Colombian Association of Rheumatology. Consensus on recommendations to decrease and discontinue biological therapy in patients with rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis / Asociación Colombiana de Reumatología. Consenso sobre recomendaciones para disminución y descontinuación de la terapia biológica en pacientes con artritis reumatoide, espondilitis anquilosante y artritis psoriásica

A B S T R A C T Objective: The objective of this study was to establish recommendations for the reduction and discontinuation of biological disease-modifying antirheumatic drugs, with the aim of becoming a guide document for health professionals involved in the management of patients with rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis. Materials and methods: The recommendations were established through consensus by a panel of experts in rheumatology, and based on the analysis of available scientific evidence obtained from systematic reviews and the clinical experience of the panellists. Results: A total of 33 rheumatoid arthritis related studies were included, with 6 psoriatic arthritis related, and 9 ankylosing Spondylitis related. The recommendations for the reduction of biological therapies were made by establishing a plan to determine when and how to reduce the biological disease-modifying antirheumatic drugs in patients with these 3 diseases, and in some cases lead to the discontinuation of these treatments. Conclusion: The recommendations established in this document will serve as a guide to improve the efficiency of biological therapy in these diseases, reduce the variability in clinical practice, and establish an adequate risk/benefit ratio.

RESUMEN Objetivo: El objetivo de este estudio fue establecer recomendaciones para la disminución y descontinuación de la terapia biológica con el fin de que se convierta en un documento guía para los profesionales de la salud involucrados en el manejo de pacientes con artritis reumatoide, espondilitis anquilosante y artritis psoriásica. Materiales y métodos: Las recomendaciones fueron establecidas mediante consenso desarrollado a través de un panel de expertos en reumatología, basado en el análisis de la evidencia científica disponible obtenida de revisiones sistemáticas y sobre la experiencia clínica de los panelistas. Resultados: Se incluyeron 33 estudios relacionados con artritis reumatoide, 6 de artritis psoriásica y 9 de espondilitis anquilosante. Las recomendaciones para la disminución de las terapias biológicas se realizaron estableciendo un plan para determinar cuándo y cómo reducir los fármacos biológicos modificadores de enfermedades reumáticas en pacientes con estas 3 enfermedades y en algunos casos conducir a la descontinuación de estos tratamientos. Conclusión: Las recomendaciones establecidas en este documento servirán de guía para mejorar la eficiencia de la terapia biológica en estas enfermedades, reducir la variabilidad en la práctica clínica y establecer de manera adecuada una relación riesgo/beneficio.

CNTO6785, a Fully Human Antiinterleukin 17 Monoclonal Antibody, in Patients with Rheumatoid Arthritis with Inadequate Response to Methotrexate: A Randomized, Placebo-controlled, Phase II, Dose-ranging Study.

OBJECTIVE: To evaluate the efficacy, safety, pharmacokinetics, and immunogenicity of CNTO6785, a fully human monoclonal antibody that binds to human interleukin 17A, in patients with active rheumatoid arthritis (RA) with inadequate response to methotrexate (MTX) therapy. METHODS: This randomized, double-blind, placebo-controlled, dose-ranging study enrolled patients aged 18 to 80 years (inclusive) with active RA (≥ 6/66 swollen and ≥ 6/68 tender joints) who were refractory to MTX treatment (7.5-25 mg weekly, inclusive). The study duration was 38 weeks, containing a 10-week safety followup. Patients were randomized 1:1:1:1:1 to receive CNTO6785 15, 50, 100, or 200 mg every 4 weeks + MTX or placebo + MTX. The primary endpoint was American College of Rheumatology 20 (ACR20) response at Week 16. RESULTS: There were no significant differences from placebo in the proportion of patients treated with CNTO6785 in the primary endpoint of ACR20 response at Week 16. There were no significant findings in any additional efficacy variables through Week 32. No dose-response relationships or specific patterns were observed in adverse event profiles among CNTO6785 treatment groups. Infections occurred with similar frequency across all groups, and injection site reactions were mild or moderate and did not demonstrate a dose-response relationship. Median serum CNTO6785 concentration increases through Week 38 were about dose-proportional; the incidence of neutralizing antidrug antibodies was 19.4% and was not associated with study drug dose level. CONCLUSION: CNTO6785 was well tolerated, but did not demonstrate clinical efficacy in patients with active RA with inadequate response to MTX.

