Objective: To evaluate the comparative efficacy and safety of Janus kinase (JAK) inhibitors and biological disease-modifying antirheumatic drugs (bDMARDs) in patients with rheumatoid arthritis (RA) and an inadequate response to at least one disease-modifying antirheumatic drug (DMARD). Methods: PubMed, Embase, Cochrane library and ClinicalTrials.gov were searched for relevant randomized controlled trials (RCTs) from inception to April 2020. The active drugs included three JAK inhibitors and eight bDMARDs while the control drugs included placebo or conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). Outcomes include American College of Rheumatology 20% response (ACR20), Disease Activity Score in 28 joints (DAS28), Health Assessment Questionnaire–Disability Index (HAQ-DI) and discontinuations for adverse events (AEs). We estimated summary odds ratios (ORs) and weighted mean differences (WMDs) using network meta-analysis with random effects. Results: Eighty-eight RCTs with 31,566 patients were included. All JAK inhibitors and bDMARDs were more effective than placebo in ACR20 (ORs ranging between 3.05 and 5.61), DAS28 (WMDs ranging between −1.91 and −0.80) and HAQ-DI (WMDs ranging between −0.34 and −0.21). Tocilizumab, certolizumab pegol and upadacitinib showed relatively good efficacy in these three outcomes according to their relative ranking. Notably, tocilizumab was more effective than other active drugs in DAS28 (WMDs ranging between −1.11 and −0.49). Compared with the lower recommended doses, increasing the doses of JAK inhibitors (baricitinib 4 mg versus 2 mg, tofacitinib 10 mg versus 5 mg and upadacitinib 30 mg versus 15 mg) cannot provide significant additional benefits. In terms of discontinuations for AEs, all active drugs showed no significant difference compared with placebo except certolizumab pegol [OR 1.65, 95% credible interval (CrI) 1.06–2.61] and rituximab (3.17, 1.11–10.80). Conclusions: Tocilizumab, certolizumab pegol and upadacitinib may have relatively good efficacy in patients with RA after treatment failure with csDMARDs. RA patients taking a JAK inhibitor may have a preference for a lower recommended dose.
OBJETIVOS: Determinar las posibles diferencias en los efectos adversos graves entre los 10 DMARD sintéticos biológicos y específicos (b / ts-DMARDs) actualmente aprobados para la AR. MÉTODOS: Revisión sistemática en bases de datos bibliográficas, registros de ensayos y sitios web de agencias reguladoras identificaron ensayos aleatorios de b / ts-DMARDs aprobados para RA. Se realizaron metanálisis de redes utilizando modelos de regresión de Poisson de efectos mixtos para calcular las proporciones de tasas de eventos adversos graves (SAE) y fallecimientos entre cada uno de los 10 fármacos y el control (es decir, ningún tratamiento b / ts-DMARD), basados en sujetos experimentando una Evento en relación a persona-años. La confianza en las estimaciones se evaluó aplicando el enfoque de evaluación, desarrollo y evaluación de calificaciones (GRADE). Resultados Se incluyó un total de 117 ensayos (47 615 pacientes). Los EAE fueron más frecuentes con el certolizumab en comparación con el abatacept (proporción de la tasa = 1,58, IC del 95%: 1,18, 2,14), adalimumab (1,36, IC del 95%: 1,02, 1,81), etanercept (1,60, IC del 95%: 1,18, 2,17) Golimumab (1,45, IC del 95%: 1,00, 2,08), rituximab (1,63, IC del 95%: 1,16, 2,30), tofacitinib (1,44; IC del 95%: 1,03; 2,02) y control (1,45; IC del 95%: 1,13; ); Y tocilizumab en comparación con abatacept (1,30, IC del 95%: 1,03, 1,65), etanercept (1,31; IC del 95%: 1,04; 1,67) y rituximab (1,34, IC del 95%: 1,01; 1,78). Ninguna otra comparación fue estadísticamente significativa. La contabilidad de la duración del estudio confirmó nuestras conclusiones para un tratamiento de hasta 6 meses, pero no para el tratamiento a largo plazo (6-24 meses). No se encontraron diferencias en la mortalidad entre b / ts-DMARDs y control. Basándose en el enfoque de GRADE, la confianza en las estimaciones fue baja debido a la ausencia de ensayos de comparación directa e imprecisión en estimaciones indirectas. CONCLUSIÓN: A pesar de la baja confianza en las estimaciones, nuestro análisis encontró diferencias potenciales en las tasas de SAEs. Nuestros datos sugieren que se debe tener precaución al decidir entre los fármacos disponibles. NÚMERO DE REGISTRO DE LA REVISIÓN SISTEMÁTICA: PROSPERO CRD42014014842.
