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  • 1. Adams, D.
    et al.
    Coelho, T.
    Conceicao, E.
    Waddington-Cruz, M.
    Schmidt, H.
    Buades, J.
    Campistol, J. M.
    Pouget, J.
    Berk, J. L.
    Polydefkis, M.
    Ziyadeh, N.
    Partisano, A. M.
    Chen, J.
    Gollob, J.
    Suhr, Ole B.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    PHASE 2 OPEN-LABEL EXTENSION (OLE) STUDY OF PATISIRAN, AN INVESTIGATIONAL RNA INTERFERENCE (RNAI) THERAPEUTIC FOR THE TREATMENT OF HEREDITARY ATTR AMYLOIDOSIS WITH POLYNEUROPATHY2017In: Value in Health, ISSN 1098-3015, E-ISSN 1524-4733, Vol. 20, no 5, p. A211-A212Article in journal (Other academic)
  • 2. Adams, D.
    et al.
    Coelho, T.
    Conceicao, I.
    Cruz, M. Waddington
    Schmidt, H.
    Buades, J.
    Campistol, J.
    Pouget, J.
    Berk, J. L.
    Ziyadeh, N.
    Partisano, A. M.
    Sweetser, M.
    Chen, J.
    Gollob, J.
    Suhr, Ole
    Umeå University.
    Phase 2 open-label extension (OLE) study of patisiran for the treatment of hereditary ATTR (hATTR) amyloidosis: 24-month safety and efficacy in subgroup of patients with cardiac involvement2017In: European Journal of Heart Failure, ISSN 1388-9842, E-ISSN 1879-0844, Vol. 19, no Suppl: 1, p. 19-19Article in journal (Refereed)
  • 3. Adams, D.
    et al.
    Coelho, T.
    Conceicao, I.
    Cruz, M. Waddington
    Schmidt, H.
    Buades, J.
    Campistol, J.
    Pouget, J.
    Berk, J.
    Ziyadeh, N.
    Partisano, A.
    Chen, J.
    Sweetser, M.
    Gollob, J.
    Suhr, Ole
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Phase 2 open-label extension (OLE) study of patisiran with or without a TTR stabilizer for the treatment of hereditary ATTR (hATTR) amyloidosis with polyneuropathy2017In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 24, p. 31-32Article in journal (Other academic)
  • 4. Adams, D.
    et al.
    Coelho, T.
    Suhr, Ole
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Conceicao, I.
    Waddington-Cruz, M.
    Schmidt, H.
    Campistol, J.
    Pouget, J.
    Buades, J.
    Falzone, R.
    Harrop, J.
    De Frutos, R.
    Butler, J.
    Cehelsky, J.
    Nochur, S.
    Vaishnaw, A.
    Gollob, J.
    Interim results from phase ii trial of aln-ttr02, a novel RNAi therapeutic for the treatment of familial amyloidotic polyneuropathy2013In: Journal of the peripheral nervous system, ISSN 1085-9489, E-ISSN 1529-8027, Vol. 18, no Supplement 2, p. 1-2Article in journal (Other academic)
  • 5. Adams, D.
    et al.
    Gonzalez-Duarte, A.
    O'Riordan, W. D.
    Yang, C. -C
    Ueda, M.
    Kristen, A. V.
    Tournev, I.
    Schmidt, H. H.
    Coelho, T.
    Berk, J. L.
    Lin, K. -P
    Vita, G.
    Attarian, S.
    Plante-Bordeneuve, V.
    Mezei, M. M.
    Campistol, J. M.
    Buades, J.
    Brannagan, T. H. , I I I
    Kim, B. J.
    Oh, J.
    Parman, Y.
    Sekijima, Y.
    Hawkins, P. N.
    Solomon, S. D.
    Polydefkis, M.
    Dyck, P. J.
    Gandhi, P. J.
    Goyal, S.
    Chen, J.
    Strahs, A. L.
    Nochur, S. V.
    Sweetser, M. T.
    Garg, P. P.
    Vaishnaw, A. K.
    Gollob, J. A.
    Suhr, Ole B.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis2018In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 379, no 1, p. 11-21Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Patisiran, an investigational RNA interference therapeutic agent, specifically inhibits hepatic synthesis of transthyretin.

    METHODS: In this phase 3 trial, we randomly assigned patients with hereditary transthyretin amyloidosis with polyneuropathy, in a 2:1 ratio, to receive intravenous patisiran (0.3 mg per kilogram of body weight) or placebo once every 3 weeks. The primary end point was the change from baseline in the modified Neuropathy Impairment Score+7 (mNIS+7; range, 0 to 304, with higher scores indicating more impairment) at 18 months. Other assessments included the Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) questionnaire (range, -4 to 136, with higher scores indicating worse quality of life), 10-m walk test (with gait speed measured in meters per second), and modified body-mass index (modified BMI, defined as [weight in kilograms divided by square of height in meters] x albumin level in grams per liter; lower values indicated worse nutritional status).

    RESULTS: A total of 225 patients underwent randomization (148 to the patisiran group and 77 to the placebo group). The mean (+/- SD) mNIS+7 at baseline was 80.9 +/- 41.5 in the patisiran group and 74.6 +/- 37.0 in the placebo group; the least-squares mean (+/- SE) change from baseline was -6.0 +/- 1.7 versus 28.0 +/- 2.6 (difference, -34.0 points; P<0.001) at 18 months. The mean (+/- SD) baseline Norfolk QOL-DN score was 59.6 +/- 28.2 in the patisiran group and 55.5 +/- 24.3 in the placebo group; the least-squares mean (+/- SE) change from baseline was -6.7 +/- 1.8 versus 14.4 +/- 2.7 (difference, -21.1 points; P<0.001) at 18 months. Patisiran also showed an effect on gait speed and modified BMI. At 18 months, the least-squares mean change from baseline in gait speed was 0.08 +/- 0.02 m per second with patisiran versus -0.24 +/- 0.04 m per second with placebo (difference, 0.31 m per second; P<0.001), and the least-squares mean change from baseline in the modified BMI was -3.7 +/- 9.6 versus -119.4 +/- 14.5 (difference, 115.7; P<0.001). Approximately 20% of the patients who received patisiran and 10% of those who received placebo had mild or moderate infusion-related reactions; the overall incidence and types of adverse events were similar in the two groups.

    CONCLUSIONS: In this trial, patisiran improved multiple clinical manifestations of hereditary transthyretin amyloidosis.

  • 6.
    Adams, David
    et al.
    Department of Neurology, French National Reference Centre for Familial Amyloidotic Polyneuropathy, CHU Bicêtre, Université Paris-Saclay APHP, INSERM U1195, Le Kremlin-Bicêtre, France.
    Ando, Yukio
    Department of Neurology, Graduate School of Medical Sciences, Kumamoto, Japan.
    Beirão, João Melo
    Ophthalmology Service, Hospital de Santo António, Porto, Portugal.
    Coelho, Teresa
    Centro Hospitalar Do Porto, Porto, Portugal.
    Gertz, Morie A.
    Mayo Clinic, Rochester, MN, United States.
    Gillmore, Julian D.
    National Amyloidosis Centre, University College London, London, United Kingdom.
    Hawkins, Philip N.
    National Amyloidosis Centre, University College London, London, United Kingdom.
    Lousada, Isabelle
    Amyloidosis Research Consortium, Boston, MA, United States.
    Suhr, Ole B.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Merlini, Giampaolo
    Amyloidosis Center Foundation, IRCCS Policlinico San Matteo, San Matteo, Italy; Department of Molecular Medicine, University of Pavia, Pavia, Italy.
    Expert consensus recommendations to improve diagnosis of ATTR amyloidosis with polyneuropathy2021In: Journal of Neurology, ISSN 0340-5354, E-ISSN 1432-1459, Vol. 268, no 6, p. 2109-2122Article, review/survey (Refereed)
    Abstract [en]

    Amyloid transthyretin (ATTR) amyloidosis with polyneuropathy (PN) is a progressive, debilitating, systemic disease wherein transthyretin protein misfolds to form amyloid, which is deposited in the endoneurium. ATTR amyloidosis with PN is the most serious hereditary polyneuropathy of adult onset. It arises from a hereditary mutation in theTTRgene and may involve the heart as well as other organs. It is critical to identify and diagnose the disease earlier because treatments are available to help slow the progression of neuropathy. Early diagnosis is complicated, however, because presentation may vary and family history is not always known. Symptoms may be mistakenly attributed to other diseases such as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), idiopathic axonal polyneuropathy, lumbar spinal stenosis, and, more rarely, diabetic neuropathy and AL amyloidosis. In endemic countries (e.g., Portugal, Japan, Sweden, Brazil), ATTR amyloidosis with PN should be suspected in any patient who has length-dependent small-fiber PN with autonomic dysfunction and a family history of ATTR amyloidosis, unexplained weight loss, heart rhythm disorders, vitreous opacities, or renal abnormalities. In nonendemic countries, the disease may present as idiopathic rapidly progressive sensory motor axonal neuropathy or atypical CIDP with any of the above symptoms or with bilateral carpal tunnel syndrome, gait disorders, or cardiac hypertrophy. Diagnosis should include DNA testing, biopsy, and amyloid typing. Patients should be followed up every 6-12 months, depending on the severity of the disease and response to therapy. This review outlines detailed recommendations to improve the diagnosis of ATTR amyloidosis with PN.

