ABSTRACT
The prevalence of amyloidosis has been increasing, driven by a combination of improved awareness, evolution of diagnostic pathways, and effective treatment options for both transthyretin and light chain amyloidosis. Due to the complexity of amyloidosis, centralised expert providers with experience in delineating the nuances of confirmatory diagnosis and management may be beneficial. There are many potential benefits of a centre of excellence designation for the treatment of amyloidosis including recognition of institutions that have been leading the way for the optimal treatment of this condition, establishing the expectations for any centre who is engaging in the treatment of amyloidosis and developing cooperative groups to allow more effective research in this disease space. Standardising the expectations and criteria for these centres is essential for ensuring the highest quality of clinical care and community education. In order to define what components are necessary for an effective centre of excellence for the treatment of amyloidosis, we prepared a survey in cooperation with a multidisciplinary panel of amyloidosis experts representing an international consortium. The purpose of this position statement is to identify the essential elements necessary for highly effective clinical care and to develop a general standard with which practices or institutions could be recognised as a centre of excellence.
ABSTRACT
BACKGROUND: Systemic amyloidosis is caused by the deposition of misfolded protein aggregates in tissues, leading to progressive organ dysfunction and death. Epidemiological studies originate predominantly from high-income countries, with few data from Latin America. Due to the non-specific clinical manifestations, diagnosing amyloidosis is often challenging and patients experience a long journey and delay in diagnosis. This study aimed to assess clinical and laboratory characteristics, the diagnostic journey, and outcomes of patients with biopsy-proven systemic amyloidosis diagnosed between 2009 and 2020 at a university referral center in a middle-income Latin American country. Patients´ medical records were retrospectively reviewed. RESULTS: One hundred and forty-three patients were included. The median age at diagnosis was 60 years and 54% were male. Until the diagnosis, most of the patients (52%) were seen by at least 3 specialists, the main ones being: general practitioners (57%), nephrologists (45%), and cardiologists (38%). The most common manifestations were renal (54%) and cardiac (41%) disorders, and cachexia was seen in 36% of patients. In 72% of the cases, ≥ 2 biopsies were required until the final diagnosis. The median time from symptoms onset to diagnosis was 10.9 months, and most patients (75%) had ≥ 2 organs involved. The following subtypes were identified: AL (68%), ATTR (13%), AA (8%), AFib (4%), and inconclusive (7%). Median OS was 74.3 months in the non-AL subgroup and 18.5 months in AL. Among AL patients, those with advanced cardiac stage had the worst outcome [median OS 8.6 months versus 52.3 for stage III versus I-II, respectively (p < 0.001)]. AL subtype, cardiac involvement, and ECOG ≥ 2 were identified as independent risk factors for reduced survival. CONCLUSIONS: Systemic amyloidosis is still an underdiagnosed condition and the delay in its recognition leads to poor outcomes. Medical education, better diagnostic tools, improvement in access to therapies, and establishment of referral centers may improve patient outcomes in middle-income countries.
Subject(s)
Amyloidosis , Immunoglobulin Light-chain Amyloidosis , Humans , Male , Female , Retrospective Studies , Amyloidosis/diagnosis , Amyloidosis/pathology , Kidney/pathology , BiopsyABSTRACT
BACKGROUND: Systemic amyloidosis is a disease with heterogeneous clinical manifestations. Diagnosis depends on clinical suspicion combined with specific complementary methods. OBJECTIVE: To describe the clinical, laboratory, electrocardiographic, and imaging profile in patients with systemic amyloidosis with cardiac involvement. METHODS: This study was conducted with a convenience sample, analyzing clinical, laboratory, electrocardiographic, echocardiographic, nuclear medicine, and magnetic resonance data. Statistical significance was set at p < 0.05. RESULTS: A total of 105 patients were evaluated (median age of 66 years), 62 of whom were male. Of all patients, 83 had transthyretin (ATTR) amyloidosis, and 22 had light chain (AL) amyloidosis. With respect to ATTR cases, 68.7% were the hereditary form (ATTRh), and 31.3% were wild type (ATTRw). The most prevalent mutations were Val142Ile (45.6%) and Val50Met (40.3%). Time from onset of symptoms to diagnosis was 0.54 and 2.15 years, in the AL and ATTR forms, respectively (p < 0.001). Cardiac involvement was observed in 77.9% of patients with ATTR and in 90.9% of those with AL. Alterations were observed in atrioventricular and intraventricular conduction in 20% and 27.6% of patients, respectively, with 33.7% in ATTR and 4.5% in AL (p = 0.006). In the ATTRw form, there were more atrial arrhythmias than in ATTRh (61.5% versus 22.8%; p = 0.001). On echocardiogram, median septum thickness in ATTRw, ATTRh, and AL was 15 mm, 12 mm, and 11 mm, respectively (p = 0.193). Elevated BNP was observed in 89.5% of patients (median 249, ICR 597.7), and elevated troponin was observed in 43.2%. CONCLUSION: In this setting, it was possible to characterize cardiac involvement in systemic amyloidosis in its different subtypes by means of clinical history and the diagnostic methods described.
