BACKGROUND: The long-term use of anti-TNF-α agents can lead to adverse effects, such as infections and immune-mediated cutaneous reactions. Whether de-escalation by dose reduction or interval lengthening reduces these adverse effects is uncertain. This systematic review aims to compare the incidence of infections and skin manifestations after anti-TNF-α dose de-escalation with standard dosing.
METHODS: MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched from inception to 14 January 2022. Randomized controlled trials (RCTs) and observational studies comparing anti-TNF-α de-escalation strategies with standard dosing among patients with inflammatory conditions, that report on infections, skin manifestations, or both, were included. The risk of bias was assessed with the revised Cochrane risk-of bias tool (RCTs) or the Newcastle-Ottawa scale (non-RCTs).
RESULTS: Fourteen RCTs and six observational studies (or 2706 patients) were included. Eight RCTs had low risk of bias or some concerns. Four non-RCTs were of good methodological quality. The studies described patients with axial spondyloarthritis (8 studies, 780 patients), rheumatoid arthritis (7 studies, 1458 patients), psoriasis (3 studies, 332 patients), or inflammatory bowel disease (2 studies, 136 patients). De-escalation strategies included interval lengthening (12 studies, 1317 patients), dose reduction (6 studies, 1130 patients), or both (2 studies, 259 patients). Overall, the occurrence of infections and skin manifestations did not differ between standard treatment and de-escalation. The disappearance of infections or skin manifestations after de-escalation was only reported in two studies. The majority of studies focused on etanercept and adalimumab. Heterogeneity in reporting of infections and skin manifestations precluded meta-analysis.
CONCLUSION: We found that anti-TNF-α de-escalation does not reduce infections or skin reactions. A de-escalation strategy should not be recommended for the sole purpose of reducing drug-related adverse effects. The meticulous documentation of adverse effects is recommended to further address this question.
REGISTRATION: PROSPERO CRD42021252977.
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).
The effects of dose reduction or spacing of all types of biologics in rheumatoid arthritis has not been consistently assessed in systematic reviews. We aimed to assess the effects of biologics reduction compared with dose maintenance in patients with rheumatoid arthritis in low disease activity or remission. We performed a systematic review with meta-analysis according to a previously registered protocol (PROSPERO registration: CRD42017069080); and searched MEDLINE, Embase, Scopus, Cochrane Library and trial registers up to July, 2020. Two researchers selected, extracted and assessed the risk of bias of controlled trials that randomized patients to reduction/spacing or dose maintenance of biologics. Low disease activity, disability and other clinically important outcomes were summarized in random effect meta-analyses. We rated the certainty of evidence according to the Grading of Recommendations Assessment, Development, and Evaluation approach. We included ten studies (n = 1331 patients), which assessed reduction or spacing of abatacept, adalimumab, certolizumab pegol, etanercept, or tocilizumab. Risk of bias was high in over half of trials, mainly due to lack of blinding. No statistically significant difference was found in low disease activity (RR = 0.90; 95% CI 0.78-1.04; I2 = 60%, very low certainty), and other outcomes. Subgroup analysis of blinded studies led to homogeneous results, which remained heterogeneous in open-label studies. Reduction or spacing biologics did not affect disease activity and other important outcome. Changes in the doses regimen should consider patient preferences, considering the low certainty of evidence.
BACKGROUND: Anti-tumour necrosis factor (TNF) agents are effective in treating people with rheumatoid arthritis (RA), but are associated with (dose-dependent) adverse effects and high costs. To prevent overtreatment, several trials have assessed the effectiveness of down-titration compared with continuation of the standard dose. This is an update of a Cochrane Review published in 2014.
OBJECTIVES: To evaluate the benefits and harms of down-titration (dose reduction, discontinuation, or disease activity-guided dose tapering) of anti-TNF agents on disease activity, functioning, costs, safety, and radiographic damage compared with usual care in people with RA and low disease activity.
SEARCH METHODS: We searched MEDLINE, Embase, Web of Science and CENTRAL (29 March 2018) and four trial registries (11 April 2018) together with reference checking, citation searching, and contact with study authors to identify additional studies. We screened conference proceedings (American College of Rheumatology and European League Against Rheumatism 2005-2017).
SELECTION CRITERIA: Randomised controlled trials (RCTs) and controlled clinical trials (CCTs) comparing down-titration (dose reduction, discontinuation, disease activity-guided dose tapering) of anti-TNF agents (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab) to usual care/no down-titration in people with RA and low disease activity.
DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodology.
