Abstract：
BACKGROUND: ATTR (ATTRv) amyloidosis neuropathy is characterized by progressive sensorimotor and autonomic nerve degeneration secondary to amyloid deposition caused by a misfolded transthyretin protein (TTR). Small nerve fiber neuropathy is an early clinical manifestation of this disease resulting from the dysfunction of the Aδ and C small nerve fibers. Tafamidis, a selective TTR stabilizer, has proven its efficacy in the earlier stages of hATTR.
OBJECTIVE: To evaluate the clinical course and utility of cutaneous pathological biomarkers in patients with ATTR amyloidosis treated with tafamidis compared to control patients.
METHODS: Forty patients diagnosed with early stages of ATTRv amyloidosis (polyneuropathy disability [PND] scores 0-II) underwent small and large nerve fiber neurological evaluations, and annual skin biopsies for intraepidermal nerve fiber density (IENFD) and amyloid deposition index (ADI) estimation. Thirty patients were allocated to receive tafamidis, and 10 patients served as controls. Tafamidis pharmacokinetics analysis was performed in patients who received the treatment.
RESULTS: At baseline, 12% of patients in stage PND 0 and 28% in PND I displayed small nerve fiber denervation in the distal thigh, whereas 23% and 38%, respectively, in the distal leg. Similarly, 72% and 84% had amyloid deposition in the distal thigh and 56% and 69% in the distal leg. Following 1 year of treatment, the tafamidis group showed significant clinical improvement compared to the control group, revealed by the following mean differences (1) -9.3 versus -4 points (p = <.00) in the patient\'s neuropathy total symptom score 6 (NTSS-6) questionnaire, (2) -2.5 versus +2.8 points (p = <.00) in the Utah Early Neuropathy Score (UENS), and (3) +1.2°C versus -0.6 (p = .01) in cold detection thresholds. Among the patients who received tafamidis, 65% had stable or increased IENFD in their distal thigh and 27% in the distal leg. In contrast, all patients in the control group underwent denervation. The ADI either decreased or remained constant in 31% of the biopsies in the distal thigh and in 24% of the biopsies in the distal leg of the tafamidis-treated patients, whereas it rose across all the biopsies in the control group. At the 4-year follow-up, the tafamidis group continued to display less denervation in the distal thigh (mean difference [MD] of -3.0 vs. -9.3 fibers/mm) and the distal leg (mean difference [MD] -4.9 vs. -8.6 fibers/mm). ADI in tafamidis-treated patients was also lower in the distal thigh (10 vs. 30 amyloid/mm2) and the distal leg (23 vs. 40 amyloid/mm2) compared to control patients. Plasma tafamidis concentrations were higher in patients with IENFD improvement and in patients with reduced amyloid deposition. Patients without amyloid deposition in the distal leg at baseline displayed delayed disease progression at 4 years.
CONCLUSIONS: Cutaneous IENFD and amyloid deposition assessments in the skin of the distal thigh and distal leg are valuable biomarkers for early diagnosis of ATTR amyloidosis and for measuring the progression of small nerve fiber neuropathy. Early treatment with tafamidis slows the clinical progression of the disease, skin denervation, and amyloid deposition in the skin. Higher plasma concentrations of tafamidis are associated with better disease outcomes, suggesting that increasing the drug dose could achieve better plasma concentrations and response rates. This study describes the longest small nerve fiber neuropathy therapeutic trial with tafamidis and is the first to report small fiber symptoms, function, and structural assessments as outcomes.
OBJECTIVE: To evaluate the clinical course and utility of cutaneous pathological biomarkers in patients with ATTR amyloidosis treated with tafamidis compared to control patients.
METHODS: Forty patients diagnosed with early stages of ATTRv amyloidosis (polyneuropathy disability [PND] scores 0-II) underwent small and large nerve fiber neurological evaluations, and annual skin biopsies for intraepidermal nerve fiber density (IENFD) and amyloid deposition index (ADI) estimation. Thirty patients were allocated to receive tafamidis, and 10 patients served as controls. Tafamidis pharmacokinetics analysis was performed in patients who received the treatment.
