BACKGROUND: This is an update of the 2009 Cochrane overview and network meta-analysis (NMA) of biologics for rheumatoid arthritis (RA).
OBJECTIVES: To assess the benefits and harms of nine biologics (abatacept, adalimumab, anakinra, certolizumab pegol, etanercept, golimumab, infliximab, rituximab, tocilizumab) and small molecule tofacitinib, versus comparator (MTX, DMARD, placebo (PL), or a combination) in adults with rheumatoid arthritis who have failed to respond to methotrexate (MTX) or other disease-modifying anti-rheumatic drugs (DMARDs), i.e., MTX/DMARD incomplete responders (MTX/DMARD-IR).
METHODS: We searched for randomized controlled trials (RCTs) in the Cochrane Central Register of Controlled Trials (CENTRAL) (via The Cochrane Library Issue 6, June 2015), MEDLINE (via OVID 1946 to June 2015), and EMBASE (via OVID 1947 to June 2015). Data extraction, risk of bias and GRADE assessments were done in duplicate. We calculated both direct estimates using standard meta-analysis and used Bayesian mixed treatment comparisons approach for NMA estimates to calculate odds ratios (OR) and 95% credible intervals (CrI). We converted OR to risk ratios (RR) which are reported in the abstract for the ease of interpretation.
MAIN RESULTS: This update included 73 new RCTs for a total of 90 RCTs; 79 RCTs with 32,874 participants provided usable data. Few trials were at high risk of bias for blinding of assessors/participants (13% to 21%), selective reporting (4%) or major baseline imbalance (8%); a large number had unclear risk of bias for random sequence generation (68%) or allocation concealment (74%).Based on direct evidence of moderate quality (downgraded for inconsistency), biologic+MTX/DMARD was associated with a statistically significant and clinically meaningful improvement in ACR50 versus comparator (RR 2.71 (95% confidence interval (CI) 2.36 to 3.10); absolute benefit 24% more patients (95% CI 19% to 29%), number needed to treat for an additional beneficial outcome (NNTB) = 5 (4 to 6). NMA estimates for ACR50 in tumor necrosis factor (TNF) biologic+MTX/DMARD (RR 3.23 (95% credible interval (Crl) 2.75 to 3.79), non-TNF biologic+MTX/DMARD (RR 2.99; 95% Crl 2.36 to 3.74), and anakinra + MTX/DMARD (RR 2.37 (95% Crl 1.00 to 4.70) were similar to the direct estimates.Based on direct evidence of moderate quality (downgraded for inconsistency), biologic+MTX/DMARD was associated with a clinically and statistically important improvement in function measured by the Health Assessment Questionnaire (0 to 3 scale, higher = worse function) with a mean difference (MD) based on direct evidence of -0.25 (95% CI -0.28 to -0.22); absolute benefit of -8.3% (95% CI -9.3% to -7.3%), NNTB = 3 (95% CI 2 to 4). NMA estimates for TNF biologic+MTX/DMARD (absolute benefit, -10.3% (95% Crl -14% to -6.7%) and non-TNF biologic+MTX/DMARD (absolute benefit, -7.3% (95% Crl -13.6% to -0.67%) were similar to respective direct estimates.Based on direct evidence of moderate quality (downgraded for inconsistency), biologic+MTX/DMARD was associated with clinically and statistically significantly greater proportion of participants achieving remission in RA (defined by disease activity score DAS < 1.6 or DAS28 < 2.6) versus comparator (RR 2.81 (95% CI, 2.23 to 3.53); absolute benefit 18% more patients (95% CI 12% to 25%), NNTB = 6 (4 to 9)). NMA estimates for TNF biologic+MTX/DMARD (absolute improvement 17% (95% Crl 11% to 23%)) and non-TNF biologic+MTX/DMARD (absolute improvement 19% (95% Crl 12% to 28%) were similar to respective direct estimates.Based on direct evidence of moderate quality (downgraded for inconsistency), radiographic progression (scale 0 to 448) was statistically significantly reduced in those on biologics + MTX/DMARDs versus comparator, MD -2.61 (95% CI -4.08 to -1.14). The absolute reduction was small, -0.58% (95% CI -0.91% to -0.25%) and we are unsure of the clinical relevance of this reduction. NMA estimates of TNF biologic+MTX/DMARD (absolute reduction -0.67% (95% Crl -1.4% to -0.12%) and non-TNF biologic+MTX/DMARD (absolute reduction, -0.68% (95% Crl -2.36% to 0.92%)) were similar to respective direct estimates.Based on direct evidence of moderate quality (downgraded for imprecision), results for withdrawals due to adverse events were inconclusive, with wide confidence intervals encompassing the null effect and evidence of an important increase in withdrawals, RR 1.11 (95% CI 0.96 to 1.30). The NMA estimates of TNF biologic+MTX/DMARD (RR 1.24 (95% Crl 0.99 to 1.57)) and non-TNF biologic+MTX/DMARD (RR 1.20 (95% Crl 0.87 to 1.67)) were similarly inconclusive and downgraded to low for both imprecision and indirectness.Based on direct evidence of high quality, biologic+MTX/DMARD was associated with clinically significantly increased risk (statistically borderline significant) of serious adverse events on biologic+MTX/DMARD (Peto OR [can be interpreted as RR due to low event rate] 1.12 (95% CI 0.99 to 1.27); absolute risk 1% (0% to 2%), As well, the NMA estimate for TNF biologic+MTX/DMARD (Peto OR 1.20 (95% Crl 1.01 to 1.43)) showed moderate quality evidence of an increase in the risk of serious adverse events. The other two NMA estimates were downgraded to low quality due to imprecision and indirectness and had wide confidence intervals resulting in uncertainty around the estimates: non-TNF biologics + MTX/DMARD: 1.07 (95% Crl 0.89 to 1.29) and anakinra: RR 1.06 (95% Crl 0.65 to 1.75).Based on direct evidence of low quality (downgraded for serious imprecision), results were inconclusive for cancer (Peto OR 1.07 (95% CI 0.68 to 1.68) for all biologic+MTX/DMARD combinations. The NMA estimates of TNF biologic+MTX/DMARD (Peto OR 1.21 (95% Crl 0.63 to 2.38) and non-TNF biologic+MTX/DMARD (Peto OR 0.99 (95% Crl 0.58 to 1.78)) were similarly inconclusive and downgraded to low quality for both imprecision and indirectness.Main results text shows the results for tofacitinib and differences between medications.
AUTHORS' CONCLUSIONS: Based primarily on RCTs of 6 months' to 12 months' duration, there is moderate quality evidence that the use of biologic+MTX/DMARD in people with rheumatoid arthritis who have failed to respond to MTX or other DMARDs results in clinically important improvement in function and higher ACR50 and remission rates, and increased risk of serious adverse events than the comparator (MTX/DMARD/PL; high quality evidence). Radiographic progression is slowed but its clinical relevance is uncertain. Results were inconclusive for whether biologics + MTX/DMARDs are associated with an increased risk of cancer or withdrawals due to adverse events.
OBJETIVO: Desarrollar una nueva pauta de tratamiento farmacológico basado en la evidencia para la artritis reumatoide (AR).
MÉTODOS: Se realizó una revisión sistemática para sintetizar la evidencia de los beneficios y los daños de diferentes opciones de tratamiento. Se utilizó la clasificación de las recomendaciones de la evaluación, la metodología de Evaluación (GRADE) Desarrollo y en evaluar la calidad de las pruebas. Empleamos un proceso de consenso del grupo para clasificar la fuerza de las recomendaciones (ya sean fuertes o condicionales). Una recomendación sólida indica que los médicos están seguros de que los beneficios de una intervención son muy superiores a los daños (o viceversa). Una recomendación condicional denota incertidumbre sobre el equilibrio entre los beneficios y los daños y / o una mayor variabilidad significativa en los valores y las preferencias del paciente.
RESULTADOS: La guía cubre el uso de los fármacos tradicionales modificadores de la enfermedad (DMARD) antirreumáticos, agentes biológicos, tofacitinib, y los glucocorticoides en los primeros 6 meses (<) y estableció (6 meses o más) RA. Además, proporciona recomendaciones sobre el uso de un enfoque de tratar al objetivo, se estrecha y descontinuar medicamentos y el uso de agentes biológicos y FAME en pacientes con hepatitis, insuficiencia cardíaca congestiva, enfermedad maligna, y las infecciones graves. La directriz se refiere a la utilización de las vacunas en pacientes que inician / recepción de FARME o agentes biológicos, la detección de la tuberculosis en pacientes que inician / recepción de agentes biológicos o tofacitinib, y la vigilancia de laboratorio para los DMARD tradicionales. La guía incluye 74 recomendaciones: 23% son fuertes y el 77% son condicionales.
