Eficácia e segurança da alfa-agalsidase e a beta-agalsidase para intervenção na doença de Fabry: revisão rápida / Effectiveness and safety of agalsidase alfa and agalsidase beta for intervention in fabry disease: rapid review

Tecnologia: Alfa-agalsidase e/ou beta-agalsidase, comparada aos cuidados paliativos e ao tratamento sintomático associado aos órgãos alvos da doença de Fabry. Indicação: Manejo e intervenção aos desfechos clínicos em pacientes com a doença de Fabry. Pergunta: A intervenção por alfa-agalsidase e/ou beta-agalsidase é mais eficaz e segura que o manejo para o tratamento de sintomas ou paliativo aos desfechos clínicos esperados para a doença de Fabry? Métodos: Estudo de revisão sistemática rápida. A base consultada foi a Medline/Pubmed por meio de estratégias de buscas predefinidas. Foi feita avaliação da qualidade metodológica das revisões sistemáticas com a ferramenta AMSTAR-2 (Assessing the Methodological Quality of Systematic Reviews version 2). Resultados: Foram selecionadas 3 revisões sistemáticas, que atendiam aos critérios de inclusão. Conclusão: A intervenção com alfa-agalsidase e/ou beta-agalsidase promove redução para acúmulo de globotriaosilceramida; no entanto a redução é dependente do período de intervenção e concentração do fármaco, assim como o tecido avaliado e o tempo de sinais clínicos da doença. Há evidências de melhora na função renal, dor, desconfortos gastrointestinais e qualidade de vida. É importante considerar a heterogeneidade para as diferentes características dos grupos afetados, como idade, sexo e estágio da doença. No entanto, a compreensão consistente da relação tratamento e os desfechos são afetados pela baixa frequência de pessoas atingidas, e isso diminui o poder para inferências entre os diferentes estudos, reportando para as limitações da geração de protocolos de intervenção mais robustos e assertivos. Portanto, há necessidade de se seguir com novas avaliações, sobretudo para os estudos clínicos aleatorizados

Technology: Alphagalsity and/or beta-agalsidase compared to palliative care and symptomatic treatment associated with target organs in Fabry disease. Indication: Management and intervention to clinical outcomes in patients with Fabry disease. Question: Is alfagalsidase and/or beta-agalsidase intervention more effective and safer than management to treat symptoms or palliate expected clinical outcomes for Fabry disease? Methods: Rapid systematic review. Medline/Pubmed was consulted using predefined search strategies. The methodological quality of systematic reviews was assessed using the AMSTAR-2 (Assessing the Methodological Quality of Systematic Reviews version 2) tool. Results: Three systematic reviews were selected that met the inclusion criteria. Conclusion: Intervention with alfagalsidase and/or beta-agalsidase promotes a reduction in the accumulation of globotriaosylceramide; however, the reduction is dependent on the period of intervention and concentration of the drug, as well as the evaluated tissue and the time of clinical signs of the disease. There is evidence for improvements in kidney function, pain, gastrointestinal discomfort and quality of life. It is important to consider heterogeneity for different characteristics of affected groups, such as age, sex and disease stage; however, the consistent understanding of the relationship between treatment and outcomes is affected by the low frequency of people affected, and this reduces the power for inferences between different studies, referring to the limitations of generating more robust and assertive intervention protocols. There is therefore a need to continue with new assessments, especially for randomized clinical studies

Reporte de caso: enfermedad de Fabry en un adulto con enfermedad renal crónica y síntomas sistémicos característicos / A case report: Fabry disease in an adult with chronic kidney disease and characteristic systemic symptoms / Relato de um caso: doença de Fabry em um adulto com doença renal crônica e sintomas sistémicos característicos

Se presenta el caso de un paciente de sexo masculino, de 62 años, con antecedentes familiares de cardiopatía y enfermedad renal, y antecedentes personales de enfermedad renal crónica severa, por la que recibió trasplante renal. Es enviado a consulta cardiológica por dolores torácicos atípicos y episodios de hipotensión sintomática, se constata en el ecocardiograma: hipertrofia ventricular izquierda concéntrica y deformación miocárdica longitudinal del ventrículo izquierdo patológica. La resonancia magnética cardíaca encuentra un patrón de realce tardío sugestivo de enfermedad de Fabry, diagnóstico que se confirma con dosificación enzimática y estudio genético. Recibe tratamiento específico con una buena respuesta inicial. Esta es una enfermedad sistémica metabólica congénita en la que el diagnóstico y el tratamiento específico se realiza en la edad adulta.

