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  • 1. Adams, David
    et al.
    Polydefkis, Michael
    Gonzalez-Duarte, Alejandra
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Kristen, Arnt, V
    Schmidt, Hartmut H.
    Berk, John L.
    Losada Lopez, Ines Asuncion
    Dispenzieri, Angela
    Quan, Dianna
    Conceicao, Isabel M.
    Slama, Michel S.
    Gillmore, Julian D.
    Kyriakides, Theodoros
    Ajroud-Driss, Senda
    Waddington-Cruz, Marcia
    Mezei, Michelle M.
    Plante-Bordeneuve, Violaine
    Attarian, Shahram
    Mauricio, Elizabeth
    Brannagan, Thomas H., III
    Ueda, Mitsuharu
    Aldinc, Emre
    Wang, Jing Jing
    White, Matthew T.
    Vest, John
    Berber, Erhan
    Sweetser, Marianne T.
    Coelho, Teresa
    Pedrosa-Domellöf, Fatima
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Long-term safety and efficacy of patisiran for hereditary transthyretin-mediated amyloidosis with polyneuropathy: 12-month results of an open-label extension study2021In: Lancet Neurology, ISSN 1474-4422, E-ISSN 1474-4465, Vol. 20, no 1, p. 49-59Article in journal (Refereed)
    Abstract [en]

    Background Hereditary transthyretin-mediated amyloidosis is a rare, inherited, progressive disease caused by mutations in the transthyretin (TTR) gene. We assessed the safety and efficacy of long-term treatment with patisiran, an RNA interference therapeutic that inhibits TTR production, in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. Methods This multicentre, open-label extension (OLE) trial enrolled patients at 43 hospitals or clinical centres in 19 countries as of Sept 24, 2018. Patients were eligible if they had completed the phase 3 APOLLO or phase 2 OLE parent studies and tolerated the study drug. Eligible patients from APOLLO (patisiran and placebo groups) and the phase 2 OLE (patisiran group) studies enrolled in this global OLE trial and received patisiran 0.3 mg/kg by intravenous infusion every 3 weeks with plans to continue to do so for up to 5 years. Efficacy assessments included measures of polyneuropathy (modified Neuropathy Impairment Score +7 [mNIS+7]), quality of life, autonomic symptoms, nutritional status, disability, ambulation status, motor function, and cardiac stress, with analysis by study groups (APOLLO-placebo, APOLLO-patisiran, phase 2 OLE patisiran) based on allocation in the parent trial. The global OLE is ongoing with no new enrolment, and current findings are based on the interim analysis of the patients who had completed 12-month efficacy assessments as of the data cutoff. Safety analyses included all patients who received one or more dose of patisiran up to the data cutoff. This study is registered with ClinicalTrials.gov, NCT02510261. Findings Between July 13, 2015, and Aug 21, 2017, of 212 eligible patients, 211 were enrolled: 137 patients from the APOLLO-patisiran group, 49 from the APOLLO-placebo group, and 25 from the phase 2 OLE patisiran group. At the data cutoff on Sept 24, 2018, 126 (92%) of 137 patients from the APOLLO-patisiran group, 38 (78%) of 49 from the APOLLO-placebo group, and 25 (100%) of 25 from the phase 2 OLE patisiran group had completed 12-month assessments. At 12 months, improvements in mNIS+7 with patisiran were sustained from parent study baseline with treatment in the global OLE (APOLLO-patisiran mean change -4.0, 95 % CI -7.7 to -0.3; phase 2 OLE patisiran -4.7, -11.9 to 2.4). Mean mNIS+7 score improved from global OLE enrolment in the APOLLO-placebo group (mean change from global OLE enrolment -1.4, 95% CI -6.2 to 3.5). Overall, 204 (97%) of 211 patients reported adverse events, 82 (39%) reported serious adverse events, and there were 23 (11%) deaths. Serious adverse events were more frequent in the APOLLO-placebo group (28 [57%] of 49) than in the APOLLO-patisiran (48 [35%] of 137) or phase 2 OLE patisiran (six [24%] of 25) groups. The most common treatment-related adverse event was mild or moderate infusion-related reactions. The frequency of deaths in the global OLE was higher in the APOLLO-placebo group (13 [27%] of 49), who had a higher disease burden than the APOLLO-patisiran (ten [7%] of 137) and phase 2 OLE patisiran (0 of 25) groups. Interpretation In this interim 12-month analysis of the ongoing global OLE study, patisiran appeared to maintain efficacy with an acceptable safety profile in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. Continued long-term follow-up will be important for the overall assessment of safety and efficacy with patisiran. Copyright (C) 2020 Elsevier Ltd. All rights reserved.

  • 2.
    Anan, Intissar
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Bång, Joakim
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Lundgren, Hans-Erik
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Westermark, Per
    A case report of osteoarthritis associated with hereditary transthyretin amyloidosis ATTRV30M2019In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 26, p. 29-30Article in journal (Refereed)
  • 3.
    Anan, Intissar
    et al.
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Suhr, Ole B.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Liszewska, Katarzyna
    Department of Medicine, Piteå Hospital, Piteå, Sweden.
    Baranda, Jorge Mejia
    Department of Medicine, Piteå Hospital, Piteå, Sweden.
    Pilebro, Björn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Ihse, Elisabet
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Amyloid fibril composition type is consistent over time in patients with Val30Met (p. Val50Met) transthyretin amyloidosis2022In: PLOS ONE, E-ISSN 1932-6203, Vol. 17, no 3, article id e0266092Article in journal (Refereed)
    Abstract [en]

    Background: We have previously shown that transthyretin (TTR) amyloidosis patients have amyloid fibrils of either of two compositions; type A fibrils consisting of large amounts of C-terminal TTR fragments in addition to full-length TTR, or type B fibrils consisting of only full-length TTR. Since type A fibrils are associated with an older age in ATTRVal30Met (p.Val50Met) amyloidosis patients, it has been discussed if the TTR fragments are derived from degradation of the amyloid deposits as the patients are aging. The present study aimed to investigate if the fibril composition type changes over time, especially if type B fibrils can shift to type A fibrils as the disease progresses.

    Material and methods: Abdominal adipose tissue biopsies from 29 Swedish ATTRVal30Met amyloidosis patients were investigated. The fibril type in the patients initial biopsy taken for diagnostic purposes was compared to a biopsy taken several years later (ranging between 2 and 13 years). The fibril composition type was determined by western blot.

    Results: All 29 patients had the same fibril composition type in both the initial and the follow-up biopsy (8 type A and 21 type B). Even patients with a disease duration of more than 12 years and an age over 75 years at the time of the follow-up biopsy had type B fibrils in both biopsies.

    Discussion: The result clearly shows that the amyloid fibril composition containing large amounts of C-terminal fragments (fibril type A) is a consequence of other factors than a slow degradation process occurring over time.

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  • 4.
    Barroso, Fabio A.
    et al.
    Institute for Neurological Research, FLENI, Buenos Aires, Argentina.
    Coelho, Teresa
    Unidade Corino Andrade, Hospital Santo António, Centro Hospitalar Universitário do Porto, Porto, Portugal.
    Dispenzieri, Angela
    Division of Hematology, Mayo Clinic, MN, Rochester, United States.
    Conceição, Isabel
    Hospital de Santa Maria–CHULN, FML Universidade de Lisboa, Lisbon, Portugal.
    Waddington-Cruz, Marcia
    CEPARM, University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Maurer, Mathew S.
    Columbia University College of Physicians and Surgeons, NY, New York, United States.
    Rapezzi, Claudio
    Cardiological Center, University of Ferrara, Ferrara, Italy; Maria Cecilia Hospital, GVM Care & Research, Cotignola (RA), Italy.
    Planté-Bordeneuve, Violaine
    Department of Neurology, East-Paris University, Hospital Henri Mondor, Assistance Publique Hopitaux de Paris, INSERM U955 Team 10 “Biology of the Neuro-Muscular System”, Crétei, France.
    Kristen, Arnt V.
    Department of Cardiology, Angiology, and Respiratory Medicine, Medical University of Heidelberg, Heidelberg, Germany.
    González-Duarte, Alejandra
    Instituto Nacional De Ciencias Medicas y Nutricion Salvador Zubiran, Mexico City, Mexico.
    Chapman, Doug
    Pfizer Inc, NY, New York, United States.
    Stewart, Michelle
    Pfizer Inc, CT, Groton, United States.
    Amass, Leslie
    Pfizer Inc, CT, Groton, United States.
    Characteristics of patients with autonomic dysfunction in the Transthyretin Amyloidosis Outcomes Survey (THAOS)2022In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 29, no 3, p. 175-183Article in journal (Refereed)
    Abstract [en]

    Background: Autonomic dysfunction is common in transthyretin amyloidosis (ATTR amyloidosis), but its frequency, characteristics, and quality-of-life (QoL) impact are not well understood.

    Methods: The Transthyretin Amyloidosis Outcomes Survey (THAOS) is an ongoing, global, longitudinal survey of patients with ATTR amyloidosis, including patients with inherited (ATTRv) and wild-type (ATTRwt) disease and asymptomatic patients with TTR mutations (ClinicalTrials.gov: NCT00628745). In a descriptive analysis, characteristics and Norfolk QoL-DN total (TQoL) scores at enrolment were compared in patients with vs without autonomic dysfunction (analysis cut-off: 1 August 2020).

    Results: Autonomic dysfunction occurred in 1181/2922 (40.4%) symptomatic patients, and more commonly in ATTRv (1107/1181 [93.7%]) than ATTRwt (74/1181 [6.3%]) amyloidosis. Time (mean [SD]) from ATTR amyloidosis symptom onset to first autonomic dysfunction symptom was shorter in ATTRv (3.4 [5.7] years) than ATTRwt disease (9.7 [10.4]). In ATTRv disease, patients with vs without autonomic dysfunction had worse QoL (TQoL, 47.3 [33.2] vs 16.1 [18.1]); in ATTRwt disease, those with vs without autonomic dysfunction had similar QoL (23.0 [18.2] vs 19.9 [20.5]).

    Conclusions: Autonomic dysfunction was more common and presented earlier in symptomatic ATTRv than ATTRwt amyloidosis and adversely affected QoL in ATTRv disease. These THAOS findings may aid clinicians in diagnosing and treating patients with ATTR amyloidosis.

    Trial registration: ClinicalTrials.gov: NCT00628745.

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  • 5.
    Caponetti, Angelo Giuseppe
    et al.
    Department of Experimental, Diagnostic, and Specialty Medicine, University of Bologna, Italy.
    Rapezzi, Claudio
    Cardiological Center, University of Ferrara, Ferrara, Italy; Maria Cecilia Hospital, GVM Care and Research, Cotignola, Emilia-Romagna, Italy.
    Gagliardi, Christian
    Department of Experimental, Diagnostic, and Specialty Medicine, University of Bologna, Italy.
    Milandri, Agnese
    Department of Cardiology, Bentivoglio Hospital, Bentivoglio, Bologna, Italy.
    Dispenzieri, Angela
    Division of Hematology, Mayo Clinic, MN, Rochester, United States.
    Kristen, Arnt V.
    Department of Cardiology, Angiology, Respiratory Medicine, Medical University of Heidelberg, Heidelberg, Germany.
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Maurer, Mathew S.
    Columbia University College of Physicians and Surgeons, NY, New York, United States.
    Garcia-Pavia, Pablo
    Department of Cardiology, Hospital Universitario Puerta de Hierro Majadahonda, Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares, Madrid, Spain; Universidad Francisco de Vitoria, Pozuelo de Alarcon, Madrid, Spain.
    Tournev, Ivailo
    Clinic of Nervous Diseases, University Hospital Aleksandrovska, Sofia, Bulgaria; Department of Neurology, Medical University, Sofia, Bulgaria; Department of Cognitive Science and Psychology, New Bulgarian University, Sofia, Bulgaria.
    Planté-Bordeneuve, Violaine
    Department of Neurology- Amyloid Network-University Hospital Henri Mondor-Assistance Publique Hopitaux de Paris, IMRB INSERM U955 Team 10 “Biology of the Neuro-Muscular System”, Créteil, France.
    Chapman, Douglass
    Pfizer, NY, New York, United States.
    Amass, Leslie
    Pfizer, NY, New York, United States.
    Sex-Related Risk of Cardiac Involvement in Hereditary Transthyretin Amyloidosis: Insights From THAOS2021In: JACC. Heart failure, ISSN 2213-1779, E-ISSN 2213-1787, Vol. 9, no 10, p. 736-746Article in journal (Refereed)
    Abstract [en]

    Objectives: Because patients with ATTRv cardiomyopathy are more likely to be male, this analysis aimed to increase information on associations between sex and genotype, phenotype, and degree of myocardial involvement in ATTRv amyloidosis.

    Background: Transthyretin amyloid cardiomyopathy is a progressive, fatal disease that occurs due to accumulation of wild-type or variant (ATTRv) transthyretin amyloid fibrils in the myocardium.

    Methods: The Transthyretin Amyloidosis Outcomes Survey (THAOS) is an ongoing global longitudinal observational survey of patients with ATTR amyloidosis and asymptomatic carriers with TTR mutations. Data from THAOS (data cutoff: January 6, 2020) were analyzed to determine any sex-based differences in genotype, phenotype, and presence of cardiac and neurological symptoms in patients with ATTRv amyloidosis and in patients with ATTRv amyloidosis and cardiomyopathy.

