Análisis de costo efectividad de everolimusmás ciclosporina y prednisona comparado con micofenolato más ciclosporina y prednisona para la inmunosupresión de mantenimiento en eltrasplantecardíacoen Colombia / Cost-effectiveness analysis of everolimusmás ciclosporin and prednisone compared to mycophenolate plus ciclosporin and prednisone for maintenance immunosuppression in the cardiac transplant in Colombia

Problema de investigación: Calcular los costos y la efectividad esperados de everolimus más ciclosporina y corticosteroide (ECC) comparado con micofenolato más ciclosporina y corticoesteroide (MCC) para el tratamiento de pacientes colombianos, adultos, receptores de trasplante de corazón por primera vez, que han iniciado la terapia de inducción de inmunosupresión y que se perfilan para el tratamiento de mantenimiento. Tipo de evaluación económica Análisis de costo-efectividad. Población objetivo: Pacientes colombianos, adultos, receptores de trasplante de corazón por primera vez, que han iniciado la terapia de inducción de inmunosupresión y que se perfilan para el tratamiento de mantenimiento. Intervención y comparadores I: Everolimus más ciclosporina (dosis reducida) y corticosteroide (ECC). C: Micofenolato más ciclosporina (dosis estándar) y corticoesteroides (MCC). Horizonte temporal: Vital. Perspectiva Sistema General de Seguridad Social en Salud (SGSSS). Tasa de descuento: Se emplea una tasa de descuento común tanto para los costos como para los desenlaces en salud equivalente al 5 % anual. Adicionalmente, se realizan análisis de sensibilidad de 0 %, 3,5 %, 7 % y 12 %. Estructura del modelo: Modelo de Markov anidado en un árbol de decisiones. Fuentes de datos de efectividad y seguridad: Fueron empleados los recursos siguientes: el Reporte de efectividad y seguridad de las alternativas a evaluar previamente publicado por el IETS, los resultados de una búsqueda de literatura económica en las bases de datos del CRD y los de una búsqueda manual de literatura económica y clínica, además de la información obtenida en la consulta a expertos clínicos. Desenlaces y valoración: Años de vida ganados. Desenlaces y valoración: Años de vida ganados. Costos incluidos: Costos directos de atención: Costos de medicamentos, Costos de procedimiento. Fuentes de datos de costos SISMED: Medicamentos Manual tarifario ISS 2001: Procedimientos. Resultados del caso base: La administración del esquema ECC como inmunosupresión de mantenimiento para pacientes receptores de trasplante es una estrategia más costosa y menos efectiva, respecto al esquema MCC por lo que se considera una estrategia dominada. Análisis de sensibilidad: La intervención ECC deja de ser dominada sólo cuando la probabilidad de muerte en rechazo agudo con la otra estrategia es del 8,70% o superior, y cuando la probabilidad de presentar rechazo agudo es de 7,88% o inferior; el costo de la atención de los eventos adversos crónicos para la estrategia MCC y el costo del esquema EEC, son las variables respecto a las cuales el costo total \r\nparece tener mayor sensibilidad. La curva de aceptabilidad muestra que para el umbral considerado de 3 veces el PIB per cápita, el esquema con everolimus tiene una probabilidad de ser costo efectiva del 15,6%.\r\nConclusiones y discusión: En la práctica clínica actual, everolimus se administra como componente de los esquemas de inmunosupresión de mantenimiento sólo en situaciones particulares tales como terapia escalada en inmunosupresión (en caso de rechazo con terapia estándar), vasculopatía del injerto, disfunción renal o neoplasias. El esquema más usado en la práctica asistencial actual es el que incluye micofenolato más ciclosporina y prednisona (un corticosteroide), que es el indicado para todos los pacientes trasplantados. Los estudios clínicos desarrollados que han comparado estos dos esquemas \r\nconcluyen que tienen un perfil semejante de efectividad y seguridad y el acá desarrollado clasifica el esquema con everolimus como una estrategia dominada.(AU)

Análisis de costo efectividad de everolimus más ciclosporina y prednisona comparado con micofenolato más ciclosporina y prednisona para la inmunosupresión de mantenimiento en el trasplante renal en Colombia / Cost-effectiveness analysis of everolimus plus ciclosporin and prednisone compared to mycophenolate plus ciclosporin and prednisone for maintenance immunosuppression in renal transplantation in Colombia

