ANTECEDENTES: Biologic estrechamiento se ha asociado a la recaída o la progresión del daño estructural en la artritis reumatoide (AR). OBJETIVOS: Comparar el impacto de una estrategia de bajada DAS28 impulsado basado en el espaciamiento de inyección de TNF-bloqueador (S brazo) a una estrategia de mantenimiento (brazo M) en un ECA equivalencia realizado en pacientes con AR establecida en remisión DAS28 con etanercept (ETA ) o adalimumab (ADA). MÉTODOS: Los criterios de inclusión fueron: ETA o ADA> 1 año, DAS28 remisión> 6 meses, daños estable en las radiografías. Los pacientes fueron asignados aleatoriamente y seguidos de 3 meses durante 18 meses. En el grupo S, el intervalo entre la inyección se incrementó cada 3 meses hasta un punto al cuarto paso. Si la remisión DAS28 se perdió, se estrecha se invirtió al paso anterior. Las radiografías de manos y pies al inicio del estudio y 18 meses. Los objetivos del ensayo fueron la actividad de la enfermedad (DAS28), recaída ({} delta DAS28> 0,6 + DAS28> 2,6), y de rayos X daño evaluado por vdH-SHS (2 lectores independientes, cegado de las características del paciente y brazo de tratamiento). La progresión se definió como {} vdH Delta-SHS> 1. Resultados: 137 pacientes fueron incluidos, 64 y 73 en el brazo de S y M (media /%: la edad de 55 años, mujeres 78%, la duración de la RA 9,5 años, RF + 68%, ACPA + 78%, erosiva 88%, DAS28 1.8, DAS44 1,0, ETA 54%, ADA 46%). A los 18 meses, 47 (73,4%) pacientes de la S-brazo cónicos bloqueantes del TNF, de los cuales 24 (37,5%) se detuvo. La media de DAS28 y HAQ significa no fueron significativamente diferentes entre los brazos. CONCLUSIONES: A pesar de las recaídas fueron más frecuentes, los resultados de la estrategia espaciado en no significativo aumento de la actividad de la enfermedad y el deterioro funcional, sin progresión estructural significativo. Meta la dosis eficaz más baja en la AR en remisión puede ser considerado como el nuevo paradigma de este tipo de pacientes (n ° ClinicalTrials.gov NCT00780793).
ANTECEDENTES: estrategias terapéuticas Step-down pueden ser considerados en la artritis reumatoide establecida (AR) una vez que se logra la remisión. OBJETIVOS: Comparar el impacto de una estrategia de bajada DAS28 impulsado basado en el espaciamiento de inyección progresiva (S brazo) a una estrategia de mantenimiento de la terapia a pleno régimen (brazo M) en una equivalencia ensayo controlado aleatorio realizado en pacientes con AR tratados con establecidos etanercept (ETA) o adalimumab (ADA) en remisión DAS28 estable. MÉTODOS: Los criterios de inclusión fueron: RA ACR1987 +, ETA o ADA> 1 año, como monoterapia o en combinación, prednisona diaria [& le;] 5 mg / d, DAS28 remisión> 6 meses, el daño estructural estable de rayos X. Los pacientes fueron aleatorizados en 2 brazos y siguieron a 3 veces al mes durante 18 meses. En el grupo S, el intervalo entre 2 inyecciones se incrementó en un 50% cada 3 meses hasta un punto al cuarto paso. Si la remisión DAS28 se perdió, se estrecha fue suspendido o revertido al paso anterior con base en el cambio DAS28. El criterio de valoración principal fue la actividad de la enfermedad en las medidas repetidas DAS28 (cada 3 meses más de 18 meses) bajo la hipótesis de no inferioridad (modelo lineal mixto). RESULTADOS: 137 pacientes fueron incluidos, 64 y 73 en los brazos S y M. Características basales principales fueron (media /%): la edad de 55 años, mujeres 78%, la duración de la RA 9,5 años, RF + 68%, ACPA + 78%, enfermedad erosiva 88%, DAS28 1.8, DAS44 1.0, HAQ 0,4, FAME previos 2,7, ETA 54%, el 46% de la ADA. A los 18 meses, 24 (37,5%) de los pacientes S-brazo se había detenido y 23 (35,9%) cónicos bloqueantes del TNF. La media DAS28 y HAQ no fueron significativamente diferentes entre los dos brazos (figuras). Sin embargo, la equivalencia entre las 2 estrategias no se demostró (p = 0,6). Los predictores de remisión persistente eran bajos DAS28 al inicio del estudio y la estrategia M. No hubo diferencia entre ETA o ADA, ya sea montotherapy o en combinación. CONCLUSIONES: El espaciamiento de bloqueantes del TNF era factible en el 87% de los pacientes. Aunque no hemos podido demostrar la equivalencia entre las 2 estrategias, la estrategia de separación no resultó en un aumento significativo de la actividad de la enfermedad o deterioro funcional. (ClinicalTrials.gov n ° NCT00780793).