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  • 7.
    Adams, David
    et al.
    CHU Bicêtre, APHP, French Reference Centre For FAP (NNERF), LE KREMLIN-BICETRE, France.
    Suhr, Ole B.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Conceicao, Isabel
    Centro Hospitalar Lisboa Norte-Hospital de Santa Maria, Department of Neurology, Lisbon, Portugal.
    Waddington-Cruz, Marcia
    Hospital Universitario Clementino Fraga Filho, UFRJ, Rio de Janeiro, Brazil.
    Schmidt, Hartmut
    University Hospital of Münster, Department of Transplantation, Münster, Germany.
    Buades, Juan
    Hospital Son Llatzer, Servicio de Medicina Interna, Palma de Mallorca, Spain.
    Campistol, Josep
    Hospital Clinic Barcelona, Instituto Clinic de Nefrologia y Urologia (ICNU), Barcelona, Spain.
    Coehlo, Teresa
    Hospital de Santo Antonio, Unidade Clinica de Paramiloidose, Porto, Portugal.
    Phase 2 open-label extention (OLE) study of patisiran, an investigational siRNA agent for familial amyloidotic polyneuropathy (FAP)2015In: Orphanet Journal of Rare Diseases, E-ISSN 1750-1172, Vol. 10, article id O20Article in journal (Refereed)
    Abstract [en]

    Background: Familial amyloidotic polyneuropathy (FAP) is a progressive and fatal, autosomal dominant disease caused by deposition of mutant and wild-type transthyretin (TTR). Patisiran is an investigational, systemically administered lipid nanoparticle (LNP) formulation of a small interfering RNA (siRNA) targeting wild-type and mutant TTR. This formulation delivers the siRNA predominantly to the liver, thereby inhibiting synthesis of TTR at the primary site of production. A recently completed multi-center, multi-dose Phase 2 trial of patisiran in FAP patients (N=29) showed >80% sustained mean knockdown of serum TTR when administered at a dose of 0.3 mg/kg every 3 weeks with a generally favorable safety profile (Suhr O, ISA 2014).

    Methods: A Phase 2 open-label extension (OLE) study of patisiran in patients with FAP who participated in the aforementioned trial, was initiated in October 2013. The primary objective of the study is to evaluate the safety and tolerability of 0.3 mg/kg patisiran administered intravenously once every 3 weeks for up to 2 years. Secondary objectives include assessment of patisiran's effect on serum TTR levels, as well as evaluation every 6 months of its impact on clinical measures, including the mNIS+7 composite neurologic impairment score and quality of life (QOL).

    Results: Twenty-seven patients were enrolled; median age 64 years (range: 29-77 years). Chronic dosing with patisiran has been generally well tolerated. Three patients experienced serious adverse events unrelated to study drug. Flushing and infusion-related reactions were observed in 22.2% and 18.5% of the patients, respectively; these were mild in severity, and did not result in any discontinuations. Sustained mean serum TTR lowering of approximately 80% was achieved, with further mean nadir of up to 88% between doses for approximately 16 months. Stabilization of quality of life (QOL) measures was observed. Among the 20 evaluable patients at the time of data cutoff, neuropathy impairment scores were stable through 12 months with a mean change in mNIS+7 and NIS of -2.5 and 0.4 points, respectively; this compares favorably to the 10-18 point increase in neurologic impairment scores estimated at 12 months from prior FAP studies in a patient population with similar baseline NIS.

    Conclusion: Data from this Phase 2 OLE study demonstrate that 12-months of patisiran administration was well-tolerated, resulted in sustained mean serum TTR lowering, and has the potential to halt neuropathy progression. As of March 2015, dosing continues for all patients; 18-month results will be presented.

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  • 8. Adams, David
    et al.
    Suhr, Ole B.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Hund, Ernst
    Obici, Laura
    Tournev, Ivailo
    Campistol, Josep M.
    Slama, Michel S.
    Hazenberg, Bouke P.
    Coelho, Teresa
    First European consensus for diagnosis, management, and treatment of transthyretin familial amyloid polyneuropathy2016In: Current Opinion in Neurology, ISSN 1350-7540, E-ISSN 1473-6551, Vol. 29, p. S14-S26Article in journal (Refereed)
    Abstract [en]

    Purpose of review Early and accurate diagnosis of transthyretin familial amyloid polyneuropathy (TTR-FAP) represents one of the major challenges faced by physicians when caring for patients with idiopathic progressive neuropathy. There is little consensus in diagnostic and management approaches across Europe. Recent findings The low prevalence of TTR-FAP across Europe and the high variation in both genotype and phenotypic expression of the disease means that recognizing symptoms can be difficult outside of a specialized diagnostic environment. The resulting delay in diagnosis and the possibility of misdiagnosis can misguide clinical decision-making and negatively impact subsequent treatment approaches and outcomes. Summary This review summarizes the findings from two meetings of the European Network for TTR-FAP (ATTReuNET). This is an emerging group comprising representatives from 10 European countries with expertise in the diagnosis and management of TTR-FAP, including nine National Reference Centres. The current review presents management strategies and a consensus on the gold standard for diagnosis of TTR-FAP as well as a structured approach to ongoing multidisciplinary care for the patient. Greater communication, not just between members of an individual patient's treatment team, but also between regional and national centres of expertise, is the key to the effective management of TTR-FAP.

  • 9. Adams, David
    et al.
    Suhr, Ole
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Conceicao, Isabel
    Waddington-Cruz, Marcia
    Schmidt, Hartmut
    Buades, Juan
    Campistol, Josep
    Pouget, Jean
    Berk, John
    Coelho, Teresa
    Phase 2 open-label extension study of patisiran, an investigational RNAi therapeutic for the treatment of familial amyloid polyneuropathy2015In: Journal of Neurology, Neurosurgery and Psychiatry, ISSN 0022-3050, E-ISSN 1468-330X, Vol. 86, no 11Article in journal (Other academic)
  • 10. Ajroud-Driss, Senda
    et al.
    Adams, David
    Coelho, Teresa
    Polydefkis, Michael
    Gonzalez-Duarte, Alejandra
    Quan, Dianna
    Kristen, Arnt
    Berk, John
    Agarwal, Sonalee
    Partisano, Angela
    Gollob, Jared
    Sweester, Marianne
    Chen, Jihong
    Suhr, Ole B.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Impact of Patisiran on overall health status in hATTR amyloidosis: Results from the APOLLO trial2018In: Journal of the peripheral nervous system, ISSN 1085-9489, E-ISSN 1529-8027, Vol. 23, no 4, p. 272-273Article in journal (Other academic)
  • 11. Ajroud-Driss, Senda
    et al.
    Adams, David
    Coelho, Teresa
    Polydefkis, Michael
    Gonzalez-Duarte, Alejandra
    Quan, Dianna
    Kristen, Arnt
    Berk, John L.
    Partisano, Angela M.
    Gollob, Jared
    Sweetser, Marianne T.
    Chen, Jihong
    Agarwal, Sonalee
    Suhr, Ole B.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Impact of Patisiran on Overall Health Status in hATTR Amyloidosis: Results from the APOLLO Trial2019In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 92, no 15Article in journal (Other academic)
  • 12.
    Alaish, Ram
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Lundgren, David
    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.
    Werner, Mårten
    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.
    Safety of azathioprine and 6-mercaptopurine in patients with inflammatory bowel disease naive to thiopurine treatment2017In: International journal of clinical pharmacology and therapeutics, ISSN 0946-1965, Vol. 55, no 7, p. 594-600Article in journal (Refereed)
    Abstract [en]

    Objectives: To determine if 6-mercaptopurine (MP) is better tolerated than azathioprine (AZA) as the initial thiopurine treatment in patients suffering from inflammatory bowel disease (IBD). Switching patients with IBD from AZA to MP is advocated in patients intolerant to AZA. However, no study has determined if MP is more suited than AZA as a first-line treatment for patients who are naive to thiopurine treatment. Study: The tolerance of AZA and MP treatments in clinical practice was retrospectively evaluated from start to 12 months after initiating treatment in 113 patients with IBD who were all naive to thiopurines (82 patients treated with AZA and 31 patients with MP). Results: 65% of the patients treated with AZA and 61% of the patients treated with MP tolerated their treatment during 12 months (i.e., no group difference, p = 0.742). No difference in reported side effects between the two treatments was observed. The mean equivalent initial dose (0.92 vs. 0.61 mg/kg; p < 0.001) and the mean equivalent dose at 12 months (1.98 vs. 1.65 mg/kg; p = 0.014) was significantly higher in the MP group vs. the AZA group. The proportion of patients with.MCV = 7 at 12 months was numerically higher in the MP group than in the AZA group (53% vs. 31%; p = 0.090). Conclusions: In this retrospective observational study, no differences in tolerance or adherence between AZA and MP were observed in patients naive to thiopurines. However, MP treatment was at a higher equivalent thiopurine dose than AZA treatment, which tended to be associated with better treatment response.

  • 13. Altland, Klaus
    et al.
    Winter, Pia
    Saraiva, Maria Joao M
    Suhr, Ole B
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Sulfite and base for the treatment of familial amyloidotic polyneuropathy: two additive approaches to stabilize the conformation of human amyloidogenic transthyretin.2004In: Neurogenetics, ISSN 1364-6745, Vol. 5, no 1, p. 61-7Article in journal (Refereed)
  • 14.
    Anan, Intissar
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    El-Salhy, M
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Ando, Y
    Forsgren, S
    Nyhlin, N
    Terazaki, H
    Sakashita, N
    Suhr, Ole B
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Colonic enteric nervous system in patients with familial amyloidotic neuropathy.1999In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 98, no 1, p. 48-54Article in journal (Refereed)
    Abstract [en]

    The colonic enteric nervous system was investigated in autopsy specimens from 12 patients with familial amyloidotic neuropathy (FAP) and 9 controls. The infiltration of amyloid deposits in the enteric nervous system was studied by double staining for amyloid and nerve elements. The myenteric plexus was immunostained for protein gene product (PGP) 9.5, vasoactive intestinal peptide (VIP), substance P and nitric oxide synthase (NOS). The immunostained nerve elements were quantified by computerised image analysis. Double staining revealed that there was no amyloid infiltration in the ganglia, or in the nerve fibres in the colonic enteric nervous system of FAP patients. The relative volume density of PGP 9.5-immunoreactive nerve fibres in both the circular and the longitudinal muscle layers in FAP patients did not differ significantly from that of controls. The relative volume density of VIP-immunoreactive nerve fibres in the circular muscle layer was significantly decreased in FAP patients compared with controls, but not in the longitudinal layer. The number of VIP-immunoreactive neurons/mm2 myenteric ganglia was significantly decreased in FAP patients. There were no statistical differences in the relative volume density for substance P- and NOS-immunoreactive nerve fibres between FAP patients and controls, nor was there any difference between FAP patients and controls regarding the number of NOS- and substance P-immunoreactive neurons/mm2 myenteric ganglia. It is concluded that the colonic enteric nervous system as a whole is intact and is not damaged by amyloid infiltration. The present observation of a reduction of VIP-immunoreactive nerve fibres and neurons in myenteric plexus of FAP patients might be one of the factors that contribute to the motility disorders seen in FAP patients.