    Results: There were 2,790 patients with ATTRv amyloidosis enrolled in THAOS, with male patients more likely to have symptoms of cardiac involvement and a cardiac phenotype. Male prevalence was greater in patients with more severe cardiac manifestations of disease, as assessed with N-terminal pro–B-type natriuretic peptide, left-ventricular (LV) ejection fraction, mean LV wall thickness divided by height, and LV mass index divided by height. Sex, age at disease onset, and genotype category were identified by multivariate analyses as risk factors for the development of cardiomyopathy (defined as increased LV septum thickness divided by height).

    Conclusions: In this analysis, myocardial involvement was more frequent and pronounced in male patients with ATTRv amyloidosis, suggesting that there may be biological characteristics that inhibit myocardial amyloid infiltration in females or facilitate it in males.

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  • 6.
    Coelho, Teresa
    et al.
    Unidade Corino Andrade, Centro Hospitalar Universitário de Santo António, Porto, Portugal.
    Dispenzieri, Angela
    Division of Hematology, Mayo Clinic, MN, Rochester, United States.
    Grogan, Martha
    Department of Cardiovascular Diseases, Mayo Clinic, MN, Rochester, United States.
    Conceição, Isabel
    CHULN-Hospital de Santa Maria, FML, Universidade de Lisboa, Lisbon, Portugal.
    Waddington-Cruz, Márcia
    National Amyloidosis Referral Center, CEPARM, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
    Kristen, Arnt V.
    Department of Cardiology, Angiology, Respiratory Medicine, Medical University of Heidelberg, Heidelberg, Germany.
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Diemberger, Igor
    Department of Medical and Surgical Sciences, DIMEC, University of Bologna, Bologna, Italy; Department of Cardiology, IRCCS Azienda Ospedaliero-Universitaria di Bologna Policlinico S Orsola-Malpighi, Bologna, Italy.
    Gonzalez-Moreno, Juan
    Hospital Son Llatzer, Palma de Mallorca, Spain.
    Maurer, Mathew S.
    Columbia University College of Physicians and Surgeons, NY, New York, United States.
    Planté-Bordeneuve, Violaine
    East Paris‐Créteil University, Hopital Henri Mondor, Assistance Publique‐Hopitaux de Paris, Créteil, France.
    Garcia-Pavia, Pablo
    Hospital Universitario Puerta de Hierro Majadahonda, CIBERCV, Madrid, Spain; Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
    Tournev, Ivailo
    Department of Neurology, Clinic of Nervous Diseases, UMBAL Aleksandrovska, Medical University‐Sofia, Sofia, Bulgaria; Department of Cognitive Science, New Bulgarian University, Sofia, Bulgaria.
    Gonzalez-Costello, Jose
    Hospital Universitari de Bellvitge, IDIBELL, CIBER-CV, Barcelona, Spain.
    Cariou, Eve
    Department of Cardiology, University Hospital Rangueil, Toulouse, France.
    González-Duarte, Alejandra
    NYU Langone School of Medicine, NY, New York, United States; Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.
    Glass, Oliver
    Pfizer Inc, NY, New York, United States.
    Chapman, Doug
    Pfizer Inc, NY, New York, United States.
    Amass, Leslie
    Pfizer Inc, NY, New York, United States.
    Patients with transthyretin amyloidosis enrolled in THAOS between 2018 and 2021 continue to experience substantial diagnostic delay2023In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 30, no 4, p. 445-448Article in journal (Refereed)
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  • 7.
    Coelho, Teresa
    et al.
    Centro Hospitalar Universitário de Santo António, Porto, Portugal.
    Marques, Wilson
    Hospital das Clínicas, Faculdade de Medicina de Ribeirão Preto, Ribeirão Preto, Brazil.
    Dasgupta, Noel R.
    Indiana University, School of Medicine, Indianapolis, United States.
    Chao, Chi-Chao
    National Taiwan University Hospital, Taipei, Taiwan.
    Parman, Yeşim
    Istanbul Universitesi-Istanbul Tip Fakültesi, Istanbul, Turkey.
    França, Marcondes Cavalcante
    Universidade Estadual de Campinas, Campinas, São Paulo, Brazil.
    Guo, Yuh-Cherng
    China Medical University Hospital, Taichung, Taiwan.
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Ro, Long-Sun
    Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan.
    Calandra, Cristian R.
    Hospital El Cruce, Buenos Aires, Argentina.
    Kowacs, Pedro A.
    Instituto de Neurologia de Curitiba, Paraná, Curitiba, Brazil.
    Berk, John L.
    Boston University School of Medicine, MA, Boston, United States.
    Obici, Laura
    Amyloidosis Research and Treatment Centre, IRCCS, Fondazione Policlinico San Matteo, Pavia, Italy.
    Barroso, Fabio A.
    Neurology Department, Fleni, Buenos Aires, Argentina.
    Weiler, Markus
    Amyloidosis Center and Department of Neurology, Heidelberg University Hospital, Heidelberg, Germany.
    Conceição, Isabel
    Centro Hospitalar Universitário Lisboa-Norte, Hospital de Santa Maria, Lisbon, Portugal.
    Jung, Shiangtung W.
    Ionis Pharmaceuticals Inc, CA, Carlsbad, United States.
    Buchele, Gustavo
    Ionis Pharmaceuticals Inc, CA, Carlsbad, United States.
    Brambatti, Michela
    Ionis Pharmaceuticals Inc, CA, Carlsbad, United States.
    Chen, Jersey
    Late-Stage Development Cardiovascular, Renal, and Metabolism, BioPharmaceuticals R&D, AstraZeneca, MD, Gaithersburg, United States.
    Hughes, Steven G.
    Ionis Pharmaceuticals Inc, CA, Carlsbad, United States.
    Schneider, Eugene
    Ionis Pharmaceuticals Inc, CA, Carlsbad, United States.
    Viney, Nicholas J.
    Ionis Pharmaceuticals Inc, CA, Carlsbad, United States.
    Masri, Ahmad
    OHSU, Center for Hypertrophic Cardiomyopathy and Amyloidosis, OR, Portland, United States.
    Gertz, Morie R.
    Mayo Clinic, MN, Rochester, United States.
    Ando, Yukio
    Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
    Gillmore, Julian D.
    National Amyloidosis Centre, University College London, London, United Kingdom.
    Khella, Sami
    University of Pennsylvania, School of Medicine, Philadelphia, United States.
    Dyck, P. James B.
    Mayo Clinic, MN, Rochester, United States.
    Waddington Cruz, Márcia
    Hospital Universitário Clementino Fraga Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
    Eplontersen for Hereditary Transthyretin Amyloidosis with Polyneuropathy2023In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 330, no 15, p. 1448-1458Article in journal (Refereed)
    Abstract [en]

    Importance: Transthyretin gene silencing is an emerging treatment strategy for hereditary transthyretin (ATTRv) amyloidosis.

    Objective: To evaluate eplontersen, an investigational ligand-conjugated antisense oligonucleotide, in ATTRv polyneuropathy.

    Design, Setting, and Participants: NEURO-TTRansform was an open-label, single-group, phase 3 trial conducted at 40 sites across 15 countries (December 2019-April 2023) in 168 adults with Coutinho stage 1 or 2 ATTRv polyneuropathy, Neuropathy Impairment Score 10-130, and a documented TTR variant. Patients treated with placebo from NEURO-TTR (NCT01737398; March 2013-November 2017), an inotersen trial with similar eligibility criteria and end points, served as a historical placebo ("placebo") group.

    Interventions: Subcutaneous eplontersen (45 mg every 4 weeks; n = 144); a small reference group received subcutaneous inotersen (300 mg weekly; n = 24); subcutaneous placebo weekly (in NEURO-TTR; n = 60).

    Main Outcomes and Measures: Primary efficacy end points at week 65/66 were changes from baseline in serum transthyretin concentration, modified Neuropathy Impairment Score +7 (mNIS+7) composite score (scoring range, -22.3 to 346.3; higher scores indicate poorer function), and Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QoL-DN) total score (scoring range, -4 to 136; higher scores indicate poorer quality of life). Analyses of efficacy end points were based on a mixed-effects model with repeated measures adjusted by propensity score weights.

    Results: Among 144 eplontersen-treated patients (mean age, 53.0 years; 69% male), 136 (94.4%) completed week-66 follow-up; among 60 placebo patients (mean age, 59.5 years; 68% male), 52 (86.7%) completed week-66 follow-up. At week 65, adjusted mean percentage reduction in serum transthyretin was -81.7% with eplontersen and -11.2% with placebo (difference, -70.4% [95% CI, -75.2% to -65.7%]; P <.001). Adjusted mean change from baseline to week 66 was lower (better) with eplontersen vs placebo for mNIS+7 composite score (0.3 vs 25.1; difference, -24.8 [95% CI, -31.0 to -18.6; P <.001) and for Norfolk QoL-DN (-5.5 vs 14.2; difference, -19.7 [95% CI, -25.6 to -13.8]; P <.001). Adverse events by week 66 that led to study drug discontinuation occurred in 6 patients (4%) in the eplontersen group vs 2 (3%) in the placebo group. Through week 66, there were 2 deaths in the eplontersen group consistent with known disease-related sequelae (cardiac arrhythmia; intracerebral hemorrhage); there were no deaths in the placebo group.

    Conclusions and Relevance: In patients with ATTRv polyneuropathy, the eplontersen treatment group demonstrated changes consistent with significantly lowered serum transthyretin concentration, less neuropathy impairment, and better quality of life compared with a historical placebo.

    Trial Registration: ClinicalTrials.gov Identifier: NCT04136184; EU Clinical Trials Register: EudraCT 2019-001698-10.

  • 8.
    Coelho, Teresa
    et al.
    Centro Hospitalar Universitário do Porto, Porto, Portugal.
    Waddington Cruz, Márcia
    Hospital Universitário Clementino Fraga Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
    Chao, Chi-Chao
    National Taiwan University Hospital, Taipei, Taiwan.
    Parman, Yeşim
    İstanbul Üniversitesi—Istanbul Tıp Fakültesi, Istanbul, Turkey.
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Weiler, Markus
    Amyloidosis Center and Department of Neurology, Heidelberg University Hospital, Heidelberg, Germany.
    Barroso, Fabio A.
    Neurology Department, Fleni, Buenos Aires, Argentina.
    Dasgupta, Noel R.
    Indiana University School of Medicine, IN, Indianapolis, United States.
    Jung, Shiangtung W.
    Ionis Pharmaceuticals, Inc., CA, Carlsbad, United States.
    Schneider, Eugene
    Ionis Pharmaceuticals, Inc., CA, Carlsbad, United States.
    Viney, Nicholas J.
    Ionis Pharmaceuticals, Inc., CA, Carlsbad, United States.
    Dyck, P. James B.
    Mayo Clinic, MN, Rochester, United States.
    Ando, Yukio
    Kumamoto University, Kumamoto, Japan.
    Gillmore, Julian D.
    Centre for Amyloidosis, University College London, London, United Kingdom.
    Khella, Sami
    Department of Neurology, University of Pennsylvania School of Medicine, PA, Philadelphia, United States.
    Gertz, Morie A.
    Division of Hematology, Mayo Clinic, MN, Rochester, United States.
    Obici, Laura
    Amyloidosis Research and Treatment Centre, IRCCS Fondazione Policlinico San Matteo, Pavia, Italy.
    Berk, John L.
    Amyloidosis Center, School of Medicine/Boston Medical Center, Boston University, 72 East Concord St., K503, MA, Boston, United States.
    Characteristics of Patients with Hereditary Transthyretin Amyloidosis-Polyneuropathy (ATTRv-PN) in NEURO-TTRansform, an Open-label Phase 3 Study of Eplontersen2023In: Neurology and Therapy, ISSN 2193-8253, Vol. 12, p. 267-287Article in journal (Refereed)
    Abstract [en]

    Introduction: Hereditary transthyretin (ATTRv) amyloidosis is a rare, severe, progressive, debilitating, and ultimately fatal disease caused by systemic deposition of transthyretin (TTR) amyloid fibrils. ATTRv amyloidosis occurs in both males and females. Eplontersen (ION-682884), a ligand-conjugated antisense oligonucleotide designed to degrade hepatic TTR mRNA, is being evaluated for the treatment of ATTRv amyloidosis with polyneuropathy (ATTRv-PN) in the phase 3, international, multicenter, open-label NEURO-TTRansform study (NCT04136184). To describe the study population of this pivotal trial, here we report the baseline characteristics of patients enrolled in the NEURO-TTRansform study.

    Methods: Patients eligible for NEURO-TTRansform were 18–82 years old with a diagnosis of ATTRv-PN and Coutinho stage 1 (ambulatory without assistance) or stage 2 (ambulatory with assistance) disease; documented TTR gene variant; signs and symptoms consistent with neuropathy associated with ATTRv; no prior liver transplant; and New York Heart Association (NYHA) functional class I or II.

