OBJECTIVE: This systematic search and review aimed to evaluate the available literature on discontinuation of adalimumab and other tumor necrosis factor inhibitors (TNFi) for patients with well-controlled chronic inflammatory arthritides.
METHODS: We conducted a publication search on adalimumab discontinuation from 2000-2023 using PubMed, CINAHL, EMBASE, and Cochrane Library. Included studies evaluated adalimumab discontinuation approaches, tapering schemes, and outcomes including successful discontinuation and recapture after flare, in patients with well-controlled disease. Studies included evaluated rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and juvenile idiopathic arthritis (JIA).
RESULTS: Forty-nine studies were included. Studies evaluating adalimumab alone were limited, and many reported TNFi outcomes as a single entity. Studies on rheumatoid arthritis (RA) (32, 8 RCTs) reported flare rates from 33-87%. Flares with medication tapering were slightly lower than with abrupt stop, and successful recapture was generally high (80-100%). Studies on spondyloarthropathy (12, 4 RCTs), focused on tapering, noting lower flare rates in tapering rather than abruptly stopping, and high recapture rates (~ 90%). Studies on JIA (5) were observational and demonstrated modestly lower flare rates with tapering (17-63%) versus abrupt stopping (28-82%). There was notable variability in study design, follow-up duration, specificity for TNFi results, and controlled pediatric studies.
CONCLUSION: The literature evaluating adalimumab and other TNFi discontinuation, flare rates, and recapture success within the inflammatory arthritis population demonstrated less flare when medications were tapered, over abrupt stop in the RA, spondyloarthropathy, and JIA populations. When medications were restarted after flare, recapture of well-controlled disease was generally high in RA and spondyloarthropathy, and generally favorable in JIA.
OBJECTIVE: To evaluate flare risk when tapering or withdrawing biological or targeted synthetic disease-modifying antirheumatic drugs (b-/tsDMARDs) compared to continuation in patients with inflammatory arthritis (IA) in sustained remission or low disease activity.
METHODS: Articles were identified in Cochrane Library, PubMed, EMBASE and Web of Science. Eligible trials were randomised, controlled trials comparing tapering and/or withdrawal of b- and/or tsDMARDs with standard dose in IA. Random-effects meta-analysis was performed with risk ratio (RR), or Peto's Odds Ratio (POR) for sparse events, and 95% confidence intervals (95%CI).
RESULTS: The meta-analysis comprised 22 trials: 11 assessed tapering and 7 addressed withdrawal (4 assessed both). Only trials with a rheumatoid arthritis (RA) or axial spondyloarthritis (axSpA) population were identified. An increased flare risk was demonstrated when b-/tsDMARD tapering was compared to continuation, RR = 1.45 (95%CI: 1.19 to 1.77, I2 = 42.5%), and potentially increased for persistent flare, POR = 1.56 (95%CI: 0.97 to 2.52, I2 = 0%). Comparing tumour necrosis factor inhibitor (TNFi) withdrawal to continuation, a highly increased flare risk (RR = 2.28, 95%CI: 1.78 to 2.93, I2 = 78%) and increased odds of persistent flare (POR = 3.41, 95%CI: 1.91 to 6.09, I2 = 49%) was observed. No clear difference in flare risk between RA or axSpA was observed.
CONCLUSION: A high risk for flare and persistent flare was demonstrated for TNFi withdrawal whereas an increased risk for flare but not for persistent flare was observed for b-/tsDMARD tapering. Thus, tapering seems to be the more favourable approach.
REGISTRATION: PROSPERO (CRD42019136905).
INTRODUCTION: Synthesis of evidence on the long-term use of first-line biologic therapy in patients with early rheumatoid arthritis (RA) is required. We compared the efficacy of up to 5 years' treatment with first-line tumor necrosis factor inhibitors (TNFis) versus other treatment strategies in this population.
METHODS: Previous systematic reviews, PubMed and the Cochrane Central Register of Controlled Trials were searched for randomized controlled trials (RCTs) involving treatment of methotrexate-naïve RA patients with first-line TNFis. Literature was synthesized qualitatively, and a meta-analysis conducted to evaluate American College of Rheumatology (ACR) responses, clinical remission defined by any standard measure, and Health Assessment Questionnaire Disability Index (HAQ) at Years 2 and/or 5.
