novamed ‘caLIDAD E INNOVACION Bogota D.C., 26 de abril de 2017 Sefiores Ministerio de Proteccién Social Administracién de Fondos de la Proteccién Social Atencién: ALVARO ROJAS FUENTES Director Informacién técr para no exclusién de tecnologia iacereina Con base en la notificacin de la Direccién de Regulacién de Beneficios, Costos y Tarifas del Aseguramiento en Salud del Ministerio de Salud sobre las tecnologias en salud que dicho Ministerio nomina para que sean excluidas, de acuerdo al interés en salud puiblica, la poblacién afectada y el impacto fiscal, se ha tenido en cuenta la resolucién 330 de 2017, para la solicitud de no exclusién de la tecnologia diacereina en virtud del principio pro-homine con el objetivo de adoptar la interpretacién que sea mas favorable a la proteccién del derecho fundamental a la salud de las personas, en el desarrollo del procedimiento técnico-cientifico y participative se anexa informacién que permita el cabal andlisis de los posibles beneficios, riesgos y efectividad de las tecndlogias que sean nominadas para exclusion. Se ha tenido en cuenta el escenario de Evaluacién de Tecnologias Sanitarias (ETES), que se trata de proceso sistematico y multidisciplinario de examen y reporte de las propiedades de efectividad, eficacia v seauridad, y las cot econémica: e nel cuidado de la salud, donde su propésito principal es informar y Proporcionar evidencia cientifica para la toma de decisiones relacionadas con tecnologias en salud. En dicho contexto evaluativo de la ETES, se hara referencia a la tecnologia / principio activo diacereina comentando los siguientes puntos para justificar la no exclusién, teniendo en cuenta: Aprobacién por el Invima Efectividad clinica Seguridad Impacto en salud piiblica Syne Pagina 1 ceoaovamed aoose CALIDAD E maNovacién Desarrollo de los puntos: 1, Aprobacién por el Invima. eats El producto cuenta con registro sanitario Invima, correspondiente al INVIMA 2010M-0010584. 2. Efectividad clinica / impacto en costos Beneficios clinicos con diacereina - Comentarios de evidencia actualizada El andlisis general de estudios clinicos controlados aleatorios y meta~ andlisis a la luz de evidencia mas reciente! de sociedades de investigacion como ESCEO, confirma la eficacia de la diacereina en el tratamiento sintomatico de la OA de rodilla y cadera. (ANEXO 1) Se ha notificado un ES (Effect Size=tamaiio de efecto) sobre dolor de 0,24 (IC del 95%: 0,08-0,39), un valor considerado bajo, pero clinicamente relevante en la OA (Osteoartrosis). Ademés, como el ES de diacereina y otros agentes anti-OA se basa en la diferencia entre el placebo y los efectos de farmacos actives, es importante sefialar que se ha demostrado inequivocamente una gran respuesta de placebo en ensayos clinicos aleatorios de OA; el ES = 0,51, IC del 95%: 0,46 - 0,55). Por lo tanto, la ES de la diacereina debe evaluarse teniendo en cuenta esta gran respuesta del placebo. La diacereina tiene eficacia semejante a la de los AINES sobre el dolor y la funcién articular después del primer mes de tratamiento. Y a diferencia de los AINE, diacereina ha mostrado un efecto prolongado de varios meses una vez que el tratamiento se detuvo y este efecto tiene evidencia de costo-efectividad demostrada*?, La evidencia publicada por + Pavelka K, Bruyére O, Cooper C, Kanis JA, Leeb BF, Maheu E, Matel-PelletierJ| Monfot J, Pelletier JP, Rizzol R, Reainster JY, Diaceren: Benefits, Risks and Place in the Management of Osteoarthris. An Oninion- Based Report fom the ESCEO. Drugs Aging. 2016 Feb33(2):75-86 Enlace en: https /hvm.ncbinin.nih.qoufpmefarticles/PMC4TS6045ioli40266 2016 Arivle 247.od 2 FagnaniF, et al: Medico-economic analysis of dlacerein with or without standard therapy in the treatment of osteoarthritis, Pharmecosconomics 1996/13(1 Pt 2):135-46 2 Deb et al: Costes sanitarios directos de los pacientes con arrosis de rodilao cadera tratados. on diacereina o con tratamiento estandar en Espafa. PharmacoEconomics 2011 » 8 (4): 126-138 htto:/adisonine.comipecspanish/Aricies/Vol%208%42OlssueY204%620pages%620 120-1 28%620201 od Pagina 22 o o S8novamed™ (CALIDAD E INNOVACION la Sociedad de Investigacién de la Osteoartritis Internacional (OARST) indicé que la diacereina tenia una mayor eficacia en la reduccién del dolor en OA que el paracetamol (ES = 0,14, IC 95% 0,05-0,22) y una eficacia similar en comparacién con los AINE (ES = 0,29, IC del 95%: 0,22 - 0,35) (ANEXO 1). Adicionaimente, se cuenta con evidencia de mejoria sintomatica y de limitacién funcional en dos meta-anilisis que sustentan la modificacién sintomatica (de accién lenta) en pacientes con OA se encuentra que el perfil de seguridad analizado no se modifica con respecto al perfil conocido * 5 ademas que demuestran la mejoria no solamente de dolor, sino también del estado funcional (ANEXO 15, ANEXO 16). Cabe destacar que las revisiones sistematicas como la de Cochrane del 2009 destacan los beneficios de! producto en artrosis esto fue diferente en 2014, atribuible a cambio en el sistema de evaluacién, a inclusion de nuevos estudios de corta duracién y metodolégicamente poco adecuados, como el estudio Brahmachari, ademas que fueron realizados sobre rodilla con énfasis en modificacién sintomatica. Al referirnos al metanélisis de Cochrane de 2014 el cual est dentro de la referencia para la nominacién a exclusién de diacereina, se encuentran tres estudios clinicos diferentes: item Articulacion Duracién del | Comentarios tratamiento Estudio Brahmachart | Rodila B semanas RCT sin doble 2008 cegamiento, estudio fue monociego Estudio Louthrenes | Rodilla Te semanas RCT multicgntrico, 2007 controlado con piroxicam Estudio Zheng Roailla amass RCT multicéntrieo, controlado con 2006 diclofenaco “Se observa que los tres nuevos estudios incorporados en la revision sistematica de 2014 (detalles en ANEXO 2) son de rodilla, y al ser de menos de 6 meses de duracién, ‘algunos con limitaciones soportan solamente evidencia de modificacién sintomatica, no “Bartels EM etal: Symptomatic efficacy and safety of diacerein inthe treatment ofosteoarthritis: a ‘meta-analysis of randomized placebo-controled trials. Osteoarthits Cartage (2010) 18, 280-208 Rinlelen B, Neumann K, Leeb BF. A meta-analysis of controlled clinical studies with diacerein in the ‘treatment of osteoarthritis. Arch Intern Med 2006;168:1899-008 Pagina 3 G: 060 ssnovamed™ de modificacién estructural 0 modificacién del curso de la enfermedad; es decir, solamente refuerzan conceptualmente la evidencia de modificacién sintomatica. Adicionalmente la versién de 2009° indica que con diacereina “en la OA de cadera, hubo una disminucién significativa estadistica de la progresién en contraste con la OA de rodilla que no demostré esta reduccién" (ANEXO 3) teniendo en cuenta que la metodologia cuando se disefié y ejecuté este estudio, eran las recomendadas por las sociedades cientificas mundiales. Cabe destacar que las recomendaciones del meta-andlisis de Cochrane versién 2009, fueron avaladas por las guias clinicas de la OARSI del 20087, (que a diferencia de las del 2014 que se enfocan solamente en OA de rodilla se enfocan en OA en general) y comentan claramente en el numeral 19 de la pagina 5, “que la diacereina puede tener efectos modificadores de Ia estructura en pacientes con OA sintomatica de la cadera". (ANEXO 4). 2.1 Acci6n modificadora estructural en osteoartrosis a. La diacereina es el unico producto que ha demostrado ejercer modificacién estructural en estudios clinicos a tres afios, sin efectos secundarios a nivel hepatico. b. El estudio pivotal o de eficacia clinica esencial ECHODIAKS, (ANEXO 5) mosiré que con tres afios de administracién de diacereina, los valores promedio de la velocidad anual de estrechamiento de la interlinea articular fueron inferiores en el grupo con diacereina vs el grupo placebo (P=0,042). c. El mismo estudio ECHODIAH demostré una reduccién en fa necesidad de reemplazos articulares en aquellos pacientes tratados en el grupo de diacereina de aproximadamente el 5% vs el grupo con placebo, lo que podria significar un impacto econémico favorable para cualquier sistema de salud que debe & Fidolix TS, Soares B, FemandesMoga Trevisan! V.Diacerein for ostecarthrtis. Cochrane Database of ‘Systematic Reviews 2006, Issue 1, Art. No.: CDO05117. DOI: 10.1902/14651858.CD005117,pub2. Version 2008 " Zhang W, Moskowitz RV, Nuki G, et al OARS! recommendations for the management of hip and kneo ‘osteoarthritis, Osteoarthritis Certlags 2008;16(2):137-162. * Dougados M, Nguyen M, Berdah L, Maziéres B, Vignon E, Laquesne M; ECHODIAH Investigators Study Group., Evaluation of the structure-moditying effects of diacerein in hip osteoarthritis: ECHODIAH, a three-year, placebo-controlled trial Arthritis Rheum. 2001 Nov;4{11):2539-47. Péginad 9 Oa6 099005 wnovamed cubrir los costos directos e indirectos del manejo quirtirgico de Ia OA. d, Este desenlace se considerd por la base racional que si un medicamento es modificador de Ja evolucién de la enfermedad, debe impactar un desenlace serio, como lo es la artroplastia. e. Por lo anterior, los medicamentos con diacereina aprobados se encuentran disponibles en 35 pafses en todo el mundo, 2.2 Otro de los hallazgos importantes del estudio pivotal ECHODIAH es el Balance costo/efectividad que justifica uso en mayores de 65. afios ya que a tres afios redujo la necesidad de reemplazos articulares en un 5% (ANEXO 6). Extrapolando este porcentaje al numero de reemplazos articulares de cadera y rodilla en Colombia, cuyas cifras segin la SCCOT indican que anualmente ascienden a casi 28.000 _ eventos imadamente, en_su_gran_mayoria_en_mayores de 65 ios, bien justificaria el uso de un medicamento que reduzca la necesidad de dichos procedimientos, siendo eventos de alto costo dentro de los cuales suele haber bastantes costos ocultos asociados como pérdida de productividad, costos de rehabilitacion, consulta, pérdida de AVISA, costos de efectos adversos de analgésicos 0 AINES, entre otros. a. Otras fuentes que resefian cifras de reemplazos articulares de cadera son el DANE segun Ultimo censo, que informa tasas entre 10 y 17 reemplazos por cada 10.000 habitantes (ANEXO 7). b. Todo esto para_subrayar_que en un [sistema de) resupuesto limitado como lo es el colombiano, es racional contar con una terapia modificadora de enfermedad como Diacereina que disminuye en 5% el numero de reemplazos articulares. c. Por otra parte, en Colombia en el afio 2009 los reemplazos de cadera y de rodilla ascendieron a un total de $ 38.125 millones con un costo individual promedio en aquel momento de 5 “055.000 pesos, d. Ahora bien, la reduccién con diacereina en 5% del requerimiento de reemplazos articulares, ahorrarfa una Pagina Sé ogaee Saovamed o006 cifra de casi $ 1.9 millardos de pesos (del afio 2009) del rubro de reemplazos articulares (ANEXO 8). 2.3 En el pais, la diacerefna de investigacién original comercializada con la marca Artrodar® leva més varios afios de comercializacién con resultados altamente satisfactorios como modificador sintomdtico y estructural en mds de 45.000 pacientes con OA en el ultimo afio en quienes se ha visto una mejoria en los sintomas de su enfermedad, menor consumo de analgésicos, menor cantidad de consultas, menores incapacidades, lo cual es de interés para la parte econémica del sistema. Si bien en Ia literatura se describen las heces blandas es el efecto secundario autorresolutivo mas frecuente con diacereina, se describe en toda la informacion para prescribir, esto no es el caso en estudios colombianos, comentado mas adelante. Dicho efecto secundario es de intensidad leve a moderada, siendo transitorio en la mayoria de los casos, no da lugar a hipopotasemia ni requiere reemplazo de electrolitos, Este efecto ocurre generalmente dentro de las primeras dos semanas (promedio 8,5 dias) de tratamiento y disminuye con la continuacién del tratamiento. Los estudios observacionales realizados en entidades acreditadas como BIOMAB, muestran EVIDENCIA EN que sobre una poblacién de 360 pacientes bien COLOMBIA con artrosis 0 con artrosis y artritis reumatoidea coexistente, mostraron: Dispepsia: 3,6% Diarrea: 2,8% Nadseas: 1,4% Elevacién de aminotransferasas hepaticas 0.5% Dicho estudio, presentado en el Congreso internacional de la Sociedad de Investigacin de la OA (OARSI), concluy6 “Los eventos gastrointestinales fueron los principalmente observados, pero solo en una pequefia proporcién de los pacientes. La diarrea no estuvo presente como previamente se describié en la literautra, siendo notorio que atin en pacientes tomando medicaciones concomitantemente para la artritis reumatoidea, no hubiera un incremento en la frecuencia de los eventos adversos. Por esta Pagina 6é a007 Snevamed 9986 ‘CALIDAD E NNOVACION raz6n, diacereina puede ser considerada como una medicacién SEGURA para el tratamiento de la OA." (ANEXO 9). Por otra parte, cabe destacar que desde el lanzamiento de la Diacereina en Colombia no ha habido ningiin reporte de reaccin hepatica (leve, moderada o severa), ni de aumento en los niveles de transaminasas ni de otros marcadores hepaticos, sienco comercializada Gnicamente por medio de prescripcién médica generada por las especialidades que tratan la osteoartrosis en sus diferentes grados, como son Reumatologia, Fisiatria, Traumatologia y Ortopedia, Medicina Interna y Medicina General, en las principales ins nes que tienen programas operativos de farmacovigilancia, como Compensar, Nueva EPS, Ecopetrol, Hospital Militar Central, Cafam, Sura, entre otros. [3, Evaluacién del balance riesgo / bene! 3.1 Seguridad hepatica a. Diacereina tiene un bajo potencial de hepatotoxicidad, confirmado por diferentes estudios toxicolégicos (de dosis repetidas por via oral en roedores y perros con dosis mucho ms altas que la utilizada en humanos), donde no indicaron que el higado fuera un érgano diana para la toxicidad, De hecho, se informs una actividad hepatoprotectora de la reina en varios experimentos preclinicos, a través de mecanismos que implican la inhibicién de la 15-Hipoxigenasa (°) y las propiedades antioxidantes de Ia reina (#9). Por otra parte se ha reportado que la reina protege contra lesién hepatica inducida por paracetamol (2). b.A partir de los datos de farmacovigilancia post-marketing disponibles (Data On File - ANEXO 10), se confirma igualmente la mas baja frecuencia de eventos hepaticos en comparacién con los AINEs. La informacién disponible equivale a 1.2 casos por cada 100.000 pacientes-aiio de 5 Malteruc KE, Farbrot TL, Huse AE, Sund RB. Antioxidant and radical scavenging effects of anthraquinones and anthrones. Pharmacology. 