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

Introduction

Hereditary transthyretin (ATTRv) amyloidosis is a rare, autosomal dominant, systemic disease caused by pathogenic transthyretin (TTR). Alongside cardiac dysfunction, the disease typically manifests with a rapidly progressive sensorimotor and autonomic polyneuropathy (ATTRv-PN), but also causes multiple other organ manifestations including ocular, gastrointestinal, and soft-tissue symptoms [1]. Based on walking ability, ATTRv-PN is commonly classified in three disease stages: a symptomatic, but fully ambulatory patient is at stage 1, the need for walking aids defines stage 2, and wheelchair dependence stage 3, while stage 0 describes a symptom-free carrier of a pathogenic variant of the TTR gene [2]. If untreated, the combination of cardiac failure, wasting, and secondary infections lead to death within seven to 11 years after the onset of disease symptoms [3].

In addition to the most frequent TTR p.Val50Met variant in endemic and non-endemic areas, more than 140 non-p.Val50Met variants underlying the disease have been described worldwide to date, most of which are amyloidogenic [4]. Comparing endemic and non-endemic areas, the clinical course varies distinctly even within carriers of the same TTR variant [1,5–7]. The early-onset and the mostly non-endemic late-onset type of the disease are distinguished with an arbitrary cut-off at the age of 50 years. In Germany where the disease is non-endemic, the estimated prevalence of ATTRv amyloidosis was reported with five cases in one million inhabitants [3].

Since more than 90% of circulating TTR are of hepatic origin, orthotopic liver transplantation has successfully been conducted for this indication since 1990 [8,9]. However, peri- and post-interventional complications, risk of transplant rejection, the necessity for permanent immunosuppression, and even secondary disease progression make liver transplantation a less than desirable treatment option [10].

In several clinical trials, the TTR kinetic stabilising oral drug tafamidis meglumine, approved in a dosage of 20 mg qd for the treatment of stage 1 ATTRv-PN, demonstrated a significant slowdown of neurologic and cardiologic aspects of the disease course [11–15], which recently led to the approval of tafamidis also for ATTR-related cardiomyopathy in a higher dosage of 61 mg qd. Notwithstanding the convincing therapeutic effects of two innovative TTR gene silencing medications, the antisense oligonucleotide inotersen [16] and the small interfering RNA patisiran [17], and their subsequent approval for ATTRv-PN stages 1 and 2 [2], tafamidis has been the only approved medication to be in in-label use for almost 10 years to date for which long-term experiences outside controlled clinical trials can reliably be evaluated.

However, most prospective studies on tafamidis have focussed on cohorts in endemic ATTRv-PN hotspots such as Portugal or Brazil recruiting mostly younger patients at early stages of the disease [11,12,18,19]. Meanwhile, patient cohorts in other parts of the world presenting with different genotypes and phenotypes are still underrepresented in the current literature [13,20]. The share of late-onset ATTRv-PN patients in some European countries has been described to be as high as 44% in some retrospective studies and may be much higher than in the typical ATTRv amyloidosis hotspots [19]. These patients are known to experience disease progression at a faster rate, are more difficult to diagnose, or are diagnosed at later disease stages than patients with endemic ATTRv-PN [13]. Little is also known about the efficacy of tafamidis in non-endemic late-onset ATTRv-PN. Disability and mortality rates in late-onset ATTRv-PN are also generally higher than in early-onset ATTRv-PN, and data on long-term outcomes in these cohorts are therefore of particular interest [21].

To address this lack of information, we report here on long-term survival and neurologic outcome analysis of a large German single-referral centre cohort of patients with non-endemic, mostly late-onset ATTRv-PN treated at the Amyloidosis Centre of Heidelberg University Hospital, including our experiences with tafamidis.