Background Flares in rheumatoid arthritis (RA) are a patient-perceived sign of disease activity which might be particularly important to assess in the context of treatment tapering. However assessment of flares in not yet well-defined. Objectives To explore the frequency of patient perceived flares during treatment tapering in RA, and to assess agreement between patient-perceived flares and other criteria including patient-reported outcomes and change in DAS28. Methods The STRASS study was a step-down randomized trial (ref). Patients had RA, were treated with adalimumab (ADA) or etanercept (ETN), and were in DAS 28-remission (DAS ≤2.6) for ≥6 months. Patients were randomized to either the “spacing”(S) arm (where the TNF blocker was tapered gradually) or “maintaining”(M) arm, over 18 months. Flares were evaluated through a patient-reported questionnaire every 3 months, asking: “Concerning the last 3 months, did you experience symptoms of a relapse of RA?”, with subquestions on pain and swollen joints. The frequency of visits where patients reported flares was compared in the M and S arms by Wilcoxon test. Disease characteristics were compared (t-test or Wilcoxon as appropriate) between visits with vs without a flare reported for both patient and physician reported outcomes. Agreement between patient-perceived-flares and DAS28 defined relapse (DAS 28>2.6 and an increase in DAS28 of at least 0.6 points at the same visit) was assessed by kappa. Results 137 patients were included in STRASS, 64 and 73 in the S and M arms respectively: age (mean ± SD) 55±11 yrs, females 78%, RA duration 9±8 years (ref). Over the 18 months of the study, the mean number of visits where the patient reported at least one flare (out of a possible total number of visits of 6 visits), was 1.87±1.74, with 2.44±1.68 visits with flares in the S arm, and 1.37±1.65 visits with flares in the M arm (p=0.0001). For the 256 visits with patient-perceived flares, the most frequent symptom (on subquestions) was pain (91.0%), rather than swollen joints (56.6%). Comparison between visits at which patients reported flares, and visits at which patients did not, showed statistically significant differences concerning all other outcomes (table). Agreement between patient-perceived flares and DAS 28-relapse was moderate: kappa was 0.40 to 0.49 [0.22-0.65] across visits. (Figure presented) Conclusions Patient-perceived flares discriminated well between the treatment arms in the STRASS study, and were related to worsenings in other usual outcomes in RA, indicating flares may be a useful study endpoint in tapering trials. However, agreement with DAS worsening was only moderate. Although flares are an important concept for patients with RA, more work is needed on the concept of flares.
Background: Once remission is achieved for patients with rheumatoid arthritis (RA), treatment down-titration should be attempted, for safety issues or economic reasons. One of the proposed strategies, recently tested in the STRASS trial [1], is to progressively space injections of TNF-blockers. Objectives: To assess the Incremental Cost-Effectiveness Ratio (ICER) of a strategy of progressive spacing of TNF-blocker injections (S-arm) over another maintaining them at full-dose (M-arm) in RA patients in stable remission. Methods: The study was a French multi-centre 18-month equivalence randomized open-label controlled trial. It included patients receiving etanercept (ETA) or adalimumab (ADA) at stable dose for ≥1 year; in remission on 28-joint Disease Activity Score (DAS28) for ≥6 months; and with stable joint damage. In the S-arm, the interval between 2 subcutaneous injections was increased every 3 months by 50% in 4 steps, to a complete stop at step 4. If remission was not maintained, spacing was suspended or reversed to the previous interval. Costs engaged within the study-period, measured in euros, were assessed using a health insurance payer perspective encompassing medical costs (drugs, consultations and medical tests, use of emergency room and hospitalizations) and costs relative to sick leave. Utilities values used to compute Quality Adjusted Life Years (QALYs) were derived from the EQ-5D, using values validated in the French population, assessed at baseline and every 6 months. The ICER was estimated. A probabilistic sensitivity analysis was performed by computing 5000 ICERs (bootstrap). The probability of cost-effectiveness (p of CE) of the maintenance strategy was computed for different Willingness to Pay (WTP) thresholds. Results: Analyses were performed on 44 patients in the S-arm and 54 in the M-arm with complete data. In the S-arm, TNF-blockers were stopped for 34.1% of the patients, tapered for 43.2%, maintained at full-dose for 18.2%. After 18 months of follow-up, 62.3% and 45.9% of the patients of the S and M-arm respectively, found their symptomatic state acceptable (p=0.08). Patients in the S-arm gained 1.106 QALYs while it was 1.264 in the M-arm (mean differences in QALYs of -0.158). After 18 months, total mean cost was 12452 euros in the S-arm and 20892 euros in the M-arm (mean cost difference of -8440 euros). The cost of TNF-blockers represented 81.0% and 92.8% of the total cost in the S and M-arms respectively. The estimated ICER was 53417 euros per QALY. The p of CE of the maintenance strategy was 0.02, 0.06, 0.22 and 0.41 for WTP thresholds fixed at 25000, 30000, 40000 and 50000 euros respectively. Conclusions: Although 62.3% of the patients found their symptomatic state acceptable, the spacing strategy was found to be less effective based on QALY measures. But, it was also found to be less costly. Thus, the maintenance strategy was assessed as the strategy with the lowest probability of being cost-effective for WTP thresholds ranging from 25000 to 50000 euros. (Figure Presented).
