Medicina y Salud Publica vol 49 by Revista Medicina y Salud Pública (MSP)

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Volumen XLIX • Año IX

de la Oftalmología a la Medicina y la Genética: 6 Contribución Las Enfermedades Hereditarias Oculares

Malformación congénita arteriovenosa intrahepática reparada por la vía percutánea

Enfermedad coronariana Resumen en cardiología Diagnóstico y manejo en pacientes con de Intervenciones de la Esclerodermia psoriasis: un estudio Pediátricas y de Adultos

El rol de la enfermería

en el manejo del paciente con artritis rematoide

en puertorriqueños

Juan Carlos Orengo Valverde, MD, MPH, PhD EDITOR JEFE Alberto Santiago Cornier, MD, PhD Ileana Santiago Álvarez VICEPRESIDENTA EDITORIAL MUNDO Y FUNDADORA Laila Paloma Lorraine CONTABILIDAD Julio Soto REDACCIÓN PERIODISMO CIENTÍFICO Carlos Lugo Marrero y Belinda Z. Burgos González ARTE Y DISEÑO GRAFICO Natalia Zoé Rivera Torres DIRECTOR GENERAL Y FUNDADOR Carlos Alexis Lugo Marrero ASISTENTE DEL DIRECTOR Y FUNDADOR Pedro Carlos Lugo III OPERACIONES Ana María Flores Pérez, Alana Isabel Lugo Hernández PERIODISTA Belinda Z. Burgos González FOTÓGRAFO Sonia Carmona DISTRIBUCIÓN OFICINAS Y TORRES MÉDICAS Editorial Mundo ENVÍO DE REVISTAS Y DISTRIBUCIÓN A GRUPOS MÉDICOS Servicio de correo postal/Comunicación Inteligente EDITOR FUNDADOR

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Comité Editorial Científico Alberto Santiago Cornier, MD, PhD

EDITOR

José Cordero, MD, MPH - Decano Escuela Graduada Salud Pública Recinto de Ciencias Médicas UPR (Puerto Rico), Olga Rodríguez, MD - Decana Escuela de Medicina de Ponce (Puerto Rico), Vivian Green, LND, MS, PhD, Sub editora y fundadora (Puerto Rico), Ángeles Rodríguez, MD, MPH (Puerto Rico), Simón Carlo, MD (Puerto Rico), Bárbara Rosado, MD (Puerto Rico), Idhaliz Flores PhD (Puerto Rico), Jesús Cruz-Correa, MD, FACOG (Puerto Rico), Rafael Bredy, MD, LicMTo, MBE, MS (Puerto Rico), David Caseida, MD, FACOG, (Puerto Rico), José Capriles, MD, MHSA (Puerto Rico) Joaquín Laboy, MD, FACOG (Puerto Rico), Luis A. Rivera Pomales, MD, MBA, MPH (Puerto Rico), Juan Fernández, MS, PhD (Puerto Rico), Nuria Sebate, MD (Puerto Rico), Pedro Amador, MD, MPH (Puerto Rico), Nydia Cappas, PsyD (Puerto Rico), Luis Franco, MD (Puerto Rico), Federico Montealegre, DVM, PhD, Msc (Puerto Rico), Nydia Ortiz, PsyD (Puerto Rico), José Pons, PhD, FPPR (Puerto Rico), Esdrás Vélez, JD, MPH (Puerto Rico), Diego Zavala, MSc, PhD, (Puerto Rico), Ana Torres-Martín, MD (Puerto Rico), Julio Cádiz, MD, MPH (Puerto Rico), Rafael Gómez-Cuevas (Colombia), José Javier Orengo, PhD(c) (España), Cesar A. Del Rey, MD (Panamá), Pedro Serrano, MD, PhD (España), Luis Serra-Majem, MD, PhD (España), José Ramón Calvo, MD, PhD (España). COMITÉ EDITORIAL

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EDITORIAL Jefe División de Genética del San Jorge Children's Hospital en San Juan, Puerto Rico. Director Centro Investigaciones Clínicas del San Jorge Children's Hospital en San Juan, Puerto Rico. Catedrático Asociado de la Universidad Central del Caribe, Departamento de Pediatría, Bayamón, Puerto Rico. Catedrático Asociado de la Escuela de Medicina de Ponce, Departamento de Bioquímica, Ponce, Puerto Rico. Práctica Privada Torre Médica Hospital San Jorge y SER de Puerto Rico

Lejos de una realidad salubrista El sistema de salud puertorriqueño se encuentra en la cúspide de la crisis de servicios donde la deuda que mantiene el gobierno con los médicos y las aseguradoras, la reducción de servicios a los pacientes, los costos que representan los tratamientos para la alta incidencia de enfermedades y la decepcionante disparidad de fondos de Medicare para los pacientes envejecientes se cuelan entre las principales escenas que están lejos de una realidad salubristas de primer orden. Gran parte del dinero del gobierno no va dirigido a la prevención de las epidemias dando la impresión que es de mayor importancia satisfacer el lucro de las aseguradoras y no en un sistema de salud enfocado y que tenga como prioridad la prevención y la calidad de vida de sus pacientes. Cada vez más se hace insostenible un modelo empresarial de salud que limita la cubierta a servicios médicos de calidad, que desaprueba referidos a estudios y procedimientos médicos importantes para la salud del paciente. Que pone en último lugar el pago a los médicos retando su estabilidad y provocando una fuga sin precedentes de excelentes profesionales en el campo de la salud hacia los Estados Unidos. Tal situación pone en contra de la pared al médico, que por vocación pondrá por encima la necesidad del paciente y tratará de garantizar que al paciente se le practique el procedimiento necesario en beneficio de su salud más allá de pensar si su servicio será pagado. Es por ello, que el dilema del lucro de las aseguradoras también afecta a los pacientes, a quienes se les niega la posibilidad de ver especialistas que cumplan con las expectativas de su tratamiento o que simplemente dejan de ver a ese médico de familia que por 30 años le atendió ya que su región de salud le cambió el panorama médico. No se puede dejar de mencionar que desde que el sistema de salud de Puerto Rico cambió con la llegada de la llamada Reforma, son más los puertorriqueños desprovistos de servicios de salud. Ha sido la propia comunidad médica de la isla dirigida por el Presidente del Colegio de Médicos-Cirujanos, Dr. Víctor Ramos, la voz imperante que ha traspasado las puertas del Capitolio, las de la Administración de Seguros de Salud y la conciencia empresarial de las aseguradoras tirándose a la calle exigiendo lo que como trabajadores les corresponde. Han sido intensos meses de batalla y frustración donde los profesionales de vocación médica aunamos esfuerzos para motivar a los nuevos médicos que heredarán la crisis salubrista de Puerto Rico y que tendrán la conciencia de que el país los necesita para continuar la lucha por mejores servicios de salud y la eliminación de entidades que se lucran de las enfermedades que enfrentan los puertorriqueños. La situación actual del sistema de salud continúa patrocinando la fuga de talento médico en la Isla. Son cada vez más los estudiantes que usan sus estudios en medicina en puerto Rico como trampolín a los Estados Unidos, donde la paga puede ser tres veces por encima de lo que se le ofrece actualmente en Puerto Rico y donde sus beneficios y derechos como profesionales de la salud no son trastocados. Debemos continuar unidos como profesionales de la salud porque somos la voz y la cara de muchos de esos pacientes. La crisis salubrista de Puerto Rico debe brindar el espacio para un nuevo renacimiento del sistema de salud donde se dirijan los esfuerzos económicos a la prevención, disminuyan los costos administrativos de aquellos que se lucran del plan de salud del gobierno y aumente el acceso de los servicios a los pacientes.

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CONTRIBUCIÓN DE LA OFTALMOLOGÍA a la Medicina y la Genética:

LAS ENFERMEDADES HEREDITARIAS OCULARES Por: Natalio J. Izquierdo, MD1 Catedrático Asociado, Departamento de Cirugía, Recinto de Ciencias Médicas, UPR El autor fue el primer oftalmólogo especializado en enfermedades hereditarias en Puerto Rico, 1

La mayoría de los casos de daltonismo se deben a un problema genético. Muy pocas mujeres son daltónicas y aproximadamente 1 de cada 10 hombres sufren alguna forma de daltonismo. La forma más grave es la acromatopsia; una rara afección en la cual una persona no puede ver ningún color, solamente sombras de gris.

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e conocen más de 900 enfermedades hereditarias que afectan los ojos. En algunas de ellas, el ojo es el único órgano afectado. En otras ocasiones, la enfermedad afecta tanto los ojos como otros órganos. D e c í a e l D r. V í c t o r McKusick1,2 en una conferencia en Johns Hopkins-, que la genética ha avanzado gracias a la oftalmología”. Tuve el privilegio de ser su alumno. McKusick1,2 nos relató que la historia de la genética médica comienza con el daltonismo, y la pobre visión de colores que padecen algunos varones. No ven los rojos o verdes de la misma forma. Una buena analogía son las luces de los semáforos de tránsito y el no tener . Este hallazgo dio paso a que se reconocieran las primeras enfermedades ligadas al cromosoma del sexo (cromosoma X). Las enfer medades “ligadas al cromosoma del sexo” son especialmente importante dados los pacientes que padecen la hemofilia. Tanto el daltonismo como la hemofilia

la padecían los varones, pero la transmitían sus madres. Se dieron cuenta, que la Reina Victoria, quien había casado a sus hijos con todas las Casas Reales de Europa, transmitió así su gen de la hemofilia a todos los Reyes y Emperadores de Europa. El caso más famoso fue el hijo de los últimos zares de Rusia, quien era hemofílico y fue asesinado junto a los demás familiares. El segundo gran paso, ocurrió con el estudio del Retinoblastoma, un tumor maligno que afecta los ojos. En la década de los 70, estos tumores oculares dieron paso al estudio de la herencia de los tumores y el cáncer. Algunos pacientes heredaban el retinoblastoma, directamente de uno de sus padres. Esto se había descrito en Brasil desde el siglo 19. Otros pacientes lo padecían sin heredarlo de nadie. Knudson 3 describió, por un análisis matemático, que debían ocurrir dos mutaciones para que un paciente desarrollara el retinoblastoma, si no lo heredaba de uno de sus padres. El hallazgo de ese gen ocurrió décadas después.

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Paciente con albininismo oculocutáneo con el síndrome de Hermansky-Pudlak. Esto es una condición muy prevalente en Puerto Rico, debido a la alta incidencia de consanguinidad, situación que conduce a la expresión de los genes recesivos.

Victor A. McKusick, fue un cardiólogo fundador de la genética médica que compiló meticulosos historiales de las pautas hereditarias y las características clínicas de numerosos síndromes. En una conferencia que supuso un hito en los estudios genéticos en un encuentro celebrado en La Haya en 1969, afirmó que había llegado el momento para compilar un mapa de todos los genes humanos como forma de entender las disfunciones básicas de los defectos de nacimiento. McKusick fue el presidente fundador de HUGO, la Organización del Genoma Humano, grupo que coordinó internacionalmente el trazado del genoma humano y los programas de secuenciación.

Se han comenzado a curar enfermedades de los ojos, como la Amaurosis Congénita, que conducen a la ceguera de nacimiento, cambiando la genética de las células. Se inyecta en las células un virus vector, que cambia los genes a las células de la retina y las células enfermas sanan y el paciente vuelve a ver.

“Leucocoria” es una palabra que se deriva del griego y que literalmente quiere decir “pupila blanca”. Este término es utilizado en pacientes generalmente pediátricos, en los cuales se observa una masa blanquecina detrás de la pupila, o en los que a la exploración no se observa el reflejo rojo de fondo normal y en su lugar se observa un reflejo blanquecino.

La retinosis pigmentaria ligada al cromosoma X es la forma de retinosis pigmentaria más común. Revista Puertorriqueña de Medicina y Salúd Pública

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Resumen Introducción: El efecto de la herencia en el desarrollo de enfermedades se describía en la ciencia. O b j e t i vo s : D e m o s t r a r c ó m o l a Oftalmología ha promovido el progreso de la medicina, la genética y la terapia de las enfermedades. Pacientes Y Métodos: Varios estudios a través de las décadas se resumen para describir la trayectoria de la genética médica con la ayuda de la oftalmología. Conclusiones: La oftalmología ha contribuido grandemente al progreso de la medicina y la genética. El cambio de la terapia de las enfermedades, desde farmacoterapia a genético-terapia acaba de comenzar.

a la expresión de los genes recesivos. Luego al casarse los parientes, sus hijos heredan la mutación de las dos padres y tienen la condición. Ahora bien, hay condiciones que pueden ser heredadas de varias maneras, como la Retinosis Pigmentaria.9 Esta afección puede heredarse de las tres formas: autosómica dominante, recesiva o ligada al cromosoma del sexo. Estos pacientes comienzan con pérdida de visión nocturna y su pérdida va progresando hasta la ceguera legal. Su enfermedad puede estar aislada al ojo, pero puede estar asociada a enfermedades que afectan otros órganos, como el oído (en pacientes con el síndrome de Usher), o con dedos extra (síndrome de Bardet Biedl), entre otros. Por último, debo mencionar los cromosomas mitocondriales. Estos son Palabras Claves: genes que solo se heredan de la madre, herencia autosómica dominante, porque están en la corona que envuelve autosómica recesiva, ligada al “La Retinosis Pigmentaria el óvulo. El espermatozoide pierde los sexo, DNA mitocondrial, Marfan, suyos cuando fecunda el óvulo y pierde Hermansky-Pudlak, Leber, Norrie puede heredarse de las su cola. Esta condición también se tres formas: autosómica describió en pacientes varones que se dominante, recesiva o quedaban ciegos en la adolescencia. Es los genes que estaban asociados al ligada al cromosoma la llamada Neuropatía Óptica de Leber. cáncer se les llama oncogenes. De del sexo. Estos pacientes El prestigioso oftalmólogo australiano, hecho, se descubrió que tenemos genes comienzan con pérdida Dr. David Mackey,10 trazó la llegada que suprimen la formación de tumores, de estos genes en familias que vinieron como es el caso del gen de retinoblastoma. de visión nocturna y su de Inglaterra a colonizar Australia. Eso Estos genes cuando mutan, o se cambian pérdida va progresando dio otro giro a la medicina y la genética. o dañan, dan paso a que aparezcan los hasta la ceguera legal” También se puede mencionar el caso tumores. de pacientes con Retinosis pigmentaria Otro caso de cáncer asociado a hallazgos oculares es el de la aniridia. Estos pacientes esqueletales y cardiovasculares (dilatación y problemas musculares (incluyendo nacen con un iris rudimentario. Se ve la y aneurismas de la aorta). La pregunta cardiacos), el llamado síndrome de Kearnspupila grande. Estos pacientes pueden que se hacían los médicos era: ¿qué tiene Sayre, causado por defectos genéticos en padecer un tumor del riñón. Recuerdo que ver el ojo con la aorta? La respuesta el DNA mitocondrial. Las deleciones de como ahora, cuando se encontró el gen la encontraron en el gen de la fibrilina,7 tamaño variable del gen es la alteración en 1992.4 Estos pacientes, a veces pierden que estaba presente en el tejido conectivo más común que causa dicho síndrome.11 Tercera Etapa parte del cromosoma. Antes describíamos tanto en la aorta como en los ojos. Las enfermedades que se heredan de Hoy día son numerosas las aplicaciones que el cáncer de seno ocurría en hermanas y primas. Con el avance de los estudios forma autosómica recesiva, eran más que la Biología Molecular ofrece a la de las genética de los tumores, hoy día difíciles, porque los hallazgos en los investigación médica y en particular, a estudiamos las pacientes con cáncer de pacientes pueden brincar generaciones. la investigación de las enfermedades seno y su familiares a ver si tienen el De las condiciones autosómicas recesivas, hereditarias que afectan la visión. Sobre deseo mencionar los pacientes con todo, la terapia génica ha comenzado por BRAC gene.5 albininismo oculocutáneo, especialmente las enfermedades oftálmicas. Es decir, se Segunda Etapa Hace 20 años describíamos las los que tienen el síndrome de Hermansky- ha comenzado a curar enfermedades de enfermedades clínicamente, es decir, Pudlak.8 La voz del pueblo les llamaba los ojos, como la Amaurosis Congénita, decíamos los hallazgos que encontrábamos “albino sangrino”. Son palabras que que conducen a la ceguera de nacimiento, en los pacientes. El proyecto del genoma riman. Es una condición muy prevalente cambiando la genética de las células. Se humano comenzó en los 90. Lo que en PR, porque en la Isla hay mucha inyecta en las células un virus vector, que pensábamos tomaría 30 años se completó consanguinidad, situación que conduce cambia los genes a las células de la retina

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en 10. Desde entonces nos dedicamos a buscar las enfermedades dentro del genoma. Encontrar el gen de una enfermedad, aseguraba una publicación en la literatura. Las enfermedades ligadas al cromosoma del sexo eran las más fáciles de encontrar. Sólo había que buscar en el cromosoma X. Ese es el caso de enfermedades que tenían manifestaciones oculares como la Enfermedad de Norrie, en que trabajaban los profesores, Dra. Irene Maumenee y Dra. DamPing Zhu.6 Las enfer medades Autosómicas dominantes eran las segundas más fáciles porque había muchos familiares con la misma condición. De estas podemos mencionar el síndrome de Marfán. Estos pacientes padecen de lentes dislocados y miopía alta, asociado a problemas

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y las células enfermas sanan y el paciente aniridia. Nature Genetics 1992; 1, 328 332. vuelve a ver. De acuerdo a los estudios,12 5. Castilla LH, Couch FJ, Erdos MR, Hoskins KF, Calzone K, Garber JE, Boyd el efecto permanece por años. Así es que estamos en ese momento J, Lubin MB, Deshano ML, Brody LC, histórico en que se pasa de la Collins FS, Weber BL. Mutations in the farmacoterapia (curar enfermedades BRCA1 gene in families with early-onset con medicamentos) a empezar a curar breast and ovarian cancer Nature Genetics. enfermedades cambiando la genética 1994; 8: 387 91. 6. Collins FA, Murphy DL, Reiss AL, del paciente. Sims KB, Lewis JG, Freund L, Karoum F, Zhu D, Maumenee IH, Antonarakis SE, Referencias 1. McKusick, V. A., Presidential Address, Clinical, biochemical, and neuropsychiatric Eighth International Congress of Human evaluation of a patient with a contiguous Genetics: Human Genetics: the Last gene syndrome due to a microdeletion 35 Years, the Present, and the Future, Xp11.3 including the Norrie disease locus American Journal of Human Genetics. and monoamine oxidase (MAOA and MAOB) genes. American Journal of Medical 1992; 50: 663-70. 2. McKusick, V. A., Medical Genetics: Genetics. 1992; Jan Vol 42 (1): 127–34. A 40-Year Perspective on the Evolution 7. Dietz HC, Pyeritz RE. Mutations in of a Medical Specialty from a Basic the human gene for fibrillin-1 (FBN1) Science, Journal of the American Medical in the Marfan syndrome and related disorders. Hum Mol Genet. 1995; 4 Spec Association. 1993; 270:2351-2356. 3. Knudson A. “Mutation and cancer: No:1799-809. statistical study of retinoblastoma”. Proc 8. Santiago Borrero PJ, Rodríguez-Pérez Natl Acad Sci USA. 1971; 68 (4): 820–823. Y, Renta JY, Izquierdo NJ, Del Fierro L, 4. Jordan T, Hanson I, Zaletayev D, Muñoz D, Molina NL, Ramírez S, PagánHodgson S, Prosser J, Seawright A, Hastie Mercado G, Ortíz I, Rivera-Caragol E, N, van Heyningen V. The human PAX6 Spritz RA, Cadilla CL. Genetic testing gene is mutated in two patients with for oculocutaneous albinism type 1 and

2 and Hermansky-Pudlak syndrome type 1 and 3 mutations in Puerto Rico. J Invest Dermatol. 2006 Jan; 126(1): 85-90. 9. Achar V, Zenteno JC. Actualidades en el tratamiento de la retinosis pigmentaria Rev Mex Oftalmol. 2008 (SeptiembreOctubre); 82(5):309-313. 10. Mackey DA, Buttery RG. Leber hereditary optic neuropathy in Australia. Aust NZ J Ophthalmol. 1992; 20: 177–84. 11. Ramírez Miranda A, Navas Pérez A, Gurria Quintana L, Vargas Ortega J, Murillo Correa C, Zenteno JC. Detección de deleciones en DNA mitocondrial heteroplásmico por medio de PCR en el síndrome de Kearns-Sayre. Arch Soc Esp Oftalmol. 2008; 83: 155-160. 12. Jacobson SG, Cideciyan AV, Ratnakaram R, Heon E, Schwartz SB, Roman AJ, Peden MC, Aleman TS, Boye SL, Sumaroka A, Conlon TJ, Calcedo R, Pang JJ, Erger KE, Olivares MB, Mullins CL, Swider M, Kaushal S, Feuer WJ, Iannaccone A, Fishman GA, Stone EM, Byrne BJ, Hauswirth WW. Gene therapy for leber congenital amaurosis caused by RPE65 mutations: safety and efficacy in 15 children and adults followed up to 3 years. Arch Ophthalmol. 2012 Jan; 130(1):9-24.

Es posible que la oftalmología sea la primera especialidad de la medicina, cuanto todavía no podía establecerse una diferencia entre lo que era medicina, brujería o religión. El procecimiento más destacable que realizaban los oftalmólogos antiguos era el mismo que en la actualidad ocupa la mayor parte de nuestra actividad: la cirugía de la catarata. Revista Puertorriqueña de Medicina y Salúd Pública

MALFORMACIÓN CONGÉNITA ARTERIOVENOSA INTRAHEPÁTICA REPARADA POR LA VÍA PERCUTÁNEA Por: Martha Arce Santiago MD†, Edwin Rodríguez Cruz MD* *Centro Cardiovascular de Puerto Rico y del Caribe, San Juan, Puerto Rico †San Juan City Hospital, San Juan, Puerto Rico

Abstract Arteriovenous malformations are vascular anomalies that can involve veins, arteries and the lymphatic system (1). The treatment for vascular anomalies is complex requiring planification and the use of an interdisciplinary team. Surgery has being the prefer treatment for theses lesions, but today the repair can be accomplished through less invasive procedures like percutaneous embolization, or sometimes a combination of both. We present a case with an intrahepatic arteriovenous malformation that was repaired through percutaneously embolization. Al procedure were done without complications and acute successful results. 10

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Resumen Las malformaciones arteriovenosas son defectos vasculares que pueden envolver arterias, venas y en ocasiones el sistema linfático (1). El tratamiento es complejo y debe ser desarrollado con mucha planificación. La cirugía a sido la manera preferida de tratar a estos pacientes. Sin embargo, hoy día el tratamiento definitivo se puede llevar a cabo a través de la vía percutánea, cirugía o ambas. Se presenta un caso de una malformación arteriovenosa intrahepática, la cual fue reparada con una embolización percutánea. Todos los procedimientos fueron realizados sin ninguna complicación y con buenos resultados agudamente.

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Keywords hematemesis, melena, pediatric catheterization, arteriovenous malformation, embolization, liver Palabras Claves hematemesis, melena, pediatría, cateterismo, malformación arteriovenosa, embolización, hígado

Figura 1 A: Aortograma, posteroanterior, la flecha enseña el detalle de la malformación arteriovenosa intrahepática. B: Vista lateral de la malformación. C y D: Se ve el llenado retrogrado de la vena Porta debido al flujo proveniente de la malformación. E: Vista lateral de la colocación del dispositivo Amplatzer en la comunicación, antes de soltarlo. Véase que no hay flujo hacia la vena Porta. F: Vista lateral del dispositivo en posición luego de soltarlo.

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“La embolización de la malformación arteriovenosa por via percutanea en nuestro paciente obtuvo resultados positivos inmediatamente mostrando como una alternativa de tratamiento”

Introducción Se presenta el caso de un varón de 2 años de edad con historial médico pasado de Síndrome de Down, ducto arterioso patente y foramen ovale patente. En una visita de seguimiento en ecocardiografía se observa dilatación de las venas hepáticas. Un sonograma abdominal encontró anatomía normal y una posible variación normal anatómica del tamaño de las venas hepáticas. El paciente se pierde al seguimiento por casi 1 año. Luego la clínica se complica con la presentación de hematemesis. El paciente es llevado a sala de emergencias y entre los laboratorios iniciales presentó una hemoglobina de 6.0 g/dL. Durante su estadía comienza a presentar melena y los laboratorios son repetidos mostrando una hemoglobina de 4.0 g/dL. Después de varias evaluaciones se encuentra que el niño tiene varices esofágicas, otro sonograma abdominal reveló una malformación arteriovenosa intrahepática compleja. Un arteriograma demostró con mayor fidelidad la malformación. Se observó un flujo complejo desde las arterias a la vena Porta, proveniente de varias tributarias. En la primera ocasión la malformación se embolizó selectivamente con “coils” del tipo Gianturco. No hubo ninguna complicación hasta 3 meses después cuando tuvo una recurrencia en el sangrado. Los aortogramas fueron repetidos encontrando la formación de 12

Revista Puertorriqueña de Medicina y Salúd Pública

una aneurisma conectando a las venas portales. Como no habían tributarias mayores envueltas se decidió abordar con otra modalidad para cerrar la aneurisma. En esta ocasión se hizo una punción a través de la pared abdominal hasta llegar a la aneurisma intrahepática. Se colocó un dispositivo Amplatzer (St. Jude Medical Co. USA). Se hicieron angiografias demostrando que la embolizacion fue efectiva con buenos resultados agudamente. No hubo complicaciones de ningún tipo durante ambos procedimientos. Sin embargo, unos 10 meses despues desarrolló nuevas colaterales por lo que se consideró para un transplante de hígado. Finamente, recibió un transplante de hígado unos 14 meses luego de la presentación inicial. Discusión Las malformaciones intrahepáticas son sumamente raras, usualmente secundarias a trauma, biopsias o tumores (2). Estas lesiones pueden ser diagnosticadas utilizando ultrasonidos, tomografía computarizada y angiografías de resonancia magnética (3). Pacientes con estas malformaciones se presentan con episodios de sangrado, acites, esplenomegalia o retraso en el crecimiento. Nuestro paciente se presentó con hematemesis y melena secundario a la hipertensión portal desarrollada por la malformación intrahepática. Estas malformaciones con frecuencia son grandes y envuelven multiples arterias y venas (4). La meta del tratamiento esta dirigida a restaurar la hemodinamia natural tanto de la vena portal como de las arterias hepáticas. Entre las opciones de tratamiento se encuentran la cirugía, embolización percutánea o la combinación de ambas (5). El transplante de hígado se ha propuesto en pacientes cuya terapia haya fallado y sufra de recurrencias. La embolización de la malformación arteriovenosa por via percutanea en

nuestro paciente obtuvo resultados positivos inmediatamente mostrando como una alternativa de tratamiento. Conclusión La utilización de la vía percutánea es una alternativa para tratar las malformaciones arteriovenosas ya que se obtuvieron resultados excelentes sin complicaciones. La utilización de la vía percutánea provee una opción para aquéllos pacientes que no desean una cirugía mayor (2). Referencias

1.Açikgöz, S.K., Taçoy, G., Önal, B., Yıldırım, B. and Çengel, A. (September, 2009) Arterial embolisation and coiling for high-output heart failure and pulmonary hypertension ınduced by hepatic arteriovenous fistula in a patient with hereditary hemorrhagic telengiectasia. Central European Journal of Medicine, 4(3), 369-373. 2. Ana Cristina Aoun Tannuri⁎, Uenis Tannuri, Fabiana Roberto Lima, Luiz Roberto Schlaich, Antonio José Gonçalves Leal, Marcos Marques da Silva (2009).Intrahepatic arterioportal fistula presenting as severe undernutrition and chronic watery diarrhea in a 2-year-old girl . Journal Pediatric Surgery, 44, E19-E22. 3.Pattaraporn Tanya Chun, Terrence Chun,Matthew Files, Nghia Vo, and Ryan M. McAdams. (2013) Embolization of Congenital Portosystemic Venous Fistula in an Infant with Down Syndrome. Case Reports in Vascular Medicine. 4. Bradley, S. M. (July,2008) Morphological Studies of Pulmonary Arteriovenous Shunting in a Lamb Model of Superior Cavopulmonary Anastomosis. Pediatric Cardiology, 29(4), 701-703. 5. Costa, S., De Carolis, M.P., Di Stasi, C., Papacci, P., Fusco, F., and Romagnoli, C. (November, 2006) Transumbilical embolization of hepatic arteriovenous malformation in a neonate with heart failure. European Journal of Pediatrics, 165(11), 807-809.

Knowing about Central Precocious Puberty can help your child. Everyone starts puberty at a different time and progresses at a different rate. But generally puberty begins around age 10 in girls and age 11 in boys. Central precocious puberty (sometimes called “CPP” or “precocious puberty”) is a condition where puberty starts too soon in children—usually before 8 years of years in girls and 9 years of age in boys.1,2

If you start seeing early signs of puberty in your child, you should talk with your child’s physician. Pediatric Endocrinologists in Puerto Rico Aguadilla Dra. Michelle Gómez

(787) 975-9458

Bayamón Dr. Angel Solla Dr. Fermín Sánchez Dr. Francisco Nieves Dr. Luis Font Caguas Dra. Adanette Wiscovich Dra. Lydia Irizarry

(787) 653-2224 (787) 653-3434

Fajardo Dr. Angel Solla

(787) 863-3737

Humacao Dra. Miriam Alicea

(787) 850-7950

Mayagüez Dr. Adolfo Pérez Dra. Lydia Irizarry Ponce Dra. Carmen Sánchez Dra. Lydia Irizarry

(787) 780-5627 (787) 787-5151 (787) 780-8034 (787) 474-3282

San Juan Dra. Adanette Wiscovich Dr. Adolfo Pérez Dr. Carlos Bourdony Dr. Carlos Leyva Dr. Fermín Sánchez Dr. Francisco Nieves Dr. Luis Font Dra. Rebecca Sáenz Dra. Yanira Pagán

(787) 758-2000 (787) 723-4728 (787) 726-0440 (787) 767-2929 (787) 781-8316 (787) 777-3243 (787) 771-7999 (787) 648-2410 (787) 688-4866

(787) 832-8190 (787) 232-8025 (787) 812-2037 (787) 844-4141

References: 1. Muir A. Precocious puberty. Pediatr Rev. 2006;27:373-381. 2. Precocious puberty. Mayo Clinic Web site. http://www.mayoclinic.com/health/precocious-puberty/DS00883. Accessed January 31, 2014. ©2015 AbbVie Inc. North Chicago, IL 60064 3410-1699910 April 2015 Printed in Puerto Rico

In the treatment of ACUTE CORONARY SYNDROME

IMPROVING CV MORTALITY

STARTS

HERE

BRILINTA CAN HELP Proven to save more lives than clopidogrel by reducing cardiovascular (CV) death at 12 months CV death secondary end point: relative risk reduction (RRR) with BRILINTA plus aspirin was 21% (absolute risk reduction [ARR] 1.1%) vs clopidogrel plus aspirin1*

AT 12 MONTHS, BRILINTA PLUS ASPIRIN SIGNIFICANTLY REDUCED THE PRIMARY COMPOSITE END POINT of CV death, myocardial infarction (MI),† or stroke by 16% RRR (ARR 1.9%) vs clopidogrel plus aspirin. The difference between treatments was driven by CV death and MI with no difference in stroke.1* BLEEDING AT 12 MONTHS, there was no signiﬁcant difference in Total Major Bleeding (which includes Fatal and Life-threatening bleeding) for BRILINTA plus aspirin vs clopidogrel plus aspirin (11.6% vs 11.2%). There was a somewhat greater risk of Non–coronary artery bypass graft surgery (CABG)-related Major plus Minor Bleeding for BRILINTA plus aspirin vs clopidogrel plus aspirin (8.7% vs 7.0%) and Non–CABG-related Major Bleeding (4.5% vs 3.8%), respectively. The PLATelet inhibition and patient Outcomes (PLATO) trial did not show an advantage for BRILINTA compared with clopidogrel for CABG-related Bleeding (Total Major 85.8% vs 86.9% and Fatal/Life-threatening 48.1% vs 47.9%, respectively). When antiplatelet therapy was stopped 5 days before CABG, Major Bleeding occurred in 75% of patients treated with BRILINTA and 79% of patients on clopidogrel.1‡ INDICATIONS FOR BRILINTA 90-MG TABLETS BRILINTA is indicated to reduce the rate of thrombotic cardiovascular (CV) events in patients with acute coronary syndrome (ACS) (unstable angina, non–ST-elevation myocardial infarction, or ST-elevation myocardial infarction). BRILINTA has been shown to reduce the rate of a combined end point of CV death, myocardial infarction (MI), or stroke compared to clopidogrel. The difference between treatments was driven by CV death and MI with no difference in stroke. In patients treated with PCI, it also reduces the rate of stent thrombosis. BRILINTA has been studied in ACS in combination with aspirin. Maintenance doses of aspirin >100 mg decreased the effectiveness of BRILINTA. Avoid maintenance doses of aspirin >100 mg daily. IMPORTANT SAFETY INFORMATION ABOUT BRILINTA WARNING: (A) BLEEDING RISK, (B) ASPIRIN DOSE AND BRILINTA EFFECTIVENESS A. BLEEDING RISK • BRILINTA, like other antiplatelet agents, can cause signiﬁcant, sometimes fatal, bleeding • Do not use BRILINTA in patients with active pathological bleeding or a history of intracranial hemorrhage • Do not start BRILINTA in patients planned to undergo urgent coronary artery bypass graft surgery (CABG). When possible, discontinue BRILINTA at least 5 days prior to any surgery

• Suspect bleeding in any patient who is hypotensive and has recently undergone coronary angiography, percutaneous coronary intervention (PCI), CABG, or other surgical procedures in the setting of BRILINTA • If possible, manage bleeding without discontinuing BRILINTA. Stopping BRILINTA increases the risk of subsequent cardiovascular events B. ASPIRIN DOSE AND BRILINTA EFFECTIVENESS • Maintenance doses of aspirin above 100 mg reduce the effectiveness of BRILINTA and should be avoided. After any initial dose, use with aspirin 75 mg - 100 mg per day CONTRAINDICATIONS • BRILINTA is contraindicated in patients with a history of intracranial hemorrhage and active pathological bleeding such as peptic ulcer or intracranial hemorrhage. BRILINTA is contraindicated in patients with severe hepatic impairment because of a probable increase in exposure; it has not been studied in these patients. Severe hepatic impairment increases the risk of bleeding because of reduced synthesis of coagulation proteins. BRILINTA is also contraindicated in patients with hypersensitivity (eg, angioedema) to ticagrelor or any component of the product WARNINGS AND PRECAUTIONS • Moderate Hepatic Impairment: Consider the risks and beneﬁts of treatment, noting the probable increase in exposure to ticagrelor

•

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Scan here or visit BRILINTATouchPoints.com • Premature discontinuation increases the risk of MI, stent thrombosis, and death • Dyspnea was reported in 14% of patients treated with BRILINTA and in 8% of patients taking clopidogrel. Dyspnea resulting from BRILINTA is self-limiting. Rule out other causes • BRILINTA is metabolized by CYP3A4/5. Avoid use with strong CYP3A inhibitors and potent CYP3A inducers. Avoid simvastatin and lovastatin doses >40 mg • Monitor digoxin levels with initiation of, or any change in, BRILINTA therapy ADVERSE REACTIONS • The most commonly observed adverse reactions associated with the use of BRILINTA vs clopidogrel were Total Major Bleeding (11.6% vs 11.2%) and dyspnea (14% vs 8%) • In clinical studies, BRILINTA has been shown to increase the occurrence of Holter-detected bradyarrhythmias. PLATO excluded patients at increased risk of bradycardic events. Consider the risks and beneﬁts of treatment Please see Brief Summary of Prescribing Information, including Boxed WARNINGS, on the adjacent pages. BRILINTA is a registered trademark of the AstraZeneca group of companies. ©2015 AstraZeneca. 3123901 4/15

*The PLATO study compared BRILINTA (180-mg loading dose, 90 mg twice daily thereafter) and clopidogrel (300-mg to 600-mg loading dose, 75 mg daily thereafter) for the prevention of CV events in 18,624 patients with ACS (unstable angina, non–ST-elevation myocardial infarction, or ST-elevation myocardial infarction). Patients were treated for at least 6 months and up to 12 months. BRILINTA and clopidogrel were studied with aspirin and other standard therapies. † Excluding silent MI. ‡ PLATO used the following bleeding severity categorization: Major Bleed– Fatal/Life threatening. Any one of the following: fatal; intracranial; intrapericardial bleed with cardiac tamponade; hypovolemic shock or severe hypotension due to bleeding and requiring pressors or surgery; clinically overt or apparent bleeding associated with a decrease in hemoglobin (Hb) of more than 5 g/dL; transfusion of 4 or more units (whole blood or packed red blood cells [PRBCs]) for bleeding. Major Bleed–Other. Any one of the following: signiﬁcantly disabling (eg, intraocular with permanent vision loss); clinically overt or apparent bleeding associated with a decrease in Hb of 3 g/dL; transfusion of 2 to 3 units (whole blood or PRBCs) for bleeding. Minor Bleed. Requires medical intervention to stop or treat bleeding (eg, epistaxis requiring visit to medical facility for packing). Minimal Bleed. All others (eg, bruising, bleeding gums, oozing from injection sites, etc) not requiring intervention or treatment. Reference: 1. BRILINTA Prescribing Information, AstraZeneca.

