Impact of Non-Cardiac Clinicopathologic Characteristics on Survival in Transthyretin Amyloid Polyneuropathy

Hereditary (variant) transthyretin amyloidosis (ATTRv) is a rare autosomal dominant disease whereby mutations in the transthyretin (TTR) gene destabilize the protein’s native homeotetrameric structure and cause it to disassociate into amyloidogenic TTR monomers. As a result, insoluble amyloid fibrils accumulate in the peripheral and autonomic nerves, heart, gastrointestinal tract, kidneys, eyes, and connective tissues [1, 2]. Three phenotypes predominate in ATTRv amyloidosis: one is almost exclusively characterized by restrictive cardiomyopathy, another predominantly by polyneuropathy (ATTR-PN), and the third is a mixed phenotype [3‐5].

ATTR-PN prevalence has been estimated at approximately 10,000 to 40,000 persons globally, with endemic foci in Portugal, Sweden, and Japan [6, 7]. Notably, disease phenotypes and penetrance across these endemic areas and elsewhere are often different, even for the same genotype [8]. For example, inaugural symptoms of early-onset disease (< 50 years old) include spontaneous burning or sharp pain, non-painful sensations (paresthesia and restless leg syndrome), and/or autonomic symptoms (sexual dysfunction, impaired bladder function, constipation alternating with diarrhea, early satiety, orthostatic dizziness and syncope) associated with damaged distal small myelinated and unmyelinated nerve fibers [1]. Conversely, in late-onset disease, the combination of well-preserved unmyelinated nerve fibers and axonal sprouting is associated with impaired superficial and deep sensation, severe neuropathic pain, early distal motor involvement, but relatively mild autonomic symptoms at initial presentation [1, 9, 10]. Absent early intervention with liver transplantation (LTx) or disease-modifying pharmacological treatments, ATTR-PN symptoms generally follow an ascending, proximally-oriented pattern as patients experience progressive debilitating polyneuropathy and inexorable loss of motor and organ functions.

Among persons with the classic disease phenotype, death has been reported to occur within 10–15 years of symptom onset, often from cachexia and malnutrition due to gastrointestinal complications [11, 12]. Prognostic survival factors include cardiac dysautonomia [3] and the presence of a mutation other than the more common Val30Met (also referred to as p.Val50Me) tgenotype [11, 13]; both of which are associated with poorer survival.

Owing partly to its phenotypic heterogeneity but also to its rarity, our understanding of survival in ATTR-PN is limited and largely based on observations of persons with the Val30Met genotype. Furthermore, the progression of associated cardiac symptoms and their effects on survival have been the predominant focus in larger studies [14]. However, as our understanding has evolved to reflect a heterogeneous disease, so too should our understanding of how this heterogeneity affects survival. This systematic review and analysis were conducted to describe the impact of non-cardiac clinicopathologic factors on survival and to assess survival trends among ATTR-PN subgroups.

The relevant evidence was assessed in a two-step process consisting of a systematic literature review to identify relevant data and a descriptive synthesis of those data. The target disease population was limited to persons with ATTR-PN.

The electronic search of the peer-reviewed literature yielded 979 unique records, and the hand search of conference materials yielded 1014 records. In total, 1993 records were assessed in full, of which 35 were retained (Fig. 1; Table 1). These reported survival outcomes assessed over 265,346 person-years [N = 11,116; median follow-up 10 (range 5–35) years]. Most of the retained studies were of a longitudinal, observational design conducted between 1990 and 2007. Risk of bias was low, and evidentiary quality of the retained studies was moderate overall (Table 1).

Disaggregated survival data were analyzed with parametric mixture modeling to assess survival differences among patient groups defined by factors known to affect survival. The most pronounced survival difference (reported here and subsequently as mean years from symptom onset to death) was observed between LTx and non-LTx patients: 26.0 (95% CI 25.0–27.9) versus 12.0 (95% CI 11.2–13.0); difference 15.0 (95% CI 13.7–16.3) (Fig. 2). Also significant was the survival difference between early-onset versus late-onset patients: 24.7 (95% CI 23.4–26.0) versus 12.9 (95% CI 11.0–13.8); difference 11.8 (95% CI 10.1–13.4) (Fig. 3). Combining these factors demonstrated that LTx patients with early-onset disease had significantly longer survival than LTx patients with late-onset disease: 26.6 (95% CI 25.6–27.4) versus 13.1 (95% CI 11.6–14.7); difference 13.5 (95% CI 11.7–15.3) (Fig. 4). However, the same comparison among non-LTx patients yielded a non-significant difference (12.7 vs. 12.5).

A comparison between V30M genotype versus non-V30M genotype indicated longer survival for V30M (22.2 vs. 10.4), but the trend was not significant owing to limited observations for non-V30M patients.