RESULTS: At baseline, 12% of patients in stage PND 0 and 28% in PND I displayed small nerve fiber denervation in the distal thigh, whereas 23% and 38%, respectively, in the distal leg. Similarly, 72% and 84% had amyloid deposition in the distal thigh and 56% and 69% in the distal leg. Following 1 year of treatment, the tafamidis group showed significant clinical improvement compared to the control group, revealed by the following mean differences (1) -9.3 versus -4 points (p = <.00) in the patient\'s neuropathy total symptom score 6 (NTSS-6) questionnaire, (2) -2.5 versus +2.8 points (p = <.00) in the Utah Early Neuropathy Score (UENS), and (3) +1.2°C versus -0.6 (p = .01) in cold detection thresholds. Among the patients who received tafamidis, 65% had stable or increased IENFD in their distal thigh and 27% in the distal leg. In contrast, all patients in the control group underwent denervation. The ADI either decreased or remained constant in 31% of the biopsies in the distal thigh and in 24% of the biopsies in the distal leg of the tafamidis-treated patients, whereas it rose across all the biopsies in the control group. At the 4-year follow-up, the tafamidis group continued to display less denervation in the distal thigh (mean difference [MD] of -3.0 vs. -9.3 fibers/mm) and the distal leg (mean difference [MD] -4.9 vs. -8.6 fibers/mm). ADI in tafamidis-treated patients was also lower in the distal thigh (10 vs. 30 amyloid/mm2) and the distal leg (23 vs. 40 amyloid/mm2) compared to control patients. Plasma tafamidis concentrations were higher in patients with IENFD improvement and in patients with reduced amyloid deposition. Patients without amyloid deposition in the distal leg at baseline displayed delayed disease progression at 4 years.
CONCLUSIONS: Cutaneous IENFD and amyloid deposition assessments in the skin of the distal thigh and distal leg are valuable biomarkers for early diagnosis of ATTR amyloidosis and for measuring the progression of small nerve fiber neuropathy. Early treatment with tafamidis slows the clinical progression of the disease, skin denervation, and amyloid deposition in the skin. Higher plasma concentrations of tafamidis are associated with better disease outcomes, suggesting that increasing the drug dose could achieve better plasma concentrations and response rates. This study describes the longest small nerve fiber neuropathy therapeutic trial with tafamidis and is the first to report small fiber symptoms, function, and structural assessments as outcomes.
