Abstract
Objective
Hereditary amyloid transthyretin (ATTRv) amyloidosis with polyneuropathy, a rare autosomal‐dominant disease, has gained attention in recent years owing to treatment improvements. However, epidemiological real‐world mega database of nationwide natural history and survival rates, especially with the specific mutation of Ala97Ser, are limited.
Methods
Taiwan National Health Insurance Research Database contains data from over 23 million individuals; Among them, 175 ATTRv amyloidosis patients validated by rare disease registry were enrolled. Multivariable Cox proportional hazard analyses were applied to investigate the association between baseline characteristics and all‐cause mortality.
Findings
From 2008 to 2020, the annual incidence and prevalence rates of specific mutations (Ala97Ser) leading to ATTRv amyloidosis with polyneuropathy were 0.04–1.14 and 0.04–4.79 per million in Taiwan, respectively. In Taiwan, these patients exhibited male predominance with a mean age at validation of 62.75 years. At the 5th year after validation, patients exhibited a survival rate of approximately 50%, with higher mortality in male patients (hazard ratio [HR]: 2.22, 95% confidence interval [CI]: 1.15–4.31) and patients older at validation (HR: 1.10, 95% CI: 1.06–1.15). The two most common departments in outpatient were neurology and family medicine, and neurology and cardiology in inpatient. The three most common causes of death registered were unspecified amyloidosis (30.6%), organ‐limited amyloidosis (20.9%), and neuropathic heredofamilial amyloidosis (9.7%).
Interpretation
The annual prevalence rate of specific mutation (Ala97Ser)‐dominant ATTRv amyloidosis with polyneuropathy in Taiwan is comparable to the mid‐ to high‐prevalence country level of the research by Schmidt et al. The extraordinarily high mortality, especially among patients older at validation, may reflect the inadequate awareness and the necessity of early intervention with novel disease‐modifying regimens.
Introduction
Hereditary amyloid transthyretin (ATTRv) amyloidosis with polyneuropathy is a rare disease that has attracted attention in recent years due to novel disease‐modifying medication and diagnostic tools. 1 This autosomal‐dominant disease is due to the accumulation of misfolded transthyretin proteins in the peripheral nerves and systemic organs. 2 , 3
The clinical manifestations of ATTRv amyloidosis are highly variable and are determined by the type of amyloid fibrils, tissue distribution, and amount of amyloid deposited. The hallmark of the disease is length‐dependent sensorimotor neuropathy with autonomic involvement due to systemic amyloid deposition and axonal degeneration of myelinated fibers. Among the prominent features of the disease, neuropathic pain, and autonomic neuropathy are common initial presentations and substantially impact activities of daily living. 4 The initial presentation and age distribution are highly variable among variants. The population with specific variants, such as Ala97Ser, particularly in Taiwan and South China, may share different characteristics from common mutation associated with ATTRv amyloidosis. 5 , 6
Over the past decades, patients with ATTRv amyloidosis worldwide have not received sufficient recognition, diagnosis, or treatment due to low public awareness and the absence of an effective therapeutic approach. However, the therapeutic improvement developed in 2012 marked a new era for disease treatment. Recent guidelines for ATTRv amyloidosis issued in 2022 highlight the importance of early detection and early management for favorable outcomes. 3 Schmidt et al. categorized the prevalence of this disease across countries into 3 categories: low, mid, and high prevalence. 2 The features of common disease variants have been explored by the national databank in endemic areas such as Portugal, Sweden, and Japan. 7 , 8 , 9 , 10 , 11 Several studies in Asia focused on case series of the VAL30MET variant from local hospitals in Japan or mainland China. 6 , 12 However, even though researchers have advanced understanding of diagnosis and treatment, the prevalence and mortality rates of ATTRv amyloidosis with polyneuropathy worldwide based on real‐world evidence remain unknown. No previous research has explored the real‐world prevalence of Ala97Ser in nationwide level; thus, further studies are needed.
This study aimed to explore longitudinal trends in the incidence and prevalence of Ala97Ser ATTRv amyloidosis and analyze the associated factors of all‐cause mortality among these patients. Real‐world data of Ala97Ser ATTRv amyloidosis will be examined to determine whether the characteristics differ from those of other mutations associated with ATTRv amyloidosis worldwide.