Tofacitinib, an oral Janus kinase inhibitor, for the treatment of Latin American patients with rheumatoid arthritis: Pooled efficacy and safety analyses of Phase 3 and long-term extension studies / Tofacitinib, un inhibidor oral de la quinasa Janus, para el tratamiento de artritis reumatoide en pacientes de Latinoamérica: eficacia y seguridad de estudios fase 3 y de extensión a largo plazo

Objective. Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We assessed tofacitinib efficacy and safety in the Latin American (LA) subpopulation of global Phase 3 and long-term extension (LTE) studies. Materials and methods. Data from LA patients with RA and inadequate response to disease-modifying antirheumatic drugs (DMARDs) were pooled across five Phase 3 studies. Phase 3 patients received tofacitinib 5 or 10mg twice daily (BID), adalimumab or placebo; patients in the single LTE study received tofacitinib 5 or 10mg BID; treatments were administered alone or with conventional synthetic DMARDs. Efficacy was reported up to 12 months (Phase 3) and 36 months (LTE) by American College of Rheumatology (ACR) 20/50/70 response rates, Disease Activity Score (DAS)28-4(erythrocyte sedimentation rate [ESR]) and Health Assessment Questionnaire-Disability Index (HAQ-DI). Incidence rates (IRs; patients with event/100 patient-years) of adverse events (AEs) of special interest were reported. Results. The Phase 3 studies randomized 496 LA patients; the LTE study enrolled 756 LA patients from Phase 2 and Phase 3. In the Phase 3 studies, patients who received tofacitinib 5 and 10mg BID showed improvements vs placebo at Month 3 in ACR20 (68.9% and 75.7% vs 35.6%), ACR50 (45.8% and 49.7% vs 20.7%) and ACR70 (17.5% and 23.1% vs 6.9%) responses, mean change from baseline in HAQ-DI (−0.6 and −0.8 vs −0.3) and DAS28-4(ESR) score (−2.3 and −2.4 vs −1.4). The improvements were sustained up to Month 36 in the LTE study. In the Phase 3 studies, IRs with tofacitinib 5 and 10mg BID and placebo were 7.99, 6.57 and 9.84, respectively, for SAEs, and 3.87, 5.28 and 3.26 for discontinuation due to AEs. IRs of AEs of special interest in tofacitinib-treated LA patients were similar to the global population. Conclusion. In Phase 3 and LTE studies in LA patients with RA, tofacitinib demonstrated efficacy up to 36 months with a manageable safety profile up to 60 months, consistent with the overall tofacitinib study population (AU)