It is presented a 62-year-old male patient with a family history of heart and kidney disease, and a personal history of chronic kidney disease, for which he received a kidney transplant. He was sent to the cardiology department due to atypical chest pain and episodes of symptomatic hypotension. The echocardiogram revealed: concentric left ventricular hypertrophy and pathological longitudinal myocardial deformation of the left ventricle. Cardiac magnetic resonance finds a pattern of late enhancement suggestive of Fabry disease, a diagnosis that is confirmed with enzyme dosage and genetic study. He receives specific treatment with a good initial response. This is a congenital metabolic systemic disease in which the diagnosis and specific treatment is carried out in adulthood.

Se apresenta o caso de um paciente do sexo masculino, 62 anos, com histórico familiar de cardiopatia e doença renal e histórico pessoal de doença renal crônica grave, para o qual recebeu transplante de rim. Foi encaminhado ao serviço de cardiologia por dor torácica atípica e episódios de hipotensão sintomática. O ecocardiograma revelou: hipertrofia ventricular esquerda concêntrica e deformação miocárdica longitudinal patológica do ventrículo esquerdo. A ressonância magnética cardíaca encontra um padrão de realce tardio sugestivo de doença de Fabry, diagnóstico confirmado com dosagem enzimática e estudo genético. Recebe tratamento específico com boa resposta inicial. Tratase de uma doença sistêmica metabólica congênita em que o diagnóstico e o tratamento específico são realizados na idade adulta.

Enfermedad de Fabry: revisión para el cardiólogo clínico / Fabry disease: review for the clinical cardiologist / Doença de Fabry: revisão para o cardiologista clínico

La enfermedad de Fabry es una afección genética producida por un déficit total o parcial de la enzima alfagalactosidasa A implicada en el catabolismo de glicoesfingolípidos. Dicha alteración genera el depósito lisosomal del residuo globotriasilceramida (Gb-3) a nivel multitisular, a predominio de los sistemas renal, cardíaco, nervioso y cutáneo. Debido a su baja prevalencia y su variada presentación clínica representa un verdadero reto diagnóstico. La combinación de antecedentes familiares de cardiopatía y afección renal, diferentes grados de hipertrofia del ventrículo izquierdo, sumado a afecciones cutáneas, neurológicas y enfermedad renal progresiva, deben hacer plantear la posibilidad de una enfermedad de Fabry. El cardiólogo que estudia un paciente con hipertrofia ventricular es quien debe sospecharla, y debe hacer un diagnóstico diferencial con miocardiopatías hipertróficas, cardiopatía hipertensiva u otras miocardiopatías por depósitos. Los aportes diagnósticos de la resonancia magnética cardíaca han sido de suma importancia en los últimos años. Los estudios enzimáticos y genéticos, antes de muy difícil adquisición en nuestro medio, son factibles en la actualidad. Un diagnóstico temprano es clave para iniciar el tratamiento enzimático sustitutivo, evitar un daño más extenso e irreversible, e identificar los familiares afectados en fases iniciales.

Fabry disease is a genetic condition caused by a total or partial deficiency of the enzyme alphagalactosidase A involved in the catabolism of glycosphingolipids. This alteration generates the lysosomal deposit of the globotriasylceramide residue (Gb-3) at the multi-tissue level, predominantly in the kidneys, heart, nervous system and skin. Due to its low prevalence and its varied clinical presentation, it represents a true diagnostic challenge. The combination of family history of heart disease and kidney disease, different degrees of hypertrophy of the left ventricle, added to skin and neurological conditions and progressive kidney disease, should raise the possibility of Fabry disease. The cardiologist who studies a patient with ventricular hypertrophy is the one who should suspect it and make a differential diagnosis of hypertrophic cardiomyopathies, hypertensive heart disease or other cardiomyopathies due to deposits. Diagnostic complementation with a cardiac resonance study has been extremely important in recent years. Enzymatic and genetic studies, previously very difficult to acquire in our environment, are currently feasible. An early diagnosis is key to starting enzyme replacement therapy, avoiding more extensive and irreversible damage, and allowing affected family members to be identified in the early stages.

