Patisiran Treatment in Patients with Transthyretin Cardiac Amyloidosis.

BACKGROUND: Transthyretin amyloidosis, also called ATTR amyloidosis, is associated with accumulation of ATTR amyloid deposits in the heart and commonly manifests as progressive cardiomyopathy. Patisiran, an RNA interference therapeutic agent, inhibits the production of hepatic transthyretin. METHODS: In this phase 3, double-blind, randomized trial, we assigned patients with hereditary, also known as variant, or wild-type ATTR cardiac amyloidosis, in a 1:1 ratio, to receive patisiran (0.3 mg per kilogram of body weight) or placebo once every 3 weeks for 12 months. A hierarchical procedure was used to test the primary and three secondary end points. The primary end point was the change from baseline in the distance covered on the 6-minute walk test at 12 months. The first secondary end point was the change from baseline to month 12 in the Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS) score (with higher scores indicating better health status). The second secondary end point was a composite of death from any cause, cardiovascular events, and change from baseline in the 6-minute walk test distance over 12 months. The third secondary end point was a composite of death from any cause, hospitalizations for any cause, and urgent heart failure visits over 12 months. RESULTS: A total of 360 patients were randomly assigned to receive patisiran (181 patients) or placebo (179 patients). At month 12, the decline in the 6-minute walk distance was lower in the patisiran group than in the placebo group (Hodges-Lehmann estimate of median difference, 14.69 m; 95% confidence interval [CI], 0.69 to 28.69; P = 0.02); the KCCQ-OS score increased in the patisiran group and declined in the placebo group (least-squares mean difference, 3.7 points; 95% CI, 0.2 to 7.2; P = 0.04). Significant benefits were not observed for the second secondary end point. Infusion-related reactions, arthralgia, and muscle spasms occurred more often among patients in the patisiran group than among those in the placebo group. CONCLUSIONS: In this trial, administration of patisiran over a period of 12 months resulted in preserved functional capacity in patients with ATTR cardiac amyloidosis. (Funded by Alnylam Pharmaceuticals; APOLLO-B ClinicalTrials.gov number, NCT03997383.).

Comparison of the efficacy and safety of intralesional injection of tranexamic acid and the topical application of Kligman combination drug in the treatment of macular amyloidosis.

Macular amyloidosis (MA) is a common form of cutaneous amyloidosis that manifests as dark spots consisting of brown pigments with a rippled pattern on the skin, and the treatment of this condition is highly challenging. The aim of this study was to compare the efficacy and safety of intralesional injection of tranexamic acid (TXA) and topical application of Kligman combination drug in the treatment of macular amyloidosis. In this double-blind clinical trial, a total of 43 patients, who were diagnosed with MA, were treated with two different methods of intralesional injection of tranexamic acid and topical application of Kligman combination drug. Both therapeutic methods were effective in improving MA and significantly reduced hyperpigmentation of the treated areas, but tranexamic acid was significantly more effective than the Kligman combination drug. Significantly, greater improvements were observed in the group of patients treated with tranexamic acid. In the tranexamic acid treatment group, ΔE was reduced from 11.39 in the first session to 8.53 in the third session, and in the Kligman treatment group, it was reduced from 8.79 in the first session to 6.32 in the third session (p < 0.05). In addition, the pruritus score in patients treated with topical tranexamic acid injection was lower compared to the patients treated with the topical application of the Kligman combination drug. The results of this study demonstrated the significant positive effects of both treatment methods, but in terms of reducing melanin content, intralesional injection of tranexamic acid was a more effective method. Both treatments considered safe for MA. In tranexamic acid group, patients logically experienced a tolerable pain during injection but they significantly had significantly lower local pruritic discomfort during study. So, based on the positive findings of this study we suggest to use tranexamic acid in combination with other effective therapeutic methods for treatment of MA especially use of its topically applied form in combination with non-aggressive needling that results in better drug delivery without the experience of injection pain. Selection of the best administration route of tranexamic acid for hyperpigmented lesions depends on the each patient characteristic and their previous theraputic results that may vary case by case.