CONCLUSIÓN: Esta directriz RA debe servir como una herramienta para los médicos y pacientes (nuestros dos audiencias objetivo) para las decisiones de tratamiento farmacológico en situaciones clínicas más frecuentes. Estas recomendaciones no son prescriptivos, y las decisiones de tratamiento deben ser tomadas por los médicos y los pacientes a través de un proceso de toma de decisiones compartida, teniendo en cuenta los valores de los pacientes, las preferencias y las comorbilidades. Estas recomendaciones no deben ser utilizados para limitar o no permitir el acceso a las terapias.
Síntesis amplia/ Revisión panorámica de revisiones sistemáticas
Background: We performed a systematic review, a standard meta-analysis and network meta-analysis (NMA), which updates the 2009 Cochrane Overview, 'Biologics for rheumatoid arthritis (RA)'. This review is focused on biologic monotherapy in people with RA in whom treatment with traditional disease-modifying anti-rheumatic drugs (DMARDs) including methotrexate (MTX) had failed (MTX/other DMARD-experienced). Objectives: To assess the benefits and harms of biologic monotherapy (includes anti-tumor necrosis factor (TNF) (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab) or non-TNF (abatacept, anakinra, rituximab, tocilizumab)) or tofacitinib monotherapy (oral small molecule) versus comparator (placebo or MTX/other DMARDs) in adults with RA who were MTX/other DMARD-experienced. Methods: We searched for randomized controlled trials (RCTs) in the Cochrane Central Register of Controlled Trials (CENTRAL; The Cochrane Library 2015, Issue 6, June), MEDLINE (via OVID 1946 to June 2015), and Embase (via OVID 1947 to June 2015). Article selection, data extraction and risk of bias and GRADE assessments were done in duplicate. We calculated direct estimates with 95% confidence intervals (CI) using standard meta-analysis. We used a Bayesian mixed treatment comparisons (MTC) approach for NMA estimates with 95% credible intervals (CrI). We converted odds ratios (OR) to risk ratios (RR) for ease of understanding. We calculated absolute measures as risk difference (RD) and number needed to treat for an additional beneficial outcome (NNTB). Main results: This update includes 40 new RCTs for a total of 46 RCTs, of which 41 studies with 14,049 participants provided data. The comparator was placebo in 16 RCTs (4,532 patients), MTX or other DMARD in 13 RCTs (5,602 patients), and another biologic in 12 RCTs (3,915 patients). Monotherapy versus placebo Based on moderate-quality direct evidence, biologic monotherapy (without concurrent MTX/other DMARDs) was associated with a clinically meaningful and statistically significant improvement in American College of Rheumatology score (ACR50) and physical function, as measured by the Health Assessment Questionnaire (HAQ) versus placebo. RR was 4.68 for ACR50 (95% CI, 2.93 to 7.48); absolute benefit RD 23% (95% CI, 18% to 29%); and NNTB = 5 (95% CI, 3 to 8). The mean difference (MD) was -0.32 for HAQ (95% CI, -0.42 to -0.23; a negative sign represents greater HAQ improvement); absolute benefit of -10.7% (95% CI, -14% to -7.7%); and NNTB = 4 (95% CI, 3 to 5). Direct and NMA estimates for TNF biologic, non-TNF biologic or tofacitinib monotherapy showed similar results for ACR50, downgraded to moderate-quality evidence. Direct and NMA estimates for TNF biologic, anakinra or tofacitinib monotherapy showed a similar results for HAQ versus placebo with mostly moderate quality evidence. Based on moderate-quality direct evidence, biologic monotherapy was associated with a clinically meaningful and statistically significant greater proportion of disease remission versus placebo with RR 1.12 (95% CI 1.03 to 1.22); absolute benefit 10% (95% CI, 3% to 17%; NNTB = 10 (95% CI, 8 to 21)). Based on low-quality direct evidence, results for biologic monotherapy for withdrawals due to adverse events and serious adverse events were inconclusive, with wide confidence intervals encompassing the null effect and evidence of an important increase. The direct estimate for TNF monotherapy for withdrawals due to adverse events