Methods

Study design

This retrospective observational cohort study was conducted at the Amyloidosis Centre of Heidelberg University Hospital between November 1999 and July 2020. The study was approved by the ethics committee of the Medical Faculty of Heidelberg University (123/2006). The diagnosis was confirmed in all subjects by positive genetic testing for variants of the TTR gene. TTR variants were described using the Human Genome Variation Society (HGVS) nomenclature [22]. For regression analyses, all TTR variants were dichotomised into the p.Val50Met and all other variants. The onset of clinical symptoms was identified based on available medical records and a patient’s history. Follow-up was obtained starting at first presentation in our centre to last known contact. General practitioners and local authorities were contacted in cases with no recent follow-up after January 2019. In the case of patients who received heart transplantation therapy, data were censored at the date of transplantation for overall survival analysis. Most patients treated at our amyloidosis centre came for medical consultations from different parts of Germany, and few patients came from abroad. For these reasons, many of these patients received treatment in local hospitals after an initial consultation at our centre.

The severity of cardiac involvement at first contact in our centre was assessed using plasma N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels. NT-proBNP levels ≥900 ng/l were assessed as indicative of acute heart failure at presentation according to the current age-adjusted (50–75 years) cut-off levels published by the European Society of Cardiology while NT-proBNP levels ≤125 ng/l were considered to rule out relevant cardiac involvement [23].

The severity of neurologic disease and clinical outcomes were estimated applying the ATTRv-PN stages according to Coutinho et al., formerly determined as familial amyloid polyneuropathy (FAP) stages [2]. For survival analyses on medication with tafamidis, the Peripheral Neuropathy Disability (PND) score was used [24]. This score comprises five disease stages (I, II, IIIa, IIIb, and IV) that sub-differentiate walking ability in more detail (e.g. one or two crutches required). Accordingly, both PND score I (‘preserved walking, sensory disturbances’) and PND score II (‘impaired walking but can walk without stick or crutch’) correspond to Coutinho stage 1 ATTRv-PN [2] for which the approval of tafamidis meglumine 20 mg qd is confined. We are aware that both scores focus on gait and do not reflect motor and sensory qualities or even small fibre-associated sensory and autonomic symptoms adequately. However, more detailed neurologic scores to quantify ATTRv-PN more precisely such as the Neuropathy Impairment Score (NIS) [25] or its reduced version only assessing the lower limbs (NIS-LL) [26] have not been consistently documented in each patient throughout the entire study period, and could thus not be reliably applied.

Patients treated with tafamidis meglumine 20 mg qd received regular neurologic follow-up examinations in 6 to 12 months intervals at our centre. The course of the disease was evaluated at each follow-up examination by a specialist in neurology with longstanding expertise in amyloidosis, based on patient-reported symptoms, neurologic examination, and neurophysiologic findings. In accordance with the approval restrictions for tafamidis 20 mg in Germany, disease progression resulted in termination or change of treatment, in particular when patients became dependent from walking aids (i.e. ATTRv-PN Coutinho stage ≥2 or PND score ≥ IIIa). Since the approval of tafamidis 61 mg for the treatment of ATTR-related cardiomyopathy, only three patients who were additionally diseased with ATTRv-PN were recently started on tafamidis 61 mg qd, but this happened after the final data cut-off in the present study.

Statistical analysis

Characteristics of patients were described by using standard descriptive statistics. In the case of missing values, given percentages relate to the effective total number of available values assessed. If not otherwise indicated, all results are documented as mean values ± standard deviations. Comparison of baseline characteristics between patients with early and late-onset ATTRv-PN was calculated using Chi-squared or ANOVA analysis. The association of predictors with overall mortality or progression on tafamidis were calculated using Cox regression analyses, and visualised with Kaplan–Meier survival curves. Multivariable analyses were added to account for multiple predictors. ATTRv-PN Coutinho stages and PND scores were dichotomised for multivariable analyses. The level of significance was set at 0.05 (two-sided), and two-sided 95% confidence intervals (CI) were calculated for all statistical tests. Analyses were carried out with SPSS 24.0 (IBM Corp., Armonk, NY).