A doença de Fabry é uma condição genética causada por uma deficiência total ou parcial da enzima alfagalactosidase A envolvida no catabolismo de glicoesfingolipídeos. Essa alteração gera o depósito lisossomal do resíduo globotriasilceramida (Gb-3) em nível multitecidual, predominantemente nos rins, coração, sistema nervoso e pele. Devido à sua baixa prevalência e à sua apresentação clínica variada, representa um verdadeiro desafio diagnóstico. A combinação de história familiar de cardiopatia e doença renal, diferentes graus de hipertrofia do ventrículo esquerdo, somada a condições dermatológicas e neurológicas e doença renal progressiva, deve levantar a possibilidade de doença de Fabry. O cardiologista que estuda um paciente com hipertrofia ventricular é quem deve suspeitar e fazer um diagnóstico diferencial de cardiomiopatias hipertróficas, cardiopatias hipertensivas ou outras cardiomiopatias por depósitos. A complementação diagnóstica com estudo de ressonância cardíaca tem sido de extrema importância nos últimos anos. Estudos enzimáticos e genéticos, anteriormente muito difíceis de adquirir em nosso meio, são atualmente viáveis. O diagnóstico precoce é fundamental para iniciar a terapia de reposição enzimática, para evitar danos mais extensos e irreversíveis, e permite que os familiares afetados sejam identificados nos estágios iniciais.

Major cardiovascular adverse events in Fabry disease patients receiving agalsidase alfa / Eventos cardiovasculares mayores en pacientes con enfermedad de Fabry tratados con agalsidasa alfa

Abstract Cardiovascular mortality (CVM) has become the major contributor to overall Fabry disease (FD) mortality in the enzyme replacement therapy (ERT) era. Our objectives were to describe causes and potential predictors of mortality in FD adult patients in Argentina, and to assess risk of major adverse cardio vascular events (MACE) in the ERT era. We retrospectively studied 93 consecutive patients treated with alpha-galactosidase A (median follow up: 9.5 years from start of ERT). Mean age at ERT starting was 35±16.3 years. Prevalence of cardiomyopathy and renal disease reached 47% and 41%, respectively. Eleven subjects (11.8%, 95%CI: 5-18%) died during follow up (1.24/100 patient-years). Mean overall survival was 71 years (95%CI: 66-75 years). Seven cases were considered as CVM; main causes were sudden death and stroke. Risk of MACE was 14% (95%CI: 6.9-21.1%; 1.47 events/100 patient-years from start of ERT). All but 2 subjects had at least one comorbid cardiovascular risk factor; however, 86% of patients remained free of MACE during follow-up. CVM remained low and our study was underpowered for detection of predictors of mortality, but it is worth noting that age at diagnosis and ERT starting, left ventricular mass index and renal disease trended to correlate with CVM. Prevalence of hypertension, diabetes and dyslipidemia were lower in FD patients when compared to population level data. As in the Argentinean general population, CVM was the leading cause of mortality among this cohort of consecutive FD patients treated with agalsidase alfa.

Resumen La mortalidad cardiovascular (MCV) se ha convertido en el principal contribuyente a la mortalidad general por enfermedad de Fabry (EF) en la era de la terapia de reemplazo enzimático (TRE). Nuestros objetivos fueron describir las causas y posibles predictores de mortalidad en pacientes adultos con EF en la Argentina, y evaluar el riesgo de eventos cardiovasculares mayores (MACE) en la actual era de TRE. Se estudiaron 93 pacientes consecutivos tratados con agalsidasa-alfa por una mediana de 9.5 años tras iniciar TRE. La edad al inicio de TRE fue 35 ± 16.3 años. La prevalencia de cardiomiopatía y enfermedad renal alcanzó 47% y 41%, respectivamente. Once sujetos (11.8%; IC95%: 5-18%) murieron durante el seguimiento (1.24/100 pacientes/año). La supervivencia global fue 71 años (IC95%: 66-75 años). Siete casos fueron considerados como MCV; las principales causas fueron muerte súbita e ictus. El riesgo de MACE fue 14% (IC95%: 6.9-21.1%; 1.47 eventos/100 pacientes/año desde la ERT). Todos menos 2 sujetos tenían al menos un factor de riesgo cardiovascular, pero el 86% permaneció libre de MACE. Los eventos de MCV fueron escasos. El estudio tuvo reducido poder estadístico para detectar predictores de mortalidad, pero la edad al diagnóstico y al iniciar la TRE, índice de masa ventricular izquierda y enfermedad renal tendieron a correlacionarse con MCV. La prevalencia de hipertensión, diabetes y dislipidemia fue menor en comparación con la población general. Como ocurre con la población general en Argentina, los eventos cardiovasculares fueron la principal causa de muerte en esta cohorte de pacientes consecutivos con EF tratados con agalsidasa-alfa.