  • 15.
    Anan, Intissar
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    El-Salhy, M
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Ando, Y
    Nyhlin, N
    Terazaki, H
    Sakashita, N
    Suhr, Ole B
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Colonic endocrine cells in patients with familial amyloidotic polyneuropathy.1999In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 245, no 5, p. 469-73Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To establish whether the endocrine cell number is affected in the colon in Japanese FAP patients.

    SETTING: Department of Medicine, Umeå University Hospital and Department of Internal Medicine and Pathology, University Hospital, Kumamoto, Japan.

    SUBJECTS: Autopsy colon tissue specimens from 11 FAP patients and nine controls as well as 12 control biopsy specimens were included in the study.

    MEASUREMENTS: Endocrine cells in the colon were detected by immunohistochemistry and quantified by computerized image analysis.

    RESULTS: The autopsy material showed a slight autolysis. Neither enteroglucagon nor pancreatic polypeptide positive cells could be detected in the autopsy material, but were present in biopsy material. There was no statistical difference between autopsy and biopsy specimens regarding the number of peptide YY (PYY), somatostatin and serotonin cells. No significant differences were noted in PYY, somatostatin and serotonin immunoreactive cells in FAP patients compared to autopsy controls, though PYY cells tended to be decreased and serotonin and somatostatin cells tended to be increased in FAP patients.

    CONCLUSION: The difference between the Swedish and Japanese patients in the endocrine cell content points to the possibility of involvement of other factors than the endocrine cell depletion of the colon might be involved in the pathogenesis of gastro-intestinal dysfunction in FAP. The tendency of PYY to decrease in Japanese FAP might contribute to the development of diarrhoea in these patients.

  • 16.
    Anan, Intissar
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    El-salhy, M
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Ando, Y
    Terazaki, H
    Suhr, Ole B
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Comparison of amyloid deposits and infiltration of enteric nervous system in the upper with those in the lower gastrointestinal tract in patients with familial amyloidotic polyneuropathy.2001In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 102, no 3, p. 227-32Article in journal (Refereed)
    Abstract [en]

    Gastrointestinal (GI) complications in familial amyloidotic polyneuropathy (FAP) are invariably present during the course of the disease. The aim of this study was to investigate amyloid deposits in the myenteric plexus of the stomach and small intestine in FAP patients and compare the results with those of the colon. Six FAP patients were included in the study. The myenteric plexus and the number of macrophages (CD68) and blood vessels were immunostained and quantified by computerised image analysis. Double staining for amyloid and nerve elements was used to detect amyloid infiltration in the myenteric plexus. Amyloid was found predominantly in the walls of blood vessels, and was detected in the nerves of five FAP patients and in 18% of the examined ganglia of the myenteric plexus of the stomach. In the small intestine, 6% of examined ganglia showed amyloid deposits. In contrast, no deposits were found in the myenteric plexus of the colon. CD68-positive cells showed no difference in three parts of the GI tract. Most amyloid deposits were noted in the stomach, followed by the small intestine. There are significantly more blood vessels in the stomach and small intestine compared with the colon, and the amount of amyloid correlated with the number of blood vessels, and not with the amount of nerves and ganglia. The enteric nerve system is not a targeted organ for amyloid deposition in FAP.

  • 17.
    Anan, Intissar
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    El-Salhy, M
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Nyhlin, N
    Suhr, Ole B
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Liver transplantation restores endocrine cells in patients with familial amyloidotic polyneuropathy.2000In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 70, no 5, p. 794-9Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The aim of this study was to investigate familial amyloidotic polyneuropathy, Portuguese type patients' endocrine cell content in the stomach and duodenum before and after liver transplantation, and to relate the findings to the patients' gastrointestinal disturbances.

    METHODS: Ten liver-transplanted familial amyloidotic polyneuropathy, Portuguese type patients and 10 healthy controls were seen. Endocrine cells were identified by immunohistochemistry and quantified with computerized image analysis. The activity of the cells was appraised by measurements of the cell secretory index and nuclear area. Clinical symptoms were obtained from the patients' medical records.

    RESULTS: After transplantation, a significant increase of several endocrine cell types were noted, and the pretransplant depletion of several types of endocrine cells disappeared. For no type of endocrine cell was any difference compared with controls noted after transplantation. There was no significant decrease of the amount of amyloid in the biopsies after liver transplantation. The patients' symptoms remained generally unchanged after transplantation, although a substantial time lapse between pretransplant evaluation and transplantation was present.

    CONCLUSIONS: Liver transplantation restores the endocrine cells in the upper part of the gastrointestinal tract. The restoration was not correlated with an improvement of the patients' symptoms. No decrease of the amyloid deposits was noted.

  • 18.
    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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  • 19.
    Andersson, Kennet
    et al.
    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, Medicine.
    Faes, Luca
    Wiklund, Urban
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Directed coherence analysis in patients with severe autonomic dysfunction2014In: 2014 8th conference of the European Study Group on Cardiovascular Oscillations (ESGCO), IEEE conference proceedings, 2014, p. 167-168Conference paper (Refereed)
    Abstract [en]

    Many different approaches have been applied to analyse the coupling between cardiovascular signals. This study evaluated the use of directed coherence, based on multivariate autoregressive modelling, for analysis of cardiovascular signals in patients with transthyretin amyloidosis, a rare disease where severe autonomic dysfunction is common.

  • 20. Ando, Y
    et al.
    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.
    Holmgren, G
    Costa, P M
    Detection of a variant protein in hair: new diagnostic method in Portuguese type familial amyloid polyneuropathy.1998In: BMJ (Clinical Research Edition), ISSN 0959-8138, Vol. 316, no 7143, p. 1500-1Article in journal (Refereed)
  • 21.
    Arvidsson, Sandra
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology.
    Henein, Michael Y
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Wikström, Gerhard
    Suhr, Ole B.
    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.
    Right ventricular involvement in transthyretin amyloidosis2018In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 25, no 3, p. 160-166Article in journal (Refereed)
    Abstract [en]

    Background: The extent of right ventricular (RV) involvement in transthyretin amyloidosis (ATTR) is unknown.

    Objectives: This study sought to establish the degree of RV involvement in ATTR amyloidosis, and compare findings with RV involvement in hypertrophic cardiomyopathy (HCM).

    Methods: Forty-two patients with ATTR amyloidosis and echocardiographic evidence of cardiac amyloidosis (cardiac ATTR), 19 ATTR patients with normal left ventricular (LV) wall thickness (non-cardiac ATTR), 25 patients with diagnosed HCM and 30 healthy controls were included in this study. Echocardiographic measurements for conventional parameters, as well as RV global and segmental strain, were recorded.

    Results: When comparing RV structure and function between cardiac ATTR amyloidosis and HCM patients, only segmental strain differed between the two groups. In cardiac ATTR amyloidosis, we found an RV apex-to-base strain gradient with highest deformation in the apex. This pattern was reversed in patients with HCM.

    Conclusions: RV involvement is common in cardiac ATTR patients. The present study also detected an RV apical sparing pattern in patients with ATTR cardiomyopathy, similar to what has previously been described for the left ventricle in these patients. This pattern was not seen in HCM patients. Further studies are needed to assess the clinical importance of these findings.

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  • 22.
    Arvidsson, Sandra
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology.
    Pilebro, Björn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Westermark, Per
    Lindqvist, Per
    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, Medicine.
    Amyloid Cardiomyopathy in Hereditary Transthyretin V30M Amyloidosis - Impact of Sex and Amyloid Fibril Composition2015In: PLOS ONE, E-ISSN 1932-6203, Vol. 10, no 11, article id e0143456Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Transthyretin V30M (ATTR V30M) amyloidosis is a phenotypically diverse disease with symptoms ranging from predominant neuropathy to exclusive cardiac manifestations. The aims of this study were to determine the dispersion of the two types of fibrils found in Swedish ATTR V30M patients -Type A consisting of a mixture of truncated and full length ATTR fibrils and type B fibrils consisting of full length fibrils, and to estimate the severity of cardiac dysfunction in relation to fibril composition and sex.

    MATERIAL AND METHODS: Echocardiographic data were analysed in 107 Swedish ATTR V30M patients with their fibril composition determined as either type A or type B. Measurements of left ventricular (LV) dimensions and evaluation of systolic and diastolic function including speckle tracking derived strain were performed. Patients were grouped according to fibril type and sex. Multivariate linear regression was utilised to determine factors of significant impact on LV thickness.

    RESULTS: There was no significant difference in proportions of the two types of fibrils between men and women. In patients with type A fibrils, women had significantly lower median septal (p = 0.007) and posterior wall thicknesses (p = 0.010), lower median LV mass indexed to height (p = 0.008), and higher septal strain (p = 0.037), as compared to males. These differences were not apparent in patients with type B fibrils. Multiple linear regression analysis revealed that fibril type, sex and age all had significant impact on LV septal thickness.

    CONCLUSION: This study demonstrates a clear difference between sexes in the severity of amyloid heart disease in ATTR V30M amyloidosis patients. Even though type A fibrils were associated with more advanced amyloid heart disease compared to type B, women with type A fibrils generally developed less cardiac infiltration than men. The differences may explain the better outcome for liver transplanted late-onset female patients compared to males.

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  • 23. Berk, JL
    et al.
    Dyck, PJ
    Obici, L
    Zeldenrust, SR
    Sekijima, Y
    Yamashita, T
    Ando, Y
    Ikeda, S-I
    Gorevic, P
    Merlini, G
    Kelly, JW
    Skinner, M
    Bisbee, AB
    Suhr, Ole B
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    The diflunisal trial: update on study drug tolerance and disease progression2011In: Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis, ISSN 1744-2818, Vol. 18, no Suppl. 1, p. 191-192Article in journal (Refereed)
    Abstract [en]

    Abstract: Familial amyloidotic polyneuropathy (FAP) is a lethal genetic disorder that affects the peripheral and autonomic nervous systems, heart, gastro-intestinal (GI) tract, and soft tissues. Disease progression is increasingly reported following liver transplantation, the only proven treatment for FAP. Small molecule thyroxine mimetics stabilize transthyretin, inhibiting FAP amyloid fibril formation under stringent in vitro conditions. We report on the progress of an international, randomized placebo-controlled study designed to determine the effect of diflunisal, a thyroxine mimetic, on neurologic disease progression in patients with active FAP. Our experience to date indicates diflunisal is well tolerated by this study cohort and that neurologic disease advances more rapidly in FAP than it does in diabetes mellitus.