Results

Baseline patient characteristics

In total, 346 subjects with variants in the TTR gene were examined at our amyloidosis centre between November 1999 and July 2020. Of these, 22 patients were excluded due to incomplete medical records. 95 patients were identified as clinically asymptomatic carriers of a variant TTR gene. Out of the remaining 229 patients with ATTRv amyloidosis, 26 patients exclusively presented with neurologic symptoms (neurologic phenotype), while 61 patients had cardiac symptoms only (cardiac phenotype), and 142 patients had a mixed neurologic/cardiologic phenotype. Hence, 168 patients with genetically confirmed ATTRv-PN (i.e. neurologic and mixed phenotype) were included in our analysis (Figure 1).

Figure 1. Study profile.

The mean age at onset of clinical symptoms was 58.2 ± 11.3 years, and the mean age of genetic confirmation of diagnosis was 60.5 ± 11.7 years. The mean time from onset of clinical symptoms to genetic confirmation of diagnosis was 2.6 ± 3.0 years. Of the 168 patients with symptomatic ATTR-PN, 124 (74%) patients received a detailed neurologic examination (Figure 1). The majority of patients (84.5%) had cardiac involvement at some point during the follow-up period. Of the 165 patients with ATTRv-PN and available documentation of first symptoms, 110 (66.7%) had developed neurologic symptoms as the initial manifestation of the disease, while 55 (33.3%) reported having experienced cardiac symptoms first. One patient (0.6%) presented with ocular amyloidosis. At the onset of manifest disease, numbness of the feet was the most frequent initial neurologic symptom experienced by 85 (51.5%) out of 165 patients. Detailed neurologic examinations at first contact in our amyloidosis centre were available for 122 patients: 77.9%, 17.2%, and 13.9% were found to have numbness, neuropathic pain, and disturbance of temperature sensation respectively; 50.0% presented with muscle weakness, and 41.0% were found to have gait difficulties as first clinical manifestation. Clinical signs of gastrointestinal involvement were observed in 32.7% of all patients, and 49.4% had a carpal tunnel syndrome.

Thirty-two different TTR variants were identified in our cohort (Table S1). 72 (42.9%) patients had the p.Val50Met variant. We found relevant differences in the rate and severity of cardiac involvement as well as mortality rates among the four most frequent TTR variants (p.Val50Met; p.Leu78His; p.Ile127Val; p.Cys30Arg) identified in our patient cohort. Multi-organ involvement, mortality rate and severity of cardiac involvement were most pronounced with the p.Cys30Arg variant. Patient characteristics depending on the underlying TTR variant are given in Table 1.

Table 1. Characteristics, mortality rates, and clinical outcome of 168 patients with ATTRv-PN according to most frequently identified TTR variants.

	TTR variant
	p.Val50Met	p.Leu78His	p.Ile127Val	p.Cys30Arg	All variants
Patient characteristics
Number of patients, n	72	15	14	10	168
Age at symptom onset, mean (SD)	58.6 (13.0)	56.9 (6.9)	61.1 (6.9)	66.5 (7.6)	58.2 (11.3)
Age at first contact, mean (SD)	61.06 (12.98)	61.67 (5.92)	66.64 (7.85)	67.80 (6.94)	60.75 (11.60)
Cardiac Tx, n (%)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	8 (4.8)
Liver Tx, n (%)	13 (18.3)	2 (13.3)	0 (0.0)	0 (0.0)	24 (14.4)
Neurologic symptoms at symptom onset, n (%)*	58 (84.1)	15 (100)	11 (78.6)	3 (30.0)	110 (66.7)
Cardiac involvement, n (%)	53 (73.6)	11 (73.3)	12 (85.7)	10 (100.0)	142 (85.0)
NT-proBNP ≤ 125 ng/l, n (%)*	16 (23.9)	5 (33.3)	3 (21.4)	0 (0.0)	28 (17.6)
NT-proBNP ≥ 900 ng/l, n (%)*	27 (40.3)	3 (21.4)	5 (35.7)	9 (90.0)	80 (50.3)
Treatment with tafamidis, n (%)	32 (45.1)	9 (60.0)	6 (42.9)	7 (70.0)	77 (46.1)
Mortality
Death, n (%)*	29 (40.8)	4 (26.7)	5 (35.7)	5 (50.0)	66 (40.5)
Clinical outcome
Follow-up period (years), mean (SD)	4.6 (2.9)	5.9 (3.8)	3.0 (2.2)	3.6 (1.4)	4.1 (2.8)
ATTRv-PN stage [2], median (IQR)	1 (1–2)	1 (1–2)	2 (1–2)	1 (0.25–1.75)	1 (1–2)

*Individual missing values.