Increased serum interleukin-6 and tumor necrosis factor alpha levels in fabry disease: correlation with disease burden

OBJECTIVES: Fabry disease (FD) is an X-linked lysosomal disease caused by variants of the GLA gene; the formation of defective alpha-galactosidase A contributes to the accumulation of substrates in several organs. Chronic inflammation is thought to contribute to organ damage in FD patients. METHODS: In total, 36 classic FD patients (15 men/21 women) and 25 healthy controls (20 men/8 women) were assessed. The Mainz Severity Score Index (MSSI) was established after conducting interviews with the patients and chart review. Serum IL-6, IL-1β, and TNF-α levels were evaluated in both groups. RESULTS: The mean age (years) for FD patients was 43.1±15.4 and that for the controls was 47.4±12.2 (p>0.05). Twenty-two patients (59.5%) were treated with enzyme replacement therapy (ERT). Serum IL-6 and TNF-α levels were significantly higher in FD patients than in the controls. Patients treated with ERT had higher serum IL-6 and TNF-α levels than those not treated with ERT. There was no difference in the serum IL-1β levels between patients treated with ERT and those who were not. The MSSI scores in the patients were correlated with serum levels of IL-6 (r=0.60, p<0.001) and TNF-α (r=0.45, p<0.001). CONCLUSION: FD was associated with elevated serum levels of IL-6 and TNF-α in this cohort. The FD patients treated with ERT, particularly, women, exhibited higher levels of serum IL-6 and TNF-α than those not treated with ERT; the serum IL-6 and TNF-α levels were correlated with the MSSI scores reflecting greater disease burden.

CD77 levels over enzyme replacement treatment in Fabry Disease Family (V269M) / Níveis de CD77 ao longo do tratamento de reposição enzimática em família com Doença de Fabry (V269M)

ABSTRACT Introduction: Fabry disease (FD) is a disorder caused by mutations in the gene encoding for lysosomal enzyme α-galactosidase A (α-GAL). Reduced α-GAL activity leads to progressive accumulation of globotriaosylceramide (Gb3), also known as CD77. The recent report of increased expression of CD77 in blood cells of patients with FD indicated that this molecule can be used as a potential marker for monitoring enzyme replacement therapy (ERT). Objective: The purpose of this study was to evaluate the CD77 levels throughout ERT in FD patients (V269M mutation). Methods: We evaluated the fluctuations in PBMC (peripheral blood mononuclear cell) membrane CD77 expression in FD patients undergoing ERT and correlated these levels with those observed in different cell types. Results: A greater CD77 expression was found in phagocytes of patients compared to controls at baseline. Interestingly, the variability in CD77 levels is larger in patients at baseline (340 - 1619 MIF) and after 12 months of ERT (240 - 530 MIF) compared with the control group (131 - 331 MFI). Furthermore, by analyzing the levels of CD77 in phagocytes from patients throughout ERT, we found a constant decrease in CD77 levels. Conclusion: The increased CD77 levels in the phagocytes of Fabry carriers together with the decrease in CD77 levels throughout ERT suggest that measuring CD77 levels in phagocytes is a promising tool for monitoring the response to ERT in FD.