Problema de investigación: Calcular los costos y la efectividad esperados del everolimus mas ciclosporina y corticosteroide (ECC) comparado con micofenolato mas ciclosporina y corticoesteroides (MCC) para el tratamiento de pacientes colombianos, adultos, receptores de trasplante de riñón por primera vez, que han iniciado la terapia de inducción de inmunosupresión y que se perfilan para el tratamiento de mantenimiento. Tipo de evaluación económica: Análisis de costo-efectividad. Población objetivo: Pacientes colombianos, adultos, receptores de trasplante de riñón por primera vez, que han iniciado la terapia de inducción de inmunosupresión y que se perfilan para el tratamiento de mantenimiento. Intervención y comparadores: I: Everolimus mas Ciclosporina (dosis reducida) y Corticosteroide (ECC). C: Micofenolato mas Ciclosporina (dosis estándar) y Corticoesteroides (MCC). Horizonte temporal: Vital. Perspectiva: Sistema General de Seguridad Social en Salud (SGSSS). Tasa de descuento: Se emplea una tasa de descuento común tanto a los costos como a los desenlaces en salud, equivalente al 5 % anual. Adicionalmente, se realizan análisis de sensibilidad de 0 %, 3,5 %, 7 % y 12 %. Estructura del modelo: Modelo de Markov anidado en un árbol de decisiones. Fuentes de datos de efectividad y seguridad. Fueron usados los recursos siguientes: el Reporte de efectividad y seguridad de las alternativas a evaluar previamente publicado por el IETS, los resultados de una búsqueda de literatura económica en las base de datos del CRD, de una búsqueda manual de literatura económica y clínica, y la información obtenida producto de la consulta a expertos clínicos. Desenlaces y\r\nvaloración: Años de vida ganados. Costos incluidos: Costos directos de atención: Costos de medicamentos\r\nCostos de procedimientos. Fuentes de datos de costos: SISMED: Medicamentos Manual tarifario ISS 2001: Procedimientos. Resultados del caso base: Los resultados del caso base para la administración del esquema ECC como inmunosupresión de mantenimiento para pacientes receptores de trasplante es una estrategia más costosa y más efectiva, respecto al esquema MCC; no obstante, si se asume que la disposición a pagar es 3 veces el PIB per cápita por un años de vida ganado, la estrategia ECC no es costo efectiva por superar dicho umbral. Análisis de sensibilidad: Este resultado se mantiene en todos los escenarios planteados excepto para los casos en los cuales la probabilidad de pérdida del injerto ante presencia de rechazo agudo en el esquema MCC toma valores superiores al 8%, cuando los costos del esquema de medicamentos ECC son inferiores a $4.083.749, y cuando la probabilidad de presentar eventos adversos crónicos con la estrategia ECC es inferior al 25%. Conclusiones y discusión: En la práctica clínica actual, everolimus se administra como componente de los esquemas de inmunosupresión de mantenimiento sólo en situaciones particulares como estrategia de conversión si se presenta toxicidad renal por ciclosporina, cáncer de piel u otro tipo de cáncer que se encuentra en riesgo de aumentar su tasa de crecimiento, o ante eventos como la hiperplasia gingival entre los más comunes. El esquema más usado en la práctica asistencial actual es el que incluye micofenolato más ciclosporina y prednisona, indicado para todos los pacientes trasplantados. Los estudios clínicos desarrollados que han comparado estos dos esquemas concluyen que tienen un perfil semejante de efectividad y seguridad y el acá desarrollado clasifica el esquema con everolimus como una estrategia no costo efectiva.

Análisis de impacto presupuestal de everolimus más ciclosporina y prednisona comparado con micofenolato más ciclosporina y prednisona para la profilaxis del rechazo en los receptores de trasplante de corazón en Colombia / Budget impact analysis of everolimus plus ciclosporin and prednisone compared to mycophenolate plus ciclosporin and prednisone for rejection prophylaxis in heart transplant recipients in Colombia

Tecnologías evaluadas: Intervención: e verolimus más ciclosporina y corticoesteroide en pacientes con trasplante de corazón. Comparador: micofenolato más ciclosporina y prednisona. Población: Adultos receptor es trasplante de corazón por primera vez. Perspectiva: ercer pagador, que en el caso colombiano corresponde al Sistema General de Seguridad Social en Salud (SGSSS). Horizonte temporal: El horizonte temporal de este AIP en el caso base corresponde a un año. Adicionalmente se reportan las estimaciones del impacto presupuestal para los años 2 y 3, bajo el supuesto de la inclusión en el POS en el año 1. Costos incluidos: Costos de los medicamentos incluidos en la terapia de mantenimiento. Fuente de costos: SISMED. Escenarios: Se realizaron análisis de escenarios que contemplaron una tasa de inserción del nuevo tratamiento inferior al 100% como terapia de conversión más no de tratamiento de primera línea y diferentes tasas de crecimiento para los años 2 y 3. Resultados: En un escenario con tasa de inserción del 100% del nuevo tratamiento, el impacto resupuestal es de $1.492.857.500,75 para el año 1.(AU)

Longitudinal Treatment Patterns and Associated Outcomes in Patients With Newly Diagnosed Systemic Lupus Erythematosus.