Methods
Data source
This study was based on nationwide claims data from the Taiwan National Health Insurance Research Database (NHIRD). Taiwan National Health Insurance (NHI) was launched in 1995; in 2021–2022, NHI covered 99.9% of Taiwan's population (23,876,603 people according to the 2021–2022 National Health Insurance Annual Report). The database was established by the National Health Insurance Administration (NHIA) and has accumulated nationwide medical claims over the years; these data contain information about the costs of outpatient or inpatient care, disease diagnoses, and prescriptions. 13 The NHIRD, which is supported by the Health and Welfare Data Science Center (HWDC), includes ambulatory care expenditures and inpatient expenditures linked to the Cause of Death Database (to determine the death status and associated death causes) and the Registry for NHI Catastrophic Illness Card database (to identify patients with rare diseases [RDs]).
An RD is any disease or condition that impacts a small percentage of the population. The criteria of RDs are different among countries. For example, in the US, RDs are defined as having fewer than 200,000 cases country‐wide according to the Rare Disease Act of 2002; in Europe, RDs are defined as having fewer than 1 case in 2,000 individuals by the Public Health Section of the European Commission. 1 In Taiwan, RDs are defined as having <10,000 cases country‐wide (or other special circumstances) according to the Taiwan Foundation for Rare Disorders. The study was approved by the Institutional Review Board (IRB) of the National Cheng Kung University Hospital (NCKUH) (IRB No. B‐ER‐109‐416) and ClinicalTrials.gov (No. NCT05367115).
Study cohort identification and follow‐up
In the International Classification of Diseases (ICD) codes, ATTRv amyloidosis with polyneuropathy is coded as 277.3/357.4 in the 9th revision, clinical modification (ICD‐9‐CM) and as E85.1 in the 10th revision, clinical modification (ICD‐10‐CM). Patients could be validated by receiving catastrophic illness certification though RD registry of the Health Promotion Administration (HPA). Before the HPA, Ministry of Health and Welfare from Taiwan, issues a certification card for ATTRv amyloidosis with polyneuropathy, several conditions must be met: provision of identifying information including disease history, clinical symptoms that include at least one symptom of peripheral neuropathy (such as weakness, neuropathic pain or carpal tunnel syndrome) or autonomic dysfunction, physical examination including tests of muscle power, deep tendon reflex and sensory capacity, laboratory examination including tests of nerve conduction velocity (NCV), electromyography (EMG) or autonomic nervous system function, and genetic evidence of a mutation in the transthyretin (TTR; such as the Ala117Ser mutation), apolipoprotein A1, gelsolin or other kind genes. The above criteria are the major mandatory information for application. Other supportive data and examinations, such as assessments of eye function, heart function (such as echocardiogram or the Tc‐99 PYP Heart Scan), and pathology, are elective. Once patients receive the RD certificate from HPA, they can apply for the NHI catastrophic illness certification card; these cards provide patients with more medical benefits for access to health care.
Thus, if patients with ATTRv amyloidosis with polyneuropathy receive an NHI catastrophic illness certification through RD registry, the diagnosis is regarded as more valid. Therefore, to avoid including patients misdiagnosed with ATTRv amyloidosis, we first identified patients from the catastrophic illness certification card database and then obtained corresponding health‐related data from the NHI database.
The index date of the cohort enrolled in this study was the valid date of inclusion in the catastrophic illness database (i.e., after 2008). To examine trends of new and cumulative cases of RDs identified in the cohort of this database, we calculated the annual case number of patients in Taiwan from 2008 to 2020 and identified cases of mortality from 2008 to 2019. Additionally, we analyzed common comorbidities from outpatient and inpatient records using ICD‐9‐CM and ICD‐10‐CM codes. For all participants who died of any cause, information on months of survival from the index date until 2018 was provided from the Cause of Death Database, and the underlying cause of death was defined by ICD‐10‐CM codes. The annual all‐cause mortality rate was calculated separately for different RD groups. To determine the survival effect, we analyzed NHIRD data in the year of interest and followed patients until a death status appeared in the next year; therefore, the study year was adjusted accordingly.