Patisiran e Inotersen en amiloidosis familiar mediada por transtiretina / Patisiran and Inotersen in familial amyloidosis transthyretin-mediated

CONTEXTO: La amiloidosis constituye un amplio espectro de enfermedades que se caracterizan por el depósito extracelular de un material fibrilar, generando depósitos insolubles y tóxicos en diferentes tejidos en forma de haces con conformación anómala de láminas beta cruzada, conocida como amiloide. El amiloide acumulado puede provocar daño celular y deterioro de la función de los órganos. Se sabe que al menos 30 proteínas humanas forman fibrillas amiloides. Una de sus formas es, la amiloidosis por transtiretina (ATTR), una enfermedad multisistémica, progresiva, que resulta del mal plegamiento, agregación y depósito de la proteína transportadora transtiretina (TTR), en varios tejidos del cuerpo. La Sociedad Internacional de Amiloidosis ha definido dos formas principales de este tipo de amiloidosis: la amiloidosis ATTR adquirida, denominada amiloidosis ATTRwt (wt por por sus siglas en inglés, wild-type) y la amiloidosis ATTR hereditaria, denominada hATTR (de sus siglas en inglés hereditary transthyretin amyloidosis), que se desarrolla como resultado de mutaciones en el gen TTR; que en consecuencia desestabiliza la proteína. Se estima que su prevalencia global es de 0,87 a 1,1 por millón de personas. Aproximadamente, 50000 personas padecen esta enfermedad en todo el mundo. Su presentación suele darse entre, la tercera y quinta década de la vida y de no tratarse, los síntomas de la ATTR son progresivos pudiendo llegar a causar la muerte, la que suele producirse entre tres y 15 años después de la presentación. TECNOLOGÍA: Los inhibidores de los precursores de amiloide, son fármacos conocidos como oligonucleótidos, que actúan en el interior de la célula a nivel del ARN. Tienen la capacidad de degradar o "silenciar" el ARN mensajero (ARNm), de esta forma, inhiben la síntesis hepática de la proteína TTR por interferência del ARNm. Por consiguiente, se bloquea la expresión de la proteína TTR, reduciendo la síntesis de la proteína precursora del amiloide. OBJETIVO: El objetivo del presente informe es evaluar la evidencia disponible acerca de la eficacia, seguridad y aspectos relacionados a las políticas de cobertura del uso de patisiran e inotersen en pacientes con amiloidosis familiar mediada por transtiretina. MÉTODOS: Se realizó una búsqueda en las principales bases de datos bibliográficas, en buscadores genéricos de internet, y financiadores de salud. Se priorizó la inclusión de revisiones sistemáticas (RS), ensayos clínicos controlados aleatorizados (ECAs), evaluaciones de tecnologías sanitarias (ETS), evaluaciones económicas, guías de práctica clínica (GPC) y políticas de cobertura de diferentes sistemas de salud. RESULTADOS: Se incluyeron tres ECAs, dos RS, tres GPC,siete evaluaciones económicas, y ocho informes de políticas de cobertura de patisirán e inotersen para amiloidosis familiar mediada por transtiretina. CONCLUSIONES: Evidencia de moderada calidad muestra que el uso de patisiran en pacientes con polineuropatia (estadio 1 y estadio 2) por amiloidosis familiar hereditaria mediada por transtiretina, probablemente presente una mejoría considerable de la polineuropatía y calidad de vida con respecto al cuidado usual. Si bien el patisirán presentó efectos adversos leves o moderados, estos fueron bien tolerados. No se observaron diferencias significativas en la mortalidad entre el patisiran y el cuidado usual. Evidencia de moderada calidad muestra que el uso de inotersen en pacientes con polineuropatia (estadio 1 y estadio 2) por amiloidosis familiar hereditaria mediada por trasntiretina, probablemente presente una mejoría considerable de la polineuropatía y calidad de vida con respecto a no usarlo. El uso de inotersen en comparación con el cuidado usual más placebo presentó efectos adversos importantes, tales como a glomerulonefritis y plaquetopenia. No se ha encontrado evidencia que compare en forma directa el patisiran con el inotersen, ni con otras drogas activas para el tratamiento de la amiloidosis familiar hereditaria mediada por transtiretina. Es por ello que la interpretación de la magnitud del beneficio neto de cada una fue realizada de manera indirecta y a través del juicio de valores del equipo de investigación. Por lo que estos efectos "comparativos" deben ser evaluados con cautela debido a las importantes diferencias entre los estudios, en cuanto a su población, tiempo de tratamiento y mínimas diferencias en las escalas utilizadas para la evaluación de la severidad de la polineuropatía. Esta evidencia sugeriría que probablemente el uso de patisiran podría favorecer a una reducción en la progresión de la polineuropatía y una mejoría en la calidad de vida en comparación con el inotersen. Hasta la fecha, no hay estudios que evalúen la seguridad y la eficacia de estas drogas en el subgrupo de pacientes con amiloidosis cardiaca. Solamente existe información basada en análisis de subgrupos de los ensayos clínicos disponibles, de los cuales no se obtuvieron resultados concluyentes. El patisiran e inotersen no se encuentran aprobadas aún en Argentina, por lo que su uso es compassivo o en el contexto de estudios clínicos. Ambas drogas se encuentran aprobadas por la Agencia Europea de Medicamentos y la Administración de Alimentos y Medicamentos de los Estados Unidos. Existe un consenso entre las guías de práctica clínica relevadas en recomendar el uso de patisiran o inotersen para el tratamiento de pacientes con polineuropatía (estadio 1 y estadio 2) en amiloidosis familiar hereditaria medida por transtiretina, considerando que la enfermedad es devastadora tanto para el paciente como para los familiares y que los resultados de los estudios, si bien, no son a largo plazo, fueron significativos para evitar la progresión de la polineuropatía. No se dispone de información económica respecto a estas drogas en Argentina, los datos son relevados de principalmente de sistemas de salud internacionales, tales como el sistema de salud del Reino Unido, que previo a un acuerdo comercial confidencial -por lo que se desconoce el precio convenido- , consideraron que ambas drogas resultaron costo efectivas para el umbral de pago de ese sistema de salud para el caso de enfermedades severas ultrararas, en las que contemplan umbrales de costo-efectividad hasta diez veces superiores al estándar. Sin embargo, no es posible realizar esa asunción para el sistema de salud de Argentina.

