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      Early intervention with tafamidis provides long-term (5.5-year) delay of neurologic progression in transthyretin hereditary amyloid polyneuropathy

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          Abstract

          Transthyretin hereditary amyloid polyneuropathy, also traditionally known as transthyretin familial amyloid polyneuropathy (ATTR-FAP), is a rare, relentless, fatal hereditary disorder. Tafamidis, an oral, non-NSAID, highly specific transthyretin stabilizer, demonstrated safety and efficacy in slowing neuropathy progression in early-stage ATTRV30M-FAP in a 1.5-year, randomized, double-blind, placebo-controlled trial, and 1-year open-label extension study, with a second long-term open-label extension study ongoing. Subgroup analysis of the effectiveness of tafamidis in the pivotal study and its open-label extensions revealed a relatively cohesive cohort of patients with mild neuropathy (i.e. Neuropathy Impairment Score for Lower Limbs [NIS-LL] ≤ 10) at the start of active treatment. Early treatment with tafamidis for up to 5.5 years (≥1 dose of tafamidis meglumine 20 mg once daily during the original trial or after switching from placebo in its extension) resulted in sustained delay in neurologic progression and long-term preservation of nutritional status in this cohort. Mean (95% CI) changes from baseline in NIS-LL and mBMI were 5.3 (1.6, 9.1) points and −7.8 (−44.3, 28.8) kg/m 2 × g/L at 5.5 years, respectively. No new safety issues or side effects were identified. These data represent the longest prospective evaluation of tafamidis to date, confirm a favorable safety profile, and underscore the long-term benefits of early intervention with tafamidis.

          Trial Registration: ClincalTrials.gov Identifier: NCT00409175, NCT00791492, and NCT00925002.

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          Longitudinal assessment of diabetic polyneuropathy using a composite score in the Rochester Diabetic Neuropathy Study cohort.

          Because there are little satisfactory data on change in severity of diabetic polyneuropathy (DP) over time from study of population-based cohorts of diabetic patients in epidemiologic surveys of DP, it is difficult to predict outcome or morbidity or to identify risk factors; it is also difficult to estimate statistical power for use in controlled clinical trials. In this longitudinal study of almost 200 patients from the Rochester Diabetic Neuropathy Study (RDNS) cohort, we assess which symptoms, clinical examinations, tests, or combinations of examinations and tests (composite scores) are best used as minimal criteria for the diagnosis of DP and as a quantitative measure of severity of DP. An abnormality (> or = 97.5th percentile) of a composite score that included the Neuropathy Impairment Score of the lower limbs plus seven tests (NIS(LL)+7 tests), was a better minimal criteria for DP than clinical judgment alone or previously published minimal criteria. First, it provided a more comprehensive assessment of neuropathic impairment. Second, it avoided the overestimated frequency of DP when the minimal criteria for DP was any one or two abnormalities from multiple measurements. Minimal criteria using nerve conduction and reduced heart beat response to deep breathing identified approximately twice as many patients with DP than did clinical examination and vibration detection threshold using CASE IV. This difference could be used to subclassify state 1 DP. Although various individual measures of DP, for example, vibration detection threshold (as evaluated by CASE IV and the 4, 2, and 1 stepping algorithm [see text]), were good measures of worsening, the composite score NIS(LL)+7 tests (assessing neuropathic impairment) was much better at showing monotone worsening. Using this composite score, the average diabetic patient in the RDNS worsened by 0.34 points per year, whereas patients with diabetic polyneuropathy worsened by 0.85 points per year. On the assumption that a therapeutic agent may prevent worsening of DP but not cause improvement, controlled clinical trials of patients with DP would need to be conducted for a period of 3 years to achieve a meaningful change of 2 NIS points (the level of abnormality considered by a Peripheral Nerve Society consensus group to be clinically meaningful).
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            Malnutrition and gastrointestinal dysfunction as prognostic factors for survival in familial amyloidotic polyneuropathy.