BACKGROUND: Methotrexate is considered the preferred disease-modifying anti-rheumatic drug (DMARD) for the treatment of rheumatoid arthritis, but controversy exists on the additional benefits and harms of combining methotrexate with other DMARDs.
OBJECTIVES: To compare methotrexate and methotrexate-based DMARD combinations for rheumatoid arthritis in patients naïve to or with an inadequate response (IR) to methotrexate.
METHODS: We systematically identified all randomised controlled trials with methotrexate monotherapy or in combination with any currently used conventional synthetic DMARD , biologic DMARDs, or tofacitinib. Three major outcomes (ACR50 response, radiographic progression and withdrawals due to adverse events) and multiple minor outcomes were evaluated. Treatment effects were summarized using Bayesian random-effects network meta-analyses, separately for methotrexate-naïve and methotrexate-IR trials. Heterogeneity was explored through meta-regression and subgroup analyses. The risk of bias of each trial was assessed using the Cochrane risk of bias tool, and trials at high risk of bias were excluded from the main analysis. The quality of evidence was evaluated using the GRADE approach. A comparison between two treatments was considered statistically significant if its credible interval excluded the null effect, indicating >97.5% probability that one treatment was superior.
MAIN RESULTS: 158 trials with over 37,000 patients were included. Methotrexate-naïve: Several treatment combinations with methotrexate were statistically superior to oral methotrexate for ACR50 response: methotrexate + sulfasalazine + hydroxychloroquine (“triple therapy”), methotrexate + several biologics (abatacept, adalimumab, etanercept, infliximab, rituximab, tocilizumab), and tofacitinib. The estimated probability of ACR50 response was similar between these treatments (range 56-67%, moderate to high quality evidence), compared with 41% for methotrexate. Methotrexate combined with adalimumab, etanercept, certolizumab, or infliximab was statistically superior to oral methotrexate for inhibiting radiographic progression (moderate to high quality evidence) but the estimated mean change over one year with all treatments was less than the minimal clinically important difference of five units on the Sharp-van der Heijde scale. Methotrexate + azathioprine had statistically more withdrawals due to adverse events than oral methotrexate, and triple therapy had statistically fewer withdrawals due to adverse events than methotrexate + infliximab (rate ratio 0.26, 95% credible interval: 0.06 to 0.91). Methotrexate-inadequate response: In patients with an inadequate response to methotrexate, several treatments were statistically significantly superior to oral methotrexate for ACR50 response: triple therapy (moderate quality evidence), methotrexate + hydroxychloroquine (low quality evidence), methotrexate + leflunomide (moderate quality evidence), methotrexate + intramuscular gold (very low quality evidence), methotrexate + most biologics (moderate to high quality evidence), and methotrexate + tofacitinib (high quality evidence). There was a 61% probability of an ACR50 response with triple therapy, compared to a range of 27% to 64% for the combinations of methotrexate + biologic DMARDs that were statistically significantly superior to oral methotrexate. No treatment was statistically significantly superior to oral methotrexate for inhibiting radiographic progression. Methotrexate + cyclosporine and methotrexate + tocilizumab (8 mg/kg) had a statistically higher rate of withdrawals due to adverse events than oral methotrexate and methotrexate + abatacept had a statistically lower rate of withdrawals due to adverse events than several treatments.