UNLABELLED: Tumour necrosis factor (TNF)-blocker tapering has been proposed for patients with rheumatoid arthritis (RA) in remission.
OBJECTIVE: The trial aims to compare the effect of progressive spacing of TNF-blocker injections (S-arm) to their maintenance (M-arm) for established patients with RA in remission.
METHODS: The study was an 18-month equivalence trial which included patients receiving etanercept or adalimumab at stable dose for ≥1 year, patients in remission on 28-joint Disease Activity Score (DAS28) for ≥6 months and patients with stable joint damage. Patients were randomised into two arms: maintenance or injections spacing by 50% every 3 months up to complete stop. Spacing was reversed to the previous interval in case of relapse, and eventually reattempted after remission was reachieved. The primary outcome was the standardised difference of DAS28 slopes, based on a linear mixed-effects model (equivalence interval set at ±30%).
RESULTS: 64 and 73 patients were included in the S-arm and M-arm, respectively, which was less than planned. In the S-arm, TNF blockers were stopped for 39.1%, only tapered for 35.9% and maintained full dose for 20.3%. The equivalence was not demonstrated with a standardised difference of 19% (95% CI -5% to 46%). Relapse was more common in the S-arm (76.6% vs 46.5%, p=0.0004). However, there was no difference in structural damage progression.
CONCLUSIONS: Tapering was not equivalent to maintenance strategy, resulting in more relapses without impacting structural damage progression. Further studies are needed to identify patients who could benefit from such a strategy associated with substantial cost savings.
TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT00780793; EudraCT identifier: 2007-004483-41.
Introduction We have limited data on the sustainability of tumour necrosis factor (TNF)-blocker tapering in rheumatoid arthritis (RA) in remission over the long term in real-life settings. This study aimed to assess the probability of sustained dose reduction of TNF-blockers in an observational 3-year extended follow-up of the Spacing of TNF-blocker injections in Rheumatoid ArthritiS Study (STRASS), a randomised controlled trial comparing progressive TNF-blocker injections (spacing arm (S-arm) to maintenance arm (M-arm)) in patients with RA in stable remission. Methods In 2015, clinical data for the completer population were retrospectively collected at 1, 2 and 3 years after the end of the trial. The endpoints were the proportion of patients free of a biological disease-modifying antirheumatic drug (bDMARD) treatment, a sustainably spaced injection of TNF-blockers and a full-dose regimen as well as the mean dose of bDMARD intake and treatment switch rate. Results Overall, 96 patients (76.8% of the completers) had data available up to 3 years; 11.5% discontinued TNF-blockers (5.8% vs 18.2% in the M-arm and S-arm, p=0.06), 30.2% had a tapered regimen (28.8% vs 31.8%, p=0.76) and 37.5% retained a full dose (44.2% vs 29.5%, p=0.14). The mean TNF-blocker dose quotient was 66% of the full dose (74% vs 58% in the M-arm and S-arm, p=0.06); 20.8% switched to another bDMARD (21.2% vs 20.5%, p=0.94). Conclusion Sustained TNF-blocker de-escalation or withdrawal is achievable in 41% of patients over 3 years with limited dose reduction. Optimal strategies remain to be determined to maintain remission after TNF-blocker tapering or discontinuation.