FUNDAMENTO: Amiloidose sistêmica é uma doença com manifestações clínicas diversas. O diagnóstico envolve suspeita clínica, aliada a métodos complementares. OBJETIVO: Descrever o perfil clínico, laboratorial, eletrocardiográfico e de imagem no acometimento cardíaco da amiloidose sistêmica. MÉTODOS: Estudo de uma amostra de conveniência, analisando dados clínicos, laboratoriais, eletrocardiográficos, ecocardiográficos, medicina nuclear e ressonância magnética. Considerou-se significância estatística quando p < 0,05. RESULTADOS: Avaliaram-se 105 pacientes (com mediana de idade de 66 anos), sendo 62 homens, dos quais 83 indivíduos apresentavam amiloidose por transtirretina (ATTR) e 22 amiloidose por cadeia leve (AL). Na ATTR, 68,7% eram de caráter hereditário (ATTRh) e 31,3% do tipo selvagem (ATTRw). As mutações mais prevalentes foram Val142Ile (45,6%) e Val50Met (40,3%). O tempo de início dos sintomas ao diagnóstico foi 0,54 e 2,15 anos nas formas AL e ATTR (p < 0,001), respectivamente. O acometimento cardíaco foi observado em 77,9% dos ATTR e 90,9% dos AL. Observaram-se alterações de condução atrioventricular em 20% e intraventricular em 27,6% dos pacientes, sendo 33,7 % na ATTR e 4,5% das AL (p = 0,006). A forma ATTRw apresentou mais arritmias atriais que os ATTRh (61,5% x 22,8%; p = 0,001). Ao ecocardiograma a mediana da espessura do septo na ATTRw x ATTRh x AL foi de 15 mm x 12 mm x 11 mm (p = 0,193). Observou-se BNP elevado em 89,5% dos indivíduos (mediana 249 ng/mL, IQR 597,7) e elevação da troponina em 43,2%. CONCLUSÃO: Foi possível caracterizar, em nosso meio, o acometimento cardíaco na amiloidose sistêmica, em seus diferentes subtipos, através da história clínica e dos métodos diagnósticos descritos.