RESULTS: Ten RCTs involving 4306 patients [first-line TNFi, n = 2234; other treatment strategies (control), n = 2072] were included in the meta-analysis. Three studies were double-blind for the first 2 years, while seven were partly/completely open label during this period. Five studies reported data at Year 5; all were open label at this time point. At Year 2, ACR50 response, ACR70 response and remission rates were significantly improved with first-line TNFi versus control in double-blind RCTs [log-odds ratio (OR) 0.32 [95% confidence interval (CI) 0.02, 0.62; p = 0.035], log-OR 0.48 (95% CI 0.20, 0.77; p = 0.001), and log-OR 0.44 (95% CI 0.13, 0.74; p = 0.005), respectively], but not in open-label studies. No significant between-group differences were observed in mean HAQ at Year 2 in double-blind or open-label RCTs or in ACR response or remission outcomes at Year 5.
CONCLUSION: In double-blind studies, 2-year efficacy outcomes were significantly improved with first-line TNFi versus other treatment strategies in patients with MTX-naïve RA. No significant differences in these outcomes were observed when data from open-label RCTs were considered on their own. Further data on the efficacy of TNFi therapy over ≥ 2 years in patients with methotrexate-naïve RA are required. Plain language summary available for this article.
OBJECTIVES: Compare the benefits and harms of drug therapies for adults with early rheumatoid arthritis (RA) within 1 year of diagnosis, updating the findings on early RA from the 2012 review.
DATA SOURCES: English-language articles identified through MEDLINE®, Cochrane Library, Embase®, International Pharmaceutical Abstracts, gray literature, the previous 2012 review, expert recommendations, reference lists of published literature, and supplemental evidence data requests from January 2011 to October 5, 2017.
REVIEW METHODS: Literature was synthesized qualitatively in narrative form and summary tables within and between corticosteroids and classes of disease-modifying antirheumatic drugs (DMARDs). Additionally, combination treatment strategies were examined. We conducted network meta-analysis for five outcomes: American College of Rheumatology 50-percent improvement (ACR50), remission based on Disease Activity Score (DAS), radiographic joint damage, all discontinuations, and discontinuations due to adverse events. Eligibility for network meta-analyses required the following: (1) patients with early RA had not attempted prior treatment with methotrexate (MTX), (2) doses of treatments were within ranges approved by the Food and Drug Administration (FDA), (3) length of followup was similar, and (4) studies were double-blinded randomized controlled trials of low or medium risk of bias.
RESULTS: We analyzed 49 studies: 41 RCTs and 8 observational studies reported in 124 published articles. All included studies enrolled patients with moderate to high disease activity at baseline as measured with mean or median DAS 28 scores. A combination of corticosteroids plus MTX achieved higher remission rates than with MTX monotherapy (low strength of evidence [SOE]). Combination therapy with TNF (tumor necrosis factor) or non-TNF biologics plus MTX improved disease control, remission, and functional capacity compared with monotherapy with either MTX or a biologic (low to moderate SOE). Network meta-analyses found higher ACR50 response for combination therapy of biologics plus MTX than for MTX monotherapy (range of relative risk, 1.20 [95% confidence interval (CI), 1.04 to 1.38] to 1.57 [95% CI, 1.30 to 1.88]). In available data, consisting mostly of clinical trials, no significant differences emerged between any DMARDs for rates of discontinuation attributable to adverse events or serious adverse events (low SOE for adalimumab, certolizumab pegol, etanercept, infliximab, or abatacept with MTX, and moderate SOE for rituximab or tocilizumab with MTX). Data about subgroups (based on disease activity, prior therapy, demographics, and the presence of other serious conditions) were insufficient. No difference in findings were noted in MTX naïve and resistant populations. We found no studies of biosimilars for patients with early RA.