1993 Oct-47 Supol 1:77-85. * Guo MZ, LIXS, XuHR, Mei ZC, Shen W, Ye XF. Rhein inhibits liver frosis induced by carbon tetrachloride in rats. Acta Pharmacol Sin, 2002 Aug:29(8).739-44. * Zhao YL, Zhou GD, Yang HB, et a. Rhein protects against acetaminophen-induced hepatic and renal toxicity. Food Chem Toxicol. 2074 Aug49(6):1706-10 Pagina,990008 S8a0evamed™ CALIDAD EIMNOVACION exposicién a diacereina, [riesgo de 0,00001] lo cual segtin COSTART es considerado una frecuencia rara. Esto contrasta con el riesgo de lesién hepatica inducida por AINEs, que asciende a 10 casos por cada 100.000 pacientes ~ afio de uso [riesgo de 0,0001 = diez veces superior vs. diacereina] (2). c. Otros datos bibliograficos disponibles estiman que la lesién hepatica inducida por AINEs resulta en hospitalizacin de 3.1 a 23.4 casos por cada 100.000 pacientes-afio de exposicién a AINEs (1); y al considerar la insuficiencia hepatica aguda inducida por paracetamol que requiere de trasplante hepatico, ésta es dos veces mas comtin con paracetamol que con AINEs (1%), todo esto demuestra que la seguridad hepatica de diacereina es superior a la de medicamentos de uso comin en OA en Colombia, como acetaminofén y AINEs. d.De los aproximadamente 2.000 casos de insuficiencia hepatica aguda que ocurren anualmente en EE,UU., mas del 50 % se debe a medicamentos tomados por via oral (de los cuales el 39 % son debidos a paracetamol) (#5), medicamento utilizado como primer escalén en el tratamiento sintomético de la OA en Colombia apenas para detener sintomas y sin ningun efecto estructural. e. A partir de los datos de Farmacovigilancia del investigador TRB Chemedica de Lugano - Suiza (ANEXO 10), se ha encontrado una muy baja frecuencia de eventos hepaticos durante la Farmacovigilancia post-marketing. La informacién disponible equivale a 1 caso por cada 100.000 pacientes- afio de exposicién a diacereina [riesgo de 0,00001], que no *2 Walker AM, Quantitative studies ofthe risk of serious hepatic injury in persons using nonsteroidal antiinflammatory drugs. Artis Rheum. 1997 Feb;40(2):2018 + Rubenstein JH, Laine L. Systematic review: the hepatotoxicity of non-steroidal ant-inflammatory drugs. Aliment Pharmacol Ther. 2004 Aug 18:20(4):373-0. + Guimez SE, Laney D, Pageaux GP. et a. Transplantation for acute liver failure in patients exposed to NSAIDs or paracetamol (acetaminophen): the multinational case-population SALT study, Drug Sef, 2043 Feb36(2}135-44 “# Mehta N, Pinsky MR. Drug-induced hepatotoxicity [Intermed]. Medscape Reference, Medscape Dawgs, Diseases & Procedures. 2012 Jun 27 fated 2043 Apr 414. Aveilable fom: ito/emedicine medscape.com/article/1628 4-overvew Pagina 8Wnovamed CALIDAD E IHOVACION ha tenido modificaciones recientes, lo cual segtin COSTART es considerado una frecuencia rara. f. Diacereina tiene un bajo potencial de hepatotoxicidad, confirmado por diferentes estudios toxicolégicos (de dosis repetidas por via oral en roedores y perros con dosis mucho més altas que la utilizada en humanos), los cuales no indicaron que el higado fuera un érgano diana para la toxicidad. De hecho, se informé una actividad hepatoprotectora de la reina en varios experimentos preciinicos, a través de mecanismos que implican la inhibicién de la 15-lipoxigenasa (3°) y las propiedades antioxidantes de la reina (#7). Por otra parte se ha reportado que la reina protege contra lesién hepatica inducida por paracetamol (3°). Todo lo anterior confirma entonces que [el higado no es un érgano diana para la toxicidad a corto y a largo plazo con diacereina, ratificando asi los hallazgos preclinicos de estudios toxicoldgicos a dosis varias veces superiores a la dosis humana en los cuales no se presenté hepatotoxicidad. Toda esta informacién que fue evaluada por la agencia europea de medicamentos y por el Invima, se condensa en el ANEXO 14 3.2 Muy baja frecuencia post-comercializacién de eventos hepaticos, en comparacién con los AINES. Otros datos bibliogréficos disponibles estiman que la lesién hepatica inducida por AINEs resulta en hospitalizacién de 3.1 a 23.4 casos por cada 100.000 pacientes ~ afio de exposicién a AINEs‘); y al considerar la Insuficiencia hepatica aguda inducida por Acetaminofén que requiere de trasplante hepatico, esta es dos veces mas comin con paracetamol que con AINEs(®), 6 Malterad KE, Ferbrot TL, Huse AE, Sund RB. Antioxidant and radical scavenging affects of anthraquinones and anthrones. Pharmacology. 1983 Oct-47 Supol 1:77-86. * Guo MZ, LIXS, Xu HR, Mei ZC, Shon W, Ye XF. Rhein inhibits liver fibrosis induced by carbon tetrachloride in rats. Acta Pharmacol Sin. 2002 Aug;25(8):739-44, "Zhao YL, Zhou GD, Yang HB, et al. Rhein protects against acotaminophen-induced hepatic and renal toxicity, Food Chem Toxicol. 2041 Aug;49(8)'1705-10. PaginasBayo Saovamed CALIDAD E HINOVACION 3.2. El perfil de seguridad gastrointestinal de diacereina es mejor que los AINEs y el paracetamol. a. Los datos de estudios clinicos no mostraron diferencias entre diacereina vs. placebo en términos de sintomas gastrointestinales superiores incluso cuando la diacereina fue tomada diariamente durante tres afios (!2). Al comparar vs. paracetamol y AINEs, se encontré que estos si se asociaban a efectos secundarios graves a nivel gastro ~ intestinal, que impiden su uso en ciertos pacientes. Igualmente, paracetamol y AINEs se asocian con un mayor riesgo de hospitalizacion como resultado de perforaciones gastrointestinales, dlceras 0 hemorragias, con un hazard ratio de 1,20 (1.03 a 1.40) en pacientes tratados con altas dosis de paracetamol (> 3 g / dia), y de 1.63 (1.44 a 1,85) en los pacientes que recibian AINEs orales (2 3.4 La accién laxante de diacereina es transitoria. a. Heces blandas y diarrea son los efectos colaterales més frecuentes con diacereina y se describen en la informacién para prescribir e insertos aprobados a nivel mundial. b. La accién laxante es de intensidad leve a moderada, siendo transitoria en la mayoria de los casos, no da lugar a hipopotasemia ni requiere reemplazo de electrolitos. Esta accién ocurre generalmente dentro de las primeras dos semanas (promedio 8,5 dias) de tratamiento y disminuye con la continuacién del tratamiento. 4_Impacto en salud ptiblica 41 Importancia de la osteoartrosis 4.1 La enfermedad articular degenerativa u osteoartrosis es una de las enfermedades més prevalentes en la poblacién general, siendo segunda en la lista de enfermedades crénicas después de los trastornos cardiovasculares y es la causa mas comin para reemplazos articulares totales en rodilla y cadera. Diversos estudios epidemiolégicos han demostrado que cerca del 60% de la poblacién adulta menor a 50 afios presenta cambios radiolégicos significativos asociados a osteoartrosis asi como sintomas inespecificos +92, " Begge E & Brooks P. Osteoarthritis in older patients. Optimum treatment. Drugs & Aging 1995; 7/3) 176-183 Pagina 10S8aevamed™ og0ot! (CALIDAD E IMNOVACION 4.2 La IL-1 actda sobre los condrocitos para incrementar la sintesis de factores catabélicos como las metaloproteasas de la matriz (MMPs) y el 6xido nitrico-ON (2 22). En los condrocitos se encuentra la forma inducible de la ON sintetasa (INOS), que es estimulada por IL-1 (7) y bajo la estimulacién de IL-1, los condrocitos producen ON en cantidades comparables a las producidas por los macréofagos, con lo cual aumenta ésttés oxidative que dafia el Acido hialurénico y lesiona las células. 4.3 Por otra parte, la obesidad inducida por la osteoartrosis se incluye ahora en_un fenotipo mayor denominado "OA metabélica", por cuanto fa artrosis se asocia con diversos parametros de indrome metab6lico (incluyendo diabetes de el exceso de mortalidad cardiovascular relacionada con lesta enfermedad] 4.3.1 De tal manera, la osteoartrosis de aparicién temprana debe hacer sospechar un sindrome metabdlico potencial. Las estrategias de pérdida de peso siguen siendo un enfoque terapéutico util para prevenir la osteoartrosis y reducir los sintomas, y deben estar asociados con la actividad fisica para permitir éptimos resultados 4, 4.4 Hay importante correlacién entre obesidad e inflamacién. Los tejidos adiposos (y la almohadilla de la grasa infrarrotuliana de Hoffa) juegan un papel importante en este contexto, ya que son la fuente principal de citocinas, quimiocinas, y mediacores metabélicamente activos llamados adipocinas (0 adipocitocinas). Estos factores metabdlicos poseen propiedades catabélicas y 2° Felson DT, Zhang Y, Hannan MT, Neimark A, Weissman BN, Allabadi P, Levy D. The incidence and ‘natural history of knee osteoarthritis in the elderly: The Framingham osteoarthritis study. Arthiis Rheum 1995; 38: 1500-1806. 2 MartePeliotier J, Mineau F, Jolicoeur FC, et al: Invitro effects of diacerhein and rhein on IL-1 and TNF- ‘a systems in human osteoarthritic synovium and chondrocytes. J Rheumatol 1996; 25: 753-762 ” nue , Tang J, Pronost S, et al Méchanismes moléculaires impliqués dans inhibition de expression de la collagenase para la diacerhéine, Rev Prat (Paris) 1996; 46 (Supp! 6): S16-S19 ® Polltisr JP, Mineau F, Femandes JC, et a: Diacerhein and rhein reduce the IL-1 stimulated inducible nitric oxide synthesis level and activity while stimulating cyclooxygenase-2 synthesis in human ‘ostooarthitic chondrocytes. J Rheumatol 1998: 26: 2417-24 ¥ Sellam J, Berenbaumn F. Osteoarthritis and obesity. Rev Prat 2012; 62(6): 621-624 Pagina 11Snovamed™ o00t2 45 ‘CALIDAD € INNOVACIOH proinflamatorias y para orquestar los procesos patofisiolégicos en la OAS, Por la naturaleza crénica de la osteoartrosis, terapéutico es la modificacién estructural, entendida como] laquella que detiene o retrasa las manifestaciones de laj losteoartrosis en estudios clinicos en humanos, 4.5.1 Las agencias regulatorias consideran que la evidencia de mejoria en los resultados clinicos es fundamental para la aprobacién de las llamados modificadores estructurales en osteoartrosis 0 DMOAD (Disease Modifying Osteoarthritis Drug). En la definicién igualmente la cirugia de reemplazo total de la articulacién es el punto final clinico mas relevante para la evaluacién de la eficacia de un DMOAD. 4.5.2 Los DMOAD deben demostrar una diferencia significativa en ‘comparacién con el placebo y el beneficio debe medirse por 3 puntos finales co-primarios que incluyen el estrechamiento del espacio articular (JSN de la literatura anglosajona, por Joint Space Narrowing), la mejoria de dolor y la funcién. 4.5.3 En los resultados finales debe estar el porcentaje de pacientes con "respuesta" (0 "falla"): donde el paciente con "fala" es aquel con progresién de JSN> 0,5 mm durante un periodo de 2-3 afios, 0 con empeoramiento significative en el dolor y / 0 funci6n, sobre la base de valores de corte validados. La definicién de los puntos de corte clinicamente relevantes para el dolor y la funcién debe basarse en datos que evalian la historia natural de la enfermedad (cohortes epidemiolégicas o grupos placebo en los estudios a largo plazo). Los puntos de corte deben reflejar si posteriormente es necesario el reemplazo articular 26, 2 Rai ME, Sandel! LJ. Infammatory mediators: trecing inks between obesty and osteverthrts. Crit Rev Eukaryot Gone Expr 2011; 24(2): 131-142. % Abaaie E, Ethgen D, Avouac B, Bouvenot G, Branco J, Bruyere O, Calvo G, Devogelaer uP, Dreiser RL, Herero-Beaumont G, Kahen A, Kreutz G, Lasiop A, Lemmel Ek, Nuki G, Van De Putte L, VanhasistL, Reginster JY; Group forthe Respect of Excellence and Ethos in Science, Recommendations for the use of new methods to assess the effeacy of disease-modiving drugs in ihe treatment of osteoarthritis Osteoarthritis Cartilage 2004; 12(4): 263-268. Pagina 12ea} S oS = bo ws novamed CALIDAD E WYNOVACION 4.6 Relaci6n entre Interleucina 1 (molécula inhibida por diacereina) y osteoartrosis Existe fuerte evidencia de una contribucién de las citocinas proinflamatorias, adicionales a la degradacién del cartflago en osteoartrosis, referida por diferentes autores 27 26 29 50, ‘a. Al menos tres citocinas a saber, interleucina-1 (IL-1), factor de necrosis tumoral alfa (TNF-a) e interleucina-6, se han identificado en el tejido articular lo cual sugiere que desempefian un papel durante la inflamacién, actuando de forma bien paracrina 0 autocrina; al estudiar condrocitos artrésicos, se ha observado que tienen una mayor sensibilidad a la estimulaci6n por IL-1 por cuanto tienen una mayor produccién de metaloproteasa vs. los condrocitos normales y dicha hiperproduccién se considera relacionada con un aumento en el nivel de receptores de IL-1 >8. Un hallazgo adicional que soporta la accién deletérea de la IL-1, es que el cartilago artrésico humano es més sensible @ IL-1 al comparer con el cartilago sano 2, En conclusién, la OA se considera cada vez mas como un proceso dindmico y metabdlicamente activo que incluye tanto la destruccién |donde Ia molécula interleucina: como la reparacién del cartilago, hhialino y alteran el normal funcionamiento de los condrocitos, el Unico cormponente celular activo del cartilago articular en los humanos. Y ademas, es una enfermedad que causa mortalidad, como se muestra a continuaci6n. 4.7 Mortalidad por Osteoartrosis 2 Arend WP. Inhibiting the effects of cytokines in human diseases. Adv intern Med 1996; 40: 368-204. 