    Background: Transthyretin-related familial amyloidotic polyneuropathy (FAP) is a lethal autosomal dominant genetic disorder that predominantly affects the peripheral nervous system. FAP amyloid fibrils result from the misfolding of transthyretin, a transport protein predominantly produced by the liver. Although liver transplantation effectively treats patients with certain FAP mutations and limited disease, reports increasingly document progressive amyloid deposition following transplantation [1,2]. Alternative treatments are needed. In vitro investigations and a phase I clinical trial have demonstrated that thyroxine and small molecule mimetics, e.g. diflunisal, inhibit tetrameric transthyretin dissociation and suppress amyloid fibril formation [3,4].

    Methods: To examine the effect of diflunisal on disease progression in FAP, we designed a randomized, placebo controlled, double blind, multicenter international study employing the validated diabetic (DM) polyneuropathy metric, Neurologic Impairment Score + 7 attributes (NIS+7®), as the primary endpoint. A two-point change in NIS+7 correlates with clinically detectable progression of peripheral neuropathy among diabetics [5]. Entry criteria include proven FAP genotype, biopsy-proven amyloid deposits, and peripheral or autonomic neuropathy. Patients with alternate causes of neuropathy, other NSAID use, severe heart or kidney dysfunction, or previous liver transplantion are excluded. Study evaluations occur at entry, 6, 12, and 24 months. Adverse are collected by monthly telephone interviews, diary entries, and study site visit interactions. Relatedness of adverse events to study drug is assigned according to documentation in the investigational brochure, the protocol, the informed consent form; or at the investigator's discretion.

    Results: To date, 90 subjects have enrolled – 62 men and 28 women with median age 63 years (range 27–76 years). Adverse events tabulated by affected organ systems predominantly involved gastrointestinal events, more often attributed to disease complications than study drug side effects (Table 1). Although rare events, congestive heart failure in two subjects and GI bleeding in another prompted study drug discontinuation. Two disease-related deaths have occurred, both off study drug. Aggregate data from all study subjects (placebo and active drug arms) followed for at least 12 months identified a 3.2 point increase in median NIS+7 summated scores. In contrast, Dyck et al. [6] reported an annual 0.85 point increase in NIS+7 median scores in a large cohort of diabetics with polyneuropathy. Taken together, NIS+7 detected neurologic disease progression in this FAP cohort after 12 months observation. Additionally, NIS+7 measured disease advanced 3.5 times faster in our aggregate FAP study population than previously reported in DM.

    Conclusions: Diflunisal is well tolerated in FAP patients participating in the study. NIS+7, a composite scoring system, appears to be an effective study instrument for ATTR neuropathy, detecting significant change over 12 months observation. Neurologic disease progresses more rapidly in FAP than DM cohorts. The exact rate of disease progression in untreated FAP subjects detected by NIS+7 awaits unblinding of the data. These data will provide basis for future study design in FAP patients.

  • 24. Berk, John L.
    et al.
    Suhr, Ole B.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Obici, Laura
    Sekijima, Yoshiki
    Zeldenrust, Steven R.
    Yamashita, Taro
    Heneghan, Michael A.
    Gorevic, Peter D.
    Litchy, William J.
    Wiesman, Janice F.
    Nordh, Erik
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Corato, Manuel
    Lozza, Alessandro
    Cortese, Andrea
    Robinson-Papp, Jessica
    Colton, Theodore
    Rybin, Denis V.
    Bisbee, Alice B.
    Ando, Yukio
    Ikeda, Shu-ichi
    Seldin, David C.
    Merlini, Giampaolo
    Skinner, Martha
    Kelly, Jeffery W.
    Dyck, Peter J.
    Repurposing Diflunisal for Familial Amyloid Polyneuropathy: A Randomized Clinical Trial2013In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 310, no 24, p. 2658-2667Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE Familial amyloid polyneuropathy, a lethal genetic disease caused by aggregation of variant transthyretin, induces progressive peripheral nerve deficits and disability. Diflunisal, a nonsteroidal anti-inflammatory agent, stabilizes transthyretin tetramers and prevents amyloid fibril formation in vitro. OBJECTIVE To determine the effect of diflunisal on polyneuropathy progression in patients with familial amyloid polyneuropathy. DESIGN, SETTING, AND PARTICIPANTS International randomized, double-blind, placebo-controlled study conducted among 130 patients with familial amyloid polyneuropathy exhibiting clinically detectable peripheral or autonomic neuropathy at amyloid centers in Sweden (Umea), Italy (Pavia), Japan (Matsumoto and Kumamoto), England (London), and the United States (Boston, Massachusetts; New York, New York; and Rochester, Minnesota) from 2006 through 2012. INTERVENTION Participants were randomly assigned to receive diflunisal, 250 mg (n=64), or placebo (n=66) twice daily for 2 years. MAIN OUTCOMES AND MEASURES The primary end point, the difference in polyneuropathy progression between treatments, was measured by the Neuropathy Impairment Score plus 7 nerve tests (NIS+7) which ranges from 0 (no neurological deficits) to 270 points (no detectable peripheral nerve function). Secondary outcomes included a quality-of-life questionnaire (36-Item Short-Form Health Survey [SF-36]) and modified body mass index. Because of attrition, we used likelihood-based modeling and multiple imputation analysis of baseline to 2-year data. RESULTS By multiple imputation, the NIS+7 score increased by 25.0 (95% CI, 18.4-31.6) points in the placebo group and by 8.7 (95% CI, 3.3-14.1) points in the diflunisal group, a difference of 16.3 points (95% CI, 8.1-24.5 points; P < .001). Mean SF-36 physical scores decreased by 4.9 (95% CI, -7.6 to -2.2) points in the placebo group and increased by 1.5 (95% CI, -0.8 to 3.7) points in the diflunisal group (P < .001). Mean SF-36 mental scores declined by 1.1 (95% CI, -4.3 to 2.0) points in the placebo group while increasing by 3.7 (95% CI, 1.0-6.4) points in the diflunisal group (P = .02). By responder analysis, 29.7% of the diflunisal group and 9.4% of the placebo group exhibited neurological stability at 2 years (<2-point increase in NIS+7 score; P = .007). CONCLUSIONS AND RELEVANCE Among patients with familial amyloid polyneuropathy, the use of diflunisal compared with placebo for 2 years reduced the rate of progression of neurological impairment and preserved quality of life. Although longer-term follow-up studies are needed, these findings suggest benefit of this treatment for familial amyloid polyneuropathy.

  • 25. Berk, John L
    et al.
    Suhr, Ole B
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Sekijima, Yoshiki
    Yamashita, Taro
    Heneghan, Michael
    Zeldenrust, Steven R
    Ando, Yukio
    Ikeda, Shu-ichi
    Gorevic, Peter
    Merlini, Giampaolo
    Kelly, Jeffrey W
    Skinner, Martha
    Bisbee, Alice B
    Dyck, Peter J
    Obici, Laura
    The diflunisal trial: study accrual and drug tolerance2012In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 19, no S1, p. 37-38Article in journal (Refereed)
    Abstract [en]

    Familial amyloidotic polyneuropathy (FAP) is a protein folding disorder that induces neuropathy and cardiomyopathy, leading to death within 7-15 years after onset of clinical disease. In vitro, small ligands binding the thyroid hormone docking site stabilize tetrameric transthyretin, inhibiting amyloid fibril formation. We undertook a randomized, placebo-controlled clinical trial to determine whether diflunisal, a well-known non-steroidal anti-inflammatory drug (NSAID) alters neurologic disease progression in FAP. We enrolled 130 subjects with wide age and FAP mutation representation. To date, few recognized complications of NSAIDs have occurred in the study cohort. Data collection will be completed by November 2012.

  • 26. Bonaïti, Bernard
    et al.
    Olsson, Malin
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Hellman, Urban
    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.
    Bonaïti-Pellié, Catherine
    Planté-Bordeneuve, Violaine
    TTR familial amyloid polyneuropathy: does a mitochondrial polymorphism entirely explain the parent-of-origin difference in penetrance?2010In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438Article in journal (Refereed)
    Abstract [en]

    The Val30Met transthyretin familial amyloid polyneuropathy (TTR-V30M-FAP) is the most frequent familial amyloidosis, with autosomal dominant transmission. This severe disease shows important differences in age of onset and penetrance. Recently, a difference in penetrance according to the gender of the transmitting parent was elicited in different geographic areas with a higher penetrance in case of maternal transmission of the trait. In addition, differences in mitochondrial haplogroup distribution in early and late onset Swedish and French cases of TTR-V30M-FAP suggested that a polymorphism of mitochondrial DNA could be one underlying mechanism of the phenotypic variation. We further investigated this hypothesis by modeling the penetrance function with a parent-of-origin and/or a mitochondrial polymorphism effect in samples of Portuguese (n=33) and Swedish families (n=86) with TTR-V30M-FAP in which several individuals had been tested for mitochondrial haplogroups. Our analysis showed that a mitochondrial polymorphism effect was sufficient to explain the observed difference in penetrance according to gender of the transmitting parent in the Portuguese sample, whereas, in the Swedish sample, a clear residual parent-of-origin effect remained. This study further supported the role of a mitochondrial polymorphism effect that might induce a higher penetrance in case of maternal inheritance of the disease. In clinical practice, these results might help to better delineate the individual disease risk and have a significant impact on the management of both patients and carriers.