    Results: The NEURO-TTRansform study enrolled 168 patients across 15 countries/territories (North America, 15.5%; Europe, 38.1%; South America/Australia/Asia, 46.4%). At baseline, the study cohort had a mean age of 52.8 years, 69.0% of patients were male, and 78.0% of patients were White. The V30M variant was most prevalent (60.1% of patients), and prevalence varied by region. Overall, 56.5% and 17.3% of patients had received previous treatment with tafamidis or diflunisal, respectively. A majority of patients (79.2%) had Coutinho stage 1 disease (unimpaired ambulation) and early (before age 50) disease onset (53.0%). Time from diagnosis to enrollment was 46.6 (57.4) months (mean [standard deviation]). Most patients had a baseline polyneuropathy disability (PND) score of I (40.5%) or II (41.1%), and the mean modified Neuropathy Impairment Score + 7 (mNIS + 7) was 79.0.

    Conclusion: The recruited population in the ongoing NEURO-TTRansform study has global representation characteristic of contemporary clinical practice. 

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  • 9.
    Damy, Thibaud
    et al.
    Department of Cardiology, Referral Center for Cardiac Amyloidosis, GRC Amyloid Research Institute, DHU A-TVB, APHP CHU Henri Mondor and Université Paris Est Créteil, Créteil, France.
    Conceição, Isabel
    Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal; Department of Neurosciences and Mental Health, CHULN-Hospital de Santa Maria, CHULN, Hospital de Santa Maria, Lisboa, Portugal.
    García-Pavía, Pablo
    Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro, CIBERCV, Madrid, Spain; Universidad Francisco de Vitoria (UFV), Pozuelo de Alarcon, Spain.
    Gillmore, Julian
    Division of Medicine, National Amyloidosis Centre, University College London, London, United Kingdom.
    Jandhyala, Ravi
    Medialis Ltd, Banbury, United Kingdom; Centre for Pharmaceutical Medicine Research, Institute of Pharmaceutical Science, Faculty of Life Science & Medicine, King’s College University, London, United Kingdom.
    Sabbat, Jan
    Akcea Therapeutics UK, Surrey, United Kingdom.
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Coelho, Teresa
    Andrade’s Center for Familial Amyloidosis, Porto, Portugal; Department of Neurosciences, Hospital de Santo António, Porto, Portugal.
    A simple core dataset and disease severity score for hereditary transthyretin (ATTRv) amyloidosis2021In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 28, no 3, p. 189-198Article in journal (Refereed)
    Abstract [en]

    Background: Hereditary transthyretin (ATTRv) amyloidosis is a progressive multisystemic disease of adult-onset that arises from an inherited mutation in the transthyretin gene. Currently available disease severity and progression evaluation tools only cover one single organ or system, impacting data collection uniformity and its use in clinical settings.

    Methods: The Jandhyala Method, including a systematic literature review and SMART interviews, was used to observe expert opinion from eight leaders in the treatment of ATTRv across Europe. The aim was to propose a multidisciplinary core dataset (CD) and disease severity scoring (DSS) tools.

    Results: The multidisciplinary team of experts identified 140 indicators that form part of the standard diagnostic and monitoring practice (SDMP) and should be collected as the ATTRv CD. Thirty-one (22%) of these indicators informed disease severity and com

    prised the ATTRv DSS, whilst 25 (18%) were deemed to monitor disease progression. Conclusions: The resulting CD and DSS have different purposes. The ATTRv CD supports the collection of high-quality data for clinical research, whereas the ATTRv DSS can be rapidly conducted in a clinical setting and aid patient management.

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  • 10.
    Dispenzieri, Angela
    et al.
    Division of Hematology, Mayo Clinic, MN, Rochester, United States.
    Coelho, Teresa
    Unidade Corino Andrade, Hospital Santo António, Centro Hospitalar Universitário do Porto, Porto, Portugal.
    Conceição, Isabel
    Department of Neurosciences, CHULN, Hospital de Santa Maria, Universidade de Lisboa, Lisbon, Portugal.
    Waddington-Cruz, Márcia
    University Hospital, Federal University of Rio de Janeiro, National Amyloidosis Referral Center, CEPARM, Rio de Janeiro, Brazil.
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Kristen, Arnt V.
    Department of Cardiology, Angiology, Respiratory Medicine, Medical University of Heidelberg, Heidelberg, Germany.
    Rapezzi, Claudio
    Cardiological Centre, University of Ferrara, Ferrara, Italy; Maria Cecilia Hospital, GVM Care & Research, Cotignola, Ravenna, Italy.
    Planté-Bordeneuve, Violaine
    Hôpital Henri Mondor – AP-HP, East Paris University, Créteil, France.
    Gonzalez-Moreno, Juan
    Servicio de Medicina Interna, Hospital Universitario Son Llatzer, Instituto de Investigación Sanitaria Illes Balears, Palma de Mallorca, Spain.
    Maurer, Mathew S.
    Columbia University College of Physicians and Surgeons, NY, New York, United States.
    Grogan, Martha
    Department of Cardiovascular Diseases, Mayo Clinic, MN, Rochester, United States.
    Chapman, Doug
    Pfizer Inc, NY, New York, United States.
    Amass, Leslie
    Pfizer Inc, NY, New York, United States.
    Pavia, Pablo Garcia
    Hospital Universitario Puerta de Hierro, Majadahonda, Spain.
    Tarnev, Ivaylo
    Alexandrovska University Hospital Clinic of Neurology, Sofia, Bulgaria.
    Costello, Jose Gonzalez
    Hospital Universitari de Bellvitge, Barcelona, Spain.
    Briseno, Maria Alejandra Gonzalez Duarte
    Instituto Nacional de Ciencia Medicas y Nutricion Salvador Zubiran, Distrito Federal, Mexico.
    Schmidt, Hartmut
    Universitatsklinikum Muenster – Transplant Hepatology, Muenster, Germany.
    Drachman, Brian
    University of Pennsylvania – Perelman Center for Advanced Medicine, PA, Philadelphia, United States.
    Barroso, Fabio Adrian
    FLENI, Ciudad Autonoma de Buenos Aires, Argentina.
    Yamashita, Taro
    Kumamoto University, Kumamoto-City, Japan.
    Lairez, Olivier
    CHU de Toulouse – Hôpital Rangueil, Toulouse, France.
    Sekijima, Yoshiki
    Shinshu University School of Medicine, Matsumoto, Japan.
    Vita, Giuseppe
    AOU Policlinico G. Martino – Messina – Dr. Vita, Messina, Italy.
    Jeon, Eun-Seok
    Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
    Hanna, Mazen
    Cleveland Clinic Foundation, OH, Cleveland, United States.
    Slosky, David
    Vanderbilt University School of Medicine, TN, Nashville, United States.
    Luigetti, Marco
    Fondazione Policlinico Gemelli, Universita Cattolica del Sacro Cuore, Rome, Italy.
    LoRusso, Samantha
    The Ohio University College of Medicine, OH, Columbus, United States.
    Beamud, Francisco Munoz
    Hospital Juan Ramon Jimenez, Huelva, Spain.
    Adams, David
    CHU de Bicêtre, Paris, France.
    Moelgaard, Henning
    Aarhus University Hospital, Skejby, Aarhus, Denmark.
    Press, Rayomand
    Karolinska University Hospital, Stockholm, Sweden.
    Cirami, Calogero Lino
    Azienda Ospedaliero-Universitaria Di Careggi, Florence, Italy.
    Nienhuis, Hans
    University Medical Center Groningen, Groningen, Netherlands.
    Plana, Josep Maria Campistol
    Institut Clinic de Nefrologia i Urologia – ICNU, Hospital Clinic i Provincial de Barcelona, Barcelona, Spain.
    Inamo, Jocelyn
    CHU de Fort-de-France, Fort-de-France, France.
    Jacoby, Daniel
    Smilow Cancer Hospital at Yale-New Haven, CT, New Haven, United States.
    Emdin, Michele
    Fondazione Toscana Gabriele Monasterio Per La Ricerca Medica E Di Sanita Pubblica, Pisa, Italy.
    Quan, Dianna
    UC Denver, CO, Aurora, United States.
    Hummel, Scott
    University of Michigan, MI, Ann Arbor, United States.
    Witteles, Ronald
    Stanford University School of Medicine, CA, Stanford, United States.
    Dori, Amir
    Sheba Medical Center, Ramat Gan, Israel.
    Shah, Sanjiv
    Northwestern University, IL, Chicago, United States.
    Lenihan, Daniel
    Washington University School of Medicine, WA, St. Louis, United States.
    Azevedo, Olga
    Centro Hospitalar Do Alto Ave, Epe, Guimaraes, Portugal.
    Murali, Srinivas
    Wexford Health and Wellness Pavillion, PA, Pittsburgh, United States.
    Zivkovic, Sasa
    University of Pittsburgh Medical Center (UPMC), PA, Pittsburgh, United States; University of Pittsburgh Medical Center (UPMC), Pittsburgh, United States.
    Low, Soon Chai
    University Malaya Medical Centre (UMMC), Kuala Lumpur, Malaysia.
    Nativi-Nicolau, Jose
    The University of Utah Health Sciences Center, UT, Salt Lake City, United States.
    Fine, Nowell
    University of Alberta Foothills Medical Centre, AB, Calgary, Canada.
    Tallaj, Jose
    University of Alabama at Birmingham, AL, Birmingham, United States.
    Tschoepe, Carsten
    Charité Campus Rudolf-Virchow-Klinikum, Berlin, Germany.
    Torrón, Roberto Fernandéz
    Hospital Universitario Donostia, Gipuzkoa, San Sebastian, Spain.
    Polydefkis, Michael
    Johns Hopkins Hospital, MD, Baltimore, United States.
    Merlini, Giampaolo
    Centro per lo Studio e la Cura delle Amiloidosi Sistemiche, Pavia, Italy.
    Badelita, Sorina
    Institutul de Cardiologie Prof. Dr. C. C. Iliescu Spitalului Fundeni, Bucharest, Romania.
    Gottlieb, Stephen
    University of Maryland, MD, Baltimore, United States.
    Tauras, James
    Montefiore Medical Center-Jack D. Weiler Hospital, NY, Bronx, United States.
    Correia, Edileide Barros
    Instituto Dante Pazzanese De Cardiologia, Sao Paulo, Brazil.
    Ventura, Hector
    John Ochsner Heart & Vascular Institute, LA, New Orleans, United States.
    Gess, Burkhard
    University Hospital of RWTH Aachen, Aachen, Germany.
    Darstein, Felix
    Johann-Gutenberg-Universität, Mainz, Germany.
    Oh, Jeeyoung
    Konkuk University Medical Center, Seoul, South Korea.
    Marburger, Tessa
    Oregon Health and Science University, OR, Portland, United States.
    Van Cleemput, Johan
    Afdeling Klinische Cardiologie, O&N I, Louvain, Belgium.
    Salutto, Valeria Lujan
    Instituto De Investigaciones Medicas Dr Alfredo Lanari, Buenos Aires, Argentina.
    Parman, Yesim
    Department of Neurology, Istanbul University, Istanbul, Turkey.
    Chao, Chi-Chao
    National Taiwan University Hospital, Taipei, Taiwan.
    Sarswat, Nitasha
    University of Chicago Medical Center, IL, Chicago, United States.
    Mueller, Christopher
    Medical College of Wisconsin, WI, Milwaukee, United States.
    Steidley, David
    Mayo Clinic Arizona, AZ, Phoenix, United States.
    Ralph, Jeffrey
    Department of Neurology, University of CA – San Francisco, CA, San Francisco, United States.
    Warner, Alberta
    VA Greater Los Angeles Healthcare System, CA, Los Angeles, United States.
    Cotts, William
    Advocate Christ Medical Centre, IL, Oak Lawn, United States.
    Hoffman, James
    University of Miami Hospital & Clinics, FL, Miami, United States.
    Rugiero, Marcelo
    Hospital Italiano de Buenos Aires (HIBA), Buenos Aires, Argentina.
    Misawa, Sonoko
    Chiba University Hospital, Chiba-shi, Japan.
    Blanco, Jose Luis Munoz
    Hospital Gregorio Marañón, Madrid, Spain.
    Davila, Lucia Galan
    Hospital Clinico San Carlos, Madrid, Spain.
    Sadeh, Menachem
    Wolfson Medical Center, Holon, Israel.
    Luo, Jin
    Temple University School of Medicine, PA, Philadelphia, United States.
    Kyriakides, Theodoros
    Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
    Wang, Annabel
    University of California Irvine, CA, Orange, United States.
    Kaufmann, Horacio
    NYU Medical Center, NY, New York, United States.
    Clinical and genetic profile of patients enrolled in the Transthyretin Amyloidosis Outcomes Survey (THAOS): 14-year update2022In: Orphanet Journal of Rare Diseases, E-ISSN 1750-1172, Vol. 17, no 1, article id 236Article in journal (Refereed)
    Abstract [en]

    Background: Transthyretin amyloidosis (ATTR amyloidosis) is a rare, life-threatening disease caused by the accumulation of variant or wild-type (ATTRwt amyloidosis) transthyretin amyloid fibrils in the heart, peripheral nerves, and other tissues and organs.

    Methods: Established in 2007, the Transthyretin Amyloidosis Outcomes Survey (THAOS) is the largest ongoing, global, longitudinal observational study of patients with ATTR amyloidosis, including both inherited and wild-type disease, and asymptomatic carriers of pathogenic TTR mutations. This descriptive analysis examines baseline characteristics of symptomatic patients and asymptomatic gene carriers enrolled in THAOS since its inception in 2007 (data cutoff: August 1, 2021).