2 Krane SM, Clinical importance of metalloproteinases and their inhibitors. Ann NY Acad Sci 1904; Sep 6; 732: 1-10, ° Lotz M, Blanco FJ, von Kempis J, Dudler J, MaiorR, Vllger PM, Geng Y. Cytokine regulation of ‘chondrocyte functions, J Rheumatol Supp! 1995 Feb; 43: 104-108, ® Shlopov BV, Lie WR, Mainardl CL, Cole AA, Chubinskaya S, Hasty KA. Osteoarthritic lesions: involvement of three different collagenasos. Artirtis Rhoum 1997; 40/1): 2065-2074 2 Pelletier JP, DiBatista JA, Roughley P, McCollum R, Martel-Pelletier J. Cytokines and inflammation in cartilage degradation. Rheum Dis Clin North Am 1993; 19/3) 545-568, Marist Pelletir J, McCollum R, DiBattste J, Faure MP, Chin JA, Fourier S, Sarfati M, Peller JP. The Intereukin-1 receptor in normal and osteoerthrc human ericular chondrocytes. identifcation as the {ype | receptor and analysis of binding kinetics and biologic function. Arthritis Rheum 1992; 35(5): 630-540. Pagina 13,i: oooo14 Saovamed CALIDAD E INNOWACION a. Hochberg,3?_ (ANEXO 11) realizé una revisidn sistematica e identificé siete estudios que proporcionaron datos sobre mortalidad o la supervivencia en personas con osteoartrosis. Aunque en general, no hubo pruebas moderadas de aumento de la mortalidad entre las personas con artrosis al comparar vs. la poblacién general, si se identificaron una serie de factores de riesgo para mortalidad en pacientes con osteoartrosis, como la edad avanzada y la presencia de condiciones comérbidas. Las posibles explicaciones para el exceso de mortalidad incluyen la reduccién de los niveles de actividad fisica en las personas con osteoartrosis debido a la alteracién de articulaciones de las extremidades inferiores y la presencia de comorbilidades, asi como los efectos adversos de los medicamentos utilizados, especialmente los antiinflamatorios no esteroideos. b, El riesgo de morbilidad especifica para osteoartrosis es de aproximadamente 25% para cadera y de 45% para la rodilla, el 3 y el trastorno es un importante contribuyente a [a rodilla, siendo responsable de aproximadamente 57.000 artroplastias de rodilla y 55.000 artroplastias de cadera realizadas cada afio, por ejemplo en Gran Bretaiia >, ¢. Por otra parte, Niiesch y colaboradores en Suiza 25 reportaron que los pacientes con artrosis tienen mayor mortalidad por cualquier causa al comparar vs. la poblacién general [proporcién de mortalidad estandarizada 1.55; intervalo de confianza (IC) del 95% 1.41 a 1.70]. Hubo un exceso de mortalidad por todas las causas especificas de la enfermedad, pero fue mayor para enfermedad cardiovascular (proporcién de mortalidad estandarizada 1.71; IC=1.49 a 1.98) y para demencia (proporcién de mortalidad estandarizada 1.99; IC=1.22 a 3.25). d. La mortalidad se incrementé con el aumento de la edad (p <0,001), con sexo mascullino (cociente de riesgo ajustado 1.59; IC=1,30 a 1,96), historia autorreportada de diabetes (1.95; IC=1.31 a 2.90), cancer (2.28; IC=1.50 a 3.47), enfermedad cardiovascular (1.38; IC=1.12 a 1.71) e 3 Hochberg MC. Morialty in ostecartis. Clin Exp Rheumatol 2008; 26(5 Suppl 61): $120-S124. % Cooper C, Arde NK. Excess mortality in osteoarthritis BltJ 2011; 342 do ito. do ora/40.4138iomi.ct40 % Ndesch E, Dieppe P, Reichenbach S, Willems S, IFS, ni P. All cause ard dlsease specific mortal in patients with knee or hip osteoarthritis: population based cohort study. BMJ 2011 Mer 8; 342:d1 185 (40 10.4136rbmidt 168}, Pagina 14s70000 Bnovamed 48 49 4.10 CALIDAD E WuNOVACION incapacidad para caminar (1.48; IC=1.17 2 1.86). Sin embargo, no hubo evidencia de aumento de la mortalidad asociada con el reemplazo articular, la obesidad, la depresion, la enfermedad inflamatoria crénica, o enfermedad ocular. Como punto relevante, a mayor incapacidad para caminar, mayor era el riesgo de muerte (p <0,001) *°, Por lo anterior, se puede afirmar que los pacientes con osteoartrosis tienen un mayor riesgo de muerte en comparacién con la poblacién general, de tal forma que es racional para la practica médica la deteccién y el tratamiento precoces en etapas tempranas de la enfermedad. La estructura poblacional colombiana de acuerdo al censo del DANE (ANEXO 12) muestra una tendencia marcadamente creciente de la poblacién mayor a 65 afios desde el afio 2012. De hecho, en el afio 2013 habia alrededor de 3.368.538 mayores de 65 afios, equivalente al 7.15% de la poblacién y se estima que lleguen en el 2016 a 3.740.375, correspondiente al 7.67% de la poblacion. Segiin la Osteoarthritis Research Society International- OARSI, (ente internacional de referencia), la prevalencia de OA es alta en mayores de 65 afios, siendo de aproximadamente 60% para OA de mano, 15% para OA de rodilla y cadera, confirmando asi el gran impacto de la enfermedad en los mayores de 65 ajios (ANEXO 13). que se traduce en incapacidades, alto consumo de medicamentos, mayor requerimiento de cirugias de alto costo como reemplazos articulares, ademas de aumentar riesgo de mortalidad por accidente cerebro vascular e infarto agudo de miocardio por sedentarismo, sin contar costos indirectos u ocultos provenientes de la iatrogenia por acetaminofén y/o AINEs Todo lo anterior obliga a atender en forma integral a este grupo etdreo de mayores de 65 afios con medicamentos que han comprobado modificacién estructural y sintomética de la enfermedad. Lo anterior, sumado a la alta prevalencia de la OA mostrada en la literatura biomédica mundial con cifras entre el 65-70%, que ubica a la OA como la tercera causa de incapacidades médicas y altos costos laborales a nivel mundial después de mlosardnpats isquémica y enfermedad cerebrovascular (ANEXO 13), |convierte lasi la OA en un objetivo de deteccién temprana y/o apoyo terapéutico por parte del sistema de seguridad social en Salud maxime que se esté ante el reto de una poblacién en Pagina 15 \SS8novamed® _g20i8 CALIDAD E INNOVACION envejecimiento, con toda la carga de enfermedades crénicas no transmisibles que ello conlleva. Consideramos que las especialidades médicas que han nominado al producto para exclusién, no tienen la perspectiva de las especialidades quirdrgicas, como ortopedistas y traumatélogos, quienes debe realizar los procedimientos de reemplazo articular una vez la artrosis deviene en falla articular, y ademas realizan las artroscopias y otros procedimientos de exploracién directa donde se comprueban los efectos de la diacereina al inhibir la TL-1 elevada. La diacereina es en este momento, la Gnica tecnologia en salud que inhibe la molécula interleucina1 que cuando esta elevada desencadena toda la cadena de eventos fisiopatolégicos de la artrosis, que ha demostrado frenar la evolucién de la enfermedad artrésica a tres afios. En caso de excluirla, los tratantes solo podran contar con medidas paliativas como analgésicos 0 aines, con todas las consecuencias de falta de efectividad de control de la enfermedad, consultas frecuentes, y seguramente, mayor cantidad de eventos de alto costo como Io son los reemplazos articulares. Por todo lo anterior, solicitamos la no exclusién de la tecnologia Diacereina a la luz de los articulos 2 y 15 de la Ley 1751 de 2015 que disponen que el derecho fundamental a la salud es autdnomo e irrenunciable en Io individual y en lo colectivo, y que el mismo comprende el acceso a los servicios de salud de manera oportuna, eficaz y con calidad para la preservacién, el mejoramiento y la promocién de la salud; debe ser garantizado a través de las prestaciones de salud, estructuradas sobre una concepcién integral de la salud, que incluya la promocién de la salud, la prevencién, la paliacién, la atencién de la enfermedad y rehabilitacién de sus secuelas. Cordialmente A Quali . Alejandro Melo Florian FACP Especialista en Medicina Interna Departamento Médico de Novamed Pagina 16Snevamed® CALIDAD E MINOVACION ANEXO 1. Evidencia reciente ‘hints tnememme EATS: of Osteoarthritis. An Opinion-Based Report from the ESCEO ara Peli! «lo Brsee= Cyr Capers A. Kani Dorabard Fg Emmaned babes hens Mathes Sor Mono = eamerre Pe” Rene Riza" Jee YsRetc® itor scot Sere E | Diacerein: Benefits, Risks and Place in the Management Pagina 17‘Droge Aging (2016) 38:75-85 Dot 10,1007/540266.016-0347-4 CURRENTION INION Diacerein: Benefits, Risks and Place in the Management of Osteoarthritis. An Opinion-Based Report from the ESCEO Karel Pavelka' - Olivier Bruydre® « Cyrus Cooper’ « John A. Kanis ‘Burkhard F. Leeb* - Emmanuel Maheu* - Johanne Martel-Pelletier” - ordi Monfort - Jean-Pierre Pelletier” - René Rizzoli? - Jean-Yves Reginster® Published online: $ Febreary 2016 © The Authons) 2016, This ae Abstract Diacerein is a symptomatic slow-acting drug in osteoarthritis (SYSADOA) with anti-infammatory, snti-catabolic and pro-anabolic properties on cartilage and synovial membrane. It has also recently been shown to have protective effects against subchondral bone remodelling. Following the end of the revision procedure by the Pharmacovigilance Risk Assessment Committee of the European Medicines Agency, the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) constituted a panel of 11 experts to better define the seal place of diacerein in the armamentarium for weating OA. Based on a lteraure review of clinical wile and meta-analyses, the ESCEO confirms that the efficacy of diacecein is similar to that of non-steroidal antiinflammatory drugs (NSAIDs) after the first month of weatment, and superior to that of (On beat ofthe European Society for Clinical and Economie Aspects of Oxeoporosis and Oxouthrss (ESCEO), EE Olivier Bryere olvierbruyere@ulg-azbe Insite of Rheumstlogy and Cline of Rhaumstology, ‘Charles Uaiversiy. Prague, Ceech Repub ® Deparment of Public Healt, Epidemiology and Health Economics, University of Lite, Litge, Belgium + MRC Lifesouse Epidemiology Unit and NINR Notion ‘Biomedical Reseach Cen, University of Soubamg.on, Southangton, UK WHO Collaborating Centre for Metbolic Bone Disestes, University of Shetctd Medical School, Sheffield, UK 2d Department of Medicine, State Host) Stockere, Cente for Rheomatology, Lower Aust, Kast Lanteiner Tustirue for Clinical Rheumatology, Stwekerey, Ausois 2s published with open acces at Spingelink.com paracetamol. Additionally, diacerein has shown a pro- Jonged effect on symptoms of several months once tueatment was stopped. The use of diacerein is associated ‘with common gastrointestinal disorders such as soft stools and diarthoea, common mild skin reactions, and ‘uncommonly, hepstobilisry disorders. However, NSAIDs and paracetamol are known to cause potentially severe hpatic, gastrointestinal, renal, cutaneous and cardiovas- cular reactions. Therefore, the ESCEO concludes thet the Denefit-risk balance of diacerein remains positive in the symptomatic treatment of hip and knee osteoarthritis, Furthermore, similarly to other SYSADOAs, the ESCEO positions digcerein as a first-line pharmacological background treatment of osteoarthritis, particularly for patients in whom NSAIDs or paracetamol are contraindicated. Rheumatology Deparment, APLHP, St-Antoine Hospital, Paris, France Oseoanhis Research Wait, Ulversty of Monsrea Hospital Research Cease (CRCHUM), Nowe- Dame Hospital, Monteal, Canada Rheumuology Service, Hospital del Mae, Unversiat “Avtinoma de Barslons, Barelone, Spain Divison of Bone Diseases, Geneva University Hosp and Faculty of Medicine, Geneve, Switerend16 99019 K. Pavel et ‘Randomised clinical trials show that diacerein has 2 similar efficacy compared with NSAIDs on ‘osteoarthritis symptoms, Digcerein has an acceptable safety profile, particularly in comparison with that of NSAIDs and paracetamol, ‘The ESCEO positions diacerein as a fist-line pharmacological background treatment of osteoarthritis 1 Introduction Osteoarthritis (OA) is the most frequent form of arthritis, sand one of the leading causes of disability among older adults worldwide (1]. For individuals, the burden of OA also includes persistent background pain (aching) and intermittent but generally more intense pain, Together with ppein contributes to a significant reduction in ‘The management of OA includes pharmacological therapies, which are mostly symptomatic [2), Parzoetamol isthe first-line oral analgesic, whilst oral non-steroidal anti- inflammatory drags (NSAIDs), including selective ‘yclooxygenase-2 (COX-2) inhibitors, are the mainstay of therapy (3, 4]. These drugs are considered as rapid-ecting drugs in OA and are recommended by theumatology societies (2, 5, 6] and government agencies [7]. ‘Symptomatic slow-acting drugs for OA (SYSADOAs) such as glucosamine, chondroitin sulphate and diacercin are used for non-acate treatment, Although there is rela- tive general agreement on many OA management recommendations aoross organisations, there is still no consensus on the place of SYSADOAS. In general, they are considered supplementary 10 analgesics and NSAIDs, ‘whereas the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) places SYSADOAs as. pharmacological background ‘weatment; that is frst chronic therapy that may improve ‘of control symproms (5) Diacereia is an anthraquinone derivative, of which the active metabolite is rhein. Its positioning in the algorithm established by the ESCEO [8] had not been formalised because, at the time of publication, diacerein was under review "by the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA). Following the assessment of the PRAC, the ESCEO felt the need to evaluate the role of diacerein in Anew clinical practice and constituted a panel of experts to define its place in the management of OA. This article expresses the reasoned conclusions drawn by the ESCEO working group on diacerein, 2 BSCEO Working Group Process ‘The ESCEO invited 11 experts in musculoskeletal diseases (cheumatologist, clinical epidemiologists and scientists) 0 be par of the working group. Four members had already been involved in clinical or preclinical research on diacerein, two of them being curtent diacecein prescribers all were proficient in analysing aad interpreting clinical ‘tial evidence related 10 OA. Five of the participants were entrusted with the task of preparing a review on the mode of action, efficacy and safety of diacerein in the weatment of OA. A literature search was conducted in May 2015 using the MEDLINE PubMed database. The search strategy included a combi- nation of the following terms: ‘diacerein’, “diacetylrhein’ ‘digcerhein’, ‘rhein’ and ‘osteoarthritis’. Filter settings ‘were "English’, ‘Freach’, ‘German’, ‘Spanish’ or ‘Italian’ languages. This literature search yielded 179 hits, of which 108 (57 original research papers, 51 reviews, meta-analyses or opinion-based articles) were retieved according to their relevance to the topics mentioned above: 42 were related to ‘the mode of action of diacerein, 60 dealt with its clinical efficacy, and 45 contained information on the safety of diacerein. AdGitional references were selected from the reference lists of the retrieved articles to broaden the Ticerature search, ‘The outcome of this review was finally discussed by the 11 experts at a one-day meeting in June 2015. 3 The Mechanism of Action of Diacerein in Osteoarthritis 34 In Vitro Studies ‘The principal mechenism of setion of diacerein iso inhibit the interleukin-I6 (HL-1f) system and related downstream signalling (9). Diacerein hes been shown to impact the activation of IL-1B vie a reduced production of IL-1 con- verting enzyme [10], 28 well as to affect the sensitivity to Tl by decceasing TL- receptor levels on the cel suface of chondrocytes [11] and by indirectly increasing TL-1 receptor antagonist production (12, 13]. Production of IL-1 may also be affected as diacerein has been shown to inhbie the TL-1f-induced activation of tansription factor NP-xB, which simulates pro-inflammatory cytokine expression (14-16). Downregulation of TL-I levels hesrein i the fanagemet of Ostoat ‘Table 1 Summary of the effects of dacerlnthein on aoular dasues Cariagelsynoviel ment Antiestaboli JL Pinduced MMP-1, MMP.3, MIMP-13, ADAMTS-4, ADAMTS-S [5,22] | Metpbinduzed INOS, NO 3, 16, 19, 252 7 MLetfbindsced PGE2, COX-2 [21] Pro-amabolie Svbchondral bone ‘Ostablacs 1 eollageo, proteoglycans, hyaluronan (15,19, 20) 1 PGE2, COx2 2) 4 vitamin D3-indueed osteocelcin + J uPA (21) I DKK-1, DKK? 24) Oneness Jom. costoclast survival, pe-eseoclas ditferetation £25] ‘Adapted with permission from Ma cathepsin K [25] leer and Peleder [9] ADAMIS disiorgrin snd metalloproteizase domain with thomborpendin mesfs, COX.2 cyclooxygenase 2, DKK Dichuopf, I-19 ineeakin-IP, antagonist, {NOS Induibe wee oxide synthase, MIP merllo- potsnase, NO nit oxide, PGE? prostaglandin 2, uPA urokinase type plasminogen seivaor ‘been confirmed in the synovial fluid of patients with knee oa 17) ‘Besides its anti-inflammatory properties, diacerein has been shown to have anti-catabolic [15, 16] and pro-ana- bolic [15, 18-20] effects on cartilage and synovial mem- Drane, as well as protective effects agsinst subchondral bone remodelling (Table 1) (21. 32 Animal Models of Osteoarthritis Beneficial effects of diacerein on cartilage and sub- ‘chondral bone have been observed in various animal models of OA. Diacerein consistently reduced cartilage loss compared with untreated controls (26-30), improved cartilage lesions in the experimental hip chondrolysis model of immamre Beagle dogs [31], and induced en increase in bone mineral density as well as a decrease in the thickness of the subchondral bone plate [28]. Finally, prophylactic treatment with diacerein has been shown to delay arthritis secondary to meniscectomy in a rat model of OA [32]. 4 Clinical Data on the Efficacy of Diacerein 4.1 Effects on Pain and Physical Function Efficacy of diacerein was evaluated in 16 published clinical tials (33-48). Patients included in these studies ‘were representative of patients in a reablife setting, so that the outcomes can be extrapolated to the general population. Four published meta-analyses assessed the symptomatic effects of 100 mg/éay diacerein [49-52]. Bach of them included a different set of clinical studies (Table 2). Tn ¢ meta-analysis of 19 published and unpublished srudies including «total of 2637 patients, Ritelen end co authors [48] showed a statistically significant superionity of disoereia over placebo at the end of treatment with respect to puin eduction and physical function improvement. At the end of the teatment-iree follow-up period, diaceein ‘was also found to be significantly better than placebo on pain (no pooled data on function), thus demonstrating a canry-over effect after stopping weatment. When compared with standard treatments (mostly NSAIDs), no statistically significant difference regarding pain and pi was observed at the end ofthe eatmenc period, However, atthe end of the weatment-free follow-up period, pocled Glass’ standardised mean differences on pain and joint function showed that diacerein was significantly superior ‘over the aetve comparator (Fig. 1). Using the strict Cochrane criteria for meta-analyses, Fidelix and co-athors reviewed seven published an. dlomised contolled trials in 8 total of 2069 patents with OA {50}. Three more clinical wils [44, 45, 47] were included in the updated Cochrane Review [51] compared with the 2006 version. The main differences in oxteomes beoween the tO metaanalyses are shown in Table 3. ‘Thus, in the Cochrane 2014 version, the mean-weighted differences (MWD) tended to increase in favour of iac- cerein compared with placebo. The authors concluded that diacerein had a small but significant effect on overall pain shor 3-36 months of treatment. In addition, results of @ subgroup analysis demonstrating « cary-over effect of diacerein compared with placebo or NSAIDs on pain and physical function were presented Finally, another meta-analysis on randomised, placebo- controlled wials with diacerein was published by Bartels et a. [52]. The authors included six studies with a total of 1533 patients. The effect size (ES) was estimated using sical function Aaaw opoe2t K. Pavella tel ‘Table 2 Clinical smdies included in the mets-analysesevalutng dicerein Saudy ‘Blinding Deraion Control Rinteen etal. Fidelin eal. (50) Bartels etal. Felix era. (53) (2006) 69] (Coehrane 2006) 2010) 52] (Coetmane 2014) Fgnani ei (1998) (36] Open 6 months Standard + ‘Chanze ot a, 2000) [38] DB 4monhk DC, + + Mastra (1985) [53] DB 3moans NSAID + Pietogrande tal. (1985) DB month NSAID + (ss) [Foravenc and Maroloags DB 2mouhs NSAID + 11985) 55] Montini etal (1986) [$6] DB 2mowhs NSAID + Mansi (1987) [57] DB 3monhe NSAID + Ponti (1989) (58) DB 3 months NSAID + Mucolongo etal (1988) DB 2 months. NSAID + 3) ‘Tang ctl. (2004) (59 DB 3monhs NSAID + + + ‘Zheng ea. (2006) [431 Lowthrenco tal. (2007) DB months NSAID + + a5] Pham eta. @004) [$1] DB 1D months NSAID + + + + HA Nguyen eal (1984) [34] DB 2months Placebo + + + + NSAID Ascher (1995) (60) DB Gmonhs Pssebo + Schultz (1994) (61) DB 3 months Placebo + Lequesne eal (1958) (37] DB 6 months Placebo + + + alleen eal. 2000) ($9) DB mouths Plcebo + + + + Dowgados et. 2001) 0] DB 36 months Placebo + + + + Pavelea otal. 2007) [44] DB 3.months Placebo + + + Brabmacher etal (2008) SB 2months Placebo + en (DB doable ind, DC Devs daw or Harpagoplyiam procunbers, HA hycurie ald, La inra-anicular, NSAID non-seridal ania ratory drug. SB single Bind Hedges’ standardised mean difference. For pain reduction, results showed thatthe combined ES was ~0.24 (95 % CL 0.39 to 0.08, p = 0.003, F = 36 %), favouring diac- ‘rein. There was also a statistically significant improve- ment in physical function (p = 001, F = 11 %) 4.2 Strueture-Modifying Effects ‘Two clinical studies assessed the impact of diacercin on radiological signs of OA: one was conducted in patients with hip OA [40], the other in patients with knee OA (41). Aaaie ‘The ECHODIAH (Evaluation of the Structure-Modify- ing Effects of Diacerein in Hip Osteoarthritis) study [40] ‘was a 3-year, multicentre, randomised, double-blind, pla- ccebo-controlled trial evaluating the potential structure modifying effects of diacerein in 507 patients with painful ‘and structurally advanced primary hip OA. Sixty-one patients did not have any pelvic X-ray after the start of treatment and were therefore excluded from the analysis. ‘The between-group comparison in the number of patients with e joint space narrowing (ISN) of at least 05 mm showed a statistically significant difference inDiacerein fn the Management of Ostecarhits » Fig. 1 Compasison of discern vs plesbo (a) and eianerin lace vs placebo, eatment period pin 4 seve compart (nosy Nano onaeer e aa iaceeinv placebo, treatment period, fncton KH plyscal fneton a: the end of baceren ve placebo, dechallenge period, pin Ke the active weatment period, 8s wells afer the weetmentee yy follow-up period Gzckllene) diacerein vs ative comparstor,westment period psi} (intlon et al (45) mete iacerin ys active comparator, weatment peri, fetion KH analysis), Error bars indice : : 95 % conienceimeral Aincerin vs ative compartir, dechallenge perio, sin —— a cers vs active comparator, dechatlenge pert, funtion Gia sandased mem | __ isria vs aetv compart, dechallenge peo co commonly repersed st nana a See ee Snicalyrelevanc 4 2 1203 faveurs compactor favour diacercin ‘Table 3 Main differences in rests berween the Cochrane Reviews 2006 [50] end 2014 is Dinceren ve placebo Pain on VAS (100 nm) 1 (oo, of siee) = F WMD (95 % CI Jadad-welghted Glass standardised mean difference idlix eal. (50) Fidei eta. 57), (Cochrane 2006) (Cochrane 2014) 1228 9) 0% 1283 ©) ~ 86% 5.16 (-9.95 © 057) 865 (“15.82 19 ~1.69) WOMAC pain subscale (0-500 mi) 1 (po. of sties) — F WMD (95 % Cl) 236 (1) = NA 24.90 (48.41 t0 -1.39) 399.@)-0% =29.33 (4845 to -1020) WOMAC fetion subscale (0-1700 mm) 2 (G0, of snadias) — F WMD (95 % CD) Diacerein ve NSAIDE 234 (1) — NA 107.50 (~187.51 © 27.49) 454.) 0% 11092 (173.88 w ~47.97) Pain oa walking on VAS (9-100 mm) 1 (oo. of stoies) = F WMD (95 CH) 184 (1) NA 461 (1069 0 Lay 218 (1) = NA. 130 (381 1 641) WOMAC pain subscale (0-500 mm) 1 (po. of staies) = P WMD (95 % C1) 161) = NA 14.90 (“10.15 3813) WOMAC fenetion subscale (0-1700 mm) 2 (oo, of stadios) = P WM (95 % CD {Woof pation, NA not applicable, F beteopencty index 188) = NA 12.28 (-7R01 t 48.45) 345 @) — 0% 29.50 (-23.17 82.17) | WMD weigh mean difference, 95 % Cl 195 6 conidence interval, VAS visual anlogse teal, WOMAC Wester Ontario snd MeMater Universes Oscoantis Index Mistakes have been cbcerved inthe reporng * values st 4 months of Tang eal. [58] have been incloced in the analysis insead of values a 3 months (end of treament;® baseline values of Tang ea (59) have been inclade inthe analysis instead of value at 3 mons from Zheng etl [3] favour of diacerein in both the intent-to-treat (TT) and the ‘Completer analyses (primary populations of analysis). The between-group comparison in JSN rate also showed a statistically significant difference in the Completer analy- sis, while no difference was observed in the ITT population using the lest-observation-carried-forward imputation method. Results in the per protocol (PP) population (see- ‘ondary analysis) were similar to those in the Completer data sot (Table 4). ‘The sbove results in the ECHODIAH sudy demon- strated the superiority of diacerein treatment versus pla- cebo in only three of four co-primary endpoints for JSN’ Daas80 K. Pevetia et Table 4 Join space mr0¥INg — Paranater 7 Sais rmetsared on pelvic Xoay at 3 year intento-ret, TTT das sx 7 mat 2s ‘Completr and per protocol datz suntart : i . ee ee 205 mm JSN, (85 % CF) 51% (as 60 6 (54-67) 0.016: Bongatos eal 40) ISN rate (mum/yas), mean (SD) 039 (078), 039 (081) se CCompleter dats Set, 3h 18 120.5 mm ISN, W (95 © CD 47% 69-56) 62% (54-70) ome SN rate (mmmlyes), mean SD) 018 025) 023 (023) naz DP data sa, 101 ne 205 mm ISN, W (95. CD) 49.8 C859) 68 5 (58-75) 008 SN rate (mye), mean SD} 018 022) 02s (028) oom TEP inencan-weat, PP per protocl, JN joint space varowing, N manber of patent, 95% C195 5% confidence incr, SD'Sandard deviation, ns nonsignieant Log rank tet, ** Msnn-Whitoey rest ‘and failed to demonstrate the structure-modifying effects of iacerein in patients with hip OA. ‘The Pham study (2004) [41] was conducted in 301 patients with knee OA. The aim of this year, randomised, double-blind, placebo-controlled, three-arm trial was to evaluate the long-term efficacy of three cycles of 3-weekly intra-articular injections of hyaluronic acid (HA) in the ‘ueatment of symptomatic knee OA compared with oral dincerein and placebo. A saline solution was used in the diacerein and placebo groups to maintain the blind. No statistically significant differences between groups ‘were observed for JSN. The percentage of patients with progression >0.5 mm was 17.7, 18.9 nd 203 % (p = 0.90) in the HA, diacerein and placebo groups, respectively. 