PURPOSE: The treatment of systemic lupus erythematosus (SLE) is complex, with a wide range of drugs commonly prescribed. The aims of this study were to identify longitudinal treatment patterns in patients with incident SLE and to estimate the associations of treatment patterns with clinical and economic outcomes. METHODS: This retrospective, observational cohort study used a US managed care claims database to identify patients with newly diagnosed SLE and 4-year treatment follow-up. Patients were aged ≥ 18 years, with continuous medical and pharmacy benefits for 12 months before and 48 months after the index date (first medical claim with a diagnosis of SLE). Longitudinal treatment patterns were grouped using a k-means cluster analysis. Therapies were included in the cluster analysis if the mean number of prescriptions in each year was ≥ 0.05. Clinical and economic outcomes were compared across clusters using multivariate regression analyses. FINDINGS: Data from 1611 patients with incident SLE were analyzed (91.4% women; mean [SD] age, 44.5 [9.5] years; 56.2% managed primarily by a specialist). Hydroxychloroquine and corticosteroids were the most commonly prescribed therapies; methotrexate, azathioprine, and mycophenolate mofetil also met the criteria for inclusion in the cluster analysis. Ten treatment clusters were identified; the most common was minimally treated patients (42.8%). Hydroxychloroquine monotherapy, corticosteroid monotherapy, and corticosteroid/hydroxychloroquine combination therapy were received by 34.0%, 11.2%, and 7.8% of patients, respectively. Methotrexate or azathioprine with a corticosteroid/hydroxychloroquine were received by 4.2% of patients. Changes in therapy, except discontinuations, were rare. Compared with the minimally treated cluster, those that received corticosteroid monotherapy (mean dose, >12.0 mg/d) had poorer clinical and economic outcomes; the hydroxychloroquine-monotherapy cluster had similar or better outcomes; and patients who received a corticosteroid/hydroxychloroquine with or without methotrexate or azathioprine demonstrated outcomes that were poorer but that appeared better than those with corticosteroid monotherapy. SLE-related visits with a nonspecialist were common (~45%) and remained unchanged over time despite better clinical and economic outcomes associated with specialist visits. IMPLICATIONS: This study utilized cluster analysis, an unsupervised machine-learning method, to systematically discern treatment patterns over 4 years and to estimate outcomes associated with the identified treatment patterns. The results suggest that minimal treatment is the most common approach in patients with newly diagnosed SLE. Clinical and economic outcomes are poorest with corticosteroid monotherapy but may improve with the addition of hydroxychloroquine and/or an immunosuppressive agent. A large proportion of SLE care is provided by nonspecialists despite the potential benefits of involving a specialist.

Micofenolato de mofetila para o tratamento de neurite óptica recorrente bilateral / Mycophenolate mofetila for the treatment of bilateral recurrent optic neuritis

CONTEXTO: A neurite óptica aguda é a neuropatia óptica mais comum que afeta adultos jovens. A neurite óptica é tradicionalmente dividida em termos clínicos nas formas típica e atípica. A forma típica é geralmente associada com a esclerose múltipla ou considerada como uma síndrome desmielinizante clinicamente isolada com risco de evolução para esclerose múltipla em pessoas brancas. A forma atípica está associada a causas imunomediadas não relacionadas a esclerose múltipla, tais como neurite óptica associada a doenças sistêmicas e neuromielite óptica. Um método alternativo realiza a classificação por causa imunomediada em neurite óptica associada a esclerose múltipla, neurite óptica associada a neuromielite óptica, neurite óptica associada a doenças sistêmicas e outras formas de neurite óptica idiopática sem doença sistêmica (neurite óptica isolada recorrente, neurite óptica inflamatória crônica recidivante e neurite óptica isolada solitária). A desmielinização ocorre tanto nas formas típica como atípica, dependendo da causa. Pacientes com neurite óptica decorrente de transtornos do espectro de neuromielite óptica ou de neurite óptica inflamatória crônica recidivante devem ser diagnosticados o mais cedo possível pois se constituem como um grupo de risco para grave perda visual. TECNOLOGIA: Micofenolato de mofetila. PERGUNTA: Eficácia e segurança do micofenolato de mofetila para o tratamento de neurite óptica. EVIDENCIAS: Não foram encontradas revisões sistemáticas e ensaios clínicos randomizados que avaliassem o micofenolato de mofetila para o tratamento da neurite óptica. Foram incluídos dois estudos observacionais retrospectivos em pacientes com neuromielite óptica (NMO) e transtorno do espectro NMO. Um estudo em 90 pacientes relatou que o tratamento inicial com rituximabe, micofenolato de mofetila, e, em menor grau, azatioprina reduz significativamente as taxas de recaída. Além disso, pacientes para os quais o tratamento inicial falhou, muitas vezes alcançam remissão quando o tratamento é trocado de um para outro desses medicamentos. Outro estudo em 59 pacientes relatou que o tratamento com micofenolato de mofetila reduz a taxa de recaída, estabiliza ou melhora a incapacidade, e é bem tolerado em pacientes com NMO e transtorno do espectro NMO. CONCLUSÕES: Ensaios clínicos randomizados que avaliem a eficácia e a segurança do microfenolato de mofetila em comparação com outros tratamentos para neurite óptica são necessários.