CONCLUSIONS: Qualitative synthesis and network meta-analyses suggest that the combination of MTX with TNF or non-TNF biologics improves disease activity and remission when compared with biologic monotherapy or a conventional synthetic DMARD (csDMARD) monotherapy in patients with moderate to high disease activity at baseline as measured with mean or median DAS 28 scores. Overall rates of adverse events and discontinuation were similar among patients given csDMARDs, TNF biologics, and non-TNF biologics. We did not find eligible studies of biosimilars.
OBJECTIVES: To assess the risk of losing remission, low disease activity (LDA) or radiographic progression in the case of (1) discontinuing or (2) tapering doses of biological disease-modifying antirheumatic drugs (bDMARDs) compared with continuation of the initial treatment regimen in rheumatoid arthritis (RA) patients with remission or LDA.
MATERIALS AND METHODS: A systematic literature analysis was carried out through May 2017 on the PubMed, Embase, Cochrane and international congress databases, selecting controlled trials comparing bDMARDs discontinuation/tapering versus continuation in RA patients with remission or LDA. The meta-analysis assessed the risk ratio (RR) and 95% CI of losing remission or LDA and the risk of radiographic progression after (1) discontinuing and (2) tapering doses of bDMARDs versus continuing the initial treatment.
RESULTS: The meta-analysis comparing bDMARDs discontinuation versus continuation performed on nine trials showed an increased risk of losing remission (RR (95% CI)=1.97(1.43 to 2.73), P<0.0001) or LDA (RR (95% CI)=2.24(1.52 to 3.30), P<0.0001) and an increased risk of radiographic progression (RR (95% CI)=1.09(1.02 to 1.17), P=0.01) in case of bDMARD discontinuation. The meta-analysis comparing bDMARDs tapering versus continuation performed on 11 trials showed an increased risk of losing remission (RR (95% CI)=1.23(1.06 to 1.42), P=0.006) but no increased risk of losing LDA (RR (95% CI)=1.02 (0.85 to 1.23), P=0.81) nor any increased risk of radiographic progression (RR (95% CI)=1.09(0.94 to 1.26), P=0.26) in case of bDMARD tapering.
CONCLUSION: Discontinuation of bDMARDs leads to an increased risk of losing remission or LDA and radiographic progression, while tapering doses of bDMARDs does not increase the risk of relapse (LDA) or radiographic progression, even though there is an increased risk of losing remission.
INTRODUCCIÓN: Aunque los bDMARD son eficaces en el tratamiento de la AR, se asocian con los efectos secundarios dependientes de la dosis, la carga del paciente y los altos costos. Recientemente, muchos estudios han investigado la posibilidad de interrumpir o disminuir los bDMARD cuando los pacientes han alcanzado su meta de tratamiento. El objetivo de esta revisión es proporcionar una descripción narrativa de la evidencia existente sobre la reducción de la dosis de bDMARD y proporcionar respuestas a preguntas específicas relacionadas con la reducción de dosis que son de interés para los médicos. MÉTODOS: Se realizaron búsquedas sistemáticas de estudios relevantes en cuatro bases de datos científicas. Además, se revisaron las referencias de revisiones y estudios relevantes. Resultados: Nuestras búsquedas resultaron en 45 estudios originales de reducción de la dosis de bDMARD en pacientes con AR (15 ECA y 30 estudios observacionales). La evidencia actual demuestra que la reducción de la dosis de bDMARD puede ser considerada en todos los pacientes de AR que alcanzan una actividad o remisión de enfermedad estable (por ejemplo, ≥ 6 meses). Las mejores estrategias parecen ser la optimización de la dosis guiada por la actividad de la enfermedad y la reducción fija de la dosis, ya que la interrupción directa de bDMARD (sin reiniciar) resulta en una alta tasa de flare, peor funcionamiento físico y más daño articular. Cuando se reduce gradualmente el tratamiento con bDMARD de un paciente, la actividad de la enfermedad debe monitorizarse de cerca, y si se produce una llamarada, la dosis debe aumentarse hasta la dosis eficaz más baja. La evidencia actual demuestra que reiniciar el tratamiento bDMARD es efectivo y seguro. Desafortunadamente, hasta ahora no se han identificado predictores claros de la reducción exitosa de la dosis. CONCLUSIÓN: La evidencia actual y los crecientes costos de la atención sanitaria exigen que se considere la reducción de la dosis para los pacientes elegibles. Sin embargo, la decisión de comenzar la reducción de la dosis debe hacerse en la toma de decisiones compartida. La investigación futura debería centrarse no sólo en una mejor comprensión de los efectos de la reducción de la dosis en los resultados clínicos, sino también en las perspectivas de los pacientes y los médicos, así como la aplicación de este nuevo principio de tratamiento.