5 Clinical Data on the Safety of Diacerein 5. Gastrointestinal Regarding the risk of gastrointestinal disorders, the most frequently reported events with diacerein were loose stools and dianhoea. The laxative effect of diacerein is well known and results from its anthraquinone chemical Bartels etal. [52] celculated that the risk ratio (RR) for developing diarrhoea under diacerein versus placebo treatment was 3.51 (95 % CI 2.55-4.83). Fidelix etal. (51) obtained an RR of 3.52 (95 % CI 2.42-5.11) for diacesein versus placebo, with an absolute risk increase of 24 9 (95 % CI 12-35). Well in line with these meta-analyses, Rintelen and co-authors [49] summarised that 39% of patients trested with dincerein versus 12% of patients receiving placebo experienced at least one episode of loose stool or diarrhoea, Diarrhoea was mentioned to be generally mild to ‘moderate in all publications that make reference to the Anse severity (35, 40, 44], and occurred in the first 2 weeks of ‘ueatment. No particular pattern of associated disorders could be detected. In all cases, the diccerein-induoed diarthoea was reversible after cessation of treatment. Fur- thermore, dismhoeal symptoms decreased in most cases after continuous treatment [62] ‘The post-marketing surveillance of diacerein showed that 25 serious eases of diasrhoes were reported. Three of them concemed elderly patients, who experienced dehy- dration and clectrolyte disorders; one case was fatal and ‘occurred in a 79-year-old female with a medical history of arterial hypertension and cardiac arshythmia (63) 52 Cutaneous ‘The skin was not a target organ for toxicity in short- and long-term animal toxicology studies. Nevertheless, the incidence of cutaneous events in the 15 published clinical tials evaluating diacerein ranged between 1.8 % (35, 36) and 9.4 % [41]. The present review identified rash, pruritus and eczema as the most common cutaneous reactions reported in clinical wials. They are appropriately reflected in the product information with a frequency of >1/100 and <1. Furthermore, the available post-marketing data revealed a fevy severe cases of cutaneous events: four erythema ‘multiform, two Stevens-Tohnson syndrome (SIS) and three toxie epidermal necrolysis (TEN) [63]. 53 Hepatic Among the 15 published clinical wials evaluating diacerein, only Zheng etal. [43] reported the occurrence of 1 hepatic adverse event: one treatment discontinuation due to increase jn hepatic enzymes. The PRAC performed « ‘more complete analysis of available data and retrieved seven clinical tials showing abnormalities of liver tests,Diacecein in the Management of Ostecarthitis COGO24 a ‘These were mostly characterised by mild/moderate liver enzyme increase (ALT, AST <5 ULN) without increases in bilirubin (63). A total of 89 cases within the post-marketing surveil lance were considered as hepatic reactions. The most fre- quent reactions were liver function test abnormalities (41 cases) (63). One case of hepatic failure had 2 fatal outcome and a close temporal association with diacerein (64). The extensive preclinical animal toxicology data with 4-5; Nice, Fracce. ‘Schult: KP. Clinical investigation of the efcacy anc colerance ‘of Dizcetycsin (DAR) in the teatment of ostooartuis of the ‘exe (sy repo]. Cologne (Germany): Madeus AG: 1984 Ox 21, 68 p, Report No, RDAIS. Combe B, Dougados M, Gouptle P, Canagrel A, Blsou JF, Sis J, et al. Progsoste factors for radiogrphle damage ie ceccly sheamstid arthritis: a multiparameter prospective study ‘ils Rheum. 2001:44(5):1 736-43. EMA. European Medicines Agency, Assessment report for iacersin contining medicinal products, 2014 Aug 28. bp ‘wen ema europa euldoesien_OBidocument ibraryMReterais_ documeayDiscereinBuropean_Commission ial decison/WC 500173145 pet, Accessed 2 Jun 2015, ‘Renan X, Lepage M, Connan D, Carhart D, Riche C, VegerP, eal Ces ciaigue d'une hépatte fale a le diacehine (Case fepon of fetal eponite som Ghaoerein). 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Acetuminephea induced seule iver flare: salts of ¢ United Sues multcemer, prospective sty. Hepaology. 2005,42(6):1362-72Diacerein in the Management of Ostooentits n, a, n. m, 1 8 n Bessone F, Nonsteroidal am-nfammatery drgs: What isthe acta ak of liver damage? World J Gestoentero, 2016:1645):5651-61. Gulmez SE, Larey D, Pagessx GP, LignotS, Lasslle R, Jove J, eal Transplaation for avte liver fture inpatients expose 9 [NSAIDs or paracetamol (acetaminophen): the multincoaal case population SALT study. Drug Saf. 2013:36():135-44 Rabe E, Barkun A, Nedjar H, Gauri S, Wasen D. Hospital izations fo upper and lower GT eveatsssociated with wads] NSAIDs and aceaminophen among the elderly in Quebec, Canada, Am J Gastroenterol 2008:103()872-82 Coxib and tational NSAID Tiss” (CNT) Collaboration, Bhale N, Emberson J, Meshi A, Abramson 8, Arbor N, ota ‘Vascular and upper geotolnestinl effec of non-seoidel at inflammatory drugs: meta-analyses of individ participant data from randomised isis. 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Fragmentos tomados del meta- analisis de Cochrane de 2014 CHARACTERISTICS OF STUDIES ‘Characteristics of included studies fondeed ly study ID} Beahmach Methods Randonised consoled isl Single lind Garccipanss were inde) Phesboontrolled Parcpans Inv becween 25 and 70 yas of as, with primar. symptom Teal (OR failing ACR eres nd Kellen Lawrence grade Tl and Il with pin sere > 235 mm on 4 100-ma VAS cle Inxeoeniont Diacersin String capsules vie dll or placebo apes ice ily ‘Durston eight wes wih luton and afer 12 wes without Gexment Outcomes sin on movement in t0 100 mam VAS WOMAC sions and phil Faxon ‘Cini lba impresion by invest on Spine kere cle ‘Wee of reser ediaion Note ‘Theseady drug wat provided by Maceods Pharmaceuticals ed Towthrenon 2007 Medd Randomised conoled id Mals-centre (ve medial schookin Tl’) Double-blind Phoscum-coaralled Parlbsoup Paricpane Paricipane wish bats Cy cone Kalle Liveece rade Moe TILA secotlng te ACR citer brwecs dO'and 6S yea oF ae. wih ne pain of 2 ea 40 rum ona leno tee hc WOMAC Ao 301 100-nm VAS sce, or a east Says incerta for onesnrece een) 3 Cpr 6 2014 Tae Cochrane Cotabato Pas by Son We & Soba Pégina 18 vo. Gacese Waovamed Z CALIDAD E RNOVACION [Fewthresoe 2007 (Conaicd? Ierenions Diacesin 100 my d (N+ $6 eeu pesca 20 mld N= 85) 16 Outcomes WOMACA, RC S36 Parccamel consumprion Notes Suppomed by agent fm TRB Chemedie eration [ee ase] Metis Tendon enol id Dosbletind eal gonp Macnee Paricipane Ourpaiot with GEOR (Cony: Cina Nes ‘Mean age. yea 583, 2% fimaes lee ale Tnterrntone Diacecn 2» $0 mg caps and tice bles of placcbo vos didofanae 325 mg ‘abl and mo table of plarso Dradon: HS on i a olom-up ptiad of enc month Se observa claramente que los tres nuevos estudios incorporados en la revisién sistematica de 2014 son de rodilla, y al ser de menos de 6 meses de duracién, son de evidencia de modificacién sintomética, no de modificacién estructural 0 modificacién del curso de la enfermedad. Pagina 19Snovamed™ CALIDAD E mNOVACION ANEXO 3 Guia Cochrane 2009 sh tb pens a li ec ee gh Pégina 20,Utatervention Review) Diacerein for osteoarthritis “Tania S.A Fidel, Bema Soares, Vigna Bormandes Moga Teva oternal Medicine and Therpeucc, UNIFESP (ESCOLA PAULISTA DE MEDICINA), Sto Bem, Bai. *Brzilan Cochrane Cease, So Paulo, Se. Rheuatlogylnternal Medicine and Therapeuts, UNISR (Senco Arco Univer UNIFESP Palin Madiine Scho), Jardiea Marjars, Beat ‘Contac rst Tain S.A. Beli, Internal Medicine and Therapeutic, UNIPESP (ESCOLA PAULISTA DE MEDICINA), Ree ‘Mederaneo 290 13, So Bersardo, Sto Paulo, 09750 420, Bra, safiela@volcom.br altoral group: Cochrane Mascsloselel Group. ‘Publication stars and dace Eid (po change to concusion), publiehed in su 1,200, Review content assessed as up-to-date: 15 November 2005 (Cations Faeln TS, Soae B,Fenandes Moca Teva! V. Dizcerin or sreoarthis. Cube Database Ssemmaie Revi! 2006, Teste 1. Ar, Nos CDOQSI17, DOI: 10.1002/14651858.CD005117 pub. (Copyright © 2009 The Cochrane Callboratin, sblshed by John Wiley 8 Sons Le ABSTRACT Background Oseoarts (OA cote of dhe mos prevalent muzclorler diese, Dian ace diferent fom tulsoral non-teoidl ant {nfemmarory drags (NSAIDs) which nhbic prostaglandin sche’, lexdng > adverse groin eles. teas bees prepbied Haein eo aoa, esti yaad perhaps Saeeatrveaeemodiing dg fot OM ae “To ass: ce efttivenes and safey of dicen fer tetaent of OA in ads with peripheral or iota acceding the American Collegeof Bheunztalogy andfo: FULAR diagnostic rei. Search seatgy ‘ReauR RDU CREO RES ENRON CRT TGA See eee per afyauniclicercencoramed Thera relnpage muon Selection criteria Rendomized controlled ws (RCT} ot qu RCT of plcebe-comroled end comparnsve rade of ice in adults pray or resondary OA fling she Amesian College of Racuraology (ACR) exert were lige for indusion. The main exe for celsion wa endence of conde dase Data callecon and analysis ‘Data sbsrcion end quay sesiment war peefocmadindepandcaly by due invesigaror scoring wo preerermined rieinsnd the ress were compared to dearmine the dee of epeemene, Quay ealason was done using Cochvane Handboole Cass, Jaad ‘nd Schule score Copsnsou oxtomne meatres were pooled wing welged mea differences (WMD), Dihoromous cxicome ‘easues wete pooled using rendom ees rode! and esl weve expressed a reais (RR). Dicer for onsares (Review) T opr 309 Ta Cochrane Colsborain. Pabssbed by J Wey Sons Lid.o & cy S japan enol Roce ena NOT AT ‘Ggteegnest ofA. When compare co placbo pain ona visual aralog see (0100 mm) was evalused in 1228 parteipans and showed « stay sigaiScan eifleeace in fivoar of ducerein WMD “5.16 (9596CT 925, -057) wth an ebolue change of points on she sae but the Reerogeciy analysis ele was importa (P.O). Wan analysed ueparatly by hip OA cad have OA, no diference was detec According the Lequesne Imgaizmeat Indes for funtion, 1006 partcipans evaluated dd noc ave improvement inthe whole grou ‘ris she subgroup azlyi with homage in al esl (P70.10). For hip OA, dee suds showed « WD -0.21 (S536C1 0.82, (0.40). For haze OA, evo seas showed WMD 0.55 (9595CI -2.64, 0.74). The summary WMD was -0.28 (9595CI-087, 0.23) ‘Two longer srade, one elassng hip OA and anocher mlsating knoe OA, arly sacrol pogresion with adingrphic rmeasrements foie space In hip OA, here wassaiscal significant slowing of progreson in contrat wih knoe OA tat di not demonstrate his reduction, lomere, the ore effect was very differen between suis (240.04 for hip OAand P» 0.85 for knee OM. “The moe equent averse eves was laren. 