showed a clinically meaningful and statistically significant result with RR 2.02 (95% CI, 1.08 to 3.78), absolute benefit RD 3% (95% CI,1% to 4%), based on moderate-quality evidence. The NMA estimates for TNF biologic, non-TNF biologic, anakinra, or tofacitinib monotherapy for withdrawals due to adverse events and for serious adverse events were all inconclusive and downgraded to low-quality evidence. Monotherapy versus active comparator (MTX/other DMARDs) Based on direct evidence of moderate quality, biologic monotherapy (without concurrent MTX/other DMARDs) was associated with a clinically meaningful and statistically significant improvement in ACR50 and HAQ scores versus MTX/other DMARDs with a RR of 1.54 (95% CI, 1.14 to 2.08); absolute benefit 13% (95% CI, 2% to 23%), NNTB = 7 (95% CI, 4 to 26) and a mean difference in HAQ of -0.27 (95% CI, -0.40 to -0.14); absolute benefit of -9% (95% CI, -13.3% to -4.7%), NNTB = 2 (95% CI, 2 to 4). Direct and NMA estimates for TNF monotherapy and NMA estimate for non-TNF biologic monotherapy for ACR50 showed similar results, based on moderate-quality evidence. Direct and NMA estimates for non-TNF biologic monotherapy, but not TNF monotherapy, showed similar HAQ improvements, based on mostly moderate-quality evidence. There were no statistically significant or clinically meaningful differences for direct estimates of biologic monotherapy versus active comparator for RA disease remission. NMA estimates showed a statistically significant and clinically meaningful difference versus active comparator for TNF monotherapy (absolute improvement 7% (95% CI, 2% to 14%)) and non-TNF monotherapy (absolute improvement 19% (95% CrI, 7% to 36%)), both downgraded to moderate quality. Based on moderate-quality direct evidence from a single study, radiographic progression (scale 0 to 448) was statistically significantly reduced in those on biologic monotherapy versus active comparator, MD -4.34 (95% CI, -7.56 to -1.12), though the absolute reduction was small, -0.97% (95% CI, -1.69% to -0.25%). We are not sure of the clinical relevance of this reduction. Direct and NMA evidence (downgraded to low quality), showed inconclusive results for withdrawals due to adverse events, serious adverse events and cancer, with wide confidence intervals encompassing the null effect and evidence of an important increase. Authors' conclusions: Based mostly on RCTs of six to 12-month duration in people with RA who had previously experienced and failed treatment with MTX/other DMARDs, biologic monotherapy improved ACR50, function and RA remission rates compared to placebo or MTX/other DMARDs. Radiographic progression was reduced versus active comparator, although the clinical significance was unclear. Results were inconclusive for whether biologic monotherapy was associated with an increased risk of withdrawals due to adverse events, serious adverse events or cancer, versus placebo (no data on cancer) or MTX/other DMARDs.
OBJECTIVES: Compare the benefits and harms of corticosteroids, oral and biologic disease-modifying antirheumatic drugs (DMARDs) for adults with rheumatoid arthritis.
DATA SOURCES: English-language articles from 1980 to February 2011 identified through PubMed, Embase, Cochrane Library, and International Pharmaceutical Abstracts; unpublished literature including dossiers from pharmaceutical companies.
METHODS: Two people independently selected relevant head-to-head trials of any sample size, prospective cohort studies with at least 100 participants, and relevant good- or fair-quality meta-analyses that compared benefits or harms of 14 drug therapies. Retrospective cohort studies were also included for harms. For biologic DMARDs, placebo-controlled, double-blind RCTs were also included. We required trials and cohort studies to have a study duration of at least 12 weeks. Literature was synthesized qualitatively within and between the two main drug classes (oral and biologic DMARDs). Network meta-analysis also was performed to examine the relative efficacy of biologic DMARDs and comparing withdrawal rates from placebo controlled trials.
