RESUMO
INTRODUCTION: Hereditary transthyretin-mediated amyloidosis (hATTR) manifests as multisystem dysfunction, including progressive polyneuropathy. Inotersen, an antisense oligonucleotide, improved the course of neuropathic impairment in patients with hATTR in the pivotal NEURO-TTR study (NCT01737398). To determine inotersen's impact on symptoms and patients' neuropathy experience, we performed a post hoc analysis of the Neuropathy Symptoms and Change (NSC) score. METHODS: Stage 1 or 2 hATTR patients were randomized to receive weekly subcutaneous inotersen or placebo for 65 weeks. NSC score was assessed at baseline and 35 and 66 weeks. RESULTS: At 66 weeks, inotersen-treated patients had symptom stabilization as compared with worsening in patients receiving placebo, based on total NSC score. There were also improvements in the subdomains of muscle weakness, sensory, pain, and autonomic symptoms, and for various individual items. DISCUSSION: Inotersen treatment stabilized neuropathy symptoms, including autonomic symptoms, in patients with hATTR according to NSC score. Thus, the NSC may be an effective measure to assess neuropathy progression and patients' neuropathy experience in clinical practice.
Assuntos
Neuropatias Amiloides Familiares/tratamento farmacológico , Progressão da Doença , Oligonucleotídeos Antissenso/uso terapêutico , Oligonucleotídeos/uso terapêutico , Qualidade de Vida , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Sintomas , Resultado do TratamentoRESUMO
INTRODUCTION: Inotersen, an antisense oligonucleotide inhibitor of transthyretin (TTR) protein production, demonstrated significant benefit versus placebo in the modified Neuropathy Impairment Score (NIS) +7 neurophysiologic tests (mNIS+7) in patients with hereditary TTR-mediated amyloidosis (hATTR) with polyneuropathy. This analysis assessed the mNIS+7 components by anatomic location and the lower limb function (LLF) test. METHODS: Adults with hATTR in the NEURO-TTR trial (NCT01737398) were randomly assigned to receive weekly doses of subcutaneous inotersen 300 mg or placebo for 65 weeks. The mNIS+7 and LLF were assessed at 35 and 66 weeks. RESULTS: All major mNIS+7 components (muscle weakness, muscle stretch reflexes, sensation) and the LLF showed significant efficacy in patients receiving inotersen versus placebo; however, NIS-reflexes (upper limb), touch pressure (upper and lower limbs), and heart rate during deep breathing did not show significant effects. DISCUSSION: The results of this analysis reinforce the beneficial effect of inotersen on slowing neuropathy progression in patients with hATTR polyneuropathy.
Assuntos
Neuropatias Amiloides Familiares/tratamento farmacológico , Extremidade Inferior/fisiopatologia , Debilidade Muscular/tratamento farmacológico , Oligonucleotídeos Antissenso/uso terapêutico , Oligonucleotídeos/uso terapêutico , Neuropatias Amiloides Familiares/fisiopatologia , Método Duplo-Cego , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Debilidade Muscular/fisiopatologia , Oligonucleotídeos/farmacologia , Oligonucleotídeos Antissenso/farmacologia , Reflexo/efeitos dos fármacos , Resultado do TratamentoRESUMO
INTRODUCTION: Polyneuropathy signs (Neuropathy Impairment Score, NIS), neurophysiologic tests (m+7Ionis ), disability, and health scores were assessed in baseline evaluations of 100 patients entered into an oligonucleotide familial amyloidotic polyneuropathy (FAP) trial. METHODS: We assessed: (1) Proficiency of grading neurologic signs and correlation with neurophysiologic tests, and (2) clinometric performance of modified NIS+7 neurophysiologic tests (mNIS+7Ionis ) and its subscores and correlation with disability and health scores. RESULTS: The mNIS+7Ionis sensitively detected, characterized, and broadly scaled diverse polyneuropathy impairments. Polyneuropathy signs (NIS and subscores) correlated with neurophysiology tests, disability, and health scores. Smart Somatotopic Quantitative Sensation Testing of heat as pain 5 provided a needed measure of small fiber involvement not adequately assessed by other tests. CONCLUSIONS: Specially trained neurologists accurately assessed neuropathy signs as compared to referenced neurophysiologic tests. The score, mNIS+7Ionis , broadly detected, characterized, and scaled polyneuropathy abnormality in FAP, which correlated with disability and health scores. Muscle Nerve 56: 901-911, 2017.