    Results: This analysis included 3779 symptomatic patients and 1830 asymptomatic gene carriers. Symptomatic patients were predominantly male (71.4%) and had a mean (standard deviation [SD]) age of symptom onset of 56.3 (17.8) years. Val30Met was the most common genotype in symptomatic patients in South America (80.9%), Europe (55.4%), and Asia (50.5%), and more patients had early- versus late-onset disease in these regions. The majority of symptomatic patients in North America (58.8%) had ATTRwt amyloidosis. The overall distribution of phenotypes in symptomatic patients was predominantly cardiac (40.7%), predominantly neurologic (40.1%), mixed (16.6%), and no phenotype (2.5%). In asymptomatic gene carriers, mean (SD) age at enrollment was 42.4 (15.7) years, 42.4% were male, and 73.2% carried the Val30Met mutation.

    Conclusions: This 14-year global overview of THAOS in over 5000 patients represents the largest analysis of ATTR amyloidosis to date and highlights the genotypic and phenotypic heterogeneity of the disease.

    ClinicalTrials.gov Identifier: NCT00628745.

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  • 11.
    Gentile, Luca
    et al.
    University of Messina, Messina, Italy.
    Coelho, Teresa
    Unidade Corino Andrade, Centro Hospitalar Universitário de Santo António, Porto, Portugal.
    Dispenzieri, Angela
    Division of Hematology, Mayo Clinic, MN, Rochester, United States.
    Conceição, Isabel
    CHULN- Hospital de Santa Maria, FML, Universidade de Lisboa, Lisbon, Portugal.
    Waddington-Cruz, Márcia
    Federal University of Rio de Janeiro, National Amyloidosis Referral Center, CEPARM, Rio de Janeiro, Brazil.
    Kristen, Arnt
    Department of Cardiology, Angiology, Respiratory Medicine, Medical University of Heidelberg, Heidelberg, Germany.
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Diemberger, Igor
    Department of Medical and Surgical Sciences, DIMEC, University of Bologna, Bologna, Italy; Cardiology Unit, IRCCS Policlinico di S. Orsola, Bologna, Italy.
    Gonzalez-Moreno, Juan
    Hospital Son Llatzer, Palma de Mallorca, Spain.
    Cariou, Eve
    Department of Cardiology, University Hospital Rangueil, Toulouse, France.
    Maurer, Mathew S.
    Columbia University College of Physicians and Surgeons, NY, New York, United States.
    Planté-Bordeneuve, Violaine
    Hopital Henri Mondor, East Paris-Créteil University, Assistance Publique-Hopitaux de Paris, Créteil, France.
    Garcia-Pavia, Pablo
    Hospital Universitario Puerta de Hierro Majadahonda, CIBERCV, Madrid, Spain; Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
    Tournev, Ivailo
    Clinic of Nervous Diseases, Department of Neurology, UMBAL Aleksandrovska, Medical University-Sofia, Sofia, Bulgaria; Department of Cognitive Science, New Bulgarian University, Sofia, Bulgaria.
    Gonzalez-Costello, Jose
    Hospital Universitari de Bellvitge, IDIBELL, CIBER-CV, Barcelona, Spain.
    Duarte, Alejandra Gonzalez
    NYU Langone School of Medicine, NY, New York, United States; Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.
    Grogan, Martha
    Department of Cardiovascular Diseases, Mayo Clinic, MN, Rochester, United States.
    Mazzeo, Anna
    University of Messina, Messina, Italy.
    Chapman, Doug
    Pfizer Inc, NY, New York, United States.
    Gupta, Pritam
    Pfizer Healthcare India Pvt Ltd, Chennai, India.
    Glass, Oliver
    Pfizer Inc, NY, New York, United States.
    Amass, Leslie
    Pfizer Inc, NY, New York, United States.
    A 15-year consolidated overview of data in over 6000 patients from the Transthyretin Amyloidosis Outcomes Survey (THAOS)2023In: Orphanet Journal of Rare Diseases, E-ISSN 1750-1172, Vol. 18, no 1, article id 350Article in journal (Refereed)
    Abstract [en]

    Background: Transthyretin amyloidosis (ATTR amyloidosis) is a progressive, multisystemic, life-threatening disease resulting from the deposition of variant or wild-type (ATTRwt amyloidosis) transthyretin amyloid fibrils in various tissues and organs.

    Methods: Established in 2007, the Transthyretin Amyloidosis Outcomes Survey (THAOS) is the largest ongoing, global, longitudinal, observational study of patients with ATTR amyloidosis, including both hereditary and wild-type disease, and asymptomatic carriers of pathogenic TTR mutations. This analysis describes the baseline characteristics of symptomatic patients and asymptomatic gene carriers enrolled in THAOS since its inception in 2007 (data cutoff: August 1, 2022), providing a consolidated overview of 15-year data from the THAOS registry.

    Results: This analysis included 4428 symptomatic patients and 1707 asymptomatic gene carriers. The majority of symptomatic patients were male (70.8%) with a mean (standard deviation [SD]) age at symptom onset of 56.6 (17.9) years. Compared with the 14-year analysis, V30M remained the most prevalent genotype in Europe (62.2%), South America (78.6%), and Japan (74.2%) and ATTRwt remained most common in North America (56.2%). Relative to the 14-year analysis, there was an increase of mixed phenotype (from 16.6 to 24.5%) and a reduction of predominantly cardiac phenotype (from 40.7 to 31.9%). The proportion of patients with predominantly neurologic phenotype remained stable (from 40.1 to 38.7%). Asymptomatic gene carriers were 58.5% female with a mean age at enrollment of 41.9 years (SD 15.5).

    Conclusions: This overview of > 6000 patients enrolled over 15 years in THAOS represents the largest registry analysis of ATTR amyloidosis to date and continues to emphasize the genotypic and phenotypic heterogeneity of the disease. Nearly a quarter of the symptomatic population within THAOS was mixed phenotype, underscoring the need for multidisciplinary management of ATTR amyloidosis.

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  • 12.
    González-Moreno, Juan
    et al.
    Servicio de Medicina Interna, Hospital Universitario Son Llatzer, Instituto de Investigación Sanitaria Illes Balears, Palma, Spain.
    Dispenzieri, Angela
    Division of Hematology, Mayo Clinic, MN, Rochester, United States.
    Grogan, Martha
    Department of Cardiovascular Diseases, Mayo Clinic, MN, Rochester, United States.
    Coelho, Teresa
    Unidade Corino Andrade, Hospital Santo António, Centro Hospitalar Universitário do Porto, Porto, Portugal.
    Tournev, Ivailo
    Department of Neurology, Clinic of Nervous Diseases, UMBAL Aleksandrovska, Medical University, Sofia, Bulgaria; Department of Cognitive Science, New Bulgarian University, Sofia, Bulgaria.
    Waddington-Cruz, Márcia
    National Amyloidosis Referral Center, CEPARM, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Diemberger, Igor
    Department of Medical and Surgical Sciences, DIMEC, University of Bologna, Bologna, Italy; UOC di Cardiologia, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Dipartimento Cardiotoraco-vascolare, via Massarenti 9, 40138, Bologna, Italy.
    Garcia-Pavia, Pablo
    Hospital Universitario Puerta de Hierro Majadahonda, IDIPHISA, CIBERCV, Madrid, Spain; Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
    Chapman, Doug
    Pfizer Inc, NY, New York, United States.
    Gupta, Pritam
    Pfizer Healthcare India Pvt. Ltd, Chennai, India.
    Glass, Oliver
    Pfizer Inc, NY, New York, United States.
    Amass, Leslie
    Pfizer Inc, NY, New York, United States.
    Clinical and genotype characteristics and symptom migration in patients with mixed phenotype transthyretin amyloidosis from the transthyretin amyloidosis outcomes survey2024In: Cardiology and Therapy, ISSN 2193-8261, Vol. 13, p. 117-135Article in journal (Refereed)
    Abstract [en]

    Introduction: Transthyretin amyloidosis (ATTR amyloidosis) is primarily associated with a cardiac or neurologic phenotype, but a mixed phenotype is increasingly described.

    Methods: This study describes the mixed phenotype cohort in the Transthyretin Amyloidosis Outcomes Survey (THAOS). THAOS is an ongoing, longitudinal, observational survey of patients with ATTR amyloidosis, including both hereditary (ATTRv) and wild-type disease, and asymptomatic carriers of pathogenic transthyretin variants. Baseline characteristics of patients with a mixed phenotype (at enrollment or reclassified during follow-up) are described (data cutoff: January 4, 2022).

    Results: Approximately one-third of symptomatic patients (n = 1185/3542; 33.5%) were classified at enrollment or follow-up as mixed phenotype (median age, 66.5 years). Of those, 344 (29.0%) were reclassified to mixed phenotype within a median 1–2 years of follow-up. Most patients with mixed phenotype had ATTRv amyloidosis (75.7%). The most frequent genotypes were V30M (38.9%) and wild type (24.3%). Conclusions: These THAOS data represent the largest analysis of a real-world mixed phenotype ATTR amyloidosis population to date and suggest that a mixed phenotype may be more prevalent than previously thought. Patients may also migrate from a primarily neurologic or cardiologic presentation to a mixed phenotype over time. These data reinforce the need for multidisciplinary evaluation at initial assessment and follow-up of all patients with ATTR amyloidosis.

    Trial Registration: ClinicalTrials.gov: NCT00628745.

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  • 13.
    Hellman, Urban
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Lång, Kenneth
    Department of Medicine, Piteå Hospital , Piteå , Sweden..
    Ihse, Elisabet
    Jonasson, Jenni
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Olsson, Malin
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Lundgren, Hans-Erik
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Pilebro, Björn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Westermark, Per
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Transthyretin Glu54Leu - an unknown mutation within the Swedish population associated with amyloid cardiomyopathy and a unique fibril type2019In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 79, no 6, p. 372-376Article in journal (Refereed)
    Abstract [en]

    For the first time, we report of a Swedish family of five individuals with a TTR Glu54Leu (p. Glu74Leu) mutation in the transthyretin gene. This mutation has been previously described a few times in the literature, but no phenotypic or clinical description has been done before. The most common mutation in the Swedish population is TTRVal30Met and is mostly found in the Northern part of Sweden. Interestingly, the TTRGlu54Leu mutation was found in the same endemic area. The main phenotype of the TTR Glu54Leu patients is severe cardiomyopathy, which resulted in heart transplantation for the index person. As previously seen for ATTR amyloidosis patients with mainly cardiomyopathy, the amyloid fibrils consisted of a mixture of full-length and fragmented TTR species. However, western blot analyses detected a previously unrecognized band, indicating that these patients may have a third, so far unrecognized, fibril composition type that is distinct from the usual type A band pattern.

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  • 14.
    Lindmark, Krister
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Pilebro, Björn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Solekrans, L.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Suhr, Ole B.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Lindqvist, Per
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology.
    Prevalence of transthyretin cardiac amyloidosis in a community-based heart failure population2019In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 40, p. 132-132Article in journal (Other academic)
  • 15.
    Löfbacka, Viktor
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology.
    Suhr, Ole B.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Pilebro, Björn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Sundström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Lindmark, Krister
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Lindqvist, Per
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology.
    Combining ECG and echocardiography to identify transthyretin cardiac amyloidosis in heart failure2021In: Clinical Physiology and Functional Imaging, ISSN 1475-0961, E-ISSN 1475-097X, Vol. 41, no 5, p. 408-416Article in journal (Refereed)
    Abstract [en]

    AIMS/BACKGROUND: Transthyretin amyloid (ATTR) amyloidosis cardiomyopathy is an underdiagnosed, causatively treatable cause of heart failure. The aim of this study was to evaluate the efficacy of electrocardiography (ECG) and echocardiography on patients with increased interventricular septum diameter (IVSd) to identify ATTR cardiac amyloidosis (ATTR-CA) patients.

    METHODS: We investigated 58 patients with heart failure and an IVSd >14mm. Included were 33 ATTR-CA patients and 25 controls that consisted of non-amyloidosis heart failure (HF) patients with negative 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) scintigraphy. We used echocardiography including 2D speckle tracking strain and a 12-lead ECG to test the accuracy to differentiate the groups.

    RESULTS: We found high diagnostic accuracy (98%) for differentiating ATTR-CA from HF controls using a combination of R amplitude in -aVR from ECG and relative wall thickness acquired from echocardiography. With this combined model (RWT/ R in -aVR), the sensitivity was 100% and specificity was 95% using a cut off value of 0.90. Furthermore, the area under the curve was 99% and the negative predictive value was 100%.

    CONCLUSION: We found that a simple combination of ECG and echocardiographic parameters used in clinical settings was able to differentiate ATTR-CA from other etiologies of HF with increased interventricular septum thickness. The high sensitivity and negative predictive value render the algorithm useful for selection of patients for further diagnostic procedures for ATTR-CA.

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  • 16.
    Marberg, Therese
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Karling, Pontus
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Söderberg, Karin
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Self-reported gastrointestinal symptoms are more common in liver transplanted transthyretin amyloidosis patients than in healthy controls and in patients transplanted for end-stage liver disease2019In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 26, p. 47-48Article in journal (Refereed)
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  • 17.
    Mejia Baranda, Jorge
    et al.
    Piteå Research Unit, Region Norrbotten, Piteå, Sweden.
    Ljungberg, Jenny
    Piteå Research Unit, Region Norrbotten, Piteå, Sweden.
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Oskarsson, Viktor
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine. Piteå Research Unit, Region Norrbotten, Piteå, Sweden.
    Epidemiology of hereditary transthyretin amyloidosis in the northernmost region of Sweden: a retrospective cohort study2022In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 29, no 2, p. 120-127Article in journal (Refereed)
    Abstract [en]

    Introduction: Epidemiological data on hereditary transthyretin (ATTRv) amyloidosis from the northernmost region of Sweden (Norrbotten) are sparse.

