Persistencia a largo plazo de agentes biológicos en el tratamiento de pacientes con Artritis Reumatoidea: una revisión sistemática de la literatura / Long-term persistence of biological agents in the treatment of patients with Rheumatoid Arthritis: a systematic literature review

La persistencia en el tratamiento es un marcador subrogante de éxito de tratamiento a largo plazo. Objetivo: Evaluar la persistencia de los agentes biológicos utilizados para el tratamiento de pacientes con artritis reumatoidea (AR) a un tiempo de 5 años y determinar las principales causas asociadas a persistencia o discontinuación. Material y métodos: Se realizó una revisión sistemática de la literatura (RSL), según las recomendaciones PRISMA, en las bases de datos Pubmed, Cochrane y Lilacs, y estudios presentados en los congresos ACR, EULAR, PANLAR (2018/2019) hasta Enero 2020. Dos revisoras independientes, evaluaron todas las publicaciones identificadas, por título y abstract y por full text, de acuerdo a la metodología PICO. Los criterios de elegibilidad fueron estudios de pacientes ≥ 18 años con diagnóstico de AR, en tratamiento con agentes biológicos, que midieran persistencia/discontinuación en un período de tiempo igual o superior a 5 años y que estuvieran en idioma inglés o español. En el caso de falta de acuerdo entre las dos revisoras, un tercer revisor fue consultado. La información extraída fue analizada mediante estadística descriptiva, se calculó el porcentaje promedio de persistencia de cada agente biológico a los 5 años. Resultados: Se seleccionaron 56 artículos luego de la remoción de los duplicados y de la exclusión por título/abstract, y por full text. De ellos 13, eran fase de extensión a largo plazo de estudios randomizados controlados, 15 cohortes retrospectivas, 18 cohortes prospectivas y 10 cohortes retro-prospectivas y correspondían a un total de 72177 (rango: 79-10396) pacientes con AR, con una edad media 53.8 años ± 12.1, 78.2% de sexo femenino y un tiempo promedio de evolución de la AR de 9.7 años ± 8.4. En 33.9% de los estudios, la terapia biológica estaba combinada con drogas modificadoras de la AR convencionales (DMARs-c), en 3.6% en monoterapia, 48.2% ambas modalidades y en 14.3% no informaba. Un estudio fue realizado en 1° línea (metotrexato näive), 29 estudios en 2° línea (respuesta inadecuada a MTX y/o DMARs-c), 5 en 3° línea (respuesta inadecuada a DMARs biológicas-b-), 12 en ≥2° línea terapéutica y en 9 no especificaban. En 30 estudios que evaluaron 2° línea terapéutica, la mayor persistencia correspondió a tocilizumab (TCZ) 66.41% (IC95% 57.8-79.94), abatacept (ABA) 57.91% (IC95% 50.96-64.87) y golimumab (GOL) 54.38% (IC95% 48.58-60.19). Y 10 estudios, en los cuales el DMAR-b había sido analizado en 3° línea terapéutica, las mayores tasas de retención correspondieron a rituximab (RTX) 61.19% (IC95% 57.53-66.22) y TCZ 61.1% (IC95% 58.81-63.32). Entre los estudios que evaluaron predictores, los más frecuentemente asociados a mayor sobrevida fueron: tratamiento combinado con DMAR-c, etanercept versus infliximab y adalimumab y 2° línea de tratamiento vs 3° o 4° línea y los asociados a menor sobrevida fueron: mayor uso de esteroides, mayor actividad basal de la enfermedad y sexo femenino. Conclusiones: En esta RSL, la persistencia de los DMAR-b a 5 años en pacientes con respuesta inadecuada a DMARs-c y DMARs-b fue numéricamente mayor para los agentes no TNFi. Y entre los TNFi, GOL presentó mayor retención en 2° línea terapéutica.