Objetivo. Tofacitinib es un inhibidor oral de la quinasa Janus para el tratamiento de la artritis reumatoide (AR). Este análisis evaluó la eficacia y la seguridad de tofacitinib en la subpoblación Latinoamericana (LA) de los estudios fase 3 y de extensión a largo plazo (ELP). Materiales y métodos. Se agruparon datos de pacientes de Latinoamérica con AR y una respuesta inadecuada a agentes modificadores de la enfermedad (DMARD) de 5 estudios fase 3. Los pacientes en estos estudios recibieron tofacitinib 5 o 10mg/2 veces al día (bid), adalimumab o placebo; los pacientes en el estudio de seguridad recibieron tofacitinib 5 o 10mg/bid; los tratamientos se administraron en monoterapia o con DMARD sintéticos convencionales. La eficacia se reporta hasta 12 (fase 3) y 36 meses (ELP) mediante las tasas de respuesta del Colegio Americano de Reumatología (ACR) 20/50/70, el índice de actividad de la enfermedad (DAS)28-4 ESR (tasa de sedimentación globular [ESR]) y el índice de discapacidad del cuestionario de evaluación de la salud (HAQ-DI). Se reportan las tasas de incidencia (IR: pacientes con evento/100 pacientes/año) de eventos adversos (EA) de interés especial. Resultados. Los estudios fase 3, incluyeron 496 pacientes de LA, el ELP reclutó 756 pacientes de fase 2 y fase 3. En los estudios de fase 3, los pacientes que recibieron tofacitinib 5 y 10mg/bid presentaron mejorías vs placebo al mes 3 en las respuestas ACR20 (68,9% y 75,7% vs 35,6%), ACR50 (45,8% y 49,7% vs 20,7%) y ACR70 (17,5% y 23,1% vs 6,9%), en cambio, desde el valor basal en el escore HAQ-DI (−0,6 y −0,8 vs −0,3) y en el escore DAS28-4(ESR) (−2,3 y −2,4 vs −1,4); estas mejorías fueron sostenidas hasta el mes 36, último mes de evaluación en el estudio de ELP. En los pacientes con tofacitinib 5 o 10mg/bid y placebo, las tasas de incidencia de SAE fueron de 7,99, 6,57 y 9,84, mientras que la incidencia de descontinuaciones por EA fueron de 3,87, 5,28 y 3,26, respectivamente. Las IR de EA de interés especial en pacientes de LA fueron similares a la población global. Conclusión. En los pacientes de LA con AR de estudios fase 3 y ELP, tofacitinib demostró eficacia hasta por 36 meses con un perfil de seguridad manejable hasta por 60 meses, en los pacientes de LA con AR, datos consistentes con el de la población global de los estudios de tofacitinib (AU)

Tofacitinib, an oral Janus kinase inhibitor, for the treatment of Latin American patients with rheumatoid arthritis: Pooled efficacy and safety analyses of Phase 3 and long-term extension studies.

OBJECTIVE: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We assessed tofacitinib efficacy and safety in the Latin American (LA) subpopulation of global Phase 3 and long-term extension (LTE) studies. MATERIALS AND METHODS: Data from LA patients with RA and inadequate response to disease-modifying antirheumatic drugs (DMARDs) were pooled across five Phase 3 studies. Phase 3 patients received tofacitinib 5 or 10mg twice daily (BID), adalimumab or placebo; patients in the single LTE study received tofacitinib 5 or 10mg BID; treatments were administered alone or with conventional synthetic DMARDs. Efficacy was reported up to 12 months (Phase 3) and 36 months (LTE) by American College of Rheumatology (ACR) 20/50/70 response rates, Disease Activity Score (DAS)28-4(erythrocyte sedimentation rate [ESR]) and Health Assessment Questionnaire-Disability Index (HAQ-DI). Incidence rates (IRs; patients with event/100 patient-years) of adverse events (AEs) of special interest were reported. RESULTS: The Phase 3 studies randomized 496 LA patients; the LTE study enrolled 756 LA patients from Phase 2 and Phase 3. In the Phase 3 studies, patients who received tofacitinib 5 and 10mg BID showed improvements vs placebo at Month 3 in ACR20 (68.9% and 75.7% vs 35.6%), ACR50 (45.8% and 49.7% vs 20.7%) and ACR70 (17.5% and 23.1% vs 6.9%) responses, mean change from baseline in HAQ-DI (-0.6 and -0.8 vs -0.3) and DAS28-4(ESR) score (-2.3 and -2.4 vs -1.4). The improvements were sustained up to Month 36 in the LTE study. In the Phase 3 studies, IRs with tofacitinib 5 and 10mg BID and placebo were 7.99, 6.57 and 9.84, respectively, for SAEs, and 3.87, 5.28 and 3.26 for discontinuation due to AEs. IRs of AEs of special interest in tofacitinib-treated LA patients were similar to the global population. CONCLUSION: In Phase 3 and LTE studies in LA patients with RA, tofacitinib demonstrated efficacy up to 36 months with a manageable safety profile up to 60 months, consistent with the overall tofacitinib study population.