ATTRv-PN: hereditary transthyretin amyloidosis with polyneuropathy; IQR: interquartile range; NT-proBNP: N-terminal prohormone of brain natriuretic peptide; SD: standard deviation; Tx: transplantation.

Comparison of patients with early and late-onset ATTRv-PN

The majority of patients in our cohort (n = 133 out of 163 patients with documented onset of symptoms; 81.6%) was diagnosed with the late-onset type of ATTRv-PN (onset of clinical symptoms ≥50 years of age). In five patients, the onset of symptoms could not be determined. Between patients with early- and late-onset ATTRv-PN, there was no difference in single neurologic symptoms or the ATTRv-PN stage [2] at first contact (p = .49). Differences were found in cardiac involvement between both groups (early vs. late-onset): Rate of cardiac involvement (67% vs. 89%; p = .002), number of patients with NT-proBNP values ≥900 ng/l at first contact (24% vs. 57%; p = .002) and median NT-proBNP levels at first contact (218 ng/l vs. 1439 ng/l; p = .004) were higher in the late-onset ATTRv-PN group. All-cause mortality rates on Cox regression analysis were similar once patients were dichotomised into the two age groups (HR 1.530 [0.763–3.067]; p = .231).

Survival and predictors of mortality in ATTRv-PN

Follow-up information on mortality was obtained for all patients except for 7 patients who presented for a single medical consultation and were lost to follow-up thereafter (n = 161 patients). The mean follow-up period was 4.1 ± 2.8 years. 41% of patients died during the follow-up period after a mean of 3.8 ± 2.6 years. Age at first contact (HR 1.036 [1.009–1.062]; p = .007), cardiac involvement (HR 8.381 [2.041–34.413]; p = .003) as well as NT-proBNP ≥900 ng/l at first presentation (HR 3.484 [1.934–6.277]; p < .001) were associated with mortality (Table 2; Figure 2). The ATTRv-PN Coutinho stage at first contact (available for n = 122 patients) was not significantly associated with mortality. However, there was a trend for ATTRv-PN stage 0 and 1 patients for prolonged overall survival compared with stage 2 and 3 patients (Table 2; Figure 3). None of the neurologic symptoms at first contact was a predictor of mortality. Overall survival was similar for p.Val50Met and non-p.Val50Met variants (HR 0.781 [0.475–1.284]; p = .329). Multivariable Cox regression analysis revealed that NT-proBNP was the strongest predictor for overall survival once adjusted for other variables, while age at first contact was no longer prognostic in multivariable analysis (Table 2).

Figure 2. Survival according to plasma NT-proBNP levels at first contact (n = 152 patients).

Figure 3. Survival according to ATTRv-PN Coutinho stage at first contact (n = 119 patients).

Table 2. Cox regression analyses for overall survival.

Variable	HR	Lower CI	Upper CI	p-Value
Univariable Cox regression analysis for overall survival
TTR variant (p.Val50Met vs. all others)	0.781	0.475	1.284	.329
Age at first contact	1.036	1.009	1.062	.007*
NT-proBNP at first contact (≥900 ng/l vs. <900 ng/l)	3.484	1.934	6.277	<.001*
ATTRv-PN Coutinho stage at first contact (stages 2 and 3 vs. stages 0 and 1)	1.705	0.746	3.898	.206
Multivariable Cox regression analysis for overall survival (111 patients)
TTR variant (p.Val50Met vs. all others)	0.605	0.297	1.233	.167
Age at first contact	1.010	0.973	1.048	.608
NT-proBNP at first contact (≥900 ng/l vs. <900 ng/l)	3.259	1.421	7.476	.005*
ATTRv-PN Coutinho stage at first contact (stages 2 and 3 vs. stages 0 and 1)	2.158	0.907	5.136	.082

*Statistically significant.