RESULTS: Head-to-head trials showed no clinically important differences in efficacy among oral DMARD comparisons (methotrexate, sulfasalazine, leflunomide). The only head-to-head trial comparing biologic DMARDs (abatacept vs. infliximab) found no clinically important differences. Combination therapy of biologic DMARDs plus methotrexate improved clinical response rates and functional capacity more than monotherapy with methotrexate. Network meta-analyses found higher odds of reaching ACR 50 response for etanercept compared with most other biologic DMARDs (abatacept, adalimumab, anakinra, infliximab, rituximab, tocilizumab) for methotrexate-resistant patients with active rheumatoid arthritis. Similar overall tolerability profiles were found among oral and biologic DMARDs, but short-term adverse events were more common with biologic DMARDs. Adjusted indirect comparisons of biologic DMARDs found that certolizumab had the most favorable overall withdrawal profile, followed by etanercept and rituximab. Certolizumab had lower relative withdrawal rates due to lack of efficacy than adalimumab, anakinra, and infliximab. Certolizumab and infliximab had more, while etanercept had fewer withdrawals due to adverse events than most other drugs. Evidence was insufficient to assess comparative risk of serious adverse events among biologic DMARDs. Combinations of biologic DMARDs have higher rates of serious adverse events than biologic DMARD monotherapy. Limited data existed for subgroups.
CONCLUSIONS: Limited head-to-head comparative evidence does not support one therapy over another for adults with rheumatoid arthritis. Network meta-analyses from placebo-controlled trials of biologics suggest some differences, including higher odds of reaching ACR 50 response, but strength of evidence was low.
Objetivo: Comparamos sistemáticamente la eficacia, la efectividad y la seguridad (eventos adversos) de abatacept, adalimumab, alefacept, anakinra, certolizumab pegol, etanercept, golimumab, infliximab, natalizumab, rituximab, tocilizumab y ustekinumab en pacientes con artritis reumatoide juvenil idiopática Artritis, espondilitis anquilosante, artritis psoriásica, enfermedad de Crohn, colitis ulcerosa y psoriasis en placas. FUENTES DE DATOS: Para identificar los estudios publicados, se realizaron búsquedas en PubMed, EMBASE, CINAHL, Centro de Revisiones y Difusión, The Cochrane Library, y International Pharmaceutical Abstracts de 2009 (enero) a 2011 (octubre). También se realizaron búsquedas en el sitio web de la Administración de Alimentos y Medicamentos de los Estados Unidos para el sitio web de Evaluación e Investigación de Medicamentos para obtener datos adicionales no publicados, se solicitaron expedientes de información de los fabricantes farmacéuticos y se obtuvieron las citas pertinentes de las listas de referencias de los estudios incluidos. MÉTODOS DE REVISIÓN: La selección del estudio, la abstracción de los datos, la evaluación de la validez, la clasificación de la fuerza de la evidencia y la síntesis de los datos se realizaron de acuerdo con nuestros métodos de revisión estándar. RESULTADOS Y CONCLUSIÓN: En general, los moduladores inmunes dirigidos son medicamentos altamente eficaces para el tratamiento de la artritis reumatoide, la artritis idiopática juvenil, la espondilitis anquilosante, la artritis psoriásica, la enfermedad de Crohn, la colitis ulcerosa y la psoriasis en placa que mejoran sustancialmente la carga de la enfermedad y son generalmente seguros Para el tratamiento a corto plazo. Para la artritis reumatoide, las pruebas de baja y moderada fuerza indicaron que algunos moduladores inmunes dirigidos son más eficaces que otros. Estos resultados se basaron en tres ensayos de cabeza a cabeza, varios estudios observacionales grandes y comparaciones indirectas de ensayos controlados con placebo. La evidencia es actualmente insuficiente para determinar de manera fiable la eficacia comparativa de otras indicaciones y en subgrupos. Las pruebas de baja resistencia indicaron que las infecciones graves son menos frecuentes con el abatacept que las otras drogas y que la tasa de eventos adversos es mayor con infliximab que con adalimumab o etanercept. Asimismo, más pacientes que recibieron infliximab se retiraron debido a eventos adversos que abatacept, adalimumab, etanercept y golimumab. La infusión o las reacciones alérgicas contribuyeron a la diferencia en el riesgo.
OBJETIVOS: Revisar la evidencia de la eficacia y la seguridad de los agentes biológicos en pacientes con artritis reumatoide (AR) para proporcionar datos para desarrollar las recomendaciones de tratamiento por parte de la Liga Europea contra el Reumatismo (EULAR) Grupo de Tareas.