BRIEF SUMMARY of PRESCRIBING INFORMATION For full Prescribing Information, see package insert. WARNING: (A) BLEEDING RISK, (B) ASPIRIN DOSE AND BRILINTA EFFECTIVENESS A. BLEEDING RISK • BRILINTA, like other antiplatelet agents, can cause significant, sometimes fatal bleeding [see Warnings and Precautions (5.1) and Adverse Reactions (6.1) in full Prescribing Information]. • Do not use BRILINTA in patients with active pathological bleeding or a history of intracranial hemorrhage [see Contraindications (4.1, 4.2) in full Prescribing Information]. • Do not start BRILINTA in patients planned to undergo urgent coronary artery bypass graft surgery (CABG). When possible, discontinue BRILINTA at least 5 days prior to any surgery [see Warnings and Precautions (5.1) in full Prescribing Information]. • Suspect bleeding in any patient who is hypotensive and has recently undergone coronary angiography, percutaneous coronary intervention (PCI), CABG, or other surgical procedures in the setting of BRILINTA [see Warnings and Precautions (5.1) in full Prescribing Information]. • If possible, manage bleeding without discontinuing BRILINTA. Stopping BRILINTA increases the risk of subsequent cardiovascular events [see Warnings and Precautions (5.5) in full Prescribing Information]. B. ASPIRIN DOSE AND BRILINTA EFFECTIVENESS • Maintenance doses of aspirin above 100 mg reduce the effectiveness of BRILINTA and should be avoided. After any initial dose, use with aspirin 75-100 mg per day [see Warnings and Precautions (5.2) and Clinical Studies (14) in full Prescribing Information]. INDICATIONS AND USAGE Acute Coronary Syndromes BRILINTA is a P2Y12 platelet inhibitor indicated to reduce the rate of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS) (unstable angina, non-ST elevation myocardial infarction, or ST elevation myocardial infarction). BRILINTA has been shown to reduce the rate of a combined endpoint of cardiovascular death, myocardial infarction or stroke compared to clopidogrel. The difference between treatments was driven by CV death and MI with no difference in stroke. In patients treated with PCI, it also reduces the rate of stent thrombosis [see Clinical Studies (14) in full Prescribing Information]. BRILINTA has been studied in ACS in combination with aspirin. Maintenance doses of aspirin above 100 mg decreased the effectiveness of BRILINTA. Avoid maintenance doses of aspirin above 100 mg daily [see Warnings and Precautions (5.2) and Clinical Studies (14) in full Prescribing Information]. DOSAGE AND ADMINISTRATION Initiate BRILINTA treatment with a 180 mg (two 90 mg tablets) loading dose and continue treatment with 90 mg twice daily. After the initial loading dose of aspirin (usually 325 mg), use BRILINTA with a daily maintenance dose of aspirin of 75-100 mg. ACS patients who have received a loading dose of clopidogrel may be started on BRILINTA. BRILINTA can be administered with or without food. A patient who misses a dose of BRILINTA should take one 90 mg tablet (their next dose) at its scheduled time. Administration Options For patients who are unable to swallow the tablet(s) whole, BRILINTA tablets can be crushed, mixed with water and drunk immediately. The glass should be refilled with water, stirred and the contents drunk. The mixture can also be administered via a nasogastric tube (CH8 or greater). It is important to flush the nasogastric tube through with water after administration of the mixture [see Clinical Pharmacology (12.3) in full Prescribing Information]. CONTRAINDICATIONS History of Intracranial Hemorrhage BRILINTA is contraindicated in patients with a history of intracranial hemorrhage (ICH) because of a high risk of recurrent ICH in this population [see Clinical Studies (14) in full Prescribing Information]. Active Bleeding BRILINTA is contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage [see Warnings and Precautions (5.1) and Adverse Reactions (6.1) in full Prescribing Information]. Severe Hepatic Impairment BRILINTA is contraindicated in patients with severe hepatic impairment because of a probable increase in exposure, and it has not been studied in these patients. Severe hepatic impairment increases the risk of bleeding because of reduced synthesis of coagulation proteins [see Clinical Pharmacology (12.3) in full Prescribing Information]. Hypersensitivity BRILINTA is contraindicated in patients with hypersensitivity (e.g. angioedema) to ticagrelor or any component of the product [see Adverse Reactions (6.2) in full Prescribing Information]. WARNINGS AND PRECAUTIONS General Risk of Bleeding Drugs that inhibit platelet function including BRILINTA increase the risk of bleeding. BRILINTA increased the overall risk of bleeding (Major + Minor) to a somewhat greater extent than did clopidogrel. The increase was seen for non-CABG-related bleeding, but not for CABG-related bleeding. Fatal and life-threatening bleeding rates were not increased [see Adverse Reactions (6.1) in full Prescribing Information]. In general, risk factors for bleeding include older age, a history of bleeding disorders, performance of percutaneous invasive procedures, and concomitant use of medications that increase the risk of bleeding (e.g., anticoagulant and fibrinolytic therapy, higher doses of aspirin, and chronic nonsteroidal antiinflammatory drugs [NSAIDS]). When possible, discontinue BRILINTA five days prior to surgery. Suspect bleeding in any patient who is hypotensive and has recently undergone coronary angiography, PCI, CABG, or other surgical procedures, even if the patient does not have any signs of bleeding. If possible, manage bleeding without discontinuing BRILINTA. Stopping BRILINTA increases the risk of subsequent cardiovascular events [see Warnings and Precautions (5.5) and Adverse Reactions (6.1) in full Prescribing Information]. Concomitant Aspirin Maintenance Dose In PLATO, use of BRILINTA with maintenance doses of aspirin above 100 mg decreased the effectiveness of BRILINTA. Therefore, after the initial loading dose of aspirin (usually 325 mg), use BRILINTA with a

maintenance dose of aspirin of 75-100 mg [see Dosage and Administration (2) and Clinical Studies (14) in full Prescribing Information]. Moderate Hepatic Impairment BRILINTA has not been studied in patients with moderate hepatic impairment. Consider the risks and benefits of treatment, noting the probable increase in exposure to ticagrelor. Dyspnea In PLATO, dyspnea was reported in 14% of patients treated with BRILINTA and in 8% of patients taking clopidogrel. Dyspnea was usually mild to moderate in intensity and often resolved during continued treatment, but occasionally required discontinuation (0.9% of patients taking BRILINTA versus 0.1% of patients taking clopidogrel). If a patient develops new, prolonged, or worsened dyspnea during treatment with BRILINTA, exclude underlying diseases that may require treatment. If dyspnea is determined to be related to BRILINTA, no specific treatment is required; continue BRILINTA without interruption. In the case of intolerable dyspnea requiring discontinuation of BRILINTA, consider prescribing another antiplatelet agent. In a substudy, 199 patients from PLATO underwent pulmonary function testing irrespective of whether they reported dyspnea. There was no significant difference between treatment groups for FEV1. There was no indication of an adverse effect on pulmonary function assessed after one month or after at least 6 months of chronic treatment. Discontinuation of BRILINTA Avoid interruption of BRILINTA treatment. If BRILINTA must be temporarily discontinued (e.g., to treat bleeding or for elective surgery), restart it as soon as possible. Discontinuation of BRILINTA will increase the risk of myocardial infarction, stent thrombosis, and death. Strong Inhibitors of Cytochrome CYP3A Ticagrelor is metabolized by CYP3A4/5. Avoid use with strong CYP3A inhibitors, such as atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin and voriconazole [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) in full Prescribing Information]. Cytochrome CYP3A Potent Inducers Avoid use with potent CYP3A inducers, such as rifampin, phenytoin, carbamazepine, and phenobarbital [see Drug Interactions (7.2) and Clinical Pharmacology (12.3) in full Prescribing Information]. ADVERSE REACTIONS The following adverse reactions are also discussed elsewhere in the labeling: Dyspnea [see Warnings and Precautions (5.4) in full Prescribing Information] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. BRILINTA has been evaluated for safety in more than 10000 patients, including more than 3000 patients treated for more than 1 year. Bleeding PLATO used the following bleeding severity categorization: • Major bleed – fatal/life-threatening. Any one of the following: fatal; intracranial; intrapericardial bleed with cardiac tamponade; hypovolemic shock or severe hypotension due to bleeding and requiring pressors or surgery; clinically overt or apparent bleeding associated with a decrease in hemoglobin (Hb) of more than 5 g/dL; transfusion of 4 or more units (whole blood or packed red blood cells (PRBCs)) for bleeding. • Major bleed – other. Any one of the following: significantly disabling (e.g., intraocular with permanent vision loss); clinically overt or apparent bleeding associated with a decrease in Hb of 3 g/dL; transfusion of 2-3 units (whole blood or PRBCs) for bleeding. • Minor bleed. Requires medical intervention to stop or treat bleeding (e.g., epistaxis requiring visit to medical facility for packing). • Minimal bleed. All others (e.g., bruising, bleeding gums, oozing from injection sites, etc.) not requiring intervention or treatment. Figure 1 shows major bleeding events over time. Many events are early, at a time of coronary angiography, PCI, CABG, and other procedures, but the risk persists during later use of antiplatelet therapy. Figure 1 - Kaplan-Meier estimate of time to first PLATO-defined ‘Total Major’ bleeding event 15

Kaplan–Meier Percentage (%)

BRILINTA® (ticagrelor) tablets, for oral use

Ticagrelor (T) 961/9235 Clopidogrel (C) 929/9186 11.58% 11.20%

5 T vs C: HR (95% CI) = 1.04 (0.95, 1.13), p–value: 0.434

0 0 N at risk T 9235 C 9186

120

180

240

300

360

Days from First Study Drug Dose 7246 7305

6826 6930

6545 6670

5129 5209

3783 3841

3433 3479

Annualized rates of bleeding are summarized in Table 1 below. About half of the bleeding events were in the ﬁrst 30 days. Table 1 - Non-CABG related bleeds (KM%) BRILINTA Clopidogrel N=9235 N=9186 Total (Major + Minor) 8.7 7.0 Major 4.5 3.8 Fatal/Life-threatening 2.1 1.9 Fatal 0.2 0.2 Intracranial (Fatal/Life-threatening) 0.3 0.2 As shown in Table 1, BRILINTA was associated with a somewhat greater risk of non-CABG bleeding than was clopidogrel. No baseline demographic factor altered the relative risk of bleeding with BRILINTA compared to clopidogrel. In PLATO, 1584 patients underwent CABG surgery. The percentages of those patients who bled are shown in Table 2. Rates were very high but similar for BRILINTA and clopidogrel.

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Table 2 - CABG bleeds (KM%) Patients with CABG BRILINTA Clopidogrel N=770 N=814 Total Major 85.8 86.9 Fatal/Life-threatening 48.1 47.9 Fatal 0.9 1.1 Although the platelet inhibition effect of BRILINTA has a faster offset than clopidogrel in in vitro tests and BRILINTA is a reversibly binding P2Y12 inhibitor, PLATO did not show an advantage of BRILINTA compared to clopidogrel for CABG-related bleeding. When antiplatelet therapy was stopped 5 days before CABG, major bleeding occurred in 75% of BRILINTA treated patients and 79% on clopidogrel. No data exist with BRILINTA regarding a hemostatic beneﬁt of platelet transfusions. Drug Discontinuation In PLATO, the rate of study drug discontinuation attributed to adverse reactions was 7.4% for BRILINTA and 5.4% for clopidogrel. Bleeding caused permanent discontinuation of study drug in 2.3% of BRILINTA patients and 1.0% of clopidogrel patients. Dyspnea led to study drug discontinuation in 0.9% of BRILINTA and 0.1% of clopidogrel patients. Common Adverse Events A variety of non-hemorrhagic adverse events occurred in PLATO at rates of 3% or more. These are shown in Table 3. In the absence of a placebo control, whether these are drug related cannot be determined in most cases, except where they are more common on BRILINTA or clearly related to the drug’s pharmacologic effect (dyspnea). Table 3 - Percentage of patients reporting non-hemorrhagic adverse events at least 3% or more in either group

Dyspnea1 Headache Cough Dizziness Nausea Atrial ﬁbrillation Hypertension Non-cardiac chest pain Diarrhea Back pain Hypotension Fatigue Chest pain

BRILINTA N=9235 13.8 6.5 4.9 4.5 4.3 4.2 3.8 3.7 3.7 3.6 3.2 3.2 3.1

Clopidogrel N=9186 7.8 5.8 4.6 3.9 3.8 4.6 4.0 3.3 3.3 3.3 3.3 3.2 3.5

1. Includes: dyspnea, dyspnea exertional, dyspnea at rest, nocturnal dyspnea, dyspnea paroxysmal nocturnal

Bradycardia In clinical studies BRILINTA has been shown to increase the occurrence of Holter-detected bradyarrhythmias (including ventricular pauses). PLATO excluded patients at increased risk of bradycardic events (e.g., patients who have sick sinus syndrome, 2nd or 3rd degree AV block, or bradycardic-related syncope and not protected with a pacemaker). In PLATO, syncope, pre-syncope and loss of consciousness were reported by 1.7% and 1.5% of BRILINTA and clopidogrel patients, respectively. In a Holter substudy of about 3000 patients in PLATO, more patients had ventricular pauses with BRILINTA (6.0%) than with clopidogrel (3.5%) in the acute phase; rates were 2.2% and 1.6% respectively after 1 month. Gynecomastia In PLATO, gynecomastia was reported by 0.23% of men on BRILINTA and 0.05% on clopidogrel. Other sex-hormonal adverse reactions, including sex organ malignancies, did not differ between the two treatment groups in PLATO. Lab abnormalities Serum Uric Acid: Serum uric acid levels increased approximately 0.6 mg/dL from baseline on BRILINTA and approximately 0.2 mg/dL on clopidogrel in PLATO. The difference disappeared within 30 days of discontinuing treatment. Reports of gout did not differ between treatment groups in PLATO (0.6% in each group). Serum Creatinine: In PLATO, a >50% increase in serum creatinine levels was observed in 7.4% of patients receiving BRILINTA compared to 5.9% of patients receiving clopidogrel. The increases typically did not progress with ongoing treatment and often decreased with continued therapy. Evidence of reversibility upon discontinuation was observed even in those with the greatest on treatment increases. Treatment groups in PLATO did not differ for renal-related serious adverse events such as acute renal failure, chronic renal failure, toxic nephropathy, or oliguria. Postmarketing Experience The following adverse reactions have been identiﬁed during post-approval use of BRILINTA. Because these reactions are reported voluntarily from a population of an unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune system disorders – Hypersensitivity reactions including angioedema [see Contraindications (4.4) in full Prescribing Information]. DRUG INTERACTIONS Effects of other drugs Ticagrelor is predominantly metabolized by CYP3A4 and to a lesser extent by CYP3A5. Ticagrelor is also a p-glycoprotein (P-gp) substrate. CYP3A inhibitors Avoid use of strong inhibitors of CYP3A (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelﬁnavir, indinavir, atazanavir and telithromycin) [see Warnings and Precautions (5.6) and Clinical Pharmacology (12.3) in full Prescribing Information].

CYP3A inducers Avoid use with potent inducers of CYP3A (e.g., rifampin, phenytoin, carbamazepine and phenobarbital) [see Warnings and Precautions (5.7) and Clinical Pharmacology (12.3) in full Prescribing Information]. Aspirin Use of BRILINTA with aspirin maintenance doses above 100 mg reduced the effectiveness of BRILINTA [see Warnings and Precautions (5.2) and Clinical Studies (14) in full Prescribing Information]. Effect of BRILINTA on other drugs Ticagrelor is an inhibitor of CYP3A4/5 and the P-glycoprotein transporter. Simvastatin, lovastatin BRILINTA will result in higher serum concentrations of simvastatin and lovastatin because these drugs are metabolized by CYP3A4. Avoid simvastatin and lovastatin doses greater than 40 mg [see Clinical Pharmacology (12.3) in full Prescribing Information]. Digoxin Digoxin: Because of inhibition of the P-glycoprotein transporter, monitor digoxin levels with initiation of or any change in BRILINTA therapy [see Clinical Pharmacology (12.3)]. Other Concomitant Therapy BRILINTA can be administered with unfractionated or low-molecular-weight heparin, GPIIb/IIIa inhibitors, proton pump inhibitors, beta-blockers, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: There are no adequate and well-controlled studies of BRILINTA use in pregnant women. In animal studies, ticagrelor caused structural abnormalities at maternal doses about 5 to 7 times the maximum recommended human dose (MRHD) based on body surface area. BRILINTA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In reproductive toxicology studies, pregnant rats received ticagrelor during organogenesis at doses from 20 to 300 mg/kg/day. The lowest dose was approximately the same as the MRHD of 90 mg twice daily for a 60 kg human on a mg/m2 basis. Adverse outcomes in offspring occurred at doses of 300 mg/kg/day (16.5 times the MRHD on a mg/m2 basis) and included supernumerary liver lobe and ribs, incomplete ossification of sternebrae, displaced articulation of pelvis, and misshapen/misaligned sternebrae. When pregnant rabbits received ticagrelor during organogenesis at doses from 21 to 63 mg/kg/day, fetuses exposed to the highest maternal dose of 63 mg/kg/day (6.8 times the MRHD on a mg/m2 basis) had delayed gall bladder development and incomplete ossification of the hyoid, pubis and sternebrae occurred. In a prenatal/postnatal study, pregnant rats received ticagrelor at doses of 10 to 180 mg/kg/day during late gestation and lactation. Pup death and effects on pup growth were observed at 180 mg/kg/day (approximately 10 times the MRHD on a mg/m2 basis). Relatively minor effects such as delays in pinna unfolding and eye opening occurred at doses of 10 and 60 mg/kg (approximately one-half and 3.2 times the MRHD on a mg/m2 basis). Nursing Mothers It is not known whether ticagrelor or its active metabolites are excreted in human milk. Ticagrelor is excreted in rat milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from BRILINTA, a decision should be made whether to discontinue nursing or to discontinue drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effectiveness of BRILINTA in pediatric patients have not been established. Geriatric Use In PLATO, 43% of patients were 65 years of age and 15% were 75 years of age. The relative risk of bleeding was similar in both treatment and age groups. No overall differences in safety or effectiveness were observed between these patients and younger patients. While this clinical experience has not identified differences in responses between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out. Hepatic Impairment BRILINTA has not been studied in the patients with moderate or severe hepatic impairment. Ticagrelor is metabolized by the liver and impaired hepatic function can increase risks for bleeding and other adverse events. Hence, BRILINTA is contraindicated for use in patients with severe hepatic impairment and its use should be considered carefully in patients with moderate hepatic impairment. No dosage adjustment is needed in patients with mild hepatic impairment [see Contraindications (4), Warnings and Precautions (5.3) and Clinical Pharmacology (12.3) in full Prescribing Information]. Renal Impairment No dosage adjustment is needed in patients with renal impairment. Patients receiving dialysis have not been studied [see Clinical Pharmacology (12.3) in full Prescribing Information]. OVERDOSAGE There is currently no known treatment to reverse the effects of BRILINTA, and ticagrelor is not expected to be dialyzable. Treatment of overdose should follow local standard medical practice. Bleeding is the expected pharmacologic effect of overdosing. If bleeding occurs, appropriate supportive measures should be taken. Other effects of overdose may include gastrointestinal effects (nausea, vomiting, diarrhea) or ventricular pauses. Monitor the ECG. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility [see section (13.1) in full Prescribing Information] PATIENT COUNSELING INFORMATION [see section (17) in full Prescribing Information] Issued: 03/2015 BRILINTA® is a trademark of the AstraZeneca group of companies. Distributed by: AstraZeneca LP, Wilmington, DE 19850 © AstraZeneca 2011, 2013, 2014 3/15 3119602 4/15

MSP ARTÍCULO ORIGINAL

ENFERMEDAD CORONARIANA en pacientes con psoriasis:

Enfermedad coronaria en pacientres con Psoriasis En estudios epidemiológicos, principalmente con pacientes caucásicos, se ha visto que aquellos que son diagnosticados con psoriasis tienden a padecer de condiciones cardiovasculares, al punto que se ha llegado a pensar que podría haber una asociación entre el padecer de psoriasis y desarrollar enfermedad cardiovascular.

CUERO CABELLUDO

un estudio en puertorriqueños

CODOS

ABDOMEN

Por: Juan Nieves Rivera, MD1; Crystal Sulia, BS2, Wilma González3; Luz Figueroa, MD4; Héctor Banchs, MD1,5; Pablo Altieri, MD1,5 Universidad de Puerto Rico, Recinto de Ciencias Médicas; Escuela de Medicina, Departamento de Medicina; San Juan, P.R. 2 Universidad de Puerto Rico, Recinto de Río Piedras; Facultad de Ciencias Naturales; San Juan, P.R. 3 Universidad de Puerto Rico, Recinto de Ciencias Médicas; Escuela Graduada de Salud Pública; San Juan, P.R. 4 Universidad de Puerto Rico, Recinto de Ciencias Médicas; Escuela de Medicina, Departamento de Dermatología; San Juan, P.R. 5 Centro Cardiovascular de Puerto Rico y del Caribe; San Juan, PR 1

ÁREA GENITAL

RODILLAS

Keywords

psoriasis, atherosclerotic disease, mellitus diabetes

Palabras Claves

psoriasis, enfermedad arteriosclerótica, diabetes mellitus

Abstract Psoriasis affects 3% of the population of Puerto Rico. This disease is not just dermatological, it can also affect the heart by producing premature arteriosclerosis, causing chest angina or heart attacks at an early age of 50 years. This is the result of the inflammatory process that causes damage to the coronary, damage to endothelial cells.

soriasis es una afección principalmente cutánea de posible origen inmunológico bien común en los Estados Unidos y en Puerto Rico que se caracteriza por una activación crónica del sistema inmunológico. Su presentación clínica consiste en lesiones gruesas, enrojecidas, tipo “escamas”, que provocan picor y dolor comúnmente localizadas en los codos, rodillas, cuero cabelludo, palma de las manos y la planta de los pies. A través de los años se ha ido aprendiendo cada vez más

Revista Puertorriqueña de Medicina y Salúd Pública

Resumen La psoriasis afecta un 3% de la población de Puerto Rico. Esta enfermedad no solo es una dermatológica, sino que puede afectar el corazón produciendo arteriosclerosis prematura, produciendo angina en el pecho o infartos a una edad prematura como los 50 años. Esto es producto de un proceso inflamatorio que produce daños a las coronarias, por daño a las células endoteliales.

de esta condición, particularmente las manifestaciones sistémicas no cutáneas que podría presentar. En estudios epidemiológicos, principalmente con pacientes caucásicos, se ha visto que aquellos que son diagnosticados con psoriasis tienden a padecer de condiciones cardiovasculares, al punto que se ha llegado a pensar que podría haber una asociación entre el padecer de psoriasis y desarrollar enfermedad cardiovascular. Se cree que la inflamación crónica asociada a esta condición activa los

mecanismos responsables de producir aterosclerosis, el causante de enfermedad coronariana y periferovascular. Hay muchos estudiosque tratan de demostrar esto, particularmente en caucásicos. No hay estudios actualmente en Hispanos, ni mucho menos en Puertorriqueños. Con este interés nos dimos a la tarea de hacer un estudio donde pudiéramos describir si, en efecto, los pacientes con psoriasis tienen mayor riesgo de desarrollar enfermedad cardiovascular, particularmente enfermedad coronariana.

MSP ARTÍCULO ORIGINAL

Se cree que la inflamación crónica asociada a esta condición activa los mecanismos responsables de producir aterosclerosis, el causante de enfermedad coronariana y periferovascular.

Buscan descifrar si los puertorriqueños con psoriasis tienen o no mayor incidencia de enfermedad cardiovascular. En un evento sin precedentes, se creó una alianza investigativa entre el Departamento de Dermatología, la Sección de Cardiología del Departamento de Medicina Interna de la Universidad de Puerto Rico y el Centro Cardiovascular de Puerto Rico y el Caribe. Con la aprobación de la Oficina para la Protección de Participantes Humanos en Investigación (OPPHI) del Recinto de Ciencias Médicas de la Universidad de Puerto Rico actualmente se está llevando a cabo un a cabo un estudio en pacientes puertorriqueños con psoriasis.

Resultados de la Fase 1 del estudio: Se analizaron 46 reportes de cateterismo cardiaco 56.8±15.28 (SD) la edad media de los pacientes 33 del sexo masculino Las comorbilidades de la población fueron las siguientes: Presión Alta (91.3%), Diabetes Mellitus (50%), Síndrome Metabólico (63%), e Hiperlipemia (73.9%) 59% de los pacientes con psoriasis tenía evidencia angiográfica de enfermedad coronariana

ESPALDA

74% tenía enfermedad coronariana obstructiva, entiéndase que tenía las arterias del corazón tapadas 26% recibió solamente tratamiento médico

de la población puertorriqueña es afectada por psoriasis

En un evento sin precedentes, se creó una alianza investigativa entre el Departamento de Dermatología, la Sección de Cardiología del Departamento de Medicina Interna de la Universidad de Puerto Rico y el Centro Cardiovascular de Puerto Rico y el Caribe. Con la aprobación de la Oficina para la Protección de Participantes Humanos en Investigación (OPPHI) del Recinto de Ciencias Médicas de la Universidad de Puerto Rico actualmente se está llevando a cabo un a cabo un estudio en pacientes puertorriqueños con psoriasis. En el mismo se intenta descifrar si los puertorriqueños con psoriasis tienen o no mayor incidencia de enfermedad cardiovascular. El estudio consta de dos fases. La primera consta de analizar los hallazgos en los cateterismos cardiacos realizados desde el año 2007 hasta el presente en pacientes con diagnóstico de psoriasis que hayan visitado el Centro

74% de los pacientes con psoriasis presentó enfermedad severa y tuvieron que ser intervenidos invasivamente con cirugía de puente aortocoronario o con angioplastia, dependiendo el caso De igual forma, no se vio significancia estadística al relacionarlo con diabetes mellitus y síndrome metabólico

Cardiovascular de Puerto Rico y el Caribe (CCPRC). La segunda fase se realiza en las Clínicas de Dermatología de la Escuela de Medicina, donde se manejan la mayoría de los pacientes con psoriasis de la isla, incluyendo aquellos con manifestaciones bien severas de la enfermedad. Esta fase consta de evaluar restrospectivamente los expedientes médicos de todos los pacientes diagnosticados con psoriasis que han visitado las clínicas para crear una base de datos que caracterice la población de psoriasis en Puerto Rico, con un interés particular en las aquellas otras condiciones que estos pacientes padecen, las complicaciones médicas más comunes, características demográficas, entre otras. Los criterios de inclusión para participar del estudio fueron: ser hombre o mujer mayor de 18 años de edad, nacido en Puerto Rico de padres puertorriqueños, con diagnóstico de psoriasis. En la Fase 1, para ser considerado en el estudio el

paciente tiene que tener el diagnóstico de psoriasis y haberse realizado un cateterismo, ya sea diagnóstico o terapéutico, en el CCPRC. La toma de datos de esta fase 1 ya se completó y los resultados preliminares se analizaron, con sorprendentes resultados. La fase 2 actualmente se encuentra en etapa de recopilación de datos. Para la fase 1 del estudio, se analizaron 46 reportes de cateterismo cardiaco. La edad media de los pacientes fue 56.8±15.28 (SD) y 33 de ellos eran del sexo masculino. Las comorbilidades de la población fueron las siguientes: Presión Alta (91.3%), Diabetes Mellitus (50%), Síndrome Metabólico (63%), e Hiperlipemia (73.9%). Se evaluaron todos los reportes de cateterismo cardiaco de los pacientes y se hizo un análisis descriptivo de los hallazgos. El mismo mostró lo siguiente: que la mayoría de los pacientes con psoriasis tenía evidencia Revista Puertorriqueña de Medicina y Salúd Pública

MSP ARTÍCULO ORIGINAL

angiográfica de enfermedad coronariana., específicamente un 59% de todos ellos. De estos, el 74% tenía enfermedad coronariana obstructiva, entiéndase que tenía las arterias del corazón tapadas. De estos, un 26% recibió solamente tratamiento médico, mientras que el restante 74% de los pacientes con psoriasis presentó enfermedad severa y tuvieron que ser intervenidos invasivamente con cirugía de puente aortocoronario o con angioplastia, dependiendo el caso. Se realizó también un estudio estadístico utilizado el “Fisher Exact Test” para determinar la relación entre desarrollar enfermedad coronariana y los distintos factores de riesgo cardiovascular y las condiciones asociadas, como diabetes mellitus y síndrome metabólico. El mismo demostró que no hubo significancia estadística entre los factores de riesgo tradicionales y el desarrollo de enfermedad coronariana. De igual forma, no se vio significancia estadística al relacionarlo con diabetes mellitus y síndrome metabólico. Con esto, podemos concluir que el riesgo de desarrollar enfermedad coronariana en los pacientes con psoriasis no necesariamente se debe a los factores de riesgo tradicionales en la población general, sino que debe de haber un componente intrínseco, particular de esta condición que los predispone a desarrollar enfermedad coronariana. Entendemos que la clave está en la activación del sistema inflamatorio, característico de esta y otras condiciones de origen autoinmune. El constantemente estar produciendo y liberando citoquinas y citotoxinas inflamatorias podría llevar a un acelerado desarrollo de ateroesclerosis y, por ende, obstrucción de las arterias del corazón. Todavía hay mucho por estudiar, para poder finalmente entender por completo la posible relación que existe entre psoriasis y enfermedad cardiovascular, pero cada vez estamos más cerca. Nuestro estudio ha sido el primer estudio realizado en puertorriqueños y, posiblemente, en Hispanos donde se describen los hallazgos angiográficos específicos en pacientes con psoriasis. Aún faltan datos por analizar, pero esto es el resultado preliminar. Estamos ansiosos de poder culminar ambas fases de este estudio que, sin duda 20

Revista Puertorriqueña de Medicina y Salúd Pública

Tabla I. Porcentaje de Factores de Riesgo en Pacientes Factor de Riesgo

Porciento %

Hypertensión (HBP al ser admitido)

Diabetes Mellitus

Síndrome Metabólico

Dislipidemia a) LDL b) HDL c) Colesterol total

73 56 12 68.7

Fumadores crónicos

alguna, ha sido una colaboración sin precedentes y que tiene una importancia clínica significativa, tanto a nivel local como internacional. Referencias

1. S.K. Kurd, J.M. Gelfand. The prevalence of previously diagnosed and undiagnosed psoriasis in US adults: results from NHANES 2003-2004. Journal of the American Academy of Dermatology. 60 (2009), 218-224. 2. V.E. Friedewald, J.C. Cather, J.M. Gelfand, K.B. Gordon, G.H. Gibbons, S.M. Grundy, et al., AJC editor’s consensus: psoriasis and coronary artery disease. American Journal of Cardiology: 102 (2008), 1631-1643. 3. J.M. Gelfand, E.D. Domasch, D.B. Shin, R.S. Azfar, S.K. Kurd, X. Wang, et al. The risk of stroke in patients with psoriasis. Journal of Investigative Dermatology: 129 (2009), 2411-2418. 4. J.M. Gelfand, A.L. Neimann, D.B.Shin, X. Wang, D.J.Margolis, A.B. Troxel. Risk of myocardial infarction in patients with psoriasis. JAMA 296 (2006), 1735-1741. 5. N.N. Mehta, R.S. Azfar, D.B. Shin, A.L.Neimann, A.B. Troxel, J.M. Gelfand. Patients with severe psoriasis are at increased risk of cardiovascular mortality: cohort study using the General Practice Research Database. European Heart Journal 31 (2010), 1000-1006. 6. N.N. Mehta, Y. Yu, R. Pinnelas, P. Krishnamoorthy, D.B. Shin, A.B. Troxel, et al. Attributable risk estimate of severe psoriasis on major cardiovascular events. American Journal of Medicine 124 (2011), 775 (el-6). 7. S. Prodanovich, R.S. Kirsner, J.D. Kravetz, F. Ma, L. Martinez, D.G.Federman, Association of psoriasis with coronary artery, cerebrovascular, and peripheral vascular diseases and mortality. Archives of Dermatology 145 (2009), 700-703.

8. C.J. McDonald, P. Calabresi. Psoriasis and occlusive vascular disease. British Journal of Dermatology. 99 (1978), 469-475. 9. A. W. Armstrong, C.T. Harskamp, E. J. Armstrong. The Association between psoriasis and Hypertension. 31 (2013), 433442 (discussion 42-3). 10. A. W. Armstrong, C.T. Harskamp, E.J.Armstrong. The Association between psoriasis and Hypertension. 31 (2013), 433442 (discussion 42-3). 11. A.A. Qureshi, H.K. Choi, A.R. Setty, G.C. Curhan. Psoriasis and tehe risk of diabetes and hypertension: a prospective study of US female nurses. Archives of Dermatology 145 (2009), 379-382. 12. Gelfand JM, Neimann AL, Shin DB, Wang X, Margolis DJ, Troxel AB. Risk of myocardial infarction in patients with psoriasis. Journal of the American Medical Association. 296 (2006), 1735-1741. 13. National Psoriasis Foundation. Report on the psyco-social impacts of psoriasis; 1 (2009); Portland, O.R. 14. I. Rodríguez, M. Marazzi. New Mortality Statistics 2000-2008. Departamento de Salud Gobierno de Puerto Rico, Insituto de Estadísticas de Puerto Rico. (2010); San Juan, P.R. 15. G. Alvarez. Et al. Psoriasis in Puerto Rico: a preliminary descriptive study. (2009) Dermatology Department, University of Puerto Rico School of Medicine; San Juan, P.R. (unpublished) 16. M. Palmieri, R. Costas, V.W. Cruz, A.M. Cortés, et al. Risk factors and prevalence of coronary heart disease in Puerto Rico. Circulation (1980); 42: 541-543. 17. P. Altieri, M. Palmieri, Sudden death in Puerto Rico: a United States Caribbean Island. Revista Latina de Cardiología. (1993); 14:17.