Efficacy and safety of a conversion from the original tacrolimus and mycophenolate mofetil to the generics Tacpan and Mowel after liver transplantation.

BACKGROUND: Expensive pharmaceuticals are a major reason for cost intensive health care systems. Long-term immunosuppressive therapy plays a relevant role after organ transplantation. Patents of original drugs have expired and cheaper products are available. Little data are available regarding efficacy and safety of generic immunosuppressive agents. METHODS: In this prospective study, 25 patients, who were clinically stable for a minimum of 2 years after liver transplantation, were converted from the original formulations of tacrolimus (TAC) and mycophenolate mofetil to the generics Tacpan (TAP) and Mowel (MOW). Patients were followed-up for 6 months. Results were compared retrospectively to 25 age- and sex-matched controls treated with the original brands. RESULTS: In the matched-pair analysis of TAC trough level/dose ratio, no significant difference was found between TAP/MOW and TAC/mycophenolate mofetil groups. No acute rejection occurred in either group. In total, 17 patients reported mild side effects in the TAP/MOW group. The most common side effects were gastrointestinal symptoms. Intra-individual analysis of costs revealed a considerable cost reduction in the TAP/MOW group (in median 25.03%; P<0.001). CONCLUSION: In summary, the use of the generics TAP/MOW is effective and seems to be safe and cost-efficient in stable liver-transplantation patients.

Safety and efficacy of the switch to generic mycophenolate mofetil and tacrolimus in heart transplant patients.

BACKGROUND: Generic immunosuppressants may offer economic advantages, but their use is still controversial. At our center, 55 heart transplant patients were switched from CellCept(®) to Myfenax Teva(®) (MT) (n = 51, 18% female, 8.1 ± 6.6 yr post-transplantation) and/or Prograf(®) to Tacrolimus Sandoz(®) (TS) (n = 17, 41% female, 6.6 ± 5.8 yr post-transplantation). METHODS: We conducted an acute monitoring and a retrospective follow-up with regard to safety and efficacy. Acute cellular rejections (ACRs) on endomyocardial biopsies (EMBs) four wk after the MT switch were specifically compared to a matched retrospective control group. RESULTS: Tacrolimus C0 levels (TS switch) as well as hemoglobin, leukocytes, and thrombocytes (MT switch) did not change (p = NS) during the three wk after each respective switch (8.7 ± 2.9 vs. 8.4 ± 1.9 µg/L, 129.1 ± 12.6 vs. 130.1 ± 12.8 g/L, 6.3 vs. 6.2 × 10(9) /L, and 217.4 ± 56.6 vs. 219.3 ± 61.8 × 10(9) /L, respectively). 0% of the EMBs in the MT switch vs. 3% of the EMBs in the control group showed ACR>grade 1R (p = NS). After six months, survival was 96% (MT switch) and 100% (TS switch), and the frequency of severe ACR was low. Safety parameters measured at the next annual follow-up were also stable following each switch. CONCLUSION: Switching to MT and/or TS several years after heart transplantation appeared safe in the short-term perspective, showing no detectable changes in tacrolimus C0 levels, safety or efficacy, during an average follow-up of six months.

Mycophenolate revisited.

The patent of mycophenolate mofetil (MMF) has expired, and for enteric-coated mycophenolate sodium (EC-MPS), this will happen in 2017. In the twenty years these drugs have been used, they have become extremely popular. In this review, the reasons for the popularity of mycophenolate are discussed, including the benefits compared to azathioprine. MMF and EC-MPS are therapeutically equivalent. Although neither is considered to be a narrow therapeutic index drug, this should not lead to careless switching between the innovator drug and generic formulations, or between one generic formulation and another. The pipeline of new immunosuppressive drugs is dry, and it is very likely that we will be using mycophenolate for many more years to come as a first-line immunosuppressive drug in our transplant population. Whether or not the development of donor-specific anti-HLA antibodies is related to drug exposure (mycophenolic acid concentrations) remains to be investigated.

Polyclonal versus monoclonal induction therapy in a calcineurin inhibitor-free immunosuppressive therapy in renal transplantation: a comparison of efficacy and costs.