Targeting transthyretin - Mechanism-based treatment approaches and future perspectives in hereditary amyloidosis.

The liver-derived, circulating transport protein transthyretin (TTR) is the cause of systemic hereditary (ATTRv) and wild-type (ATTRwt) amyloidosis. TTR stabilization and knockdown are approved therapies to mitigate the otherwise lethal disease course. To date, the variety in phenotypic penetrance is not fully understood. This systematic review summarizes the current literature on TTR pathophysiology with its therapeutic implications. Tetramer dissociation is the rate-limiting step of amyloidogenesis. Besides destabilizing TTR mutations, other genetic (RBP4, APCS, AR, ATX2, C1q, C3) and external (extracellular matrix, Schwann cell interaction) factors influence the type of onset and organ tropism. The approved small molecule tafamidis stabilizes the tetramer and significantly decelerates the clinical course. By sequence-specific mRNA knockdown, the approved small interfering RNA (siRNA) patisiran and antisense oligonucleotide (ASO) inotersen both significantly reduce plasma TTR levels and improve neuropathy and quality of life compared to placebo. With enhanced hepatic targeting capabilities, GalNac-conjugated siRNA and ASOs have recently entered phase III clinical trials. Bivalent TTR stabilizers occupy both binding groves in vitro, but have not been tested in trials so far. Tolcapone is another stabilizer with the potential to cross the blood-brain barrier, but its half-life is short and liver failure a potential side effect. Amyloid-directed antibodies and substances like doxycycline aim at reducing the amyloid load, however, none of the yet developed antibodies has successfully passed clinical trials. ATTR-amyloidosis has become a model disease for pathophysiology-based treatment. Further understanding of disease mechanisms will help to overcome the remaining limitations, including application burden, side effects, and blood-brain barrier permeability.

Clinical resolution of generalized lichen amyloidosis with dupilumab: a new alternative therapy.

Lichen amyloidosis is a subtype of primary localized cutaneous amyloidosis characterized by deposition of amyloid protein in the skin without visceral involvement. Although it is usually limited to localized areas of the body, it rarely can present in a generalized fashion and is severely pruritic. The limited form is treated with skin directed therapies such as topical or intralesional corticosteroids or topical tacrolimus but the generalized type is more difficult to treat. We present a patient with generalized primary cutaneous lichen amyloidosis successfully treated with dupilumab.

