Objective. To compare the efficacy and tolerability of tofacitinib, an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA), as monotherapy and combined with disease-modifying antirheumatic drugs (DMARDs) versus biological DMARDs (bDMARDs) and other novel DMARDs for second-line moderate-to-severe rheumatoid arthritis (RA) patients by means of a systematic literature review (SLR) and network meta-analysis (NMA). Methods. MEDLINE®, EMBASE®, and Cochrane Central Register of Controlled Trials were searched to identify randomized clinical trials (RCTs) published between 1990 and March 2015. Efficacy data based on American College of Rheumatology (ACR) response criteria, improvements in the Health Assessment Questionnaire Disability Index (HAQ-DI) at 6 months, and discontinuation rates due to adverse events were analyzed by means of Bayesian NMAs. Results. 45 RCTs were identified, the majority of which demonstrated a low risk of bias. Tofacitinib 5 mg twice daily (BID) and 10 mg BID monotherapy exhibited comparable efficacy and discontinuation rates due to adverse events versus other monotherapies. Tofacitinib 5 mg BID and 10 mg BID + DMARDs or methotrexate (MTX) were mostly comparable to other combination therapies in terms of efficacy and discontinuation due to adverse events. Conclusion. In most cases, tofacitinib had similar efficacy and discontinuation rates due to adverse events compared to biologic DMARDs.
Nuestro objetivo fue establecer la eficacia comparativa de la artritis reumatoide (AR) biológicos, utilizando una revisión sistemática y de la red meta-análisis. La revisión sistemática utilizó ensayos controlados aleatorios (ECA) en adultos con AR que fracasaron en el tratamiento con agentes modificadores de enfermedades convencionales para la enfermedad reumatoide (cDMARDs). Se comparó la eficacia de abatacept, adalimumab, etanercept, infliximab, certolizumab pegol, golimumab y rituximab tocilizumab, un biológico reciente con un mecanismo de acción diferente (receptor anti-IL-6). Un meta-análisis de red (NMA) incluyó la evidencia indirecta y directa previamente seleccionada. En total, se incluyeron 207 artículos que describieron 68 ECA. La NMA demostró que el tocilizumab en monoterapia era superior al tratamiento estándar (ACR20, OR 13,27, IC95% [3,958, 43,98], ACR50, 17,45 [10,18, 31,24], ACR70, 37,77 [7,226, 216,3], EULAR 10,42 [ 54,8]); Y metotrexato (MTX, ACR50, OR 5.44 [4.142, 7.238], ACR70, 7.364 [1.4, 30.83], EULAR, 4.226 [1.184, 15.58]) a las 26 semanas. Del mismo modo, la combinación de tocilizumab + MTX fue significativamente mejor que el tratamiento estándar / placebo y MTX solo para ACR20, ACR50, ACR70 y EULAR a las 26 semanas (OR 18.63 [5.32, 66.81], 24.27 [14.5, 41.91], 46.13 [10.08 , 277], 14.23 [2.493, 84.02], 4.169 [2.267, 7.871], 5.44 [4.142, 7.238], 8.731 [4.203, 19.29], 7.306 [4.393, 13.04], respectivamente). A las 52 semanas, en comparación con MTX solo, tocilizumab + MTX fue significativamente mejor para ACR20 y ACR50 respuesta. Se encontraron pocas diferencias significativas entre tocilizumab (solo o en combinación) y cualquier otro biológico. Los resultados deben ser considerados en contexto con las limitaciones de la evidencia disponible. Esta NMA sugiere que tocilizumab fue superior a cDMARDs y tan eficaz como otros biológicos para la AR.
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: tofacitinib es un inhibidor oral quinasa Janus para el tratamiento de la artritis reumatoide (RA). Tofacitinib modula la señalización de citoquinas que son esenciales para la activación de linfocitos, proliferación y función. Así, la terapia tofacitinib puede resultar en la supresión de varios elementos de la respuesta inmune. Las infecciones graves han sido reportados en los ensayos tofacitinib con AR. Sin embargo, estaban disponibles dentro del programa de desarrollo de tofacitinib RA para comparar directamente las tasas de infecciones graves con tofacitinib en relación con agentes biológicos limitados datos de comparación de cabeza a cabeza, y, específicamente, adalimumab (empleado como un agente de control activo en dos ensayos controlados aleatorios de tofacitinib controlado) .