Covariates
Patient characteristics at baseline included sex, age, and score on the Charlson‐Deyo Comorbidity Index (CCI) 14 on the index date of cohort enrolment in this study. The CCI score was calculated for ambulatory visits within 1 year after the index date.
Statistical analysis
Statistical analyses were performed by t tests to compare continuous variables, and by χ 2 tests for categorical variables. Survival analysis was performed by Kaplan–Meier analysis. The multivariable Cox proportional hazard model was used to estimate the hazard ratio (HR) with a 95% confidence interval (CI) of significant differences with the impact of sex, age at onset of the disease, and duration of the disease. A two‐sided probability value of 0.05 was used to indicate statistical significance. The E‐value approach was performed for unmeasured confounders, evaluating the minimum strength of association that one could have influence on the outcome. All the data were analyzed with SAS® software, version 9.4 (SAS Institute Inc., Cary, NC, USA).
Results
The average national population from 2008 to 2020 was approximately 23.1 million. Among this population, a total of 175 patients with ATTRv amyloidosis were identified over the same period. As the cause of death registry was examined up to 2019 (excluding 27 patients newly validated in 2020), only 148 patients with ATTRv amyloidosis were included in the final analysis. As shown in Table 1, patients with ATTRv were typically male (77.7%), the mean age at validation of ATTRv amyloidosis with polyneuropathy, defined as the time when the catastrophic illness certification was issued, was 62.75 (SD 7.65) years, and the mean follow‐up duration was 2.41 (SD 2.03) years. The age at validation and follow‐up duration were significantly different between the survivor and nonsurvivor groups; however, these groups did not differ in sex ratios. The three most common causes of death were unspecified amyloidosis (30.6%), organ‐limited amyloidosis (20.9%), and neuropathic heredofamilial amyloidosis (9.7%).
Table 1.
Basic characteristics of the Ala97Ser ATTRv amyloidosis with polyneuropathy cohort in the index date.
| Total | Survivor | Nonsurvivor | χ 2/t | P | |
|---|---|---|---|---|---|
| Sex | 148 (100.0) | 86 (58.1) | 62 (41.9) | ||
| Male | 115 (77.7) | 65 (56.5) | 50 (43.5) | 0.53 | 0.4653 |
| Female | 33 (22.3) | 21 (63.6) | 12 (36.4) | ||
| Age at validation | |||||
| Mean ± SD | 62.75 ± 7.65 | 60.47 ± 7.85 | 65.92 ± 6.14 | −4.74 | <0.0001 |
| CCI score | |||||
| Mean ± SD | 1.60 ± 1.64 | 1.31 ± 1.61 | 2.00 ± 1.61 | −2.56 | 0.0117 |
| Follow‐up (year) | |||||
| Mean ± SD | 2.41 ± 2.03 | 2.12 ± 2.08 | 2.82 ± 1.90 | −2.11 | 0.0366 |
| Min | 0 | 0 | 0 | ||
| Max | 8 | 8 | 7 | ||
The new, cumulative, and death case numbers are shown in Table 2, and the corresponding incidence and prevalence rates were 0.04–1.14 and 0.04–4.79 per million, respectively, from 2008 to 2020 (Figure 1). A 1‐year increase in age at validation was associated with an 11% increase in the risk of death in patients with ATTRv amyloidosis (HR: 1.11, 95% CI: 1.06–1.16) (Table S1). Males also had higher mortality than females (HR: 2.22, 95% CI: 1.15–4.31) (Figure 2 and Table S1). The estimated median survival duration was in the 5th years according to the Kaplan–Meier method (Figure 2).
Table 2.