  • 27. Buxbaum, Joel
    et al.
    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.
    Serum transthyretin levels in Swedish TTR V30M carriers2010In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 17, no 2, p. 83-85Article in journal (Refereed)
    Abstract [en]

    Serum transthyretin (TTR) levels have been reported to be reduced in Portuguese and Japanese patients with TTR V30M familial amyloidotic polyneuropathy and pre-symptomatic carriers of the allele as well as in the carriers of a number of other mutant TTRs. The only published report of serum TTR levels in Swedish TTR V30M carriers suggested that serum TTR levels were elevated in a small number of cases. Since Swedish V30M carriers have a lower degree of clinical penetrance than those from other countries we wished to determine if the reportedly elevated serum TTR concentrations and the lower clinical penetrance were part of a pathologic process that differed between the Swedish carriers and those of other ethnic groups. We compared the serum TTR levels, as determined by ELISA, in 42 documented Swedish TTR V30M carriers with 16 control individuals from the same geographic area in northern Sweden. Serum TTR concentrations in the controls were statistically significantly higher than in the TTR V30M carriers, which were in the same range as those in African-Americans carrying the TTR V122I allele. Thus, Swedish TTR V30M carriers have the same reduction in serum TTR as do other ethnic groups carrying the same or other TTR mutations.

  • 28. Coelho, T
    et al.
    Maia, L
    Martins da Silva, A
    Waddington Cruz, M
    Plante-Bordeneuve, V
    Suhr, Ole B
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Conceicao, I
    Schmidt, H
    Trigo, P
    Packman, J
    Harnett, M
    Grogan, DR
    Long-term effects of tafamidis: a new therapeutic option for patients with transthyretin familial amyloid polyneuropathy (ttr-fap)2012In: Journal of Hepatology, ISSN 0168-8278, E-ISSN 1600-0641, Vol. 56, no Suppl 2, p. S543-S543Article in journal (Other academic)
  • 29. Coelho, T.
    et al.
    Suhr, Ole
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Conceicao, I
    Waddington-Cruz, M.
    Schmidt, H.
    Buades, J.
    Campistol, J.
    Pouget, J.
    Berk, J.
    Falzone, R.
    White, L.
    Bettencourt, B.
    Cehelsky, J.
    Nochur, S.
    Vaishnaw, A.
    Gollob, J.
    Adams, D.
    Phase 2 open-label extension study (ole) of patisiran, an investigational sIRNA investigational agent for familial amyloid polyneuropathy (fap)2015In: Journal of the peripheral nervous system, ISSN 1085-9489, E-ISSN 1529-8027, Vol. 20, no 2, p. 117-118Article in journal (Other academic)
  • 30. Coelho, Teresa
    et al.
    Adams, David
    Conceicao, Isabel
    Waddington-Cruz, Marcia
    Schmidt, Hartmut H.
    Buades, Juan
    Campistol, Josep
    Berk, John L.
    Polydefkis, Michael
    Wang, Jing Jing
    Chen, Jihong
    Sweetser, Marianne T.
    Gollob, Jared
    Suhr, Ole B.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    A phase II, open-label, extension study of long-term patisiran treatment in patients with hereditary transthyretin-mediated (hATTR) amyloidosis2020In: Orphanet Journal of Rare Diseases, E-ISSN 1750-1172, Vol. 15, no 1, article id 179Article in journal (Refereed)
    Abstract [en]

    Background: Patisiran, an RNA interference therapeutic, has demonstrated robust reduction of wild-type and mutant transthyretin protein and was able to improve polyneuropathy and quality of life following 18 months of treatment in patients with hereditary transthyretin-mediated (hATTR) amyloidosis.In this 24-month Phase II open-label extension study, we evaluated the effects of patisiran treatment (0.3 mg/kg intravenously every 3 weeks) on safety, serum transthyretin levels, and clinical parameters. Efficacy assessments included modified Neuropathy Impairment Score +7 (mNIS+7) and multiple disease-relevant measures. Cardiac assessments were performed in a pre-specified cardiac subgroup.

    Results: Twenty-seven patients entered this study, including 12 (44%) with ambulation difficulties due to their neuropathy and 11 (41%) who met criteria for the cardiac subgroup. During treatment, the majority of adverse events were mild/moderate in severity; there were no drug-related adverse events leading to treatment discontinuation. The most common drug-related adverse events were flushing and infusion-related reactions (22% each). Patisiran resulted in rapid, robust (similar to 82%), and sustained reduction of mean transthyretin levels over 24 months. A mean 6.95-point decrease (improvement) in mNIS+7 from baseline was observed at 24 months. Patisiran's impact on mNIS+7 was irrespective of concomitant tafamidis or diflunisal use, sex, or age. Clinical assessments of motor function, autonomic symptoms, disease stage, and quality of life remained stable over 24 months. No significant changes were observed for echocardiographic measures or cardiac biomarkers in the cardiac subgroup. Exploratory analyses demonstrated improvements in nerve-fiber density with corresponding reductions in amyloid burden observed in skin biopsies over 24 months.

    Conclusions: Long-term treatment with patisiran had an acceptable safety profile and was associated with halting/improvement of polyneuropathy progression in patients with hATTR amyloidosis.

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  • 31. Coelho, Teresa
    et al.
    Adams, David
    Silva, Ana
    Lozeron, Pierre
    Hawkins, Philip N
    Mant, Timothy
    Perez, Javier
    Chiesa, Joseph
    Warrington, Steve
    Tranter, Elizabeth
    Munisamy, Malathy
    Falzone, Rick
    Harrop, Jamie
    Cehelsky, Jeffrey
    Bettencourt, Brian R
    Geissler, Mary
    Butler, James S
    Sehgal, Alfica
    Meyers, Rachel E
    Chen, Qingmin
    Borland, Todd
    Hutabarat, Renta M
    Clausen, Valerie A
    Alvarez, Rene
    Fitzgerald, Kevin
    Gamba-Vitalo, Christina
    Nochur, Saraswathy V
    Vaishnaw, Akshay K
    Sah, Dinah W Y
    Gollob, Jared A
    Suhr, Ole B
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Safety and efficacy of RNAi therapy for transthyretin amyloidosis2013In: The New England journal of medicine, ISSN 1533-4406, Vol. 369, no 9, p. 819-29Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Transthyretin amyloidosis is caused by the deposition of hepatocyte-derived transthyretin amyloid in peripheral nerves and the heart. A therapeutic approach mediated by RNA interference (RNAi) could reduce the production of transthyretin. METHODS: We identified a potent antitransthyretin small interfering RNA, which was encapsulated in two distinct first- and second-generation formulations of lipid nanoparticles, generating ALN-TTR01 and ALN-TTR02, respectively. Each formulation was studied in a single-dose, placebo-controlled phase 1 trial to assess safety and effect on transthyretin levels. We first evaluated ALN-TTR01 (at doses of 0.01 to 1.0 mg per kilogram of body weight) in 32 patients with transthyretin amyloidosis and then evaluated ALN-TTR02 (at doses of 0.01 to 0.5 mg per kilogram) in 17 healthy volunteers. RESULTS: Rapid, dose-dependent, and durable lowering of transthyretin levels was observed in the two trials. At a dose of 1.0 mg per kilogram, ALN-TTR01 suppressed transthyretin, with a mean reduction at day 7 of 38%, as compared with placebo (P=0.01); levels of mutant and nonmutant forms of transthyretin were lowered to a similar extent. For ALN-TTR02, the mean reductions in transthyretin levels at doses of 0.15 to 0.3 mg per kilogram ranged from 82.3 to 86.8%, with reductions of 56.6 to 67.1% at 28 days (P<0.001 for all comparisons). These reductions were shown to be RNAi-mediated. Mild-to-moderate infusion-related reactions occurred in 20.8% and 7.7% of participants receiving ALN-TTR01 and ALN-TTR02, respectively. CONCLUSIONS: ALN-TTR01 and ALN-TTR02 suppressed the production of both mutant and nonmutant forms of transthyretin, establishing proof of concept for RNAi therapy targeting messenger RNA transcribed from a disease-causing gene. (Funded by Alnylam Pharmaceuticals; ClinicalTrials.gov numbers, NCT01148953 and NCT01559077.).

  • 32. Coelho, Teresa
    et al.
    Ericzon, Bo-Göran
    Falk, Rodney
    Grogan, Donna
    Ikeda, Shu-ichi
    Maurer, Mathew
    Planté-Bordeneuve, Violaine
    Suhr, Ole B
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Trigo, Pedro
    A Physician's Guide to Transthyretin Amyloidosis2008Report (Other academic)
  • 33. Coelho, Teresa
    et al.
    Maia, Luis F.
    da Silva, Ana Martins
    Cruz, Marcia Waddington
    Plante-Bordeneuve, Violaine
    Lozeron, Pierre
    Suhr, Ole B.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Campistol, Josep M.
    Conceicao, Isabel Maria
    Schmidt, Hartmut H. -J.
    Trigo, Pedro
    Kelly, Jeffery W.
    Labaudinie, Richard
    Chan, Jason
    Packman, Jeff
    Wilson, Amy
    Grogan, Donna R.
    Tafamidis for transthyretin familial amyloid polyneuropathy: A randomized, controlled trial2012In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 79, no 8, p. 785-792Article in journal (Refereed)
    Abstract [en]

    Objectives: To evaluate the efficacy and safety of 18 months of tafamidis treatment in patients with early-stage V30M transthyretin familial amyloid polyneuropathy (TTR-FAP). Methods: In this randomized, double-blind trial, patients received tafamidis 20 mg QD or placebo. Coprimary endpoints were the Neuropathy Impairment Score-Lower Limbs (NIS-LL) responder analysis (<2-point worsening) and treatment-group difference in the mean change from baseline in Norfolk Quality of Life-Diabetic Neuropathy total score (TQOL) in the intent-to-treat (ITT) population (n = 125). These endpoints were also evaluated in the efficacy-evaluable (EE; n = 87) population. Secondary endpoints, including changes in neurologic function, nutritional status, and TTR stabilization, were analyzed in the ITT population. Results: There was a higher-than-anticipated liver transplantation dropout rate. No differences were observed between the tafamidis and placebo groups for the coprimary endpoints, NIS-LL responder analysis (45.3% vs 29.5% responders; p = 0.068) and change in TQOL (2.0 vs 7.2; p = 0.116) in the ITT population. In the EE population, significantly more tafamidis patients than placebo patients were NIS-LL responders (60.0% vs 38.1%; p = 0.041), and tafamidis patients had better-preserved TQOL (0.1 vs 8.9; p = 0.045). Significant differences in most secondary endpoints favored tafamidis. TTR was stabilized in 98% of tafamidis and 0% of placebo patients (p < 0.0001). Adverse events were similar between groups. Conclusions: Although the coprimary endpoints were not met in the ITT population, tafamidis was associated with no trend toward more NIS-LL responders and a significant reduction in worsening of most neurologic variables, supporting the hypothesis that preventing TTR dissociation can delay peripheral neurologic impairment. Classification of evidence: This study provides Class II evidence that 20 mg tafamidis QD was associated with no difference in clinical progression in patients with TTR-FAP, as measured by the NIS-LL and the Norfolk QOL-DN score. Secondary outcomes demonstrated a significant delay in peripheral neurologic impairment with tafamidis, which was well tolerated over 18 months. Neurology (R) 2012;79:785-792