RESUMO Introdução: A doença de Fabry (DF) é um distúrbio causado por mutações no gene que codifica a enzima lisossômica α-galactosidase A (α-GAL). A redução da atividade de α-GAL leva ao acúmulo progressivo de globotriaosilceramida (Gb3), também conhecida como CD77. O recente relato de aumento da expressão de CD77 em células sanguíneas de pacientes com DF indicou que essa molécula pode ser utilizada como um potencial marcador para o monitoramento da terapia de reposição enzimática (TRE). Objetivo: O objetivo deste estudo foi avaliar os níveis de CD77 ao longo da TRE em pacientes com DF (mutação V269M). Métodos: Foram avaliadas as flutuações na expressão de CD77 nas membranas das CMSP (células mononucleares do sangue periférico) em pacientes com DF submetidos à TRE e correlacionados com aqueles observados em diferentes tipos de células. Resultados: Uma maior expressão de CD77 foi encontrada em fagócitos de pacientes em comparação aos controles no início do estudo. Curiosamente, a variabilidade nos níveis de CD77 é maior em pacientes no início do estudo (340 - 1619 MIF) e após 12 meses de TRE (240 - 530 MIF) em comparação com o grupo controle (131 - 331 MFI). Além disso, analisando os níveis de CD77 em fagócitos de pacientes ao longo da TRE, encontramos uma diminuição constante nos níveis de CD77. Conclusão: O aumento nos níveis de CD77 nos fagócitos de portadores de Fabry, juntamente com a diminuição nos níveis de CD77 ao longo da TRE, sugerem que medir os níveis de CD77 nos fagócitos é uma ferramenta promissora para monitorar a resposta à TRE na DF.

Compromiso neuropático y autonómico en Enfermedad de Fabry: presentación de casos clínicos / Neuropathy and Fabry's disease: report of five cases

Fabry's disease is an X-linked multisistemic lisosomal storage disorder caused by deficiency or absence in α-Galatosidase A. Symptoms develop early in childhood with small fiber neuropathy, autonomic disorders and skin lesions (angiokeratomas). More severe in males, patients develop over years heart disease (hypertrophic cardiomyopathy, bradycardia), proteinuria, renal failure, transient ischemic attacks and stroke, associated with decreased life expectancy. We report five patients with Fabry's disease aged between 21 to 56 years and with family history. Neuropathic symptoms are described and neurophysiological testing findings of nerve conduction studies, quantitative sensory testing, autonomic testing and sympathetic skin response are presented.

Switch from agalsidase beta to agalsidase alfa in the enzyme replacement therapy of patients with fabry disease in Latin America

There are currently two available enzyme replacement therapies for Fabry disease and little information regarding efficacy and safety of switching therapies. Between 2009 and 2012 there was a worldwide shortage of agalsidase beta and patients on that enzyme were switched to agalsidase alfa. This retrospective observational study assessed a 2-year period of efficacy and safety in a population of Fabry patients, in Argentina (30 patients) and Venezuela (3 patients), who switched therapies from algasidase beta to agalsidase alfa. Thirty-three patients completed 24-months follow-up after the switch (age 32.4 ± 2.0, range 10.0-55.9 years; male: female 23:10). Measures of renal function such as estimated glomerular filtration rate remained almost unchanged in 31 patients without end stage renal disease over the 2 years after switching and urine protein excretion continued stable. Cardiac functional parameters: left ventricular mass index, interventricular septum, left ventricular posterior wall showed no significant change from baseline in the 33 patients. Quality of life, pain and disease severity scores were mostly unchanged after 24-months and agalsidase alfa was generally well tolerated. Our findings showed there is no significant change in the efficacy measured through the renal or cardiac function, quality of life, pain, disease severity scoring and safety for at least 2 years after switching from agalsidase beta to agalsidase alfa.

Actualmente hay disponibles dos terapias de reemplazo enzimático en enfermedad de Fabry y existe poca información sobre la eficacia y seguridad del cambio de una a la otra. Entre 2009 y 2012 hubo falta a nivel mundial de agalsidasa beta y los pacientes tratados hasta entonces con esa enzima iniciaron tratamiento con agalsidasa alfa. El presente estudio retrospectivo, observacional evaluó la eficacia y seguridad a 2 años en pacientes con enfermedad de Fabry en Argentina (30 pacientes) y Venezuela (3 pacientes), que cambiaron su tratamiento de agalsidasa beta a agalsidasa alfa. Treinta y tres pacientes completaron 24 meses de seguimiento post-cambio (edad 32.4 ± 2.0; rango 10.0-55.9; hombre: mujer 23:10). La función renal, medida con la tasa de filtrado glomerular, se mantuvo sin cambios en 31 pacientes sin enfermedad renal terminal durante 2 años post-cambio. La secreción de proteína en orina continuó estable. Los parámetros de función cardíaca -índice de masa ventricular izquierda, septum interventricular, espesor de la pared posterior ventricular- no mostraron cambios significativos post-cambio de terapia en los 33 pacientes. La calidad de vida, el dolor y la gravedad de la enfermedad se mantuvieron mayormente estables luego de 24 meses, y la agalsidasa alfa fue generalmente bien tolerada. Nuestros resultados muestran que no hay cambios significativos en la eficacia medida por la función renal y cardíaca, en la seguridad y en los valores de la calidad de vida, el dolor o la gravedad de la enfermedad durante al menos 2 años luego del cambio de agalsidasa beta a agalsidasa alfa.