Of the 35 retained studies, eight reported the outcomes of multivariate survival analysis (Table 2). Other than LTx status, the clinicopathologic survival factors identified as having a statistically significant impact on survival included sex/gender, pre-LTx disease duration, and symptoms of disease progression [e.g., modified body mass index (mBMI), serum albumin levels at the time of LTx, and the presence/absence of urinary incontinence at the time of LTx]. These observations indicated that female sex/gender, ≤ 7-year disease duration by the time of LTx, mBMI > 600, and a lack of urinary incontinence at LTx were all associated with improved survival versus matched comparisons.

This synthesis of published evidence illustrates the heterogenous nature of survival among persons with ATTR-PN and highlights a number of patient subgroups for whom survival differs from the commonly-cited 10–15 years—in some cases markedly less [52]. For non-LTx patients, heterogeneity was most evident among those with non-Val30Met genotypes for whom median survival was poorer compared to persons with the ATTRv Val30Met (6.3 vs. 12.1 years after onset). Furthermore, those who underwent LTx had better survival than those who were untreated (21.8 vs. 9.6 years). Evidence of the impact of disease-modifying pharmacological treatments was limited but demonstrated survival benefits of tafamidis versus no treatment and potentially versus LTx.

Aside from genotype and treatment experience, other baseline non-cardiac clinicopathologic characteristics associated with shorter survival included longer disease duration before LTx, late-onset disease, and lower mBMI. Given the previously known associations of many of the non-cardiac clinicopathologic survival factors identified in this study with baseline disease progression and the negative relationship between baseline disease progression and survival time [53], some of our findings are unsurprising. There were, however, notable studies demonstrating the impact of competing prognostic factors on survival. For example, at 20 years of follow-up after ATTRv Val30Met onset, Okamoto et al. [40] reported a non-significant effect of sex on survival at 15 years of follow-up after disease onset for those with early-onset disease (76 vs. 78%, p = 0.33); in contrast, when the same comparison was evaluated among LTx patients with late-onset disease, the difference was significant [69% (females) vs. 37% (males); p = 0.02]. The significant effect of sex in late-onset patients—who typically present with more advanced cardiac symptoms—despite no such finding in early-onset patients highlights intra-genotype survival differences that may be mitigated by sex and disease onset. Another example was reported by Adams et al. [19] who demonstrated that the survival benefits of LTx can be entirely negated by advanced disease progression at baseline, as indicated by a Norris score ≤ 55.

We also assessed the risk of bias and evidentiary quality of the records retained in this review and, notably, both were within acceptable limits overall. These metrics were largely based on the definitiveness of the ATTRv amyloidosis diagnosis (i.e., genetic and histological testing) and the transparency by which diagnoses were reported. Given that many of the retained records reported LTx cohorts and that histological and genetic testing are often required for LTx [25, 53], it follows that the records retained for this review would be scored highly.

This study has limitations which should be noted. First, in 1996 there began a more concerted, evidence-driven effort to optimize patient selection for LTx globally [40, 53]. LTx-associated survival benefits reported here may have been downwardly biased due to our having grouped data from patients who underwent LTx in pre- and post-1996 time periods, whereas survival after LTx in a contemporary treatment setting may be longer. This implies a related limitation: that due to lack of evidence it was not possible to control for patients having been at different stages of disease progression at the time of LTx or starting other treatments. Third, this study is limited to patients who received no treatment, underwent LTx, or received tafamidis due to these being the only ATTR-PN patients with long-term survival outcomes (i.e., ≥ 5 years). There are other treatments available or currently being evaluated to treat ATTR-PN, but there are as yet insufficient survival follow-up data on these treatments. Lastly, survival is only one outcome—albeit a critical one—for evaluating ATTR-PN disease progression, whereas progression of neuropathy would also have been an informative endpoint had sufficient evidence been available. Similarly, our survival analysis did not consider the implications of cardiac sequelae, which have been reported extensively in the literature and are important because our objective was to look at the impact of non-cardiac factors.

Notwithstanding the aforementioned limitations, this study evaluates survival in individual ATTR-PN subgroups for whom survival has often been imprecisely defined. Our estimates indicate that 10- to 15-year survival is an overly-optimistic assumption for many patients. Median survival for untreated patients with non-Val30Met genotypes is considerably worse than that for Val30Met disease, with survival approximately 6 years from symptom onset in the former and approximately 12 years in the latter. Conversely, the 10- to 15-year survival estimate that is commonly used may underestimate the benefits of definitive treatment with LTx or disease-modifying treatment with medications. Median survival may range from 14 to 25 years from symptom onset in treated patients, depending on the genotype of the disease and the extent of disease progression by the time treatment is started. Nevertheless, the evidence presented here demonstrates that ATTR-PN is quite heterogenous and, consequently, that our understanding of the prognosis of these patients should be similarly nuanced.