New and cumulative case numbers of the patients with Ala97Ser ATTRv amyloidosis with polyneuropathy.
| Year | New case (incidence) | Cumulative case (prevalence) | Death | ||
|---|---|---|---|---|---|
| No | Rate (per 1 M population) a | No | Rate (per 1 M population) a | No | |
| 2008 | 1 | 0.04 | 1 | 0.04 | |
| 2009 | 9 | 0.39 | 10 | 0.43 | 1 |
| 2010 | 3 | 0.13 | 12 | 0.52 | 2 |
| 2011 | 10 | 0.43 | 20 | 0.86 | 3 |
| 2012 | 11 | 0.47 | 28 | 1.20 | 4 |
| 2013 | 13 | 0.56 | 37 | 1.58 | 4 |
| 2014 | 11 | 0.47 | 44 | 1.88 | 8 |
| 2015 | 18 | 0.77 | 54 | 2.30 | 8 |
| 2016 | 16 | 0.68 | 62 | 2.64 | 9 |
| 2017 | 12 | 0.51 | 65 | 2.76 | 4 |
| 2018 | 18 | 0.76 | 79 | 3.35 | 12 |
| 2019 | 26 | 1.10 | 93 | 3.94 | 7 |
| 2020 | 27 | 1.14 | 113 | 4.79 | ‐ |
The population means the mid‐year population in Taiwan, N = 148.
Figure 1.
New and cumulative case rate of Ala97Ser ATTRv amyloidosis with polyneuropathy in Taiwan. The new case (incidence) rate (per 1 M) and cumulative case (prevalence) rate in Taiwan are represented as bar chart and line graph, respectively. The numbers are calculated by patients with catastrophic illness identification of ATTRv based on the record of National Health Insurance Research Database during 2008 to 2020. The annual population is defined as mid‐year population.
Figure 2.
Multivariable Cox proportional regression analysis of the survival estimation in patients with Ala97Ser ATTRv amyloidosis with polyneuropathy. Adjusted with sex, age at validation and Charlson‐Deyo Comorbidity Index. The dashed line with “+” on it represented the survival estimate of women. The dashed line with “x” on it represented the survival estimate of men. The line with “o” on it represented overall survival estimate.
Table S2 shows the age groups of patients with ATTRv amyloidosis. Of the age groups, age at validation most commonly fell in the 60–69‐year‐old group, followed by the 50–59‐year‐old group. The age at death most commonly occurred in the 60–69‐year‐old group, followed by the 70–89‐year‐old group. The two Unidentified most common departments visited by these patients were neurology and family medicine (for outpatient care) and neurology and cardiology (for inpatient care) (see Table S3).
Discussion
The amyloid protein widely reported to be associated with ATTRv amyloidosis is transthyretin (TTR), as genetic mutations lead to disease; the most common variants of this gene worldwide are Val30Met, Val122Ile, and Glu89Gln. Our study is the first nationwide cohort to determine the overall prevalence rate, demographic characteristics, disease course, and survival rate of patients with Ala97Ser ATTRv amyloidosis with polyneuropathy, which is the most unique mutation in Taiwan and Asia. 15 , 16 , 17
Schmidt et al. 2 reported the highest disease prevalence in Northern Portugal (1631.20 per 1 million general population) and the lowest in Sicily (0.20 per 1 million general population). In this study cohort, compared with the same general population from Schmidt et al.'s study, 2 the adjusted prevalence was 2.76 per 1 million in 2017, which is within the range of moderate‐prevalence countries worldwide. In the present study, the new case (incidence) rate was relatively stable. However, the increasing prevalence of ATTRv amyloidosis with polyneuropathy is noteworthy; the rate in 2020 (4.79 per 1 million general population) is similar to the ranges of moderate‐ to high‐prevalence countries worldwide, and the number is even higher than some endemic countries. For example, in Japan, the prevalence rate is between 0.99 and 12.9. 2 The increases in the prevalence rate of ATTRv amyloidosis with polyneuropathy might be due to gradual improvements in awareness and diagnosis in recent years. In this study, we found that males had a higher mortality risk than females and that the average onset age was approximately 62 years, which is consistent with the late onset of the Ala97Ser mutation according to previous studies. 5 , 15 , 17 In addition, the risk of mortality increased with increased age at validation, which indicates that early diagnosis and intervention may result in better outcomes. 4 , 16 , 18 In addition, a lower mean follow‐up time also contributed to the risk of mortality, which might be the consequence of worse care during functional decline. The main cause of death in ATTRv amyloidosis cases is cardiovascular events 4 , 16 ; however, our result might be equivocal due to the limitations of the death‐coding algorithm.