Protocolo de evaluación rápida de seguridad y efectividad del uso de Agalsidasa beta en el tratamiento de pacientes con enfermedad de Fabry / Protocol of rapid evaluation of security and effectiveness of the use of Agalsidasa beta in the treatment of patients with Fabry disease

La enfermedad de Fabry es una enfermedad progresiva heterogénea multisistémica hereditaria que afecta tanto a hombres como a mujeres. Se caracteriza por la deficiencia de α-galactosidasa. La actividad reducida o inexistente de la α-glucosidasa provoca la acumulación de GL-3 en los lisosomas de muchos tipos celulares, incluyendo las células endoteliales y parenquimatosas, lo que, en último lugar, provoca deterioros clínicos que pueden provocar la muerte como resultado de las complicaciones renales, cardiacas y cerebrovasculares. El Fondo Intangible Solidario de Salud solicita la evaluación de la tecnología sanitaria agalsidasa beta como tratamiento para Enfermedad de Fabry, la cual a su vez fue solicitada Instituto Nacional de Salud del Niño y el Hospital Hipólito Unánue de la Región Tacna, a raíz de la aparición de un caso. Luego de una primera revisión, se determina que la tecnología agalsidasa beta, comercializada en el Perú como Fabrazyme 35 mg, supera la tolerancia al riesgo para evaluación de tecnologías sanitarias en el Seguro Integral de Salud, por lo se consideró sea evaluada por el área de Evaluación de Tecnologías Sanitarias en el SIS Central.(AU)

Home infusion program for Fabry disease: experience with agalsidase alfa in Argentina / Programa de infusión domiciliaria para la enfermedad de Fabry: experiencia con agalsidasa alfa en la Argentina

Fabry disease is an X-linked lysosomal storage disorder caused by inherited deficiency of the enzyme α-galactosidase A. Enzyme replacement treatment using agalsidase alfa significantly reduces pain, improves cardiac function and quality of life, and slows renal deterioration. Nevertheless, it is a life-long treatment which requires regular intravenous infusions and entails a great burden for patients. Our objective was to evaluate retrospectively the safety and tolerability of the home infusion of agalsidase alfa in patients with Fabry disease in Argentina. We evaluated all the patients with Fabry disease who received home infusion with agalsidase alfa 0.2 mg/kg between January 2005 and June 2011. The program included 87 patients; 51 males (mean age: 30 years) and 36 females (mean age: 34 years). A total of 5229 infusions (mean: 59 per patient; range: 1-150) were administered. A total of 5 adverse reactions were seen in 5 patients (5.7% of patients and 0.9% of the total number of infusions). All were mild in severity and resolved by reducing the rate of infusion and by using antihistaminics. All these 5 patients were positive for IgG antibodies, but none of them presented IgE antibodies and none suffered an anaphylactic shock. In our group 18 patients were switched from agalsidase beta to agalsidase alfa without complications. Home infusion with agalsidase alfa is safe, well tolerated and is associated to high compliance.