    Methods: We reviewed the medical records of all incident cases of ATTRv amyloidosis in Norrbotten between 2006 and 2018. Official population and mortality statistics were used to estimate incidence rates and standardised mortality ratios (SMRs).

    Results: Ninety-three patients were diagnosed with ATTRv amyloidosis between 2006 and 2018 (median age, 72.8 years; 68.8% men; 95.7% Val30Met [p.Val50Met] mutation). The incidence rate per 100,000 persons and year increased from 1.50 (95% confidence interval [CI], 0.84–2.47) cases in 2006–2009 to 4.92 (95%CI, 3.46–6.78) cases in 2016–2018. The SMR in the ATTRv amyloidosis cohort was 2.64 times higher than in the general population in 2006–2018 (95%CI, 1.78–3.77). However, there were indications of lower SMRs over time (2006–2012, 2.96 [95%CI, 1.73–4.74]; 2013–2018, 2.32 [95%CI, 1.23–3.96]) and by use of disease-modifying drugs (no, 3.21 [95%CI, 1.87–5.13]; yes, 2.09 [95%CI, 1.08–3.64]).

    Conclusion: The incidence of ATTRv amyloidosis increased 3-fold in Norrbotten between 2006 and 2018, most likely due to a previous underdiagnosis–with suggestions of lowered mortality during later years, possibly due to the introduction of disease-modifying drugs.

  • 18. Muñoz-Beamud, Francisco
    et al.
    Coelho, Teresa
    Gillmore, Julian D.
    Adams, David
    Mazzeo, Anna
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Planté-Bordeneuve, Violaine
    Lladó, Laura
    Arum, Seth
    White, Matthew T.
    Jay, Patrick Y.
    Schmidt, Hartmut H.
    Patisiran in patients with hATTR amyloidosis post-orthotopic liver transplant: 12-month results2021In: Journal of the peripheral nervous system, ISSN 1085-9489, E-ISSN 1529-8027, Vol. 26, no 3, p. 307-307Article in journal (Other academic)
  • 19.
    Nakov, Radislav
    et al.
    Department of Gastroenterology, Clinic of Gastroenterology, Tsaritsa Joanna University Hospital, Medical University of Sofia, Sofia, Bulgaria.
    Suhr, Ole B.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Ianiro, Gianluca
    Department of Gastroenterology, Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Sacred Heart, Rome, Italy.
    Kupcinskas, Juozas
    Department of Gastroenterology and Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania.
    Segal, Jonathon P.
    Department of Gastroenterology and Hepatology, St Mary's Hospital, London, United Kingdom.
    Dumitrascu, Dan L.
    Second Department of Internal Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.
    Heinrich, Henriette
    Department of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland.
    Stojkovic-Lalosevic, Milica
    Department of Gastroenterology and Hepatology, Clinical Centre of Serbia, Belgrade, Serbia.
    Barbov, Ivan
    Department of Neurology, University Clinic for Neurology, Republic of North Macedonia, Skopje.
    Sarafov, Stayko
    Department of Neurology, Expert Center for Hereditary Neurological and Metabolic Disorders, ATTR Amyloidosis Expert Center, Clinic of Nervous Diseases, Alexandrovska University Hospital, Medical University of Sofia.
    Tournev, Ivailo
    Department of Neurology, Expert Center for Hereditary Neurological and Metabolic Disorders, ATTR Amyloidosis Expert Center, Clinic of Nervous Diseases, Alexandrovska University Hospital, Medical University of Sofia; Department of Cognitive Science and Psychology, New Bulgarian University, Sofia, Bulgaria.
    Nakov, Ventsislav
    Department of Gastroenterology, Clinic of Gastroenterology, Tsaritsa Joanna University Hospital, Medical University of Sofia, Sofia, Bulgaria.
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Recommendations for the diagnosis and management of transthyretin amyloidosis with gastrointestinal manifestations2021In: European Journal of Gastroenterology and Hepathology, ISSN 0954-691X, E-ISSN 1473-5687, Vol. 33, no 5, p. 613-622Article, review/survey (Refereed)
    Abstract [en]

    Transthyretin amyloid (ATTR) amyloidosis is an adult-onset, rare systemic disorder characterized by the accumulation of misfolded fibrils in the body, including the peripheral nerves, the heart and the gastrointestinal tract. Gastrointestinal manifestations are common in hereditary (ATTRv) amyloidosis and are present even before the onset of the polyneuropathy in some cases. Delays in diagnosis of ATTRv amyloidosis with gastrointestinal manifestations commonly occur because of fragmented knowledge among gastroenterologists and general practitioners, as well as a shortage of centers of excellence and specialists dedicated to disease management. Although the disease is becoming well-recognized in the societies of Neurology and Cardiology, it is still unknown for most gastroenterologists. This review presents the recommendations for ATTRv amyloidosis with gastrointestinal manifestations elaborated by a working group of European gastroenterologists and neurologists, and aims to provide digestive health specialists with an overview of crucial aspects of ATTRv amyloidosis diagnosis to help facilitate rapid and accurate identification of the disease by focusing on disease presentation, misdiagnosis and management of gastrointestinal symptoms.

  • 20.
    Okamoto, Sadahisa
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Ericzon, B-G
    Friman, S
    Lindqvist, Per
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Henein, Michael
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Suhr, Ole B
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Prognostic value of pre-transplant cardiomyopathy in Swedish liver transplanted patients for familial amyloidotic polyneuropathy2011In: Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis, ISSN 1744-2818, Vol. 18 Suppl 1, p. 166-8Article in journal (Refereed)
    Abstract [en]

    Liver transplantation (LTx) for familial amyloidotic polyneuropathy (FAP) is a recognized treatment for halting disease progression. Since cardiac complications are the main cause of postoperative death in FAP patients, we studied the potential relationship between pre-LTx amyloid heart disease and post-LTx mortality. Seventy-five Swedish patients who underwent LTx (72 Val30Met and 3 non-Val30Met patients) were available for the study. An intra-ventricular septal (IVS) thickness more than 15 mm at the pre-LTx evaluation was defined as cardiomyopathy. Nine patients out of 75 patients died, all were males and all belonged to the late onset group (age at onset ≥50 years). Four had cardiomyopathy at the pre-LTx evaluation. Survival rate was significantly higher in patients without cardiomyopathy at LTx compared to those with cardiomyopathy. Our results suggest that cardiomyopathy at LTx has an impact on the outcome of LTx for FAP.Read More: http://informahealthcare.com/doi/full/10.3109/13506129.2011.574354064

  • 21.
    Okamoto, Sadahisa
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Obayashi, Konen
    Ando, Yukio
    Ericzon, Bo-Göran
    Friman, Styrbjörn
    Uchino, Makoto
    Suhr, Ole B
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Liver transplantation for familial amyloidotic polyneuropathy: impact on Swedish patients' survival2009In: Liver transplantation, ISSN 1527-6465, E-ISSN 1527-6473, Vol. 15, no 10, p. 1229-1235Article in journal (Refereed)
    Abstract [en]

    Liver transplantation (LTx) for familial amyloidotic polyneuropathy (FAP) is an accepted treatment for this fatal disease. However, the long-term outcome with respect to that of nontransplanted patients has not been fully elucidated. The aim of this study was to compare the long-term survival of Swedish LTx FAP patients with that of historical controls, especially with respect to the age at onset of the disease and gender. In order to evaluate the outcome of LTx as a treatment for FAP, survival was calculated from the onset of disease. One hundred forty-one FAP patients, 108 transplanted and 33 not transplanted, were included in the study. Significantly increased survival was noted for LTx patients in comparison with controls. The outcome was especially favorable for those with an early onset of the disease (age at onset < 50 years) in comparison with early-onset controls (P < 0.001). In contrast, no significant difference for late-onset cases (> or = 50 years) was found. Transplanted late-onset females had significantly improved survival in comparison with transplanted late-onset males (P = 0.02). We were unable to find significant differences in survival between patients with long (> or = 7 years) or short (<7 years) disease duration at transplantation. The survival of male patients with late-onset disease appeared not to improve with LTx. LTx is an efficacious treatment for improving the survival of early-onset FAP patients. Further studies are needed to analyze the cause of the poorer outcome for late-onset male patients.

  • 22.
    Olsson, Malin
    et al.
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Hellman, Urban
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Metabolomics analysis for diagnosis and biomarker discovery of transthyretin amyloidosis2021In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 28, no 4, p. 234-242Article in journal (Refereed)
    Abstract [en]

    Untargeted metabolomics is a well-established technique and a powerful tool to find potential plasma biomarkers for early diagnosing hereditary transthyretin amyloidosis. Hereditary transthyretin amyloidosis (ATTRv) is a disabling and fatal disease with different clinical features such as polyneuropathy, cardiomyopathy, different gastrointestinal symptoms and renal failure. Plasma specimens collected from 27 patients with ATTRv (ATTRV30M), 26 asymptomatic TTRV30M carriers and 26 control individuals were subjected to gas chromatography (GC)- and liquid chromatography (LC)-mass spectrometry (MS)-based metabolomics analysis. Partial least squares discriminant and univariate analysis was used to analyse the data. The models constructed by Partial least squares-discriminant analysis (PLS-DA) could clearly discriminate ATTRV30M patients from controls and asymptomatic TTRV30M carriers. In total, 24 plasma metabolites (VIP > 1.0 and p <.05) were significantly altered in ATTRV30M patient group (6 increased and 18 decreased). Eleven of these distinguished the ATTRV30M group from both controls and TTRV30M carriers. Plasma metabolomics analysis revealed marked changes in several pathways in patients with ATTRV30M amyloidosis. Statistical analysis identified a panel of biomarkers that could effectively separate controls/TTRV30M carriers from ATTRV30M patients. These biomarkers can potentially be used to diagnose patients at an early stage of the disease.

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  • 23.
    Paulsson Rokke, Hedvig
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Sadat Gousheh, Nima
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Westermark, Per
    Suhr, Ole B.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Ihse, Elisabet
    Pilebro, Björn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Abdominal fat pad biopsies exhibit good diagnostic accuracy in patients with suspected transthyretin amyloidosis2020In: Orphanet Journal of Rare Diseases, E-ISSN 1750-1172, Vol. 15, no 1, article id 278Article in journal (Refereed)
    Abstract [en]

    Background: The diagnostic accuracy of histopathological detection of transthyretin amyloid (ATTR) by Congo red staining of abdominal fat samples has been questioned since low sensitivity has been reported, especially for patients with ATTR cardiomyopathy. However, the outcome of surgically obtained fat pad biopsies has not yet been evaluated. The aim was to evaluate the diagnostic accuracy of skin punch biopsies from abdominal fat in patients with suspected ATTR amyloidosis.

    Material and methods: Data were evaluated from patients who had undergone abdominal fat pad biopsies using a skin punch due to suspected amyloidosis from 2006 to 2015. The biopsies had been analysed using Congo red staining to determine the presence of amyloid, and immunohistochemistry or Western blot to determine the type of amyloidosis. The final diagnosis was based on the clinical picture, biopsy results and DNA sequencing. Minimum follow-up after the initial biopsy was 3 years.

    Results: Two hundred seventy-four patients (61% males) were identified, and in 132 (48%), a final diagnosis of amyloidosis had been settled. The majority (93%) had been diagnosed with hereditary transthyretin (ATTRv) amyloidosis, and therefore subsequent analyses were focused on these patients. Overall, our data showed a test specificity of 99% and a sensitivity of 91%. Ninety-eight (94%) of the patients had neuropathic symptoms at diagnosis, whereas 57 (55%) had signs of amyloid cardiomyopathy. Subgroup analyses showed that patients with merely neuropathic symptoms displayed the highest test sensitivity of 91%, whereas patients with pure cardiomyopathy displayed the lowest sensitivity of 83%. However, no significant differences in sensitivity were found between patients with or without cardiomyopathy or between the sexes.

    Conclusions: Abdominal fat pad biopsies exhibit good diagnostic accuracy in patients with suspect ATTRv amyloidosis, including patients presenting with cardiomyopathy. In addition, the method enables typing not only of the precursor protein but also of the amyloid fibril type, which is related to the phenotype and to the outcome of the disease.