Treatment persistence is a surrogate marker for long-term treatment success. Objective: To assess the persistence of the biological agents used for treatment of patients with rheumatoid arthritis (RA) over 5 years period and to determine the main causes associated with persistence or discontinuation. Material and methods: A systematic literature review (SLR) was carried out, according to PRISMA recommendations, including Pubmed, Cochrane and Lilacs databases, and studies presented at the ACR, EULAR, PANLAR congresses (2018/2019) until January 2020. Two independent reviewers evaluated the identified publications, by title and abstract and full text, according to PICO methodology. Eligibility criteria were: studies including RA patients ≥ 18 years, treated with biological agents, which measured persistence/ discontinuation for a period of time equal to or greater than 5 years and who were in English or Spanish language. In the case of lack of agreement between the two reviewers, a third reviewer was consulted. The extracted information was analyzed using descriptive statistics, an average percentage of persistence for each biological agent at 5 years was calculated. Results: 56 articles were selected after removal of duplicates and exclusion by title/abstract, and by full text. Long-term extension phase of randomized controlled studies were 13, another 15 retrospective cohorts, 18 prospective cohorts and 10 retro-prospective cohorts and corresponded to a total of 72177 (range: 79-10396) patients with RA, with a mean age of 53.8 years ± 12.1, 78.2% female and an average RA disease duration of 9.7 years ± 8.4. In 33.9% of the studies, biological therapy was combined with conventional disease modifying anti-rheumatic drugs (c-DMARDs), in 3.6% monotherapy, 48.2% both modalities, and in 14.3% not reported. One study was in the 1st line (methotrexate näive), 29 studies in 2nd line (inadequate response to MTX and/or c-DMARDs), 5 in 3rd line (inadequate response to biological b-DMARDs), 12 in ≥2nd therapeutic line and in 9 studies did not specify this condition. In 30 studies which evaluated the 2nd therapeutic line, the highest persistence corresponded to tocilizumab (TCZ) 66.41% (95% CI 57.8-79.94), abatacept (ABA) 57.91% (95% CI 50.96-64.87) and golimumab (GOL) 54.38% (95% CI 48.58-60.19). In 10 studies, in which b-DMARD had been analyzed in 3rd therapeutic line, highest retention rates corresponded to rituximab (RTX) 61.19% (95% CI 57.53-66.22) and TCZ 61.1% (95% CI 58.81-63.32). Among studies that evaluated predictors, the most frequently associated with higher survival were: combined treatment with c-DMARD, etanercept versus infliximab and adalimumab and 2nd line of treatment vs. 3rd or 4th line whereas those associated with lower survival rates were: greater use of steroids, higher baseline disease activity, and female gender. Conclusions: In this SLR, the 5-year persistence of b-DMARD in patients with inadequate response to DMARs-c and DMARs-b was numerically greater for non-TNFi agents. And among TNFi, GOL presented a higher retention in 2nd therapeutic line.

Monoterapia biológica en pacientes con artritis reumatoidea en Argentina / Biological monotherapy in patients with rheumatoid arthritis in Argentina

Introducción: La utilización de agentes biológicos para el tratamiento de la Artritis Reumatoidea (AR) es habitualmente usada en aquellos pacientes con enfermedad activa que no hayan respondido al tratamiento con drogas modificadoras de la Artritis Reumatoidea convencionales (DMARD, por sus siglas en inglés) o que hayan presentado intolerancia a las mismas. Al estado actual de la evidencia, la terapia combinada de agentes biológicos más un DMARD convencional (principalmente metotrexato) constituye el estándar de tratamiento. Sin embargo existen algunos escenarios como la intolerancia, la falta de adherencia y la aparición de eventos adversos a las DMARDs convencionales donde la monoterapia biológica emerge como una opción terapéutica válida. Según los distintos registros a nivel internacional, la frecuencia de utilización de agentes biológicos en monoterapia oscila entre 12 a 39%. Debido a la ausencia de estos datos a nivel local decidimos realizar este estudio para conocer el porcentaje de pacientes que se encuentran en monoterapia biológica y analizar las causas que llevaron a este tipo de tratamiento. Materiales y métodos: Estudio de tipo corte transversal donde se invitó a participar a diferentes centros reumatológicos distribuidos a lo largo de Argentina. Cada centro revisó las historias clínicas de los últimos 30 a 50 pacientes consecutivos vistos con AR, mayores de 18 años, que habían presentado inadecuada respuesta al tratamiento con DMARDs y que estaban bajo tratamiento biológico. Se completaba una ficha por cada paciente incluido, registrando datos demográficos, de la enfermedad y tratamientos previos. Resultados: Se incluyeron 32 centros y se evaluaron 1148 historias clínicas de pacientes con AR durante el mes de octubre y noviembre del 2012. Un 21,4% (246) de los pacientes al momento del estudio se encontraba bajo tratamiento biológico en monoterapia...

Introduction: The use of biological agents for the treatment of rheumatoid arthritis (RA) is commonly used in patients with active disease who have not responded to treatment with conventional rheumatoid arthritis-modifying drugs (DMARDs) or Who have presented intolerance to them. At the present state of evidence, combined therapy of biological agents plus conventional DMARD (mainly methotrexate) is the standard of treatment. However, there are some scenarios such as intolerance, lack of adherence and the appearance of adverse events to conventional DMARDs where biological monotherapy emerges as a valid therapeutic option. According to different international registries, the frequency of use of biological agents in monotherapy ranges from 12 to 39%. Due to the absence of these data at the local level we decided to carry out this study to know the percentage of patients who are in biological monotherapy and to analyze the causes that led to this type of treatment. Materials and methods: A cross-sectional study where different rheumatologic centers throughout Argentina were invited to participate. Each center reviewed the medical records of the last 30 to 50 consecutive patients seen with RA, older than 18 years, who had inadequate response to treatment with DMARDs and who were under biological treatment. One card was completed for each patient included, recording demographic, disease and previous treatment data. Results: Thirty-two centers were included and 1148 clinical records of patients with RA were evaluated during October and November 2012. A total of 244 patients (246) at the time of the study were under monotherapy...

Subcutaneous abatacept versus intravenous abatacept: a phase IIIb noninferiority study in patients with an inadequate response to methotrexate.