MAIN RESULTS: One previously included trial was excluded retrospectively in this update because it was not an RCT/CCT. We included eight additional trials, for a total of 14 studies (13 RCTs and one CCT, 3315 participants in total) reporting anti-TNF down-titration. Six studies (1148 participants) reported anti-TNF dose reduction compared with anti-TNF continuation. Eight studies (2111 participants) reported anti-TNF discontinuation compared with anti-TNF continuation (three studies assessed both anti-TNF discontinuation and dose reduction), and three studies assessed disease activity-guided anti-TNF dose tapering (365 participants). These studies included data on all anti-TNF agents, but primarily adalimumab and etanercept. Thirteen studies were available in full text, one was available as abstract. We assessed the included studies generally at low to moderate risk of bias; our main concerns were bias due to open-label treatment and unblinded outcome assessment. Clinical heterogeneity between the trials was high. The included studies were performed at clinical centres around the world and included people with early as well as established RA, the majority of whom were female with mean ages between 47 and 60. Study durations ranged from 6 months to 3.5 years.We found that anti-TNF dose reduction leads to little or no difference in mean disease activity score (DAS28) after 26 to 52 weeks (high-certainty evidence, mean difference (MD) 0.06, 95% confidence interval (CI) -0.11 to 0.24, absolute risk difference (ARD) 1%) compared with continuation. Also, anti-TNF dose reduction does not result in an important deterioration in function after 26 to 52 weeks (Health Assessment Questionnaire Disability Index (HAQ-DI)) (high-certainty evidence, MD 0.09, 95% CI 0.00 to 0.19, ARD 3%). Next to this, anti-TNF dose reduction may slightly reduce the proportion of participants switched to another biologic (low-certainty evidence), but probably slightly increases the proportion of participants with minimal radiographic progression after 52 weeks (moderate-certainty evidence, risk ratio (RR) 1.22, 95% CI 0.76 to 1.95, ARD 2% higher). Anti-TNF dose reduction may cause little or no difference in serious adverse events, withdrawals due to adverse events and proportion of participants with persistent remission (low-certainty evidence).Results show that anti-TNF discontinuation probably slightly increases the mean disease activity score (DAS28) after 28 to 52 weeks (moderate-certainty evidence, MD 0.96, 95% CI 0.67 to 1.25, ARD 14%), and that the RR of persistent remission lies between 0.16 and 0.77 (low-certainty evidence). Anti-TNF discontinuation increases the proportion participants with minimal radiographic progression after 52 weeks (high-certainty evidence, RR 1.69, 95% CI 1.10 to 2.59, ARD 7%) and may lead to a slight deterioration in function (HAQ-DI) (low-certainty evidence). It is uncertain whether anti-TNF discontinuation influences the number of serious adverse events (due to very low-certainty evidence) and the number of withdrawals due to adverse events after 28 to 52 weeks probably increases slightly (moderate-certainty evidence, RR 1.46, 95% CI 0.75 to 2.84, ARD 1% higher).Anti-TNF disease activity-guided dose tapering may result in little or no difference in mean disease activity score (DAS28) after 72 to 78 weeks (low-certainty evidence). Furthermore, anti-TNF disease activity-guided dose tapering results in little or no difference in the proportion of participants with persistent remission after 18 months (high-certainty evidence, RR 0.89, 95% CI 0.75 to 1.06, ARD -9%) and may result in little or no difference in switching to another biologic (low-certainty evidence). Anti-TNF disease activity-guided dose tapering may slightly increase proportion of participants with minimal radiographic progression (low-certainty evidence) and probably leads to a slight deterioration of function after 18 months (moderate-certainty evidence, MD 0.2 higher, 0.02 lower to 0.42 higher, ARD 7% higher), It is uncertain whether anti-TNF disease activity-guided dose tapering influences the number of serious adverse events due to very low-certainty evidence.
AUTHORS' CONCLUSIONS: We found that fixed-dose reduction of anti-TNF, after at least three to 12 months of low disease activity, is comparable to continuation of the standard dose regarding disease activity and function, and may be comparable with regards to the proportion of participants with persistent remission. Discontinuation (also without disease activity-guided adaptation) of anti-TNF is probably inferior to continuation of treatment with respect to disease activity, the proportion of participants with persistent remission, function, and minimal radiographic damage. Disease activity-guided dose tapering of anti-TNF is comparable to continuation of treatment with respect to the proportion of participants with persistent remission and may be comparable regarding disease activity.Caveats of this review are that available data are mainly limited to etanercept and adalimumab, the heterogeneity between studies, and the use of superiority instead of non-inferiority designs.Future research should focus on the anti-TNF agents infliximab and golimumab; assessment of disease activity, function, and radiographic outcomes after longer follow-up; and assessment of long-term safety, cost-effectiveness, and predictors for successful down-titration. Also, use of a validated flare criterion, non-inferiority designs, and disease activity-guided tapering instead of fixed-dose reduction or discontinuation would allow researchers to better interpret study findings and generalise to clinical practice.
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.