Serious liver disease induced by infliximab.

Infliximab, a chimeric monoclonal antibody that binds the tumor necrosis factor alpha (TNFalpha), is used in the treatment of rheumatoid arthritis (RA) and Crohn's disease (CD). Previous cases of significant secondary liver disease associated with infliximab treatment have been reported in patients with RA, CD, and psoriatic arthritis. Two additional patients with RA who developed a serious liver disease associated with infliximab treatment are reported here. A 39-year old RA patient was admitted with cholestatic liver disease after 8 months of treatment with infliximab. She had no history of hepatic diseases, exposure to hepatotoxic or illicit drugs, or alcohol abuse. A liver biopsy showed severe ductal proliferation with collapse and enucleation of the hepatocytes. Despite aggressive treatment with oral prednisolone, she developed hepatic failure. On the 45th day, a liver transplant was performed. The second patient, a 54-year old RA patient, was diagnosed with autoimmune hepatitis after 12 infliximab infusions. She fulfilled autoimmune hepatitis type 1 criteria. A liver biopsy disclosed an altered lobulillar structure with chronic inflammation and the formation of collagen bands. She was treated with prednisolone and azatioprine and a complete recovery was noted 1 month later. These cases should alert rheumatologists to the possibility of new adverse reactions (liver injury) associated with the use of TNFalpha blockers in an autoimmune setting.

Estudio multicéntrico para evaluar la efectividad y seguridad de una presentación de alendronato de sodio en cápsulas de gelatina blanda (Neobon 70 ®), en el tratamiento de osteoporosis posmenopáusica / Multicentre study to evaluate the effectiveness and security of sodium alendronate in a soft gelatin capsules in the treatment of postmenopausal osteoporosis

Objetivos: el objetivo del estudio fue evaluar la respuesta al tratamiento y seguridad del alendronato de sodio en una presentación de cápsulas blandas de gelatina (Neobon 70 ®), en mujeres posmenopáusicas con osteoporosis u osteopenia. Métodos: estudio clínico multicéntrico abierto a un año de tratamiento en mujeres postmenopáusicas. Las pacientes fueron asignadas a recibir 70 mg cada semana de alendronato sódico en presentación de cápsulas de gelatina blanda. Los desenlaces primarios fueron la densidad mineral ósea medida por DEXA y el valor plasmático del C-Telopéptido. La condición ósea fue evaluada por densitometría al inicio del estudio, al mes 6 y a los 12 meses de tratamiento. La resorción ósea fue evaluada por los niveles de C-Telopéptido basal, a los 3, 6 y 12 meses de tratamiento. Como desenlace secundario se evaluó la presentación de eventos adversos secundarios. Resultados: el estudio incluyó 146 mujeres reclutadas en diez centros de consulta externa de reumatología en cuatro ciudades de Colombia, que tuvieran diagnóstico de osteoporosis u osteopenia. La media de edad fue de 67±8 años (rango entre 45,7 y 92,8 años), y el promedio de tiempo transcurrido desde el inicio de la menopausia fue de 16±7,8 años. Treinta pacientes (20,54%) tenían una historia de fracturas previas. Al mes 12 de tratamiento se observó una reducción clínica y estadísticamente significativa en el nivel del C-Telopéptido (basal 0,53, tercer mes 0,22, sexto mes 0,17 y al año 0,17, p < 0,00001). Adicionalmente, se observó una mejoría estadísticamente significativa con el tratamiento en los valores del T-score a nivel de vértebras lumbares L2-L4 (basal -2,57, al sexto mes -2,27 y -2,29 al año), en el cuello de fémur (basal -2,37, al sexto mes -1,98 y al año -1,99), en el trocánter (basal -1,95, al sexto mes -1,55, y al año -1,41) y en la cadera (basal -1,73, al sexto mes -1,6 y -1,57 al año). También se observó mejoría en los parámetros de densidad mineral ósea, con un incremento de 2,3% a nivel vertebral lumbar y 2,59% en cadera. No hubo cambios en la densidad mineral ósea a nivel de cuello de fémur y trocánter. Estos cambios son similares a los observados con otras presentaciones de alendronatos y bifosfonatos. Como eventos adversos relacionados, solo se observó en el 8,2% la presencia de síntomas dispépticos, vértigo en el 3,4%, cefalea en el 2,7% y estreñimiento en el 1,4%. Conclusiones: estos resultados muestran que la presentación de alendronato sódico en cápsulas de gelatina blanda produce una gran mejoría en los parámetros evaluados por la densitometría y en el C-Telopéptido en mujeres posmenopáusicas con osteoporosis u osteopenia, y es una presentación farmacológica segura en mujeres jóvenes y de mayor edad.