OBJECTIVE: To compare the efficacy and safety of subcutaneous (SC) and intravenous (IV) abatacept. METHODS: In this phase IIIb double-blind, double-dummy, 6-month study, patients with rheumatoid arthritis (RA) and inadequate responses to methotrexate were randomized to receive 125 mg SC abatacept on days 1 and 8 and weekly thereafter (plus an IV loading dose [∼10 mg/kg] on day 1) or IV abatacept (∼10 mg/kg) on days 1, 15, and 29 and every 4 weeks thereafter. The primary end point for determining the noninferiority of SC abatacept to IV abatacept was the proportion of patients in each group meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at month 6. Other efficacy end points, immunogenicity, and safety were also assessed. RESULTS: Of 1,457 patients, 693 of 736 (94.2%) treated with SC abatacept and 676 of 721 (93.8%) treated with IV abatacept completed 6 months. At month 6, 76.0% (95% confidence interval 72.9, 79.2) of SC abatacept-treated patients versus 75.8% (95% confidence interval 72.6, 79.0) of IV abatacept-treated patients achieved an ACR20 response (estimated difference between groups 0.3% [95% confidence interval -4.2, 4.8]), confirming noninferiority of SC abatacept to IV abatacept. Onset and magnitude of ACR responses and disease activity and physical function improvements were comparable between the SC and IV abatacept-treated groups. The proportions of adverse events (AEs) and serious AEs over 6 months were 67.0% and 4.2%, respectively, in the SC abatacept-treated group and 65.2% and 4.9%, respectively, in the IV abatacept-treated group, with comparable frequencies of serious infections, malignancies, and autoimmune events between groups. SC injection site reactions (mostly mild) occurred in 19 SC abatacept (IV placebo)-treated patients (2.6%) and 18 IV abatacept (SC placebo)-treated patients (2.5%). Abatacept-induced antibodies occurred in 1.1% of SC abatacept-treated patients and 2.3% of IV abatacept-treated patients. CONCLUSION: SC abatacept provides efficacy and safety comparable with that of IV abatacept, with low immunogenicity and high retention rates, consistent with the established IV abatacept profile. Rates of injection site reactions were low. SC abatacept will provide additional treatment options, such as an alternative route of administration, for patients with RA.

Catastrophic antiphospholipid syndrome complicating orthotopic liver transplantation.

Catastrophic antiphospholipid syndrome (CAPS) is an acutely devastating situation characterized by widespread thrombotic microangiopathy in the presence of elevated titers of antiphospholipid antibodies. We describe a 57-year old woman who underwent liver transplantation for primary sclerosing cholangitis and developed this malignant variant of the antiphospholipid syndrome.

Levels of soluble Fas/APO-1/CD95 in systemic lupus erythematosus and juvenile rheumatoid arthritis.

OBJECTIVE: To quantify soluble Fas/APO-1 (sFas/APO-1) protein in the serum of patients with systemic lupus erythematosus (SLE) and juvenile rheumatoid arthritis (JRA). METHODS: Soluble Fas/APO-1 was quantified using a sandwich enzyme-linked immunosorbent assay. Disease activity in SLE patients was assessed by the SLE Disease Activity Index. RESULTS: Increased serum sFas/APO-1 levels were observed in only 1 of the 27 SLE patients (4%) and 3 of the 10 JRA patients (30%). CONCLUSION: Increased levels of sFas/APO-1 occurred infrequently in SLE, and the levels were lower than 10 ng/ml. Increased levels of sFas/APO-1 are not specific for SLE. Soluble Fas/APO-1 is unlikely to be of major pathogenetic significance in SLE.

The apoptosis-1/Fas protein in human systemic lupus erythematosus.

Three independent mutations involving the apoptosis-1 (APO-1)/Fas receptor or its putative ligand have led to lupuslike diseases associated with lymphadenopathy in different strains of mice. To determine whether humans with SLE also have a defect in this apotosis pathway, we analyzed the expression of APO-1 on freshly isolated blood mononuclear cells and on lymphocytes activated in vitro using flow cytometry and the monoclonal antibody anti-APO-1. Significantly higher level of APO-1 expression were detected on freshly isolated peripheral B cells and both CD4+ and CD8+ T lymphocyte populations obtained from lupus patients when compared with normal controls (P < 0.001). Almost 90% of the cells that stained positive for APO-1 also expressed the CD29 antigen, suggesting that APO-1 was upregulated after lymphocyte activation in vivo. No defect in APO-1 regulation was detected after activation of SLE T (with anti-CD3) or B (with Staphylococcus aureus Cowan 1) lymphocytes in the presence of IL-2 in vitro. Similarly, the anti-APO-1 antibody induced apoptosis in 74 +/- 5% of activated SLE T cells in vitro compared with 79 +/- 6% of the normal controls (P > 0.05). These results reveal that, while APO-1/Fas may play an important role in the regulation of lymphocyte survival in SLE, no consistent defect in the expression or function of the receptor could be detected in these studies.