MÉTODOS: bases de datos Medline, Embase y Cochrane en busca de artículos pertinentes sobre infliximab (IFX), etanercept (ETN), adalimumab (ADA), certolizumab pegol-(CZP), golimumab (GLM), anakinra (ANA), abatacept (ABT) , rituximab (RTX) y tocilizumab (TCZ) publicados entre 1962 y febrero de 2009; Se obtuvieron los resúmenes publicados desde el 2007-2008 del Colegio Americano de Reumatología (ACR) y la conferencia EULAR.
Se identificaron 87 artículos y 40 resúmenes: RESULTADOS. En el metotrexato (MTX) pacientes no tratados previamente, la terapia biológica con IFX, ETN, ADA, GLM o ABT ha demostrado mejorar los resultados clínicos (nivel de evidencia 1B). En MTX / otras drogas sintéticas (DMARD) fallas de los nueve agentes biológicos confieren beneficios (1B), con menor eficacia que destaca por ANA modificador de la enfermedad. RTX, ABT, TCZ y GLM demuestran eficacia en inhibidores del factor de necrosis tumoral (TNFi) fracasos (1B). Existe menos evidencia para cambiar de IFX, ETN y ADA (3B). La terapia de combinación Biológica y MTX es más eficaz que un agente biológico solo (1B). Una revisión de seguridad no muestra un aumento del riesgo de malignidad en comparación con FAME convencionales (3B). TNFi generalmente están asociados con un mayor riesgo de infección bacteriana grave, sobre todo en los primeros 6 meses del inicio del tratamiento; aumento de la tuberculosis (TB) con tasas TNFi son más altos con los anticuerpos monoclonales (3B).
CONCLUSIONES: Hay buena evidencia de la eficacia de los agentes biológicos en pacientes con AR. Los datos de seguridad confirman un aumento del riesgo de infección bacteriana y TB con TNFi comparación con DMARDs convencionales.
Los moduladores inmunes dirigidos, conocidos comúnmente como modificadores de la respuesta biológica o simplemente biológicos, son una categoría relativamente nueva de medicamentos utilizados en el tratamiento de ciertos tipos de enfermedades inmunológicas e inflamatorias, incluyendo artritis reumatoide, artritis idiopática juvenil, espondilitis anquilosante, artritis psoriásica, placa Psoriasis, enfermedad de Crohn y colitis ulcerosa. La Administración de Drogas y Alimentos de los Estados Unidos aprobó el primero de los productos biológicos (infliximab) en 1998 y aprobó 9 agentes adicionales desde ese momento para tratar varias condiciones reumáticas y psoriasis en placas: etanercept (1998), anakinra (2001), adalimumab (2002), alefacept (2003), efalizumab (2003), abatacept (2005), rituximab (2006), natalizumab (2008) y certolizumab pegol (2008). En este informe, revisamos la efectividad comparativa, la seguridad y la tolerabilidad de los moduladores inmunes dirigidos.
Síntesis amplia/ Revisión panorámica de revisiones sistemáticas/ Revisión sistemática
ANTECEDENTES: Hemos tratado de comparar los beneficios y la seguridad de 6 productos biológicos (abatacept, adalimumab, anakinra, etanercept, infliximab y rituximab) en pacientes con artritis reumatoide.
MÉTODOS: En este meta-análisis de la red, se incluyeron todos completos y actualizados revisiones Cochrane sobre tratamientos biológicos para la artritis reumatoide. Se incluyeron los datos de todos los ensayos controlados con placebo que utilizaron regímenes de dosis estándar. Los principales resultados fueron los beneficios (que se define como una mejora del 50% en el paciente y el médico-reporte de los criterios del American College of Rheumatology [ACR50]) y la seguridad (determinado por el número de retiros relacionados con eventos adversos). Se utilizó efectos mixtos de regresión logística para llevar a cabo una comparación indirecta de los efectos del tratamiento entre los biológicos.