BACKGROUND: Induction therapy in renal transplantation reduces the incidence of acute rejection (AR) in expanded criteria donation (ECD) and donation after cardiac death (DCD). We compared the efficacy of Thymoglobulin (Sanofi-Aventis, Spain), ATG Fresenius (ATG-Fresenius, Spain), and Simulect (Novartis Farm, Spain) in a calcineurin-free protocol in ECD and DCD renal transplantation by evaluating patient survival, graft survival, and AR at 1 year and overall costs. METHODS: An observational retrospective study was performed using our database of 289 consecutive cadaveric ECD renal transplant recipients (n = 178) and DCD recipients (n = 111) from April 1999 to December 2011. Induction therapy consisted of Simulect, Thymoglobulin, and ATG Fresenius. Calcineurin-inhibitor (CNI)-free maintenance therapy consisted of mycophenolate mofetil or sodium and steroids. RESULTS: There were no differences in the patients' demographic characteristics or patient and graft survival. One-year AR rates were equivalent (ECD: 10%, 19.1%, 17.7% versus DCD: 14.3%, 7.1%, 16.7%). Leukopenia and thrombopenia were significantly more frequent in the ECD group treated with polyclonal induction. The average total cost of transplantation was higher in the ECD group but there were no significant differences in the average total cost between ECD and DCD: 39,970.31 ± 7,732€ versus 35,058.34 ± 6,801€ (P = NS). CONCLUSION: Our study shows the same efficacy with polyclonal and monoclonal antibody induction and a CNI-free treatment regimen in ECD and DCD renal transplantation with no differences in overall costs at 1 year after transplantation.

Mycophenolic acid in dermatology a century after its discovery.

Mycophenolic acid was first discovered in 1913 and first used clinically in the 1970s as an immunosuppressant to prevent organ transplantation rejection. It was later used in the treatment of psoriasis. However due to its side-effect profile and fears over its carcinogenic potential it was abandoned. From the late 1990s a prodrug, mycophenolate mofetil (MMF), was developed and more recently, enteric-coated mycophenolate sodium (EC-MPS), both of which have gained increasing use in the field of dermatology for a variety of skin conditions. This review discusses the pharmacology, mechanisms of action, side-effects and current clinical applications in dermatology of MMF and EC-MPS.

Low-dose RATG with or without basiliximab in renal transplantation: a matched-cohort observational study.

BACKGROUND/AIMS: In renal transplantation, peri-operative low-dose rabbit-antithymocyte-globulin (RATG) plus basiliximab induction prevented acute allograft rejection more effectively than post-operative RATG plus basiliximab induction. We investigated the specific antirejection contribution of basiliximab in this context. METHODS: This single-center, observational, matched-cohort study evaluated allograft rejections (primary outcome), steroid exposure and side effects, GFR (iohexol plasma clearance) and treatment costs in 16 deceased-donor renal transplant recipients induced with RATG (0.5 mg/kg/day) and 32 age-, gender- and treatment-matched reference-patients given RATG plus basiliximab (20 mg on days 0 and 4). RESULTS: Induction was well tolerated. At 18 months, 8 patients (50%) vs. 3 reference-patients (9.4%) rejected the graft [HR (95% CI): 6.53 (1.73-24.70), p = 0.006]. Difference was significant (p < 0.01) even after adjusting for recipient/donor age and gender, cold ischemia time and HLA mismatches. There were 1 antibody-mediated rejection and 2 moderate cellular rejections in patients vs. none in reference-patients (p = 0.032). The median (interquartile range) prednisone cumulative dose was remarkably higher in patients than reference-patients [4.78 (1.12-6.10) vs. 0.19 (0.18-3.81) grams, p = 0.002]. Three patients vs. 24 reference-patients were off-steroid at study end (p < 0.001). Three patients vs. no reference-patient developed new-onset diabetes (p = 0.003). Both inductions similarly depleted B-cells. Outcomes of AZA- vs. MMF-treated participants were similar. GFR was similar in all groups. Compared to MMF, AZA therapy saved ≈ EUR 2,500/year and by month 14.3 post-transplant compensated basiliximab costs. CONCLUSION: In renal transplantation, basiliximab plus peri-operative low-dose RATG more efficiently prevented allograft rejection than RATG monotherapy, and minimized steroid exposure and toxicity. AZA- vs MMF-based maintenance immunosuppression largely compensated the extra costs of basiliximab.

Cost-effectiveness of modern mTOR inhibitor based immunosuppression compared to the standard of care after renal transplantation in Germany.