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In moderate to severe plaque psoriasis

Itâ&#x20AC;&#x2122;s about time to consider

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ALSO

APPROVED FOR ACTIVE

years of efficacy and safety data in plaque psoriasis

times-a-year dosing (after 2 starter doses)

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PSORIATIC ARTHRITIS

L unique mechanism of action

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It’s about time to consider prescribing STELARA® as a first-line biologic in moderate to severe plaque psoriasis

S S a h S a L

Please see indications and Selected Safety Information to the right.

*O u p †

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GROWING DEMAND,* GREATER ACCESS 1 STELARA® is available as a first-line biologic option on the 3 largest national plans and 2 largest PBMs in the country.† Learn more at STELARAhcp.com. STELARA® is indicated for the treatment of adult patients (18 years or older) with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy. STELARA® is indicated for the treatment of adult patients (18 years or older) with active psoriatic arthritis. STELARA® can be used alone or in combination with methotrexate (MTX). STELARA®, available as 45 mg and 90 mg, is a subcutaneous injection intended for use under the guidance and supervision of a physician with patients who will be closely monitored and have regular follow-up. Patients may self-inject with STELARA® after physician approval and proper training. Patients should be instructed to follow the directions provided in the Medication Guide.2 Selected Safety Information STELARA® is an immunosuppressant and may increase the risk of infections, reactivation of latent infections, and malignancies. Serious adverse reactions have been reported in STELARA®-treated patients, including bacterial, fungal, and viral infections, malignancies, hypersensitivity reactions and one case of Reversible Posterior Leukoencephalopathy Syndrome (RPLS). STELARA® should not be given to patients who have had clinically significant hypersensitivity to ustekinumab (or excipients) or patients with any clinically important active infection. Patients should be evaluated for tuberculosis prior to initiating treatment with STELARA®. Live vaccines should not be given to patients receiving STELARA®. If RPLS is suspected, discontinue STELARA®.

†

Largest national plans represent health plans with the greatest number of overall patient lives.1

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*Over 93,000 patients treated with STELARA® in the United States from September 2009 to February 2015. Estimations are based on calculations using product utilization data collected in the United States for STELARA® to determine patient type, average dose per administration, total number of administrations, and patient persistency rates.1

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Please see related and other Important Safety Information for STELARA® within this advertisement.

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A THERAPY TO START WITH

PHOENIX 2: PASI 75 response by weight after 2 doses at Week 122 100

Patients responding (%)

90 80

70 60 50 40 30 20 10 0

vs 4% (12/290) of placebo

vs 3% (3/120) of placebo

(218/297) 45 mg

(86/121) 90 mg

( ≤220 lbs)

Week 12

( >220 lbs)

• The primary endpoint was PASI 75 at Week 12 (45 mg: 67% [273/409]; 90 mg: 76% [311/411]; placebo: 4% [15/410]; P<0.0001 vs placebo for each dose).2,3

P e c W

• Treatment success (defined as PGA score of Cleared or Minimal) was achieved at Week 12 in 7 out of 10 patients in the 45-mg and 90-mg groups (68% [277/409] and 73% [300/411], respectively) compared with 4% (18/410) of placebo patients (P<0.0001).2,3 PHOENIX 2 evaluated 1,230 patients who began the study receiving STELARA® 45 mg or 90 mg or placebo. Patients randomized to STELARA® received STELARA® at Weeks 0 and 4, followed by the same dose every 12 weeks through Week 28. Patients in the placebo group (n=410) crossed over to receive either STELARA® 45 mg or 90 mg at Weeks 12 and 16, followed by the same dose every 12 weeks. Eligible patients were adults with a diagnosis of plaque psoriasis for ≥6 months involving ≥10% body surface area (BSA), PASI score ≥12, and who were candidates for phototherapy or systemic therapy.2,3

QUARTERLY MAINTENANCE DOSING (EVERY 12 WEEKS) AFTER 2 STARTER DOSES AT WEEKS 0 AND 42 STELARA® IS THE ONLY BIOLOGIC THAT SELECTIVELY TARGETS IL-12 AND IL-232

• STELARA® is a human IgG1κ monoclonal antibody that binds with specificity to the p40 protein subunit used by both the IL-12 and IL-23 cytokines.2

S ≥

STELARA® is indicated for the treatment of adult patients (18 years or older) with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy. STELARA® is indicated for the treatment of adult patients (18 years or older) with active psoriatic arthritis. STELARA® can be used alone or in combination with methotrexate (MTX). STELARA®, available as 45 mg and 90 mg, is a subcutaneous injection intended for use under the guidance and supervision of a physician with patients who will be closely monitored and have regular follow-up. Patients may self-inject with STELARA® after physician approval and proper training. Patients should be instructed to follow the directions provided in the Medication Guide.2 Selected Safety Information STELARA® is an immunosuppressant and may increase the risk of infections, reactivation of latent infections, and malignancies. Serious adverse reactions have been reported in STELARA®-treated patients, including bacterial, fungal, and viral infections, malignancies, hypersensitivity reactions and one case of Reversible Posterior Leukoencephalopathy Syndrome (RPLS). STELARA® should not be given to patients who have had clinically significant hypersensitivity to ustekinumab (or excipients) or patients with any clinically important active infection. Patients should be evaluated for tuberculosis prior to initiating treatment with STELARA®. Live vaccines should not be given to patients receiving STELARA®. If RPLS is suspected, discontinue STELARA®. Please see related and other Important Safety Information for STELARA® within this advertisement.

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CONSISTENT RESULTS OVER TIME PHOENIX 1: PASI 75 response at Week 76 and in an open-label extension through Week 244 in patients who were rerandomized to continue every-12-week dosing after responding to STELARA® at Weeks 28 and 40 1,4 100 90 80

Patients responding (%)

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84%

Open-label extension*

78%

83%

80%

70 60 50 40 30 20 10 0

(134/159)

(123/158)

(123/149)

(112/140)

45 mg or 90 mg

Week 76

Week 100

Week 148

Week 244

*After Week 76, treatment was unblinded and concomitant topicals were allowed.1,4

• The primary endpoint was PASI 75 at Week 12 (45 mg: 67% [171/255]; 90 mg: 66% [170/256]; placebo: 3% [8/255]; P<0.0001 vs placebo for each dose).2,5 • Treatment success (defined as PGA score of Cleared or Minimal) was achieved in 6 out of 10 patients taking STELARA® (45 mg: 59% [151/255] and 90 mg: 61% [156/256]) at Week 12 vs 4% (10/255) of patients taking placebo (P<0.0001 vs placebo for each dose).2,5 PHOENIX 1 evaluated 766 patients who received STELARA® or placebo. The study design was identical to PHOENIX 2 through Week 28. Inclusion criteria were consistent with PHOENIX 2. At Week 40, 322 of the 511 patients initially randomized to STELARA® who were PASI 75 responders at both Weeks 28 and 40 were rerandomized either to continue every-12-week dosing with STELARA® (n=162) or to placebo (n=160). Patients rerandomized to STELARA® at Week 40 were considered treatment failures if they discontinued STELARA® due to unsatisfactory therapeutic effect, experienced an adverse event of worsening of psoriasis, or started nontopical protocol-prohibited medications.1,2,5 After Week 76, treatment was unblinded and treatment failure rules were relaxed to allow for use of concomitant topical medications, except for highpotency corticosteroids. The analyses at Weeks 76, 100, 148, and 244 include all patients rerandomized at Week 40 to continue every-12-week dosing with STELARA®, except those who discontinued STELARA® due to an adverse event or were lost to follow-up.4,5

In the placebo-controlled period of clinical studies of psoriasis patients (average follow-up of 12.6 weeks for placebo-treated patients and 13.4 weeks for STELARA®-treated patients): 27% of STELARA®-treated patients reported infections (1.39 per patient-year of follow-up) compared with 24% of placebo-treated patients (1.21 per patient-year of follow-up); serious infections occurred in 0.3% of STELARA®-treated patients (0.01 per patient-year of follow-up) and in 0.4% of placebo-treated patients (0.02 per patient-year of follow-up).2 In the controlled and non-controlled portions of psoriasis clinical trials (median follow-up of 3.2 years, representing 8,998 patient-years of exposure): 72.3% of STELARA®-treated patients reported infections (0.87 per patient-year of follow-up); serious infections were reported in 2.8% of patients (0.01 per patient-year of follow-up); 1.7% of STELARA®-treated patients reported malignancies excluding non-melanoma skin cancers (NMSC) (0.60 per hundred patient-years of follow-up); NMSC was reported in 1.5% of STELARA®-treated patients (0.52 per hundred patient-years of follow-up).2 The most frequently observed malignancies other than NMSC during the clinical trials were prostate, melanoma, colorectal, and breast.2 Malignancies other than NMSC in STELARA®-treated patients during the controlled and uncontrolled portions of studies were similar in type and number to what would be expected in the general US population according to the SEER database (adjusted for age, gender, and race).2,6‡ Placebo patients who crossed over at Week 12 are included in the ≥4.5-year but not in the ≥5-year exposure category (ie, ≥240 weeks between first and last doses of STELARA®).6 Surveillance, Epidemiology, and End Results (SEER) database (2009), adjusted for age, gender, and race, compared with STELARA® through the 2011 analysis.6

† ‡

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Safety data reflect exposure in 3,117 psoriasis patients, including 1,855 exposed for ≥1 year; 1,653 exposed for ≥2 years; 1,569 exposed for ≥3 years; 1,482 exposed for ≥4 years; 1,435 exposed for ≥4.5 years†; and 838 exposed for ≥5 years.2,6

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SAFETY DATA IN PATIENTS WITH UP TO 5 YEARS OF EXPOSURE

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IMPORTANT SAFETY INFORMATION Infections STELARA® (ustekinumab) may increase the risk of infections and reactivation of latent infections. Serious bacterial, fungal, and viral infections, some requiring hospitalization, were reported. Serious infections included diverticulitis, cellulitis, pneumonia, appendicitis, cholecystitis, sepsis, osteomyelitis, viral infections, gastroenteritis and urinary tract infections. STELARA® should not be given to patients with a clinically important active infection and should not be administered until the infection resolves or is adequately treated. Instruct patients to seek medical advice if signs or symptoms suggestive of an infection occur. Exercise caution when considering use of STELARA® in patients with a chronic infection or a history of recurrent infection.

Theoretical Risk for Vulnerability to Particular Infections Individuals genetically deficient in IL-12/IL-23 are particularly vulnerable to disseminated infections from mycobacteria, Salmonella, and Bacillus Calmette-Guerin (BCG) vaccinations. Serious infections and fatal outcomes have been reported in such patients. It is not known whether patients with pharmacologic blockade of IL-12/IL-23 from treatment with STELARA® will be susceptible to these types of infections. Consider appropriate diagnostic testing as dictated by clinical circumstances.

Pre-Treatment Evaluation of Tuberculosis (TB) Evaluate patients for TB prior to initiating treatment with STELARA®. STELARA® should not be given to patients with active TB. Initiate treatment of latent TB before administering STELARA®. Patients should be monitored closely for signs and symptoms of active TB during and after treatment with STELARA®.

Malignancies STELARA® is an immunosuppressant and may increase the risk of malignancy. Malignancies were reported among patients who received STELARA® in clinical studies. The safety of STELARA® has not been evaluated in patients who have a history of malignancy or who have a known malignancy. There have been reports of the rapid appearance of multiple cutaneous squamous cell carcinomas in patients receiving STELARA® who had risk factors for developing non-melanoma skin cancer (NMSC). All patients receiving STELARA®, especially those >60 years or those with a history of PUVA or prolonged immunosuppressant treatment, should be monitored for the appearance of NMSC.

Hypersensitivity Reactions STELARA® is contraindicated in patients with clinically significant hypersensitivity to ustekinumab or excipients. Hypersensitivity reactions, including anaphylaxis and angioedema, have been reported. If an anaphylactic or other clinically significant hypersensitivity reaction occurs, institute appropriate therapy and discontinue STELARA®. S:11.25 in

One case of RPLS has been reported in a STELARA®-treated patient. If RPLS is suspected, administer appropriate treatment and discontinue STELARA®. RPLS is a neurological disorder, which is not caused by an infection or demyelination. RPLS can present with headache, seizures, confusion, and visual disturbances. RPLS has been associated with fatal outcomes.

Immunizations Prior to initiating therapy with STELARA®, patients should receive all immunizations recommended by current guidelines. Patients being treated with STELARA® should not receive live vaccines. BCG vaccines should not be given during treatment or within one year of initiating or discontinuing STELARA®. Exercise caution when administering live vaccines to household contacts of STELARA® patients, as shedding and subsequent transmission to STELARA® patients may occur. Non-live vaccinations received during a course of STELARA® may not elicit an immune response sufficient to prevent disease.

Concomitant Therapies The safety of STELARA® in combination with other immunosuppressive agents or phototherapy has not been evaluated. Ultraviolet-induced skin cancers developed earlier and more frequently in mice. In psoriasis studies, the relevance of findings in mouse models for malignancy risk in humans is unknown. In psoriatic arthritis studies, concomitant MTX use did not appear to influence the safety or efficacy of STELARA®.

Allergen Immunotherapy

Most Common Adverse Reactions The most common adverse reactions (≥3% and higher than that with placebo) in psoriasis clinical trials for STELARA® 45 mg, STELARA® 90 mg, or placebo were: nasopharyngitis (8%, 7%, 8%), upper respiratory tract infection (5%, 4%, 5%), headache (5%, 5%, 3%), and fatigue (3%, 3%, 2%), respectively. In psoriatic arthritis (PsA) studies, a higher incidence of arthralgia and nausea was observed in patients treated with STELARA® when compared with placebo (3% vs 1% for both).

Please see Brief Summary of Prescribing Information for STELARA® within this advertisement. References: 1. Data on file. Janssen Biotech, Inc. 2. STELARA® Prescribing Information. Horsham, PA: Janssen Biotech, Inc. 3. Papp KA, Langley RG, Lebwohl M, et al; for the PHOENIX 2 study investigators. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2). Lancet. 2008;371(9625):1675-1684. 4. Kimball AB, Papp KA, Wasfi Y, et al; on behalf of the PHOENIX 1 investigators. Long-term efficacy of ustekinumab in patients with moderate-to-severe psoriasis treated for up to 5 years in the PHOENIX 1 study. J Eur Acad Dermatol Venereol. 2013;27(12):1535-1545. 5. Leonardi CL, Kimball AB, Papp KA, et al; for the PHOENIX 1 study investigators. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet. 2008;371(9625):1665-1674. 6. Papp KA, Griffiths CEM, Gordon K, et al; on behalf of the PHOENIX 1, PHOENIX 2, and ACCEPT Investigators. Long-term safety of ustekinumab in patients with moderate-to-severe psoriasis: final results from 5 years of follow-up. Br J Dermatol. 2013;168(4):844-854. © Janssen Biotech, Inc. 2015 7/15 035584-150611

011842-140312

STELARA® may decrease the protective effect of allergen immunotherapy (decrease tolerance) which may increase the risk of an allergic reaction to a dose of allergen immunotherapy. Therefore, caution should be exercised in patients receiving or who have received allergen immunotherapy, particularly for anaphylaxis.

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Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

Brief Summary of Prescribing Information for STELARA® (ustekinumab) STELARA® Injection, for subcutaneous use See package insert for Full Prescribing Information

INDICATIONS AND USAGE: Psoriasis (Ps) STELARA® is indicated for the treatment of adult patients (18 years or older) with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy. Psoriatic Arthritis (PsA) STELARA® is indicated for the treatment of adult patients (18 years or older) with active psoriatic arthritis. STELARA® can be used alone or in combination with methotrexate (MTX). CONTRAINDICATIONS: Clinically significant hypersensitivity to ustekinumab or to any of the excipients (see Warnings and Precautions). WARNINGS AND PRECAUTIONS: Infections STELARA® may increase the risk of infections and reactivation of latent infections. Serious bacterial, fungal, and viral infections were observed in subjects receiving STELARA® (see Adverse Reactions). STELARA® should not be given to patients with any clinically important active infection. STELARA® should not be administered until the infection resolves or is adequately treated. Instruct patients to seek medical advice if signs or symptoms suggestive of an infection occur. Exercise caution when considering the use of STELARA® in patients with a chronic infection or a history of recurrent infection. Serious infections requiring hospitalization occurred in the psoriasis and psoriatic arthritis development programs. In the psoriasis program, serious infections included diverticulitis, cellulitis, pneumonia, appendicitis, cholecystitis, sepsis, osteomyelitis, viral infections, gastroenteritis and urinary tract infections. In the psoriatic arthritis program, serious infections included cholecystitis. Theoretical Risk for Vulnerability to Particular Infections Individuals genetically deficient in IL-12/IL-23 are particularly vulnerable to disseminated infections from mycobacteria (including nontuberculous, environmental mycobacteria), salmonella (including nontyphi strains), and Bacillus Calmette-Guerin (BCG) vaccinations. Serious infections and fatal outcomes have been reported in such patients. It is not known whether patients with pharmacologic blockade of IL-12/IL-23 from treatment with STELARA® will be susceptible to these types of infections. Appropriate diagnostic testing should be considered, e.g., tissue culture, stool culture, as dictated by clinical circumstances. Pre-treatment Evaluation for Tuberculosis Evaluate patients for tuberculosis infection prior to initiating treatment with STELARA®. Do not administer STELARA® to patients with active tuberculosis. Initiate treatment of latent tuberculosis prior to administering STELARA®. Consider anti-tuberculosis therapy prior to initiation of STELARA® in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed. Patients receiving STELARA® should be monitored closely for signs and symptoms of active tuberculosis during and after treatment. Malignancies STELARA® is an immunosuppressant and may increase the risk of malignancy. Malignancies were reported among subjects who received STELARA® in clinical studies (see Adverse Reactions). In rodent models, inhibition of IL-12/IL-23p40 increased the risk of malignancy (see Nonclinical Toxicology). The safety of STELARA® has not been evaluated in patients who have a history of malignancy or who have a known malignancy. There have been post marketing reports of the rapid appearance of multiple cutaneous squamous cell carcinomas in patients receiving STELARA® who had pre-existing risk factors for developing non-melanoma skin cancer. All patients receiving STELARA® should be monitored for the appearance of non-melanoma skin cancer. Patients greater than 60 years of age, those with a medical history of prolonged immunosuppressant therapy and those with a history of PUVA treatment should be followed closely (see Adverse Reactions). Hypersensitivity Reactions Hypersensitivity reactions, including anaphylaxis and angioedema, have been reported post-marketing. If an anaphylactic or other clinically significant hypersensitivity reaction occurs, institute appropriate therapy and discontinue STELARA® (see Adverse Reactions). Reversible Posterior Leukoencephalopathy Syndrome One case of reversible posterior leukoencephalopathy syndrome (RPLS) was observed in the clinical trial safety databases for psoriasis and psoriatic arthritis. The subject, who had received 12 doses of STELARA® over approximately two years, presented with headache, seizures and confusion. No additional STELARA® injections were administered and the subject fully recovered with appropriate treatment. RPLS is a neurological disorder, which is not caused by demyelination or a known infectious agent. RPLS can present with headache, seizures, confusion and visual disturbances. Conditions with which it has been associated include preeclampsia, eclampsia, acute hypertension, cytotoxic agents and immunosuppressive therapy. Fatal outcomes have been reported. If RPLS is suspected, administer appropriate treatment and discontinue STELARA®. Immunizations Prior to initiating therapy with STELARA®, patients should receive all immunizations appropriate for age as recommended by current immunization guidelines. Patients being treated with STELARA® should not receive live vaccines. BCG vaccines should not be given during treatment with STELARA® or for one year prior to initiating treatment or one year following discontinuation of treatment. Caution is advised when administering live vaccines to household contacts of patients receiving STELARA® because of the potential risk for shedding from the household contact and transmission to patient. Non-live vaccinations received during a course of STELARA® may not elicit an immune response sufficient to prevent disease. Concomitant Therapies In psoriasis studies the safety of STELARA® in combination with other immunosuppressive agents or phototherapy has not been evaluated. In psoriatic arthritis studies, concomitant MTX use did not appear to influence the safety or efficacy of STELARA® (see Drug Interactions). Ultraviolet-induced skin cancers developed earlier and more frequently in mice genetically manipulated to be deficient in both IL-12 and IL-23 or IL-12 alone (see Nonclinical Toxicology). ADVERSE REACTIONS: The following serious adverse reactions are discussed elsewhere in the label: • Infections (see Warnings and Precautions) • Malignancies (see Warnings and Precautions) • Reversible Posterior Leukoencephalopathy Syndrome (see Warnings and Precautions) Clinical Studies Experience Because clinical trials are conducted

STELARA® (ustekinumab)

under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Psoriasis Clinical Studies The safety data reflect exposure to STELARA® in 3117 psoriasis subjects, including 2414 exposed for at least 6 months, 1855 exposed for at least one year,1653 exposed for at least two years, 1569 exposed for at least three years, 1482 exposed for at least four years and 838 exposed for at least five years. Adverse reactions listed below are those that occurred at a rate of at least 1% and at a higher rate in the STELARA® groups than the placebo group during the placebo-controlled period of Ps STUDY 1 and Ps STUDY 2 (see Clinical Studies). The numbers (percentages) of adverse reactions reported for placebo-treated patients (n=665), patients treated with 45 mg STELARA® (n=664), and patients treated with 90 mg STELARA® (n=666), respectively, were: Nasopharyngitis: 51 (8%), 56 (8%), 49 (7%); Upper respiratory tract infection: 30 (5%), 36 (5%), 28 (4%); Headache: 23 (3%), 33 (5%), 32 (5%); Fatigue: 14 (2%), 18 (3%), 17 (3%); Diarrhea: 12 (2%), 13 (2%), 13 (2%); Back pain: 8 (1%), 9 (1%), 14 (2%); Dizziness: 8 (1%), 8 (1%), 14 (2%); Pharyngolaryngeal pain: 7 (1%), 9 (1%), 12 (2%); Pruritus: 9 (1%), 10 (2%), 9 (1%); Injection site erythema: 3 (<1%), 6 (1%), 13 (2%); Myalgia: 4 (1%), 7 (1%), 8 (1%); Depression: 3 (<1%), 8 (1%), 4 (1%). Adverse reactions that occurred at rates less than 1% in the controlled period of Ps STUDIES 1 and 2 through week 12 included: cellulitis, herpes zoster, diverticulitis and certain injection site reactions (pain, swelling, pruritus, induration, hemorrhage, bruising, and irritation). One case of RPLS occurred during clinical trials (see Warnings and Precautions). Infections In the placebo-controlled period of clinical studies of psoriasis subjects (average follow-up of 12.6 weeks for placebo-treated subjects and 13.4 weeks for STELARA®-treated subjects), 27% of STELARA®-treated subjects reported infections (1.39 per subject-year of follow-up) compared with 24% of placebo-treated subjects (1.21 per subject-year of follow-up). Serious infections occurred in 0.3% of STELARA®-treated subjects (0.01 per subjectyear of follow-up) and in 0.4% of placebo-treated subjects (0.02 per subject-year of follow-up) (see Warnings and Precautions). In the controlled and non-controlled portions of psoriasis clinical trials (median follow up of 3.2 years), representing 8998 subject-years of exposure, 72.3% of STELARA®-treated subjects reported infections (0.87 per subject-years of follow-up). Serious infections were reported in 2.8% of subjects (0.01 per subject-years of follow-up). Malignancies In the controlled and noncontrolled portions of psoriasis clinical trials (median follow up of 3.2 years, representing 8998 subject-years of exposure), 1.7% of STELARA®-treated subjects reported malignancies excluding non-melanoma skin cancers (0.60 per hundred subject-years of follow-up). Non-melanoma skin cancer was reported in 1.5% of STELARA®-treated subjects (0.52 per hundred subject-years of follow-up) (see Warnings and Precautions). The most frequently observed malignancies other than non-melanoma skin cancer during the clinical trials were: prostate, melanoma, colorectal and breast. Malignancies other than non-melanoma skin cancer in STELARA®-treated patients during the controlled and uncontrolled portions of studies were similar in type and number to what would be expected in the general U.S. population according to the SEER database (adjusted for age, gender and race).1 Psoriatic Arthritis Clinical Studies The safety of STELARA® was assessed in 927 patients in two randomized, double-blind, placebo-controlled studies in adult patients with active psoriatic arthritis (PsA). The overall safety profile of STELARA® in patients with PsA was consistent with the safety profile seen in psoriasis clinical studies. A higher incidence of arthralgia, nausea, and dental infections was observed in STELARA®-treated patients when compared with placebo-treated patients (3% vs. 1% for arthralgia and 3% vs. 1% for nausea; 1% vs. 0.6% for dental infections) in the placebo-controlled portions of the PsA clinical trials. Immunogenicity Approximately 6% of patients treated with STELARA® in psoriasis and psoriatic arthritis clinical studies developed antibodies to ustekinumab, which were generally low-titer. No apparent association between the development of antibodies to ustekinumab and the development of injection site reactions was seen. No ustekinumab-related serious hypersensitivity reactions were observed in psoriasis and psoriatic arthritis clinical trials. In psoriasis studies, the majority of patients who were positive for antibodies to ustekinumab had neutralizing antibodies. The data above reflect the percentage of subjects whose test results were positive for antibodies to ustekinumab and are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications and underlying disease. For these reasons, comparison of the incidence of antibodies to ustekinumab with the incidence of antibodies to other products may be misleading. Post-marketing Experience Adverse reactions have been reported during postapproval use with STELARA®. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to STELARA® exposure. Immune system disorders: Serious hypersensitivity reactions (including anaphylaxis and angioedema), other hypersensitivity reactions (including rash and urticaria). Skin reactions: Pustular psoriasis, erythrodermic psoriasis. DRUG INTERACTIONS: Drug interaction studies have not been conducted with STELARA®. Live Vaccines Live vaccines should not be given concurrently with STELARA® (see Warnings and Precautions). Concomitant Therapies In psoriasis studies the safety of STELARA® in combination with immunosuppressive agents or phototherapy has not been evaluated. In psoriatic arthritis studies, concomitant MTX use did not appear to influence the safety or efficacy of STELARA® (see Warnings and Precautions). CYP450 Substrates The formation of CYP450 enzymes can be altered by increased levels of certain cytokines (e.g., IL-1, IL-6, IL-10, TNFα, IFN) during chronic inflammation. Thus, STELARA®, an antagonist of IL-12 and IL-23, could normalize the formation of CYP450 enzymes. Upon

STELARA® (ustekinumab)

initiation of STELARA® in patients who are receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index, monitoring for therapeutic effect (e.g., for warfarin) or drug concentration (e.g., for cyclosporine) should be considered and the individual dose of the drug adjusted as needed (see Clinical Pharmacology). Allergen Immunotherapy STELARA® has not been evaluated in patients who have undergone allergy immunotherapy. STELARA® may decrease the protective effect of allergen immunotherapy (decrease tolerance) which may increase the risk of an allergic reaction to a dose of allergen immunotherapy. Therefore, caution should be exercised in patients receiving or who have received allergen immunotherapy, particularly for anaphylaxis. USE IN SPECIFIC POPULATIONS: Pregnancy Pregnancy Category B Pregnancy Registry There is a pregnancy registry that monitors pregnancy outcomes in women exposed to STELARA® during pregnancy. Patients should be encouraged to enroll by calling 1-877-311-8972. There are no adequate and well controlled studies of STELARA® in pregnant women. Developmental toxicity studies conducted with monkeys found no evidence of harm to the fetus due to ustekinumab. STELARA® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Ustekinumab was tested in two embryo-fetal development toxicity studies with cynomolgus monkeys. No teratogenic effects or other adverse developmental effects were observed in fetuses from pregnant monkeys that were administered ustekinumab during the period of organogenesis either twice weekly via subcutaneous injections or weekly by intravenous injections at doses up to 45 times the maximum recommended human dose (MRHD) (on a mg/kg basis at a maternal dose of 45 mg/kg). In a combined embryo-fetal development and pre- and post-natal development toxicity study, pregnant cynomolgus monkeys were administered subcutaneous doses of ustekinumab twice weekly up to 45 times the MRHD (on a mg/kg basis at a maternal dose of 45 mg/kg) from the beginning of organogenesis to Day 33 after delivery. Neonatal deaths occurred in the offspring of one monkey administered ustekinumab at 22.5 mg/kg and one monkey dosed at 45 mg/kg. No ustekinumab-related effects on functional, morphological, or immunological development were observed in the neonates from birth through six months of age. Nursing Mothers Caution should be exercised when STELARA® is administered to a nursing woman. The unknown risks to the infant from gastrointestinal or systemic exposure to ustekinumab should be weighed against the known benefits of breast-feeding. Ustekinumab is excreted in the milk of lactating monkeys administered ustekinumab. IgG is excreted in human milk, so it is expected that STELARA® will be present in human milk. It is not known if ustekinumab is absorbed systemically after ingestion; however, published data suggest that antibodies in breast milk do not enter the neonatal and infant circulation in substantial amounts. Pediatric Use Safety and effectiveness of STELARA® in pediatric patients have not been evaluated. Geriatric Use Of the 4031 subjects exposed to STELARA®, a total of 248 were 65 years or older (183 patients with psoriasis and 65 patients with psoriatic arthritis), and 29 subjects were 75 years or older. Although no differences in safety or efficacy were observed between older and younger subjects, the number of subjects aged 65 and over is not sufficient to determine whether they respond differently from younger subjects. OVERDOSAGE: Single doses up to 6 mg/kg intravenously have been administered in clinical studies without dose-limiting toxicity. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment be instituted immediately. PATIENT COUNSELING INFORMATION: See FDA-approved patient labeling (Medication Guide and Instructions for Use). Instruct patients to read the Medication Guide before starting STELARA® therapy and to reread the Medication Guide each time the prescription is renewed. Infections Inform patients that STELARA® may lower the ability of their immune system to fight infections. Instruct patients of the importance of communicating any history of infections to the doctor, and contacting their doctor if they develop any symptoms of infection. Malignancies Patients should be counseled about the risk of malignancies while receiving STELARA®. Allergic Reactions Advise patients to seek immediate medical attention if they experience any symptoms of serious allergic reactions. Instruction on Injection Technique The first self-injection should be performed under the supervision of a qualified healthcare professional. If a patient or caregiver is to administer STELARA®, he/she should be instructed in injection techniques and their ability to inject subcutaneously should be assessed to ensure the proper administration of STELARA® [see Medication Guide and Instructions for Use]. Patients should be instructed to inject the full amount of STELARA® according to the directions provided in the Medication Guide and Instructions for Use. The needle cover on the prefilled syringe contains dry natural rubber (a derivative of latex), which may cause allergic reactions in individuals sensitive to latex. Needles and syringes should be disposed of in a puncture-resistant container. Patients or caregivers should be instructed in the technique of proper syringe and needle disposal, and be advised not to reuse these items. REFERENCES: 1Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov) SEER*Stat Database: Incidence - SEER 6.6.2 Regs Research Data, Nov 2009 Sub (1973-2007) - Linked To County Attributes - Total U.S., 1969-2007 Counties, National Cancer Institute, DCCPS, Surveillance Research Program, Surveillance Systems Branch, released April 2010, based on the November 2009 submission. Prefilled Syringe Manufactured by: Janssen Biotech, Inc., Horsham, PA 19044, US License No. 1864 at Baxter Pharmaceutical Solutions, Bloomington, IN 47403 and at Cilag AG, Schaffhausen, Switzerland Vial Manufactured by: Janssen Biotech, Inc., Horsham, PA 19044, US License No. 1864 at Cilag AG, Schaffhausen, Switzerland © Janssen Biotech, Inc. 2012 Revised: 03/2014 011841-140312

Resumen en cardiología de INTERVENCIONES PEDIÁTRICAS Y DE ADULTOS Por: Edwin Rodríguez Cruz, MD Director, Sección de Cardiología Hospital de Niños San Jorge, San Juan, P.R. Facultativo Departamento de Medicina y Pediatría Centro Cardiovascular de Puerto Rico y del Caribe

Abstract Interventional Cardiology is a science that has been in continuous progress since the early 20th Century. The investigations, perseverance and creation of catheters and procedures to treat different medical conditions have been the motive of important discoveries, developments and the recipient of international recognitions. Several of these procedures are briefly discussed in this article. The field of interventional cardiology is an ample area where many important steps are reached daily, and it is available to us, here in Puerto Rico. Keywords catheterization, angiographies, pediatrics, interventions, cardiology Resumen La cardiología intervencionista se ha estado desarrollando desde sus inicios en el 1929. Durante años, los avances han sido impresionantes y de mucha utilidad para la humanidad. Hoy día somos capaces de dar tratamientos y ofrecer curaciones a pacientes a través de catéteres que, en el pasado, sólo se podían realizar por cirugías. Diferentes tipos de procedimientos, los cuales se realizan en Puerto Rico también se discuten en este artículo, para el conocimiento de los lectores. Palabras Claves cateterismo, angiografias, pediatría, intervenciones, cardiología

MSP ARTÍCULO DE REVISIÓN

Foto 3

A- Stent en la arteria renal derecha antes de implantarse. B- Stent ya inflado. Las flechas señalan el lugar donde el “stent” está fracturado, varios meses luego de su colocación. Vistas inferiores- Angiografía tomada un año después del procedimiento, se puede ver la arteria abierta y con buen flujo. (Foto suministrada: Edwin Rodríguez, MD)

Foto 1

Globo de Rashkind/Miller inflado en el corazón de un neonato, específicamente en el atrio izquierdo, listo para realizar una septostomía. (Foto suministrada: Edwin Rodríguez, MD)

Foto 2

Izquierda- Inflación del globo con la malla intravascular en posición del septo interatrial. Se puede apreciar el globo en forma de "reloj de arena". esto se logra luego de poner una sutura alrededor del medio de la malla antes de ser liberada. Derecha- Se puede ver la malla en posición, por si sola, al terminar el procedimiento. (Foto suministrada: Edwin Rodríguez, MD)

