NIS 的一种变体，包括神经传导研究以及定量感觉和自主终点）已被使用⁵。

尽管 Yarlas 博士仔细强调了不精确性，但我们审查的主要信息仍然存在，即没有具体的措施来评估 ATTR 淀粉样变性患者的生活质量，甚至没有 QualityMetric 的 SF-36v2 ^®健康调查。临床医生、研究人员和私营公司面临的挑战是开发此类指标以改善对这些患者的管理。