459 perlzanes mang 1033 partipans that ecelved dice (4294) were fied, 1886 in che ueatmene group compared with 1396 in he placebo group withdrew deo advere events. ‘Author? condasions ‘These i'l’ level evidence thas dzcrsin ha a small, content boas in improvement in pain, Funher search B azcesery confirm the shor and longer effecsivenes and roi of zerin therapy x OA. PLAIN LANGUAGE SUMMARY Diacetein for osteoarthritis Docs diacesin woo to test cetenarthcis ands it aft ‘Seven seuies of moderate high quality were eviewed ad prove the het evidence we have oda. The sedis tested over 2000 people with onecachis ofthe hip or koe. The sues compued people who wok 100 mg face 0 people who took placebo (Gke pill, or nomseaidal anc-infamenanaey drugs (NSAIDS) ox aches sow acting erthits deus, The suds lasted 2 most 0 3 yan “Whats osteoarchrie and could diacecein work (Oneoarhrigs (OA) ithe mort common form of rth thr can act dhe hand, hips shoulse and lex. Is OA, the erage ‘ha prove the ene ofthe bone een down and eaves pin and ewaling Drugand non-drug treane ae wd to zeieve pain anelor swelling. Diacwein ix slowaering drug ren st a pl dat ray slow down ake bealedoum of eatlage and reeve pia and ‘selling I may abo besafe onthe stomach Tels no eu whether diaesin woks and whether cis safe han othe: drugs sed co vest OA. ‘What did che sae show? Pia inpeoved shout th ze whether people ook dlaceein, «placebo, NSAIDs or ther dw acting drugs. Bus, pain does cam to improve abit more in people who tke diacenin, RAPES (One dy shows tha pal, sf, and physical faction veal improved more in people who cook daccein chan apace, ‘Geese pes ROMSEGEAD RATE er dvs popes e OAs Horr sles diacerein? Diner or ortanartvile Row) 3 ‘Cepyght 8 200 The Cocrane Cataboraton. Pb by John Wiley & Sons La co oOSie fees such ae davthows, extn, fe stool, semach pais and Bequent bowel movement, Diarhoes was the most common ‘dz afer and usally oocured during she Sto weeks of raring Sacre 421 of 100 people who sae discern had dlahoca 18 out of 100 people who sok dices wishdeew fom the sds de 0 ‘de effect compared with 13 ou of 100 peopl inthe leech gos. ‘What is the bottom line? THESE aN i SA GALE HEAR Ancemin hae «sll ein improving pin and ‘eesti (hei), arbors a common aie elec of dace “Longer sade ned we done to decerine che Ing term benefit and hams af dae, BACKGROUND ‘Omeoarthes (OA) is che mose common join disorder isthe word In Western populaions, radiographic evidence of OA oe ‘urs in che mort of people by 65 yeas of age andi about 3095 ofthese aged over 75 years Inthe USA, isseoad only © luckemic hear dcase sx case of work dissin men ever) yeu of ge, and accounts for more espizatone chan hem ‘wid arches (RA) each year Hochberg 2003), ‘Despce his public heh impact, OA remains an enigmatic on- dion och epidemioogie, Contenaus ha cl cently eexged 1519 deiion: che eng linia earues and natura is tory rain the subject ofntenaeinvenigaton andthe gnertion ‘of efectveprevenive eztegieseppeas a more anainale gol “ocberg 2003) ‘Today, more precisely inthe at ro demas, the concep oF OA ie acspted eran egerelsed dynamic rein paren ofa joint In esponse to nse rinjurs Altes ofthe jin are inolred, slthough the lst of arcalarcardlage and changes in ajar ‘bore retain the mos striking enue. In his regard QA pee sors ilar fhe jin san engan, analogous wo rend or cade ‘lure, and the pathological observations ia advance ro dsase ae ‘much a produce of tempted repaicaof che priser nel ‘damage tac contributed to inten ofthe proce (Hochberg, 2003). The defriton for OA according tothe American Calege ‘of Rheumatology surmarns eis des“ etexogencous group ‘fconiioes that lead wo joint gmpenms and siges which rear seigad with defeaive ite of aria erage, in aldion 1 related changes inch underlying bone a he ose marge ( Aleman 1985). In site of he hemrogensiy FO, he gpa ‘of pain the main aspect ofthe disse and eudcogie changes fae visble at an early nage even before dhe symptom of pala resent ‘The ACR wis the evaluation of hard, hip snd base inser ‘ern for dagnoring OA (Amen 1986; Aleman 1990). OA can be cisified as primary or econdary, Sometimes i i iffiule wo singh both forms, bur fr purpose of his wesk we are con- ‘sdeing ony he primary form (oparie) because there was nd revived sy incidingseondary emesarchvti. Tee poles das she OA aecondiag co the jin involved . There may be ‘mone, oligo or plyanicalar OA and in each oi. according co he parc afeced: lata, meal or paelfemorl compartments 4g the hoes; pole supa, pole mel or eoacennic ia the hip, Inezphalangeal andr thumb base sad in she spine spophyoed joins oriaerverebri die dts, According to specie eacue ‘we can have infummatory eneoanthrod, resi oneness, aEzophe o dertrotveontecathois, and OA wich ehondroci- “Enablshed indvidul ri etn neue: «ete inl for plyanicalr forms with hands Invlvement + bes only or knee OA), hypeemobiiy 1 mechanical ever euch a ctuma 4 joe shape 1 secupason, sport ad eeu physical slgy Anew undessanding of pthogenutia of the OA brings new dest about new weumment posibiles. Nowadays, OA is nor consd- eed depenceie avige dineuc, burs blomechaniaa and bee chemied inflammatory diese ofthe ene jen This brings the incr or orem Raven), ‘oprah 290 The Cochran Caabraton. bite yh Way Sonsposi of wing medicines with poretl for sructural modi Featon, With his objective there ome esearch evaluating zyme inhibitors, cytokine Mockers and nustional supplements. Ingeserl, he hesapy of OA includes sharmacolgial nomphar= ‘macologial and surgical ones, Pharmacological therapies incl topical agents orl ystemid) agents adjunc theses, aurceu+ ‘eas and inverigutioal cherie. Postble suc, disaemodijing agen in OA are gue cosamine, degradative enzyme inhibites, eg. exagyelines, spe- cBcmeulloproiaues inhibitors bisphosphonst dacerinso toldneinhibioes and clap sepaiz Although some drugeandlor ‘compounde have been aelble fer sever decides, and ate inte (gaedasundard pracizeia soe counties, theireeacy wa fat om being demonsested unl he la decade In it, revison af the egisrsin of rugs by heath auhortes in varos Baropean ‘countriesin the 199 reshedin the esablshmen:ofapproprne sical wis forbodh aval deugs uch svocada exact and drain developmen a tht time (uch at dines). Tis po ‘on ofthe health anchors has grey faced coproverent in our knowledge of he level oF eidence andthe chasceiice ‘ofthe observed trearmene eae ofthese drugs (onset of actin, cary-over fin) (Hdkberg 2001), Discenn, specify ashe acer! dentine sein ita ee terleckn-! inibicer Rhein ian anthaquinone found in plane ‘of the goers Cans and hat mosesteantinfaramatory and alge acbity and weak lasiveeffess(Spancee 1997) 18 22- {mal and in vero human experienc hein demonstced prope ‘ee of inhibin ofineleakia- bess, inhibin of collagenase ‘expresion, reduced Srnobyic acy ia syovial ld and su ‘vial Shroblem, inbibiton of upetesde anion producti, lo ‘somal ennyne rele and chemotnts(Berda 1955; Bolin 1993; ‘Cruz 1996; Del Ros 1890; Mian 1987). There wat inprove: iment of OA induced in animal models when reed with ise cela (Mbaites 1985; Maires 1996). Unlike nonsteroidal ani= {nfamamatory drugs (NSAIDS which inhibi prostaglandin sy hess dace stiles o7 oer noe ae promaglandin yn- ‘ess, with mo prejudice ro gue mucosa] Persil 1991) or end fanction( La Vill 1939), Since 1982 (Linge 1982), ws have been done to show he ‘eFecsf ices he OA [n 1992, dscerin received cening -pprovalin Fanceforthesympeomatic earment oforeoerthis ‘ane the dg har ben macketed since Seprember 1994 ig ee spodiing dg FA. inner cation th efter of his rg ané wher tari ers ha mee cued aie ere. OBJECTIVES 880035 “To sec the econ nd fy of discern for weament of (OA. The flloning hypotheer were rested 1) Tasman: with dncrin ieee for 8 1) Teeament wih dice is sae fr OA, METHODS Criteria for considering studies for this review ‘Types of studies All digibleeadonined contolied wile (RCT) oe gutsi-random ined clinica sale (QRCT) were include in thi review “Types of participanes All aul (age 18 yes and oct) witha diagnosis of eicher rie rary or secondary OA at eny sit including the ail and peiph- ol shelton, fulling she Amerien College of Rhexmatology (ACR) etter (Aleman 1986; Aleman 1990), Primary OA it ay (OA where define etiology (ase) is not found. Secondary OA Iswhewadefnitecnase cane found; for ecample aura, sbsity orhypenebiiy. ‘The ain eter for caution wis dence of econdary diese, Inflammatory or menbolic sheumati dense, oneonecrosis and previou inemarielainecxon,srgery during the tzee monthe Porc inclaton in che aay, use of cesvensonl" “noncon- ‘enon or “skernabe eament? that can porily ave serious effers nthe rents ef a sry. Co-morbidies such 25 hepatic o: rena insulicency or sve inet disurbess dat ca peje safe craluation af diacerin were al ecuded “Types of interventions Seudies comparing daca any dose co ‘Azother acve phaesealgia neenton, auc as eer low sexing moijng eymproms deus (SYSADOAS, Placebo, “Types of outcome measures Primary, “The pimary meatus of fervent pin rie, ggetad by the tied conference of Ostome Manze in Rheumatology (OMBRACD (Bellamy 1987). The core OMERACT measares fockip, kee and band esearch ince Pain Physi faseion Daten bal asses ‘incr r entanaribve Rav) Coprine 200 The Code Cataboraton Pbha by Joha Wiley & Son LeJoin imaging (for sues Fone year o+ Longe) Health elated quality of ife mensre Dhysician goal asessmene ‘According o OMERACT 3 (Bellamy 1997, with is last review in che OMERACT 6 Phar 2003) ia oxder eo evaluate these ‘uscomes, sandared aided insroment such a visual ane logic sal (VAS) Carlson 1983), pai vee included in the Werem Onsaro and McMaster Unive xeoatissindeu( WOMAC) (Bellamy 1988) andthe LequesneFunesional Seer Index (Lequeme 1967 recommend. Seoondary: Secondary ostomes inches Indaromation ‘Staes Parformancobured menses, endeas, ime co sugary (or reoromy and aroplany of he Laze), ausber of ates, and lon Dexth Da weresough forthe number ofidhdnwalsovealland num ber of pople with ie eo (gutriacstnal, mal edie, lei haemasoepie. Search methods for identification of studies 1, Hlscteoniedatabasr: there wat no cession with rgd 20 leaguage or dae of publicaion A.speaiicsazch phase for diacein in OA was developed 'W Onecarhrs OR Oneoarthstic OR Oseontheds OR De snerve Arve OR Arras 172 Diacersin OR Dinesh OR Rhein OR Anssequisenss OR Disewpiehsin OR ART 50 #5 S1AND #2 “Tals search is ssocared with a phrase of entifetion of RCTEoe QRCT: spe for exch databace, exept forthe Cochrane Cen teal Register of Conuoll Tiss (CENTRAL) which i pei oe dhs design of sud. The search suaegy was tha from Dick ‘ern{ Dickarsin 1998), madiied by the Cochrane Moreaosele ‘al Group. The following elcwons daabases vers inched: (CENTRAL (2004 Isue3) LILACS (982-2008 EMBASE (1980-2008), MEDLINE (1966-2006) 2. Refrences of the published lnerses. 5 Peon communication - withthe authors ofthe published Arce: and expereince ae, aking Fron publced relevant ace 4, Contact wit che pharmaceutical induc abost the devlop- rent of che product (Nepns-Lerad/TRB Pharm). 5. Had seesching in ebsets of conferences in rheemrolgy ‘were earch since 2000 unl 2005, at ZULAR and ACR mee Coo93G ings Data collection and analysis ‘Tace reviewer: (TSAR. VEMT and BGOS) indesendenlyte- viewed the reference ound wid she seach sateny and apied {he incavon crs, Direncs in the evaluation were resolved by consensus end if necessary, one independese researcher at oquted to mike the nal decon, There wa net impertzt dlageement among che thee reviewer, andthe Kepps te 5 tot dane, The excluded ences were cessrbed with te resto ety sated Quality Assessment ‘The cuir of the sled sxaies was independendly evaluated, cording 0 the folowing: ‘The Cechrane Handbcoe Crteis (Alderson 2008), aeiing ‘he mies according dei aside 2 low deo igh (A,B, 2d) “The validated tol introduced by dad tad 1996) and Schule (Gehulee 1885) as ako modified o deemine an veal qua- Jy sore each selects, Ths ro! consis he bas of sandemizsion, adequate concealment of randomization, degree (of blnding, uo of inwaton treat able and derision oF ropous and wihdvavale Fach tem serves one polar chean- seri positive. In addition, «poi can be deducted if ether the ‘aademsation 07 the Bindiag/ mashing proceduesdseisad ae inadequate Dilfenoe beeen dita extraction and che ascamaen ofthe quality was dscusced,decisons documented end faeces the sochor of he eid or consisted so rele dobre. De Michel Lequene wat ated for otal dat fom bate line rable for ade. ‘quate compiz heoween groups and outcomes even with spective sumber of pens evalared ar dead point, in oder so daly PITT analysis was conecty done. Dr. Miche! Lequesne rerpooded snd sggeted consacing the Negra Leads Laborto- et De Masize Dougadoa was cone fr give sda ebour ‘otome messrement in SMD (stacdaedsed mens difecence) br he did nor answer the email De. Jean-Pere Dalletr wat conmced by email and fx atkng fr daa in SMD and be re sponded by fs suggesting 10 conduc the quetons to Nags “ernds NogmeLerdslaborstoies (De Paved) ware onacted by emalland didnot send dhe data equated, ‘The flowing was exacted fom ech dy General Taformaton: published oc no, il, authors, conczeesd- dress, country eure, publation yea duplication of the pab- lishing, sponsor CCaaracetscs of the rudy: design, lengthy randomisation and method, llstion procedure, Minding (paents, administer Ceres outcome appraiser lation chock how many te ‘aes wer involved inthe dy. Diner fo onasarivi Raen) Coppi 200 The CocraneCatahoraticn. Publhed by Juha Wiley & Sons LtIncervenion: placebo inckion, aumber af perdcpens of ech sum, wth dove and length of teaement. arian number age, xe fo agnosis, inclusion and a= Clason, Sueline chraceice and similar of these date be. ‘ween compasion groups, sex, inary and seng ‘Oueomes all oxcomessepoced in papess were described mainly seated 1 eBcacy and ay, using conriauous andlor dichot- ross dt, eal: some dete about dropout snd impormant aberaton® were deserbed, af ntenson to teat analyse wes done. Dats Analyser ‘Anais compared acer, wasal dove (100 mgd) and aer- nate doses (50 ngeday and 150 mgr) wih leche and dae rein usual doe was compared with other drugs Comparcle da snd were pooled and dats analy was undertaken sing RevMan ‘ack erdichoremous outcome, esults were expressed arariaive di (RR); shat, che proporsion of evens in the weamene group ia ‘elation tthe poporion of evensin the con group, wth the 95% confidence inrerals. When over rele were serially Signifeane dhe cumber needed wo wear (NNT) othe eumber ‘nceded 10 harm (NN) wer ale clelted The NNT isthe nomber of paints thar aed wo be traced withthe interension to prevent a event The NNT wat elesleted fr dhe ouzomes radiographic progresion and adveve afte 2 relevance ble, Daa wereandiysed and presenredprimarly wingarendom-efecs ‘mode (Der Simorian 1986). Continuous outsonmes wee snayed second wo weghted mean dlifrences (WMD). Hecerogenisyin he sels ofthe mes aalys wes assed bth bynepecson of aphicl preseason (unsal pls) (Egger 1957) and