Comparative study of fractional CO2 laser and fractional CO2 laser-assisted drug delivery of topical steroid and topical vitamin C in macular amyloidosis.

Macular amyloidosis (MA) represents a common variant of primary localized cutaneous amyloidosis. It has a characteristic female predominance; none of the treatment modalities described is either curative or uniformly effective in patients with macular amyloidosis. To determine the effect of fractional CO2 laser in macular amyloidosis in comparison to fractional CO2 laser-assisted drug delivery of topical steroids and topical vitamin C, the study includes 10 female patients with cutaneous macular amyloidosis aged between 20 and 62 years. Patients were treated with four sessions of fractional CO2 laser with 4 weeks interval. Laser treatments were performed using fractional CO2 laser with the following parameters (power 18 W, spacing 800 µm, dwell time 600 µs, stacking 3). The lesion is divided into three areas: area 1, treated by fractional laser only; area 2, treated by fractional laser followed by topical corticosteroid application under occlusion for 24 h; and area 3, treated by fractional laser followed by topical vitamin C serum application under occlusion for 24 h. All lesions were examined clinically and histologically before the therapy and 1 month after the end of the therapy to evaluate the degree of improvement. All treated areas show significant decrease in pigmentation score after treatment, significant drop in rippling (P value < 0.016), and improvement of lichenification; as regards the histological improvement, there was a significant decrease of the amyloid amount after treatment. As regards the amyloid amount, results show significant decrease in the amount of amyloid in all of the three treated areas. Area 2 reported the highest decrease in the amyloid amount followed by areas 1 and 3. One patient (10%) was highly satisfied by the treatment, 6 (60%) reported moderate degree of satisfaction, while only 3 (30%) reported mild satisfaction. Minimal complication occurred in the form of post-inflammatory hyperpigmentation in 1 patient. None of the patients suffered pain, ulceration, or infection. Fractional CO2 alone can be used to improve the texture of macular amyloidosis. If used to assist the delivery of topical steroids and topical vitamin C, improvement can be highly increased.

Primary cutaneous amyloidosis associated with autoimmune hepatitis-primary biliary cirrhosis overlap syndrome and Sjögren syndrome: A case report.

RATIONALE: Primary cutaneous amyloidosis (PCA) is a localized skin disorder characterized by the abnormal deposition of amyloid in the extracellular matrix of the dermis. The association between PCA and other diseases, although rare, has been documented for various autoimmune diseases. PCA associated with autoimmune hepatitis-primary biliary cirrhosis (AIH-PBC) overlap syndrome and Sjögren syndrome (SS) has not been previously reported in the literature. PATIENT CONCERNS: A 50-year-old woman presented with progressive abnormal liver enzyme levels and was referred to our department. DIAGNOSES: Due to the patient's symptoms, laboratory test results, radiographic findings, and pathologic results, she was diagnosed with PCA associated with AIH-PBC overlap syndrome and SS. INTERVENTIONS: She was subsequently treated with a combination of ursodeoxycholic acid (UDCA), prednisone, and azathioprine. OUTCOMES: While this treatment can achieve therapeutic success, it cannot prevent complications from cirrhosis. This patient remains alive but experienced an emergent gastrointestinal hemorrhage. LESSONS: While we acknowledge that this is a single case, these findings extend our knowledge of immunological diseases associated with PCA and suggest a common, immune-mediated pathogenic pathway between PCA, AIH-PBC overlap syndrome, and SS. After 12 years of follow up, clinical manifestations have developed, and these autoimmune diseases have progressed. The combination of UDCA, prednisone, and azathioprine can achieve therapeutic success but cannot prevent disease progression. Routine follow up for this patient is necessary to document disease progression.