OBJECTIVES: Standards of immunosuppression in renal transplantation have changed dynamically in recent years. We here provide a refined advanced pharmacoeconomic model which uses state-of-the-art methods including a mixed treatment comparison (MTC) analysis. The aim was to assess the cost-effectiveness of current immunosuppressive therapy regimens (TR): "sirolimus + early withdrawal of cyclosporine + steroids" (TR1), "sirolimus-early transition" (TR2), "everolimus-early transition" (TR3) and "tacrolimus low dose + mycophenolate mofetil (MMF) + steroids" (TR4). METHODS: An up-to-date Markov model with current source data was employed to assess the cost-effectiveness of modern immunosuppressive regimens over 12-month and 10-year time periods. Transition probabilities for the occurrence of events for the first year were based on an MTC analysis. The robustness of the model was tested in extensive sensitivity analyses. RESULTS: Within the 12-month time period TR2 yields the highest life years (0.987 LY), generating costs of 17,500 . In terms of years with functioning graft (FG), TR4 yields the best efficacy over the 12-month model duration (0.970 years with FG). For the 10-year time period, TR2 yields the lowest costs (107,246 ) and dominates both TR3 and TR1, as it is simultaneously more effective. Within the 10-year model duration, TR4 reaches slightly higher effects compared with TR2 (6.493 vs. 6.474 LY) resulting in an incremental cost-effectiveness ratio of 387,684 per LY gained. CONCLUSIONS: The early transition to sirolimus provides long-term efficiency results comparable with a tacrolimus-based regimen, which represents a common treatment standard after kidney transplantation. Both are superior to other investigated immunosuppressive regimens.

Evaluación de efectividad y seguridad de everolimus más ciclosporina y esteroides o everolimus más tacrolimus y esteroide comparado con ciclosporina más micofenolato y esteroides, tacrolimus más micofenolato y esteroides, sirolimus con micofenolato y esteroides, en pacientes receptores de trasplante de riñón, hígado y corazón / Efficacy and safety assessment of everolimus plus ciclosporin and steroids or everolimus plus tacrolimus and steroid compared to cyclosporine plus mycophenolate and steroids, tacrolimus plus mycophenolate and steroids, sirolimus with mycophenolate

Introducción: Everolimus es un medicamento perteneciente a un grupo de inmunosupresores selectivos que inhiben la vía del m- TOR (mammalian target of rapamycin) y es empleado para evitar el rechazo de trasplante de órganos sólidos. Esta evaluación tecnológica se desarrolló en el marco de la actualización integral del Plan Obligatorio de Salud para el año 2015. Objetivo: Evaluar la efectividad y seguridad del uso de everolimus más ciclosporina y esteroides o everolimus más tacrolimus y esteroide comparado con ciclosporina más micofenolato y esteroides, tacrolimus más micofenolato y esteroides, sirolimus con micofenolato y esteroides, en pacientes receptores de trasplante de riñón, hígado y corazón. Metodología: La evaluación fue realizada de acuerdo con un protocolo definido a priori por el grupo desarrollador. Se realizó una búsqueda sistemática en MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects y LILACS, con restricción al idioma inglés y español y limitada a revisiones sistemáticas publicadas en los últimos cinco años y ensayos clínicos sin restricción de tiempo. Las búsquedas electrónicas fueron hechas entre octubre y diciembre de 2014 y se complementaron mediante búsqueda manual en bola de nieve y una consulta con expertos temáticos. La tamización de referencias se realizó por un revisor. La selección de estudios fue realizada mediante la revisión en texto completo de las referencias preseleccionadas, verificando los criterios de elegibilidad. La calidad de los estudios fue valorada con la herramienta de riesgo de sesgo de la Colaboración Cochrane. Las características de los estudios fueron extraídas a partir de las publicaciones originales. Se realizó una síntesis narrativa de las estimaciones del efecto para las comparaciones y desenlaces de interés a partir de los estudios de mejor calidad. Se estimaron medidas combinadas del efecto a través de un metanálisis con el método de Mantel-Haenszel y un modelo de efectos aleatorios, empleando el programa RevMan 5.2. Resultados: Everolimus, en terapia combinada con ciclosporina o tacrolimus presenta un perfil semejante a su comparador micofenolato en terapia combinada en los desenlaces supervivencia del injerto al año (para riñón RR=1.00 IC95% 0.97, 1.01), para hígado p=0.50 y para corazón RR=1.0, IC95% 0.98, 1.02) y supervivencia del paciente al año (para riñón RR=0.99 IC95% 0.97, 1.01, para hígado p=0.60 y para corazón RR=0.97 IC95% 0.94, 1.01), pues no se encontraron diferencias con significancia estadística en ninguno de estos desenlaces. En relación al desenlace rechazo agudo en el primer año en trasplante de riñón y corazón se desempeña de manera semejante everolimus más CyA más PRED comparado con micofenolato con igual combinación. En trasplante de hígado al comparar everolimus más tacrólimus a dosis baja más PRED se desempeña mejor que everolimus más tacrólimus a dosis estándar en el mismo desenlace (p=0.003). Al evaluar la función renal al año everolimus más CyA más PRED se comporta de manera semejante a micofenolato con igual combinación en pacientes receptores de trasplante renal, sin embargo en los pacientes receptores de trasplante de corazón es mejor everolimus en conservar la función renal (RR= -4.86, IC95% -8.68, -1.04). En receptores de trasplante de hígado tiene mejor desempeño everolimus más TAC a dosis baja más esteroide comparado con EVE más TAC a dosis estándar más esteroide pues conserva mejor la función renal a los doce meses (80.9±27.3 vs 70.3±23.1, p<0.0001). En relación a seguridad everolimus, en terapia combinada presenta un perfil semejante a micofenolato, en la presentación de eventos adversos de manera global, malignidad, diabetes de novo, diarrea y temblor. El evento adverso infección por citomegalovirus en el primer año fue menor en los pacientes que recibieron everolimus. Los eventos adversos edema periférico, hiperlipidemia y anemia fueron más frecuentes en los pacientes del grupo de everolimus. Además everolimus tiene efecto protector sobre el evento vasculopatía del trasplante cardíaco (RR=0.47 IC95% 0.25, 0.89).\r\nEn receptores de trasplante de hígado se presentaron en mayor proporción los eventos adversos edema periférico e hiperlipidemia los 24 meses (p<0,0001) con EVE más TAC a dosis baja más PRED al compararlo con EVE más TAC dosis estándar. Los eventos adversos edema periférico e hiperlipidemia a los 24 meses (p<0.0001) son más frecuentes con EVE mas TAC a dosis baja. No se encontraron diferencias para los eventos adversos diarrea, anemia y proteinuria. Conclusiones: En pacientes receptores de trasplante de riñón, hígado y corazón everolimus en terapia combinada con ciclosporina y esteroide tiene un perfil semejante de efectividad y seguridad que el micofenolato en terapia combinada, excepto en los desenlaces rechazo del trasplante de hígado a un año y función renal al año en el que everolimus es mejor, además de que tener una menor proporción de infección por citomegalovirus al año.(AU)