The mean overall survival in the study (2.82 ± 1.90 years, ranging from 0 to 7 years) and the very low estimated survival probability in the 8th year are both lower than those in the natural course of ATTRv amyloidosis reported in other countries, including those in Western Europe, Northern Europe, the United States, and Japan, 7 , 8 , 12 , 19 , 20 which could be related to the late onset of the Ala97Ser mutation or delayed diagnosis and treatment due to poor awareness and treatment in the past decade.
Therapeutic approaches for ATTRv amyloidosis with polyneuropathy have significantly improved in recent years. Since 1990, such improvements include liver transplantation (in Sweden) and tetramer stabilizers or gene‐silencing therapies in 21st century. 3 Novel treatment can be categorized into 3 groups: suppression of synthesis, such as through liver transplantation or gene‐silencing therapy. Vutrisiran, 21 a small interfering RNA(siRNA) agent that targets and inhibits the production of transthyretin protein, also demonstrate its effectiveness of preventing the buildup of amyloid deposits in various organs, including the heart, nerves, and kidneys.; tetramer stabilizers, such as diflunisal and tafamidis; and removal of amyloid fibrils, such as anti‐TTR misfolded monoclonal antibodies. 22 Organ transplantation to reduce amyloidosis, especially liver transplantation in the early onset population with the Val30Met mutation among countries with high prevalence 18 , 23 has declined in the past 10 years as novel pharmacological approaches such as tafamidis, 4 , 24 patisiran, 25 inotersen, and vutrisiran have appeared. 3 Thus, there was only one official record of liver transplantation in Taiwan in 2020. In addition, trials of antibodies against serum amyloid protein are also under development. 26 , 27 Other treatments currently in trials include the new kinetic stabilizers acoramidis 28 and talcapone 30 or CRISPR/Cas9 for direct TTR knockout. 31 Supportive care with symptomatic treatment also plays an important role in the treatment of ATTRv amyloidosis with polyneuropathy. 4 , 15 The improvement in treatments and increased use of noninvasive diagnostic tools have had a substantial impact on international awareness since early detection became meaningful and prognosis improved. 1 , 3 Thus, the improvement in treatment has led to an increased diagnostic rate in recent years since ATTRv amyloidosis is no longer regarded as an incurable disease. The cumulative number of cases (prevalence) in our study increased dramatically since 2019, which could contribute to the approval of local clinical trials in Taiwan, including those for onpattro (patisiran) and tafamidis in 2019. Since disease awareness is strongly associated with novel treatment, the prevalence rates prior to the availability of these novel treatments may be underestimated. These findings reflected the necessity of early intervention with a novel disease‐modifying regimen in National reimbursement policy.
This study has several limitations. First, the survival rate may have been overestimated due to selection bias. Early diagnosis and appropriate care may result in a better prognosis. However, early in the study period, patients with ATTRv amyloidosis were not well recognized and thus not correctly identified and included in the cohort. Indeed, the annual increase in prevalence is likely due to improved diagnostic approaches and doctor awareness, indicating that such data may have been previously underestimated. The pleomorphic nature of the manifestations may also increase the difficulty of identifying such patients without family history, further contributing to underestimation. In addition, the real‐world prevalence and incidence rates of ATTRv amyloidosis with polyneuropathy in Taiwan from 2008 to 2020 were calculated by a conservative method, the validation of catastrophic illness database, to avoid overestimation from the accumulation of false‐positive cases. Moreover, the influence of novel treatments on outcomes is lacking in Taiwan. The Taiwan Food and Drug Administration granted medication licenses to Onpattro in December 2020 for treating ATTRv amyloidosis, and to Tafamidis in July 2020 for treating ATTRv amyloidosis with cardiomyopathy. Since neither drug is currently covered by the National Health Insurance, most patients with ATTRv amyloidosis in Taiwan underwent a natural course of the disease. Several clinical trials are currently ongoing in Taiwan, such as onpattro (patisiran; 2 mg/mL infusion) and tafamidis (meglumine; 20‐mg soft capsules). The onpattro trial in Taiwan was approved on January 19, 2019, with a total of 18 patients enrolled to date, including 8 receiving patisiran and 10 receiving the placebo. The tafamidis trial in Taiwan was approved on July 18, 2019, with no participants yet despite the compassionate use from Pfizer for patients with transthyretin amyloidosis cardiomyopathy in Taiwan since 2020. Additionally, 4 patients in Taiwan have been recruited for the Vutrisiran Helios‐A study. To date, only a small number of patients are able to receive novel medical treatments. Second, the cause of death was analyzed by using the NHI database. However, further follow‐up regarding the specific cause of death is needed due to the limitations of the death‐coding algorithm. Third, there could be potential unmeasured confounders that influenced the outcomes. However, the E‐value indicated that such unmeasured confounders would have to increase the risk of ATTRv amyloidosis by a factor of 2.85 to nullify our observation. Finally, the epidemiology of different variants of ATTRv amyloidosis may differ; thus, worldwide studies are needed.