  • 34. Coelho, Teresa
    et al.
    Maia, Luis F
    da Silva, Ana Martins
    Cruz, Márcia W
    Planté-Bordeneuve, Violaine
    Suhr, Ole B
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Conceiçao, Isabel
    Schmidt, Hartmut H-J
    Trigo, Pedro
    Kelly, Jeffery W
    Labaudinière, Richard
    Chan, Jason
    Packman, Jeff
    Grogan, Donna R
    Long-term effects of tafamidis for the treatment of transthyretin familial amyloid polyneuropathy2013In: Journal of Neurology, ISSN 0340-5354, E-ISSN 1432-1459, Vol. 260, no 11, p. 2802-2814Article in journal (Refereed)
    Abstract [en]

    Tafamidis, a transthyretin (TTR) kinetic stabilizer, delayed neuropathic progression in patients with Val30Met TTR familial amyloid polyneuropathy (TTR-FAP) in an 18-month randomized controlled trial (study Fx-005). This 12-month, open-label extension study evaluated the long-term safety, tolerability, and efficacy of tafamidis 20 mg once daily in 86 patients who earlier received blinded treatment with tafamidis or placebo. Efficacy measures included the Neuropathy Impairment Score in the Lower Limbs (NIS-LL), Norfolk Quality of Life-Diabetic Neuropathy total quality of life (TQOL) score, and changes in neurologic function and nutritional status. We quantified the monthly rates of change in efficacy measures, and TTR stabilization, and monitored adverse events (AEs). Patients who continued on tafamidis had stable rates of change in NIS-LL (from 0.08 to 0.11/month; p = 0.60) and TQOL (from -0.03 to 0.25; p = 0.16). In patients switched from placebo, the monthly rate of change in NIS-LL declined (from 0.34 to 0.16/month; p = 0.01), as did TQOL score (from 0.61 to -0.16; p < 0.001). Patients treated with tafamidis for 30 months had 55.9 % greater preservation of neurologic function as measured by the NIS-LL than patients in whom tafamidis was initiated later. Plasma TTR was stabilized in 94.1 % of patients treated with tafamidis for 30 months. AEs were similar between groups; no patients discontinued because of an AE. Long-term tafamidis was well tolerated, with the reduced rate of neurologic deterioration sustained over 30 months. Tafamidis also slowed neurologic impairment in patients previously given placebo, but treatment benefits were greater when tafamidis was begun earlier.

  • 35. Coelho, Teresa
    et al.
    Maurer, Mathew S.
    Suhr, Ole B.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    THAOS - The Transthyretin Amyloidosis Outcomes Survey: initial report on clinical manifestations in patients with hereditary and wild-type transthyretin amyloidosis2013In: Current Medical Research and Opinion, ISSN 0300-7995, E-ISSN 1473-4877, Vol. 29, no 1, p. 63-76Article in journal (Refereed)
    Abstract [en]

    Background: Transthyretin (TTR) amyloidosis is a rare, life-threatening, systemic, autosomal dominant condition occurring in adults, with two main forms: hereditary (associated with TTR gene mutations) and wild-type. Studies indicate considerable heterogeneity in disease presentation, with predominantly polyneuropathic, predominantly cardiac, or mixed phenotypes. Methods: THAOS - the Transthyretin Amyloidosis Outcomes Survey - is the first global, multicenter, longitudinal, observational survey that collects data on the natural history of TTR amyloidosis (ClinicalTrials.gov: NCT00628745). This paper presents data on signs and symptoms, neurological and cardiac assessments, biomarkers and quality of life in the patients enrolled in THAOS from its inception in December 2007 to September 2011. Results: At the time of this analysis, data were available from 611 symptomatic patients with hereditary TTR amyloidosis, 67 symptomatic patients with wild-type TTR amyloidosis, and 274 currently asymptomatic individuals with a TTR mutation. Nineteen countries were participating in the registry. The largest patient groups came from Portugal (n = 453), the USA (n = 129), Italy (n = 70), and Japan (n = 68). Predominant symptom presentation in patients with hereditary TTR amyloidosis differed according to the underlying disease-causing mutation (polyneuropathy for Val30Met, cardiomyopathy for Val122Ile and Leu111Met, and mixed for Glu89Gln). However, each mutation was associated with clear multisystem involvement. Similarly, although cardiomyopathy was predominant in patients with wild-type TTR amyloidosis, many also showed symptoms consistent with neuropathy. Quality of life in patients with hereditary TTR amyloidosis, but not asymptomatic carriers of disease-causing mutations, was severely impaired relative to that of the age-matched general US population. Conclusions: This preliminary analysis highlights the considerable phenotypic heterogeneity for neurological and cardiac manifestations in patients with hereditary and wild-type TTR amyloidosis and the necessity of providing multidisciplinary care. THAOS registry data will help better characterize the diverse presentation and course of TTR amyloidosis worldwide and aid in improving and standardizing diagnosis and treatment.

  • 36. Coelho, Teresa
    et al.
    Suhr, Ole
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Quan, Dianna
    Brannagan, Thomas
    Gollob, Jared
    Goyal, Sunita
    Altincatal, Arman
    Agarwal, Sonalee
    Lin, Hollis
    Adams, David
    Longitudinal changes in mNIS+7 are associated with changes in ambulatory status in hereditary transthyretin-mediated amyloidosis2018In: Journal of the peripheral nervous system, ISSN 1085-9489, E-ISSN 1529-8027, Vol. 23, no 4, p. 354-355Article in journal (Other academic)
  • 37. Conceicao, I
    et al.
    Coelho, T
    Plante-Bordeneuve, V
    Waddington Cruz, M
    Ericzon, BG
    Falk, RN
    Ikeda, S
    Maurer, M
    Suhr, Ole B
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Ando, Y
    Mazzeo, A
    Grogan, DR
    Baseline neurologic function in symptomatic patients in the Transthyretin Amyloidosis Outcomes Survey (THAOS)2011Conference paper (Refereed)
  • 38. Conceicao, I.
    et al.
    Suhr, Ole
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Coelho, T.
    Waddington Cruz, M.
    Schmidt, H.
    Buades, J.
    Campistol, J.
    Pouget, J.
    Berk, I.
    Adams, D.
    Phase 2 open-label extension study of patisiran, an investigational siRNA agent for hereditary ATTR amyloidosis with polyneuropathy (hATTR-PN)2016In: Neuromuscular Disorders, ISSN 0960-8966, E-ISSN 1873-2364, Vol. 26, p. S142-S142Article in journal (Other academic)
    Abstract [en]

    Hereditary ATTR amyloidosis with polyneuropathy (hATTR-PN), also known as familial amyloidotic polyneuropathy (FAP), is an inherited, progressive disease that can cause sensory, motor, and autonomic dysfunction, resulting in significant disability and death. Patisiran is an investigational, systemically administered small interfering RNA (siRNA) targeting wild-type and mutant TTR. A recently completed multi-center, multi-dose Phase 2 trial of patisiran in hATTR-PN patients (N = 29) showed >80% sustained mean knockdown of serum TTR when administered at a dose of 0.3 mg/kg every 3 weeks with a generally favorable safety profile. Phase 2 open label (OLE) study to evaluate patisiran's safety effect on serum TTR levels, impact on neuropathy impairment scores and QOL. Twenty-seven patients with hATTR-PN were enrolled; median age 64 years (range: 29–77 years). Patisiran was well tolerated throughout the23-months of follow-up. Five patients experienced SAEs (unrelated) including one discontinuation and subsequent death (gastroesophageal cancer). Flushing (25.9%) and infusion-related reactions (18.5%) were mild AEs; and did not result in any discontinuations. Approximately 80% sustained mean serum TTR lowering was obtained with a mean nadir of up to 93% between doses. Among the 20 evaluable patients, neuropathy impairment scores were stable with a mean change in mNIS+7 and NIS of 1.7 and 4.2 points, respectively. This compares favorably to 17–26 point mNIS+7/NIS increase at 18-months from prior hATTR-PN studies. Stabilization of quality of life (QOL) measures and significant improvement of distal thigh sweat gland nerve fiber density was observed. Long-term (>18 months) patisiran administration was generally well tolerated, resulted in sustained mean serum TTR lowering; supporting the hypothesis that TTR knockdown potentially halts neuropathy progression. As of March 2016, dosing continues; updated results will be presented.

  • 39.
    Damy, Thibaud
    et al.
    Referral Center for Cardiac Amyloidosis, Department of Cardiology, Mondor Amyloidosis Network, GRC Amyloid Res. Institute, Clin. Invest. Center, 006, DHU A-TVB INSERM U955 All at CHU Henri Mondor, UPEC, Créteil, France.
    Kristen, Arnt V
    Department of Cardiology, Amyloidosis Center, Heidelberg University, Heidelberg, Germany.
    Suhr, Ole B.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Maurer, Mathew S
    Columbia University College of Physicians and Surgeons, NY, New York, United States.
    Planté-Bordeneuve, Violaine
    Department of Neurology, Mondor Amyloid Network, Inserm U955-Team10, East Paris University Hospital Henri-Mondor, France.
    Yu, Ching-Ray
    Pfizer Inc, NY, New York, United States.
    Ong, Moh-Lim
    Pfizer Inc, NY, New York, United States.
    Coelho, Teresa
    Department of Neurosciences, Hospital de Santo António, Centro Hospitalar Do Porto, Porto, Portugal.
    Rapezzi, Claudio
    Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.
    Transthyretin cardiac amyloidosis in continental Western Europe: An insight through the Transthyretin Amyloidosis Outcomes Survey (THAOS)2019In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 43, no 5, p. 391-400Article in journal (Refereed)
    Abstract [en]

    Aims: Transthyretin amyloidosis (ATTR amyloidosis) is a heterogeneous disorder with cardiac, neurologic, and mixed phenotypes. We describe the phenotypic and genotypic profiles of this disease in continental Western Europe as it appears from the Transthyretin Amyloidosis Survey (THAOS).