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  • 24. Polydefkis, Michael
    et al.
    Gonzalez-Duarte, Alejandra
    Coelho, Teresa
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Berber, Erhan
    Adams, David
    Long-term safety and efficacy of Patisiran in patients with hATTR amyloidosis: Global OLE study2020In: Journal of the peripheral nervous system, ISSN 1085-9489, E-ISSN 1529-8027, Vol. 25, p. S13-S13Article in journal (Refereed)
  • 25. Polydefkis, Michael
    et al.
    Gonzalez-Duarte, Alejandra
    Coelho, Teresa
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Kristen, Arnt
    Schmidt, Hartmut
    Berk, John L.
    Berber, Erhan
    Sweetser, Marianne
    White, Matthew
    Wang, Jing Jing
    Adams, David
    Long-term Safety and Efficacy of Patisiran in Patients with hATTR Amyloidosis: Global OLE Study2020In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 94, no 15Article in journal (Other academic)
  • 26.
    Rutegård, Martin
    et al.
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Häggström, Jenny
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Back, Erik
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Holmgren, Klas
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Rutegård, Jörgen
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Matthiessen, Peter
    Department of Surgery, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Sjöström, Olle
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Defunctioning loop ileostomy in anterior resection for rectal cancer and subsequent renal failure: nationwide population-based study2023In: BJS Open, E-ISSN 2474-9842, Vol. 7, no 3, article id zrad010Article in journal (Refereed)
    Abstract [en]

    Background: Electrolyte disturbances and dehydration are common after anterior resection for rectal cancer with a defunctioning loop ileostomy. High-quality population-based studies on the impact of a defunctioning loop ileostomy on renal failure are lacking.

    Methods: This was a nationwide observational study, based on the Swedish Colorectal Cancer Registry of patients undergoing anterior resection for rectal cancer between 2008 and 2016, with follow-up until 2017. Patients with severe co-morbidity, with age greater than 80 years, and with pre-existing renal failure were excluded. Loop ileostomy at index surgery constituted exposure, while a diagnosis of renal failure was the outcome. Acute and chronic events were analysed separately. Inverse probability weighting with adjustment for confounding derived from a causal diagram was employed. Hazards ratios (HRs) with 95 per cent c.i. are reported.

    Results: A total of 5355 patients were eligible for analysis. At 5-year follow-up, all renal failure events (acute and chronic) were 7.2 per cent and 3.3 per cent in the defunctioning stoma and no stoma groups respectively. In the weighted analysis, a HR of 11.59 (95 per cent c.i. 5.68 to 23.65) for renal failure in ostomates was detected at 1 year, with the largest effect from acute renal failure (HR 24.04 (95 per cent c.i. 8.38 to 68.93)). Later follow-up demonstrated a similar pattern, but with smaller effect sizes.

    Conclusion: Patients having a loop ileostomy in combination with anterior resection for rectal cancer are more likely to have renal failure, especially early after surgery. Strategies are needed, such as careful fluid management protocols, and further research into alternative stoma types or reduction in stoma formation.

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  • 27.
    Samuelsson, Kristin
    et al.
    Department of Neurology, Karolinska University Hospital, Stockholm, Sweden; Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Jovanovic, Ana
    Department of Neurology, Karolinska University Hospital, Stockholm, Sweden.
    Egervall, Karl
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Press, Rayomand
    Department of Neurology, Karolinska University Hospital, Stockholm, Sweden; Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Hereditary transthyretin amyloidosis in Sweden: Comparisons between a non-endemic and an endemic region2022In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 29, no 4, p. 220-227Article in journal (Refereed)
    Abstract [en]

    Introduction: Hereditary transthyretin amyloidosis (ATTRv) is endemic in northern Sweden (Västerbotten). The awareness of ATTRv amyloidosis is lower in Stockholm, a non-endemic region in Sweden. The aim of this study was to compare the possible differences in diagnostic delay, disease phenotypes, treatment and survival between a non-endemic and an endemic region in Sweden.

    Methods: The in- and outpatient diagnosis registry at the Department of Neurology at Karolinska University Hospital and the Amyloidosis Centre at University Hospital of Umeå were used to identify patients between January 2006 and November 2017.

    Results: In total, 21 patients in Stockholm and 134 patients in Västerbotten were included. The time between symptom onset to time-point of diagnosis was significantly longer in Stockholm vs Västerbotten. This corresponded to a longer median time between first visit at amyloidosis centre to time-point of diagnosis in Stockholm vs in Västerbotten. The most common reason for a diagnostic delay was negative tissue biopsies.

    Conclusion: There was a diagnostic-, but no patient-delay in non-endemic Stockholm vs endemic Västerbotten. Despite a more severe neuropathic phenotype in Stockholm at the onset, the systemic affection over the course of disease and of survival seems not to be influenced by the diagnosis delay in Stockholm.

  • 28.
    Schmidt, Hartmut H.
    et al.
    Department of Gastroenterology, Hepatology and Transplant Medicine, University Hospital Essen, University of Duisburg-Essen (formerly of University Hospital Munster, Munster, Germany), Essen, Germany.
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Planté-Bordeneuve, Violaine
    Department of Neurology, East Paris University, Hospital Henri Mondor – Public Assistance Hospital of Paris, Créteil, France; Mondor Biomedical Research Institute – IMRB, INSERM, U955 Team 10 “Biology of the Neuro-Muscular System”, Créteil, France.
    Muñoz-Beamud, Francisco
    Hereditary Amyloidosis Unit, Department of Internal Medicine, Juan Ramón Jiménez Hospital, Huelva, Spain.
    Lladó, Laura
    Liver Transplantation Unit, Department of Surgery, and the Multidisciplinary Familial Amyloidosis Unit, Hospital Universitari de Bellvitge, Barcelona, Spain; Biomedical Research Institute, IDIBELL, University of Barcelona, Barcelona, Spain.
    Gillmore, Julian D.
    National Amyloidosis Centre, Division of Medicine, University College London Medical School, London, United Kingdom.
    Mazzeo, Anna
    Unit of Neurology and Neuromuscular Diseases, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.
    Li, Xingyu
    Alnylam Pharmaceuticals, Inc, MA, Cambridge, United States.
    Arum, Seth
    Alnylam Pharmaceuticals, Inc, MA, Cambridge, United States.
    Jay, Patrick Y.
    Alnylam Pharmaceuticals, Inc, MA, Cambridge, United States.
    Adams, David
    Neurology Department, Université Paris-Saclay, U1195, INSERM, Le Kremlin Bicêtre, France; Neurology Department, AP-HP, CHU Bicêtre, Le Kremlin Bicêtre, France.
    Anan, Intissar (Contributor)
    Umeå University Hospital.
    Nordh, Erik (Contributor)
    Umeå University Hospital.
    Unéus, Erica (Contributor)
    Umeå University Hospital.
    Pilebro, Björn (Contributor)
    Umeå University Hospital.
    Patisiran treatment in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy after liver transplantation2022In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 22, no 6, p. 1646-1657Article in journal (Refereed)
    Abstract [en]

    Hereditary transthyretin-mediated (hATTR) amyloidosis, or ATTRv amyloidosis, is a progressive disease, for which liver transplantation (LT) has been a long-standing treatment. However, disease progression continues post-LT. This Phase 3b, open-label trial evaluated efficacy and safety of patisiran in patients with ATTRv amyloidosis with polyneuropathy progression post-LT. Primary endpoint was median transthyretin (TTR) reduction from baseline. Twenty-three patients received patisiran for 12 months alongside immunosuppression regimens. Patisiran elicited a rapid, sustained TTR reduction (median reduction [Months 6 and 12 average], 91.0%; 95% CI: 86.1%–92.3%); improved neuropathy, quality of life, and autonomic symptoms from baseline to Month 12 (mean change [SEM], Neuropathy Impairment Score, −3.7 [2.7]; Norfolk Quality of Life-Diabetic Neuropathy questionnaire, −6.5 [4.9]; least-squares mean [SEM], Composite Autonomic Symptom Score-31, −5.0 [2.6]); and stabilized disability (Rasch-built Overall Disability Scale) and nutritional status (modified body mass index). Adverse events were mild or moderate; five patients experienced ≥1 serious adverse event. Most patients had normal liver function tests. One patient experienced transplant rejection consistent with inadequate immunosuppression, remained on patisiran, and completed the study. In conclusion, patisiran reduced serum TTR, was well tolerated, and improved or stabilized key disease impairment measures in patients with ATTRv amyloidosis with polyneuropathy progression post-LT (www.clinicaltrials.gov NCT03862807).

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  • 29.
    Suhr, Ole B
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Pilebro, Björn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Lundgren, Hans-Erik
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    The Swedish landscape of hereditary ATTR amyloidosis2017In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 24, no 1, p. 93-94Article in journal (Refereed)
    Abstract [en]

    Northern Sweden is a well-known clustering area for hereditary transthyretin (TTR) amyloid (ATTR) amyloidosis caused by the Val30Met mutation. However, several additional mutations have been found in the Swedish population, of which many, such as the Ala45Ser, Gly57Arg and His88Arg mutations, have not been reported outside of Sweden to the best of our knowledge. We aim to give an overview of the various mutations found in the Swedish population.

  • 30.
    Suhr, Ole Bernt
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Lundgren, Hans-Erik
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Wijayatunga, Priyantha
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Westermark, Per
    Ihse, Elisabet
    Amyloid fibril composition within hereditary Val30Met (p. Val50Met) transthyretin amyloidosis families2019In: PLOS ONE, E-ISSN 1932-6203, Vol. 14, no 2, article id e0211983Article in journal (Refereed)
    Abstract [en]

    Background: The amyloid fibril in hereditary transthyretin (TTR) Val30Met (pVal50Met) amyloid (ATTR Val30Met) amyloidosis is composed of either a mixture of full-length and TTR fragments (Type A) or of only full-length TTR (Type B). The type of amyloid fibril exerts an impact on the phenotype of the disease, and on the outcome of diagnostic procedures and therapy. The aim of the present study was to investigate if the type of amyloid fibril remains the same within ATTR Val30Met amyloidosis families. Methods: Fifteen families were identified in whom at least two first-degree relatives had their amyloid fibril composition determined. The type of ATTR was determined by Western blot in all but two patients. For these two patients a positive 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy indicated ATTR Type A. Results: In 14 of the 15 families, the same amyloid fibril composition was noted irrespective of differences in age at onset. In the one family, different ATTR fibril types was found in two brothers with similar ages at onset. Conclusions: Family predisposition appears to have an impact on amyloid fibril composition in members of the family irrespective of their age at onset of disease, but if genetically determined, the gene/genes are likely to be situated at another location than the TTR gene in the genome.

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  • 31.
    Thörn, Richard
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Christensen, Evelina
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Karling, Pontus
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Werner, Mårten
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Survival after first diagnosis of oesophageal or gastric varices in a single centre in northern Sweden: a retrospective study2022In: Clinical and Experimental Hepatology, ISSN 2392-1099, Vol. 8, no 2, p. 103-110Article in journal (Refereed)
    Abstract [en]

    Aim of the study: Oesophageal and gastric varices are well-known causes of morbidity and mortality in patientswith liver cirrhosis. The aim of this retrospective observational study was to analyse clinical characteristics andoutcomes for patients with oesophageal and gastric varices at Norrland’s University Hospital, Umeå, Sweden.

    Material and methods: Data from medical records were collected retrospectively from 246 patients with oesophageal and gastric varices between 2006 and 2019.

    Results: At the end of the study 60.1% of the patients had died at a median age of 69 years (range 26-95).Mortality of patients with gastro-oesophageal varices was significantly greater than that of the general population. Median survival from the time of variceal diagnosis was 59 months (confidence interval [CI] 95%:45-73 months). Five-year and 10-year cumulative survival rates in the entire cohort were 49.7% and 27.7%,respectively, with no sex-related differences. The highest mortality rate was seen in alcoholic cirrhosis with concomitant hepatitis. Mortality was higher in Child-Turcotte-Pugh (CTP) B and C compared to CTP A. Liver failureand liver cancer were the most common causes of death (43.8%). Thirty-one percent of the patients had avariceal haemorrhage. Eleven percent were subjected to liver transplantation, whereas 3.9% of the patients had beensubmitted to a transjugular intrahepatic portosystemic shunt (TIPS) procedure.

    Conclusions: Despite the latest therapeutic advances, the survival of patients with gastro-oesophageal varicesremains significantly reduced. All-cause mortality was significantly related to CTP class, aetiology, occurrence ofvariceal bleeding, whether variceal bleeding was the primary symptom and whether patients had undergoneliver transplantation or not. 

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  • 32.
    Thörn, Richard
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Hemmingsson, Oskar
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Danielsson Borssén, Åsa
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Werner, Mårten
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Karling, Pontus
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Improved survival in at-risk patients undergoing surveillance for hepatocellular carcinoma: a nationwide Swedish register-based study2023In: Journal of Hepatocellular Carcinoma, E-ISSN 2253-5969, Vol. 10, p. 1573-1586Article in journal (Refereed)
    Abstract [en]

    Purpose: Surveillance for hepatocellular carcinoma (HCC) is recommended in at-risk patients, but its effectiveness in Western populations has been questioned. The purpose was to evaluate the effect of surveillance in patients with HCC in a Northern European setting.

    Patients and Methods: Data on patients diagnosed with HCC between 2009 and 2019 were collected from the nationwide Swedish National Registry for Tumors of the Liver and Bile Ducts (SweLiv). Patients who had undergone HCC surveillance were compared to those who had not (but had an obvious indication for surveillance, ie, liver cirrhosis or hepatic porphyria and an age of ≥50 years) regarding etiology, tumor burden, presence of extrahepatic spread, treatment and lead-time adjusted overall survival.