by caledaing 3 chisquae test defining sigan Pe Func! plot graphs were done forthe outcomes pain fn 0-100 ‘VAS scale and fnetion by Lequesne impatient ince fr che snuies computing dicescin oplacbo, Double rezone fr hese ‘crogeaciy ate: dilerearpopulaonsinteremtionsesesmeats of ‘ouromes and methedolgial problems A ses arly was ‘conduc inorder event te reason for she heceogensity of ‘the fe mew-anlysis graph that compared diaerin ro passbo forthe VAS for pin. When pose, subgroup acl was done, as fallow: Dilleent dons of dacerin ip OA vert knse QA vere spine OA yess band OA. Dilferentfanesanal elas of OA a tha binning of the study. ‘We considered all sedi with mention to wae analyse (77), collerng das from she authors f necessary Grading of idence ‘The patling sucom described ia the 2004 hook Fvideace-baed Rhesmacclogy (Tageall 2004) and reacmamended by Maseu- lostleral Group a descibed below was performed. Platinum ~ A publshed systematic review that bas atlas ev ‘nv conroled eile ach satsying teflon: cue yy 1 Sample ies ofa least 50 pec group ~ ifthe do not find seatnialysigaificene dferencey sey ar adeswasy powered for 20% eltve ference inthe eleane outcome, 1 Rioding ofpasents and aun for omteomer + Handling of wihdrowae> 8% fellow wp (imparaoas asd oa methods suck x Last Observation Cased Forward (OCF) ar accepble © Concealment of uexenenrdlloation. + Biting of pases and assesoi for suc -» Handling of widdtiwals > 80% follow ap fimpuations tied on method sch sf LOGE se necepble 1 Gondeadment oferatnese dlocion, ‘Sver-A randomised wal that doe aoe mee the above ct ‘Siversoking would se include evidence Som acleut oases ‘of non randomized cohors tha did aor rosie the thesspy oF ‘oidenoe fom a lear one high qual cate-contol rd. A an donised el with a ‘bea-orhead’ comparison of agents would be considered shee erl ankngunler a refeesce were provided tm. compazizon of ne of he agent place showing a asa 2096 elaine deen Bronne- The bronze ranking is given to evidence ia leat one high cal ewe erie wishou conto (aclading simple before! er ties in which paces ac echelon cone) oF che ‘conclusion i desve fm expert opinion based on clinic = patience without rfsence 0 any of che foregoing (for example, sugument from physiology beach esearch or fst pricipls). (Gini selevance bles Cnc eleanc ublerwerecompledusder Mena Tiblss iexprve she rede of the eves Foe dichotomous outcome, the nurber needed to ea i eleleed from the cone) rou enc ate and the lave rk using the Visual Rx NNT eles tor (Cass 2003). This was done forthe main outeame mex sued ia dichotomous daa, adiogeaphic propeson, and forthe main advent ele -diarthee, Continuous outcome data isso peeated unde addons tables, Abselte beefs calculated se lnmproveent inthe inrrvenson group minus the impeovement in the eonel group inthe origin] wit, Relative diference in the change fom battne ie caleulaed 2s the absolute bene die vided the baseline mean of ae consol group. There ableswere done forthe main outcomes and comparisons painona VAS sale 0-100 mm and funcio, measured by the Lequese implement index RESULTS Dineen rover Roe) ‘Capygit 8200 Tae Cocrane Cotaboraton Pubahad by Joha Wiley & Sans LedDescription of studies ‘Sez, Characteristics oFincudad aden Churecesnicsoferiuded srudie, Real of Search Sune ‘The MEDLINE (Pub Med) search saregy (193662004) sessed {ns toal of 72 dadons. From thse 72 eatlons, 06 RCT were denied. The EMBASE serch srasegy (1980-2004) idetiSed 14 sitions Pom thew 14 cieions no addionel RCTS were ‘dete, The LILACS darbase (1982-2004 had no reference shoot dicesin, and Cochrane Cenc Regier howe 17 r= ences, with no eddonal RCTs. ally, fom conference mee ngs, wsselecred one poser peesnee at 1 th Asia Pace Leagne of Assoclaons fo: Rheumatology Congas er comace with a phasmsceutcl company TRB Phar). Atora of dies wee included aie ago overall agreement beewee he thre inves peor (TSAR VEMT AND BGOS) in tome oftheir sharon fom the 7 RCT. The gre of concordance es 909% oval. ‘Consents we reached on the dicepancee ‘The 7 identified adic ae lied in the incladed chanere- tice Table The years of publication sange fom 1994 to 2004. ‘All were double bind, zandomiznl pale group tials and eon tained a eel of 2069 adulksubjess with & mea age of 60 (610) years. A roal of 1083 sabjens were randomized to tea ‘ment wits dacesen and 986 were endomlaed co che compure- toc groups (NSAIDs or plabo or other symproms modifying lowaring drt for OA). The une orig inciadad France (equesne 1998: Nguyen 1994 Dougrdos 2001; Pham 2004; ‘Chancre 2600), UK (Pham 2004), Canads Peller 2000). s+ ‘al (Peller 2060), Cina (Tang 2008), ie ofthe seven sues compued dacereia wo placebo (Dougades 200%; Leqeare 1998; ‘aleer 2000; Pham 2004; Nguyen 1994), cwo compared diac ‘ein to other aymptom-modijing eow-acing drug for OA — “Hapado! andthe hyslrorc acd compound NRDIOW(Chance 2000; Pham 2004), evo compared dicen ro NSAIDs tenoe- ‘am (Npjen 1994) and dibofena (Tang 2004, and only one ‘compued dizcesia given in combinadon with NSAID vesus placebo (Nguyen 1994), The method of aeiniracon of diac ‘rin was onl and quite similar im the redies 60 mg expel “The dosage used was 100 mg per diy (ovo $0 mg capes). Ia ‘one sedi Pelee 2000), dacnin was given Sn 30-mgp and 150, mg doses ‘Kace and hip joints were enlunted in dhe selected sad, Thee ‘wae noendy har evalua OA in othe ogee cher thas he lee of hip. In two ted, only eh Bip joins was evaluced ( [Ngeyen 199%; Dougedor 2001). The nce as erslsted in svee [RCT Pei 2000; Pham 2004 Tg 2008), ann vo RCT ‘Chance 2000; Lequsne 1988 both sense ard hip weeks ‘zed, The wal sumber fois evaaced was 89 hipsand 1170, nese ‘Sobjec with primary OA wor erluted in all sad andadio- mph ofthe srpexjoine were obsined in i of ee serene ‘The ducacan of the OA wae based on valid cera defining oe te (OAclnial and sasiogapiclly at Amescen College ofRheums. tology Cries, Lequein cere, BULAR crite and Keligren and Lamrencercicgaphicpadusion oF OR. ‘Thedusion of sein was two months wo thee yee Ta our ‘sudies (Chance 2000; Dougades 2001; Nguyen 1994; Peller 200), he daraion of disease was measioned andthe mean was S ‘yeas Al dhe ude were mul-cnts, The charcerinia of he sade were Lied blows ‘Mean duration 9.7 months ‘Mean andomized bjs 298 Mean dropouts -75.8 All sadies were supported in part or tuly by pharmecetcl eborcties(Acopharma, Negra Leads Avent) ‘The eucomevaablesincuded (numberof RCTS: ‘ain score na 100 mm VAS cae (6 (Plier 200; Pars 2004; “Leguesne 1958; Naujen 1994 Chante 2000; Dougades 2001) Leguesne Index of Functional Inpsiment (5)Pham_ 2004: ‘Leguesne 1958: Nguyen 1994; Chante 2000; Dougedas 2001) Radiographic eraluation with Join: Space Width (2) Dougados 200%; Phar 2004) “Handicap on «100 mm VAS Sele (1),Palleis 2000) ‘ais on walling 20 in 100 man VAS cle (1)(Tang 2008) ‘WOMAC Indes (2) Teng 2006 Fleer 2000) SF36 0)(Tang 2009) ‘Analgesic Ike (5}(Tang 2006; Doagades 2001; Nexen 1894; ‘Chanzre 2000; Leguese 1988) ‘Toa Jone Replacement (}(Doxgados 2001) Effuson or vellng of oft dtc (1)(Tang 2004) “Tenders o2 palpsion(2)(Tag 2004) Jone Mobily metsted by « goniomeer (1}(eleier 2000) Dati af morning sien 1) Peles 2000) Global Saucy judged by invesigatoe@)(Pham 2004; Chane 2000: Laquesne 1998: Tang 2004) Global Eficacy ued by pasent (5) Pham 2004: Ngyen 1994 Lequesne 1996; Ting 2006 Peller 2000) (Oven sefeyevlamtion was done spacey in all dis. Ques ‘on about adie etc: were performed at each ve end the invergacr had to expres 20 opinion about che selatonship of the adverse eeceto the sn context, Risk of bias in included studies ‘The gualiy ofthe sclecad seis was independently eluted bythe che ceviewes scoring othe lowing: The Cochrane Handscok Cries (Aldavon 2008), dashing she radieeaeding Saisie le ow, le o igh (A.B, 20) “The vated tool intoduced by Jadad Gadd 1996) and Schult, (etul 1995) was wed as described above According the Cochrane Handbook Crain hee ies were {Seiged ar A (Dougpdor 2001; Peller 2000; Pings 2004) an bad adeguc allocation coneelmens tac de were casi’ Dinca or antemartvl Ravow) ‘eprgh 8 2900 The CocraneCaabraton. Paha by Jn Wey 8 Sons Li ey oO6B (Tang 2004: Nguyen 1994 Lequesne 1998) and had ina ‘sue alloason concealment: ane study was sid as Cand dad noe deseibed allocaion meod (Chastze 200) ‘According Jadad Sele, che score was 5 in four suis Cante ‘2000; Dougedos 2001s Pelleti- 2000; Pham 2004) 4in oneseudy (iguven 1994 Jose the rendamizaon procedure was not de- rine, and 3 in two reds Lequame 1998; Tang 2008) be- ‘cute cherewae no rerenceabour the randomisation and doxble- Minded procedures ‘There wee some problems with thes: RCT, For example here was ack of eandardiation of te OA diagnose and lack of andaediaon oFoureme sent Themed ued for en- sing Binding oF robjocs and invengeses, 2 well sander Ing aubjace co westment groupe were weal not provided. Se- ple sla clealaions were provided in ve RCTS (Pham 2004 ‘Dougdes 2001: gwen 1994: Pellei:2000; Chante2000). A ‘hough intensioo-o-reat analysis had been describe in x sade fey, Stas modified o inadequate in fou (Lequssse 1998; Tang 2004; Pacer 2000, Chansre 2000). The auchors were onccted ‘ur there war no annver about it Presndomiztion intusion ad eclasion erin wer provided by all seven RCT bur were ‘not explained adoqury Ts one study (Dougades 2007, eighteen paint fom placebo _roup and cwengy mo pains from dzcerin group di ao have joint space narow a this adoguphs the buelice able ‘Thogmadingoferidence (sho xen) fr this seviewispesinu becre includes seven sues deserved ac randomized concoled tls, Byooreome, psi sad sacral modicaon scored god. Effects of interventions ‘The ress agned here were thet ones inporan 9 emphasice to provide concitions about the ieerenion studied. Tht o> tematic review conene i gre aad shar ones with validated ‘ovrcome to eae dicen in OM are descbed. 1 -Dincerein compared to Pacebo: Comparison 1 + Outcome 1. Visual Analog Seale for Pin (0-100 mm), 1228 participant from fvesadien( Nguyen 1884; Dougados 20015 Lequsne 198; Pesie 2000; Pham 2004), ‘The summary WMD (random ele) was -5.26(95% CI-$.75,- 057) and hvrogeniy anys with 20.08. The dy that = cided knee and hip OA atthe sate anaes Lequeme 1998) Aemonersing WMD -11.50 (958 Cl 18.88, 422) was the incin reson for this heterogenciy. Subgroup analysis was per med scoring othe jine involved, with rnueton of hee: _geaciy for hip OA, 683 parcipens showed WMD -3.37 (95% (C1-11:12,437 and fo knee OA 44, parceipancs howe? WMD “£04 (953% C1-I1.78, 3.70). Tes for hererogenety i bh sub- ‘groups showed P=0.10 000039 "The seions duc could explain chi herrogeely wore the ue of [NSAIDs a zeseue medications in swo studies Dougaet 2001; ham 2004) and che chore rum seus included rogecher with oageem erie (Dougados 20015 Phar 2006 eroding sen “stvy ana, Theana ys ofthe tbrovrsieclassied at aving she bee allocaan concediment(Dougadas 2001, Peller 2000, Pham 2008) showed hetrogeniy. The exclusion ofthe sade ‘hacpermined thet of on-erodal ancvinfammarory drgses seseue and more unforminy of pais cbse rele included conlyevoradie( Nguyen 1994 Paeer2000) and shoved homo- fencing: When we anhend the ovo seuias wth adequate loc ‘don concealment and longterm rain tha permite NSAIDs sees the ul showed homogenei. ln pte ofthis heso- gene the value of? round 60%, acoring ro Higgins Pligiss 2003), isnot too high compromise the efecivenesofdincin in OA reste. + Ourcome 2. Lequesne Impairment Index (0-24 points ‘sale; 1006 partipams ftom four seas: Lequesne 1998: [Nayen 1994: Dowgados 2001; Pham 2008, “This analyse was divided in abgroupe whese she herrogenciy analy was ip OA PO53 wc 723 pariipanc wich WMD - (0.210958 C1-0.82, 040) and knee OA Pu. with 283 pao Janes with WMD 095 (9594CI-2.64, 074, ‘The summary WMD (andoa: cfs) was-0.29 (95% CI-0.87, 028, 1+ Outcome 6. WOMAC (coral) 234 parcipanes from ‘one seady: (Peter 2000) “This andy included only one study with 254 poripanes and the WMD (anders eft was 20.0959 CI-23.38, 6.62). Ie iewortbubile sting sar ll WOMAC domains (pain, sifies, snd physica funcion reached sii sgaeance Thesumnary BR (random ef) was 0.85 (95% C10.72.0.99). + Ouicome 12. Total Hip Replacoments 521 paricipanss ‘of one smdy (Dovgedes 2001). “The summary RR candom) ws 0.73 (95% 10.50, 1.08 2-Dincerein competed ro Non - steroidal Aasé-inflanunatory ‘Drugs (NSAIDs): Comparison 2 “Two RCTs (Nguyen 1994; Tang 2008) wih 150 and 184 par Uisipant sepecvels, compared dicen to NSAIDs, bue hey ‘valued dierent osteomesexeepe snag ince, + Outcome 1. Visual Analog Seale for Pain (0-100 mss)s 150 participants from one study Nguyen 1994). “The summary WMD (random eff) was 200 05% C1648 1048, ‘incari oor (Renew) ‘Coprgne 308 The Ctra caaorson. Pbshe By J Wey & Sons Ld+ Octeame 3. WOMAC subscore (Physical Function); 184 parcipants from one sady Tang 2004) ‘The summary WMD (random effed was 12.28 (95% CL-73.01, 48.65}, ++ Ouscome 5, Analgesic Intakes 293 participants of two seadis (Nguyen 1994; Tang 2008) ‘Thesurumary WMD (random eee) wat-7.05 95% CI-22.46 18.30. The impornt hecrogenciry deed was dererained by {theuse of NSAIDs as rescue medication and inedeguae intention to sa: analysis in one rad (Tang 2004). ‘3 Diacersin + NSAIDs compared to Plaeshor Comparison 3 + Ouscome I. Viral Analog Seale foe Pin (0-100 mm)s 138 pardcipans Som one sad: (Nesyes 1984) "The summary WMD (random effec} was-16.00(95%6C1-23.36 86H, + Outcome 2. LequesneLipirment Index (0-24 points scale 138 parcipant from one study (gayes 1994) "The summary WMD (Gee feu) was 2.10 (9540 3.42. 