    Methods and results: THAOS is an ongoing, worldwide, longitudinal, observational survey established to study differences in presentation, diagnosis, and natural history in ATTR amyloidosis subjects. At data cut-off, 1411 symptomatic subjects from nine continental Western European countries were enrolled in THAOS [1286 hereditary (ATTRm) amyloidosis; 125 wild-type ATTR (ATTRwt) amyloidosis]. Genotypes and phenotypes varied notably by country. Four mutations (Val122Ile, Leu111Met, Thr60Ala, and Ile68Leu), and ATTRwt, were associated with a mainly cardiac phenotype showing symmetric left ventricular (LV) hypertrophy, normal diastolic LV dimensions and volume, and mildly depressed LV ejection fraction (LVEF). Morphologic and functional abnormalities on echocardiogram were significantly more severe in subjects with cardiac (n = 210), compared with a mixed (n = 298), phenotype: higher median (Q1-Q3) interventricular septal thickness [18 (16-21) vs. 16 (13-20) mm; P = 0.0006]; and more frequent incidence of LVEF <50% (38.1 vs. 17.5%; P = 0.0008). Subjects with cardiac mutations or ATTRwt (or cardiac or mixed phenotype) had a lower survival rate than subjects in other genotype (or the neurologic phenotype) categories (P < 0.0001, for both).

    Conclusion: ATTR amyloidosis genotypes and phenotypes are highly heterogeneous in continental Western Europe. A geographic map of the different disease profiles and awareness that a subset of subjects have a dominant cardiac phenotype, mimicking hypertrophic cardiomyopathy, at presentation can facilitate the clinical recognition of this underdiagnosed disease.

    Trial registration: ClinicalTrials.gov: NCT00628745.

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  • 40. Damy, Thibaud
    et al.
    Maurer, Mathew S
    Rapezzi, Claudio
    Planté-Bordeneuve, Violaine
    Karayal, Onur N
    Mundayat, Rajiv
    Suhr, Ole B
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Kristen, Arnt V
    Clinical, ECG and echocardiographic clues to the diagnosis of TTR-related cardiomyopathy2016In: Open heart, E-ISSN 2053-3624, Vol. 3, no 1, article id e000289Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Signs of cardiac transthyretin (TTR) amyloidosis (ATTR) in patients with echocardiographic increase in interventricular septal thickness (IVST) are lacking.

    OBJECTIVES: To identify clinical and ECG/echocardiographic signs associated with increased IVST in ATTR.

    METHODS: Analysis of patients with baseline echocardiography in the Transthyretin Amyloidosis Outcomes Survey (THAOS) registry (N=1682). Patients were categorised into IVST classes according to the American Society of Echocardiography classification adapted to gender (ie, normal, mild, moderate, severe); then into two combined IVST classes (normal-mild and moderate-severe).

    RESULTS: 425 patients were included: 336 with a TTR mutation (m-TTR) and 89 with wild-type TTR (WT-TTR). 72% were men. Median (25th, 75th centile) age was 62 (45, 72) years. Non-Val30Met and WT-TTR were frequent in moderate (41% and 35%) and severe (50% and 33%) IVST classes. Median IVST was 15?mm (14, 16) (moderate) and 20?mm (18, 22) (severe). In the combined moderate-severe class, 85% of patients were ?55?years of age; 81% were men; 86% had blood pressure <140?mm?Hg; and 77% had increased right ventricle thickness (?7?mm). Up to 66% of patients had cardiac sparkling. Systolic dysfunction (left ventricular ejection fraction <50%), restrictive pattern and low voltage were less frequent, and observed in 49%, 18% and 33% of patients, respectively.

    CONCLUSIONS: Increased IVST, especially in men ?55?years with normal systolic blood pressure, increase in right ventricle free wall and valve thicknesses, and sparkling, should alert practitioners to the possibility of ATTR. Absence of restrictive pattern and low voltage should not rule out the suspicion.

    TRIAL REGISTRATION NUMBER: NCT00628745 (clinicaltrials.gov).

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  • 41. Denoncourt, R. N.
    et al.
    Adams, D.
    Gonzalez-Duarte, A.
    O'Riordan, W.
    Yang, C.
    Yamashita, T.
    Kristen, A.
    Tournev, I
    Schmidt, H.
    Coelho, T.
    Berk, J.
    Lin, K.
    Chen, J.
    Gollob, J.
    Suhr, Ole
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Burden of Illness for Patients with Hereditary Attr Amyloidosis with Polyneuropathy Begins with Symptom Onset and Increases with Disease Progression2016In: Value in Health, ISSN 1098-3015, E-ISSN 1524-4733, Vol. 19, no 7, p. A436-A436, article id PND63Article in journal (Refereed)
    Abstract [en]

    Objectives: Hereditary ATTR amyloidosis with polyneuropathy (hATTR-PN), also known as familial amyloidotic polyneuropathy (FAP), is an inherited, progressive disease leading to death within 5-15 years. hATTR-PN is due to a mutation in the transthyretin (TTR) gene. Patisiran is an investigational, RNA interference (RNAi) therapeutic targeting TTR. This abstract aims to further characterize hATTR-PN burden of illness.

    Methods: The ongoing, patisiran Phase 3 APOLLO trial was utilized to collect patient-reported EQ-5D, Norfolk-DN, Rasch-built Overall Disability Scale (R-ODS), and healthcare resource utilization from hATTR-PN patients with symptomatic disease.

    Results: APOLLO included 225 patients; median age of 62 years (range: 24-82), median neurological impairment score (NIS) of 6-141.6 and representative of the global patient population (19 countries) with a broad range of mutations and disease severities. At baseline, 57 patients had a Polyneuropathy Disability (PND) Score I and 168 patients had a PND Score ≥ II. By FAP Stage, 104 were FAP Stage 1 and 121 were FAP Stage 2. 41 patients (PND Score ≥ II) reported ≥1 hospitalization of ≥3 nights in duration due to hATTR-PN in the 12 months prior to enrollment. Mean EQ-5D scores were 0.76 (PND Score I) and 0.59 (PND Score ≥ II). Patients reported perceived health status on the EQ-VAS with mean scores of 66.9 (PND Score I) and 51.3 (PND Score ≥ II). Mean Norfolk-QoL-DN scores were 35.5 (PND Score I) and 66.0 (PND Score ≥ II). 145 patients (131 PND Score ≥ II) reported they cannot work because of hATTR-PN. Mean R-ODS scores were 40.9 and 25.9 for PND Score I and PND Score ≥ II, respectively.

    Conclusions: These data, from the largest controlled study of patients with hATTR-PN to date, further demonstrate that patients experience considerable burden of illness early in the course of disease and this burden increases with disease progression.

  • 42. Dyck, P. James
    et al.
    Adams, David
    Coelho, Teresa
    Kristen, Arnt
    Gonzalez-Duarte, Alejandra
    Berk, John
    Partisano, Angela
    Gollob, Jared
    Sweester, Marianne
    Chen, Jihong
    Suhr, Ole
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Neuropathy progression in patients with hATTR amyloidosis: Analysis of the APOLLO placebo arm2018In: Journal of the peripheral nervous system, ISSN 1085-9489, E-ISSN 1529-8027, Vol. 23, no 4, p. 274-275Article in journal (Other academic)
  • 43. Eldhagen, P.
    et al.
    Berg, S.
    Lund, L. H.
    Sörensson, P.
    Suhr, Ole B.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Westermark, P.
    Transthyretin amyloid deposits in lumbar spinal stenosis and assessment of signs of systemic amyloidosis2021In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 289, no 6, p. 895-905Article in journal (Refereed)
    Abstract [en]

    Background: Wild‐type transthyretin (ATTRwt) amyloidosis is the most common systemic amyloidosis in Western countries and manifests mainly as progressive restrictive cardiomyopathy.

    Objective: To study the prevalence of ATTR deposits in ligament tissue in patients undergoing surgery for lumbar spinal stenosis and to assess whether these deposits are associated with cardiac amyloidosis.

    Materials and methods: A total of 250 patients, aged 50–89 (57% women), none with known cardiovascular disease, were included. Ligaments were investigated microscopically for amyloid. ATTR type was determined by immunohistochemistry and fibril type by Western blot. The amount of amyloid was graded 0‐4. All patients with grade 3‐4 ATTR deposits were offered cardiac investigation including ECG, cardiac ultrasound, plasma NT‐proBNP and cardiac magnetic resonance (CMR), including modern tissue characterization.

    Results: Amyloid was identified in 221 of the samples (88.4%). ATTR appeared in 93 samples (37%) of whom 42 (17 women and 25 men) were graded 3‐4; all had fibril type A (mixture of full‐length TTR and fragmented TTR). Twenty‐nine of 42 patients with grade 3‐4 ATTR deposits accepted cardiovascular investigations; none of them had definite signs of cardiac amyloidosis, but five men had a history of carpal tunnel syndrome.

    Conclusions: The prevalence of ATTR deposits in ligamentum flavum in patients with lumbar spinal stenosis was high but not associated with manifest ATTR cardiac amyloidosis. However, the findings of fibril type A, the prevalence of previous carpal tunnel syndrome and ATTR amyloid in surrounding adipose and vascular tissue indicate that amyloid deposits in ligamentum flavum may be an early manifestation of systemic ATTR disease.

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  • 44.
    Engvall, Christer
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology.
    Henein, Michael
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Holmgren, Anders
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Suhr, Ole B
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Mörner, Stellan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Lindqvist, Per
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Can myocardial strain differentiate hypertrophic from infiltrative etiology of a thickened septum?2011In: Echocardiography, ISSN 0742-2822, E-ISSN 1540-8175, Vol. 28, no 4, p. 408-415Article in journal (Refereed)
    Abstract [en]

    Septal systolic strain measurements showed reduced longitudinal function but its localized nature failed to demonstrate radial disturbances in patients with pathologically thickened septum. No difference was found in systolic strain between patients according to the etiology of septal thickness. This limitation might be either technical or is explained by the maintained radial function in all patient groups.