摘要：
背景：ATTR（ATTRv）淀粉样变性神经病的特征是由错误折叠的转甲状腺素蛋白（TTR）引起的淀粉样蛋白沉积继发的进行性感觉运动和自主神经变性。小神经纤维神经病是这种疾病的早期临床表现，由Aδ和C小神经纤维功能障碍引起。Tafamidis,选择性TTR稳定剂，在hATTR的早期阶段已经证明了它的功效。
目的：评价与对照组相比，用tafamidis治疗的ATTR淀粉样变性患者皮肤病理生物标志物的临床病程和效用。
方法：40例被诊断为早期ATTRv淀粉样变性（多发性神经病残疾[PND]评分0-II）的患者接受了小神经纤维和大神经纤维神经评估，和每年的皮肤活检以估计表皮内神经纤维密度（IENFD）和淀粉样蛋白沉积指数（ADI）。30名患者被分配接受tafamidis，10名患者作为对照。在接受治疗的患者中进行Tafamidis药代动力学分析。
结果：在基线时，12％的PND0期患者和28％的PNDI期患者在大腿远端表现出较小的神经纤维去神经支配，而23%和38%，分别,在腿的远端.同样，72％和84％的大腿远端有淀粉样蛋白沉积，56％和69％的腿远端有淀粉样蛋白沉积。治疗1年后，与对照组相比，tafamidis组显示出显着的临床改善，在患者的神经病变症状总评分6（NTSS-6）问卷中，通过以下平均差异（1）-9.3与-4分（p=<.00）揭示，（2）-2.5对+2.8点（p=<.00）在犹他州早期神经病变评分（UENS），和(3)+1.2°C与-0.6(p=.01)的冷检测阈值。在接受tafamidis的患者中，65％的大腿远端IENFD稳定或增加，腿远端27％。相比之下,对照组患者均接受去神经支配.在接受tafamidis治疗的患者的大腿远端31％的活检和远端腿24％的活检中，ADI降低或保持不变。而在对照组的所有活检中，它都上升了。在4年的随访中，Tafamidis组继续显示较少大腿远端神经支配(平均差[MD]为-3.0vs.-9.3纤维/毫米）和远端腿（平均差[MD]-4.9vs.-8.6纤维/毫米)。Tafamidis治疗患者的ADI在大腿远端也较低（10vs.30淀粉样蛋白/mm2）和远端腿（23vs.40淀粉样蛋白/mm2）与对照患者相比。IENFD改善的患者和淀粉样蛋白沉积减少的患者的血浆tafamidis浓度较高。基线时下肢远端无淀粉样蛋白沉积的患者在4年时显示疾病进展延迟。
结论：大腿远端和腿远端皮肤的IENFD和淀粉样蛋白沉积评估是早期诊断ATTR淀粉样变性和测量小神经纤维神经病变进展的有价值的生物标志物。Tafamidis的早期治疗减缓了疾病的临床进展，去皮肤神经支配,和淀粉样蛋白沉积在皮肤上.较高的tafamidis血浆浓度与更好的疾病结局相关，这表明增加药物剂量可以获得更好的血浆浓度和反应率。这项研究描述了最长的小神经纤维神经病治疗试验与tafamidis，是第一个报告小纤维症状，函数,和结构评估作为结果。
目的：评价与对照组相比，用tafamidis治疗的ATTR淀粉样变性患者皮肤病理生物标志物的临床病程和效用。
方法：40例被诊断为早期ATTRv淀粉样变性（多发性神经病残疾[PND]评分0-II）的患者接受了小神经纤维和大神经纤维神经评估，和每年的皮肤活检以估计表皮内神经纤维密度（IENFD）和淀粉样蛋白沉积指数（ADI）。30名患者被分配接受tafamidis，10名患者作为对照。在接受治疗的患者中进行Tafamidis药代动力学分析。
结果：在基线时，12％的PND0期患者和28％的PNDI期患者在大腿远端表现出较小的神经纤维去神经支配，而23%和38%，分别,在腿的远端.同样，72％和84％的大腿远端有淀粉样蛋白沉积，56％和69％的腿远端有淀粉样蛋白沉积。治疗1年后，与对照组相比，tafamidis组显示出显着的临床改善，在患者的神经病变症状总评分6（NTSS-6）问卷中，通过以下平均差异（1）-9.3与-4分（p=<.00）揭示，（2）-2.5对+2.8点（p=<.00）在犹他州早期神经病变评分（UENS），和(3)+1.2°C与-0.6(p=.01)的冷检测阈值。在接受tafamidis的患者中，65％的大腿远端IENFD稳定或增加，腿远端27％。相比之下,对照组患者均接受去神经支配.在接受tafamidis治疗的患者的大腿远端31％的活检和远端腿24％的活检中，ADI降低或保持不变。而在对照组的所有活检中，它都上升了。在4年的随访中，Tafamidis组继续显示较少大腿远端神经支配(平均差[MD]为-3.0vs.-9.3纤维/毫米）和远端腿（平均差[MD]-4.9vs.-8.6纤维/毫米)。Tafamidis治疗患者的ADI在大腿远端也较低（10vs.30淀粉样蛋白/mm2）和远端腿（23vs.40淀粉样蛋白/mm2）与对照患者相比。IENFD改善的患者和淀粉样蛋白沉积减少的患者的血浆tafamidis浓度较高。基线时下肢远端无淀粉样蛋白沉积的患者在4年时显示疾病进展延迟。
结论：大腿远端和腿远端皮肤的IENFD和淀粉样蛋白沉积评估是早期诊断ATTR淀粉样变性和测量小神经纤维神经病变进展的有价值的生物标志物。Tafamidis的早期治疗减缓了疾病的临床进展，去皮肤神经支配,和淀粉样蛋白沉积在皮肤上.较高的tafamidis血浆浓度与更好的疾病结局相关，这表明增加药物剂量可以获得更好的血浆浓度和反应率。这项研究描述了最长的小神经纤维神经病治疗试验与tafamidis，是第一个报告小纤维症状，函数,和结构评估作为结果。