Subject(s)
Amyloid Neuropathies, Familial , Amyloidosis , Cardiology , Cardiomyopathies , Aged , Amyloid Neuropathies, Familial/diagnostic imaging , Amyloidosis/diagnostic imaging , Brazil , Cardiomyopathies/diagnostic imaging , Echocardiography , Female , Humans , Male , Prealbumin/genetics , Referral and ConsultationABSTRACT
Resumo Fundamento Amiloidose sistêmica é uma doença com manifestações clínicas diversas. O diagnóstico envolve suspeita clínica, aliada a métodos complementares. Objetivo Descrever o perfil clínico, laboratorial, eletrocardiográfico e de imagem no acometimento cardíaco da amiloidose sistêmica. Métodos Estudo de uma amostra de conveniência, analisando dados clínicos, laboratoriais, eletrocardiográficos, ecocardiográficos, medicina nuclear e ressonância magnética. Considerou-se significância estatística quando p < 0,05. Resultados Avaliaram-se 105 pacientes (com mediana de idade de 66 anos), sendo 62 homens, dos quais 83 indivíduos apresentavam amiloidose por transtirretina (ATTR) e 22 amiloidose por cadeia leve (AL). Na ATTR, 68,7% eram de caráter hereditário (ATTRh) e 31,3% do tipo selvagem (ATTRw). As mutações mais prevalentes foram Val142Ile (45,6%) e Val50Met (40,3%). O tempo de início dos sintomas ao diagnóstico foi 0,54 e 2,15 anos nas formas AL e ATTR (p < 0,001), respectivamente. O acometimento cardíaco foi observado em 77,9% dos ATTR e 90,9% dos AL. Observaram-se alterações de condução atrioventricular em 20% e intraventricular em 27,6% dos pacientes, sendo 33,7 % na ATTR e 4,5% das AL (p = 0,006). A forma ATTRw apresentou mais arritmias atriais que os ATTRh (61,5% x 22,8%; p = 0,001). Ao ecocardiograma a mediana da espessura do septo na ATTRw x ATTRh x AL foi de 15 mm x 12 mm x 11 mm (p = 0,193). Observou-se BNP elevado em 89,5% dos indivíduos (mediana 249 ng/mL, IQR 597,7) e elevação da troponina em 43,2%. Conclusão Foi possível caracterizar, em nosso meio, o acometimento cardíaco na amiloidose sistêmica, em seus diferentes subtipos, através da história clínica e dos métodos diagnósticos descritos.
Abstract Background Systemic amyloidosis is a disease with heterogeneous clinical manifestations. Diagnosis depends on clinical suspicion combined with specific complementary methods. Objective To describe the clinical, laboratory, electrocardiographic, and imaging profile in patients with systemic amyloidosis with cardiac involvement. Methods This study was conducted with a convenience sample, analyzing clinical, laboratory, electrocardiographic, echocardiographic, nuclear medicine, and magnetic resonance data. Statistical significance was set at p < 0.05. Results A total of 105 patients were evaluated (median age of 66 years), 62 of whom were male. Of all patients, 83 had transthyretin (ATTR) amyloidosis, and 22 had light chain (AL) amyloidosis. With respect to ATTR cases, 68.7% were the hereditary form (ATTRh), and 31.3% were wild type (ATTRw). The most prevalent mutations were Val142Ile (45.6%) and Val50Met (40.3%). Time from onset of symptoms to diagnosis was 0.54 and 2.15 years, in the AL and ATTR forms, respectively (p < 0.001). Cardiac involvement was observed in 77.9% of patients with ATTR and in 90.9% of those with AL. Alterations were observed in atrioventricular and intraventricular conduction in 20% and 27.6% of patients, respectively, with 33.7% in ATTR and 4.5% in AL (p = 0.006). In the ATTRw form, there were more atrial arrhythmias than in ATTRh (61.5% versus 22.8%; p = 0.001). On echocardiogram, median septum thickness in ATTRw, ATTRh, and AL was 15 mm, 12 mm, and 11 mm, respectively (p = 0.193). Elevated BNP was observed in 89.5% of patients (median 249, ICR 597.7), and elevated troponin was observed in 43.2%. Conclusion In this setting, it was possible to characterize cardiac involvement in systemic amyloidosis in its different subtypes by means of clinical history and the diagnostic methods described.
Subject(s)
Humans , Male , Female , Adult , Cardiology , Amyloid Neuropathies, Familial/diagnostic imaging , Amyloidosis/diagnostic imaging , Cardiomyopathies/diagnostic imaging , Referral and Consultation , Brazil , Prealbumin/genetics , EchocardiographyABSTRACT
Currently, there is growing evidence in the literature warning of misdiagnosis involving amyloidosis and chronic inflammatory demyelinating polyneuropathy (CIDP). Although inducing clinical manifestations outside the peripheral nervous system, light chain and transthyretin amyloidosis may initially present with peripheral neuropathy, which can be indistinguishable from CIDP, leading to a delay in the correct diagnosis. Besides, the precise identification of the amyloid subtype is often challenging. This case report exemplifies clinical and laboratory pitfalls in diagnosing amyloidosis and subtyping amyloid, exposing the patient to potentially harmful procedures.