Diagnóstico y tratamiento de la amiloidosis cardiaca por transtiretina. Progreso y esperanza / Diagnosis and treatment of transthyretin cardiac amyloidosis. Progress and hope

La amiloidosis cardiaca es una enfermedad infiltrativa por depósito extracelular de proteínas. De las proteínas proamiloidóticas a nivel cardiaco, la transtiretina produce una de las formas más frecuentes de amiloidosis cardiaca, bien por mutaciones o bien en su forma natural (wild-type) conocida previamente como amiloidosis senil. Hasta muy recientemente, el diagnóstico de amiloidosis por transtiretina (ATTR) se producía en reducidas ocasiones y requería confirmación histológica, por lo que establecer el diagnóstico constituía un verdadero reto en la práctica clínica habitual. Además, las opciones terapéuticas específicas para alterar el curso clínico de la enfermedad eran muy limitadas. Sin embargo, avances en el campo de la imagen cardiaca y en la estrategia diagnóstica de la enfermedad están facilitando un reconocimiento creciente de la ATTR. De forma adicional, diversos compuestos capaces de modificar la historia de la enfermedad se encuentran en fases finales de investigación, con resultados prometedores. Dado que una terapia efectiva parece estar cada vez más próxima, se hace imprescindible que los cardiólogos conozcan esta patología en profundidad y estén familiarizados con su diagnóstico y tratamiento. En esta revisión se repasará detalladamente el amplio espectro clínico de la ATTR, así como los recientes avances en el diagnóstico y tratamiento de esta entidad (AU)

Cardiac amyloidosis is an infiltrative disorder caused by extracellular protein deposition. Transthyretin is a proamyloidotic protein that produces one of the most frequent forms of cardiac amyloidosis, either through mutations or a wild-type form (previously known as senile amyloidosis). Until very recently, diagnosis of transthyretin amyloidosis (ATTR) was very uncommon and histological confirmation was mandatory, making diagnosis of ATTR a real challenge in daily clinical practice. Moreover, the specific therapeutic options to alter the clinical course of the disease were very limited. However, advances in cardiac imaging and diagnostic strategies have improved recognition of ATTR. In addition, several compounds able to modify the natural history of the disease are in the final phases of research, with promising results. Given that effective therapies are on the horizon, cardiologists should be well-versed in this disease and be familiar with its diagnosis and treatment. This review describes the broad clinical spectrum of ATTR in detail, as well as recent advances in the diagnosis and treatment of this condition (AU)

Alitretinoin treatment of lichen amyloidosis.

Lichen amyloidosis (LA) is characterized by the deposition of amyloid that may respond to chronic scratching that may be secondary to atopic dermatitis, stasis dermatitis, or interface dermatitis. Despite the development of several therapeutic strategies, including topical steroids, oral antihistamines, cyclosporine, and retinoids, an effective treatment for LA has not been established. A 49-year-old woman who has been treated irregularly for atopic dermatitis for 7 years presented with localized brownish papules on the left forearm and right elbow. They developed 3 months prior and were becoming more prominent despite of treatment with cyclosporine, oral antihistamines, and topical steroids for 5 months prior to presentation. A skin biopsy revealed amyloid deposition in the dermal papillae and the patient was diagnosed with LA associated with atopic dermatitis. A 6-month course of daily oral alitretinoin 30 mg produced marked improvement in the thickness and color of the hyperkeratotic papules without aggravation of the patient's atopic dermatitis. Histologic evaluation showed clearance of amyloid deposition and almost normalization of the epidermal changes. Herein, we report a case of LA treated with alitretinoin and suggest that it could be a potential treatment option for LA, especially in patients with inflammatory skin diseases including atopic dermatitis.

Primary localized cutaneous amyloidosis with lichen and poikiloderma-like lesions and an excellent response to systemic acitretin.

Primary localized cutaneous amyloidosis is a skin-limited amyloidosis that does not involve internal organs. It is clinically subclassified into 3 general categories and some rare variants. However, there is considerable overlap within the classification. Though there are a variety of therapeutic measures, the treatment is often unsatisfactory, particularly when the disease is severe and extensive. We describe a rare case of primary localized cutaneous amyloidosis with lichen and poikiloderma-like lesions that showed an excellent response to systemic acitretin.

Primary localized cutaneous amyloidosis with lichen and poikiloderma-like lesions and an excellent response to systemic acitretin

Abstract: Primary localized cutaneous amyloidosis is a skin-limited amyloidosis that does not involve internal organs. It is clinically subclassified into 3 general categories and some rare variants. However, there is considerable overlap within the classification. Though there are a variety of therapeutic measures, the treatment is often unsatisfactory, particularly when the disease is severe and extensive. We describe a rare case of primary localized cutaneous amyloidosis with lichen and poikiloderma-like lesions that showed an excellent response to systemic acitretin.