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

INTRODUCTION: Hereditary (variant) transthyretin amyloidosis (ATTRv) with polyneuropathy (ATTR-PN) is a rare genetic disorder that causes progressive autonomic and sensorimotor neuropathy, severe disability, and death within 10 years of onset. Previous studies have primarily focused on how baseline cardiac characteristics affect mortality, but the impact of non-cardiac baseline characteristics is less defined. METHODS: We systematically searched PubMed/Medline (1990-2019) to identify studies that assessed the impact of baseline ATTR-PN characteristics on survival. Outcomes were first summarized descriptively. Extracted survival data were then disaggregated, and parametric mixture models were used to assess survival differences among patient groups defined by factors known to affect survival. RESULTS: The search yielded 1193 records, of which 35 were retained for analysis. Median survival ranged from 0.5 to > 25 years. The largest survival differences were between cohorts who underwent liver transplantation (LTx) versus those who did not. Among LTx cohorts, pre-LTx ATTR-PN disease duration ≥ 7 years, poor nutritional status, and late disease onset reduced median survival by 13, 12, and 10 years, respectively. Other prognostic survival factors included non-Val30Met genotype and baseline presence of urinary incontinence, erectile dysfunction, or muscle weakness. CONCLUSION: Survival in patients with ATTR-PN is highly variable and affected by non-cardiac baseline characteristics, such as autonomic dysfunction, large fiber involvement, late-onset disease, and non-Val30Met mutation. Careful interpretation of these findings is warranted given that this synthesis did not control for differences between studies. Survival in patients with ATTR-PN remains poor among those who are untreated or with delayed diagnosis.

Epidemiological and clinical characteristics of symptomatic hereditary transthyretin amyloid polyneuropathy: a global case series.

We describe 542 cases of symptomatic hereditary transthyretin amyloid polyneuropathy (ATTR-PN) identified through a review of the literature published between 2005 and 2016. Approximately 18% of the cases were from countries where ATTR-PN is traditionally considered to be endemic (i.e., Portugal, Japan, and Sweden). East Asia (Japan, China, Taiwan, and South Korea) contributed a sizeable combined proportion (37.0%, n = 200) with Japan (n = 92) and China (n = 71) being the primary contributors. The most common genotypes among the 65 genotypes represented in the sample were Val30Met (47.6%), Ser77Tyr (10%), Ala97Ser (6.5%), and Phe64Leu (4.4%). Cases with genotypes other than the aforementioned four had the lowest ages at onset (mean 49.2 [standard deviation {SD} 21.0; inter-quartile range {IQR}14.7]) and diagnosis (mean 53.4 [SD 21.0; IQR 14.7]). Conversely, Phe64Leu mean age of onset was 67.5 (SD 8.8; IQR 5.2) and mean age of diagnosis was 71.3 (SD 8.8; IQR 5.4). The prevalence of upper and lower limb involvement at the time of diagnosis (67 and 41%) observed across all cases is consistent with the typical presentation of ATTR-PN. Other notable findings at the time of diagnosis included a high rate of impotence among the Ala97Ser cases versus all others (67% vs. 21%) and a high rate of non-motor visual symptoms (i.e., visual opacities and glaucoma) in the Ser77Tyr cases versus all others (93% vs. 16%). Though comparisons were made descriptively and were hindered by inconsistency of reporting across the cases, these findings support the notion that ATTR-PN is a more phenotypically and geographically variable disease than is typically considered.

Economic Burden of Atopic Dermatitis in High-Risk Infants Receiving Cow's Milk or Partially Hydrolyzed 100% Whey-Based Formula.

OBJECTIVE: To estimate the health and economic impact of feeding partially hydrolyzed formula-whey (PHF-W) instead of standard cow's milk formula (CMF) for the first 4 months of life among US infants at high risk for developing atopic dermatitis (AD). STUDY DESIGN: A Markov model was developed integrating published data, a survey of US pediatricians, costing sources and market data, and expert opinion. Key modeled outcomes included reduction in AD risk, time spent post AD diagnosis, days without AD flare, and AD-related costs. Costs and clinical consequences were discounted at 3% annually. RESULTS: An estimated absolute 14-percentage point reduction in AD risk was calculated with the use of PHF-W compared with CMF (95% CI for difference, 3%-22%). Relative to CMF, PHF-W decreased the time spent post-AD diagnosis by 8.3 months (95% CI, 2.78-13.31) per child and increased days without AD flare by 39 days (95% CI, 13-63) per child. The AD-related, 6-year total cost estimate was $495 less (95% CI, -$813 to -$157) per child with PHF-W ($724 per child; 95% CI, $385-$1269) compared with CMF ($1219 per child; 95% CI, $741-$1824). CONCLUSION: Utilization of PHF-W in place of CMF as the initial infant formula administered to high-risk US infants not exclusively breastfed during the first 4 months of life may reduce the incidence and economic burden of AD. Broad implementation of this strategy could result in a minimum savings of $355 million per year to society.

Patterns of clinical management of atopic dermatitis in infants and toddlers: a survey of three physician specialties in the United States.

OBJECTIVE: To describe atopic dermatitis (AD) management patterns in children ≤36 months old as reported by pediatricians, dermatologists, and allergists in the US. STUDY DESIGN: A nationally-representative survey was administered to pediatricians (n = 101), dermatologists (n = 26), and allergists (n = 26). Main outcomes included referrals to health care professionals, suggested/ordered laboratory tests, management approach (dietary, pharmacologic, or combination of both) by age, AD location, and severity. RESULTS: Significant differences were observed in referrals to healthcare professionals (P < .001). Pediatricians more frequently referred to dermatologists than allergists in mild (52.4% vs 32.0%) and moderate/severe (60.6% vs 38.1%) cases. Dermatologists referred to allergists less frequently for mild (9.1%) than moderate/severe (40.7%) AD cases. Pediatricians (59%), allergists (61.5%), and dermatologists (26.9%) reported treating at least some of their patients with AD with dietary management (infant formula change) alone (with or without emollients). Soy-based formulas were often used. For mild AD, the most commonly reported first-line pharmacologic treatments included topical emollients, topical corticosteroids, and barrier repair topical therapy/medical devices. Over 80% of physicians used a dietary and pharmacologic combination approach. Dermatologists were most likely to manage AD symptoms with a pharmacologic-only approach. AD lesion location influenced pharmacologic treatment in >80% of physicians. CONCLUSIONS: Significant and distinct differences in AD treatment approach exist among physicians surveyed. Most pediatricians and allergists use formula change as a management strategy in some patients, whereas dermatologists favor a pharmacologic approach. This diversity may result from inadequate evidence for a standard approach. Consistent methods for managing AD are needed.