In conclusion, raising clinician awareness of ATTRv amyloidosis with polyneuropathy as a differential diagnosis of patients who initially present with otherwise idiopathic polyneuropathy is important since symptoms such as carpal tunnel syndrome may precede the diagnosis by years 1 and the outpatient department that patients with ATTRv amyloidosis may visit can vary due to variable initial presentation (Table S3). Clinicians should keep red‐flag signs in mind, 23 as early detection accompanied by early treatment with the latest therapeutic approaches provides better outcomes. 3
Author Contributions
Chih‐Hsing Wu, Kong‐Pin Lin, and Han‐Wei Huang contributed to conception and design of the study. Chia‐Chun Li contributed to statistical analyses. Chih‐Hsing Wu and Chia‐Chun Li contributed to acquisition of data. Wei‐Hsiang Tseng, Han‐Wei Huang, Chih‐Hsing Wu, and Kong‐Pin Lin contributed to drafting the article. Chih‐Hsing Wu, Wing P. Chan, and Chin‐Sung Chang contributed to funding raise. All authors contributed to research data interpretation, suggestions and discussion, final approval of the manuscript, and critical revision of the manuscript. Institute of Allied Health Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan(Chia‐Chun Li) Department of Family Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan(Chia‐Chun Li, Chih‐Hsing Wu), Department of Neurology, National Cheng Kung University Hospital, Medical College, National Cheng Kung University, Tainan, Taiwan(Han‐Wei Huang), Department of Neurology, Taipei Veterans General Hospital, Taipei, Taiwan(Kong‐Pin Lin), Department of Neurology, National Yang‐Ming University School of Medicine, Taipei, Taiwan(Kong‐Pin Lin), Department of Radiology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan(Wing P. Chan), Department of Radiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan(Wing P. Chan), Department of Family Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan(Wei‐Hsiang Tseng, Chin‐Sung Chang, Chih‐Hsing Wu) Institute of Gerontology, Medical College, National Cheng Kung University, Tainan, Taiwan(Chih‐Hsing Wu).
Conflict of Interest
All authors declare no competing interests.
Supporting information
Table S1. Multivariable Cox proportional regression analysis of the patients with Ala97Ser ATTRv amyloidosis with polyneuropathy.
Table S2. The age groups of the patients with Ala97Ser ATTRv amyloidosis with polyneuropathy.
Table S3. The common medical department of outpatient and inpatient visit in patients with Ala97Ser ATTRv amyloidosis with polyneuropathy during 2008–2020.
Acknowledgments
We are grateful to the Health Data Science Center, National Cheng Kung University Hospital, for providing administrative and technical support.
Co‐Corresponding author: Kong‐Pin Lin.
Funding information
This study was supported by the educational grant from the Taiwanese Osteoporosis Association (partially provided by Alnylam) and Ministry of Science and Technology, Taiwan, R.O.C., under grant nos. TOA‐2020‐B‐01, MOST 108‐2314‐B‐006‐043‐MY2, and MOST 110‐2314‐B‐006‐054‐MY2 (recipient: CH Wu). The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Wei‐Hsiang Tseng and Han‐Wei Huang contributed equally to this work.