OBJETIVOS: Actualizar las pruebas de la eficacia de los fármacos antirreumáticos modificadores de la enfermedad biológica (bDMARDs) en pacientes con artritis reumatoide (AR) para informar a las recomendaciones de tratamiento de la European League Against Rheumatism (EULAR). Métodos: Se realizaron búsquedas en las bases de datos MEDLINE, EMBASE y Cochrane para los ensayos controlados aleatorios (ECA) entre los meses de enero de 2013 y febrero de 2016. Resúmenes del Colegio Americano de Reumatología y conferencias EULAR se obtuvieron. RESULTADOS: Los ECA confirmaron una mayor eficacia con un DMARD sintético convencional bDMARD + (csDMARD) versus un solo csDMARDs (evidencia de nivel 1A). El uso de un enfoque de estrategia de tratar a la meta, el inicio y la escalada de la terapia csDMARD y la adición de un bDMARD en casos de falta de respuesta, es un enfoque eficaz (1B). Si un bDMARD había fracasado, se observaron mejoras en la respuesta clínica al cambiar a otro bDMARD (1A), pero no se observó ninguna ventaja clara para cambiar a un agente con otro modo de acción. El mantenimiento de la respuesta clínica en pacientes en remisión o baja actividad de la enfermedad fue mejor cuando se continuó en lugar de detener un bDMARD, pero bDMARD reducción de la dosis o "espaciamiento" fue posible, con una proporción sustancial de los pacientes bDMARD-free remisión (2B). Los ECA también han demostrado la eficacia de varios nuevos DMARB y DMAR biosimilares (1B). CONCLUSIONES: Esta revisión sistemática de la literatura confirmó consistentemente la eficacia reportada previamente de los bDMARDs en la AR y proporcionó información adicional sobre la conmutación bDMARD y la reducción de la dosis.
La eficacia de las terapias biológicas ahora significa que la remisión o la baja actividad de la enfermedad son objetivos realistas para el tratamiento. Sin embargo, después de alcanzar la remisión / baja actividad de la enfermedad, los próximos pasos siguen siendo poco claros. El objetivo de esta publicación fue realizar una amplia revisión sistemática de la literatura para evaluar la dosificación de los productos biológicos. Tras la selección de trabajos y resúmenes de relevancia y aplicación de criterios de inclusión / exclusión, se utilizó un proceso de extracción estructurada para recopilar información sobre los estudios incluidos. Cincuenta y dos artículos fueron incluidos en el análisis a través de la enfermedad reumática. En los pacientes que interrumpen el tratamiento, la remisión no suele ser sostenida, con tasas reportadas de recaída y erupción a través de AR temprana (48-54%), AR establecida (2-84%), espondiloartritis axial (11-53%) y PSA %). En muchos casos, una actividad de la enfermedad aceptable puede ser recuperada tras el retratamiento. Se necesitan más investigaciones para comprender los impactos a largo plazo de estas estrategias sobre la eficacia, la seguridad y el costo.