    Results: A total of 4979 patients with index HCC were identified and information regarding surveillance was available in 4116 patients. Among these, 1078 had got their HCC diagnosis during surveillance, whereas 1647 had been diagnosed without surveillance despite a presumed indication. The most common underlying etiologies for HCC were hepatitis C (28.2%) and alcoholic liver disease (26.9%), and 94.8% had cirrhosis. The surveillance cohort more frequently met the University of California San Francisco-criteria (79% vs 53%, p <0.001), more often received a potentially curative treatment (62% vs 28%, p <0.001) and had less extrahepatic spread (7.6% vs 22.4% p <0.001). After adjustment for lead-time bias (sojourn time of 270 days), the surveillance group had a significantly longer estimated median survival time than the non-surveillance group (34 months vs 11 months, p <0.001). A multivariable cox regression analysis showed an adjusted hazard ratio of 0.59 (95% CI 0.51–0.67) in favor of surveillance.

    Conclusion: Surveillance for HCC in at-risk patients is associated with diagnosis at an earlier tumor stage, treatment with curative intent and with improved lead-time adjusted overall survival. These findings encourage HCC surveillance of at-risk patients also in a Western population.

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  • 33.
    Unéus, Erica Irene
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Wilhelmsson, Christer
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Bäckström, David
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Pilebro, Björn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Riklund, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Ögren, Mattias
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Ögren, Margareta
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Axelsson, Jan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Suhr, Ole B.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Sundström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Cerebellar and Cerebral Amyloid Visualized by [18F]flutemetamol PET in Long-Term Hereditary V30M (p.V50M) Transthyretin Amyloidosis Survivors2022In: Frontiers in Neurology, E-ISSN 1664-2295, Vol. 13, article id 816636Article in journal (Refereed)
    Abstract [en]

    Introduction: Hereditary transthyretin (ATTRv) amyloidosis caused by the V30M (p. V50M) mutation is a fatal, neuropathic systemic amyloidosis. Liver transplantation has prolonged the survival of patients and central nervous system (CNS) complications, attributed to amyloid angiopathy caused by CNS synthesis of variant transthyretin, have emerged. The study aimed to ascertain amyloid deposition within the brain in long-term ATTRv amyloidosis survivors with neurological symptoms from the CNS.

    Methods: A total of 20 patients with ATTR V30M having symptoms from the CNS and a median disease duration of 16 years (8–25 years) were included in this study. The cognitive and peripheral nervous functions were determined for 18 patients cross-sectionally at the time of the investigation. Amyloid brain deposits were examined by [18F]flutemetamol PET/CT. Five patients with Alzheimer's disease (AD) served as positive controls.

    Result: 60% of the patients with ATTRv had a pathological Z-score in the cerebellum, compared to only 20% in the patients with AD. 75% of the patients with transient focal neurological episodes (TFNEs) displayed a pathological uptake only in the cerebellum. Increased cerebellar uptake was related to an early age of onset of the ATTRv disease. 55% of the patients with ATTRv had a pathological Z-score in the global cerebral region compared to 100% of the patients with AD.

    Conclusion: Amyloid deposition within the brain after long-standing ATTRv amyloidosis is common, especially in the cerebellum. A cerebellar amyloid uptake profile seems to be related to TFNE symptoms.

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  • 34.
    Unéus, Erica
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Wilhelmsson, Christer
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Suhr, Ole
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Pilebro, Björn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Åhlström Riklund, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Sundström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Visualisation of amyloid deposition within the brain of long-term hereditary transthyretin amyloidosis survivors by 18F-flutemetamol positron emission tomography2019In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 26, no S1, p. 287-287, article id EPR3027Article in journal (Other academic)
    Abstract [en]

    Background and aims: Hereditary transthyretin amyloid (ATTRv) amyloidosis caused by the transthyretin (TTR) Val30Met (p.V50M) mutation is characterised by peripheral neuropathy, and central nervous (CNS) complications has rarely been reported. However, liver transplantation has prolonged the patients’ survival, and CNS complications attributed to amyloid angiopathy caused by CNS synthesis of variant TTR have been reported. The aim of the study was to ascertain CNS amyloid deposition in long-term ATTRv survivors.

    Methods: 20 ATTR Val30Met patients with symptoms from the CNS and a median disease duration of 16 years (9-25 years) together with five Alzheimer (AD) patients, who served as positive controls were included in the study. Amyloid CNS deposits were assessed by 18F- flutemetamol PET/CT examination utilising relative z scores with pons as reference.

    Results: Expectedly, all Alzheimer patients had an clearly increased global composite z score above 2.0 compared with 55% of the ATTRv patients. There was an increased local uptake corresponding to cerebellum in 12 ATTRv patients compared to only one in the AD group (fig 1). Four of these ATTRv patients had a global composite z score within the normal range. No correlation between duration after 9 years and amyloid CNS deposition was noted.

    Conclusion: Amyloid deposition within the brain after long-standing ATTRv amyloidosis is increased and is often noted in the cerebellum. However, not all patient display amyloid CNS deposition, thus, additional causes for CNS complications should always be considered.

  • 35.
    Waddington-Cruz, Márcia
    et al.
    CEPARM, National Amyloidosis Referral Center, University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Amass, Leslie
    Pfizer Inc, NY, New York, United States.
    Kiszko, Jan
    Pfizer Inc, NY, New York, United States.
    Chapman, Doug
    Pfizer Inc, NY, New York, United States.
    Ando, Yukio
    Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
    Characteristics of Patients with Late- vs. Early-Onset Val30Met Transthyretin Amyloidosis from the Transthyretin Amyloidosis Outcomes Survey (THAOS)2021In: Neurology and Therapy, ISSN 2193-8253, Vol. 10, no 2, p. 753-766Article in journal (Refereed)
    Abstract [en]

    Introduction: Hereditary transthyretin amyloidosis (ATTRv amyloidosis) is a clinically heterogeneous disease caused by mutations in the transthyretin (TTR) gene. The most common mutation, Val30Met, can manifest as an early- or late-onset disease.

    Methods: The Transthyretin Amyloidosis Outcomes Survey (THAOS) is an ongoing, global, longitudinal, observational survey of patients with transthyretin amyloidosis, including both inherited and wild-type disease and asymptomatic patients with TTR mutations. This is a descriptive analysis of symptomatic patients with ATTRv Val30Met amyloidosis with late- (age at least 50 years) vs. early-onset (age less than 50 years) disease in THAOS (data cutoff August 1, 2019).

    Results: Of 1389 patients with ATTRv Val30Met amyloidosis, 491 (35.3%) had late-onset disease. Compared with early-onset, patients with late-onset were more likely to be male (66.2% vs. 53.6%) and have a longer mean (standard deviation [SD]) time from onset to diagnosis (3.8 [3.4] vs. 2.7 [4.1] years). Late-onset disease was associated with more severe neurological impairment at enrollment (median [10th, 90th percentile] derived Neuropathy Impairment Score in the Lower Limbs, 25.0 [4.0, 69.3] vs. 8.0 [0, 54.8]; Neurologic Composite Score, 42.0 [2.0, 155.0] vs. 21.0 [0, 102.0]). Cardiac findings were more prominent in late-onset disease. An overall interpretation of electrocardiogram as abnormal was reported in 72.1% of late-onset patients (vs. 44.3% early-onset). A left-ventricular septal thickness of at least 12 mm was reported in 69.7% of late-onset patients (vs. 14.6% early-onset). All differences were statistically significant (p < 0.001).

    Conclusion: In THAOS, late-onset ATTRv Val30Met amyloidosis is common, presenting with more severe neurologic and cardiac findings at enrollment. Heterogeneity of disease may make it more difficult to diagnose. Increased recognition of late-onset ATTRv Val30Met amyloidosis could lead to more timely diagnosis and improve patient outcomes.

    Trial Registration: ClinicalTrials.gov NCT00628745.

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  • 36.
    Wange, Niklas
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Ericzon, Bo-Göran
    Pennlert, Johanna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Pilebro, Björn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Suhr, Ole B.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Atrial Fibrillation and Central Nervous Complications in Liver Transplanted Hereditary Transthyretin Amyloidosis Patients2018In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 102, no 2, p. e59-e66Article in journal (Refereed)
    Abstract [en]

    Background. Central nervous system (CNS) complications are increasingly noted in liver transplanted (LTx) hereditary transthyretin amyloid (ATTRm) amyloidosis patients; this suggests that the increased survival allows for intracranial ATTRm formation from brain synthesized mutant TTR. However, atrial fibrillation (AF), a recognised risk factor for ischemic CNS complications, is also observed after LTx. The aim of the study was to investigate the occurrence of CNS complications and AF in LTx ATTRm amyloidosis patients. Methods. The medical records of all LTx ATTRm amyloidosis patients in the county of Vasterbotten, Sweden, were investigated for information on CNS complications, AF, anticoagulation (AC) therapy, hypertension, cardiac ischemic disease, hypertrophy, and neurological status. Results. Sixty-three patients that had survived for 3 years or longer after LTx were included in the analysis. Twenty-five patients had developed 1 or more CNS complications at a median of 21 years after onset of disease. AF was noted in 21 patients (median time to diagnosis 24 years). Cerebrovascular events (CVE) developed in 17 (median time to event 21 years). CVEs occurred significantly more often in patients with AF (P < 0.002). AC therapy significantly reduced CVEs, including bleeding in patients with AF (P = 0.04). Multivariate analysis identified AF as the only remaining regressor with a significant impact on CVE (hazard ratio, 3.8; 95% confidence interval 1.1-9.5; P = 0.029). Conclusions. AF is an important risk factor for CVE in LTx ATTRm amyloidosis patients, and AC therapy should be considered. However, the increased bleeding risk with AC therapy in patients with intracranial amyloidosis should be acknowledged.

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  • 37.
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Gastrointestinal disturbances in hereditary transthyretin amyloidosis2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background

    Transthyretin amyloid (ATTR) amyloidosis is a systemic disorder caused by amyloid deposits formed by misfolded transthyretin (TTR) monomers. Two main forms exist – wild-type and hereditary ATTR amyloidosis, the latter associated with TTR gene mutations. Wild-type ATTR amyloidosis has a late onset and primarily cardiac manifestations, whereas hereditary ATTR amyloidosis is a rare autosomal dominant condition with a considerable phenotypic diversity. Both disorders are present all over the world, but endemic areas of the hereditary form are found in Sweden, Portugal, Brazil and Japan. Gastrointestinal (GI) complications are common in hereditary ATTR amyloidosis and play an important role in the patients’ morbidity and mortality. Malfunction of the autonomic and enteric nervous systems has been proposed to contribute to the GI disturbances, but the underlying mechanisms have not been fully elucidated. The aims of this thesis were to assess the prevalence of GI disturbances for different subtypes of ATTR amyloidosis, to further explore the mechanisms behind these disturbances, and to evaluate the outcome of the patients’ GI function after liver transplantation, which currently is the standard treatment for hereditary ATTR amyloidosis.

    Methods

    The Transthyretin Amyloidosis Outcomes Survey (THAOS) is the first global, multicenter, longitudinal, observational survey that collects data on patients with ATTR amyloidosis. THAOS enrollment data were used to assess the prevalence of GI symptoms and to evaluate their impact on nutritional status (mBMI) and health-related quality of life (EQ-5D Index Score). Data from routine investigations of heart-rate variability and cardio-vascular response to tilt tests were utilized to evaluate the impact of autonomic neuropathy on the scintigraphically measured gastric emptying half-times in Swedish patients with hereditary ATTR amyloidosis. Gastric wall autopsy specimens from Japanese patients with hereditary ATTR amyloidosis and Japanese non-amyloidosis controls were analyzed with immunohistochemistry and computerized image analysis to assess the densities of interstitial cells of Cajal (ICC) and nervous tissue. Data from gastric emptying scintigraphies and validated questionnaires were used to evaluate the outcome of Swedish patients’ GI function after liver transplantation for hereditary ATTR amyloidosis.

    Results

    Sixty-three percent of the patients with TTR mutations and 15 % of those with wild-type ATTR amyloidosis reported GI symptoms at enrollment into THAOS. Subsequent analyses focused on patients with TTR mutations and, among them, unintentional weight loss was the most frequent symptom (32 %) followed by early satiety (26 %). Early-onset patients (<50 years of age) reported GI symptoms more frequently than late-onset cases (70 % vs. 50 %, p <0.01), and GI symptoms were more common in patients with the V30M mutation than in those with non-V30M mutations (69 % vs. 56 %, p <0.01). Both upper and lower GI symptoms were significant negative predictors of nutritional status and health-related quality of life (p <0.01 for both). Weak but significant correlations were found between gastric emptying half-times and the function of both the sympathetic (rs = -0.4, p <0.01) and parasympathetic (rs = -0.3, p <0.01) nervous systems. The densities of c-Kit-immunoreactive ICC were significantly lower in the circular (median density 0.0 vs. 2.6, p <0.01) and longitudinal (median density 0.0 vs. 1.8, p <0.01) muscle layers of the gastric wall in patients compared to controls. Yet, no significant differences in protein gene product 9.5-immunoreactive nervous cells were found between patients and controls either in the circular (median density 3.0 vs. 6.8, p = 0.17) or longitudinal (median density 1.4 vs. 2.5, p = 0.10) muscle layers. Lastly, the patients’ GI symptoms scores had increased slightly from before liver transplantation to the follow-ups performed in median two and nine years after transplantation (median score 7 vs. 10 vs. 13, p <0.01). However, their gastric emptying half-times (median half-time 137 vs. 132 vs. 125 min, p = 0.52) and nutritional statuses (median mBMI 975 vs. 991 vs. 973, p = 0.75) were maintained at follow-ups in median two and five years after transplantation.