Study design: Retrospective longitudinal observational study.
Funding Statement
This work was funded by Ministry of Science and Technology, Taiwan grants MOST 108‐2314‐B‐006‐043‐MY2 and MOST 110‐2314‐B‐006‐054‐MY2; Taiwanese Osteoporosis Association grant TOA‐2020‐B‐01.
Data Availability Statement
All data presented in the manuscript can be found in Taiwan's National Health Insurance Research Database (NHIRD).
References
- 1. Obi CA, Mostertz WC, Griffin JM, Judge DP. ATTR epidemiology, genetics, and prognostic factors. Methodist Debakey Cardiovasc J. 2022;18(2):17‐26. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Schmidt HH, Waddington‐Cruz M, Botteman MF, et al. Estimating the global prevalence of transthyretin familial amyloid polyneuropathy. Muscle Nerve. 2018;57(5):829‐837. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Ando Y, Adams D, Benson MD, et al. Guidelines and new directions in the therapy and monitoring of ATTRv amyloidosis. Amyloid. 2022;29:143‐155. [DOI] [PubMed] [Google Scholar]
- 4. Çakar A, Durmuş‐Tekçe H, Parman Y. Familial amyloid polyneuropathy. Noro Psikiyatr Ars. 2019;56(2):150‐156. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Hsu H‐C, Liao M‐F, Hsu J‐L, et al. Phenotypic expressions of hereditary transthyretin Ala97Ser related amyloidosis (ATTR) in Taiwanese. BMC Neurol. 2017;17(1):178. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Du K, Li F, Wang H, et al. Hereditary transthyretin amyloidosis in mainland China: a unicentric retrospective study. Ann Clin Transl Neurol. 2021;8(4):831‐841. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Lane T, Fontana M, Martinez‐Naharro A, et al. Natural history, quality of life, and outcome in cardiac transthyretin amyloidosis. Circulation. 2019;140(1):16‐26. [DOI] [PubMed] [Google Scholar]
- 8. Lauppe R, Liseth Hansen J, Fornwall A, et al. Prevalence, characteristics, and mortality of patients with transthyretin amyloid cardiomyopathy in the Nordic countries. ESC Heart Fail. 2022;9(4):2528‐2537. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Jang SC, Nam JH, Lee SA, et al. Clinical manifestation, economic burden, and mortality in patients with transthyretin cardiac amyloidosis. Orphanet J Rare Dis. 2022;17(1):262. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Sekijima Y, Yazaki M, Ueda M, Koike H, Yamada M, Ando Y. First nationwide survey on systemic wild‐type ATTR amyloidosis in Japan. Amyloid. 2018;25(1):8‐10. [DOI] [PubMed] [Google Scholar]
- 11. Inês M, Coelho T, Conceição I, Duarte‐Ramos F, de Carvalho M, Costa J. Epidemiology of transthyretin familial amyloid polyneuropathy in Portugal: a Nationwide study. Neuroepidemiology. 2018;51(3–4):177‐182. [DOI] [PubMed] [Google Scholar]
- 12. Yamada T, Takashio S, Arima Y, et al. Clinical characteristics and natural history of wild‐type transthyretin amyloid cardiomyopathy in Japan. ESC Heart Fail. 2020;7(5):2829‐2837. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Hsieh CY, Su CC, Shao SC, et al. Taiwan's National Health Insurance Research Database: past and future. Clin Epidemiol. 2019;11:349‐358. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Quan H, Sundararajan V, Halfon P, et al. Coding algorithms for defining comorbidities in ICD‐9‐CM and ICD‐10 administrative data. Med Care. 2005;43:1130‐1139. [DOI] [PubMed] [Google Scholar]
- 15. Hsieh ST. Amyloid neuropathy with transthyretin mutations: overview and unique Ala97Ser in Taiwan. Acta Neurol Taiwan. 2011;20(2):155‐160. [PubMed] [Google Scholar]
- 16. Lai HJ, Huang KC, Liang YC, et al. Cardiac manifestations and prognostic implications of hereditary transthyretin amyloidosis associated with transthyretin Ala97Ser. J Formos Med Assoc. 2020;119(3):693‐700. [DOI] [PubMed] [Google Scholar]