ABSTRACT
Chronic graft-versus-host disease (cGVHD) remains a major barrier to successful hematopoietic stem cell transplantation (HSCT). In cases refractory to first-line therapy with steroids, there is no standard of care for second-line therapy. As such, ruxolitinib is a promising drug in this scenario. We retrospectively analyzed the efficacy and safety of ruxolitinib in treating steroid-refractory cGVHD in 35 patients from 2 transplantation centers, with the longest follow-up described to date. The evaluated patients had a median of 3 organs affected (range, 1 to 7 organs), with most (64%) having moderate cGVHD. The median number of previous therapy lines was 2 (range, 1 to 6). The overall response rate was 89% (complete response, 26%) after a median of 4 weeks of therapy. The median follow-up was 43 months (range, 11 to 59 monts). At follow-up, of the 27 patients still alive, 18 (67%) were free of any immunosuppression, and 6 (22%) were receiving ruxolitinib as their sole immunosuppressive drug. Failure-free survival was 77.1% at 6 months, 68.6% at 12 months, 54% at 24 months, and 51.4% at 36 months. The median overall survival was not reached. Toxicities were mostly hematologic and resolved after dosage reduction in most cases. Overall, our data, which represent the cohort of patients with cGVHD treated with ruxolitinib with the longest follow-up to date, support the use of this drug as a safe and effective option for refractory cGVHD.
Subject(s)
Graft vs Host Disease , Follow-Up Studies , Graft vs Host Disease/drug therapy , Humans , Nitriles , Pyrazoles , Pyrimidines , Retrospective Studies , SteroidsABSTRACT
Currently, there is growing evidence in the literature warning of misdiagnosis involving amyloidosis and chronic inflammatory demyelinating polyneuropathy (CIDP). Although inducing clinical manifestations outside the peripheral nervous system, light chain and transthyretin amyloidosis may initially present with peripheral neuropathy, which can be indistinguishable from CIDP, leading to a delay in the correct diagnosis. Besides, the precise identification of the amyloid subtype is often challenging. This case report exemplifies clinical and laboratory pitfalls in diagnosing amyloidosis and subtyping amyloid, exposing the patient to potentially harmful procedures.
Subject(s)
Humans , Male , Aged , Amyloidosis, Familial/complications , Paraproteinemias , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/complications , Diagnostic Errors , Immunoglobulin Light-chain Amyloidosis/complicationsABSTRACT
BACKGROUND: Malnutrition is a common finding in allogeneic hematopoietic stem cell transplantation (alloHSCT) patients, and there is some evidence that malnutrition might negatively affect the transplant outcomes. METHOD: We performed a retrospective study with 148 patients aged 18-75 years, who underwent alloHSCT between 2011 and 2017. Patients were classified according to the body mass index (BMI) and the Subjective Global Assessment (SGA). The SGA was assessed on the day of hospitalization for the transplant, and classifies patients into three groups: A (well-nourished), B (moderately malnourished) and C (severely malnourished). RESULTS: The SGA classified 49 (33%) patients as well-nourished, 54 (37%) as moderately malnourished, and 45 (30%) as severely malnourished. SGA-C was also associated with severe acute graft versus host disease (aGVHD) with a cumulative incidence (CI) of 31% vs. a CI of 14% for combined well-nourished or moderately malnourished group (SGA-A or -B, P = 0.017). In multivariate analysis, SGA-C compared to SGA-A or -B, remained as an independent risk factor for aGVHD (hazard ratio - HR 1.68, 95% confidence interval - 95% CI 1.02-2.74), and nonrelapse mortality (NRM - HR 3.63, 95% CI 1.76-7.46), worse progression free survival (HR 2.12, 95% CI 1.25-3.60), and worse overall survival (HR 3.27, 95% CI 1.90-5.64). CONCLUSION: Malnutrition increases the risk of aGVHD and NRM and has a negative impact on survival.