078). 4- Diacersn compared to ther Symptom Modifies Slow Ac sion Drugs for Osteoarthritis (SYSADOAS}: Comparison 4 “Two RGIe (Pham 2004; Chasers 2000) with 338 paripans soalyred so drug ae SYSADOAc NRD 101 (ane yaloronic ‘a high-molecular weight (1.900 KD) pelyscchaie) ier ‘eur for 12 months and Haspadol or dels law ( penta south Aficanhebnceous plan with anc-inammaocy and anal psi feos arabe ro dod gyn) forfour months. Te ecpaate subgroup analyses rests were nt satiealy signi feealy dierent inthe following outcomes: pain on visu ns Fogeeae (0-100 sn), Laquerneimpsiement nde, gobs eczey seresmane by pant, pinfl days inthe previous month anc :adiogaphic progesion. ‘5-Diacerein 50 mgday compared to Placebor Comparison § ‘One RCTPelieder 2000) with 250 parcipants did nt show significant cifferencusbeoneen cacerein 50 malay and lseebo sven primary and secondary effcacy ourcomes were elas (ual Analog Sale fo Pls (0-100 m)); WOMAC ror and subscors handicap in VAS Seale 0-100 mm}, 6 Diacercin 150 mg/day compared tw Placebo: Comparison 6 ++ Outcome 1 Visual Analog Scale for Ps (0-100 ms 244 participants from one study: (eles 2000), ‘The summary WMD (random eff) was 3.40 (9596C1 8.89, 208). + Outcome 2. WOMAC: 244 participant from one sudy: (Pelee 2000) GaaUCS “Thesommary WMD (random lls) was-1240 (95961-2478 +902). Iwas aoted tac discern 250 mléy caused mese adverse of ‘cc mainly daten sche bogiing of he weement 18.99 foe 122 parcpentediconinaad the sry, 53.386 due oda thes + Safey of Diacreine a 1083 paseosusing diane sicompsisons demenseate that isthe were preset in 439 patents, a ze of bout 429%, The seergyo ices nat mild. co modestand cccsted within the fre ro wees ofthe rentmert. Diath was the mast feabest cause of drop ous among all compacnon groups-Thice suds selced the numb of dropouts cused by dichess Pale 2000: 18 out of 359 paien (50), Nguyen 1994: out of 142 paints (3.5%) and Dougados 2001: 31 ous of 255, plete (12%), Widharavale de to sll adveze evens vas 1892 {nthe ducezen group and 54% inthe placebo group a diference of S06, Wiihdcavals duet nefcacy were 169 and 2496 inthe acscin an placebo group especie. ‘These was ao diferene berneen acerca end placsho in tems of appr gucoinuasieal gmptoms. The second mos preaent svar fee wisout dnl slevance wes ditcoorten of rine (259 in the discern group versus 1.7% in the plssbo group). esha be ned that thier doer ne dea eal Fanon. ‘Aerie event aflaing sn (paris, ash were more fequent fn dincarein groups (2650, DISCUSSION COscoarhiie(OA) ithe mos pralenr nd cost form of mar ‘ulostlel dienes. Seve appecacheshavebees nvestgned for ‘eae weaument of OA, including deg and nom drug the spi of which non-steroidal aaiinfarnmatry deags (NSAIDS) save been gey ocommended forthe enzalofraptoms n- ‘hele jor grcointrinal eompleasons occ, especially in the day (where OA is more preva’, COsevurhie was poeviouly considered Wegener dzee the ineiable acompanimenc of ageing, wich ‘wer and ra? ‘he principle pahogeaeri: mechanism, Now, OA ir incresnaly ‘ioned ta mesaelil active, dyzamie proces incading bots Adetruen and eels which my begged by vay of o- chemi at wel mecharcal insu, ‘Based onan increase nour undesstanding of pathogenetic eck nme uncesring damage fo iss of the OA joint, prmace- logie agen: have boon deroped whose main mechanism oF a tin ie aimed a inhibition of ware depracng enzymes, such 2 clligenase, gelatinase or comes or inhibition of crokines suchas TNF-a or nsleakin-1,ocsgnaling pawns ivolved in the synthesis of ruck yokine (Brande 2008). Dice bas ‘aceran or ntesart Revie) ‘Copies 008 Tne Cochrane Cotaborson Paste by oha Wey & Sons Libesa shown so aki, in vito ced in vv, the preduction and the acti cfinlekin- and dhe sereon of merlot, vithow fing the sche of prosaglandins (Boitin 1983 : ‘Moore 1998; Pelle: 1998; Pelle J? 1998). ‘Thisrview sought vo invest the fecvenaseandsafery of ceca by pooling the ests of individual wa. When compared ‘placebo, pain on avira analog ele (0-100 zz) was ealsted in 1228 purcipaats and showed a marily gnifcane diler- noe in fvour of discerns but che hewerogeneiy snags ele wes important (P2.08), The subgroup anass for kne# O8 and hip OA card the alifference, and showed an abeeaceoffecve: fess. One seady (Lequesne 1998) include inthis metwanabyss thar ha knee ead hip OA in she same group infuenced the su mary posive eer with i postive efiee(WMD -11.60(95% CL “1898, 4.22), Thi heterogencins with an value erouzd 6056, ‘seonsidered moderate The WOMAC orl swelasscbéomsin ort in pi, ane and funtion were saa sgniant, ‘indicating tall, consizen beneficial improvement in pan, Acctng oh Laguna Inde, 109 pape cred dnt tre improvement ne wile rp on he Suipoup ass wis Romopency in al el (010 For ip OA hie aes Loqucre 198 Nesren 1994 Dowedse 2101) shoved WMD 8.21 659% -082, 00) For nes OA ‘no sats Pham 206; Lege 1598) showed WMD -0.95 (039802265078). The amsnary WMD was 0.29 S5ACE- 987,028. “Two longterm studies (Dougaos 2002; Pham 2004), the fis ‘one evalatng hip OA and che secoed one eatatng knee QA, analysed seueurl progression with rdiogaphie measzemen's ‘ofjlar space. Tn hip OA, cere was stata ignifeantlowingaf rogrenionin contest wid nee OA tard notdemonseae his Felten. Homeve the ovr ect war very ditent bene ‘tie (P-0.04 fr hip OA and P= 0.85 for knee OA). “Two suds (Nguyen 1994; Tang 2008) anand discern com- pated with NSAIDr and di nor demensate asipaicane die fence benosen che ov inervensors. The dies were heeogs cous and heels were expres with ery Inge confident ine saval Ivar nor poaibleto poo he resus of the sedis beanie they wed dierent oucomes. In ation, they evaluated differ ‘xt joie: nee (Tang. 2004) and hip (Nguyen 1994) fors shor period (mean af 25 sand) and in one of thers (Tang 2006), ITT analyse was noe done ‘The smady shat assdatd dlacereia and NSAID in oxdeto com pate her o placebo (Nguyen 195) showed ecer resus in the Termer group inal oucomes. inept ofits yery shore (eight eck] dansion. ‘Osher Syrptom Modis, Slow-Aetion Drugs (SYSADOAS) were compated ro disceein inasulyroup asl evaiuatng knee ‘OA foroneyeat(Pham2004) and kee orhip OA forfourmonths (Chance 2000) Thee was no diference betwen the group ‘One ey anchaedciaerin in dierent dose 50 malay and 150 mpiday (Pelee 2000). Thesis no evidence of fecveness for the us of dzcerin 50 magfdny a6 cemonstaed in this four _monch soy when compared wish placebo “Thetame study (Puli: 2000) used dacersin 150 mgldayandthe ‘eompsion with pladho showed small effec in sere oucomes| (WOMAC woul and WOMAC subscore stiffs) and no effee inthe other ones thandieap, WOMAC subscors for pain and physical netion, and vial analogue sae os pan (0-100 mo) Inshor seven doubleinde,randomioed conoid linia r= is wee include in chia merwanayis and have desonstared mild benef effr of diacerein on she discal signs or symp- tome of OA. Dinsrein hasbeen dence ats lng-ecing dup, eh sympromasie fe eppeating far wesks eer Degiaring ‘resumen (Linguer 1982-Maseslongo 1988). According wo chs rey, shaw effeas showed a fvounble rend afer combing ‘he semlte nx mernanais ‘Aecotting wo prevos mus of dap, hein to of actin Sr she pene i Berar tan se of NSAIDs ( evel 1993). Tht imporen ily eee an dey pope slo nano mle dap tent ade aes of [NSAIDs ae dangerous in longtem admininrason (Belcy 1991) Bais contan:Sacercn Bsa imposter no ‘ee inal RCT hese of repo dren as we 4055 were: he dioput ieee ma fi owe Seren Brand 12s Toe RCTs here deed ndesore aml fe dae ne man spon of, ad he pomiby fearon ofarctl dare ad ond poh ip bor aes ae eis inporanto amp tar area he tna ining fcr proton. “Theappliasion of igorous mechodelogicsisveryimporant whe asgning and condacing OA clic we, The prvematic re ‘ow shomed prolems mainly slated ro uniform outcomes mex- surment, ITT analsicend madomization ad allocation onceal> ‘ent methods Ine recommended the for mice should we sandardized, andomied eonealled wis following che model ‘rabid by doe Consort Suzement (Maher 2001) awe cece eligiulcualdimgeindelipavdlwinkses badiecd ‘Sine eis imporane 0 deign edie where dhe outcomes cule ‘be more uniform and rely provide presi infoumatian sbose the coun ofthe dee wishou so many qualitative messes Diacerinforoneoeris (Rio) ‘Capri 82000 The Cocrae Caabraion. Pbahed by Jn Wey & Sons Ledperhaps by using bielogia mashes ofcartage degradation and ‘re appropriate radiographic evaluation, in which the crags extortion can be moniord “The inodezate heterogeneity detectd among the wal is shi e- view increases the uacetalny around the results and makes ear ‘thezced or more wall-dsgned sues (king no coneideation the devgn inves outlined eve) and wish long-erm of obser ‘ation (lee one year). would be yer inteseing vo design rio to ela ciferee joiner ave dicen eles wih he same tresment. Therewar no dy to ale hand oespiae OA, ‘Wenecd mare sues wo rif now o deal wit such ahereroge- anus and fequene disease. Purhe esearch is neded 0 discover ‘drug chat ae he silt change the cours of edie AUTHORS’ CONCLUSIONS Implications for practice ‘Theses gold lee evidence has lacereinhasa smal consent teneft in improvement in pain Further rere i neste «© confirm se shoreand longer: sflecveness and wesc of diac ‘ein ergy in OA. Only mores wing alidated owcomes, ‘scare of biomarkers and more presi radiographic was ‘tharcan tithe pogrenion ofdivesein longterm cbeenation ‘ss annver these questans. Implications for research Many quetions remain uncnswerd cegaing the asecf icesin ‘herp in OA, Forher march enemy. ‘ion wharf ch og term elf and sly of dacrin? Second, i aera help fr al pavems with OA involving (Seen jones and arden sages of seven? ‘Thin posible co manufacure a proce that tsa for he ‘owe ia sexs of duh ncidence? Fourth dacerein can indeed mosily the rsa peogeesion of ox “We nad ang tx sds wih uniform osrome messiremenss re anower this quetions ACKNOWLEDGEMENTS T would ike wo shank the Cochrune Muscuoselets Editorial “Team, nny Me, Lae Masel frhershoughul comments and suggestions. REFERENCES ‘References to studies included in this review Chane 2000 (pubis dane ont ‘Chanze 2 Ceppdae A eblanD, Galea D, Vindcands Faun 3 ity and Telenee of HarpgephyiyPocubene ‘eas Doon Terrace of Oneonta pomene 2007.177-183 Dwg 2001 publ dere ony) "Dougedoe Mt. isyen M, Beda, Males B.VignonE, equine M.Eauaion of Scucrar- Moding sof ‘Daan in Ep Ona, Arie Rin 200104 canjasss-2507, Legere 1998 fui dea om) Tune My Beis , Gls: ya Say of ican forte enact of Kean ip Oana ‘ole dela echoed ralunet dela orto ede Inessaae) Le Re Pain 1995683835. Nien 1996 ube det omy) iver M, DoupdorM Bash L Amor & Dich io The “Touma ef Omri of Th Hip Arh Remain 19945 707528-36. Pace 200 publi dat ob} ele J Yr M, Haut 8, Chen 2 Nabe MA, Chaguee Deal icy sd Say of iain in Onn fhe Kao Abi an Raman 2005 10).2595-2348, Phas 2006 fubied dae on) Pham I Henan A, Rood Bigger a Blution of raprmade and sansa ec of anew Byala sd (HAD Compound ORDION} whee compared occa rd eesbo ‘i onepearratdonias! cones sy in pmpenrate ee nse nal ef Rr Die 2004631211817. “Tang 206 (publi date) "Bag FL Wo DE, La 2G, Haugh Zhow ¥ The fey nd ay of Gowen nsec of inal omar oles 1s Ase Pci egos of Asciion for Reumlgy Congr an, Kan. 1-15 Sepebar 2006 References to studies excluded from this review dso 1995 (pablsed det on) ‘dani, HorsestX Guar G, Mat G, Roi, Zanpi ‘k La Gado V. Dinan inh Testun of Degeive repay (Dien Tan dle Arzopaie Degenerate. Le Gn Tapeso 965A 3, ‘incr or onesie) ‘Copyeght.o Seo The Cocirane Cataboraton Pushed y Jana Whey & Sony, Ledeoglala 1991 (pxblished date ob Boglo A Li PepiganaG. "agence and ‘Diss nthe Trane of Hip nd Kase Oscars [Fuagoneotaps¢ Daconng al Trams del Oncaea aKa el Glee Trspeatie91:1373-8 Carrabb 1987 (peblsbed dete ob) (Carab M, Mele, Chole M, Aga M. Dacian origin” approach the exanent of degen andlc ‘eared beurnos [Dacaine: un aproioorilé ‘leaeemente do unin dagen lo emai ‘Sacro des 9ET7O179-185, Dekabre 1996 (publned den nh alc B Taccen A. ARS $0 Syn be Vere Rhcurasogic Paice [Ene DART Sden Panga Rhomorlgiue Cour. Rane Da Phamaime 29461 Mas-i46s- Deere 1996 fubled dae ony) ‘lcm By Teen A Say oF ART $0 theses daly paces ade GART 30 en paige rhaaologqee ‘oti, Le Rr Pate IGAGSIS-S52 ‘Dongs 2002 fone date mb) oogadas M, lhe Trl Replutnent ofthe Hp an Ouse (Cia fr he Omens ofthe ip (La Preheeld ance Un Cee D'Braden dels Coarse, Le Rue Da Prsien 200252:511-513. Fagnani 1998 (publi das ony ‘gna BoureacG, Vee 2 Bein Bare L Lins A, Banal, Hrchng Ecker RL Malco Espoo Anais af Diaaria Wah or Wikow Sadat They ie Tae of (Snwaunts, Phematemne 19813 28-145, xy 1960 ible des ony} Kay AGE, Gate LG, lara GN, GabaneR Peng ‘pins wih cach in he emma of ener Cnet tis! Rae nd Opiion 886858851, Lela 2000 (publed des on Tubln D, Chance 8 ous B Hapagopyeam proces ‘Herronee of ka an hip tears. Forsnouk ads of 2 psmpeniv alec; double bind wil vans ecb. Bone Sie 20074627, opus 1982 (pln dae nb! ‘ngoe M, D'Antoni PL, Di Gri Soatng Linge. ‘A Cosel Sas int Trent of Oscars wth Biacythin (ARTRODAR). Caren These Rare 1982, 103Hs05-412| owhenoe 2006 publi date on) owtaencn WF, lgarewongS, AisannagibaS, Aswanaskadse 2 Seema Tai Stay Grup. The eccy snd er of

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