ATTRv-PN: hereditary transthyretin amyloidosis with polyneuropathy; CI: confidence interval; HR: hazard ratio; NT-proBNP: N-terminal prohormone of brain natriuretic peptide.

Survival following organ replacement therapy

In total, 8 (4.8%) patients received heart transplants. Mean follow-up after the date of heart transplantation was 6.9 ± 6.0 years. Only 2 patients died within this follow-up period. Orthotopic liver transplantation was performed in 24 (14.4%) patients. 12 (50.0%) patients died within a follow-up period of 4.2 ± 5.7 years after the date of liver transplantation. Four (16.7%) patients died within 3 months of liver transplantation. Two patients received a combined heart and liver transplantation.

Long-term neurologic outcomes and efficacy and safety of treatment with tafamidis

Neurologic outcomes were estimated using the ATTRv-PN stages (0–3) in 122 patients who received neurologic examinations on a regular basis [2]. At first contact, 20 (16.0%) patients had no relevant neurologic dysfunction (stage 0), and 81 (66.4%) patients had some symptoms but had preserved walking ability (stage 1). Only 18 (14.8%) and 3 (2.4%) patients required one- or two-sided assistance with ambulation (stage 2) and were wheelchair-bound or bed-ridden (stage 3), respectively. ATTRv-PN stages at the end of the follow-up period could be determined in 49 surviving patients: 31 (63.3%) patients were ambulatory without assistance (stage 1); 13 (26.5%) patients needed walking aids (stage 2), and 5 (10.2%) patients were either wheelchair-bound or bedridden (stage 3) (Table 3).

Table 3. Characteristics, mortality rates, and clinical outcome of 168 patients depending on treatment with tafamidis.

	Treatment with tafamidis
	Yes	No
Patient characteristics
Patients, n	77	91
Age at symptom onset (years), mean (SD)	58.82 ± 10.36	57.6 ± 12.1
Age at first contact, mean (SD)	60.99 (10.59)	60.54 (12.46)
Age at beginning of treatment, mean (SD)	61.57 (10.49)	N/A
Cardiac Tx, n (%)	3 (3.9)	5 (5.5)
Liver Tx, n (%)	5 (6.5)	19 (20.9)
Neurologic symptoms at symptom onset, n (%)*	53 (68.8)	57 (64.8)
Cardiac involvement, n (%)	62 (80.5)	80 (87.9)
NT-proBNP ≤ 125 ng/l, n (%)*	15 (20.0)	13 (15.5)
NT-proBNP ≥ 900 ng/l, n (%)*	37 (49.3)	43 (51.2)
Mortality
Death, n (%)*	16 (21.3)	50 (56.8)
Clinical outcome
Follow-up period (years), mean (SD)	4.1 ± 2.5	4.2 ± 3.1
ATTRv-PN stage [2], median (IQR)	1 (1–2)	2 (1–2)

*Individual missing values.

ATTRv-PN: hereditary transthyretin amyloidosis with polyneuropathy; IQR: interquartile range; NT-proBNP: N-terminal prohormone of brain natriuretic peptide; SD: standard deviation; Tx: transplantation.

In total, 77 (45.8%) patients were treated first-line with tafamidis meglumine during the follow-up period. Of these, 64 patients presented for regular follow-up examinations at our centre (Figure 1; Table 3). The mean follow-up period on tafamidis was 34.1 ± 28.94 months. Tafamidis was very well tolerated by all patients. At the start of treatment with tafamidis, 36 (60.0%) patients had sensory disturbances with preserved walking (PND score I) while in 24 (40.0%) patients walking was impaired but independent from any assistance (PND score II), data of which was available for 60 patients. 36 (56.3%) patients experienced disease progression on tafamidis after 28.6 ± 19.2 months. The mean time until progression was different between patients with a baseline PND score of I (34.6 ± 21.9 months) and II (25.8 ± 16.6 months) indicating that the severity of neurologic disease at the start of treatment with tafamidis was associated with progression (Table 4; Figure 4). Type of TTR variant (p.Val50Met versus non-p.Val50Met), age at beginning of treatment, NT-proBNP ≥900 ng/l at first contact, and cardiac involvement were not associated with neurologic progression on tafamidis (Table 4). After adjustment for other variables, multivariable Cox regression analysis confirmed that the PND score at the beginning of treatment was the only predictor for progression on tafamidis (Table 4).