Introducción Los cateterismos cardiacos se remontan al siglo pasado, cuando en el 1929 el Dr. Werner Forssmann (1904- 1979), alemán, realizó la primera inserción de un catéter desde el brazo hasta el corazón en si mismo. El galeno tenía la idea de que si se le daba medicamentos directamente al corazón, a un paciente críticamente enfermo, se podría mejorar su condición. Además, hipotetizó que, a través de este catéter, se podría inyectar tintes para el diagnóstico más certero de algunas condiciones cardiacas y también medir la presión de los pacientes. De esa manera se ayudaría al tratamiento de los enfermos. Luego de realizar el pro-cedimiento en si mismo, fue despedido del hospital donde trabajaba, pasando a otros hospitales. La Segunda Guerra Mundial estaba en pleno apogeo cuando el médico fue apresado y tuvo un receso de sus labores en la medicina por unos años hasta que la Segunda Guerra Mundial finalizó. Más adelante prosiguió sus labores pero como urólogo y no como cardiólogo. Esta hazaña, aunque con-troversial en ese tiempo, se reconoció como el primer cateterismo realizado en un ser humano. El Dr. Forssmann fue recipiente del premio Nobel de Medicina por este logro en el 1956. De allí en adelante los cateterism os c ardíac os que se re a l i z a b a n e r a n m e r a m e n t e diagnósticos. Sin embargo, otros grandes pensadores e investigadores

de esos años, pudieron ver la gran virtud de estos procedimientos y la cantidad de aplicaciones que se podrían hacer con estos catéteres. Ya para los años 1960’s se estaban realizando algunas terapias a través de los cateterismos. Además, se comenzaron a crear algunos catéteres especiales para niños. Poco a poco algunos de-sarrollos de los adultos, se incorporaron a la pediatría. Desde entonces, el cielo es el límite. Procedimientos Septostomías Los doctores Rashkind y Miller desarrollaron una técnica con un catéter que posee un globo en la punta. Este globo se inserta por las venas del paciente hasta el corazón y alli el globo se infla. (Foto #1) Este procedimiento se ha mantenido esencialmente inalterado desde sus comienzos. El mismo se realiza en niños y adultos con enfermedades congénitas cianosantes y algunas variaciones del mismo se han utilizado en otras enfermedades adquiridas. E s t e p ro c e d i m i e n t o s e h a r e a l i z a d o, e n n e o n a t o s, e n incalculables ocasiones por los cardiólogos pediátricos en Puerto Rico desde mitad de los años 70’s, con muy buenos resultados. A la llegada del siglo 21 y con los nuevos conocimientos, este procedimiento se le ha realizado a varios puertorriqueños con enfermedades adquiridas, como lo es la hipertensión pulmonar. En esta

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Foto 4

Fistulograma. Las flechas superiores indican las obstrucciones causadas por trombosis en la fístula. Las vistas inferiores enseñan la restauración del flujo. (Foto suministrada: Edwin Rodríguez, MD)

Foto 5

A y B: Angiografías desde la vena Subclavia izquierda. Se pueden observar las venas Subclavia e Innominada llenas de trombos (flechas blancas) con obstrucción total de la Vena Cava Superior (flecha negra). C: Angiografía final. (Foto suministrada: Edwin Rodríguez, MD)

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enfermedad, la sangre no corre eficientemente por los pulmones debido al daño que hay en los vasos sanguíneos. Por lo que se crea un orificio entre las cámaras superiores del corazón (atrios) para que la sangre pase por el mismo y ayude a aumentar el gasto cardíaco de estos pacientes, mejorandoles su capacidad funcional. La sangre en este caso pasará de derecha a izquierda. (Foto #2) No obstante, los pacientes se pondrán más cianóticos, su habilidad para hacer sus tareas diarias aumentará. En nuestra experiencia, preferimos, el colocar una malla intravascular en forma de “mariposa” o “reloj de arena”, para mantener la septostomía abierta por más tiempo. Esto sirve sólo como un puente al tan necesitado transplante de pulmones que el paciente requiere para poder sobrevivir. De estos pacientes hemos intervenido unos 5 pacientes, con sólo 1 muerte temprana, la cual ocurrió menos de 24 horas luego del cateterismo. Aquí en Puerto Rico podemos realizar todos estas intervenciones menos el transplante de pulmones. Mallas Intravasculares (“Stents”) Los stents se comenzaron a usar en la cardiología desde los años 1970’s. La colocación de ellos se comenzó de manera escalonada y hoy día son la columna vertebral de las intervenciones coronarianas en la cardiología de adultos. Los mismos se han desarrollado de decenas de formas y maneras, de diferentes materiales y aleaciones. Hoy día, inclusive, tenemos algunos con cubiertas de medicamentos, que hacen

que las obstrucciones en vasos pequños se tarden más en recurrir. En algunos casos se han utilizado algunos de estos “stents” en lugares como las piernas, brazos y arterias renales. En niños también lo hemos utilizado, como una novedad en nuestra institución en una paciente, bajo el aval de los padres y los comités concernientes. La misma era una niña de 8 años, la cual necesitó varias intervenciones que, aunque tuvieron resultados exelentes inicialmente, la duración de los mismos fue terrible. La paciente tenía hipertensión severa. Se le diagnosticó estenosis de la arteria renal derecha. Luego de varias angioplastías y recurrencia de la obstrucción, se le colocó una malla intravascular regular. Sin embargo, esta también se obstruyó por proliferación del tejido intimal del vaso y, peor aún, se fracturó en el medio. Por eso, se decidió implantarle un “stent” medicado. (Foto #3) Luego de hacerlo no ha habido recurrencia de la obstrucción por 8 años. Estas mallas las hemos utilizado para mejorar las obstrucciones en las arterial pulmonares, así como en la arteria aorta, además de otros vasos sanguíneos. Intervenciones Venosas Las intervenciones venosas representan un nuevo reto en el tratamiento de enfermedades y condiciones que afectan esta circulación. En adición, es un área donde grandes progresos se están realizando en la última década. Por ejemplo, los pacientes de fallo renal que poseen un catéter para diálisis, muchas veces desarrollan obstrucciones en las venas

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donde esos catéteres han sido insertados. Esto a largo plazo le causa un problema de acceso difícil debido a que las venas se tapan. También, las fístulas que muchos de ellos poseen se trombosan y obstruyen con los años de uso. (Foto #4) Por estos procedimientos sencillos, pero a la misma vez de alto riesgo, podemos reestablecer la circulación de las venas y fístulas. En la reapertura de estas venas se necesita una gran habilidad y conocimiento de la anatomía normal del ser humano para que se puedan reparar algunos de ellos sin causar daño. (Foto #5) Luego de la apertura se hacen angioplastías y en casos se colocan mallas intravasculares también. Cada caso es diferente y posee sus propios retos, por supuesto. Embolizaciones arteriales y venosas Varias razones existen para la necesidad de que se hagan embolizaciones: entre las más comúnes son los sangrados, o, la presencia de malformaciones o fístulas arteriovenosas. Algunas de éstas fístulas pueden ser pequeñas, pero otras tan grandes que causen problemas, simplemente por su tamaño. Casos como el presentado (Foto #6) representan uno de varios que se han hecho con excelentes resultados. Se presenta una malfor mación arteriovenosa grande en el pulmón derecho de una paciente con el síndrome de Osler Weber Rendu. La misma causaba que la sangre venosa pasara directamente hacia las venas pulmonares, lo que evitaba que se oxigenara. Luego de conversar con la paciente se determinó el intentar cerrar la malformación con un dispositivo de Amplatzer (St. Jude Co, Minnesota, USA). El procedimiento se llevó a cabo sin complicaciones y la paciente se encuentra en perfectas condiciones casi 5 años luego de la intervención. Casos como este se han llevado a cabo con buenos resultados y sin complicaciones.

El cierre de los defectos septales es de Cierre de defectos septales Fue a finales del año 2002 que se gran ayuda por la mínima complejidad cerró por primera vez en Puerto Rico del procedimiento y las baja morbilidad un defecto del septo interatrial en una del mismo. niña de 5 años. Ahora, aproximadamente Cierre de defectos perivalvulares 15 años después de ese primer caso, se han hecho cerca de 250 pacientes con post-operatorios Cuando estos defectos aparecen son estas anomalías, algunas congénitas y otras adquiridas. Las complicaciones, un dolor de cabeza para los galenos. Los en estos casos han sido leves con menos mismos pueden ser asimptomáicos, pero de 10 pacientes en este grupo. Las tambien pueden tener grandes problemas. complicaciones que se cuentan han El mayor problema de estos presentan es sido, la embolización del dispositivo la hemólisis. Algunos pacientes pueden luego de colocado (3 pacientes), la tener más de un defecto. Estos requieren la inhabilidad de cerrar el defecto (4 atención del facultativo y el que se decida pacientes), pseudoaneurisma con si se arreglarán por la vía quirúrgica o necesidad de reparación quirúrgica (1 percutánea. Ambas maneras conllevan paciente), necesidad de reintervención mortalidad y morbilidades altas. Además, por defecto residual importante (1 ambos procedimientos toman muchas paciente). No ha habido ninguna muerte horas en la sala de procedimientos. Se directa ,o indirectamente asociada a este han llevado a cabo 5 pacientes con estos defectos en Puerto Rico. Cuatro procedimiento. En casos de defectos del septo pacientes han tenido defectos mitrales ventricular la mayoría han sido en y 2 aórticos. De los defectos aórticos, 1 casos de emergencia o urgencia. (Foto no se pudo terminar el procedimiento #7) Se le ha cerrado a unos 6 pacientes, debido a un sangrado el cual requirió que 1 de ellos electivo. Los otros 5 han sido el paciente fuera a sala de operaciones. adquiridos por infartos al miocardio con De los casos mitrales, todos se pudieron cerrar sin complicaciones. tres de ellos rotura del septo interventricular. Una complicación, que aunque rara, con alta mortalidad. De los 5 pacientes, a 4 se les ha cerrado efectivamente. A 2 de los pacientes a quienes se les cerró, murieron, pero no debido al procedimiento, si no 1 como resultado del Foto 6 infarto, y el otro Foto Izquierda: Malformación arteriovenosa, grande, en pulmón desarrolló fallo derecho, en un paciente con Síndrome de Osler Weber Rendu. renal por choque El catéter se encuentra en la arteria pulmonar derecha. La cardiogénico, malformación comunica, directamente, la arteria pulmonar derecha con las venas pulmonares derechas (asteriscos muriendo días blancos). Foto Derecha: Luego de implantado un dispositivo de más tarde; de 1 embolización, se hace otra arteriografia y se puede notar que la paciente no se malformación ha sido sellada por completo. (Foto suministrada: tiene seguimiento.

Edwin Rodríguez, MD)

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3. König K, Gellermann J, Querfeld U, Schneider MBE. Treatment of severe artery stenosis by percutaneous transluminal renal angioplasty and stent implantation. Review of the pediatric experience: apropos of two cases. Pediatr Nephrol. 2006; 21: 663- 671 4. Arce-Santiago M, Rodríguez-Cruz E. Treatment of a recurrent renal artery stenosis and stent fracture using a drug eluting stent in a pediatric patient. CEN Case Reports. DOI: 10.1007/s13730-015-0182-1. March 2015 5. Rodríguez-Cruz E, Matos N, Montañez-Leduc A. Catheter-Directed Thrombolysis and Percutaneous Thrombectomy for Acute Arterial Ischemia in Children. Vascular Disease Management. March/April 2008;5(2):41Foto 7 46. Angiogramas en el ventriculo izquierdo. En la izquierda podemos 6. Salgado V, Martinez-Toro J, Rodríguez E. Primary ver el defecto del septo interventricular. (asterisco) causado Stenting in a Young Adult with Aortic Coarctation. P R luego de un infarto al miocardio. Derecha; luego de unos minutos Health Sci J. 2006 Sep;25(3):279-82. PMID: 17203800 ahora el dispositivo Amplatzer se ha colocado en el defecto 7. Rodríguez-Cruz E, Pérez JO, Bonilla M. Percutaneous interventriculas. Aún el paciente tiene flujo residual, sin embargo, translumbar inferior vena cava catheter placement for el mismo desapareció unas horas más tarde. (Foto suministrada: long-term hemodialysis treatment. Epub 2006 Nov 23: Edwin Rodríguez, MD) Pediatr Nephrol DOI 10.1007/s00467-006-0373-2. Pediatr Nephrol. 2007 Apr;22(4):612-5. Epub 2006 Nov 23. PMID: 17123114 a través de la vía transeptal y retrograda (combinada), y 1 de manera híbrida, con un acceso transapical luego de 8. Rodríguez-Cruz E, Rosario-Pagán G, Muñoz-Rosario una toracotomía lateral mínima. En este caso el cirujano y A, Duque S. Long term patency of the ductus arteriosus cardiólogo invasivo realizaron el procedimiento en conjunto. after stent placement: report of two cases and review of Todos los pacientes con defectos mitrales se les mejoró su the literature. Bol Asoc Med P R. 2007 Jn-Mar;99(1):40-3. PMID: 17616045 hemólisis y fueron dados de alta. 9. Rihal CS, et al. Principles of Percutaneous Paravalvular Leak Closure. J Am Coll Cardiol Intv 2012;5:121–30 Conclusión Hoy día en Puerto Rico po-demos ofrecerle a pacientes Agradecimiento de enfermedades cardiovasculares, muchos procedimientos Agradecemos a todos los técnicos, enfermeras, médicos, que en el pasado sólo se podían dar fuera de la isla. Hay centros lo suficientemente capacitados para atenderlos, y técnologos y demás personal del Centro Cardiovascular de médicos con el entrenamiento necesario para lidiar con Puerto Rico y del Caribe por su apoyo, profesionalismo los mismos. Sin embargo, necesitamos más apoyo de las y dedicación para que todos estos pacientes recibieran y agencias gubernamentales para que más galenos con continúen recibiendo un trato de alta calidad como se lo especialidades especiales regresen a nuestra isla para dar merecen. tratamiento a los pacientes que tanto lo necesitan. Referencias 1. Emmanoulides GC, et al eds. Moss and Adams: Heart Disease in Infants, Children, and Adolescents, Including the Fetus and Young Adult. Vol 1. 5th ed. Williams & Wilkins. Philadelphia, PA 2. Nichols DG, et al. Critical Heart Disease in Infants and Children. 2nd ed. Mosby Elsevier. Philadelphia, PA

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MSP ACTUALIZACIÓN MÉDICA

Poniendo al día nuestro conocimiento

en la reparación de

ANEURISMA DE LA AORTA ABDOMINAL en Puerto Rico

Por: Luis A. López Galarza MD,FACS Presidente de Sociedad de Cirujanos Vasculares y Endovasculares de PR (SCVEPR)

Abstract Aneurism Endovascular Preparation has become the preferred technique of elective procedure for the infra renal abdominal aortic aneurisms. Since this technique was introduced in 1991, when Volodos et al and Parodi et al. independently demonstrated the possibility for the implant of the endoprothesis through the femoral arteries for the exclusion of the aneurism sac of the circulation 1-2.

Resumen Preparación Endovascular de Aneurisma ha pasado a ser la técnica preferida para el tratamiento electivo de los aneurismas de la aorta abdominal (AAA) infra renal. Desde que esta técnica se introdujo en 1991, cuando Volodos et al y Parodi et al independientemente demostraron la posibilidad del implante de la endoprotesis a través de las arterias femorales para la exclusión del saco aneurismático de la circulación1-2.

Keywords abdominal aortic aneurism, abdominal endoprothesis, Puerto Rican Society of Vascular and Endovascular Surgeons

Palabras Claves aneurisma de la aorta abdominal, endoprotesis abdominal, Sociedad de Cirujanos Casculares y Endovasculares de Puerto Rico

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MSP ACTUALIZACIÓN MÉDICA

reparación Endovascular de Aneurisma ha pasado a ser la técnica preferida para el tratamiento electivo de los aneurismas de la aorta abdominal (AAA) infra renal. Desde que esta técnica se introdujo en 1991, cuando Volodos et al y Parodi et al independientemente demostraron la posibilidad del implante de la endoprotesis a través de las arterias femorales para la exclusión del saco aneurismático de la circulación. 1-2 Endoprotesis Abdominal La endoprótesis abdominal es un tubo de tejido sintético sostenido por una estructura de metal. Se coloca en la aorta con un catéter. El diseño de la endoprótesis permite excluir el aneurisma. La endoprótesis reduce la presión en el aneurisma y ofrece una nueva vía para el flujo sanguíneo. Esto reduce el riesgo de ruptura. Una década después de estos acontecimientos se empezó a usar estas técnicas en Puerto Rico, para el tratamiento Endovascular de Aneurisma de la Aorta Abdominal y en los últimos 10 años el avance a sido tal que cientos de Aneurisma Abdominales han sido tratados en diferentes Hospitales a través de la Isla por integrantes de la Sociedad de Cirujanos Vasculares y Endovasculares de Puerto Rico, con un rotundo éxito. De cierto es que a pesar que la técnica se ha ido depurando aun nivel cada vez más sencillo. El procedimiento debe de ser hecho en sala de operaciones híbridas las cuales permitirían no tan solo prestar la posibilidad del tratamiento endovascular bajo fluroscopia, si no que cualquier complicación o necesidad de cirugía abierta pueda ser hecha al mismo tiempo.

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Procedimiento de la Endoprótesis Abdominal Se trata de un procedimiento mínimamente invasivo. Este pro-cedimiento se realiza bajo anestesia local, regional o general. Se realiza de manera percutánea ó a través de una pequeña incisión en ambos lados de la ingle como inicio de la preparación para el procedimiento de colocación de la endoprótesis a través de la arteria femoral. La fluroscopia se usa para guiar el catéter al AAA. El catéter es un dispositivo tubular largo y delgado que se utiliza para colocar y liberar la endoprótesis en la aorta para excluir el saco aneurismático y permitir el flujo de sangre a través de la endoprótesis hacia las extremidades inferiores.

Con el pasar del tiempo ya contamos en Puerto Rico con 10 Hospitales en los cuales dichos procedimientos pueden ser efectuados La SCVEPR es parte de la World Federation of Vascular Society que abarca sociedades vasculares en todos los continentes. Referencias

1. Parodi JC, Palmaz JC , Ba rone H D. Transfemoral graft i mpla nt at ion for a b d o m i n a l a or t ic aneurysm. Ann Vasc Riñón Surg.1991;5:491-499. 2 . Vo l o d o s N L , Karpovich IP, Troyan V I, et al. Clinical Ancho experience of the use normal de la of self-fixing synthetic aorta Prostheses for remote endoprost het ics of the thoracic an the abdominal aorta and iliac arteries through the femoral arter y and as intraoperative endoprosthesis for aorta reconstruction. Vasa Suppl.1991;33:93-95.

Aneurisma aórtico abdominal Arterias ilíacas

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Entrevista a la Dra. Elivette Zambrana Flores

MEJORA EL TRATAMIENTO

para los pacientes de

Artritis Rematoide

Asociación de Reumatólogos de Puerto Rico refuerza mensaje para concienciar sobre condiciones reumáticas en la niñez Por: Belinda Z. Burgos Gonzalez bburgos@editorialmundo.com

PERFIL CIENTÍFICO La Dra. Zambrana Flores completó su formación en la subespecialidad de reumatología pediátrica en el Baylor College of Medicine en Houston, Texas, en 2002 Ha sido profesora asistente en el Departamento de Reumatología Pediátrica de la Universidad de Emory en Atlanta, Georgia Posee un Doctorado en Medicina Recinto de Ciencias Médicas y realizó residencia en Hospital Pediátrico Universitario de Puerto Rico en el área de Pediatría Realizó una Subespecialidad en Reumatología Pediátrica en Baylor College of Medicine en Houston, Texas Practicó Reumatología Pediátrica por varios años en Emory University en Atlanta, Georgia como Catedrática Auxiliar Estando en Atlanta, el hospital HIMA la recluta para formar parte del Centro de Subespecialistas Pediátricos en su Red Médica

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“Nos enfrentamos a una falta de mentalización, porque el diagnóstico precoz no se ha establecido como prioridad” - Dra. Elivette Zambrana, pasada presidenta de la Asociación de Reumatólogos de Puerto Rico.

ada año se diagnostican en Puerto Rico más casos de artritis reumatoide al punto de que se estima que aproximadamente 40,000 puertorriqueños tienen la enfermedad. La doctora Elivette Zambrana, pasada presidenta de la Asociación de Reumatólogos de Puerto Rico, nos habló sobre los principales tratamientos que han revolucionado el manejo de la enfermedad, y destaca la importancia de garantizar el acceso del paciente al reumatólogo que produzca un diagnóstico precoz, sobre todo en la población pediátrica, cuyos síntomas podrían pasar desapercibidas si no se logra una conciencia social sobre la importancia de intervenir a tiempo para tratar las condiciones reumáticas. Cabe destacar que la Reumatología Pediátrica es un área limitada donde solo existen alrededor de 300 profesionales certificados en Estados Unidos para tratar las diversas condiciones como la artritis juvenil, dolores de crecimiento en niños, espondiloartritis, lupus eritematoso sistémico, dermatomiositis, síndrome de Sjögren, vasculitis, esclerodermia, sarcoidosis, púrpura de Henoch-Schönlein, artritis reactiva y la enfermedad de Kawasaki.

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hacer ejercicios, la dieta balanceada MSP: ¿Se tratan iguales las y utilizar los medicamentos según condiciones reumáticas entre recomendado por el reumatólogo. adultos y niños? Existe un porcentaje bajo de pacientes Las condiciones reumatológicas no son que no responde a medicamentos lo mismo en adultos y niños y no se pero la artritis reumatoide puede ser pueden tratar igual. Son condiciones controlada eficazmente. Hay pacientes que se comportan de manera distinta, de artritis reumatoide que cuando pero se tratan igual aunque de manera uno los ve, no se da ni cuenta que lo diferente para adultos y para niños. tienen y hasta corren en maratones. La literatura y experiencia nos ha Cada paciente es único. Su tratamiento dicho que los niños no son pequeños puede incluir desde medicamentos, adultos, que las condiciones de terapias, exámenes de laboratorio, reumatología no se asemejan entre etc. No hay una contestación simple adultos y niños. Estamos hablando de para determinar un tratamiento. Es genética y de otros componentes y por según el paciente. eso se comportan de manera distinta. En Puerto Rico ya tenemos más reumatólogos pediátricos accesibles MSP: ¿Cómo se relaciona la artritis reumatoide con la para esta población de niños. migraña? No hay una relación directa de los MSP: ¿Un diagnóstico de artritis dolores de cabeza con artritis pero sí hay reumatoide es sinónimo de una relación directa de la migraña con incapacidad? Tú puedes tener una vida normal. pacientes de lupus. La migraña más bien Con los tratamientos de hoy día se está asociada a problemas hormonales puede llegar a la vejez sin ningún y por eso es más frecuente en mujeres tipo de problema. Cuando tú estás y por eso está asociada a condiciones bien tratado y la condición bien reumatológicas controlada se espera que se tenga una longevidad comparable a la MSP: ¿Y con la artritis población general. Aunque es una psoriásica? Es una clasificación aparte por tratarse condición multifactorial, que afecta a otros sistemas, no quiere decir que si de una condición asociada a la presencia tienes una artritis reumatoide durarás de soriasis en el paciente o familiar de este. Afecta más bien el eje del cuerpo, la tantos años. Las mujeres son las más que se ven espina dorsal y evidencia de un familiar afectadas en un 75 por ciento debido de primer grado que tenga soriasis. al cambio hormonal. También las Mucho de los medicamentos que usamos enfermedades cardiovasculares se para la artritis reumatoide se usan para convierten en un riesgo mayor cuando la artritis soriásica. Los medicamentos los pacientes no tienen un balance biológicos y antiinflamatorios han sido entre ejercicios, tratamientos y la aprobados para este tipo de artritis. nutrición y que hoy día ya los pacientes no tienes que estar incapacitados de MSP: ¿Existen investigaciones para buscar mejores avances en las realizar actividades. condiciones reumatológicas? Son realizadas en el Recinto de MSP: Cuénteme de los últimos Ciencias Médicas que es la entidad avances en tratamientos para la que contribuye junto con las esta condición. investigaciones realizadas en los Desde que están los medicamentos Estados Unidos a que los reumatólogos biológicos ya es bien raro tu ver a de la isla tengan conocimiento un paciente que tenga discapacidad sobre los medicamentos nuevos y su (para hacer actividades cotidianas). modalidad de tratamiento. Es importante mantenerse activo y

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12%

ACR20 response rates1,2 Week 2 Week 14 (primary endpoint) Week 24

25%

59% (P<0.001)

63%

32%

(P<0.001)

1.09

* vdH-S=van der Heijde Modified Sharp score. The total modified vdH-S score (0-448) is a composite score of structural damage that measures the number and size of joint erosions and the degree of joint space narrowing in the hands and feet. †

Missing data (linear extrapolation) rules were applied. For patients who early escaped, linear extrapolation was performed on the Week 16 data to the Week 24 endpoint.

‡

Percentage is the difference in mean total vdH-S scores divided by the placebo + MTX value.

GO-FURTHER™ was a global, multicenter, randomized, double-blind, placebo-controlled study in 592 adults who had moderately to severely active RA despite a stable dose of MTX (15-25 mg/week) for ≥3 months and who had not been previously treated with an anti-TNF agent. Moderately to severely active RA was defined as ≥6 swollen joints (out of 66 total) and ≥6 tender joints (out of 68 total), RF-positive and/or anti-CCP antibody–positive, and CRP ≥1.0 mg/dL. Patients were randomized to receive SIMPONI ARIA® 2 mg/kg + MTX (n=395) or placebo + MTX (n=197) as a 30-minute IV infusion at Weeks 0 and 4, and then q8 weeks through Week 100. At Week 16, patients in the placebo + MTX group with <10% improvement from baseline in both swollen joint count and tender joint count began receiving SIMPONI ARIA® 2 mg/kg beginning with an induction regimen at Weeks 16 and 20, followed by maintenance infusions q8 weeks in a blinded manner. At Week 24, all patients remaining in the placebo + MTX group began receiving SIMPONI ARIA® 2 mg/kg beginning with an induction regimen at Weeks 24 and 28, followed by maintenance infusions q8 weeks in a blinded manner. All patients continued to receive MTX. The primary endpoint was the percentage of patients achieving an ACR20 response at Week 14.

Learn more: www.SimponiAria.com/hcp

Re-envision infusion

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97% inhibition vs control group‡

0.03

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Total vdH-S score (mean change from baseline at Week 24)1,3*†

(P<0.001)

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Important Safety Information SERIOUS INFECTIONS Patients treated with SIMPONI ARIA® (golimumab) are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. Discontinue SIMPONI ARIA® if a patient develops a serious infection. Reported infections with TNF blockers, of which SIMPONI ARIA® is a member, include: • Active tuberculosis (TB), including reactivation of latent TB. Patients frequently presented with disseminated or extrapulmonary disease. Test patients for latent TB before SIMPONI ARIA® use and during therapy. Initiate treatment for latent infection prior to SIMPONI ARIA® use. • Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, and pneumocystosis. Patients with histoplasmosis or other invasive fungal infections may present with disseminated, rather than localized, disease. Consider empiric anti-fungal therapy in patients at risk for invasive fungal infections who develop severe systemic illness. • Bacterial, viral, and other infections due to opportunistic pathogens, including Legionella and Listeria.

MALIGNANCIES Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, of which SIMPONI ARIA® is a member. Approximately half the cases were lymphomas, including Hodgkin’s and non-Hodgkin’s lymphoma. The other cases represented a variety of malignancies, including rare malignancies usually associated with immunosuppression and malignancies not usually observed in children or adolescents. Malignancies occurred after a median of 30 months after the first dose of therapy. Most of the patients were receiving concomitant immunosuppressants. In the controlled portions of clinical trials of TNF blockers including the subcutaneous formulation of golimumab, more cases of lymphoma have been observed among patients receiving antiTNF treatment compared with patients in the control groups. In clinical trials, the incidence of malignancies other than lymphoma and non-melanoma skin cancer per 100 patient-years of follow-up was 0.56 (95% CI: 0.01, 3.11) in the SIMPONI ARIA® group compared with an incidence of 0 (95% CI: 0.00, 3.79) in the placebo group. Cases of acute and chronic leukemia have been reported with postmarketing TNF-blocker use. The risks and benefits of TNF-blocker therapy should be considered prior to initiating therapy in patients with a known malignancy or who develop a malignancy.

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Risk of infection may be higher in patients greater than 65 years of age, patients with co-morbid conditions and/or patients taking concomitant immunosuppressant therapy. Other serious infections observed in patients treated with SIMPONI ARIA® included sepsis, pneumonia, cellulitis, and abscess.

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Consider the risks and benefits of treatment with SIMPONI ARIA® prior to initiating therapy in patients with chronic or recurrent infection. Do not start SIMPONI ARIA® in patients with clinically important active infections, including localized infections. Closely monitor patients for the development of signs and symptoms of infection during and after treatment with SIMPONI ARIA®, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy, who are on treatment for latent TB, or who were previously treated for TB infection.

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Important Safety Information (continued) MALINGNANCIES (continued) Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers. These cases have had a very aggressive disease course and have been fatal. Nearly all reported cases have occurred in patients with Crohn’s disease or ulcerative colitis, and the majority were in adolescent and young adult males. Almost all of these patients had received treatment with azathioprine or 6-mercaptopurine concomitantly with a TNF blocker at or prior to diagnosis. A risk for the development for HSTCL in patients treated with TNF blockers cannot be excluded. Melanoma has been reported in patients treated with TNF-blocking agents, including the subcutaneous formulation of golimumab. Merkel cell carcinoma has been reported in patients treated with TNF-blocking agents. Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer. HEPATITIS B REACTIVATION The use of TNF blockers, of which SIMPONI ARIA® (glolimumab) is a member, has been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic hepatitis B carriers. In some instances, HBV reactivation occurring in conjunction with TNF-blocker therapy has been fatal. The majority of these reports have occurred in patients who received concomitant immunosuppressants.

DEMYELINATING DISORDERS Use of TNF blockers, of which SIMPONI ARIA® is a member, has been associated with rare cases of new-onset or exacerbation of demyelinating disorders, including multiple sclerosis (MS) and Guillain-Barré syndrome. Cases of central demyelination, MS, optic neuritis, and peripheral demyelinating polyneuropathy have rarely been reported in patients treated with the subcutaneous formulation of golimumab. Exercise caution in considering the use of SIMPONI ARIA® in patients with these disorders. Consider discontinuation if these disorders develop. USE WITH OTHER DRUGS The concomitant use of a TNF blocker and abatacept or anakinra was associated with a higher risk of serious infections, therefore the use of SIMPONI ARIA® in combination with these products is not recommended. Care should be taken when switching from one biologic to another since overlapping biological activity may further increase the risk of infection. A higher rate of serious infections has also been observed in RA patients treated with rituximab who received subsequent treatment with a TNF blocker. The concomitant use of SIMPONI ARIA® with biologics approved to treat RA is not recommended because of the possibility of an increased risk of infection.

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HEART FAILURE Cases of worsening congestive heart failure (CHF) and new-onset CHF have been reported. Exercise caution in CHF patients receiving SIMPONI ARIA® and monitor them closely during therapy. Discontinue SIMPONI ARIA® if new or worsening symptoms of heart failure appear.

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All patients should be tested for HBV infection before initiating TNF-blocker therapy. For patients who test positive for hepatitis B surface antigen, consult a physician with expertise in the treatment of hepatitis B before initiating TNF-blocker therapy. Exercise caution when prescribing SIMPONI ARIA® for patients identified as carriers of HBV and closely monitor for active HBV infection during and following termination of therapy with SIMPONI ARIA®. Discontinue SIMPONI ARIA® in patients who develop HBV reactivation, and initiate antiviral therapy with appropriate supportive treatment. Exercise caution when considering resumption of SIMPONI ARIA®, and monitor patients closely.

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Important Safety Information (continued) HEMATOLOGIC CYTOPENIAS There have been reports of pancytopenia, leukopenia, neutropenia, and thrombocytopenia in patients receiving SIMPONI ARIA® (golimumab) in clinical trials. Additionally, aplastic anemia has been reported in patients receiving TNF blockers. Exercise caution when using SIMPONI ARIA® in patients who have or had significant cytopenias.

HYPERSENSITIVITY REACTIONS Serious systemic hypersensitivity reactions (including anaphylactic reaction) have been reported following administration of the subcutaneous formulation of golimumab, some occurring after the first dose. If an anaphylactic or other serious allergic reaction occurs, discontinue SIMPONI ARIA® immediately and institute appropriate therapy. ADVERSE REACTIONS The most serious adverse reactions were serious infections and malignancies.

References: 1. SIMPONI ARIA® (golimumab) [Prescribing Information]. Horsham, PA. Janssen Biotech, Inc. 2. Weinblatt ME, Bingham CO III, Mendelsohn AM, et al. Intravenous golimumab is effective in patients with active rheumatoid arthritis despite methotrexate therapy with responses as early as Week 2: results of the phase 3, randomised, multicentre, double-blind, placebo-controlled GO-FURTHER trial. Ann Rheum Dis. 2013;72:381-389. 3. Data on file. Janssen Biotech, Inc.

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Please see brief summary of Prescribing Information for SIMPONI ARIA® on following pages.

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Upper respiratory tract infection was the most common adverse reaction reported in the Phase 3 trial through Week 24, occurring in 6.5% of patients treated with SIMPONI ARIA® as compared with 7.6% of patients in the control group. The rate of infusions associated with an infusion reaction was reported in 1.1% of SIMPONI ARIA® infusions compared with 0.2% of infusions in the control group.

025923-150107

VACCINATIONS/THERAPEUTIC INFECTIOUS AGENTS People receiving SIMPONI ARIA® can receive vaccinations, except for live vaccines. Use of live vaccines could result in clinical infections, including disseminated infections. Administration of live vaccines to infants exposed to SIMPONI ARIA® in utero is not recommended for 6 months following the mother’s last SIMPONI ARIA® infusion during pregnancy due to an increased risk of infection. It is recommended that therapeutic infectious agents not be given concurrently with SIMPONI ARIA® due to the possibility of clinical infections, including disseminated infections.