La enfermedad de Fabry es un trastorno de almacenamiento lisosomal hereditario ligado al cromosoma X ocasionado por el déficit de la enzima alfa galactosidasa A. La terapia de reemplazo enzimático utilizando agalsidasa alfa reduce significativamente el dolor, mejora la función cardíaca y la calidad de vida y enlentece el deterioro renal. Sin embargo, es un tratamiento de por vida que requiere infusiones intravenosas regulares y supone una gran carga para los pacientes. Nuestro objetivo fue evaluar retrospectivamente la tolerabilidad y la seguridad del procedimiento de infusión domiciliaria de agalsidasa alfa en pacientes con enfermedad de Fabry en Argentina. Evaluamos a todos los pacientes con enfermedad de Fabry que recibieron infusiones domiciliarias de 0.2 mg/kg de agalsidasa alfa entre enero del 2005 y junio del 2011. El programa incluyó 87 pacientes; 51 hombres (edad media: 30 años) y 36 mujeres (edad media: 34 años). Se administraron un total de 5229 infusiones (media: 59 por paciente; rango: 1-50). Se observaron un total de 5 reacciones adversas en 5 pacientes (5.7% de los pacientes y 0.9 % del número total de infusiones). Todas fueron de gravedad leve y se resolvieron reduciendo la velocidad de la infusión o usando antihistamínicos. Los 5 pacientes fueron positivos para anticuerpos IgG, pero ninguno presentó anticuerpos IgE o sufrió un shock anafiláctico. En nuestro grupo, 18 pacientes fueron cambiados de agalsidasa beta a agalsidasa alfa sin complicaciones. La infusión domiciliaria de agalsidasa alfa es segura, bien tolerada y logra una alta adherencia al tratamiento.

Judicialização do acesso ao tratamento de doenças genéticas raras: a doença de Fabry no Rio Grande do Sul / Court-ordered access to treatment of rare genetic diseases: Fabry Disease in the state of Rio Grande do Sul, Brazil

A judicialização do acesso a medicamentos de alto custo para doenças genéticas raras, como a doença de Fabry (deficiência de alfa-galactosidase A), é um fenômeno crescente e pouco estudado de forma sistemática. Realizou-se um estudo observacional, transversal e retrospectivo para caracterizar as ações judiciais relativas ao acesso ao tratamento da doença de Fabry por terapia de reposição enzimática no estado do Rio Grande do Sul até 2007. Foram identificadas 13 ações e 17 demandantes. Onze solicitaram alfa e 6 betagalsidase. Figuraram como réus o estado do RS, a União e 5 municípios, em litisconsórcio ou não. Houve 13 pedidos de antecipação da tutela, 12 concedidos, e 2 sentenças, ambas procedentes. "Risco de morte" foi alegado, por médicos, em 4 prescrições e, por advogados, nas 13 ações. Os dados sugerem a ausência de discussões que envolvam conjuntamente aspectos de eficácia e segurança médicas, custo-efetividade, impacto econômico e argumentos jurídico-constitucionais, sendo necessária uma política específica para doenças genéticas raras que padronize o acesso aos tratamentos.

Court-ordered access to high-cost drugs for rare genetic diseases, such as Fabry Disease (alpha-galactosidase-A deficiency), is a growing phenomenon as yet lacking systematic study. An observational, cross-sectional and retrospective study was conducted to characterize the lawsuits related to access to treatment for Fabry Disease by Enzyme Replacement Therapy in the State of Rio Grande do Sul prior to 2007. The study identified 13 lawsuits and 17 plaintiffs, 11 requesting alfa and 6 betagalsidase. The State of RS, the Federal Government, and 5 municipalities figured as defendants, in the form of joinder of parties or otherwise. There were 13 requests for interlocutory relief of which 12 were granted, and 2 sentences were handed down, both favorable. "Risk of death" was alleged by doctors in 4 prescriptions and by lawyers in the 13 lawsuits. The data suggest the lack of discussions combining aspects of medical efficacy and safety, cost-effectiveness, economic impact, and legal and constitutional arguments, which requires a specific policy for rare genetic diseases to standardize access to treatment.

Medicamentos de alto custo para doenças raras no Brasil: o exemplo das doenças lisossômicas / High cost drugs for rare diseases in Brazil: the case of lysosomal storage disorders

Este artigo aborda, de forma crítica, aspectos das políticas públicas brasileiras para medicamentos, com ênfase nos de alto custo dirigidos às doenças raras. As doenças lisossômicas foram utilizadas como exemplo pela sua raridade e pela tendência mundial para o desenvolvimento de novos fármacos para seu tratamento. Três doenças foram abordadas: doença de Gaucher, doença de Fabry e mucopolissacaridose tipo I. Embora todas tenham medicamentos registrados no Brasil, a doença de Gaucher é a única com protocolo clínico e diretrizes de tratamento balizadas pelo Ministério da Saúde. Os autores almejam, com este artigo, fomentar a discussão sobre o papel da avaliação de tecnologias em saúde para o tratamento das doenças raras no Brasil, enfatizando a necessidade de políticas legitimadas dirigidas especialmente a elas. A despeito das dificuldades de se estabelecer uma política de saúde específica para cada doença rara, é possível o estabelecimento de modelos racionais para lidar com esse crescente desafio.