    Conclusion

    GI disturbances are common in hereditary ATTR amyloidosis and have a negative impact on the patients’ nutritional status and health-related quality of life. Fortunately, a liver transplantation appears to halt the progressive GI involvement of the disease, although the patients’ GI symptoms tend to increase after transplantation. An autonomic neuropathy and a depletion of gastrointestinal ICC seem to contribute to the GI disturbances, but additional factors must be involved.

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  • 38.
    Wixner, Jonas
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Karling, Pontus
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Rydh, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Hornsten, Rolf
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology.
    Wiklund, Urban
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Suhr, Ole B.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Gastric emptying in hereditary transthyretin amyloidosis: the impact of autonomic neuropathy2012In: Neurogastroenterology and Motility, ISSN 1350-1925, E-ISSN 1365-2982, Vol. 24, no 12, p. 1111-e568Article in journal (Refereed)
    Abstract [en]

    Background: Gastrointestinal (GI) complications are common in hereditary transthyretin amyloidosis and an autonomic dysfunction has been considered to explain these symptoms. The aim of this study was to investigate the impact of autonomic neuropathy on gastric emptying in hereditary transthyretin amyloidosis and to relate these findings to nutritional status, GI symptoms, gender, and age at disease onset.

    Methods: Gastric emptying was evaluated with gastric emptying scintigraphy. Spectral analysis of the heart rate variability and cardiovascular responses after tilt test were used to assess the autonomic function. The nutritional status was evaluated with the modified body mass index (s-albumine x BMI).

    Key Results: Gastric retention was found in about one-third of the patients. A weak correlation was found between the scintigraphic gastric emptying rate and both the sympathetic (rs = -0.397, P < 0.001) and parasympathetic function (rs = -0.282, P = 0.002). The gastric emptying rate was slower in those with lower or both upper and lower GI symptoms compared with those without symptoms (median T50 123 vs 113 min, P = 0.042 and 192 vs 113 min, P = 0.003, respectively). Multiple logistic regression analysis showed that age of onset (OR 0.10, CI 0.020.52) and sympathetic dysfunction (OR 0.23, CI 0.100.51), but not gender (OR 0.76, CI 0.311.84) and parasympathetic dysfunction (OR 1.81, CI 0.724.56), contributed to gastric retention.

    Conclusions and Inferences: Gastric retention is common in hereditary transthyretin amyloidosis early after onset. Autonomic neuropathy only weakly correlates with gastric retention and therefore additional factors must be involved.

  • 39.
    Wixner, Jonas
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Mundayat, Rajiv
    Pfizer Inc, New York, NY, USA.
    Karayal, Onur N
    Pfizer Inc, New York, NY, USA.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Karling, Pontus
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Suhr, Ole B
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    THAOS: Gastrointestinal manifestations of transthyretin amyloidosis - common complications of a rare disease2014In: Orphanet Journal of Rare Diseases, E-ISSN 1750-1172, Vol. 9, no 1, p. 61-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Transthyretin amyloidosis is a systemic disorder caused by amyloid deposits formed by misfolded transthyretin monomers. Two main forms exist: hereditary and wild-type transthyretin amyloidosis, the former associated with transthyretin gene mutations. There are several disease manifestations; however, gastrointestinal complications are common in the hereditary form. The aim of this study was to explore the prevalence and distribution of gastrointestinal manifestations in transthyretin amyloidosis and to evaluate their impact on the patients' nutritional status and health-related quality of life (HRQoL).

    METHODS: The Transthyretin Amyloidosis Outcomes Survey (THAOS) is the first global, multicenter, longitudinal, observational survey that collects data on patients with transthyretin amyloidosis and the registry is sponsored by Pfizer Inc. This study presents baseline data from patients enrolled in THAOS as of June 2013. The modified body mass index (mBMI), in which BMI is multiplied with serum albumin, was used to assess the nutritional status and the EQ-5D Index was used to assess HRQoL.

    RESULTS: Data from 1579 patients with hereditary transthyretin amyloidosis and 160 patients with wild-type transthyretin amyloidosis were analyzed. Sixty-three percent of those with the hereditary form and 15% of those with the wild-type form reported gastrointestinal symptoms at enrollment. Unintentional weight loss and early satiety were the most frequent symptoms, reported by 32% and 26% of those with transthyretin gene mutations, respectively. Early-onset patients (<50 years) reported gastrointestinal complaints more frequently than those with a late onset (p < 0.001) and gastrointestinal symptoms were more common in patients with the V30M mutation than in those with other mutations (p < 0.001). For patients with predominantly cardiac complications, the prevalence of gastrointestinal manifestations was not evidently higher than that expected in the general population. Both upper and lower gastrointestinal symptoms were significant negative predictors of mBMI and the EQ-5D Index Score (p < 0.001 for all).

    CONCLUSIONS: Gastrointestinal symptoms were common in patients with hereditary transthyretin amyloidosis and had a significant negative impact on their nutritional status and HRQoL. However, patients with wild-type transthyretin amyloidosis or transthyretin mutations associated with predominantly cardiac complications did not show an increased prevalence of gastrointestinal disturbances.

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  • 40.
    Wixner, Jonas
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Obayashi, Konen
    Department of Diagnostic Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
    Ando, Yukio
    Department of Diagnostic Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
    Karling, Pontus
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Loss of gastric interstitial cells of Cajal in patients with hereditary transthyretin amyloidosis2013In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 20, no 2, p. 99-106Article in journal (Refereed)
    Abstract [en]

    Background: Hereditary transthyretin (TTR) amyloidosis is a systemic neuropathic disorder caused by TTR gene mutations. Gastrointestinal complications are common and the underlying mechanisms remain unclear. The interstitial cells of Cajal (ICC) function as pacemaker cells in the gastrointestinal tract and are important for gastrointestinal motility. The aim of this study was to investigate the densities of gastric ICC and nerves in patients with TTR amyloidosis compared to non-amyloidosis controls.

    Methods: Antral wall autopsy specimens from 11 Japanese ATTR V30M patients and 10 controls were analyzed with immunohistochemistry and computerized analysis. Antibodies to c-Kit and TMEM16A were used to assess ICC and an antibody to PGP 9.5 was used to assess nervous tissue. The study was approved by a Japanese ethical committee.

    Results: The densities of c-Kit-immunoreactive (IR) ICC were significantly lower in the circular and longitudinal muscle layers of patients compared to controls (p = 0.004 for both). Equivalent results were found for TMEM 16A-IR ICC. There were no significant differences in PGP 9.5-IR cells in the circular or longitudinal muscle layers between patients and controls (p = 0.173 and 0.099, respectively).

    Conclusions: A loss of gastrointestinal ICC may be an important factor for the digestive disturbances in hereditary TTR amyloidosis.

  • 41.
    Wixner, Jonas
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Pilebro, Bjorn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Lundgren, Hans-Erik
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Olsson, Malin
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Effect of doxycycline and ursodeoxycholic acid on transthyretin amyloidosis2017In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 24, no 1, p. 78-79Article in journal (Refereed)
    Abstract [en]

    Doxycycline has been shown to disrupt transthyretin amyloid (ATTR) fibrils [1] and tauro-ursodeoxycholic acid (TUDCA) has been shown to reduce TTR toxic aggregates in mice [2]. Further, in 2010 Cardoso et al. showed that a combined doxycycline/TUDCA treatment had a synergistic effect, decreasing ATTR deposition. Ursodeoxycholic acid (UDCA) is a bile acid used for the treatment of certain cholestatic syndromes with an efficacy similar to that of TUDCA. Based on this knowledge, we wanted to explore if treatment with doxycycline and UDCA (Dox/Urso) would prevent disease progression in ATTR amyloidosis. UDCA was selected since TUDCA is not available in Sweden.

  • 42.
    Wixner, Jonas
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Suhr, Ole B.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Management of gastrointestinal complications in hereditary transthyretin amyloidosis: a single-center experience over 40 years2018In: Expert Review of Gastroenterology & Hepatology, ISSN 1747-4124, E-ISSN 1747-4132, Vol. 12, no 1, p. 73-81Article, review/survey (Refereed)
    Abstract [en]

    Introduction: Hereditary transthyretin amyloidosis (ATTRm amyloidosis) is a rare disease caused by the deposition and accumulation of insoluble non-native transthyretin fibrils in the body. The disease inevitably results in widespread organ disruption, and poor life expectancy. The GI tract is one organ system vulnerable to disruption and, although the clinical presentation of the disease varies, GI involvement affects most patients with ATTRm amyloidosis.

    Areas covered: This article presents our experience with diagnosing and treating the GI symptoms of ATTRm amyloidosis patients at our center over the last 40 years, in the Swedish clustering area of the disease. Our aim is to help other physicians to better manage GI complications in patients with this rare but widespread condition.

    Expert commentary: GI symptoms are debilitating complications for ATTRm amyloidosis patients to experience, yet with the appropriate questioning and diagnosis methods, symptomatic treatments of these symptoms can be implemented to provide relief. Further, patients with fewer GI complications and a good nutritional status are also better candidates for liver transplantation which, in selected cases, is the best disease-modifying treatment of ATTRm amyloidosis to date.

  • 43.
    Wixner, Jonas
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Sundström, Torbjorn
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Karling, Pontus
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Suhr, Ole B.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Outcome of gastric emptying and gastrointestinal symptoms after liver transplantation for hereditary transthyretin amyloidosis2015In: BMC Gastroenterology, E-ISSN 1471-230X, Vol. 15, article id 51Article in journal (Refereed)
    Abstract [en]

    Background: Hereditary transthyretin amyloid (ATTR) amyloidosis is a rare but fatal autosomal dominant condition that is present all over the world. A liver transplantation has been shown to halt the progress of the disease in selected patients and is currently considered to be the standard treatment. Gastrointestinal manifestations are common in hereditary ATTR amyloidosis and are important for the patients' morbidity and mortality. The aim of this study was to evaluate the long-term outcome of gastric emptying, gastrointestinal symptoms and nutritional status after liver transplantation for the disease.

    Methods: Swedish patients with hereditary ATTR amyloidosis transplanted between 1990 and 2012 were included. A standardized method for measuring gastric emptying with a Tc-99m-labelled meal followed by scintigraphy was utilized. Validated questionnaires were used to assess gastrointestinal symptoms and the modified body mass index (mBMI), in which BMI is multiplied by s-albumin, was used to evaluate nutritional status. Non-parametrical statistical tests were used.

    Results: Gastric emptying rates and nutritional statuses were evaluated approximately eight months before and two and five years after liver transplantation, whereas gastrointestinal symptoms were assessed in median nine months before and two and nine years after transplantation. No significant change was found in gastric emptying (median half-time 137 vs. 132 vs. 125 min, p = 0.52) or nutritional status (median mBMI 975 vs. 991 vs. 973, p = 0.75) after transplantation. Gastrointestinal symptom scores, however, had increased significantly over time (median score 7 vs. 10 vs. 13, p < 0.01).

    Conclusions: Gastric emptying and nutritional status were maintained after liver transplantation for hereditary ATTR amyloidosis, although gastrointestinal symptom scores had increased over time.

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  • 44.
    Wixner, Jonas
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Törnblom, H.
    Karling, Pontus
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Lindberg, G.
    Abnormal small bowel motility in patients with hereditary transthyretin amyloidosis2018In: Neurogastroenterology and Motility, ISSN 1350-1925, E-ISSN 1365-2982, Vol. 30, no 9, article id e13354Article in journal (Refereed)
    Abstract [en]

    Background: Gastrointestinal complications are common in hereditary transthyretin amyloid (ATTRm) amyloidosis. The underlying mechanisms have not been fully elucidated, and the patients' small bowel function remains largely unexplored. The aim of the present study was to compare the small bowel motility in ATTRm amyloidosis patients with that in non-amyloidosis patient controls.

    Methods: ATTRm amyloidosis patients undergoing evaluation for liver transplantation were consecutively investigated with 24-hour duodenojejunal manometry (n=19). The somatostatin analogue octreotide was used to induce fasting motility. Patients with age at onset of 50years were defined as late-onset cases. For each patient, three age- and sex-matched patient controls (n=57) were selected from the total pool of investigated patients.

    Key Results: Manometry was judged as abnormal in 58% of the patients and in 26% of the patient controls (P=.01). Patients displayed significantly more daytime phase III migrating motor complexes than patient controls (median 4 vs 2, P<.01), and had a higher frequency of low-amplitude complexes (16% vs 4%; however, this difference did not reach statistical significance, P=.10). Furthermore, late-onset patients showed a delay in octreotide response (5.4 vs 3.8minutes, P<.01), but this was not observed for early-onset patients or within the control group.

    Conclusions and Inferences: Patients with ATTRm amyloidosis displayed abnormalities in their small bowel motility more frequently than non-amyloidosis patient controls, and the manometric pattern was probably best consistent with a combined neuromyopathic disorder. The delayed octreotide response in late-onset patients warrants further investigation.

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  • 45.
    Wixner, Jonas
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Westermark, Per
    Ihse, Elisabet
    Pilebro, Björn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Lundgren, Hans-Erik
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    The Swedish open-label diflunisal trial (DFNS01) on hereditary transthyretin amyloidosis and the impact of amyloid fibril composition2019In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 26, p. 39-40Article in journal (Refereed)
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