Figure 4. Disease progression on tafamidis according to baseline PND score at start of treatment (n = 60 patients).

Table 4. Cox regression analyses for progression on tafamidis.

Variable	HR	Lower CI	Upper CI	p-Value
Univariable Cox regression analysis for progression on tafamidis
TTR variant (p.Val50Met vs. all others)	1.360	0.704	2.630	.360
Age at beginning of treatment	0.987	0.953	1.021	.449
NT-proBNP at first contact (≥900 ng/l vs. <900 ng/l)	0.622	0.315	1.227	.171
PND score at beginning of treatment (II vs. I)	2.338	1.171	4.671	.016*
Multivariable Cox regression analysis for progression on tafamidis (58 patients)
TTR variant (p.Val50Met vs. other)	1.132	0.543	2.360	.741
Age at beginning of treatment	0.984	0.941	1.030	.496
NT-proBNP at first contact (≥900 ng/l vs. <900 ng/l)	0.603	0.250	1.449	.258
PND score at beginning of treatment (II vs. I)	2.718	1.258	5.873	.011*

*Statistically significant.

CI: confidence interval; HR: hazard ratio; NT-proBNP: N-terminal prohormone of brain natriuretic peptide; PND score: polyneuropathy disability score.

Discussion

Here, we present long-term data on a cohort of patients with genetically confirmed ATTRv-PN who presented to the interdisciplinary Amyloidosis Centre of Heidelberg University Hospital between November 1999 and July 2020 (Figure 1). Most of these patients experienced the late-onset type of ATTRv-PN. We found 32 different underlying TTR variants indicating a heterogeneous non-endemic patient population (Table 1 and Table S1) being representative of all genotypic and phenotypic specificities of ATTRv-PN known in the German population. All-cause mortality rates for patients with late-onset ATTRv-PN were high. Age, cardiac involvement, and severity of cardiac involvement measured by NT-proBNP at first contact in our centre were the most important risk factors for mortality (Table 2; Figure 2). NT-proBNP was the strongest predictor of mortality amongst the variables compared in multivariable analysis, while age at first contact was no longer significant in multivariable analysis. The type of neurologic symptoms and the severity of neurologic disease as estimated by the ATTRv-PN (Coutinho) stage [2] did not predict mortality (Table 2; Figure 3). Patients with late-onset ATTRv-PN experienced more frequent and severe cardiac involvement than patients with early-onset ATTRv-PN. Progression rates of neurologic symptoms within the first 4 years were high. Severity of ATTRv-PN symptoms at the start of treatment with tafamidis, as assessed with PND score I or II, was identified as the main predictor for disease progression in multivariable analysis (Tables 3 and 4; Figure 4).

The results of our study largely confirm a number of essential findings from previous studies conducted in other countries: Late-onset ATTRv-PN was found to be more difficult to diagnose and to be associated with higher neurologic disease severity and frequent cardiac involvement [19,21,27]. Muscle weakness and impairment of gait, both clinical indicators of advanced polyneuropathy, were also frequently met in our patient cohort. In line with findings from previous studies, all-cause mortality was high in patients with late-onset ATTRv-PN and cardiac involvement [21,28], and baseline NT-proBNP was confirmed as a strong predictor of survival (Table 2; Figure 2) [28].