Brief Summary of Prescribing Information for SIMPONI ARIA® (golimumab) SIMPONI ARIA® injection, for intravenous use See package insert for full Prescribing Information. WARNING: SERIOUS INFECTIONS AND MALIGNANCY SERIOUS INFECTIONS Patients treated with SIMPONI ARIA are at increased risk for developing serious infections that may lead to hospitalization or death (see Warnings and Precautions). Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. Discontinue SIMPONI ARIA if a patient develops a serious infection. Reported infections with TNF-blockers, of which SIMPONI ARIA is a member, include: • Active tuberculosis, including reactivation of latent tuberculosis. Patients with tuberculosis have frequently presented with disseminated or extrapulmonary disease. Test patients for latent tuberculosis before SIMPONI ARIA use and during therapy. Initiate treatment for latent tuberculosis prior to SIMPONI ARIA use. • Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis and pneumocystosis. Patients with histoplasmosis or other invasive fungal infections may present with disseminated, rather than localized, disease. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Consider empiric anti-fungal therapy in patients at risk for invasive fungal infections who develop severe systemic illness. • Bacterial, viral, and other infections due to opportunistic pathogens, including Legionella and Listeria. Consider the risks and benefits of treatment with SIMPONI ARIA prior to initiating therapy in patients with chronic or recurrent infection. Monitor patients closely for the development of signs and symptoms of infection during and after treatment with SIMPONI ARIA, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy (see Warnings and Precautions). MALIGNANCY Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, of which SIMPONI ARIA is a member (see Warnings and Precautions). INDICATIONS AND USAGE: Rheumatoid Arthritis SIMPONI ARIA, in combination with methotrexate, is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis. CONTRAINDICATIONS: None. WARNINGS AND PRECAUTIONS: Serious Infections Patients treated with SIMPONI ARIA are at increased risk for developing serious infections involving various organ systems and sites that may lead to hospitalization or death. Opportunistic infections due to bacterial, mycobacterial, invasive fungal, viral, or parasitic organisms including aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, legionellosis, listeriosis, pneumocystosis, and tuberculosis have been reported with TNF-blockers. Patients have frequently presented with disseminated rather than localized disease. The concomitant use of a TNF-blocker and abatacept or anakinra was associated with a higher risk of serious infections; therefore, the concomitant use of SIMPONI ARIA and these biologic products is not recommended (see Warnings and Precautions and Drug Interactions). Treatment with SIMPONI ARIA should not be initiated in patients with an active infection, including clinically important localized infections. Patients greater than 65 years of age, patients with co-morbid conditions and/or patients taking concomitant immunosuppressants such as corticosteroids or methotrexate may be at greater risk of infection. Consider the risks and benefits of treatment prior to initiating SIMPONI ARIA in patients: • with chronic or recurrent infection; • who have been exposed to tuberculosis; • with a history of an opportunistic infection; • who have resided or traveled in areas of endemic tuberculosis or endemic mycoses, such as histoplasmosis, coccidioidomycosis, or blastomycosis; or • with underlying conditions that may predispose them to infection. Monitoring Closely monitor patients for the development of signs and symptoms of infection during and after treatment with SIMPONI ARIA. Discontinue SIMPONI ARIA if a patient develops a serious infection, an opportunistic infection, or sepsis. For patients who develop a new infection during treatment with SIMPONI ARIA, perform a prompt and complete diagnostic workup appropriate for an immunocompromised patient and initiate appropriate antimicrobial therapy and closely monitor them. Tuberculosis Cases of reactivation of tuberculosis or new tuberculosis infections have been observed in patients receiving TNF-blockers, including patients who have previously received treatment for latent or active tuberculosis. Evaluate patients for tuberculosis risk factors and test for latent infection prior to initiating SIMPONI ARIA and periodically during therapy. Treatment of latent tuberculosis infection prior to therapy with TNF-blockers has been shown to reduce the risk of tuberculosis reactivation during therapy. Prior to initiating SIMPONI ARIA, assess if treatment for latent tuberculosis is needed; An induration of 5 mm or greater is a positive tuberculin skin test, even for patients previously vaccinated with Bacille Calmette-Guerin (BCG). Consider antituberculosis therapy prior to initiation of SIMPONI ARIA in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but having risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision whether initiating anti-tuberculosis therapy is appropriate for an individual patient. Cases of active tuberculosis have occurred in patients treated with the subcutaneous formulation of golimumab during and after treatment for latent tuberculosis. Monitor patients for the development of signs and symptoms of tuberculosis including patients who tested negative for latent tuberculosis infection prior to initiating therapy, patients who are on treatment for latent tuberculosis, or patients who were previously treated for tuberculosis infection. Consider tuberculosis in the differential diagnosis in patients who develop a new infection during SIMPONI ARIA treatment, especially in patients who have previously or recently traveled to countries with a high prevalence of tuberculosis, or who have had close contact with a person with active tuberculosis. Invasive Fungal Infections If patients develop a serious systemic illness and they reside or travel in regions where mycoses are endemic, consider invasive fungal infection in the differential diagnosis. Consider appropriate empiric antifungal therapy and take into account both the risk for severe fungal infection and the risks of antifungal therapy while a diagnostic workup is being performed. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. To aid in the management of such patients, consider consultation with a physician with expertise in the diagnosis and treatment of invasive fungal infections. Hepatitis B Virus Reactivation The use of TNF-blockers, of which SIMPONI ARIA is a member, has been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic hepatitis B carriers (i.e., surface antigen positive). In some instances, HBV reactivation occurring in conjunction with TNF-blocker therapy has been fatal. The majority of these reports have

SIMPONI ARIA® (golimumab) occurred in patients who received concomitant immunosuppressants. All patients should be tested for HBV infection before initiating TNF-blocker therapy. For patients who test positive for hepatitis B surface antigen, consultation with a physician with expertise in the treatment of hepatitis B is recommended before initiating TNF-blocker therapy. The risks and benefits of treatment should be considered prior to prescribing TNF-blockers, including SIMPONI ARIA, to patients who are carriers of HBV. Adequate data are not available on whether anti-viral therapy can reduce the risk of HBV reactivation in HBV carriers who are treated with TNF-blockers. Patients who are carriers of HBV and require treatment with TNF-blockers should be closely monitored for clinical and laboratory signs of active HBV infection throughout therapy and for several months following termination of therapy. In patients who develop HBV reactivation, TNF-blockers should be stopped and antiviral therapy with appropriate supportive treatment should be initiated. The safety of resuming TNF-blockers after HBV reactivation has been controlled is not known. Therefore, prescribers should exercise caution when considering resumption of TNF-blockers in this situation and monitor patients closely. Malignancies Malignancies in Pediatric Patients Malignancies, some fatal, have been reported among children, adolescents, and young adults who received treatment with TNF-blocking agents (initiation of therapy ≤ 18 years of age), of which SIMPONI ARIA is a member. Approximately half the cases were lymphomas, including Hodgkin’s and non-Hodgkin’s lymphoma. The other cases represented a variety of malignancies, including rare malignancies that are usually associated with immunosuppression, and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months (range 1 to 84 months) after the first dose of TNF-blocker therapy. Most of the patients were receiving concomitant immunosuppressants. These cases were reported post-marketing and are derived from a variety of sources, including registries and spontaneous post-marketing reports. Use of SIMPONI ARIA in patients under 18 years of age has not been established. Malignancies in Adult Patients The risks and benefits of TNF-blocker treatment including SIMPONI ARIA should be considered prior to initiating therapy in patients with a known malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing a TNF-blocker in patients who develop a malignancy. In the controlled portions of clinical trials of TNF-blockers including the subcutaneous formulation of golimumab more cases of lymphoma have been observed among patients receiving anti-TNF treatment compared with patients in the control groups. Patients with RA and other chronic inflammatory diseases, particularly patients with highly active disease and/or chronic exposure to immunosuppressant therapies, may be at higher risk (up to several fold) than the general population for the development of lymphoma, even in the absence of TNF-blocking therapy. Cases of acute and chronic leukemia have been reported with post-marketing TNF-blocker use in rheumatoid arthritis and other indications. Even in the absence of TNF-blocker therapy, patients with rheumatoid arthritis may be at a higher risk (approximately 2-fold) than the general population for the development of leukemia. Rare post-marketing cases of hepatosplenic T-cell lymphoma (HSTCL) have been reported in patients treated with TNF-blocking agents. This rare type of T-cell lymphoma has a very aggressive disease course and is usually fatal. Nearly all of the reported TNF-blocker associated cases have occurred in patients with Crohn’s disease or ulcerative colitis. The majority were in adolescent and young adult males. Almost all these patients had received treatment with azathioprine (AZA) or 6-mercaptopurine (6–MP) concomitantly with a TNFblocker at or prior to diagnosis. A risk for the development for hepatosplenic T-cell lymphoma in patients treated with TNF-blockers cannot be excluded. Melanoma has been reported in patients treated with TNF-blocking agents, including the subcutaneous formulation of golimumab. Merkel cell carcinoma has been reported in patients treated with TNF-blocking agents. Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer. In controlled trials of other TNF-blockers in patients at higher risk for malignancies (e.g., patients with COPD, patients with Wegener’s granulomatosis treated with concomitant cyclophosphamide) a greater portion of malignancies occurred in the TNF-blocker group compared to the controlled group. In an exploratory clinical trial evaluating the use of the subcutaneous formulation of golimumab in patients with severe persistent asthma, more patients treated with golimumab reported malignancies compared with control patients. The significance of this finding is unknown. During the controlled portion of the Phase 3 trial in RA for SIMPONI ARIA, the incidence of malignancies other than lymphoma and NMSC per 100-patient-years of follow-up was 0.56 (95% CI: 0.01, 3.11) in the SIMPONI ARIA group compared with an incidence of 0 (95% CI: 0.00, 3.79) in the placebo group. Congestive Heart Failure Cases of worsening congestive heart failure (CHF) and new onset CHF have been reported with TNF-blockers, including SIMPONI ARIA. In several exploratory trials of other TNF-blockers in the treatment of CHF, there were greater proportions of TNF-blocker treated patients who had CHF exacerbations requiring hospitalization or increased mortality. SIMPONI ARIA has not been studied in patients with a history of CHF and SIMPONI ARIA should be used with caution in patients with CHF. If a decision is made to administer SIMPONI ARIA to RA patients with CHF, these patients should be closely monitored during therapy, and SIMPONI ARIA should be discontinued if new or worsening symptoms of CHF appear. Demyelinating Disorders Use of TNF-blockers, of which SIMPONI ARIA is a member, has been associated with rare cases of new onset or exacerbation of central nervous system (CNS) demyelinating disorders, including multiple sclerosis (MS) and peripheral demyelinating disorders, including Guillain-Barré syndrome. Cases of central demyelination, MS, optic neuritis, and peripheral demyelinating polyneuropathy have rarely been reported in patients treated with the subcutaneous formulation of golimumab. Prescribers should exercise caution in considering the use of TNF-blockers, including SIMPONI ARIA, in patients with central or peripheral nervous system demyelinating disorders. Discontinuation of SIMPONI ARIA should be considered if these disorders develop. Use with Abatacept In controlled trials, the concurrent administration of another TNF-blocker and abatacept was associated with a greater proportion of serious infections than the use of a TNF-blocker alone; and the combination therapy, compared to the use of a TNF-blocker alone, has not demonstrated improved clinical benefit in the treatment of RA. Therefore, the combination of TNF-blockers including SIMPONI ARIA and abatacept is not recommended (see Drug Interactions). Use with Anakinra Concurrent administration of anakinra (an interleukin-1 antagonist) and another TNF-blocker, was associated with a greater portion of serious infections and neutropenia and no additional benefits compared with the TNF-blocker alone. Therefore, the combination of anakinra with TNF-blockers, including SIMPONI ARIA, is not recommended (see Drug Interactions). Switching Between Biological Disease Modifying Antirheumatic Drugs (DMARDs) Care should be taken when switching from one biologic product to another biologic product since overlapping biological activity may further increase the risk of infection. Hematologic Cytopenias There have been post-marketing reports of pancytopenia, leukopenia, neutropenia, aplastic anemia, and thrombocytopenia in patients receiving TNF-blockers. In clinical studies, cases of pancytopenia, leukopenia, neutropenia, and thrombocytopenia have also occurred in SIMPONI ARIA-treated patients. Caution should be exercised when using TNF-blockers, including SIMPONI ARIA, in patients who have or have had significant cytopenias. Vaccinations/Therapeutic Infectious Agents Live Vaccines Patients treated with SIMPONI ARIA may receive vaccinations, except for live vaccines. In patients receiving anti-TNF

SIMPONI ARIA® (golimumab)

therapy, limited data are available on the response to live vaccination, or on the secondary transmission of infection by live vaccines. Use of live vaccines could result in clinical infections, including disseminated infections. Therapeutic Infectious Agents Other uses of therapeutic infectious agents such as live attenuated bacteria (e.g., BCG bladder instillation for the treatment of cancer) could result in clinical infections, including disseminated infections. It is recommended that therapeutic infectious agents not be given concurrently with SIMPONI ARIA. Hypersensitivity Reactions In post-marketing experience, serious systemic hypersensitivity reactions (including anaphylactic reaction) have been reported following administration of the subcutaneous formulation of golimumab. Some of these reactions occurred after the first administration of golimumab. If an anaphylactic or other serious allergic reaction occurs, administration of SIMPONI ARIA should be discontinued immediately and appropriate therapy instituted. ADVERSE REACTIONS: The most serious adverse reactions were: • Serious Infections (see Warnings and Precautions) • Malignancies (see Warnings and Precautions) Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety data described below are based on one, randomized, double-blind, controlled Phase 3 trial in patients with RA receiving SIMPONI ARIA by intravenous infusion (Trial 1). The protocol included provisions for patients taking placebo to receive treatment with SIMPONI ARIA at Week 16 or Week 24 either by patient response (based on uncontrolled disease activity) or by design, so that adverse events cannot always be unambiguously attributed to a given treatment. Comparisons between placebo and SIMPONI ARIA were based on the first 24 weeks of exposure. Trial 1 included 197 control-treated patients and 463 SIMPONI ARIA-treated patients (which includes controltreated patients who switched to SIMPONI ARIA at Week 16). The proportion of patients who discontinued treatment due to adverse reactions in the controlled phase of Trial 1 through Week 24 was 3.5% for SIMPONI ARIA-treated patients and 0.5% for placebo-treated patients. Upper respiratory tract infection was the most common adverse reaction reported in the trial through Week 24 occurring in 6.5% of SIMPONI ARIA-treated patients as compared with 7.6% of control-treated patients, respectively. Infections Serious infections observed in SIMPONI ARIA-treated patients included sepsis, pneumonia, cellulitis, abscess, opportunistic infections, tuberculosis (TB), and invasive fungal infections. Cases of TB included pulmonary and extrapulmonary TB. The majority of the TB cases occurred in countries with a high incidence rate of TB (see Warnings and Precautions). In the controlled phase of Trial 1 through Week 24, infections were observed in 27% of SIMPONI ARIA-treated patients compared with 24% of control-treated patients, and serious infections were observed in 0.9% of SIMPONI ARIA-treated patients and 0.0% of control-treated patients. Through Week 24, the incidence of serious infections per 100 patient-years of follow-up was 2.2 (95% CI 0.61, 5.71) for the SIMPONI ARIA group, and 0 (0.00, 3.79) for the placebo group. In the controlled and uncontrolled portions of Trial 1, 958 total patient-years of follow-up with a median follow-up of approximately 92 weeks, the incidence per 100 patient-years of all serious infections was 4.07 (CI: 2.90, 5.57) in patients receiving SIMPONI ARIA (see Warnings and Precautions). In the controlled and uncontrolled portions of Trial 1, in SIMPONI ARIA treated patients, the incidence of active TB per 100 patient-years was 0.31 (95% CI: 0.06; 0.92) and the incidence of other opportunistic infections per 100 patient-years was 0.42 (95% CI: 0.11, 1.07). Malignancies One case of malignancy other than lymphoma and NMSC with SIMPONI ARIA was reported through Week 24 during the controlled phase of Trial 1. In the controlled and uncontrolled portions through approximately 92 weeks, the incidence of malignancies per 100 patient-years, other than lymphoma and NMSC, in SIMPONI ARIA-treated patients was 0.31 (CI: 0.06, 0.92) and the incidence of NMSC was 0.1 (95% CI: 0.00, 0.58). Liver Enzyme Elevations There have been reports of severe hepatic reactions including acute liver failure in patients receiving TNF-blockers. In the controlled phase of Trial 1, through Week 24, ALT elevations ≥ 5 x ULN occurred in 0.8% of SIMPONI ARIA-treated patients and 0% of control-treated patients and ALT elevations ≥ 3 x ULN occurred in 2.3% of SIMPONI ARIA-treated patients and 2.5% of controltreated patients. Since many of the patients in the Phase 3 trial were also taking medications that cause liver enzyme elevations (e.g., nonsteroidal anti-inflammatory drugs [NSAIDs], methotrexate [MTX], or isoniazid prophylaxis), the relationship between SIMPONI ARIA and liver enzyme elevation is not clear. Autoimmune Disorders and Autoantibodies The use of TNF-blockers, of which SIMPONI ARIA is a member, has been associated with the formation of autoantibodies and, rarely, with the development of a lupus-like syndrome. At Week 20 in Trial 1, 17% of SIMPONI ARIA-treated patients and 13% of control patients were newly ANA-positive (at titers of 1:160 or greater). Of these patients, one SIMPONI ARIA-treated patient and no control-treated patients had newly positive anti-dsDNA antibodies. Administration Reactions In the controlled phase of Trial 1 through Week 24, 1.1% of SIMPONI ARIA infusions were associated with an infusion reaction compared with 0.2% of infusions in the control group. The most common infusion reaction in SIMPONI ARIA treated patients was rash. No serious infusion reactions were reported. Immunogenicity Antibodies to SIMPONI ARIA were detected in 13 (3%) golimumab-treated patients following IV administration of SIMPONI ARIA in combination with MTX through Week 24 of Trial 1. All patients who were positive for antibodies to golimumab had neutralizing antibodies based on an in vitro cell-based assay. The small number of patients positive for antibodies to SIMPONI ARIA limits the ability to draw definitive conclusions regarding the relationship between antibodies to golimumab and clinical efficacy or safety measures. The data above reflect the percentage of patients whose test results were considered positive for antibodies to SIMPONI ARIA in an ELISA assay. The ELISA assay is subject to interference by co-present golimumab and thus the results are an underestimate of the rate of product immunogenicity and are in addition highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to SIMPONI ARIA with the incidence of antibodies to other products may be misleading. Other Adverse Reactions The adverse drug reactions that occurred at a rate of at least 1% in the SIMPONI ARIA + MTX group and with a higher incidence than in the placebo + MTX group during the controlled period of Trial 1 through Week 24 are summarized below. The numbers (percentages) of adverse drug reactions for Placebo + MTX treated patients (n=197) and SIMPONI ARIA + MTX-treated patients (n=463), respectively, were: Infections and Infestations: Upper respiratory tract infection (such as upper respiratory tract infection, nasopharyngitis, pharyngitis, laryngitis, and rhinitis) 12%, 13%; Viral infections (such as influenza and herpes) 3%, 4%; Bacterial infections 0%, 1%; Bronchitis 1%, 3%; Vascular disorders: Hypertension 2%, 3%; Skin and subcutaneous disorders: Rash 1%, 3%; General disorders and administration site conditions: Pyrexia 1%, 2%; Blood and lymphatic disorders: Leukopenia 0%, 1% Other and less common clinical trial adverse drug reactions Adverse drug reactions that occurred <1% in SIMPONI ARIA-treated patients during Trial 1 through Week 24 that do not appear in the Warnings and Precautions section included the following events listed by system organ class: Infections and Infestations: Superficial fungal infection, sinusitis, abscess, lower respiratory tract infection (pneumonia), pyelonephritis Investigations: Alanine

aminotransferase increased, aspartate aminotransferase increased, neutrophil count decreased Nervous system disorders: Dizziness, paresthesia Gastrointestinal disorders: Constipation Post-marketing Experience There is no post-marketing experience available for SIMPONI ARIA. The following adverse reactions have been identified during post-approval use of the subcutaneous formulation of golimumab. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to golimumab exposure. Neoplasm Benign and Malignant: Melanoma (see Warnings and Precautions) Immune System Disorders: Serious systemic hypersensitivity reactions (including anaphylactic reaction) (see Warnings and Precautions), sarcoidosis Respiratory, thoracic and mediastinal disorders: Interstitial lung disease Skin and subcutaneous tissue disorders: Skin exfoliation, bullous skin reactions DRUG INTERACTIONS: Methotrexate SIMPONI ARIA should be used with methotrexate (MTX) (see Clinical Studies). Following IV administration, concomitant administration of methotrexate decreases the clearance of SIMPONI ARIA by approximately 9% based on population PK analysis. In addition, concomitant administration of methotrexate decreases the SIMPONI ARIA clearance by reducing the development of anti-golimumab antibodies. Biologic Products for RA An increased risk of serious infections has been seen in clinical RA studies of other TNF-blockers used in combination with anakinra or abatacept, with no added benefit; therefore, use of SIMPONI ARIA with other biologic products, including abatacept or anakinra is not recommended (see Warnings and Precautions). A higher rate of serious infections has also been observed in RA patients treated with rituximab who received subsequent treatment with a TNF-blocker. The concomitant use of SIMPONI ARIA with biologics approved to treat RA is not recommended because of the possibility of an increased risk of infection. Live Vaccines/ Therapeutic Infectious Agents Live vaccines should not be given concurrently with SIMPONI ARIA (see Warnings and Precautions). Therapeutic infectious agents should not be given concurrently with SIMPONI ARIA (see Warnings and Precautions) Infants born to women treated with SIMPONI ARIA during their pregnancy may be at increased risk of infection for up to 6 months. Administration of live vaccines to infants exposed to SIMPONI ARIA in utero is not recommended for 6 months following the mother’s last SIMPONI ARIA infusion during pregnancy (see Use in Specific Populations). Cytochrome P450 Substrates The formation of CYP450 enzymes may be suppressed by increased levels of cytokines (e.g., TNFα) during chronic inflammation. Therefore, it is expected that for a molecule that antagonizes cytokine activity, such as golimumab, the formation of CYP450 enzymes could be normalized. Upon initiation or discontinuation of SIMPONI ARIA in patients being treated with CYP450 substrates with a narrow therapeutic index, monitoring of the effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) is recommended and the individual dose of the drug product may be adjusted as needed. USE IN SPECIFIC POPULATIONS: Pregnancy Pregnancy Category B – There are no adequate and well-controlled studies of SIMPONI ARIA in pregnant women. Because animal reproduction and developmental studies are not always predictive of human response, it is not known whether SIMPONI ARIA can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. SIMPONI ARIA should be used during pregnancy only if clearly needed. An embryofetal developmental toxicology study was performed in which pregnant cynomolgus monkeys were treated subcutaneously with golimumab during the first trimester with doses up to 50 mg/kg twice weekly (200 times greater than the maximum recommended human doseMRHD) and has revealed no evidence of harm to maternal animals or fetuses. Umbilical cord blood samples collected at the end of the second trimester showed that fetuses were exposed to golimumab during gestation. In this study, in utero exposure to golimumab produced no developmental defects to the fetus. A pre- and post-natal developmental study was performed in which pregnant cynomolgus monkeys were treated with golimumab during the second and third trimesters, and during lactation at doses up to 50 mg/kg twice weekly (33 times and 12 times greater than the maximal steady state human blood levels for maternal animals and neonates, respectively) and has revealed no evidence of harm to maternal animals or neonates. Golimumab was present in the neonatal serum from the time of birth and for up to six months postpartum. Exposure to golimumab during gestation and during the postnatal period caused no developmental defects in the infants. IgG antibodies are known to cross the placenta during pregnancy and have been detected in the serum of infants born to patients treated with these antibodies. Since SIMPONI ARIA is an IgG antibody, infants born to women treated with SIMPONI ARIA during their pregnancy may be at increased risk of infection for up to 6 months. Administration of live vaccines to infants exposed to SIMPONI ARIA in utero is not recommended for 6 months following the mother’s last SIMPONI ARIA infusion during pregnancy (see Warnings and Precautions). Nursing Mothers It is not known whether SIMPONI ARIA is excreted in human milk or absorbed systemically after ingestion. Because many drugs and immunoglobulins are excreted in human milk, and because of the potential for adverse reactions in nursing infants from SIMPONI ARIA, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. In the pre- and post-natal development study in cynomolgus monkeys in which golimumab was administered subcutaneously during pregnancy and lactation, golimumab was detected in the breast milk at concentrations that were approximately 400-fold lower than the maternal serum concentrations. Pediatric Use Safety and effectiveness of SIMPONI ARIA in pediatric patients less than 18 years of age have not been established. Malignancies, some fatal, have been reported among children, adolescents, and young adults who received treatment with other TNF-blocking agents (see Warnings and Precautions). Geriatric Use In Trial 1 in RA, the number of patients ages 65 or older was too small to make comparisons with younger SIMPONI ARIA-treated patients. Because there is a higher incidence of infections in the geriatric population in general, caution should be used in treating geriatric patients with SIMPONI ARIA. OVERDOSAGE: In a clinical study, 5 patients received single infusions of up to 1000 mg of SIMPONI ARIA without serious adverse reactions or other significant reactions. PATIENT COUNSELING INFORMATION: See FDA-approved patient labeling (Medication Guide) Advise patients of the potential benefits and risks of SIMPONI ARIA. Instruct patients to read the Medication Guide before starting SIMPONI ARIA therapy and to read it each time the prescription is renewed. Infections Inform patients that SIMPONI ARIA may lower the ability of their immune system to fight infections. Instruct the patient of the importance of contacting their doctor if they develop any symptoms of infection, including tuberculosis, invasive fungal infections, and hepatitis B reactivation. Malignancies Patients should be counseled about the risk of lymphoma and other malignancies while receiving SIMPONI ARIA. Other Medical Conditions Advise patients to report any signs of new or worsening medical conditions such as congestive heart failure, demyelinating disorders, autoimmune diseases, liver disease, cytopenias, or psoriasis. © Janssen Biotech, Inc. 2013 Horsham, PA 19044 1-800-JANSSEN (1-800-526-7736) US License No. 1864 at Cilag AG, Schaffhausen, Switzerland Revised: 12/2014 025924-141204

SUPLEMENTO REUMATOLOGÍA

Esclerodermia localizada Lesión de esclerosis de alrededor de 6 x 10 cm de diámetro, con leve hiperpigmentación, hombre de 28 años Crédito: Dra. Lilia Maria de la Torre Navarro

Diagnóstico y Manejo de la

ESCLERODERMIA Por: Liza B. Vázquez Cobián, MD Reumatóloga Pediátrica

Resumen La esclerodermia constituye un desorden autoinmune órgano específico, que compromete sobre todo la piel. Se caracteriza por inflamación seguida de esclerosis e incluye distintas formas clínicas. La etiología de la esclerodermia localizada no ha sido establecida. El diagnóstico diferencial incluye cuadros esclerodermiformes, desencadenados por factores intrínsecos y extrínsecos que están siendo estudiados. Aunque al momento no existe cura y el tratamiento está dirigido al manejo de las complicaciones de la enfermedad, particularmente en la Esclerosis Sistémica, un diagnóstico temprano y pronto tratamiento durante la fase activa, es de suma importancia para el pronóstico de estos pacientes. Palabras Claves esclerodermia localizada, diagnóstico diferencial, manifestaciones clínicas, tratamiento de esclerodermia 48

Revista Puertorriqueña de Medicina y Salúd Pública

Esclerodermia difusa, mujer de 62 años Crédito: Dra. Lilia Maria de la Torre Navarro

MSP ARTÍCULO DE REVISIÓN

ESCLERODERMIA

Es una enfermedad del tejido conjuntivo que involucra cambios en la piel, los vasos sanguíneos, los músculos y los órganos internos. Ocurre cuando el sistema inmunitario ataca por error y destruye tejido corporal sano.

SÍNTOMAS:

Pérdida de cabello

Dificultad respiratoria

Rigidez y tensión de los dedos de las manos, manos y antebrazos

Distensión después de las comidas

Acidez gástrica

Uno de los síntomas iniciales más comunes es el Síndrome de Raynaud: los dedos de las manos y los pies se entumecen con el frío, primero se ponen blanquecinos y luego se tornan de un color azulado-púrpura. Pero de cien pacientes con el síndrome, probablemente sólo diez presenten esclerodermia u otra enfermedad reumática.

Estreñimiento Dolor de muñeca

Diarrea Dedos de las manos y de los pies se tornan azulados o blancos en respuesta a las temperaturas frías (Fenómeno de Raynaud)

Ulceraciones en las puntas de los dedos de las manos y/o pies

Dolor articular Entumecimiento y dolor en los pies

Entre

30 y 50

años generalmente es la edad de las personas afectadas

5 a 12 CASOS NUEVOS se dan al año por cada millón de personas

80% de los casos se presentan en mujeres

EXISTEN DOS TIPOS DE ESCLERODERMIA: Esclerodermia localizada:

Afecta sólo a la piel en las manos y la cara. Se desarrolla lentamente y en muy pocas ocasiones se propaga en el cuerpo o causa problemas serios.

Esclerodermia o esclerosis sistémica:

Afecta grandes áreas de la piel y órganos como el corazón, pulmones o riñones.

Revista Puertorriqueña de Medicina y Salúd Pública

SUPLEMENTO REUMATOLOGÍA

DIAGNÓSTICO • Examen de orina • Examen de sangre • Examen físico • Biopsia de la piel • Eco cardiografía

• Radiografía del tórax • Pruebas metabólicas, incluso creatina

Keywords localized scleroderma, differential diagnosis, differential diagnosis, clinical manifestations, treatment of scleroderma

TRATAMIENTO No existe ningún tratamiento específico para la esclerodermia. El doctor recetará medicamentos y otros tratamientos para controlar los síntomas y prevenir complicaciones. Los fármacos utilizados para tratar la esclerodermia abarcan: • Corticosteroides • Inmunodepresores como Metotrexano y Cytoxan • Antiinflamatorios no esteroides (AINES)

Otros tratamientos para síntomas específicos pueden incluir: • Fármacos para la pirosis o problemas de deglución • Medicamentos para la presión arterial (como inhibidores ICEA) para problemas renales o de hipertensión arterial. • Fototerapia para aliviar el engrosamiento de la piel. • Medicamentos para mejorar la respiración

Histología correspondiente a esclerodermia, donde se ve desde la zona subepidérmica la presencia de haces de colágeno gruesos, toscos, sin espacio interfascicular.

Revista Puertorriqueña de Medicina y Salúd Pública

Abstract Localized scleroderma is an autoimmune organ specific disorder with an important skin compromise. It is an inflammatory process with several distinct clinical characteristics. The etiology of localized scleroderma has not been established yet. Differential diagnosis includes sclerodermiform onset unchained by intrinsic and extrinsic factors that are presently studied. Even when there is no cure, management is directed toward the management of complications particularly in Systemic Scleroderma. An early diagnosis is the best way to improve the prognosis of these patients.

l término esclerodermia deriva de la palabra Griega skleros que significa dura o indurada y la palabra derma que significa piel dando así nombre a esta enfermedad caracterizada por induración y endurecimiento de la piel como resultado de un proceso autoinmune de origen desconocido que se caracteriza por un exceso de la deposición de colágeno en en la piel y órganos internos. Las manifestaciones de la enfermedad van desde localizada hasta sistémica. La Esclerodermia lo-calizada o Morfea, es una condición inflamatoria que tiene como resultado la esclerosis de la dermis y tejido conectivo, pero puede extenderse y envolver la fascia, músculo y hueso subyacente. La distribución de las lesiones es asimétrica y usualmente limitada a un área del cuerpo. No hay envolvimiento de órganos internos, fenómeno de Raynaud ni anomalías en los capilares del pliegue de la uña. Los cuatros tipos principales de Esclerodermia Localizada/ Morfea son: - Esclerodermia Circunscrita. Es el subtipo más común. Las lesiones usualmente ubican en el tronco y comienzan como placas violaceas, edematosas las cuales crecen en diámetro durante varios años hasta convertirse en lesiones atróficas. - Esclerodermia Lineal (incluye Síndrome Parry Romberg) Es más común en niños y adolescentes. Presenta como induración lineal en el cuero cabelludo, frente,

MSP ARTÍCULO DE REVISIÓN

tronco o extremidades. Puede envolver el ojo, la fascia, músculo y hueso lo cual en ocasiones tiene como resultado atrofia y pérdida de movimiento de la articulación. Aquellos pacientes con Síndrome de Parry-Romberg pueden presentar convulsiones, dolor de cabeza y hallazgos positivos en MRI intracraneano. Estos pacientes suelen tener serologías positivas de Anticuerpo Anti Nuclear (AAN), ssDNA y anticuerpos anti histona. - Esclerodermia Generalizada Subtipo que se caracteriza por la presencia de cuatro o más lesiones en placa, envuelve dos o más áreas anatómicas o lesión en placa en el tronco que progresa lentamente hasta envolver todo el tronco causando disnea progresiva como consecuencia de la restricción mecánica de la expansión torácica. Al igual que aquellos pacientes con esclerodermia linear, los pacientes en este grupo suelen tener serologías positivas de

Anticuerpo Anti Nuclear (AAN), ssDNA y anticuerpos anti histona en adición a síntomas constitucionales. - Grupo Misceláneo Comprende variedad del lesiones fenotípicamente diferentes incluyendo lesiones nodulares, bulosas, guttatas, antropoderma de Pasini y Pierini, además del grupo mixto que presenta dos o más de dos tipos de lesiones. La Esclerodermia o Esclerosis Sistémica afecta no sólo la piel, sino que se caracteriza por envolvimiento de órganos internos, esclerodactilia, anomalías en los capilares del pliegue de la uña y la presencia del fenómeno de Raynaud. La Esclerodermia Sistémica se divide en dos tipos, en base a la extensión y patrón de las manifestaciones en piel. En estos casos el tracto gastrointestinal, sistema cardiaco, pulmonar, renal, musculoesqueletal, endocrino y genitourinario pueden estar afectados.

AGENTE ETIOLÓGICO

Histologia de tejido con presencia de infiltrado linfomonocitario.

- Esclerosis Sistémica Limitada Manifestaciones en piel ocurren distales a los codos y rodillas. Pueden tener lesiones en cuello y cara. El Síndrome de CREST es una variante de la Esclerosis Sistémica Limitada dónde, adicional a las lesiones en piel, los pacientes presentan calcinosis, fenómeno de Raynaud, disfunción esofágica, esclerodactilia y telangiectasias.

Raynaud 70%,

casi 100% en CREST

Sin Raynaud varones,

Base genética

compromiso renal y miocárdico, escasa sobrevida

Alteraciones moleculares y celulares en células blanco

fibroblastos

Células endoteliales

Células B

Difusa:

Células T

tumefacción difusa de manos, artritis, evidencia de lesión de órganos internos, esclerodermia

El edema

en manos puede ser punteado

Edemas en MMSS, cara y tronco Tissue Fibrosis

Obliteration of Small Arteries and Arterioles

Production of Autoantibodies

Cellular infiltration and Cytokine and Growth Factor Dysregulation

Síndrome de túnel carpiano

Revista Puertorriqueña de Medicina y Salúd Pública

SUPLEMENTO REUMATOLOGÍA

MANIFESTACIONES MUSCULOESQUELÉTICAS

MANIFESTACIONES PULMONARES

• Artralgias, artritis • Frotes tendinosos • Debilidad muscular proximal y distal • Miositis • Osteopenia • Calcinosis subcutánea

• Derrame pleural • Fibrosis pulmonar • Hipertensión pulmonar

MANIFESTACIONES CARDÍACAS

MANIFESTACIONES RENALES

• Derrame pericárdico • Fibrosis miocárdica • Cardiopatía isquémica • Taquiarritmias supraventriculares y ventriculares

• • • • • •

Hipertensión arterial “Crisis renal esclerodérmica” Anemia hemolítica microangiopática Albuminuria HTA maligna Insuficiencia renal

MANIFESTACIONES GASTROINTESTINALES Esófago

Gástricas

Intestino delgado

• Dismotilidad • Disfunción y estenosis del EEI • Complicaciones: esófago de Barrett

• Retardo en evacuación • Dilatación aguda • Estómago en “sandía”

VASCULOPATÍA

Fenómeno de Raynaud

• Constipación • Seudodivertículos • Prolapso rectal e incontinencia anal

Hígado • Fibrosis tracto biliar o hepático • Cirrosis biliar primaria en superposición

SÍNDROME DE RAYNAUD Vasoespástico

Fase eritematosa

Fase isquémica

• Diarrea intermitente o crónica • Síndrome de asa ciega

Intestino grueso

Fase cianótica

- Drogas (ergotamina, metisergida, β bloqueantes) - Feocromocitoma - Síndrome carcinoide - Otros síndromes vasoespásticos 1° (migraña, angina variante)

Estructural - Arterias grandes y medianas

PRUEBAS DE LABORATORIOS

(síndrome de salida toráxica, presión muletas)

- Arterias pequeñas y arteriolas (enfermedad

ANA + (>95%) Anticentrómero (20-40%)

Revista Puertorriqueña de Medicina y Salúd Pública

Anti Esclero 70 (20-40%) antiTh/To (cutáneopulmonar)

por vibración, arteriosclerosis y tromboangeítis obliterante, lesión por frío, enfermedad por cloruro de polivinilo, bleomicina, vinblastina, ETC)

Hemorreológico - Crioglobulinemia - Criofibrinogenemia - Síndromes de hiperviscosidad - Enfermedad por crioaglutininas - Policitemia vera

MSP ARTÍCULO DE REVISIÓN

AUTOANTICUERPOS CARACTERÍSTICOS EN ESCLEROSIS SISTÉMICA Anticuerpo Anti-Scl70 (Topo1) Anti-centrómero Anti-nucleolares

Patrón IF Granulado fino difuso Moteado discreto

Prevalencia ES total: 20-30% difusa: 20-40% ES total: 30% Limitada: 50-90%

Nucleolar

ES total: 30-40% (> difusa)

PM-Scl

Nucleolar homogéneo

ES/PM

ARN polimerasa 1

Nucleolar homogéneo

ES difusa

Fibrilarina

Nucleolar “Clumpy”

Hipertensión pulmonar?