  • 45.
    Ericzon, Bo-Göran
    et al.
    Head Division of Transplantation Surgery, CLINTEC, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Lundgren, Erik
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Suhr, Ole B.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Liver Transplantation for Transthyretin Amyloidosis2009In: Recent Advances in Transthyretin Evolution, Structure and Biological Functions / [ed] Dr. Samantha J. Richardson, Dr. Vivian Cody, New York: Springer Berlin/Heidelberg, 2009, p. 239-260Chapter in book (Other academic)
    Abstract [en]

    Liver transplantation has until now proved to be the only treatment available that halts the progression of hereditary transthyretin (TTR) associated amyloidosis. The rationale behind the procedure is to replace the liver producing variant TTR with one that produces wild type TTR only, and thereby cease the production of amyloidogenic TTR (ATTR). Even though the transplantation does not improve the patient's symptoms, the progression of the disease comes to a halt for a majority of patients. However, unforeseen complications after the transplantation have emerged, in particular a continuous amyloid formation in the heart observed in non-ATTR Val30Met mutations. Thus, combined liver and heart transplantation has been performed in selected cases. Since the ATTR liver functions normally apart from a synthesis of the variant TTR, utilisation of ATTR-amyloid patients' livers for transplantation of liver disease patients has been performed. In a few patients, development of amyloid disease has been reported, but the procedure remains an important source of organs, especially for patients with hepatocellular cancer.

  • 46. Ericzon, Bo-Göran
    et al.
    Wilczek, Henryk E.
    Larsson, Marie
    Wijayatunga, Priyantha
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Stangou, Arie
    Pena, João Rodrigues
    Furtado, Emanuel
    Barroso, Eduardo
    Daniel, Jorge
    Samuel, Didier
    Adam, Rene
    Karam, Vincent
    Poterucha, John
    Lewis, David
    Ferraz-Neto, Ben-Hur
    Cruz, Márcia Waddington
    Munar-Ques, Miguel
    Fabregat, Juan
    Ikeda, Shu-Ichi
    Ando, Yukio
    Heaton, Nigel
    Otto, Gerd
    Suhr, Ole
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Liver transplantation for hereditary transthyretin amyloidosis: after 20 years still the best therapeutic alternative?2015In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 99, no 9, p. 1847-1854Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Until recently, liver transplantation (Ltx) was the only available treatment for hereditary transthyretin (TTR) amyloidosis; today, however, several pharmacotherapies are tested. Herein, we present survival data from the largest available database on transplanted hereditary TTR patients to serve as a base for comparison.

    METHODS: Liver transplantation was evaluated in a 20-year retrospective analysis of the Familial Amyloidosis Polyneuropathy World Transplant Registry.

    RESULTS: From April 1990 until December 2010, data were accumulated from 77 liver transplant centers. The Registry contains 1940 patients, and 1379 are alive. Eighty-eight Ltx were performed in combination with a heart and/or kidney transplantation. Overall, 20-year survival after Ltx was 55.3%. Multivariate analysis revealed modified body mass index, early onset of disease (<50 years of age), disease duration before Ltx, and TTR Val30Met versus non-TTR Val30Met mutations as independent significant survival factors. Early-onset patients had an expected mortality rate of 38% that of the late-onset group (P < 0.001). Furthermore, Val30Met patients had an expected mortality rate of 61% that of non-TTR Val30Met patients (P < 0.001). With each year of duration of disease before Ltx, expected mortality increased by 11% (P < 0.001). With each 100-unit increase in modified body mass index at Ltx, the expected mortality decreased to 89% of the expected mortality (P < 0.001). Cardiovascular death was markedly more common than that observed in patients undergoing Ltx for end-stage liver disease.

    CONCLUSIONS: Long-term survival after Ltx, especially for early-onset TTR Val30Met patients, is excellent. The risk of delaying Ltx by testing alternative treatments, especially in early-onset TTR Val30Met patients, requires consideration.

  • 47. Fuchs, Uwe
    et al.
    Zittermann, Armin
    Suhr, Ole B
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Holmgren, Gösta
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Tenderich, Gero
    Minami, Kazutomo
    Koerfer, Reiner
    Heart transplantation in a 68-year-old patient with senile systemic amyloidosis.2005In: Am J Transplant, ISSN 1600-6135, Vol. 5, no 5, p. 1159-62Article in journal (Refereed)
  • 48. Gertz, Morie
    et al.
    Adams, David
    Ando, Yukio
    Beirao, Joao Melo
    Bokhari, Sabahat
    Coelho, Teresa
    Comenzo, Raymond L.
    Damy, Thibaud
    Dorbala, Sharmila
    Drachman, Brian M.
    Fontana, Marianna
    Gillmore, Julian D.
    Grogan, Martha
    Hawkins, Philip N.
    Lousada, Isabelle
    Kristen, Arnt V.
    Ruberg, Frederick L.
    Suhr, Ole B.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Maurer, Mathew S.
    Nativi-Nicolau, Jose
    Quarta, Candida Cristina
    Rapezzi, Claudio
    Witteles, Ronald
    Merlini, Giampaolo
    Avoiding misdiagnosis: expert consensus recommendations for the suspicion and diagnosis of transthyretin amyloidosis for the general practitioner2020In: BMC Family Practice, E-ISSN 1471-2296, Vol. 21, no 1, article id 198Article in journal (Refereed)
    Abstract [en]

    Background Transthyretin amyloidosis (also known as ATTR amyloidosis) is a systemic, life-threatening disease characterized by transthyretin (TTR) fibril deposition in organs and tissue. A definitive diagnosis of ATTR amyloidosis is often a challenge, in large part because of its heterogeneous presentation. Although ATTR amyloidosis was previously considered untreatable, disease-modifying therapies for the treatment of this disease have recently become available. This article aims to raise awareness of the initial symptoms of ATTR amyloidosis among general practitioners to facilitate identification of a patient with suspicious signs and symptoms. Methods These consensus recommendations for the suspicion and diagnosis of ATTR amyloidosis were developed through a series of development and review cycles by an international working group comprising key amyloidosis specialists. This working group met to discuss the barriers to early and accurate diagnosis of ATTR amyloidosis and develop a consensus recommendation through a thorough search of the literature performed using PubMed Central. Results The cardiac and peripheral nervous systems are most frequently involved in ATTR amyloidosis; however, many patients often also experience gastrointestinal and other systemic manifestations. Given the multisystemic nature of symptoms, ATTR amyloidosis is often misdiagnosed as a more common disorder, leading to significant delays in the initiation of treatment. Although histologic evaluation has been the gold standard to confirm ATTR amyloidosis, a range of tools are available that can facilitate early and accurate diagnosis. Of importance, genetic testing should be considered early in the evaluation of a patient with unexplained peripheral neuropathy. Conclusions A diagnostic algorithm based on initial red flag symptoms and manifestations of cardiac or neurologic involvement will facilitate identification by the general practitioner of a patient with clinically suspicious symptoms, enabling subsequent referral of the patient to a multidisciplinary specialized medical center.

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  • 49. Gonzalez-Duarte, Alejandra
    et al.
    Adams, David
    O'Riordan, William
    Yang, Chih-Chao
    Yamashita, Taro
    Kristen, Arnt
    Tournev, Ivaylo
    Schmidt, Hartmut
    Coelho, Teresa
    Berk, John
    Ghandi, Pritesh
    Chen, Jihong
    Gollob, Jared
    Goyal, Sunita
    Suhr, Ole
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Changes in neuropathy stage in patients with hATTR amyloidosis following patisiran treatment: Analysis from APOLLO2018In: Journal of the peripheral nervous system, ISSN 1085-9489, E-ISSN 1529-8027, Vol. 23, no 4, p. 400-400Article in journal (Other academic)
  • 50. Gorram, Farida
    et al.
    Olsson, Malin
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Alarcon, Flora
    Hebrard, Berenice
    Funalot, Benoit
    Nuel, Gregory
    Suhr, Ole B.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Plante-Bordeneuve, Violaine
    Variation of Penetrance estimates in a wide spectrum of TTR-FAP families: implication for management of carriers2018In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 90Article in journal (Other academic)
    Abstract [en]

    Objective: Refine estimation of penetrance in TTR-FAP families, unravelling the role of covariates. Background: TTR-FAP is an autosomal dominant neuropathy caused by mutations in the TTR gene. Recently, therapeutic advances including gene modifying approaches proved effective to halt disease progression. Val30Met, the most common variant in Portugal and Latin America is associated to age at onset (AO) below 50 y-o. In Western Europe, US, Japan, heterogeneity of TTR variants is associated to AO above 50 y-o, a mixed polyneuropathy and cardiomyopathy. Determining the risk of being affected (penetrance) is essential to guide gene carrier management.

    Design/Methods: NPSE is a non-parametric method developed to estimate penetrance, taking into account covariates. Genealogical data from 227 kindreds were collected. There were 92 Val30Met families from Sweden, 64 Val30Met from Portugal and 73 from France including 37 Val30Met and 36 families carrying other TTR variants frequently identified: Ser77Tyr (15), Ile107Val (12), Ser77Phe (9).

    Results: We found highly significant differences of penetrance between Val30Met families from various origins. Risk estimates also differed between the TTR variants (French Val30Met, Ser77Tyr, Ile107Val, Ser77Phe) (p < 0.004). In the French and Swedish Val30Met families, the disease risk remained below 10% until age 40 years then increased to 72% and 63% at 80 years, respectively. In Portuguese families, the risk was above 20% from age 30 years then up to 92% at 80 y-o. In Ile107Val, Ser77Tyr and Ser77Phe families the risk was virtually null until 50 years of age and raised to 54%, 70%, and 86% at age 80 years, respectively. A higher risk is observed when the disease is maternally inherited in Portuguese and Swedish kindreds (p <0.001).

    Conclusions: Important variation of penetrance is observed in TTR-FAP families according covariates. Such data will help for management of gene carriers, allowing early diagnosis and therapeutic initiation timely.

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