Also in line with previous findings, treatment with tafamidis was very well tolerated and no drug-related adverse events were reported in our study [29,30]. Time to neurologic progression was far longer in our patients with PND score I compared to PND score II (Figure 4) confirming that treatment with tafamidis is most efficacious when initiated as early as possible at Coutinho stage 1 ATTR-PN, that is, when the PND score is still I [31,32]. This finding is noteworthy in that the PND score may be useful in clinical practice to assist therapeutic decision-making in ATTRv-PN stage 1 patients for whom all three approved disease-modifying medications, that is, tafamidis, inotersen and patisiran, can be prescribed now. Regarding our findings, first-line treatment with tafamidis (at 20 mg qd in its meglumine salt form, or 61 mg qd depending on concurrent cardiac involvement) seems justified in patients with a PND score of I, whereas patients with more advanced disease manifestation and a PND score of II tend to qualify for first-line treatment with a TTR gene silencing drug (or tafamidis at 61 mg qd given cardiac comorbidity).

As demonstrated previously [33], time to progression was also similar in our patients with either p.Val50Met or non-p.Val50Met variants. In one of the largest studies on tafamidis to date, Monteiro et al. reported treatment outcomes in 210 patients for a follow-up period of 18 to 66 months [34]. In their study, 29.5% were categorised as non-responders and 36.2% as partial responders to treatment with tafamidis. This is similar to the progression rate of 38.9% in our patients with a baseline PND score of I.

The main limitation of our study consists in its retrospective design which can be subject to a number of potential biases: Information on the onset of disease symptoms was collected retrospectively from medical records that are vulnerable to recall bias. Information on general health condition, for example, through the (modified) body mass index, and organ involvement was also retrieved from partially incomplete records which make it likely that some organ manifestations may be underreported (e.g. autonomic or gastrointestinal manifestations). Moreover, neurologic follow-up data on patients who had undergone liver transplantation were too scarce to allow a systematic postoperative outcome analysis. Furthermore, disease progression on tafamidis was defined by the treating physician on the basis of routine clinical and neurophysiologic findings. We cannot exclude that the availability of recently approved medical treatment alternatives (i.e. inotersen and patisiran) influenced the physician’s decision to terminate treatment with tafamidis earlier in some cases. Finally, we used the ATTRv-PN stages [2] and PND scores [24] as a compromise for outcome assessments because more complex neurologic scores (e.g. NIS [25], NIS-LL [26]) applied in most prospective clinical trials were not consistently documented in our patients throughout the entire length of the study period.

However, the present dataset is unprecedented in that it represents the largest patient cohort with ATTRv-PN reported in the German-speaking countries to date where the disease is non-endemic. Most of our patients were diagnosed with the late-onset type of ATTRv-PN. This allowed us to contribute relevant real-world data on clinical presentation and long-term outcomes in a genetically and phenotypically heterogeneous patient population that has typically been underrepresented in the current literature. The main strengths of our study consist in the length of the follow-up period, the high number of different TTR variants and patients who were all treated outside controlled clinical trials, and the completeness of collected data. We were able to report follow-up information for up to 13 years in individual patients following the first contact at our centre. We found that the severity of cardiac involvement is the strongest predictor of mortality. Moreover, treatment with tafamidis is safe and efficacious, irrespective of the underlying amyloidogenic TTR variant, especially when the medication is started at the earliest timepoint possible in stage 1 ATTRv-PN (PND score I). Continued studies at our centre according to a sensitive neurologic monitoring schedule [35] will provide further long-term real-world data on the therapeutic impact of tafamidis, now approved in two different dosages depending on cardiac manifestation, in relation to novel TTR gene silencing drugs in this mostly late-onset patient population.

Abbreviations
ATTRv amyloidosis	=	hereditary transthyretin amyloidosis
ATTRv-PN	=	hereditary transthyretin amyloidosis with polyneuropathy
CI	=	confidence interval
FAP	=	familial amyloid polyneuropathy
HGVS	=	Human Genome Variation Society
NIS	=	Neuropathy Impairment Score
NIS-LL	=	Neuropathy Impairment Score in the Lower Limbs
NT-proBNP	=	N-terminal prohormone of brain natriuretic peptide
PND	=	Peripheral Neuropathy Disability
qd	=	quaque die
TTR	=	transthyretin

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.