ES: Esclerosis Sistémica PM: polimiositis

TRATAMIENTO Crisis renal: 1. Inhibidor de la enzima convertidora de angiotensina (IECA) 2. Agregar un bloqueante de los canales de calcio (BCC) o un bloqueante del receptor de angiotensina (BRA) 3. Agregar un alfa bloqueante Hipertensión pulmonar: 1. Leve: 1º inhibidor del receptor de endotelina (ERA), 2º inhibidor de la 5-fosfodiesterasas (PDE5i) y 3º prostanoide 2. Severa: prostanoides o combinaciones de ERAs con PDE5i o con prostanoides Raynaud: 1. BCC 2. Agregar un PDE5i, probar un o un BRA y luego un prostanoide. Prevención de úlceras digitales: • 1º BCC, luego agregar PDE5i, después un ERA y después un prostanoide Enfermedad pulmonar intersticial o fibrosis: • Inducir con ciclofosfamida, micofenolato o azatioprina • Mantenimiento generalmente con micofenolato Reflujo gastroesofágico: • Inhibidores de bomba de protones Compromiso cutáneo: • Metotrexato o micofenolato Artritis • Metotrexato, corticoides, hidroxicloroquina

- Esclerosis Sistémica Difusa El engrosamiento de la piel ocurre proximal a los codos y rodillas en adición a envolvimiento facial. En casos de “Scleroderma sine Scleroderma’ los pacientes presentan manifestaciones sintéticas sin envolvimiento de la piel. Tanto la Esclerodermia Localizada como la Sistémica, se caracterizan por tres fases de enfermedad: activa o edematosa, inactiva, esclerotica o fibrosis y por último, lesiones atróficas y/o atrofia de órganos envueltos. Aunque al momento no existe cura y el tratamiento está dirigido al manejo de las complicaciones de la enfermedad, particularmente en la Esclerosis Sistémica, un diagnóstico temprano y pronto tratamiento durante la fase activa, es de suma importancia para el pronóstico de estos pacientes. Referencias

1. Jimenez, SA; Cronin, PM; Koenig, AS; O’Brien, MS; Castro, SV (15 February 2012). Varga, J; Talavera, F; Goldberg, E; Mechaber, AJ; Diamond, HS, ed.”Scleroderma”. Medscape Reference. WebMD. Retrieved 5 March 2014 2. Hajj-ali, RA (June 2013). “Systemic Sclerosis”. Merck Manual Professional. Merck Sharp & Dohme Corp. Retrieved 5 March 2014. 3. Gabrielli A, Avvedimento EV, Krieg T (2009). “Scleroderma”. New England Journal of Medicine 360 (19): 1989–2003. doi:10.1056/NEJMra0806188. PMID 19420368. 4. Longo, D; Fauci, A; Kasper, D; Hauser, S; Jameson, J; Loscalzo, J (2011). Harrison’s Principles of Internal Medicine (18 ed.). New York: McGraw-Hill Professional. ISBN 978-0-07174889-6. 5. Valančienė G, Jasaitienė D, Valiukevičienė S (2010). “Pathogenesis and treatment modalities of localized scleroderma.” (PDF). Medicina 46 (10): 649–56.PMID 21393982. 6. Fett N (July–August 2013). “Scleroderma: nomenclature, etiology, pathogenesis, prognosis, and treatments: facts and controversies.”. Clinics in dermatology 31 (4): 432–7.doi:10.1016/j.clindermatol.2013.01.010. PMID 23806160. 7. Sticherling M (October 2012). “Systemic sclerosis-dermatological aspects. Part 1: Pathogenesis, epidemiology, clinical findings.”. Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG 10 (10): 705–18; quiz 716. doi:10.1111/j.1610-0387.2012.07999.x. PMID 22913330. Revisado por nuestro Editor Revista Puertorriqueña de Medicina y Salúd Pública

SUPLEMENTO REUMATOLOGÍA

El reumatólogo y el uso en su oficina de la Ultrasonografía Musculoesqueletal Por: Ramón L. Ortega Colón, MD Reumatólogo Miembro de la Asociación de Reumatólogos de Puerto Rico

Keywords musculoskeletal ultrasonography, inflammatory arthritis, synovitis Palabras claves ultrasonografía musculoesqueletal, artritis inflamatoria sinovitis

Revista Puertorriqueña de Medicina y Salúd Pública

Abstract The use of musculoskeletal ultrasonography is a powerful tool in the field of rheumatology. It is a safe, affordable and accessible way to help in the diagnosis and monitoring of inflammatory arthritis. Nowadays, more and more indications are added for its use with our patients.

Resumen El uso de la ultrasonografía musculoesqueletal tiene cada vez mayor utilidad en el campo de la reumatología. Es una forma segura, económica y accesible para ayudar en el diagnóstico y seguimiento de las artritis inflamatorias. Cada vez se añaden más indicaciones para su uso en nuestros pacientes.

MSP ARTÍCULO MÉDICO

“En Reumatología ya está formando parte de los currículos de adiestramiento y cada vez se le encuentra más utilidad en nuevas condiciones”

a ultrasonografía musculoesqueletal tiene una historia que abarca más de 50 años. En el 1942 Karl Theodore Dussik se convirtió en el primer médico en utilizar el ultrasonido como una herramienta de diagnóstico. En su escrito, del 1958, sobre esta materia él narra su examen de diferentes tejidos articulares y periarticulares como cartílago articular, la cápsula articular, tendones, músculos, tejido adiposo, hueso y piel. Con los avances en la tecnología, mejor resolución, máquinas portátiles y una mejor comprensión de la patofisiología de las enfermedades reumáticas, esta técnica se está convirtiendo en una extensión del examen físico del reumatólogo. Su uso en condiciones no inflamatorias musculoesqueletales, evaluación de tejidos blandos luego de trauma y su uso para guiar procedimientos ya está siendo más común en las oficinas de fisiatras y ortopedas. En Reumatología ya está formando parte de los currículos de adiestramiento y cada vez se le encuentra más utilidad en nuevas condiciones. En los últimos años ha habido una explosión en el entendimiento, manejo y nuevas formas de tratamiento de condiciones como artritis reumatoide, artritis psoriásica, las espondiloartropatías y gota entre otros. Los medicamentos biológicos, el tener parámetros y medidas de resultado de tratamiento para llevar

el paciente a un nivel de actividad inflamatoria baja o si posible remisión, requieren detectar la presencia de inflamación sinovial. El ultrasonido es más sensitivo que el examen clínico en la evaluación articular para la detección de sinovitis. Puede detectar sinovitis subclínica y hacer diferencia en las decisiones clínicas de tratamiento. Se puede utilizar para monitorear la respuesta a tratamiento. Se pueden ver erosiones antes de que aparezcan en rayos X y es mucho más económico que un estudio de resonancia magnética. En la artritis psoriásica y espondiloartropatías nos ayuda a examinar las entesis para detectar inflamación activa, erosiones o la presencia de entesofitos. En Gota, que sabemos que en muchos pacientes es una proceso continuo y crónico, nos ayuda a diagnosticar la presencia de depósitos de urato en áreas articulares y periarticulares que pueden resultar en un manejo más agresivo y adecuado. No debo dejar de mencionar su uso para procedimientos como inyecciones articulares en áreas realmente incómodas, en rodillas de pacientes obesos, definitivamente para inyectar la articulación de la cadera y para inyectar viscosuplementación entre otros usos. En general va en vías a convertirse, como mencioné antes, en una extensión del examen físico que es y seguirá siendo siempre nuestra herramienta más importante de diagnóstico.

Revista Puertorriqueña de Medicina y Salúd Pública

MSP ARTÍCULO ORIGINAL

Moderate to Severe Rheumatoid Arthritis (RA)

The jeans didn’t last.

Revista Puertorriqueña de Medicina y Salúd Pública

MSP ARTÍCULO ORIGINAL

Because the joints did. Improving physical function and preventing further joint damage are key goals in managing RA. HUMIRA clinical trials provide more than 16 years of evidence to support the Rheumatology community in treating RA.2*

Greater Radiographic Inhibition: In a study of 619 moderate to severe RA patients

with an inadequate response to MTX, those treated with HUMIRA + MTX demonstrated a mean change from baseline of 2.6 fewer Sharp score units vs placebo + MTX-treated patients at 1 year.1

2×

Greater improvement

Improved Physical Function: In the same study at 1 year, a greater mean

improvement in HAQ-DI was achieved with HUMIRA + MTX vs placebo + MTX (–0.59 vs –0.25, respectively).3

Open-label Extension: Patients originally treated with HUMIRA + MTX maintained Years

inhibition of structural damage and improvement of physical function through 5 years.1 55% (n=113) of patients originally randomized to HUMIRA 40 mg EOW + MTX were evaluated at 5 years; of these patients, 50% (n=57) showed no progression of structural damage (change in mTSS ≤0) and the overall mean change in mTSS was 0.8.1,2

HUMIRA specifically targets TNF-α, one of the key cytokines in inﬂammation. Elevated levels of TNF- α are found in the synovial fluid of patients with RA.1 TNF- α plays an important role in pathologic inflammation and joint destruction, which are hallmarks of this disease.1

Indication1 Moderate to Severe Rheumatoid Arthritis: HUMIRA is indicated, alone or in combination with methotrexate or other non-biologic DMARDs, for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in adult patients with moderately to severely active rheumatoid arthritis.

Safety Considerations1 Serious Infections: Patients treated with HUMIRA are at increased risk for developing serious infections that may lead to hospitalization

or death. These infections include active tuberculosis (TB), reactivation of latent TB, invasive fungal infections, and bacterial, viral, and other infections due to opportunistic pathogens. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.

Malignancies: Lymphoma, including a rare type of T-cell lymphoma, and other malignancies, some fatal, have been reported in patients treated with TNF blockers, including HUMIRA.

Other Serious Adverse Reactions: Patients treated with HUMIRA also may be at risk

for other serious adverse reactions, including anaphylaxis, hepatitis B virus reactivation, demyelinating disease, cytopenias, pancytopenia, heart failure, and a lupus-like syndrome.

*Beginning with RA, first patient dosed in April 1997.

Please see additional Important Safety Information, including BOXED WARNING on Serious Infections and Malignancy, on the following page of this advertisement. Please see Brief Summary of full Prescribing Information on last pages of this advertisement.

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Psoriatic Arthritis (PsA)

The jeans didnâ&#x20AC;&#x2122;t last.

Thanks to living a life in action. Improving physical function—while preventing further joint damage on the inside and improving psoriatic skin symptoms on the outside—are key goals in managing PsA.

Improvement in Physical Function, as measured by the HAQ-DI, was greater in patients treated with HUMIRA 40 mg EOW vs placebo at 24 weeks (mean decrease of 49% vs 3%, respectively) in a study of 313 patie nts with ac tive Ps A . H U M I R A -t r e a te d p a t i e n t s experienced a mean change in HAQ-DI of −0.4 vs −0.1 in the placebo group at Week 24 (P<0.0 01). Ba se line me a n HAQ-DI score for both groups was 1.0. Improvement in physical function was maintained for up to 84 weeks through the open-label portion of the study.1,2

Greater Radiographic Inhibition was achieved in patients treated with HUMIRA 40 mg EOW vs placebo at Week 24 in the same study, as measured by mean change from baseline in mTSS. This effect was maintained at 48 weeks.1

Improvement in Psoriatic Skin Symptoms, as measured by PASI response in patients with at least 3% body surface area invo l ve m e n t (n =13 8), wa s achieved by more patients in the HUMIRA group vs the placebo group in the same study. At 24 we e ks, 59% a n d 42% of H U M I R A -t r e a te d p a t i e n t s achieved PASI75 and PASI90, respectively, compared to 1% and 0% of placebo-treated patients (P<0.001).1

HUMIRA specifically targets TNF-α, one of the key cytokines in inflammation.

Indication1 Psoriatic Arthritis: HUMIRA is indicated, alone or in combination with non-biologic DMARDs, for reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in adult patients with active psoriatic arthritis.

Safety Considerations1 Serious Infections: Patients treated with HUMIRA are at increased risk for developing serious infections that may lead to hospitalization or death. These infections include active tuberculosis (TB), reactivation of latent TB, invasive fungal infections, and bacterial, viral, and other infections due to opportunistic pathogens. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. Malignancies: Lymphoma, including a rare type of T-cell lymphoma, and other malignancies, some fatal, have been reported in patients treated with TNF blockers, including HUMIRA.

Other Serious Adverse Reactions: Patients treated with HUMIRA also may be at risk

for other serious adverse reactions, including anaphylaxis, hepatitis B virus reactivation, demyelinating disease, cytopenias, pancytopenia, heart failure, and a lupus-like syndrome.

References: 1. HUMIRA Injection [package insert]. North Chicago, IL: AbbVie Inc. 2. Data on file, AbbVie Inc.

Results that matter, inside and out

IMPORTANT SAFETY INFORMATION 1 SERIOUS INFECTIONS Patients treated with HUMIRA are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. Discontinue HUMIRA if a patient develops a serious infection or sepsis. Reported infections include: • Active tuberculosis (TB), including reactivation of latent TB. Patients with TB have frequently presented with disseminated or extrapulmonary disease. Test patients for latent TB before HUMIRA use and during therapy. Initiate treatment for latent TB prior to HUMIRA use. • Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, and pneumocystosis. Patients with histoplasmosis or other invasive fungal infections may present with disseminated, rather than localized, disease. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Consider empiric anti-fungal therapy in patients at risk for invasive fungal infections who develop severe systemic illness. • Bacterial, viral, and other infections due to opportunistic pathogens, including Legionella and Listeria. Carefully consider the risks and benefits of treatment with HUMIRA prior to initiating therapy in patients with chronic or recurrent infection. Monitor patients closely for the development of signs and symptoms of infection during and after treatment with HUMIRA, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy. • Do not start HUMIRA in patients with an active infection, including localized infections. • Patients older than 65 years, patients with co-morbid conditions, and/or patients taking concomitant immunosuppressants may be at greater risk of infection. • Consider the risks and benefits of treatment in patients with chronic or recurrent infection or with underlying conditions which may predispose them to infection, patients who have been exposed to TB, patients with a history of opportunistic infection, or patients who have resided or traveled in regions where TB or mycoses are endemic. • Patients who develop a new infection should undergo a prompt and complete diagnostic workup, and appropriate antimicrobial therapy should be initiated. • Drug interactions with biologic products: A higher rate of serious infections has been observed in rheumatoid arthritis patients treated with rituximab who received subsequent treatment with a TNF blocker. Concurrent use of HUMIRA with biologic DMARDs (e.g., anakinra or abatacept) or other TNF blockers is not recommended based on the possible increased risk for infections and other potential pharmacological interactions. MALIGNANCY Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, including HUMIRA. Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers, including HUMIRA. These cases have had a very aggressive disease course and have been fatal. The majority of reported TNF blocker cases have occurred in patients with Crohn’s disease or ulcerative colitis and the majority were in adolescent and young adult males. Almost all of these patients had received treatment with azathioprine or 6-mercaptopurine concomitantly with a TNF blocker at or prior to diagnosis. It is uncertain whether the occurrence of HSTCL is related to use of a TNF blocker or a TNF blocker in combination with these other immunosuppressants. • Consider the risks and benefits of HUMIRA treatment prior to initiating or continuing therapy in a patient with known malignancy. • More cases of malignancies were observed among HUMIRA-treated patients compared to control patients in clinical trials.

• Non-melanoma skin cancer (NMSC) has been reported during clinical trials for HUMIRA-treated patients. Examine all patients, particularly those with a history of prolonged immunosuppressant or PUVA therapy, for the presence of NMSC prior to and during treatment with HUMIRA. • In HUMIRA clinical trials, there was an approximate 3-fold higher rate of lymphoma than expected in the general U.S. population. Patients with chronic inflammatory diseases, particularly those with highly active disease and/or chronic exposure to immunosuppressant therapies, may be at higher risk of lymphoma than the general population, even in the absence of TNF blockers. • Postmarketing cases of acute and chronic leukemia were reported with TNF blocker use. Approximately half of the postmarketing cases of malignancies in children, adolescents, and young adults receiving TNF blockers were lymphomas; other cases included rare malignancies associated with immunosuppression and malignancies not usually observed in children and adolescents. HYPERSENSITIVITY • Anaphylaxis and angioneurotic edema have been reported following HUMIRA administration. • If a serious allergic reaction occurs, stop HUMIRA and institute appropriate therapy. HEPATITIS B VIRUS REACTIVATION • Use of TNF blockers, including HUMIRA, may increase the risk of reactivation of hepatitis B virus (HBV) in patients who are chronic carriers. Some cases have been fatal. • Evaluate patients at risk for HBV infection for prior evidence of HBV infection before initiating TNF blocker therapy. • Exercise caution in patients who are carriers of HBV and monitor them during and after treatment with HUMIRA. • Discontinue HUMIRA and begin antiviral therapy in patients who develop HBV reactivation. • Exercise caution when considering resumption of HUMIRA therapy after appropriate treatment for HBV. NEUROLOGIC REACTIONS • TNF blockers, including HUMIRA, have been associated in rare cases with new onset or exacerbation of central nervous system and peripheral demyelinating diseases, including multiple sclerosis, optic neuritis, and Guillain-Barré syndrome. • Exercise caution when considering HUMIRA for patients with these disorders. HEMATOLOGIC REACTIONS • Rare reports of pancytopenia, including aplastic anemia, have been reported with TNF blockers. Medically significant cytopenia (e.g., thrombocytopenia, leukopenia) has been infrequently reported with HUMIRA. • Consider stopping HUMIRA in patients with significant hematologic abnormalities. CONGESTIVE HEART FAILURE • Worsening or new onset congestive heart failure (CHF) may occur. • Exercise caution in patients with CHF and monitor them carefully. AUTOIMMUNITY • Treatment with HUMIRA may result in the formation of autoantibodies and, rarely, in development of a lupus-like syndrome. • Discontinue treatment if symptoms of a lupus-like syndrome develop. IMMUNIZATIONS • Patients on HUMIRA should not receive live vaccines. • It is recommended that juvenile idiopathic arthritis patients, if possible, be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating HUMIRA therapy. ADVERSE REACTIONS • The most common adverse reactions in HUMIRA clinical trials (incidence >10%) were: infections (e.g., upper respiratory, sinusitis), injection site reactions, headache, and rash.

References: 1. HUMIRA Injection [package insert]. North Chicago, IL: AbbVie Inc. 2. Data on file, AbbVie Inc. 3. Keystone EC, Kavanaugh AF, Sharp JT, et al. Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti–tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled, 52-week trial. Arthritis Rheum. 2004;50(5):1400-1411.

Please see Brief Summary of full Prescribing Information on the last pages of this advertisement.

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HUMIRA® (adalimumab) WARNING: SERIOUS INFECTIONS AND MALIGNANCY SERIOUS INFECTIONS Patients treated with HUMIRA are at increased risk for developing serious infections that may lead to hospitalization or death [see Warnings and Precautions]. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. Discontinue HUMIRA if a patient develops a serious infection or sepsis. Reported infections include: • Active tuberculosis (TB), including reactivation of latent TB. Patients with TB have frequently presented with disseminated or extrapulmonary disease. Test patients for latent TB before HUMIRA use and during therapy. Initiate treatment for latent TB prior to HUMIRA use. • Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, and pneumocystosis. Patients with histoplasmosis or other invasive fungal infections may present with disseminated, rather than localized, disease. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Consider empiric anti-fungal therapy in patients at risk for invasive fungal infections who develop severe systemic illness. • Bacterial, viral and other infections due to opportunistic pathogens, including Legionella and Listeria. Carefully consider the risks and benefits of treatment with HUMIRA prior to initiating therapy in patients with chronic or recurrent infection. Monitor patients closely for the development of signs and symptoms of infection during and after treatment with HUMIRA, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy [see Warnings and Precautions and Adverse Reactions]. MALIGNANCY Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers including HUMIRA [see Warnings and Precautions]. Post-marketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers including HUMIRA. These cases have had a very aggressive disease course and have been fatal. The majority of reported TNF blocker cases have occurred in patients with Crohn’s disease or ulcerative colitis and the majority were in adolescent and young adult males. Almost all these patients had received treatment with azathioprine or 6-mercaptopurine (6–MP) concomitantly with a TNF blocker at or prior to diagnosis. It is uncertain whether the occurrence of HSTCL is related to use of a TNF blocker or a TNF blocker in combination with these other immunosuppressants [see Warnings and Precautions]. INDICATIONS AND USAGE Rheumatoid Arthritis HUMIRA is indicated for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in adult patients with moderately to severely active rheumatoid arthritis. HUMIRA can be used alone or in combination with methotrexate or other non-biologic diseasemodifying anti-rheumatic drugs (DMARDs). Juvenile Idiopathic Arthritis HUMIRA is indicated for reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis in pediatric patients 4 years of age and older. HUMIRA can be used alone or in combination with methotrexate. Psoriatic Arthritis HUMIRA is indicated for reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in adult patients with active psoriatic arthritis. HUMIRA can be used alone or in combination with non-biologic DMARDs. Ankylosing Spondylitis HUMIRA is indicated for reducing signs and symptoms in adult patients with active ankylosing spondylitis. Crohn’s Disease HUMIRA is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in adult patients with moderately to severely active Crohn’s disease who have had an inadequate response to conventional therapy. HUMIRA is indicated for reducing signs and symptoms and inducing clinical remission in these patients if they have also lost response to or are intolerant to infliximab. Ulcerative Colitis HUMIRA is indicated for inducing and sustaining clinical remission in adult patients with moderately to severely active ulcerative colitis who have had an inadequate response to immunosuppressants such as corticosteroids, azathioprine or 6-mercaptopurine (6-MP). The effectiveness of HUMIRA has not been established in patients who have lost response to or were intolerant to TNF blockers. Plaque Psoriasis HUMIRA is indicated for the treatment of adult patients with moderate to severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy, and when other systemic therapies are medically less appropriate. HUMIRA should only be administered to patients who will be closely monitored and have regular follow-up visits with a physician [see Boxed Warning and Warnings and Precautions]. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Serious Infections Patients treated with HUMIRA are at increased risk for developing serious infections involving various organ systems and sites that may lead to hospitalization or death [see Boxed Warning]. Opportunistic infections due to bacterial, mycobacterial, invasive fungal, viral, parasitic, or other opportunistic pathogens including aspergillosis,

03-A883 Humira PB-7.625 x 10.5 (3).indd 1

PROFESSIONAL BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, legionellosis, listeriosis, pneumocystosis and tuberculosis have been reported with TNF blockers. Patients have frequently presented with disseminated rather than localized disease. The concomitant use of a TNF blocker and abatacept or anakinra was associated with a higher risk of serious infections in patients with rheumatoid arthritis (RA); therefore, the concomitant use of HUMIRA and these biologic products is not recommended in the treatment of patients with RA [see Warnings and Precautions and Drug Interactions]. Treatment with HUMIRA should not be initiated in patients with an active infection, including localized infections. Patients greater than 65 years of age, patients with co-morbid conditions and/or patients taking concomitant immunosuppressants (such as corticosteroids or methotrexate), may be at greater risk of infection. Consider the risks and benefi ts of treatment prior to initiating therapy in patients: • with chronic or recurrent infection; • who have been exposed to tuberculosis; • with a history of an opportunistic infection; • who have resided or traveled in areas of endemic tuberculosis or endemic mycoses, such as histoplasmosis, coccidioidomycosis, or blastomycosis; or • with underlying conditions that may predispose them to infection. Tuberculosis Cases of reactivation of tuberculosis and new onset tuberculosis infections have been reported in patients receiving HUMIRA, including patients who have previously received treatment for latent or active tuberculosis. Reports included cases of pulmonary and extrapulmonary (i.e., disseminated) tuberculosis. Evaluate patients for tuberculosis risk factors and test for latent infection prior to initiating HUMIRA and periodically during therapy. Treatment of latent tuberculosis infection prior to therapy with TNF blocking agents has been shown to reduce the risk of tuberculosis reactivation during therapy. Consider anti-tuberculosis therapy prior to initiation of HUMIRA in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but having risk factors for tuberculosis infection. Despite prophylactic treatment for tuberculosis, cases of reactivated tuberculosis have occurred in patients treated with HUMIRA. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision whether initiating anti-tuberculosis therapy is appropriate for an individual patient. Strongly consider tuberculosis in the differential diagnosis in patients who develop a new infection during HUMIRA treatment, especially in patients who have previously or recently traveled to countries with a high prevalence of tuberculosis, or who have had close contact with a person with active tuberculosis. Monitoring Closely monitor patients for the development of signs and symptoms of infection during and after treatment with HUMIRA, including the development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy. Tests for latent tuberculosis infection may also be falsely negative while on therapy with HUMIRA. Discontinue HUMIRA if a patient develops a serious infection or sepsis. For a patient who develops a new infection during treatment with HUMIRA, closely monitor them, perform a prompt and complete diagnostic workup appropriate for an immunocompromised patient, and initiate appropriate antimicrobial therapy. Invasive Fungal Infections If patients develop a serious systemic illness and they reside or travel in regions where mycoses are endemic, consider invasive fungal infection in the differential diagnosis. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Consider appropriate empiric antifungal therapy, taking into account both the risk for severe fungal infection and the risks of antifungal therapy, while a diagnostic workup is being performed. To aid in the management of such patients, consider consultation with a physician with expertise in the diagnosis and treatment of invasive fungal infections. Malignancies Consider the risks and benefi ts of TNF-blocker treatment including HUMIRA prior to initiating therapy in patients with a known malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing a TNF blocker in patients who develop a malignancy. Malignancies in Adults In the controlled portions of clinical trials of some TNF-blockers, including HUMIRA, more cases of malignancies have been observed among TNF-blocker-treated adult patients compared to control-treated adult patients. During the controlled portions of 34 global HUMIRA clinical trials in adult patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), Crohn’s disease (CD), ulcerative colitis (UC) and plaque psoriasis (Ps), malignancies, other than non-melanoma (basal cell and squamous cell) skin cancer, were observed at a rate (95% confidence interval) of 0.6 (0.38, 0.91) per 100 patient-years among 7304 HUMIRA-treated patients versus a rate of 0.6 (0.30, 1.03) per 100 patient-years among 4232 control-treated patients (median duration of treatment of 4 months for HUMIRA-treated patients and 4 months for control-treated patients). In 47 global controlled and uncontrolled clinical trials of HUMIRA in adult patients with RA, PsA, AS, CD, UC, and Ps, the most frequently observed malignancies, other than lymphoma and NMSC, were breast, colon, prostate, lung, and melanoma. The malignancies in HUMIRA-treated patients in the controlled and uncontrolled portions of the studies were similar in type and number to what would be expected in the general U.S. population according to the SEER database (adjusted for age, gender, and race). In controlled trials of other TNF blockers in adult patients at higher risk for malignancies (i.e., patients with COPD with a significant smoking history and cyclophosphamide-treated patients with Wegener’s granulomatosis), a greater portion of malignancies occurred in the TNF blocker group compared to the control group.

Non-Melanoma Skin Cancer During the controlled portions of 34 global HUMIRA clinical trials in adult patients with RA, PsA, AS, CD, UC, and Ps, the rate (95% confidence interval) of NMSC was 0.7 (0.49, 1.08) per 100 patientyears among HUMIRA-treated patients and 0.2 (0.08, 0.59) per 100 patient-years among control-treated patients. Examine all patients, and in particular patients with a medical history of prior prolonged immunosuppressant therapy or psoriasis patients with a history of PUVA treatment for the presence of NMSC prior to and during treatment with HUMIRA. Lymphoma and Leukemia In the controlled portions of clinical trials of all the TNF-blockers in adults, more cases of lymphoma have been observed among TNFblocker-treated patients compared to control-treated patients. In the controlled portions of 34 global HUMIRA clinical trials in adult patients with RA, PsA, AS, CD, UC and Ps, 3 lymphomas occurred among 7304 HUMIRA-treated patients versus 1 among 4232 controltreated patients. In 47 global controlled and uncontrolled clinical trials of HUMIRA in adult patients with RA, PsA, AS, CD, UC and Ps with a median duration of approximately 0.6 years, including 23,036 patients and over 34,000 patient-years of HUMIRA, the observed rate of lymphomas was approximately 0.11 per 100 patient-years. This is approximately 3-fold higher than expected in the general U.S. population according to the SEER database (adjusted for age, gender, and race). Rates of lymphoma in clinical trials of HUMIRA cannot be compared to rates of lymphoma in clinical trials of other TNF blockers and may not predict the rates observed in a broader patient population. Patients with RA and other chronic inflammatory diseases, particularly those with highly active disease and/or chronic exposure to immunosuppressant therapies, may be at a higher risk (up to several fold) than the general population for the development of lymphoma, even in the absence of TNF blockers. Post-marketing cases of acute and chronic leukemia have been reported in association with TNF-blocker use in RA and other indications. Even in the absence of TNF-blocker therapy, patients with RA may be at a higher risk (approximately 2-fold) than the general population for the development of leukemia. Malignancies in Pediatric Patients and Young Adults Malignancies, some fatal, have been reported among children, adolescents, and young adults who received treatment with TNF-blockers (initiation of therapy ≤ 18 years of age), of which HUMIRA is a member [see Boxed Warning]. Approximately half the cases were lymphomas, including Hodgkin’s and non-Hodgkin’s lymphoma. The other cases represented a variety of different malignancies and included rare malignancies usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months of therapy (range 1 to 84 months). Most of the patients were receiving concomitant immunosuppressants. These cases were reported post-marketing and are derived from a variety of sources including registries and spontaneous postmarketing reports. Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers including HUMIRA [see Boxed Warning]. These cases have had a very aggressive disease course and have been fatal. The majority of reported TNF blocker cases have occurred in patients with Crohn’s disease or ulcerative colitis and the majority were in adolescent and young adult males. Almost all of these patients had received treatment with the immunosuppressants azathioprine or 6-mercaptopurine (6–MP) concomitantly with a TNF blocker at or prior to diagnosis. It is uncertain whether the occurrence of HSTCL is related to use of a TNF blocker or a TNF blocker in combination with these other immunosuppressants. The potential risk with the combination of azathioprine or 6-mercaptopurine and HUMIRA should be carefully considered. Hypersensitivity Reactions Anaphylaxis and angioneurotic edema have been reported following HUMIRA administration. If an anaphylactic or other serious allergic reaction occurs, immediately discontinue administration of HUMIRA and institute appropriate therapy. In clinical trials of HUMIRA in adults, allergic reactions (e.g., allergic rash, anaphylactoid reaction, fixed drug reaction, non-specified drug reaction, urticaria) have been observed. Hepatitis B Virus Reactivation Use of TNF blockers, including HUMIRA, may increase the risk of reactivation of hepatitis B virus (HBV) in patients who are chronic carriers of this virus. In some instances, HBV reactivation occurring in conjunction with TNF blocker therapy has been fatal. The majority of these reports have occurred in patients concomitantly receiving other medications that suppress the immune system, which may also contribute to HBV reactivation. Evaluate patients at risk for HBV infection for prior evidence of HBV infection before initiating TNF blocker therapy. Exercise caution in prescribing TNF blockers for patients identified as carriers of HBV. Adequate data are not available on the safety or efficacy of treating patients who are carriers of HBV with anti-viral therapy in conjunction with TNF blocker therapy to prevent HBV reactivation. In patients who develop HBV reactivation, stop HUMIRA and initiate effective anti-viral therapy with appropriate supportive treatment. The safety of resuming TNF blocker therapy after HBV reactivation is controlled is not known. Neurologic Reactions Use of TNF blocking agents, including HUMIRA, has been associated with rare cases of new onset or exacerbation of clinical symptoms and/ or radiographic evidence of central nervous system demyelinating disease, including multiple sclerosis (MS) and optic neuritis, and peripheral demyelinating disease, including Guillain-Barré syndrome. Exercise caution in considering the use of HUMIRA in patients with preexisting or recent-onset central or peripheral nervous system demyelinating disorders. Hematological Reactions Rare reports of pancytopenia including aplastic anemia have been reported with TNF blocking agents. Adverse reactions of the hematologic system, including medically significant cytopenia (e.g., thrombocytopenia, leukopenia) have been infrequently reported with HUMIRA. The causal relationship of these reports to HUMIRA remains unclear. Advise all patients to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias or infection (e.g., persistent fever, bruising, bleeding, pallor) while on HUMIRA.