            To describe the evolution of nutritional and neurological complications in a Swedish population of patients with familial amyloidotic polyneuropathy, and to identify prognostic factors and useful tests for monitoring the progress of the disease. Prospective and retrospective study of patients with familial amyloidotic polyneuropathy. Tertiary referral centre. Twenty-seven patients with familial amyloidotic polyneuropathy, and a symptomatic onset before the age of 50. Age at onset, duration of disease before death, serum albumin, body mass index (BMI), duration and grade of peripheral neuropathy and gastrointestinal disturbances. Faecal fat, xylose test and 75selenohomocholic acid-taurine (SeHCAT) test were used for assessment of malabsorption. Thirteen patients died during the study period after a disease duration of between 9 and 18 years (mean 13). A short time interval between the onset of neurological and of gastrointestinal symptoms had greater impact on survival than age at onset in this selected group of patients (r = 0.65; P = 0.017). Malnutrition was evaluated by multiplying the [body weight (kg)/height2 (m)] with the serum albumin to compensate for oedema. This modified body mass index (mBMI) was significantly correlated to the number of years before death (r = 0.89; P < 0.0005) and to the duration of gastrointestinal symptoms (r = -0.66; P < 0.0005), but not to duration of disease (r = -0.2; P = 0.20). Polyneuropathy was graded according to functional capacity from I to IV (PND score) and was correlated to the number of years before death and mBMI, but not to serum albumin. The SeHCAT test for bile acid malabsorption was significantly correlated to the duration of gastrointestinal symptoms and to mBMI (r = -0.67; P = 0.0003 and r = -0.62; P = 0.003, respectively). The investigation disclosed that a short time interval between the onset of neurological and of gastrointestinal symptoms is associated with a decreased survival time. The mBMI was closely related to time before death, duration of gastrointestinal disturbances, malabsorption and functional capacity. The mBMI appears to be well suited to monitoring disease progress and gives prognostic information.
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              Safety and efficacy of long-term diflunisal administration in hereditary transthyretin (ATTR) amyloidosis.

              A recent 2-year randomized controlled trial indicated that the transthyretin (TTR) tetramer stabilizer, diflunisal, inhibits polyneuropathy progression and preserves quality of life in hereditary ATTR amyloidosis. However, its long-term outcomes are unknown. Here, we report tolerance and efficacy of long-term diflunisal administration in hereditary ATTR amyloidosis.
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                Author and article information

                Journal
                Amyloid
                Amyloid
                IAMY
                iamy20
                Amyloid
                Taylor & Francis
                1350-6129
                1744-2818
                2 July 2016
                5 August 2016
                : 23
                : 3
                : 178-183
                Affiliations
                [ a ]Hospital Universitário Clementino Fraga Filho (HUCFF), Universidade Federal do Rio de Janeiro (UFRJ) , Rio de Janeiro, Brazil
                [ b ]Pfizer , New York, NY, USA
                [ c ]inVentiv Health Inc. , Burlington, MA, USA
                Author notes
                Address for correspondence: Márcia Waddington Cruz, Hospital Universitário Clementino Fraga Filho, Federal University of Rio de Janeiro , Ilha do Fundao, Rio de Janeiro, CEP21941-913, Brazil. Tel: +55 21 2568 9166. E-mail: mwaddingtoncruz@ 123456gmail.com
                Article
                1207163
                10.1080/13506129.2016.1207163
                5359776
                27494299
                e338eae0-4e9c-45a5-b6ed-f513100ae5e7
                © 2016 Pfizer Inc. Published by Informa UK Limited, trading as Taylor & Francis Group.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License ( http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.

                History
                : 27 January 2016
                : 20 June 2016
                : 26 June 2016
                Page count
                Pages: 7
                Categories
                Article
                Original Article

                Neurosciences
                amyloidosis,attrv30m,disease modification,transthyretin amyloidosis,ttr val30met
                Neurosciences
                amyloidosis, attrv30m, disease modification, transthyretin amyloidosis, ttr val30met

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