Assessment of the therapeutic benefit of oral prednisolone and common adjuvant therapy in stage II of randomized controlled trial study for management of pemphigus vulgaris.

BACKGROUND: Pemphigus is an autoimmune blistering mucocutaneous disorder. Common treatments include corticosteroids and immunosuppressive drugs. This study aimed to assess the therapeutic effects of oral prednisolone along with the common adjuvant therapy in pemphigus vulgaris. METHODS:   Eighty-seven patients with pemphigus vulgaris from the first stage of a previously randomized clinical trial were enrolled in the present non-blinded clinical trial. The patients were divided into four groups and treated accordingly with prednisolone alone (P; N = 23), prednisolone and azathioprine (P/A; N = 23), prednisolone and mycophenolate mofetil (P/M; N = 21), and prednisolone and cyclophosphamide (P/C; N = 20). These patients were followed-up for an extended one-year period. RESULTS: The primary localization of the recurrence occurred in the oral cavity of 7, 6, 2, and 5 patients in the P, P/A, P/M, and P/C groups, respectively. There was no significant difference between them (P = 0.40). The mean total dose of prednisolone administered in groups P, P/A, P/M, and P/C was accordingly 7.5, 8.4, 9.2, and 8.6 mg/day. Minor recurrence of the disease in the above-mentioned groups was observed in 7 (30.4%), 5 (21.7%), 6 (28.6%), and 7 (35.0%) of the patients, respectively. With regard to the minor recurrence of the disease, there was no significant difference among the four treatment groups (P = 0.80). CONCLUSION: Since in this follow-up study no therapeutic benefit of oral prednisolone and common adjuvant therapy was found in terms of the number of minor and major recurrences, the extent to which treatment of PV can be improved upon treatment with these agents remains to be elucidated.

Immunophenotyping and efficacy of low dose ATG in non-sensitized kidney recipients undergoing early steroid withdrawal: a randomized pilot study.

UNLABELLED: Rabbit antithymocyte globulin (ATG) is commonly used as an induction therapy in renal transplant recipients, but the ideal dosage in tacrolimus-based early steroid withdrawal protocols has not been established. The purpose of this pilot study was to determine the immunophenotyping and efficacy of lower dose ATG in low immunological-risk kidney transplant recipients. In this prospective study, 45 patients were randomized (1∶1) to our standard dose ATG (total dose 3.75 mg/kg)(sATG) vs. lower dose 2.25 mg/kg (lowATG). All patients underwent early steroid withdrawal within 7 days. The primary end point was biopsy-proven acute rejection at 12 months. Prospective immunophenotyping of freshly isolated PBMCs was performed at baseline, 3, 6, 12 months post-transplant. The rate of acute rejection was 17% and 10% in the sATG and lowATG, respectively. Effector memory T cells, Tregs and recent thymic emigrants T cells had similar kinetics post-transplant in both groups. No statistically significant differences were found in graft survival, patient survival or infections between the two groups, though there was a non-significant increase in leukopenia (43%v s. 30%), CMV (8% vs. 0) and BK (4% vs. 0) infections in sATG group vs. lowATG. In sum, in low immunological risk kidney recipients undergoing steroid withdrawal, low dose ATG seems to be efficacious in preventing acute rejection and depleting T cells with potentially lower infectious complications. A larger study is warranted to confirm these findings. TRIAL REGISTRATION: ClinicalTrials.gov NCT00548405.