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Consider discontinuation of HUMIRA therapy in patients with confirmed significant hematologic abnormalities. Use with Anakinra Concurrent use of anakinra (an interleukin-1 antagonist) and another TNF-blocker, was associated with a greater proportion of serious infections and neutropenia and no added benefi t compared with the TNF-blocker alone in patients with RA. Therefore, the combination of HUMIRA and anakinra is not recommended [see Drug Interactions]. Heart Failure Cases of worsening congestive heart failure (CHF) and new onset CHF have been reported with TNF blockers. Cases of worsening CHF have also been observed with HUMIRA. Exercise caution when using HUMIRA in patients who have heart failure and monitor them carefully. Autoimmunity Treatment with HUMIRA may result in the formation of autoantibodies and, rarely, in the development of a lupus-like syndrome. If a patient develops symptoms suggestive of a lupus-like syndrome following treatment with HUMIRA, discontinue treatment [see Adverse Reactions]. Immunizations In a placebo-controlled clinical trial of patients with RA, no difference was detected in anti-pneumococcal antibody response between HUMIRA and placebo treatment groups when the pneumococcal polysaccharide vaccine and influenza vaccine were administered concurrently with HUMIRA. Patients on HUMIRA may receive concurrent vaccinations, except for live vaccines. No data are available on the secondary transmission of infection by live vaccines in patients receiving HUMIRA. It is recommended that JIA patients, if possible, be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating HUMIRA therapy. Patients on HUMIRA may receive concurrent vaccinations, except for live vaccines. Use with Abatacept In controlled trials, the concurrent administration of TNF-blockers and abatacept was associated with a greater proportion of serious infections than the use of a TNF-blocker alone; the combination therapy, compared to the use of a TNF-blocker alone, has not demonstrated improved clinical benefi t in the treatment of RA. Therefore, the combination of abatacept with TNF-blockers including HUMIRA is not recommended [see Drug Interactions]. ADVERSE REACTIONS The most serious adverse reactions described elsewhere in the labeling include the following: • Serious Infections [see Warnings and Precautions] • Malignancies [see Warnings and Precautions] Clinical Trials Experience The most common adverse reaction with HUMIRA was injection site reactions. In placebo-controlled trials, 20% of patients treated with HUMIRA developed injection site reactions (erythema and/or itching, hemorrhage, pain or swelling), compared to 14% of patients receiving placebo. Most injection site reactions were described as mild and generally did not necessitate drug discontinuation. The proportion of patients who discontinued treatment due to adverse reactions during the double-blind, placebo-controlled portion of studies in patients with RA (i.e., Studies RA-I, RA-II, RA-III and RA-IV) was 7% for patients taking HUMIRA and 4% for placebo-treated patients. The most common adverse reactions leading to discontinuation of HUMIRA in these RA studies were clinical flare reaction (0.7%), rash (0.3%) and pneumonia (0.3%). Infections In the controlled portions of the 34 global HUMIRA clinical trials in adult patients with RA, PsA, AS, CD, UC and Ps, the rate of serious infections was 4.6 per 100 patient-years in 7304 HUMIRA-treated patients versus a rate of 3.1 per 100 patient-years in 4232 control-treated patients. Serious infections observed included pneumonia, septic arthritis, prosthetic and post-surgical infections, erysipelas, cellulitis, diverticulitis, and pyelonephritis [see Warnings and Precautions]. Tuberculosis and Opportunistic Infections In 47 global controlled and uncontrolled clinical trials in RA, PsA, AS, CD, UC and Ps that included 23,036 HUMIRA-treated patients, the rate of reported active tuberculosis was 0.22 per 100 patient-years and the rate of positive PPD conversion was 0.08 per 100 patient-years. In a subgroup of 9396 U.S. and Canadian HUMIRA-treated patients, the rate of reported active TB was 0.07 per 100 patient-years and the rate of positive PPD conversion was 0.08 per 100 patient-years. These trials included reports of miliary, lymphatic, peritoneal, and pulmonary TB. Most of the TB cases occurred within the first eight months after initiation of therapy and may reflect recrudescence of latent disease. In these global clinical trials, cases of serious opportunistic infections have been reported at an overall rate of 0.08 per 100 patient-years. Some cases of serious opportunistic infections and TB have been fatal [see Warnings and Precautions]. Autoantibodies In the rheumatoid arthritis controlled trials, 12% of patients treated with HUMIRA and 7% of placebo-treated patients that had negative baseline ANA titers developed positive titers at week 24. Two patients out of 3046 treated with HUMIRA developed clinical signs suggestive of new-onset lupus-like syndrome. The patients improved following discontinuation of therapy. No patients developed lupus nephritis or central nervous system symptoms. The impact of long-term treatment with HUMIRA on the development of autoimmune diseases is unknown. Liver Enzyme Elevations There have been reports of severe hepatic reactions including acute liver failure in patients receiving TNF-blockers. In controlled Phase 3 trials of HUMIRA (40 mg SC every other week) in patients with RA, PsA, and AS with control period duration ranging from 4 to 104 weeks, ALT elevations ≥ 3 x ULN occurred in 3.5% of HUMIRA-treated patients and 1.5% of control-treated patients. Since many of these patients in these trials were also taking medications that cause liver enzyme elevations (e.g., NSAIDS, MTX), the relationship between HUMIRA and the liver enzyme elevations is not clear. In controlled Phase 3 trials of HUMIRA (initial doses of 160 mg and 80 mg, or 80 mg and 40 mg on Days 1 and 15, respectively, followed by 40 mg every other week) in patients with CD with control period duration ranging from 4 to 52 weeks, ALT elevations ≥ 3 x ULN occurred in 0.9% of HUMIRA-treated patients and 0.9% of control-treated patients. In controlled Phase 3

03-A883 Humira PB-7.625 x 10.5 (3).indd 2

trials of HUMIRA (initial doses of 160 mg and 80 mg on Days 1 and 15 respectively, followed by 40 mg every other week) in patients with UC with control period duration ranging from 1 to 52 weeks, ALT elevations ≥3 x ULN occurred in 1.5% of HUMIRA-treated patients and 1.0% of control-treated patients. In controlled Phase 3 trials of HUMIRA (initial dose of 80 mg then 40 mg every other week) in patients with Ps with control period duration ranging from 12 to 24 weeks, ALT elevations ≥ 3 x ULN occurred in 1.8% of HUMIRA-treated patients and 1.8% of control-treated patients. Immunogenicity Patients in Studies RA-I, RA-II, and RA-III were tested at multiple time points for antibodies to adalimumab during the 6- to 12-month period. Approximately 5% (58 of 1062) of adult RA patients receiving HUMIRA developed low-titer antibodies to adalimumab at least once during treatment, which were neutralizing in vitro. Patients treated with concomitant methotrexate (MTX) had a lower rate of antibody development than patients on HUMIRA monotherapy (1% versus 12%). No apparent correlation of antibody development to adverse reactions was observed. With monotherapy, patients receiving every other week dosing may develop antibodies more frequently than those receiving weekly dosing. In patients receiving the recommended dosage of 40 mg every other week as monotherapy, the ACR 20 response was lower among antibody-positive patients than among antibody-negative patients. The long-term immunogenicity of HUMIRA is unknown. In patients with JIA, adalimumab antibodies were identified in 16% of HUMIRA-treated patients. In patients receiving concomitant MTX, the incidence was 6% compared to 26% with HUMIRA monotherapy. In patients with AS, the rate of development of antibodies to adalimumab in HUMIRA-treated patients was comparable to patients with RA. In patients with PsA, the rate of antibody development in patients receiving HUMIRA monotherapy was comparable to patients with RA; however, in patients receiving concomitant MTX the rate was 7% compared to 1% in RA. In patients with CD, the rate of antibody development was 3%. In patients with moderately to severely active UC, the rate of antibody development in patients receiving HUMIRA was 5%. However, due to the limitation of the assay conditions, antibodies to adalimumab could be detected only when serum adalimumab levels were < 2 ug/ml. Among the patients whose serum adalimumab levels were < 2 ug/ml (approximately 25% of total patients studied), the immunogenicity rate was 20.7%. In patients with Ps, the rate of antibody development with HUMIRA monotherapy was 8%. However, due to the limitation of the assay conditions, antibodies to adalimumab could be detected only when serum adalimumab levels were < 2 ug/ml. Among the patients whose serum adalimumab levels were < 2 ug/ml (approximately 40% of total patients studied), the immunogenicity rate was 20.7%. In Ps patients who were on HUMIRA monotherapy and subsequently withdrawn from the treatment, the rate of antibodies to adalimumab after retreatment was similar to the rate observed prior to withdrawal. Other Adverse Reactions Rheumatoid Arthritis Clinical Studies The data described below reflect exposure to HUMIRA in 2468 patients, including 2073 exposed for 6 months, 1497 exposed for greater than one year and 1380 in adequate and well-controlled studies (Studies RA-I, RA-II, RA-III, and RA-IV). HUMIRA was studied primarily in placebo-controlled trials and in long-term follow up studies for up to 36 months duration. The population had a mean age of 54 years, 77% were female, 91% were Caucasian and had moderately to severely active rheumatoid arthritis. Most patients received 40 mg HUMIRA every other week. Table 1 summarizes reactions reported at a rate of at least 5% in patients treated with HUMIRA 40 mg every other week compared to placebo and with an incidence higher than placebo. In Study RA-III, the types and frequencies of adverse reactions in the second year open-label extension were similar to those observed in the one-year double-blind portion. Table 1. Adverse Reactions Reported by ≥5% of Patients Treated with HUMIRA During Placebo-Controlled Period of Pooled RA Studies (Studies RA-I, RA-II, RA-III, and RA-IV) HUMIRA Placebo 40 mg subcutaneous Every Other Week (N=705) (N=690) Adverse Reaction (Preferred Term) Respiratory Upper respiratory infection 17% 13% Sinusitis 11% 9% Flu syndrome 7% 6% Gastrointestinal Nausea 9% 8% Abdominal pain 7% 4% Laboratory Tests* Laboratory test abnormal 8% 7% Hypercholesterolemia 6% 4% Hyperlipidemia 7% 5% Hematuria 5% 4% Alkaline phosphatase increased 5% 3% Other Headache 12% 8% Rash 12% 6% Accidental injury 10% 8% Injection site reaction ** 8% 1% Back pain 6% 4% Urinary tract infection 8% 5% Hypertension 5% 3% * Laboratory test abnormalities were reported as adverse reactions in European trials ** Does not include injection site erythema, itching, hemorrhage, pain or swelling

Juvenile Idiopathic Arthritis Clinical Studies In general, the adverse reactions in the HUMIRA-treated pediatric patients in the juvenile idiopathic arthritis (JIA) trial were similar in frequency and type to those seen in adult patients [see Warnings and Precautions and Adverse Reactions]. Important findings and differences from adults are discussed in the following paragraphs. HUMIRA was studied in 171 pediatric patients, 4 to 17 years of age, with polyarticular JIA. Severe adverse reactions reported in the study included neutropenia, streptococcal pharyngitis, increased aminotransferases, herpes zoster, myositis, metrorrhagia, appendicitis. Serious infections were observed in 4% of patients within approximately 2 years of initiation of treatment with HUMIRA and included cases of herpes simplex, pneumonia, urinary tract infection, pharyngitis, and herpes zoster. A total of 45% of children experienced an infection while receiving HUMIRA with or without concomitant MTX in the first 16 weeks of treatment. The types of infections reported in HUMIRA-treated patients were generally similar to those commonly seen in JIA patients who are not treated with TNF blockers. Upon initiation of treatment, the most common adverse reactions occurring in the pediatric population treated with HUMIRA were injection site pain and injection site reaction (19% and 16%, respectively). A less commonly reported adverse event in children receiving HUMIRA was granuloma annulare which did not lead to discontinuation of HUMIRA treatment. In the first 48 weeks of treatment, non-serious hypersensitivity reactions were seen in approximately 6% of children and included primarily localized allergic hypersensitivity reactions and allergic rash. Isolated mild to moderate elevations of liver aminotransferases (ALT more common than AST) were observed in children with JIA exposed to HUMIRA alone; liver enzyme test elevations were more frequent among those treated with the combination of HUMIRA and MTX than those treated with HUMIRA alone. In general, these elevations did not lead to discontinuation of HUMIRA treatment. In the JIA trial, 10% of patients treated with HUMIRA who had negative baseline anti-dsDNA antibodies developed positive titers after 48 weeks of treatment. No patient developed clinical signs of autoimmunity during the clinical trial. Approximately 15% of children treated with HUMIRA developed mildto-moderate elevations of creatine phosphokinase (CPK). Elevations exceeding 5 times the upper limit of normal were observed in several patients. CPK levels decreased or returned to normal in all patients. Most patients were able to continue HUMIRA without interruption. Psoriatic Arthritis and Ankylosing Spondylitis Clinical Studies HUMIRA has been studied in 395 patients with psoriatic arthritis (PsA) in two placebo-controlled trials and in an open label study and in 393 patients with ankylosing spondylitis (AS) in two placebo-controlled studies. The safety profile for patients with PsA and AS treated with HUMIRA 40 mg every other week was similar to the safety profile seen in patients with RA, HUMIRA Studies RA-I through IV. Crohn’s Disease Clinical Studies HUMIRA has been studied in 1478 patients with Crohn’s disease (CD) in four placebo-controlled and two open-label extension studies. The safety profile for patients with CD treated with HUMIRA was similar to the safety profile seen in patients with RA. Ulcerative Colitis Clinical Studies HUMIRA has been studied in 1010 patients with ulcerative colitis (UC) in two placebo-controlled studies and one open-label extension study. The safety profile for patients with UC treated with HUMIRA was similar to the safety profile seen in patients with RA. Plaque Psoriasis Clinical Studies HUMIRA has been studied in 1696 patients with plaque psoriasis (Ps) in placebo-controlled and open-label extension studies. The safety profile for patients with Ps treated with HUMIRA was similar to the safety profile seen in patients with RA with the following exceptions. In the placebo-controlled portions of the clinical trials in Ps patients, HUMIRA-treated patients had a higher incidence of arthralgia when compared to controls (3% vs. 1%). Postmarketing Experience The following adverse reactions have been identified during postapproval use of HUMIRA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to HUMIRA exposure. Gastrointestinal disorders: Diverticulitis, large bowel perforations including perforations associated with diverticulitis and appendiceal perforations associated with appendicitis, pancreatitis General disorders and administration site conditions: Pyrexia Hepato-biliary disorders: Liver failure Immune system disorders: Sarcoidosis Neoplasms benign, malignant and unspecified (incl cysts and polyps): Merkel Cell Carcinoma (neuroendocrine carcinoma of the skin) Nervous system disorders: Demyelinating disorders (e.g., optic neuritis, Guillain-Barré syndrome), cerebrovascular accident Respiratory disorders: Interstitial lung disease, including pulmonary fibrosis, pulmonary embolism Skin reactions: Stevens Johnson Syndrome, cutaneous vasculitis, erythema multiforme, new or worsening psoriasis (all sub-types including pustular and palmoplantar), alopecia Vascular disorders: Systemic vasculitis, deep vein thrombosis DRUG INTERACTIONS Methotrexate Although methotrexate (MTX) reduces the apparent adalimumab clearance, the data do not suggest the need for dose adjustment of either HUMIRA or MTX. Biological Products In clinical studies in patients with RA, an increased risk of serious infections has been seen with the combination of TNF blockers with anakinra or abatacept, with no added benefi t; therefore, use of HUMIRA with abatacept or anakinra is not recommended in patients with RA [see Warnings and Precautions]. A higher rate of serious infections has also been observed in patients with RA treated with rituximab who received subsequent treatment with a TNF blocker. There is insufficient information regarding the concomitant use of HUMIRA and other biologic products for the treatment of RA, PsA, AS, CD, UC, and Ps. Concomitant administration of HUMIRA with

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DO NOT RE-SIZE Ad unit Project # must match this project # 64C-1439576

other biologic DMARDS (e.g., anakinra and abatacept) or other TNF blockers is not recommended based upon the possible increased risk for infections and other potential pharmacological interactions. Live Vaccines Avoid the use of live vaccines with HUMIRA [see Warnings and Precautions]. Cytochrome P450 Substrates The formation of CYP450 enzymes may be suppressed by increased levels of cytokines (e.g., TNFα, IL-6) during chronic inflammation. It is possible for a molecule that antagonizes cytokine activity, such as adalimumab, to influence the formation of CYP450 enzymes. Upon initiation or discontinuation of HUMIRA in patients being treated with CYP450 substrates with a narrow therapeutic index, monitoring of the effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) is recommended and the individual dose of the drug product may be adjusted as needed. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category B Risk Summary Adequate and well controlled studies with HUMIRA have not been conducted in pregnant women. Adalimumab is an IgG1 monoclonal antibody and IgG1 is actively transferred across the placenta during the third trimester of pregnancy. Adalimumab serum levels were obtained from ten women treated with HUMIRA during pregnancy and eight newborn infants suggest active placental transfer of adalimumab. No fetal harm was observed in reproductive studies performed in cynomolgus monkeys. Because animal reproductive studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Clinical Considerations In general, monoclonal antibodies are transported across the placenta in a linear fashion as pregnancy progresses, with the largest amount transferred during the third trimester. Human Data In an independent clinical study conducted in ten pregnant women with inflammatory bowel disease treated with HUMIRA, adalimumab concentrations were measured in maternal blood as well as in cord (n=10) and infant blood (n=8) on the day of birth. The last dose of HUMIRA was given between 1 and 56 days prior to delivery. Adalimumab concentrations were 0.16-19.7 μg/mL in cord blood, 4.2817.7 μg/mL in infant blood, and 0-16.1 μg/mL in maternal blood. In all but one case, the cord blood level of adalimumab was higher than the maternal level, suggesting adalimumab actively crosses the placenta. In addition, one infant had levels at each of the following: 6 weeks (1.94 μg/mL), 7 weeks (1.31 μg/mL), 8 weeks (0.93 μg/mL), and 11 weeks (0.53 μg/mL), suggesting adalimumab can be detected in the serum of infants exposed in utero for at least 3 months from birth. Nursing Mothers Limited data from published literature indicate that adalimumab is present in low levels in human milk and is not likely to be absorbed by a breastfed infant. However, no data is available on the absorption of adalimumab from breastmilk in newborn or preterm infants. Caution should be exercised when HUMIRA is administered to a nursing woman.

03-A883 Humira PB-7.625 x 10.5 (3).indd 3

Pediatric Use Safety and efficacy of HUMIRA in pediatric patients for uses other than juvenile idiopathic arthritis (JIA) have not been established. Due to its inhibition of TNFα, HUMIRA administered during pregnancy could affect immune response in the in utero-exposed newborn and infant. Data from eight infants exposed to HUMIRA in utero, suggest adalimumab crosses the placenta [see Use in Specific Populations]. The clinical significance of elevated adalimumab levels in infants is unknown. The safety of administering live or live-attenuated vaccines in exposed infants is unknown. Risks and benefi ts should be considered prior to vaccinating (live or live-attenuated) exposed infants. Post-marketing cases of lymphoma, including hepatosplenic T-cell lymphoma and other malignancies, some fatal, have been reported among children, adolescents, and young adults who received treatment with TNF-blockers including HUMIRA [see Boxed Warning and Warnings and Precautions]. Juvenile Idiopathic Arthritis In the JIA trial, HUMIRA was shown to reduce signs and symptoms of active polyarticular JIA in patients 4 to 17 years of age. HUMIRA has not been studied in children less than 4 years of age, and there are limited data on HUMIRA treatment in children with weight <15 kg. The safety of HUMIRA in pediatric patients in the JIA trial was generally similar to that observed in adults with certain exceptions [see Adverse Reactions]. Geriatric Use A total of 519 RA patients 65 years of age and older, including 107 patients 75 years of age and older, received HUMIRA in clinical studies RA-I through IV. No overall difference in effectiveness was observed between these subjects and younger subjects. The frequency of serious infection and malignancy among HUMIRA treated subjects over 65 years of age was higher than for those under 65 years of age. Because there is a higher incidence of infections and malignancies in the elderly population, use caution when treating the elderly. OVERDOSAGE Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies of HUMIRA have not been conducted to evaluate the carcinogenic potential or its effect on fertility. No clastogenic or mutagenic effects of HUMIRA were observed in the in vivo mouse micronucleus test or the Salmonella-Escherichia coli (Ames) assay, respectively. PATIENT COUNSELING INFORMATION Patient Counseling Provide the HUMIRA “Medication Guide” to patients or their caregivers, and provide them an opportunity to read it and ask questions prior to initiation of therapy and prior to each time the prescription is renewed. If patients develop signs and symptoms of infection, instruct them to seek medical evaluation immediately. Advise patients of the potential benefi ts and risks of HUMIRA.

• Infections Inform patients that HUMIRA may lower the ability of their immune system to fight infections. Instruct patients of the importance of contacting their doctor if they develop any symptoms of infection, including tuberculosis, invasive fungal infections, and reactivation of hepatitis B virus infections. • Malignancies Counsel patients about the risk of malignancies while receiving HUMIRA. • Allergic Reactions Advise patients to seek immediate medical attention if they experience any symptoms of severe allergic reactions. Advise latex-sensitive patients that the needle cap of the prefilled syringe contains latex. • Other Medical Conditions Advise patients to report any signs of new or worsening medical conditions such as congestive heart failure, neurological disease, autoimmune disorders, or cytopenias. Advise patients to report any symptoms suggestive of a cytopenia such as bruising, bleeding, or persistent fever. AbbVie Inc. North Chicago, IL 60064, U.S.A. Ref: 03-A883 - Revised September, 2013 64C-1301110 MASTER 64C-1439576

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OSTEOARTRITIS ¿proceso inflamatorio o degenerativo?

Por: María L. Recurt, MD Reumatóloga Miembro de la Asociación de Reumatólogos de Puerto Rico

Keywords osteoarthritis, arthritis, articular cartilage, proteolytic enzymes, subchondral bone Palabras claves osteoartritis, artritis, cartílago articular, enzimas proteolíticas, hueso subcondral

Abstract Osteoarthritis is the most common type of arthritis and it affects 80% of the people over the age of 70. For a long time OA has been defined as the inevitable result from deterioration of articular cartilage. Over the years research has produced evidence that suggests that this is a more complicated process. An initial event, possibly a mechanical cause, in addition to other endogenous factors (such as mutations in collagen type II ) in a genetically predisposed patient, generates a chain of events in which proteolytic enzymes are produced that promote and amplify an inflammatory response, eventually causing the destruction of articular cartilage and subchondral bone that we see in OA. The goal of the OA treatment is not only to reduce symptoms and minimize disability, but to understand the processes involved on its development, which could limit the progression of structural damage and stop this condition in its early stages.

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Resumen La Osteoartritis (OA) afecta un 80% de la población sobre la edad de 70 años, lo que la hace el tipo de artritis más común. Por mucho tiempo esta artritis se ha definido como el producto inevitable del desgaste eventual del cartílago articular. A través de los años la investigación ha producido evidencia que apunta a que esto es un proceso más complicado. Un evento inicial, posiblemente de origen mecánico, además de factores endógenos (como mutaciones en el colágeno tipo II), en el paciente genéticamente predispuesto, generan una cadena de eventos en la cual se producen enzimas proteolíticas que promueven y amplifican una respuesta inflamatoria produciendo eventualmente la destrucción del cartílago articular y hueso subcondral que vemos en OA. La meta del tratamiento de OA no solamente es reducir los síntomas y minimizar la incapacidad. Si entendemos bien los procesos envueltos en el desarrollo de OA, podremos algún día limitar la progresión del daño estructural y detener esta condición en sus etapas tempranas.

MSP ARTÍCULO MÉDICO

“La Osteoartritis (OA) es el tipo de artritis más común que, tradicionalmente, se ha asociado al proceso de envejecimiento” Introducción A medida que la población de edad avanzada va aumentando, se ha convertido en una de las primeras causas de incapacidad y dolor en personas mayores. Probablemente debido a ésto, en los últimos años ha habido un enfoque en tratar de entender cuáles son los factores que desencadenan en el daño articular, a veces devastador, de esta condición. Estas investigaciones han producido varias sorpresas, como veremos. Primero, se ha visto que el cartílago (que es el tejido con un coeficiente de fricción bajo, que permite el deslizamiento durante el movimiento articular) no es un tejido inerte, si no bastante activo que responde a factores externos al igual que endógenos. Segundo, el proceso de OA no solo afecta el cartílago, si no también afecta todos los otros tejidos adyacentes: la membrana sinovial, el hueso subcondral, los ligamentos y los músculos peri articulares. Tercero, se han encontrado varios marcadores biológicos que correlacionan con inflamación de la membrana sinovial, apuntando a un mecanismo inflamatorio que multiplica el daño a la articulación. Factores de Riesgo El factor de riesgo primordial para el desarrollo de OA sigue siendo la edad avanzada. Los demás son: trauma previo a la articulación, obesidad, predisposición genética y factores mecánicos incluyendo mal alineamiento y deformidad articular. Los factores mecánicos tienen un rol primordial en iniciar el proceso. Factores endógenos, como mutaciones en el Colágeno Tipo II también pueden iniciar el proceso de OA. ¿Desgaste o inflamación? Aunque no está del todo claro, la evidencia ha ido aumentando hacia un proceso inflamatorio en el desarrollo de OA. El daño inicial ocurre a nivel

del cartílago. Este daño estimula a los condrocitos, que normalmente están en un estado de “descanso”, a activarse y producir ciertas sustancias químicas (colagenasas, metaloproteinasas) que degradan la red del colágeno articular hasta el punto que ya no hay marcha atrás. En la membrana sinovial también se ven cambios inflamatorios con infiltrados de macrófagos y linfocitos. Además, hay aumento en mediadores de inflamación en el líquido sinovial. Las citoquinas IL-1B y TNF-alfa han sido las más estudiadas. Sin embargo, cuando se han estudiado los bloqueadores de TNF-alfa en pacientes de OA, la mejoría sintomática ha sido mínima. Esto apunta a que hay otros factores envueltos y que nos queda mucho por aprender. En cuanto a mediadores de inflamación, un estudio detectó que en el suero de mujeres con OA progresiva de rodillas hubo un aumento en los niveles de Proteína C Reactiva (CRP por sus siglas en inglés). Esto nos indica que hay un mecanismo sistémico de inflamación envuelto, y no solo un evento mecánico localizado. En adición, los cambios que vemos en el examen físico de los pacientes de OA activa son los cambios típicos de inflamación: hinchazón, enrojecimiento, entumecimiento, y efusión, entre otros. Al igual que en la Artritis Reumatoide se desarrollaron medicamentos que efectivamente modifican la progresión de la enfermedad (DMARD’s por sus siglas en inglés), en OA se están investigando activamente varias sustancias que se espera modifiquen y retrasen la progresión de OA. Estas sustancias, que se han denominado DMOAD’s (modificadores de enfermedad de OA), son por ejemplo: inhibidores de metaloproteinasas, inhibidores de actividad de citoquinas (IL-1B, TNF), inhibidores de Oxido Nítrico, y terapia genética dirigida, entre otros. Conclusión En resumen, hay ya suficiente evidencia que apunta a un proceso inflamatorio activo en el desarrollo del daño articular en OA. Sin embargo, podemos concluir que lo que inicia todo este proceso es un daño mecánico inicial al cartílago, en personas con los factores de riesgo que predisponen a ésto. Definitivamente, hace falta más investigación. La meta

del tratamiento de OA no solamente es reducir los síntomas de dolor y minimizar la incapacidad, si no también poder llegar al punto de detener la progresión del daño estructural antes de que sea irreversible. Si pudiéramos intervenir en el proceso de destrucción articular y detenerlo en sus fases tempranas, tendríamos mucho más que ofrecerles a los pacientes para hacer un cambio sustancial en sus vidas. Al presente, el énfasis debe estar dirigido a minimizar las probabilidades de desarrollar OA severa y atacar aquellos factores de riesgo que sí podemos modificar. Mantener un peso ideal es crucial para evitar la sobrecarga al cartílago articular con el eventual desarrollo de micro fracturas subcondrales y los procesos inflamatorios que terminan destruyendo la articulación. Los ejercicios de fortalecimiento son también importantes para mantener la integridad de los componentes articulares (músculos y ligamentos) que le ofrecen protección a las coyunturas. Las personas que tienen trabajos de alto impacto y movimientos repetitivos, deben proteger sus articulaciones con soportes, ejercicios de estiramiento y periodos frecuentes de descanso, al igual que asumir posiciones adecuadas en el trabajo que minimicen lastimaduras. Los antiinflamatorios y las inyecciones locales de esteroides pueden ayudar temporeramente una vez que el proceso inflamatorio esté establecido, pero no intervienen en detener la progresión de la OA. Esperemos que en un futuro cercano la investigación dirigida a los DMOAD’s dé fruto y podamos llegar a detener la progresión de esta condición que puede ser potencialmente dolorosa e incapacitante. Referencias:

1. Loeser, R. et.al. Osteoarthritis, a disease of the joint as an organ. Arthr.Rheum. 2012;64:1697-1707 2. Abramson, S. Osteoarthritis, an inflammatory disease. Arthr.Rheum.2001;44:1237-1247 3. Zhang, L. et.al. Mechanical and biologic link between cartilage and subchondral bone in osteoarthritis. Arthr.Care & Research. 2012;64:960-967 4. Spector, T.D. et.al. Low level increases in serum C-reactive protein are present in early osteoarthritis of the knee and predict prog ressive disease. Arthr. Rheum.1997;40:723-7 Revista Puertorriqueña de Medicina y Salúd Pública

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El rol de la enfermería en el manejo del paciente con artritis rematoide Por: Lisandra Santana Delgado, RN, BSN Certificada por la Sociedad de Enfermeras Reumatológicas

Abstract This article demonstrates the role of the nurses in their interaction with patients with Rheumatoid Arthritis and their contribution and support for these patients’ welfare.

Resumen Este artículo presenta el rol de las enfermeras en su interacción con el paciente de Artritis Reumatoide, así como su contribución y apoyo para el bienestar de estos pacientes.

Keywords: rheumatoid arthritis, treatment, rheumatologist, nurse

Palabras claves: artritis reumatoide, tratamiento, reumatólogo, enfermera

“La mayoría de los estudios muestran un aumento significativo de la satisfacción con la información, empatía, actitud y acceso rápido a cuidados en los pacientes con Artritis Reumatoide cuando estos están monitorizados por enfermeras” 66

n reumatología las enfer meras a menudo actúan como intermediarias entre pacientes y reumatólogos. Como resultado de los nuevos tratamientos de las enfermedades reumáticas el papel de la enfermera debe experimentar una evolución. La función que desarrollan estas profesionales de la salud en la atención y en el tratamiento de los pacientes con artritis crónicas (artritis reumatoide, espondilitis anquilosante, artritis psoriásica) varía de una manera importante, debido a su distinto nivel de formación, entrenamiento y experiencia. En el contenido de su trabajo también influyen las diferentes regulaciones de los servicios de salud, así como

Revista Puertorriqueña de Medicina y Salúd Pública

la estructura del consultorio médico, hospital o en cualquier otro lugar donde se dedique de manera profesional a ofrecer servicios de salud especializados. Desde mi perspectiva como enfermera; los pacientes deben recibir respeto, atención, comprensión y educación. Una vez llegan a la oficina médica deben sentir la confianza para expresar los síntomas presentados durante los últimos meses con el objetivo de obtener un historial sobre el progreso de su enfermedad. Los objetivos principales son favorecer el auto cuidado mediante el aumento de conocimientos y proporcionar herramientas que faciliten la toma de decisiones sobre cómo manejar su enfermedad.

La educación es indispensable en el manejo del paciente al punto de representar una de las intervenciones más costo efectivas en el paciente reumático. En la oficina o consultorio médico la enfermera es una facilitadora. La educación permite que el paciente pueda participar de manera activa en la toma de decisiones sobre el tratamiento. La educación del paciente debe ser un proceso planificado que tenga como meta mejorar las estrategias de cuidado y aumentar las capacidades de autocuidado para aumentar el conocimiento de los pacientes del proceso de su enfermedad, de las estrategias y objetivos del tratamiento (conseguir la remisión clínica

MSP ARTÍCULO ORIGINAL

de la enfermedad o una baja actividad de la misma), rehabilitación, estrategias de autocuidado (técnicas de protección articular). La implicación en el tratamiento de estos enfermos permite a las enfermeras ofrecer información oportuna a los pacientes con la enfermedad inicial o con la enfermedad ya evolucionada. La educación también debe de dirigirse hacia la detección de los factores de riesgo para desarrollar otras enfermedades que presentan los pacientes con artritis. Las enfermeras deben jugar un papel importante en alcanzar los principios básicos del tratamiento médico al paciente con artritis, esto es: intentar conseguir la remisión de la enfermedad o el nivel de actividad más bajo posible, mediante el fomento de la adherencia de los pacientes al tratamiento. En conjunto, la literatura médica demuestra que la educación impartida por enfermeras mejora el conocimiento de la enfermedad y de sus consecuencias. Los tratamientos para estos pacientes en la mayoría de las veces son sumamente costosos, y la mayoría de los pacientes tienen problemas para poder costearlos. Como parte del servicio que se le ofrece al

paciente, las enfermeras pueden canalizar las recetas y orientar al paciente para determinar a cual programa de los existentes puede cualificar para obtener ayuda de asistencia económica o para la compra de sus medicamentos. Esta intervención es importante pues de ello depende la adherencia que tenga el paciente con su tratamiento. Una vez el paciente es diagnosticado y requiere el uso de medicamentos intravenosos o subcutáneos la enfermera se encarga de coordinar las citas y administrar los medicamentos prescritos. Durante las visitas para administración de medicamentos se aclaran dudas del paciente y se corrobora que no presente complicaciones ni posibles reacciones adversas al tratamiento. Otras intervenciones generales que realiza una enfermera con los pacientes de artritis son; recomendar que descansen de ocho a diez horas diarias, fomentar la actividad física realizando ejercicios de bajo impacto para mantener flexibilidad de la articulación (si se encuentra inflamada mantener en reposo debido a que puede ocasionar daños irreversibles), recomendar eliminar el consumo de tabaco, fomentar la ingesta de alimentos bajos en calorías

y carbohidratos, altos en proteínas y calcio. Los pacientes que están utilizando medicamentos orales, subcutáneos y/o intravenosos se orientan sobre uso, indicación, reacciones adversas, manejo y almacenamiento. Las intervenciones con cada paciente serán de acuerdo al grado y las necesidades de cada paciente y del estadio de su enfermedad. Intervenciones de enfermería Educativas • La Educación al Paciente (EP) incluye todas aquellas actividades estructuradas orientadas a aumentar los conocimientos del paciente sobre temas afines a la enfermedad, diseñadas para mejorar comportamientos relacionados con la salud y, por lo tanto, el automanejo. El objetivo no es sólo obtener conocimiento, sino saber qué hacer ante determinadas situaciones. La enfermera especialista en Reumatología puede ocuparse de la EP a nivel individual, grupal (pacientes y familiares), comunitario (actividades de promoción de la salud y preventivas en centros de salud, centros sociales de mayores, asociaciones en la comunidad) y mediante el asesoramiento a asociaciones de pacientes.

Ventajas de la inclusión de la enfermera en el equipo multidisciplinar Para el paciente:

• La enfermera especializada proporciona un cuidado integral a los pacientes reumáticos, atendiendo no sólo las manifestaciones clínicas propias de su enfermedad sino también los problemas derivados de la incapacidad y/o la falta de apoyo laboral o familiar, logrando así un cuidado más efectivo. • La enfermera podría proporcionar mayor accesibilidad y continui-dad en la atención. La naturaleza imprevisible de las enfermedades reumáticas hace que los pacientes valoren especialmente la posibilidad de acceder de un modo rápido y eficiente a los servicios que garanticen la resolución de su problema. • La enfermera especializada proporciona información y formación al paciente sobre su enfermedad y para el seguimiento de ciertos medicamentos.

Para el reumatólogo:

• Constituye un apoyo en las revisiones periódicas del paciente: seguimiento analítico, evaluación periódica del enfermo, resolución de dudas y cuestiones simples; evitando así, la saturación de las agendas de citación. • Realizar recuentos articulares y recoger los demás parámetros incluidos en la evaluación clínica sistemática del enfermo. • Facilitar la cumplimentación de cuestionarios. • Colaborar en la monitorización de los efectos adversos de FAMEs, tratamientos biológicos u otros fármacos. • Colaborar con el reumatólogo en técnicas específicas de la especialidad: Infiltraciones articulares y periarticulares, artrocentesis, test de Schirmer, ecografías, capilaroscopias, etc.

Conclusión Un entrenamiento enfocado al manejo de los pacientes con alguna enfermedad de las integradas en el grupo de artritis es necesario para que las intervenciones de las enfermeras resulten efectivas y provean la información adecuada al paciente. Las enfermeras que trabajan con Reumatólogos deben mantenerse educadas en todo momento para cumplir con su rol en su lugar de trabajo, ser facilitadoras, y aportar al bienestar de estos pacientes. Es imperativo, urgente y necesario que en Puerto Rico se creen y se ofrezcan foros de educación dirigidos a preparar a las enfermeras para el manejo de esta enfermedad.

Referencias Huizinga TW, Pincus T. In the clinic. Rheumatoid arthritis. Ann Intern Med. 2010 Jul 6;153(1). Scott DL, Wolfe F, Huizinga TW. Rheumatoid arthritis. Lancet. 2010 Sep 25;376(9746):1094-108. Firestein GS. Etiology and pathogenesis of rheumatoid arthritis. In: Firestein GS, Budd RC, Gabriel SE, et al, eds. Kelley's Textbook of Rheumatology. 9th ed. Philadelphia, Pa: Saunders Elsevier; 2012:chap 69. Sociedad Española de Reumatología, GUIPCAR: Guía de práctica clínica para el manejo de la artritis reumatoide en España.2007, Sociedad Española de Reumatología: Madrid.