AUTHORS' CONCLUSIONS: We found moderate to high quality evidence that combination therapy with methotrexate + sulfasalazine+ hydroxychloroquine (triple therapy) or methotrexate + most biologic DMARDs or tofacitinib were similarly effective in controlling disease activity and generally well tolerated in methotrexate-naïve patients or after an inadequate response to methotrexate. Methotrexate + some biologic DMARDs were superior to methotrexate in preventing joint damage in methotrexate-naïve patients, but the magnitude of these effects was small over one year.
OBJECTIVE: To compare methotrexate based disease modifying antirheumatic drug (DMARD) treatments for rheumatoid arthritis in patients naive to or with an inadequate response to methotrexate.
DESIGN: Systematic review and Bayesian random effects network meta-analysis of trials assessing methotrexate used alone or in combination with other conventional synthetic DMARDs, biologic drugs, or tofacitinib in adult patients with rheumatoid arthritis.
DATA SOURCES: Trials were identified from Medline, Embase, and Central databases from inception to 19 January 2016; abstracts from two major rheumatology meetings from 2009 to 2015; two trial registers; and hand searches of Cochrane reviews.
STUDY SELECTION CRITERIA: Randomized or quasi-randomized trials that compared methotrexate with any other DMARD or combination of DMARDs and contributed to the network of evidence between the treatments of interest.
MAIN OUTCOMES: American College of Rheumatology (ACR) 50 response (major clinical improvement), radiographic progression, and withdrawals due to adverse events. A comparison between two treatments was considered statistically significant if its credible interval excluded the null effect, indicating >97.5% probability that one treatment was superior.
RESULTS: 158 trials were included, with between 10 and 53 trials available for each outcome. In methotrexate naive patients, several treatments were statistically superior to oral methotrexate for ACR50 response: sulfasalazine and hydroxychloroquine ("triple therapy"), several biologics (abatacept, adalimumab, etanercept, infliximab, rituximab, tocilizumab), and tofacitinib. The estimated probability of ACR50 response was similar between these treatments (range 56-67%), compared with 41% with methotrexate. Methotrexate combined with adalimumab, etanercept, certolizumab, or infliximab was statistically superior to oral methotrexate for inhibiting radiographic progression, but the estimated mean change over one year with all treatments was less than the minimal clinically important difference of 5 units on the Sharp-van der Heijde scale. Triple therapy had statistically fewer withdrawals due to adverse events than methotrexate plus infliximab. After an inadequate response to methotrexate, several treatments were statistically superior to oral methotrexate for ACR50 response: triple therapy, methotrexate plus hydroxychloroquine, methotrexate plus leflunomide, methotrexate plus intramuscular gold, methotrexate plus most biologics, and methotrexate plus tofacitinib. The probability of response was 61% with triple therapy and ranged widely (27-70%) with other treatments. No treatment was statistically superior to oral methotrexate for inhibiting radiographic progression. Methotrexate plus abatacept had a statistically lower rate of withdrawals due to adverse events than several treatments.
CONCLUSIONS: Triple therapy (methotrexate plus sulfasalazine plus hydroxychloroquine) and most regimens combining biologic DMARDs with methotrexate were effective in controlling disease activity, and all were generally well tolerated in both methotrexate naive and methotrexate exposed patients.
ANTECEDENTES: fármacos antirreumáticos modificadores de la enfermedad biológicos (MBE) amplían las opciones de tratamiento para los pacientes con artritis reumatoide con respuesta subóptima o intolerancia a FAME convencionales. El objetivo de esta revisión sistemática y meta-análisis fue comparar la eficacia relativa de la terapia de combinación MBE con licencia de la UE o en monoterapia para pacientes con intolerancia o contraindicados a la continua metotrexato.