MÉTODOS: Una búsqueda bibliográfica sistemática de datos de ensayos controlados aleatorios de intervención y los estudios de extensión a largo plazo con fármacos biológicos en la AR se llevó a cabo. Informes preferido Elementos para una revisión sistemática y meta-análisis (PRISMA) consenso se siguió para informar de los resultados de la revisión y meta-análisis. Se estimaron las tasas de incidencia (pacientes únicos con eventos / 100 pacientes-año) para cada terapia basada en datos de ensayos controlados aleatorios y estudios de extensión a largo plazo utilizando un modelo de efectos aleatorios. comparaciones de riesgos relativos y absolutos versus placebo utilizan métodos de Mantel-Haenszel.
RESULTADOS: La búsqueda produjo 657 golpes. En total, 66 ensayos controlados aleatorios y 22 estudios de extensión a largo plazo cumplen los criterios de selección. inhibidores del factor de tasas estimadas de incidencia (95% intervalo de confianza [IC]) para abatacept, rituximab, tocilizumab, y la necrosis del tumor eran 3,04 (2,49, 3,72), 3,72 (2,99, 4,62), 5,45 (4,26, 6,96), y 4,90 (4,41 , 5,44), respectivamente. Las tasas de incidencia (95% IC) para tofacitinib 5 y 10 mg dos veces al día (BID) en ensayos de fase 3 fueron 3,02 (2,25, 4,05) y 3,00 (2,24, 4,02), respectivamente. Las tasas de incidencia correspondientes en los estudios de extensión a largo plazo fueron 2,50 (2,05, 3,04) y 3,19 (2,74, 3,72). Los cocientes de riesgos (IC del 95%) versus placebo para tofacitinib 5 y 10 mg dos veces fueron 2,21 (0,60, 8,14) y 2,02 (0,56, 7,28), respectivamente. diferencias de riesgo (IC del 95%) versus placebo para tofacitinib 5 y 10 mg BID fueron 0,38% (-0,24%, 0,99%) y 0,40% (-0,22%, 1,02%), respectivamente.
Conclusiones: En los estudios de intervención, el riesgo de infecciones graves con tofacitinib es comparable a las tasas publicadas para los fármacos antirreumáticos modificadores de la enfermedad biológicos en pacientes con AR moderada a severamente activa.
Objective. To compare the efficacy and tolerability of tofacitinib, an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA), as monotherapy and combined with disease-modifying antirheumatic drugs (DMARDs) versus biological DMARDs (bDMARDs) and other novel DMARDs for second-line moderate-to-severe rheumatoid arthritis (RA) patients by means of a systematic literature review (SLR) and network meta-analysis (NMA). Methods. MEDLINE®, EMBASE®, and Cochrane Central Register of Controlled Trials were searched to identify randomized clinical trials (RCTs) published between 1990 and March 2015. Efficacy data based on American College of Rheumatology (ACR) response criteria, improvements in the Health Assessment Questionnaire Disability Index (HAQ-DI) at 6 months, and discontinuation rates due to adverse events were analyzed by means of Bayesian NMAs. Results. 45 RCTs were identified, the majority of which demonstrated a low risk of bias. Tofacitinib 5 mg twice daily (BID) and 10 mg BID monotherapy exhibited comparable efficacy and discontinuation rates due to adverse events versus other monotherapies. Tofacitinib 5 mg BID and 10 mg BID + DMARDs or methotrexate (MTX) were mostly comparable to other combination therapies in terms of efficacy and discontinuation due to adverse events. Conclusion. In most cases, tofacitinib had similar efficacy and discontinuation rates due to adverse events compared to biologic DMARDs.