OBJECTIVES: To evaluate the efficacy and safety of down-titration (dose reduction/tapering) strategies compared with continuation of biological disease-modifying anti-rheumatic drugs (DMARDs) in patients with rheumatoid arthritis (RA) who achieved and maintained low disease activity or remission.
METHODS: We searched the following electronic database up to March 2016: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), and conference proceedings of the American College of Rheumatology (ACR) and European League against Rheumatism (EULAR). Our meta-analysis included randomized controlled trials (RCTs) of RA patients with low disease activity or in remission that compared down-titration treatment with continuation treatment. Data on flare, defined as a 28-joint Disease Activity Score of ≥3.2, had to have been reported. Outcomes on efficacy or safety were collected.
RESULTS: Of 1136 references identified, five RCTs (total, 771 participants) were included. The incidence of disease relapse in the down-titration and continuation groups was similar (risk ratio (RR)=1.14, 95% CI=0.88-1.49). There was no statistical difference in the number of serious adverse events (RR=1.15, 95% CI=0.53-2.49). Withdrawals due to inefficacy or toxicity were similar between groups and no clinically meaningful difference in efficacy outcomes was observed by continuation treatment.
CONCLUSIONS: Our findings indicated that continuing a standard dose of biological DMARDs in patients with low disease activity conveyed no significant benefit as compared with down-titration therapy, suggesting that a down-titration strategy is as effective as a continuation strategy. Since the number of trials meeting the criteria for this meta-analysis was relatively low, future analyses with additional prospective RCTs are required to compare other biological agents and evaluate the long-term efficacy of these two strategies.
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.
Biologic therapies have improved the management of rheumatoid arthritis (RA) and the treat-to-target approach has resulted in many patients achieving remission. In the current treatment landscape, clinicians have begun considering dose reduction/tapering for their patients. Rheumatology guidelines in Asia, Europe, and the United States include down-titration of biologics but admit that the level of evidence is moderate. We conducted a systematic literature review to assess the published studies that evaluate down-titration of biologics in RA. The published literature was searched for studies that down-titrated the following biologics: abatacept, adalimumab, certolizumab, etanercept, golimumab, infliximab, rituximab, and tocilizumab. Eligible studies included randomized controlled trials (RCTs), non-RCTs, observational, and pharmacoeconomic studies. The outcomes of interest were (1) efficacy and health-related quality of life, (2) disease flares, and (3) impact on cost. Eleven full-text publications were identified; only three were RCTs. Study results suggest that dosing down may be an option in many patients who have achieved remission or low disease activity. However, some patients are likely to experience a disease flare. Across the studies, the definition of disease flare and the down-titration criteria were inconsistent, making it difficult to conclude which patients may be appropriate and when to attempt down-titration. Studies have evaluated the practice of dosing down biologic therapy in patients with RA; however, a relatively small number of RCTs have been published. Although down-titration may be an option for some patients in LDA or remission, additional RCTs are needed to provide guidance on this practice.
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.
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.
The long-term use of anti-TNF-α agents can lead to adverse effects, such as infections and immune-mediated cutaneous reactions. Whether de-escalation by dose reduction or interval lengthening reduces these adverse effects is uncertain. This systematic review aims to compare the incidence of infections and skin manifestations after anti-TNF-α dose de-escalation with standard dosing.
METHODS:
MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched from inception to 14 January 2022. Randomized controlled trials (RCTs) and observational studies comparing anti-TNF-α de-escalation strategies with standard dosing among patients with inflammatory conditions, that report on infections, skin manifestations, or both, were included. The risk of bias was assessed with the revised Cochrane risk-of bias tool (RCTs) or the Newcastle-Ottawa scale (non-RCTs).
RESULTS:
Fourteen RCTs and six observational studies (or 2706 patients) were included. Eight RCTs had low risk of bias or some concerns. Four non-RCTs were of good methodological quality. The studies described patients with axial spondyloarthritis (8 studies, 780 patients), rheumatoid arthritis (7 studies, 1458 patients), psoriasis (3 studies, 332 patients), or inflammatory bowel disease (2 studies, 136 patients). De-escalation strategies included interval lengthening (12 studies, 1317 patients), dose reduction (6 studies, 1130 patients), or both (2 studies, 259 patients). Overall, the occurrence of infections and skin manifestations did not differ between standard treatment and de-escalation. The disappearance of infections or skin manifestations after de-escalation was only reported in two studies. The majority of studies focused on etanercept and adalimumab. Heterogeneity in reporting of infections and skin manifestations precluded meta-analysis.
CONCLUSION:
We found that anti-TNF-α de-escalation does not reduce infections or skin reactions. A de-escalation strategy should not be recommended for the sole purpose of reducing drug-related adverse effects. The meticulous documentation of adverse effects is recommended to further address this question.