Merck Sharp y Dohme de México. (1973). “Tratamiento de la artritis Reumatoide Ed. Merck Sharp y Dohme de México. Smeltzer, S.C. y Bare, B.G. (2005). Enfermería medicoquirúrgica de Brunner y Suddart (10ma. ed.). México: McGraw-Hill Interamericana, S.A. de C.V Karen I. Swanson, FNP-C Stancey Pfenning DNP. (2011). The Nurse Practitioner's Role in the Management of Rheumatoid Arthritis. Journal of Nurse Practitioners (858-862) Revista Puertorriqueña de Medicina y Salúd Pública

PARA ARTRITIS REUMATOIDE (AR) DE MODERADA A SEVERA

Los pies se hicieron para salpicar, no para la AR. Descubra XELJANZ® XELJANZ es una píldora pequeña, no una inyección ni infusión. Puede aliviar el dolor articular y la rigidez de la AR y ayudar a detener un mayor daño articular, incluso sin metotrexato. XELJANZ es un medicamento con receta para adultos con artritis reumatoide de moderada a severa para los cuales el metotrexato no funcionó bien. Visite XELJANZ.com para conocer más. PREGUNTE A SU REUMATÓLOGO SI XELJANZ ES ADECUADO PAR A USTED

¿Qué es XELJANZ? XELJANZ es un medicamento con receta llamado inhibidor de cinasa de Janus (JAK, por sus siglas en inglés). XELJANZ se utiliza para tratar adultos con artritis reumatoide activa de moderada a severa, para los cuales el metotrexato no funcionó bien. • Se desconoce si XELJANZ es seguro y eficaz en personas con hepatitis B o C. • XELJANZ no es para personas con problemas hepáticos severos. • Se desconoce si XELJANZ es seguro y efectivo en niños. INFORMACIÓN IMPORTANTE DE SEGURIDAD ¿Cuál es la información más importante que debe conocer sobre XELJANZ? Infecciones graves. XELJANZ puede reducir la capacidad de su sistema inmunológico para combatir infecciones. Algunas personas tienen infecciones graves mientras toman XELJANZ, incluida la tuberculosis (TB), e infecciones causadas por bacterias, hongos o virus que pueden extenderse por todo el cuerpo. Algunas personas han fallecido por causa de dichas infecciones. Su profesional del cuidado de la salud debe hacerle una prueba de TB antes de comenzar a tomar XELJANZ y monitorearlo para ver si existen indicios y síntomas de una infección de TB durante el tratamiento. No debe comenzar a tomar XELJANZ si tiene algún tipo de infección, a menos que su profesional del cuidado de la salud le diga que está bien. Cáncer y problemas del sistema inmunológico. XELJANZ puede aumentar el riesgo de ciertos tipos de cáncer, cambiando la forma en que funciona su sistema inmunológico. Han ocurrido linfomas y otros cánceres, incluidos cánceres de la piel, en pacientes que toman XELJANZ. Algunas personas que han tomado XELJANZ con otros medicamentos específicos para prevenir el rechazo del trasplante de riñón, han tenido problemas con ciertos glóbulos blancos que se descontrolaban (trastorno linfoproliferativo asociado con el virus de Epstein Barr). Desgarres (perforación) en el estómago o los intestinos. Algunas personas que toman XELJANZ presentan desgarres en el estómago o intestino. Esto ocurre con mayor frecuencia en personas que también toman medicamentos antiinflamatorios no esteroides (NSAID, por sus siglas en inglés), corticosteroides o metotrexato. Hable cuanto antes con su profesional del cuidado de la salud si tiene fiebre y dolor en la zona del estómago que no desaparece y/o algún cambio en los hábitos de movimientos intestinales.

Cambios en resultados de análisis de laboratorio. Su profesional del cuidado de la salud debe realizar análisis de sangre antes de que comience a recibir XELJANZ, y en ciertos momentos mientras toma XELJANZ, para ver si se producen los siguientes efectos secundarios: • cambios en recuento de linfocitos. Los linfocitos son glóbulos blancos que ayudan al cuerpo a combatir infecciones. • recuentos bajos de neutrófilos. Los neutrófilos son glóbulos blancos que ayudan al cuerpo a combatir infecciones. • recuentos bajos de glóbulos rojos. Esto puede indicar que tiene anemia, lo cual puede hacerle sentir débil y cansado. Su profesional del cuidado de la salud debe realizar rutinariamente ciertos análisis de hígado. No debe recibir XELJANZ si su recuento de linfocitos, de neutrófilos o de glóbulos rojos es demasiado bajo, o si sus análisis de hígado son demasiado altos. Su profesional del cuidado de la salud puede parar su tratamiento con XELJANZ por un período de tiempo, si es necesario, debido a cambios en los resultados de estos análisis de sangre. Su profesional del cuidado de la salud debe realizar análisis de sangre para verificar sus niveles de colesterol de 4-8 semanas después de que haya comenzado a tomar XELJANZ, y según sea necesario después de este tiempo. Antes de tomar XELJANZ, hable con su profesional del cuidado de la salud si: • piensa que tiene una infección o si tiene síntomas de una infección, como: fiebre, sudor o escalofríos, dolores musculares, tos, falta de aliento, sangre en la flema, pérdida de peso, calor, enrojecimiento o dolor en la piel o aftas en el cuerpo, diarrea o dolor de estómago, quemazón al orinar o ganas de orinar más frecuente de lo normal, o sentirse muy cansado • lo están tratando para una infección • suele padecer de muchas infecciones o tiene infecciones que son recurrentes • tiene diabetes, VIH o un sistema inmunológico débil. Las personas con estas condiciones tienen mayor probabilidad de contraer infecciones • tiene TB, o ha estado en contacto cercano con alguien que tiene TB • vive o ha vivido o ha viajado a ciertos lugares del país (como los valles Ohio y el Río Mississippi y el Suroeste de EE. UU.), donde hay una mayor posibilidad de contraer ciertos tipos de infecciones micóticas (histoplasmosis, coccidioidomicosis o blastomicosis). Estas infecciones pueden producirse o volverse más severo si usa XELJANZ. Pregúntele a su profesional del cuidado de la salud si no sabe si ha vivido en un área en donde estas infecciones sean comunes • tiene, o ha tenido, hepatitis B o C o tiene problemas de hígado

Las radiografías muestran que XELJANZ ayuda a detener un mayor daño articular.

• alguna vez ha tenido algún tipo de cáncer • tiene problemas de riñón • tiene dolor en la zona del estómago (abdominal) o le han diagnosticado diverticulitis (una inflamación en partes del intestino grueso), o úlceras estomacales o intestinales • ha tenido una reacción a tofacitinib o a alguno de los ingredientes de XELJANZ • ha recibido recientemente, o tiene planes recibir, una vacuna. Las personas que toman XELJANZ no deben recibir vacunas de microbios vivos, pero sí pueden recibir vacunas inactivas • tiene otras condiciones médicas • tiene planes de quedar embarazada o está embarazada. Se desconoce si XELJANZ perjudicará al bebé por nacer Registro del Embarazo: Pfizer tiene un registro para mujeres embarazadas que toman XELJANZ. El propósito de este registro es comprobar la salud de la madre embarazada y su bebé. Si está embarazada o queda embarazada mientras está tomando XELJANZ, hable con su profesional del cuidado de la salud sobre cómo inscribirse en este registro del embarazo, o puede llamar directamente al registro, al 1-877-311-8972 para inscribirse • tiene planes de lactar o está lactando a su bebé Después de haber comenzado a tomar XELJANZ, llame a su profesional del cuidado de la salud cuanto antes si tiene síntomas de infección. XELJANZ puede aumentar la probabilidad de que contraiga infecciones, o empeorar una infección que usted ya tenga. Hable con su profesional del cuidado de la salud sobre todos los medicamentos que usa, en especial cualquier otro medicamento para tratar la artritis reumatoide. Usted no debe tomar tocilizumab (Actemra®), etanercept (Enbrel®), adalimumab (Humira®), infliximab (Remicade®), rituximab (Rituxan®), abatacept (Orencia®), anakinra (Kineret®), certolizumab pegol (Cimzia®), golimumab (Simponi®), azatioprina, ciclosporina u otros medicamentos inmunosupresores mientras tome XELJANZ. Tomar XELJANZ con estos medicamentos puede aumentar su riesgo de infección. • Informe a su profesional del cuidado de la salud si está utilizando medicamentos que afectan la forma en que trabajan ciertas enzimas hepáticas. Pregúntele a su profesional del cuidado de la salud si no está seguro de si su medicamento es uno de estos. ¿Cuáles son otros posibles efectos secundarios de XELJANZ? XELJANZ puede causar efectos secundarios graves, incluyendo infección por activación de la hepatitis B o C en personas que tienen el virus en la sangre.

Si porta el virus de la hepatitis B o C en la sangre (virus que afecta el hígado), este puede activarse mientras usa XELJANZ. Hable con su profesional del cuidado de la salud si tiene algunos de los siguientes síntomas de una posible infección de hepatitis B o C: se siente muy cansado, tiene la piel o los ojos amarillentos, tiene poco o nada de apetito, vómitos, movimientos intestinales de color arcilla, fiebre, escalofríos, molestias estomacales, dolores musculares, orina oscura o erupción de la piel. Los efectos secundarios comunes de XELJANZ incluyen infecciones de las vías respiratorias superiores (resfriado común, sinusitis), dolor de cabeza, diarrea y congestión nasal, dolor de garganta y descarga nasal (nasofaringitis). Se le exhorta a informar los efectos secundarios negativos de los medicamentos con receta a la FDA. Visite www.fda.gov/medwatch o llame al 1-800-FDA-1088. Por favor, vea la Información del Paciente adicional en la próxima página. Todas las marcas comerciales son propiedad de sus respectivos dueños. TRA686117-03 © 2014 Pfizer Inc. Derechos reservados. Septiembre 2014

Una píldora. Dos veces al día.

RESUMEN BREVE PARA EL CONSUMIDOR XELJANZ (ZEL’ JANS’) (tofacitinib) Lea la Guía del Medicamento que viene con XELJANZ antes de comenzar a tomarlo y cada vez que repita la receta. Puede haber información nueva. Este resumen breve no reemplaza la conversación con su profesional del cuidado de la salud sobre su condición médica o su tratamiento. ¿Cuál es la información más importante que debo conocer sobre XELJANZ? XELJANZ puede causar efectos secundarios graves, incluyendo: 1. Infecciones graves. XELJANZ es una medicina que puede afectar su sistema inmunitario. XELJANZ puede reducir la capacidad de su sistema inmunológico para combatir infecciones. Algunas personas tienen infecciones graves mientras toman XELJANZ, incluida la tuberculosis (TB) e infecciones causadas por bacterias, hongos o virus que pueden extenderse por todo el cuerpo. Algunas personas han fallecido por causa de dichas infecciones. • Su profesional del cuidado de la salud debe hacerle una prueba de TB antes de comenzar a tomar XELJANZ. • Su profesional del cuidado de la salud debe monitorearlo para ver si existen indicios y síntomas de una infección de TB durante el tratamiento con XELJANZ. No debe comenzar a tomar XELJANZ si tiene algún tipo de infección, a menos que su profesional del cuidado de la salud le diga que está bien. Antes de comenzar a tomar XELJANZ, dígale a su profesional del cuidado de la salud si: • piensa que tiene una infección o si tiene síntomas de una infección como: - fiebre, sudor o escalofríos - calor, enrojecimiento o dolor en la piel, - dolores musculares aftas en el cuerpo - tos - diarrea o dolor de estómago - falta de aliento - quemazón al orinar o ganas de orinar - sangre en la flema más frecuente de lo normal - pérdida de peso - sentirse muy cansado • lo están tratando para una infección • suele padecer de muchas infecciones o tiene infecciones que son recurrentes • tiene diabetes, VIH o un sistema inmunológico débil. Las personas con estas condiciones tienen mayor probabilidad de contraer infecciones • tiene TB, o ha estado en contacto cercano con alguien que tiene TB • vive o ha vivido o ha viajado a ciertos lugares del país (como los valles Ohio y el Río Mississippi y el Suroeste de EE. UU.), donde hay una mayor posibilidad de contraer ciertos tipos de infecciones micóticas (histoplasmosis, coccidioidomicosis o blastomicosis). Estas infecciones pueden producirse o volverse más severo si usa XELJANZ. Pregúntele a su profesional del cuidado de la salud si no sabe si ha vivido en un área en donde estas infecciones sean comunes • tiene, o ha tenido, hepatitis B o C Después de haber comenzado a tomar XELJANZ, llame a su profesional del cuidado de la salud cuanto antes si tiene síntomas de infección. XELJANZ puede aumentar la probabilidad de que contraiga infecciones, o empeorar una infección que usted ya tenga. 2. Cáncer y problemas del sistema inmunológico. XELJANZ puede aumentar el riesgo de ciertos tipos de cáncer, cambiando la forma en que funciona su sistema inmunológico. • Pueden ocurrir linfomas y otros cánceres, incluidos cánceres de la piel, en pacientes que toman XELJANZ. Hable con su profesional del cuidado de la salud si ha tenido algún tipo de cáncer. • Algunas personas que han tomado XELJANZ con otros medicamentos específicos para prevenir el rechazo del trasplante de riñón, han tenido problemas con ciertos glóbulos blancos que se descontrolaban (trastorno linfoproliferativo asociado con el virus de Epstein Barr). 3. Desgarres (perforación) en el estómago o los intestinos. • Hable con su profesional del cuidado de la salud si ha tenido diverticulitis (una inflamación en partes del intestino grueso), o úlceras estomacales o intestinales. Algunas personas que toman XELJANZ presentan desgarres en el estómago o intestino. Esto ocurre con mayor frecuencia en personas que también toman medicamentos antiinflamatorios no esteroides (NSAID, por sus siglas en inglés), corticosteroides o metotrexato. • Hable cuanto antes con su profesional del cuidado de la salud si tiene fiebre y dolor en la zona del estómago que no desaparece y algún cambio en los hábitos de movimientos intestinales. 4. Cambios en ciertos resultados de análisis de laboratorio. Su profesional del cuidado de la salud debe realizar análisis de sangre antes de que comience a recibir XELJANZ, y mientras tome XELJANZ, para ver si se producen los siguientes efectos secundarios: • cambios en recuento de linfocitos. Los linfocitos son glóbulos blancos que ayudan al cuerpo a combatir infecciones. • recuentos bajos de neutrófilos. Los neutrófilos son glóbulos blancos que ayudan al cuerpo a combatir infecciones. • recuentos bajos de glóbulos rojos. Esto puede indicar que tiene anemia, lo cual puede hacerle sentir débil y cansado. Su profesional del cuidado de la salud debe realizar rutinariamente ciertos análisis de hígado. No debe recibir XELJANZ si su recuento de linfocitos, de neutrófilos o de glóbulos rojos es demasiado bajo, o si sus análisis de hígado son demasiado altos. Su profesional del cuidado de la salud puede parar su tratamiento con XELJANZ por un período de tiempo, si es necesario, debido a cambios en los resultados de estos análisis de sangre. También puede tener cambios en otros análisis de laboratorio, como en sus niveles de colesterol en la sangre. Su profesional del cuidado de la salud debe realizar análisis de sangre para verificar sus niveles de colesterol de 4-8 semanas después de que haya comenzado a tomar XELJANZ y según sea necesario después de este tiempo. Tener niveles normales de colesterol es importante para la buena salud cardiaca. Vea, “¿Cuáles son los posibles efectos secundarios de XELJANZ?” para más información sobre los efectos secundarios. ¿Qué es XELJANZ? XELJANZ es un medicamento con receta llamado inhibidor de cinasa de Janus (JAK, por sus siglas en inglés). XELJANZ se utiliza para tratar adultos con artritis reumatoide activa de moderada a severa, para los cuales el metotrexato no funcionó bien. Se desconoce si XELJANZ es seguro y eficaz en personas con hepatitis B o C. XELJANZ no es para personas con problemas hepáticos severos.

Respuestas y Apoyo *Ciertos servicios son impulsados por Pfizer RxPathwaysTM

¿Necesita ayuda para pagar por sus medicamentos? XELSOURCETM puede ayudar independientemente de su situación de seguro.* Aprenda cómo en www. XELSOURCEHelps.com

• Se desconoce si XELJANZ es seguro y eficaz en niños. ¿Qué debo decirle a mi profesional de la salud antes de tomar XELJANZ? XELJANZ puede no ser adecuado para su caso. Antes de tomar XELJANZ, hable con su profesional del cuidado de la salud si: • tiene una infección. Vea, “¿Cuál es la información más importante que debe saber sobre XELJANZ?” • tiene problemas de hígado • tiene problemas de riñón • tiene dolor en la zona del estómago (abdominal) o le han diagnosticado diverticulitis (una inflamación en partes del intestino grueso), o úlceras estomacales o intestinales • ha tenido una reacción a tofacitinib o a alguno de los ingredientes de XELJANZ • ha recibido recientemente, o tiene planes de recibir una vacuna. Las personas que toman XELJANZ no deben recibir vacunas de microbios vivos, pero sí pueden recibir vacunas inactivas • tiene otras condiciones médicas • tiene planes de quedar embarazada o está embarazada. Se desconoce si XELJANZ perjudicará al bebé por nacer. Registro del Embarazo: Pfizer tiene un registro para mujeres embarazadas que toman XELJANZ. El propósito de este registro es comprobar la salud de la madre embarazada y su bebé. Si está embarazada o queda embarazada mientras está tomando XELJANZ, hable con su profesional del cuidado de la salud sobre cómo inscribirse en este registro del embarazo, o puede llamar directamente al registro, al 1-877-311-8972 para inscribirse • tiene planes de lactar o está lactando a su bebé. Usted y su profesional del cuidado de la salud deben decidir entre tomar XELJANZ o lactar. No debe hacer ambos Hable con su profesional del cuidado de la salud sobre todos los medicamentos que usa, incluidos medicamentos con receta y medicamentos sin receta, vitaminas y suplementos herbarios. XELJANZ, y otros medicamentos pueden, afectar otros tratamientos y causar efectos secundarios. En especial, informe a su profesional del cuidado de la salud si usa: • cualquier otro medicamento para tratar su artritis reumatoide. Usted no debe tomar tocilizumab (Actemra®), etanercept (Enbrel®), adalimumab (Humira®), infliximab (Remicade®), rituximab (Rituxan®), abatacept (Orencia®), anakinra (Kineret®), certolizumab pegol (Cimzia®), golimumab (Simponi®), azatioprina, ciclosporina u otros medicamentos inmunosupresores mientras tome XELJANZ. Tomar XELJANZ con estos medicamentos puede aumentar su riesgo de infección. • medicamentos que afectan la forma en que trabajan ciertas enzimas hepáticas. Pregúntele a su profesional del cuidado de la salud si no está seguro de si su medicamento es uno de éstos. Conozca los medicamentos que usa. Mantenga una lista de estos para mostrarla a su profesional del cuidado de la salud y al farmacéutico cuando obtenga un medicamento nuevo. ¿Cómo debo tomar XELJANZ? • Tome XELJANZ como se lo indique su profesional del cuidado de la salud. • Tome XELJANZ 2 veces al día, con o sin comida. • Si toma demasiado XELJANZ, llame a su profesional del cuidado de la salud o acuda de inmediato a la sala de emergencia más cercana. ¿Cuáles son posibles efectos secundarios de XELJANZ? XELJANZ puede causar efectos secundarios graves incluyendo: • Vea, “¿Cuál es la información más importante que debe saber sobre XELJANZ?” • Infección por activación de la de hepatitis B o C en personas que tienen el virus en la sangre. Si porta el virus de la hepatitis B o C en la sangre (virus que afecta el hígado), este puede activarse mientras usa XELJANZ. Su profesional del cuidado de la salud puede hacer los análisis de sangre antes de que comience el tratamiento con XELJANZ, y mientras use XELJANZ. Hable con su profesional del cuidado de la salud si tiene alguno de los siguientes síntomas de una posible infección de hepatitis B o C: - fiebre - se siente muy cansado - escalofríos - piel o los ojos amarillentos - molestias estomacales - poco o ningún apetito - dolores musculares - vómitos - orina oscura - movimientos intestinales de color - erupción de la piel arcilla Los efectos secundarios comunes de XELJANZ incluyen • infecciones de las vías respiratorias superiores (resfriado común, sinusitis) • dolor de cabeza • diarrea • congestión nasal • dolor de garganta • descarga nasal (nasofaringitis). Hable con su profesional del cuidado de la salud si tiene efectos secundarios que le molestan, o que no desaparece. Éstos no son todos los efectos secundarios posibles de XELJANZ. Para más información, pregúntele a su profesional del cuidado de la salud o a su farmacéutico. Llame a su médico para consejos médicos sobre los efectos secundarios. Puede reportar efectos secundarios a la FDA, llamando al 1-800-FDA-1088. También puede reportar efectos secundarios a Pfizer al 1-800-438-1985. Información general sobre el uso seguro y eficaz de XELJANZ. A veces se recetan medicamentos para fines que no son los mencionados en un resumen breve. No utilice XELJANZ para una condición para la cual no haya sido recetado. No dé XELJANZ a otras personas, incluso aunque tengan los mismos síntomas que usted. Puede causarles daño. Este resumen breve resume la información más importante sobre XELJANZ. Si desea más información, hable con su profesional del cuidado de la salud. Puede pedirle a su farmacéutico o a su profesional del cuidado de la salud la información sobre XELJANZ que está escrita para profesionales médicos. Este resumen breve está basado en la Información de Prescripción de XELJANZ LAB-0445-7.0 y la Guía del Medicamento LAB-0535-2.0. Emitido: Mayo 2014. © 2014 Pfizer Inc. Derechos reservados.

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MSP Somos Ciencia 31 de julio 2 de agosto

Convención Anual Asociación de Reumatólogos de Puerto Rico

St. Regis Bahía Beach Resort

5-8 de agosto

3er Cumbre de l as Américas de Nutrición y Salud

Sheraton Puerto Rico Hotel ycuadrado@nutricionpr.org & Casino, San Juan,PR

7-9 de agosto

Convención Anual Caribe Gyn

Hilton Ponce Golf & Casino Resort, Ponce, PR

7-9 de agosto

4th Annual Convention Sociedad de Cirugía Vascular y Endovascular de PR (SCVEPR)

Ritz Carlton, Isla Verde, PR

AMEC amec@amec-pr.com

787-289-8989

8 de agosto

Taller de Medicamentos Manejo del Dolor

Ritz Carlton, Isla Verde, PR

AMEC amec@amec-pr.com

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8 de agosto

Simposio Gastroenterología Pediátrica Asociación de Gastroenterología y Hepatología Pediátrica de Puerto Rico

Caribe Hilton, San Juan, PR

Business Planners, Inc.

14-16 de agosto

Convencion Anual Sociedad Puertorriqueña de Cardiología Intervencional

Ritz Carlton Reserve, Dorado, PR

Ideas PREP, Inc.

Enid Rivera 787-925-6555

29 de agosto

Taller de Medicamentos Manejo del Dolor

Ritz Carlton, Isla Verde, PR

AMEC amec@amec-pr.com

787-289-8989

29-30 de agosto

Convención Asociación Puertorriqueña de Médicos Alergistas

Condado Plaza Hotel, San Juan, PR

Educational Partners & Coaching, Inc

787-646-0780

4-6 de septiembre

Convención Anual Asociación de Hematología y Oncología Médica de Puerto Rico

Hilton Ponce Golf & Casino Resort, Ponce, PR

ahomprgq@gmail.com

Germaine Quiñones 787-608-1477

4-7 de septiembre

33 Convención Anual Asociación de Médicos Pediatras Región Oeste (AMPRO)

Mayagüez Resort & Casino

mlizco@gmail.com

Mignaliz Vega Morales 302-893-2136/ 939-245-1257

5-7 de septiembre

56 Convención Sociedad de Médicos Graduados Escuela de Medicina UPR

Ritz Carlton Hotel, Isla Verde, PR

sgem.rcm@upr.edu

787-758-2525 ext. 2038

12 de septiembre

Taller de Medicamentos Manejo del Dolor

Intercontinental Hotel Isla Verde, PR

AMEC amec@amec-pr.com

25-27 de septiembre

1er Congreso de Hipertensión Pulmonar

San Juan, PR

2 de octubre

2nd Puerto Rico Cancer Research Meeting

Hotel Condado Plaza Hilton, San Juan, PR

Serra & Serra Group info@serrayserra.com

787-406-4571

Germaine Quiñones 787-608-1477

Business Planners, Inc.

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Meredith Herrera 787-798-3010 ext. 2163

17-18 de octubre

Emergency Neurological Life Support

Sheraton Puerto Rico Hotel Serra & Serra Group & Casino, San Juan,PR info@serrayserra.com

787-406-4571

24-25 de octubre

SOCRAD Breast Summit 2015

Hotel San Juan & Casino, Isla Verde

Serra & Serra Group info@serrayserra.com

787-406-4571

30 de oct1 de nov

2do Simposio Academia de Medicina General

Ponce Hilton Ponce, PR

SR Consultants & Events srconsultantsandevents@gmail.com

6-8 de noviembre

14th Annual Convention Puerto Rico HIV Treaters Medical Association

Embassy Suites Dorado del Educational Partners & Mar, Dorado, PR Coaching, Inc.

6-8 de noviembre

11ma Convención Annual Asociación de Médicos Pediatras Región Este (AMPRE)

Embassy Suites, Isla Verde, San Juan, PR

Business Planners, Inc.

Merna Morales 787-706-0442 / 787-706-0480 fax

20-22 de noviembre

18va Convención Anual Sociedad Puertorriqueña de Neumología

Sheraton Convention Center, San Juan, PR

Business Planners, Inc.

Merna Morales 787-706-0442 / 787-706-0480 fax

11-13 de diciembre

37th Annual Scientific & 7th Joint SPED-AACE International Meeting: Endocrine Update Puerto Rican Endocrinology and Diabetes Society

San Juan Hotel, San Juan, PR

Educational Partners & Coaching, Inc.

787-646-0780

Santiago Rivera 939-292-4115 787-646-0780

N OT I C I A S

Belinda Z. Burgos González: Periodista. Carlos Alexis Lugo Marrero*: Director Fundador. Fotos: Sonia Carmona * Afiliado a la Asociación de Periodistas de Puerto Rico (ASPRO)

Los nacimientos en Puerto Rico han mermado en grupos de todas las edades y los embarazos se están posponiendo para edades más tardías.

Disminuye la tasa de nacimientos en Puerto Rico

La tasa de nacimientos en Puerto Rico ha disminuido casi en un 50%, según relataron en exclusiva con la Revista Puertorriqueña de Medicina y Salud Pública (MSP) los doctores José Cordero y Hernando Mattei, ambos de la Escuela Graduada de Salud Pública del Recinto de Ciencias Médicas (RCM). “Para el 1990 teníamos cerca de 64 mil nacimientos al año y para el 2014, estamos en 34,500. Han disminuido en casi un 50% de reducción en

el número de nacimientos no solo en los últimos 20 años. Y si retrocedemos un poco más, hacia el 1950, teníamos 90 mil nacimientos”, detalló el Doctor Cordero. “Se están posponiendo los nacimientos para una edad más tarde. Esto ha tenido mucha importancia no solo a nivel de la salud pública, sino a nivel de la educación porque serán menos los niños los que acudan a los salones de clases. Son aspectos que se necesitan evaluar”, apuntó.

De izquierda a derecha los doctores Edwin Rodríguez Cruz y Francisco Díaz Sotomayor, únicos cardiólogos pediátricos intervencionales de la isla.

Puerto Rico sólo cuenta con dos cardiólogos pediátricos intervencionales Puerto Rico sólo cuenta con dos cardiólogos pediátricos intervencionales quienes se esfuerzan diariamente para poder atender las condiciones cardíacas en la población pediátrica ante la falta se especialistas en la isla. Son Edwin Rodríguez Cruz, Director de Cardiología en el San Jorge Children’s Hospital y el Doctor Francisco J. Díaz Sotomayor y quienes tienen practica en el Centro Cardiovascular de Puerto Rico y el Caribe, los únicos dos cardiólogos pediátricos intervencionales que realizan procedimientos quirúrgicos en niños puertorriqueños. “Más que intervenciones, hay falta de especialistas en cardiología pediátrica general. Los números no cambian en los pacientes, si no en el número de especialistas que vemos esos pacientes. Nuestros casos han aumentado porque estamos haciendo muchas cosas que solo antes se resolvían solo con cirugía”, explicó.

Buscan aprobar el primer medicamento para fibromialgia juvenil en Puerto Rico Investigadores puertorriqueños se han unido al esfuerzo de buscar el primer medicamento que trate la fibromialgia juvenil en la isla, mientras la incidencia de la condición reumática ha aumentado su incidencia en la población pediátrica, según reveló en entrevista con la Revista Puertorriqueña de Medicina y Salud Pública (MPS), la doctora Annette López, reumatóloga pediátrica del San Jorge Children’s Hospital. La doctora López junto con otros científicos, como el doctor y especialista en genética, Doctor Alberto Santiago Cornier, prueban actualmente dosis del medicamento Cymbalta, actualmente utilizado en pacientes con depresión y en fibromialgia en adultos. “En niños no hay ningún medicamento aprobado hasta ahora. Este es el primer estudio en el que se está buscando que se apruebe un medicamento para tratar la condición niños El objetivo es tratar de probar de que el medicamento Cymbalta es seguro tanto para adultos como para niños”, manifestó la Doctora. 72

Revista Puertorriqueña de Medicina y Salúd Pública

Actualmente no existe ningún medicamento que trate la fibromialgia juvenil en niños.

N OT I C I A S

De izquierda a derecha: Hon. Liana Fiol Matta, jueza Presidenta del Tribunal Supremo de Puerto Rico junto a el doctor Hamid Galib, nuevo Presidente del Ateneo Puertorriqueño.

Doctor Enrique Vélez García, primer hematólogooncólogo certificado de Puerto Rico.

Fusionada la medicina y la cultura con el nombramiento oficial del Dr. Hamid Galib como presidente del Ateneo Puertorriqueño

Conozca al primer oncólogohematólogo certificado de Puerto Rico, el Doctor Enrique Vélez García

Entre reconocidos representantes de la cultura puertorriqueña fue oficialmente nombrado el doctor Hamid Galid como nuevo presidente del Ateneo Puertorriqueño, escenario de la emotiva ceremonia donde quedó fusionada la cultura y la ciencia puertorriqueña. El evento contó con representantes del gobierno como Jorge Irizarry Vizcarrondo, Director del Instituto de Cultura Puertorriqueña. Además, el ambiente fue matizado por el orgullo y la emoción de la familia del doctor Galib, encabezada por su esposa, la juez del Tribunal

Supremo, Lcda. Liana Fiol Matta. “Son 137 años de lucha constante para sobrevivir como institución cultural en la historia de Puerto Rico. La salud de los individuos e instituciones consisten en la transformación día día sin dejar de ser lo que se era al principio. Desde que nombraron a esta gran junta que me honro en presidir, hemos estado implementando nuevos cambios. Los clubes privados deben desaparecer. Hemos decidido tener un ateneo totalmente inclusivo”, indicó.

Investigadores puertorriqueños evidencian que la cirugía bariátrica cura la diabetes

El doctor Enrique Vélez García fue el primer oncólogo-hematólogo certificado de Puerto Rico que sembró los primeros cimientos para que más médicos especialistas contra el cáncer se unieran a la misión de la carrera médica . Vélez García se graduó en el 1960 de la Escuela de Medicina del Recinto de Ciencias Medicas (RCM). Estuvo dos años en la Fuerza Aérea de los Estados Unidos en Japón y luego hizo su residencia en hematología y oncología médica en continente estadounidense. El resto de su carrera médica y crecimiento científico por 40 años fue dentro del RCM, donde fungió gran parte del tiempo como director de la residencia de los “fellows” de hematología y oncología. “Hoy día existen hasta pastillas que evitan que tengan que ponerse la quimioterapia clásica intravenosa. Hoy día el internet ya nos deja saber quién tiene una droga nueva, o protocolo nuevo para combinación de medicamentos y ya no hay que esperar a la próxima reunión para estar al día”, relató sonriendo.

Aproximadamente el 25% de las personas obesas de la isla que necesitan de este tipo de operación, solo un 3% se realiza la cirugía.

Un estudio realizado por cardiólogos puertorriqueños en el Hospital de la Universidad de Puerto Rico (UPR), Dr. Federico Trilla, en Carolina, evidenció que cirugía bariátrica en pacientes mórbidos cura la Diabetes tipo 2, según indicó en entrevista el profesor de Cardiología del Recinto de Ciencias Medicas (RCM), el doctor Pablo Iván

Altieri. La investigación fue hecha junto con el estudiante Gil de la Madrid, “fellow” del RCM, quien analizó en conjunto con el doctor Altieri, un corte de 100 pacientes los que se le realizó la cirugía bariátrica. Dicha operación fue hecha por el doctor Alberto Suárez Domínguez, Director del Centro de Cirugía Bariátrica del Hospital de la UPR en Carolina. “Este es

el primer trabajo publicado en el mundo latinoamericano y se hace en Puerto Rico. Este tipo de cirugías produce unos cambios fascinantes en estos pacientes con obesidad mórbida porque cura específicamente la diabetes mellitus en muchos pacientes”, indicó el doctor Altieri. Revista Puertorriqueña de Medicina y Salúd Pública

Un lugar respetuoso en la historia de una Ciudad, de la medicina y el baloncesto “Puedo concebir perfectamente que se queme Mayagüez, que se hunda San Juan, que desaparezca cualquier otro pueblo de la isla y que, a pesar de tan terribles catástrofes, Puerto Rico siga siendo Puerto Rico. Pero no puedo concebir, de ningún modo, ni le permito a nadie que lo conciba, que falte Ponce y que siga siendo todavía Puerto Rico un país habitable”.

Nemesio Canales

Legislador, periodista, ensayista, dramaturgo, novelista y poeta.

xisten personas que trascienden por su aportación al quehacer diario de los pueblos como lo es el doctor Oscar Santiago, quien a pesar de su ardua tarea como médico, le devolvió a La Ciudad Señorial el orgullo y la pasión por el deporte del baloncesto, rescatando a una de las franquicias de mayor tradición y campeonatos en la historia nacional de este deporte. El Dr. Santiago, patólogo anatómico clínico demostró un gran espíritu de compromiso con la ciudadanía. En una liga donde todos los días sus jugadores denuncian falta de pago e incumplimientos por parte de los apoderados y dueños de equipo, el doctor Santiago administró con decoro, honestidad y con la mayor responsabilidad su franquicia, para hacer de su proyecto deportivo uno ganador y una institución grande que sirve como modelo para los apoderados del Baloncesto Superior Nacional. No hay duda que la formación del doctor Santiago ha sido la clave para sus logros. En su tercer año como apoderado el doctor Santiago, paladín de la medicina, llevó al equipo de Ponce a otro campeonato como

Revista Puertorriqueña de Medicina y Salúd Pública

lo hizo en la temporada anterior, luego de debutar con un subcampeonato en su primer año como apoderado. Es imposible remunerar con dinero todo lo que ha hecho este profesional de la salud sin mayores ganancias que el aplauso de la fanaticada, de corazón y con mucha dedicación, poniendo en alto el nombre de la medicina, del deporte y de una ciudad que orgullosa de su historia y sus logros. Podemos decir, A Ciencia Cierta, que el paso por el baloncesto nacional del doctor Santiago despertó el orgullo de una ciudad que nunca ha aceptado no ser la capital de su país. Despertó la alegría de vivir el sentimiento del ponceño, el intenso amor de una sociedad orgullosa de su pueblo al punto de que se pueden distinguir del resto de los puertorriqueños. El orgullo de Ponce que viene de una tradición extraordinaria nacida en el Siglo 19 y manifestada a través de las artes, la cultura, la música, el periodismo y la política recibe hoy de manos de un médico otra razón mas para seguir diciendo que Ponce es Ponce.

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