OBJETIVO: Determinar si una estrategia de mantenimiento combinado de la terapia combinada (metotrexato (MTX) + TNF) seguido de la suspensión de TNFi podría dar mejores resultados a largo plazo que una estrategia con MTX en monoterapia, ya que No está claro si los beneficios de una fase de inducción con la terapia combinada se mantienen si se retira TNFi. MÉTODOS: Se realizó un metaanálisis de los ensayos que utilizaron la combinación inicial de MTX + TNFi en pacientes con artritis reumatoide precoz (AR) antirreumática modificadora de enfermedad sintomática convencional. Se realizó una búsqueda sistemática de literatura para los ensayos controlados aleatorios de mantenimiento de inducción (ECA) en los que se comparó la terapia de combinación inicial con la monoterapia con MTX en pacientes con RA temprana clínicamente activa. Nuestro resultado primario fue la proporción de pacientes que alcanzaron una baja actividad de la enfermedad (LDA, Score de la actividad de la enfermedad (DAS) 28 <3.2) y / o remisión (DAS28 <2.6) a las 12-76 semanas de seguimiento. Se utilizó un modelo de efectos aleatorios para agrupar la razón de riesgo (RR) para LDA y la remisión y la heterogeneidad fue explorada por análisis de subgrupos. RESULTADOS: Se identificaron 6 ECA publicados, 4 de ellos en los que se administró MTX + adalimumab como tratamiento inicial y donde se retiró adalimumab en un subgrupo de pacientes después de alcanzar la LDA / remisión. 2 ensayos adicionales utilizaron MTX + infliximab como terapia combinada. Los RR combinados para lograr LDA y la remisión clínica en el seguimiento después de la retirada de TNFi fueron 1,41 (IC del 95%: 1,05 a 1,89) y 1,34 (IC del 95%: 0,95 a 1,89), respectivamente. Hubo una heterogeneidad significativa entre los ensayos debido a diferentes estrategias de tratamiento, lo que constituyó una limitación para este estudio. CONCLUSIONES: La terapia inicial con MTX + TNFi se asocia con una mayor probabilidad de retener LDA y / o remisión incluso después de suspender TNFi.
To date, the significance of early intervention with methotrexate and biological disease-modifying anti-rheumatic drugs for rheumatoid arthritis (RA) has not been realized. Longitudinal safety and cost have arisen as new concerns. The concept of a treatment holiday, drug discontinuation after achieving remission, may solve these problems. The authors performed a systematic literature review and identified 13 reports from 10 studies (TNF20, BeSt, OPITMA, HIT-HARD, IMPROVED, PRIZE, IDEA, EMPIRE, tREACH and AVERT) for early RA (≤2 years). Eight out of 13 reports (61.5%) were published in 2013 or 2014, indicating emerging interest in recent years. Also, the authors performed a sub-analysis of the HONOR study (n = 51) to compare early (≤2 years) and established RA. The proportions of remission (REM) and low disease activity were higher in early RA (REM 63.0 vs 33.3%, p = 0.0346; low disease activity: 77.8 vs 45.8%, p = 0.0185). In conclusion, early intervention is beneficial for successful treatment holiday, which may lead to risk and cost reduction. However, further investigation is required.
This systematic search and review aimed to evaluate the available literature on discontinuation of adalimumab and other tumor necrosis factor inhibitors (TNFi) for patients with well-controlled chronic inflammatory arthritides.
METHODS:
We conducted a publication search on adalimumab discontinuation from 2000-2023 using PubMed, CINAHL, EMBASE, and Cochrane Library. Included studies evaluated adalimumab discontinuation approaches, tapering schemes, and outcomes including successful discontinuation and recapture after flare, in patients with well-controlled disease. Studies included evaluated rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and juvenile idiopathic arthritis (JIA).
RESULTS:
Forty-nine studies were included. Studies evaluating adalimumab alone were limited, and many reported TNFi outcomes as a single entity. Studies on rheumatoid arthritis (RA) (32, 8 RCTs) reported flare rates from 33-87%. Flares with medication tapering were slightly lower than with abrupt stop, and successful recapture was generally high (80-100%). Studies on spondyloarthropathy (12, 4 RCTs), focused on tapering, noting lower flare rates in tapering rather than abruptly stopping, and high recapture rates (~ 90%). Studies on JIA (5) were observational and demonstrated modestly lower flare rates with tapering (17-63%) versus abrupt stopping (28-82%). There was notable variability in study design, follow-up duration, specificity for TNFi results, and controlled pediatric studies.
CONCLUSION:
The literature evaluating adalimumab and other TNFi discontinuation, flare rates, and recapture success within the inflammatory arthritis population demonstrated less flare when medications were tapered, over abrupt stop in the RA, spondyloarthropathy, and JIA populations. When medications were restarted after flare, recapture of well-controlled disease was generally high in RA and spondyloarthropathy, and generally favorable in JIA.