- 17. Chao H‐C, Liao Y‐C, Liu Y‐T, et al. Clinical and genetic profiles of hereditary transthyretin amyloidosis in Taiwan. Ann Clin Transl Neurol. 2019;6(5):913‐922. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. Yamashita T, Ando Y, Okamoto S, et al. Long‐term survival after liver transplantation in patients with familial amyloid polyneuropathy. Neurology. 2012;78(9):637‐643. [DOI] [PubMed] [Google Scholar]
- 19. Damy T, Kristen AV, Suhr OB, et al. Transthyretin cardiac amyloidosis in continental Western Europe: an insight through the transthyretin amyloidosis outcomes survey (THAOS). Eur Heart J. 2019;43:391‐400. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Grogan M, Scott CG, Kyle RA, et al. Natural history of wild‐type transthyretin cardiac amyloidosis and risk stratification using a novel staging system. J Am Coll Cardiol. 2016;68(10):1014‐1020. [DOI] [PubMed] [Google Scholar]
- 21. Adams D, Tournev IL, Taylor MS, et al. Efficacy and safety of vutrisiran for patients with hereditary transthyretin‐mediated amyloidosis with polyneuropathy: a randomized clinical trial. Amyloid. 2022;30:1‐9. [DOI] [PubMed] [Google Scholar]
- 22. Suhr O, Grogan M, Martins de Silva A. Neurological and cardiac improvements with PRX004 in amyloidosis patients: results of a phase 1 study, 2021 emerging science abstracts. 2021 AAN annual meeting abstracts. Neurology. 2021;96(22):e2783‐e2788. [Google Scholar]
- 23. Sekijima Y, Ueda M, Koike H, Misawa S, Ishii T, Ando Y. Diagnosis and management of transthyretin familial amyloid polyneuropathy in Japan: red‐flag symptom clusters and treatment algorithm. Orphanet J Rare Dis. 2018;13(1):6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. Coelho T, Maia LF, Martins da Silva A, et al. Tafamidis for transthyretin familial amyloid polyneuropathy: a randomized, controlled trial. Neurology. 2012;79(8):785‐792. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25. Adams D, Pritesh JG. Outcomes of patients with hereditary transthyretin‐mediated amyloidosis with early onset V30M versus all other mutations in APOLLO, a phase 3 study of patisiran. Rev Neurol. 2019;175:S129. [Google Scholar]
- 26. Richards DB, Cookson LM, Berges AC, et al. Therapeutic clearance of amyloid by antibodies to serum amyloid P component. N Engl J Med. 2015;373(12):1106‐1114. [DOI] [PubMed] [Google Scholar]
- 27. Higaki JN, Chakrabartty A, Galant NJ, et al. Novel conformation‐specific monoclonal antibodies against amyloidogenic forms of transthyretin. Amyloid. 2016;23(2):86‐97. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28. BridgeBio Pharma Reports Month 12 Topline Results From Phase 3 ATTRibute‐CM Study. BridgeBio company; 2021. [Google Scholar]
- 30. Pinheiro F, Varejão N, Esperante S, et al. Tolcapone, a potent aggregation inhibitor for the treatment of familial leptomeningeal amyloidosis. FEBS J. 2021;288(1):310‐324. [DOI] [PubMed] [Google Scholar]
- 31. Gillmore JD, Gane E, Taubel J, et al. CRISPR‐Cas9 in vivo gene editing for transthyretin amyloidosis. N Engl J Med. 2021;385(6):493‐502. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Table S1. Multivariable Cox proportional regression analysis of the patients with Ala97Ser ATTRv amyloidosis with polyneuropathy.
Table S2. The age groups of the patients with Ala97Ser ATTRv amyloidosis with polyneuropathy.
Table S3. The common medical department of outpatient and inpatient visit in patients with Ala97Ser ATTRv amyloidosis with polyneuropathy during 2008–2020.
Data Availability Statement
All data presented in the manuscript can be found in Taiwan's National Health Insurance Research Database (NHIRD).