Recent clinical trials in lupus nephritis.

Recent clinical trials have provided evidence for the efficacy of low-dose intravenous cyclophosphamide and mycophenolate mofetil as induction treatment for patients with proliferative lupus nephritis in comparative trials with standard-dose intravenous cyclophosphamide. Trials of maintenance treatments have had more variable results, but suggest that the efficacy of mycophenolate mofetil may be similar to that of quarterly standard-dose intravenous cyclophosphamide and somewhat more efficacious than azathioprine. Differential responses to mycophenolate mofetil based on ethnicity suggest that it may be more effective in black and Hispanic patients. Rituximab was not efficacious as an adjunct to induction treatment with mycophenolate mofetil.

Significant racial differences in the key factors associated with early graft loss in kidney transplant recipients.

BACKGROUND: There is continued and significant debate regarding the salient etiologies associated with graft loss and racial disparities in kidney transplant recipients. METHODS: This was a longitudinal cohort study of all adult kidney transplant recipients, comparing patients with early graft loss (<5 years) to those with graft longevity (surviving graft with at least 5 years of follow-up) across racial cohorts [African-American (AA) and non-AA] to discern risk factors. RESULTS: 524 patients were included, 55% AA, 151 with early graft loss (29%) and 373 with graft longevity (71%). Consistent within both races, early graft loss was significantly associated with disability income [adjusted odds ratio (AOR) 2.2, 95% CI 1.1-4.5], Kidney Donor Risk Index (AOR 3.2, 1.4-7.5), rehospitalization (AOR 2.1, 1.0-4.4) and acute rejection (AOR 4.4, 1.7-11.6). Unique risk factors in AAs included Medicare-only insurance (AOR 8.0, 2.3-28) and BK infection (AOR 5.6, 1.3-25). Unique protective factors in AAs included cardiovascular risk factor control: AAs with a mean systolic blood pressure <150 mm Hg had 80% lower risk of early graft loss (AOR 0.2, 0.1-0.7), while low-density lipoprotein <100 mg/dl (AOR 0.4, 0.2-0.8), triglycerides <150 mg/dl (AOR 0.4, 0.2-1.0) and hemoglobin A1C <7% (AOR 0.2, 0.1-0.6) were also protective against early graft loss in AA, but not in non-AA recipients. CONCLUSIONS: AA recipients have a number of unique risk factors for early graft loss, suggesting that controlling cardiovascular comorbidities may be an important mechanism to reduce racial disparities in kidney transplantation.

Engraftment versus immunosuppression: cost-benefit analysis of immunosuppression after intrahepatic murine islet transplantation.

OBJECTIVE: Immunosuppression (IS) in islet transplantation (Tx) is a double-edged sword: it prevents immunoreaction but has the potential to impair islet engraftment. The aim of this study was to identify in murine animal models the IS platform with the best balance between these two opposite effects. METHODS: To study the impact of IS on islet engraftment diabetic C57BL/6 mice were transplanted with 350 syngeneic islets through the portal vein and treated once-daily with either rapamycin (RAPA; 0.1-0.5-1 mg/kg ip), tacrolimus (FK506; 0.1-0.5-1 mg/kg ip), mycophenolate mofetil (MMF; 60-120-300 mg/kg oral) or vehicle for 14 days. Islet function was evaluated by measuring not-fasting glycemia and by performing an IVGTT on days 15 and 30 post-Tx. RESULTS: RAPA ≥0.5 mg/Kg, FK506 ≥0.5 mg/Kg, and MMF ≥120 mg/kg had detrimental effects on islet engraftment but not on the function of islets already engrafted in the liver. The effect on engraftment was irreversible and persisted even after IS withdrawal. The lower dose of IS that did not affect engraftment was tested for preventing rejection in the full mismatch allogeneic Tx BALB/c to C57BL/6 model. RAPA and/or FK506 were inefficient in preventing rejection, even when anti-IL2R mAb was added to the IS regimen. On the other hand, MMF alone or in association with FK506 significantly prolonged the time to islet rejection. CONCLUSION: IS showed profound dose-dependent deleterious effects on islet cell engraftment. The MMF/FK506 combination proved the best balance with less toxicity at the time of engraftment and more efficacy in controlling graft rejection.