Assuntos
Neuropatias Amiloides Familiares/tratamento farmacológico , Técnicas de Diagnóstico Neurológico , Neurologistas , Oligonucleotídeos/uso terapêutico , Índice de Gravidade de Doença , Adulto , Idoso , Idoso de 80 Anos ou mais , Neuropatias Amiloides Familiares/diagnóstico , Neuropatias Amiloides Familiares/fisiopatologia , Estudos de Coortes , Avaliação da Deficiência , Feminino , Humanos , Cooperação Internacional , Masculino , Pessoa de Meia-Idade , Condução Nervosa/efeitos dos fármacos , Condução Nervosa/fisiologia , Avaliação de Resultados em Cuidados de SaúdeRESUMO
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 (Umeå), 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. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00294671.
Assuntos
Neuropatias Amiloides Familiares/tratamento farmacológico , Anti-Inflamatórios não Esteroides/uso terapêutico , Diflunisal/uso terapêutico , Idoso , Neuropatias Amiloides Familiares/fisiopatologia , Índice de Massa Corporal , Progressão da Doença , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Análise de Sobrevida , Resultado do TratamentoAssuntos
Doenças dos Nervos Cranianos/complicações , Doenças dos Nervos Cranianos/diagnóstico , Paraganglioma Extrassuprarrenal/diagnóstico , Neoplasias da Base do Crânio/diagnóstico , Síncope/diagnóstico , Síncope/etiologia , Diagnóstico Diferencial , Feminino , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/etiologia , Humanos , Hipertensão/complicações , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Paraganglioma Extrassuprarrenal/complicações , Neoplasias da Base do Crânio/complicações , Tomografia Computadorizada por Raios XRESUMO
A patient with primary (AL) systemic amyloidosis developed mononeuropathy multiplex complicated by diaphragmatic failure. High dose melphalan and autologous stem cell transplantation did not ameliorate neuropathy or diaphragm dysfunction. Nocturnal non-invasive ventilation lowered arterial carbon dioxide levels and improved daytime dyspnea. This is the first case associating AL amyloid-induced neuropathy with diaphragm dysfunction.
Assuntos
Neuropatias Amiloides/fisiopatologia , Amiloidose/fisiopatologia , Paralisia Respiratória/fisiopatologia , Idoso , Diafragma/diagnóstico por imagem , Diafragma/fisiopatologia , Feminino , Humanos , RadiografiaRESUMO
Thalidomide is an effective therapy for multiple myeloma, although its mechanisms of action remain unclear. Light chain-associated (AL) amyloidosis is a plasma cell disorder related to multiple myeloma, but in AL amyloidosis, fibrillar tissue deposits of clonal immunoglobulin light chains produce organ dysfunction. To test the toxicity and efficacy of thalidomide in AL amyloidosis we initiated a phase I/II trial for patients with AL amyloidosis, most of whom had failed prior therapy with high-dose melphalan and autologous stem cell transplantation. This trial was designed as an individualized 6-month dose-escalation study with reevaluation of bone marrow plasmacytosis and serum and urine monoclonal proteins after 3 and 6 months. Sixteen patients were enrolled in the study with a median age of 62 years (range, 37-70 years). Fourteen patients had renal involvement, 4 had cardiac involvement, 4 had liver involvement, and 2 had predominant soft tissue or lymph node involvement. The median maximum tolerated dose was 300 mg, with fatigue and other central nervous system side effects being the major dose-limiting toxicities. Side effects not frequently reported for other patient populations included exacerbation of peripheral and pulmonary edema and worsening azotemia. In all, 50% of patients experienced grade 3/4 toxicity, and 25% had to discontinue the study drug. No complete hematologic responses were seen, but 25% of patients had a significant reduction in Bence-Jones proteinuria. Thus, while thalidomide has activity in AL amyloidosis, it also has significant toxicity in this patient population.