Objectives: the purpose of this study was to evaluate the response to treatment and safety of Sodium Alendronate in a soft gelatin capsules presentation (Neobon 70 ®), in a postmenopausal women with osteoporosis or osteopenia. Methods: open multicenter clinical trial during one year was conducted in postmenopausal women. The patients were assigned to receive 70 mg of Sodic Alendronate in a soft gelatin capsule presentation, once time per week. The primaries endpoints were the bone density mineral measured by DEXA and the C-telopeptide serum level. The bone condition was evaluated by basal bone densitometry, 6 and 12 months. The bone resortion was evaluated by basal C-telopeptide serum levels, to 3, 6 and 12 months. The secondary endpoint was the presentation of secondary adverse events. Results: the study included 146 patients recruited in 10 rheumatologic clinical centers in Colombia, with diagnosis of osteopenia or osteporosis. Mean aged was 67±8 years (range 45.7 to 92.8 years) and the mean duration of menopausal time was 16±7.8 years. Thirty patients (20.54%) had a history of previous fracture bone. At month 12, a statistically significant reduction from base line in mean of C-telopeptide serum level was observed (basal 0.53, 3 month 0.22, 6 month 0.17 and 12 month 0.17, p < 0.00001). In addition, there was a clinical and statistically significant improvement in the T-score with the treatment in lumbar vertebrae L2-L4 (basal -2.57, 6 month -2.27 and 12 month -2.29), femur (basal -2.37, 6 month -1.98 and 12 month -1.99), trochanter (basal -1.95, 6 month -1.55 and 12 month -1.41), and in hip (basal -1.73, 6 month -1.6 and 12 month -1.57). Also it was observed an improvement in the parameters of bone density of 2.3% at lumbar vertebral level and of 2.59% in hip. No significant changes were observed in a left neck femur and trochanter. These increases are similar to observed with other presentations of alendronates and biphosphonates. Among this population, only the 8.2% had dyspeptic symptoms, 3.4% vertigo, 2.7% cephalea and 1.4% constipation. Conclusion: these findings showed that the presentation of sodium Alendronate in soft gelatin capsules produced a greater improvement in bone markers and densitometry scores in postmenopausal women with osteoporosis and osteopenia and is a safety pharmacological presentation in young and older patients.

Influencia del factor reumatoide (FR) en la severidad asociada a la artritis reumatoidea (AR) en población colombiana / Influence of the rheumatoid factor (RF) in the severity of rheumatoid arthritis (RF) in Colombian Patients

Los pacientes con RF positivo a titulos altos, tuvieron mayor discapacidad funcional medida por HAQ y mayor utilización de DMARD (medicamentos modificadores de la AR). Es importante titular siempre el FR.