Métodos, búsquedas bibliográficas exhaustivas estructuradas se llevaron a cabo en Medline, Embase y la Cochrane Library, así como búsquedas manuales de actas de congresos y listas de referencias. Fase II o III ensayos controlados aleatorios que informaron Colegio Americano de Reumatología (ACR) anota criterios de 20, 50, y el seguimiento de 70 entre 12 y 30 semanas y se matriculan pacientes adultos que cumplían los criterios de clasificación del ACR para la artritis reumatoide tratados previamente con y con una respuesta inadecuada a FAME convencionales fueron elegibles. Para estimar la eficacia relativa de los tratamientos, mientras que la preservación de las comparaciones aleatorias dentro de cada ensayo, se llevó a cabo una red bayesiana metaanálisis en WinBUGS utilizando fijos y de efectos aleatorios, modelos logit de enlace instalados en los ACR 20/50/70 datos de ensayos binomiales.
Resultados: La revisión sistemática identificó 10.625 citas, y después de una revisión de 2.450 documentos en texto completo, había 29 y 14 estudios elegibles para la combinación y la monoterapia metanálisis, respectivamente. En el análisis combinación, todas las combinaciones de MBE con licencia tenían probabilidades significativamente mayores de ACR 20/50/70 en comparación con DMARDs solo, excepto para la comparación rituximab, que no alcanzó significación para el resultado ACR 70 (basado en el intervalo de credibilidad 95%) . La combinación etanercept fue significativamente mejor que la de necrosis tumoral inhibidores del factor-α adalimumab e infliximab en la mejora de ACR 20/50/70 resultados, sin diferencias significativas entre la combinación etanercept y certolizumab pegol o tocilizumab. Etanercept dosis licencia, adalimumab, y la monoterapia con tocilizumab fueron significativamente mejores que el placebo en la mejora de ACR 20/50/70 resultados. El análisis de sensibilidad indica que la inclusión de los estudios fuera de la población objetivo podrían afectar los resultados.
CONCLUSIÓN: Licenciado MBE son eficaces en pacientes con una respuesta inadecuada a la terapia convencional, pero las terapias de combinación inhibidor de factor de necrosis tumoral-α no son igualmente efectivos.
Objective: To evaluate the comparative efficacy and safety of Janus kinase (JAK) inhibitors and biological disease-modifying antirheumatic drugs (bDMARDs) in patients with rheumatoid arthritis (RA) and an inadequate response to at least one disease-modifying antirheumatic drug (DMARD). Methods: PubMed, Embase, Cochrane library and ClinicalTrials.gov were searched for relevant randomized controlled trials (RCTs) from inception to April 2020. The active drugs included three JAK inhibitors and eight bDMARDs while the control drugs included placebo or conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). Outcomes include American College of Rheumatology 20% response (ACR20), Disease Activity Score in 28 joints (DAS28), Health Assessment Questionnaire–Disability Index (HAQ-DI) and discontinuations for adverse events (AEs). We estimated summary odds ratios (ORs) and weighted mean differences (WMDs) using network meta-analysis with random effects. Results: Eighty-eight RCTs with 31,566 patients were included. All JAK inhibitors and bDMARDs were more effective than placebo in ACR20 (ORs ranging between 3.05 and 5.61), DAS28 (WMDs ranging between −1.91 and −0.80) and HAQ-DI (WMDs ranging between −0.34 and −0.21). Tocilizumab, certolizumab pegol and upadacitinib showed relatively good efficacy in these three outcomes according to their relative ranking. Notably, tocilizumab was more effective than other active drugs in DAS28 (WMDs ranging between −1.11 and −0.49). Compared with the lower recommended doses, increasing the doses of JAK inhibitors (baricitinib 4 mg versus 2 mg, tofacitinib 10 mg versus 5 mg and upadacitinib 30 mg versus 15 mg) cannot provide significant additional benefits. In terms of discontinuations for AEs, all active drugs showed no significant difference compared with placebo except certolizumab pegol [OR 1.65, 95% credible interval (CrI) 1.06–2.61] and rituximab (3.17, 1.11–10.80). Conclusions: Tocilizumab, certolizumab pegol and upadacitinib may have relatively good efficacy in patients with RA after treatment failure with csDMARDs. RA patients taking a JAK inhibitor may have a preference for a lower recommended dose.
Pregunta de la revisión sistemática»Revisión sistemática de intervenciones