RESULTADOS: En comparación con el placebo, los agentes biológicos se asociaron con un mayor índice de importancia clínica ACR50 (odds ratio [OR] 3,35, intervalo de confianza del 95% [IC]: 2.62-4.29) y un número necesario a tratar para el beneficio de 4 (95% CI 4 -6). Sin embargo, los productos biológicos se asociaron con más retiros relacionados con eventos adversos (OR 1,39, IC 95%: 1,13 a 1,71), con un número necesario a tratar para el daño de 52 (IC 95%: 29-152). La anakinra fue menos eficaz que todos los otros productos biológicos, aunque esta diferencia fue estadísticamente significativa sólo para la comparación con adalimumab (OR 0,45, IC 95% 0,21 a 0.99) y etanercept (OR 0,34, IC 95% 0.14-0.81). El adalimumab, anakinra e infliximab tuvieron más probabilidades de etanercept para liderar a los retiros relacionados con eventos adversos (OR 1,89 adalimumab, IC 95% 1.18-3.04; anakinra OR 2,05, IC 95% 1,27-3,29, y OR infliximab 2,70, IC del 95%: 1,43 -5,26).
INTERPRETACIÓN: Dadas las limitaciones de las comparaciones indirectas, anakinra fue menos eficaz que el etanercept y adalimumab, etanercept y era más seguro que adalimumab, anakinra e infliximab. Este resumen de la prueba ayudará a los médicos ya los pacientes a tomar decisiones basadas en la evidencia sobre productos biológicos para el tratamiento de la artritis reumatoide.
This is an update of the 2009 Cochrane overview and network meta-analysis (NMA) of biologics for rheumatoid arthritis (RA).
OBJECTIVES:
To assess the benefits and harms of nine biologics (abatacept, adalimumab, anakinra, certolizumab pegol, etanercept, golimumab, infliximab, rituximab, tocilizumab) and small molecule tofacitinib, versus comparator (MTX, DMARD, placebo (PL), or a combination) in adults with rheumatoid arthritis who have failed to respond to methotrexate (MTX) or other disease-modifying anti-rheumatic drugs (DMARDs), i.e., MTX/DMARD incomplete responders (MTX/DMARD-IR).
METHODS:
We searched for randomized controlled trials (RCTs) in the Cochrane Central Register of Controlled Trials (CENTRAL) (via The Cochrane Library Issue 6, June 2015), MEDLINE (via OVID 1946 to June 2015), and EMBASE (via OVID 1947 to June 2015). Data extraction, risk of bias and GRADE assessments were done in duplicate. We calculated both direct estimates using standard meta-analysis and used Bayesian mixed treatment comparisons approach for NMA estimates to calculate odds ratios (OR) and 95% credible intervals (CrI). We converted OR to risk ratios (RR) which are reported in the abstract for the ease of interpretation.
MAIN RESULTS:
This update included 73 new RCTs for a total of 90 RCTs; 79 RCTs with 32,874 participants provided usable data. Few trials were at high risk of bias for blinding of assessors/participants (13% to 21%), selective reporting (4%) or major baseline imbalance (8%); a large number had unclear risk of bias for random sequence generation (68%) or allocation concealment (74%).Based on direct evidence of moderate quality (downgraded for inconsistency), biologic+MTX/DMARD was associated with a statistically significant and clinically meaningful improvement in ACR50 versus comparator (RR 2.71 (95% confidence interval (CI) 2.36 to 3.10); absolute benefit 24% more patients (95% CI 19% to 29%), number needed to treat for an additional beneficial outcome (NNTB) = 5 (4 to 6). NMA estimates for ACR50 in tumor necrosis factor (TNF) biologic+MTX/DMARD (RR 3.23 (95% credible interval (Crl) 2.75 to 3.79), non-TNF biologic+MTX/DMARD (RR 2.99; 95% Crl 2.36 to 3.74), and anakinra + MTX/DMARD (RR 2.37 (95% Crl 1.00 to 4.70) were similar to the direct estimates.Based on direct evidence of moderate quality (downgraded for inconsistency), biologic+MTX/DMARD was associated with a clinically and statistically important improvement in function measured by the Health Assessment Questionnaire (0 to 3 scale, higher = worse function) with a mean difference (MD) based on direct evidence of -0.25 (95% CI -0.28 to -0.22); absolute benefit of -8.3% (95% CI -9.3% to -7.3%), NNTB = 3 (95% CI 2 to 4). NMA estimates for TNF biologic+MTX/DMARD (absolute benefit, -10.3% (95% Crl -14% to -6.7%) and non-TNF biologic+MTX/DMARD (absolute benefit, -7.3% (95% Crl -13.6% to -0.67%) were similar to respective direct estimates.Based on direct evidence of moderate quality (downgraded for inconsistency), biologic+MTX/DMARD was associated with clinically and statistically significantly greater proportion of participants achieving remission in RA (defined by disease activity score DAS < 1.6 or DAS28 < 2.6) versus comparator (RR 2.81 (95% CI, 2.23 to 3.53); absolute benefit 18% more patients (95% CI 12% to 25%), NNTB = 6 (4 to 9)). NMA estimates for TNF biologic+MTX/DMARD (absolute improvement 17% (95% Crl 11% to 23%)) and non-TNF biologic+MTX/DMARD (absolute improvement 19% (95% Crl 12% to 28%) were similar to respective direct estimates.Based on direct evidence of moderate quality (downgraded for inconsistency), radiographic progression (scale 0 to 448) was statistically significantly reduced in those on biologics + MTX/DMARDs versus comparator, MD -2.61 (95% CI -4.08 to -1.14). The absolute reduction was small, -0.58% (95% CI -0.91% to -0.25%) and we are unsure of the clinical relevance of this reduction. NMA estimates of TNF biologic+MTX/DMARD (absolute reduction -0.67% (95% Crl -1.4% to -0.12%) and non-TNF biologic+MTX/DMARD (absolute reduction, -0.68% (95% Crl -2.36% to 0.92%)) were similar to respective direct estimates.Based on direct evidence of moderate quality (downgraded for imprecision), results for withdrawals due to adverse events were inconclusive, with wide confidence intervals encompassing the null effect and evidence of an important increase in withdrawals, RR 1.11 (95% CI 0.96 to 1.30). The NMA estimates of TNF biologic+MTX/DMARD (RR 1.24 (95% Crl 0.99 to 1.57)) and non-TNF biologic+MTX/DMARD (RR 1.20 (95% Crl 0.87 to 1.67)) were similarly inconclusive and downgraded to low for both imprecision and indirectness.Based on direct evidence of high quality, biologic+MTX/DMARD was associated with clinically significantly increased risk (statistically borderline significant) of serious adverse events on biologic+MTX/DMARD (Peto OR [can be interpreted as RR due to low event rate] 1.12 (95% CI 0.99 to 1.27); absolute risk 1% (0% to 2%), As well, the NMA estimate for TNF biologic+MTX/DMARD (Peto OR 1.20 (95% Crl 1.01 to 1.43)) showed moderate quality evidence of an increase in the risk of serious adverse events. The other two NMA estimates were downgraded to low quality due to imprecision and indirectness and had wide confidence intervals resulting in uncertainty around the estimates: non-TNF biologics +
MTX/DMARD:
1.07 (95% Crl 0.89 to 1.29) and anakinra: RR 1.06 (95% Crl 0.65 to 1.75).Based on direct evidence of low quality (downgraded for serious imprecision), results were inconclusive for cancer (Peto OR 1.07 (95% CI 0.68 to 1.68) for all biologic+MTX/DMARD combinations. The NMA estimates of TNF biologic+MTX/DMARD (Peto OR 1.21 (95% Crl 0.63 to 2.38) and non-TNF biologic+MTX/DMARD (Peto OR 0.99 (95% Crl 0.58 to 1.78)) were similarly inconclusive and downgraded to low quality for both imprecision and indirectness.Main results text shows the results for tofacitinib and differences between medications.
AUTHORS' CONCLUSIONS:
Based primarily on RCTs of 6 months' to 12 months' duration, there is moderate quality evidence that the use of biologic+MTX/DMARD in people with rheumatoid arthritis who have failed to respond to MTX or other DMARDs results in clinically important improvement in function and higher ACR50 and remission rates, and increased risk of serious adverse events than the comparator (MTX/DMARD/PL; high quality evidence). Radiographic progression is slowed but its clinical relevance is uncertain. Results were inconclusive for whether biologics + MTX/DMARDs are associated with an increased risk of cancer or withdrawals due to adverse events.
Síntesis amplia»Revisión panorámica de revisiones sistemáticas