This paper approaches in a critical way aspects of Brazilian public policies for drugs, emphasizing those classified as high cost and for rare diseases. The lysosomal storage diseases was taken as an example because of their rarity and the international trend for the development of new drugs for their treatment, all at high costs. Three lysosomal storage diseases were approached: Gaucher disease, Fabry disease and mucopolysaccharidosis type I. Gaucher disease has its treatment drug licensed in Brazil and guidelines for its use are established through a clinical protocol by the Ministry of Health. The others have their drug treatments registered in Brazil; however, no treatment guidelines for them have been developed by the government. The objective of the paper was to foster the discussion on the role of health technology assessment for high-cost drugs for rare diseases in Brazil, emphasizing the need for establishing health policies with legitimacy towards these diseases. Despite the difficulties in establishing a health policy for each rare disease, it is possible to create rational models to deal with this growing challenge.

Fabry disease: A treatable lysosomal storage disorder.

Fabry disease is a lysosomal storage disease with an X-linked inheritance pattern, which presents in childhood as acroparaesthesias. Its non-specific symptoms often lead to delays in the diagnosis. We report the case of a 13-year-old boy who presented with typical acroparaesthesia of Fabry disease, his younger brother had gastrointestinal manifestations of the disease and their mother’s symptoms suggested that she is a carrier. Enzyme replacement therapy helped in ameliorating the patient’s symptoms and preventing complications such as renal failure, stroke and cardiovascular disorders.

White matter lesions in Fabry disease before and after enzyme replacement therapy: a 2-year follow-up / Lesões da substância branca na doença de Fabry antes e depois da terapia de reposição enzimática: um seguimento de 2 anos

PURPOSE: To report the clinical and neuroimaging, central nervous system (CNS) findings of patients with Fabry disease (FD) during 24 months of enzyme replacement therapy (ERT) with agalsidase-alpha. METHOD: Eight patients were included. Six completed 24 months of ERT. Clinical and magnetic resonance imaging (MRI) data were obtained at 0, 12 and 24 months of ERT. White matter lesions (WML) were evaluated as well as their relation to age, symptoms and neurological examination (CNS score). RESULTS: MRI was stable in 3 patients. WML and CNS score worsened in one patient, fluctuated in another, and improved in the sixth patient. In the whole series, there were 15 WML at baseline, and 19 at the 24th month. In two years, 4 lesions disappeared, whereas 8 appeared. CONCLUSION: A widespread pattern of silent WML in FD was seen. In two years, some WML appeared, and some disappeared. If these phenomena were related to the natural history, remains to be demonstrated.

OBJETIVO: Relatar os achados neurológicos e de imagem do sistema nervoso central (SNC), observados durante 24 meses de tratamento de reposição enzimática (ERT) com agalsidase-alfa, em pacientes com a doença de Fabry (FD). MÉTODO: 8 pacientes foram incluídos; 6 completaram 24 meses de ERT. Os dados foram obtidos aos 0, 12 e 24 meses de ERT. Lesões de substância branca (WML) foram avaliadas assim como sua relação com a idade e o exame neurológico (escore SNC). RESULTADOS: Os achados de ressonância nuclear magnética foram estáveis em 3 pacientes. As WML e o escore SNC pioraram em um caso; flutuaram em um outro caso; e melhoraram no sexto paciente. No todo, havia 15 WML antes da ERT e 19 WML depois de 24 meses de ERT. Em dois anos, 4 lesões desapareceram e 8 novas surgiram. CONCLUSÕES: Viu-se um padrão difuso de WML assintomáticas, na FD. Em dois anos, algumas WML surgiram, enquanto outras desapareceram. Resta demonstrar se esses fenômenos fazem parte da história natural da doença.