Background: Tapering trials confirmed the feasibility of TNF inhibitors (TNFi) tapering for a relevant proportion of patients in remission and/or low disease activity. However, there are no consensual predictors of a good response to therapeutic spacing among patients with rheumatoid arthritis (RA) in remission. Objectives: To determine the most predictive tool and threshold of a successful TNFi tapering. Methods: Population: The Spacing of TNF-blocker injections in Rheumatoid Arthritis Study (STRASS) trial included 137 RA patients fulfilled the ACR 1987 criteria with sustained (at least 6 months) DAS28 <2.6. Patients were randomly assigned to one of the two following strategies: in the Maintain arm, patients continued to receive TNFi at the standard full regimen and in the Spacing arm, the strategy applied progressive spacing of ADA or ETN subcutaneous injections up to discontinuation at the forth step in the spacing arm. We used the data of the Spacing arm. Analysis: The performances of several variables (DAS28, SDAI, CDAI, CRP, ACPA status, HAQ, patient/physician global assessment, and booleen remission criteria) were assessed for the prediction of successful TNFi tapering, defined as reaching at least 25% tapering of the full regimen during at least 6 months, using sensitivity and specificity for dichotomous variables, or the area under the ROC curve (AUC) and its 95% confidence interval for continuous variables. A predictive score of successful tapering was constructed using LASSO regression modeling technique to avoid overfitting (R software version 3.2.1). Results: The main characteristic of the 64 patients of the Spacing arm were the following (mean ± SD): age 54.3±10.7 years, disease duration 8.3±5.4 years, and DAS 28 1.9±0.6. The baseline variables were similar between patients who failed or succeeded at TNFi spacing, except for the HAQ score (0.30 in the group success and 0.89 in the failure group, p=0.01) and the CRP (2.35 mg/l versus 3.48 mg/l, respectively, p=0.02). Baseline variables performance in predicting successful TNFi spacing: None of the tested variables was able to predict successful TNFi spacing, except the HAQ score and the CRP. A HAQ threshold ≥1.125 had a specificity (Spe) of 93% and an AUC: 0.713 (CI95%: 0.540-0.886). A CRP threshold ≥6.8 mg/l had a Spe of 0.97 and an AUC: 0.689 (CI95%: 0.547-0.831). Composite criteria: A composite criteria able to predict successful TNFi spacing has been elaborated, including ACPA status, Boolean criteria, SDAI, CRP and HAQ. A composite score lower than 0.502 was able to predict a successful TNFi spacing: Spe: 100%; Se: 54%; AUC: 0.829 (CI95%: 0.671 - 0.986). Conclusions: The remission maintenance in rheumatoid arthritis after TNFi spacing is possible. Our results showed that in a population of RA patients in remission with TNFi, baseline HAQ and CRP are independent predictor factors of successful tapering. We have developed a composite index able to predict successful TNFi spacing, with an AUC of 0.829 and a specificity of 100%. A validation study will be needed to confirm its ability to select patients for treatment decrease.
BACKGROUND: In patients with rheumatoid arthritis in remission, a disease activity-driven tapering of adalimumab or etanercept relying on progressive injection spacing has not been shown to be equivalent to a maintenance strategy at full dose in terms of disease activity in the Spacing of TNF-blocker injections in Rheumatoid ArthritiS Study (STRASS) trial.
OBJECTIVES: To evaluate the cost-effectiveness of such a spacing strategy based on the data of the STRASS trial.
METHODS: This is a cost-utility analysis of the STRASS trial, a French multicenter 18-month equivalence randomized open-label controlled trial that included patients at stable dose for at least 1 year, in remission for at least 6 months. Effectiveness was assessed in quality-adjusted life-years (QALYs). Costs involved in the study period were assessed from a payer perspective. The decremental cost-effectiveness ratio (DCER) was calculated in the complete cases sample (n = 98). Several sensitivity analyses were conducted and the impact of missing data on DCER estimate was investigated. An acceptability analysis was performed.
RESULTS: In the spacing arm, TNF-blockers were stopped for 34.1% of the patients, tapered for 43.2%, and maintained at full dose for 18.2%. The spacing strategy was associated with less QALYs gain (mean difference of -0.158; 95% confidence interval [CI] -0.085 to -0.232) and reduced costs (mean difference of -€8,440; 95% CI -6,507 to -10,212). The estimated DCER of the spacing strategy over the maintenance at full dose was €53,417 saved per QALY lost (95% CI 32,230 to 104,700).
CONCLUSIONS: The spacing strategy appears cost-effective, but the acceptability of such a QALY loss reported to the cost avoided remains to be evaluated, because no consensual threshold has been determined for willingness to accept as compared with willingness to pay.
Background: Rheumatoid arthritis (RA) patients in sustained remission are candidates for tapering of disease modifying anti-rheumatic drugs (DMARDs). However, no predictors of relapse have been clearly identified so far. The STRASS trial included 137 RA patients in sustained DAS28 remission with TNF blockers (TNFb) who were randomized to 2 strategy arms: maintenance of TNFb at full dose or progressive DAS28-driven spacing of TNFb injections 1. RA relapses were significantly more common with TNFb spacing in STRASS but no baseline characteristics predicted the risk of relapse in either strategy arm. The multi-biomarker disease activity (MBDA) blood test measures 12 serum protein biomarkers and uses a validated algorithm to produce a score for RA disease activity on a scale of 1-100. In some studies, the MBDA score was a significant predictor of flare following DMARD tapering in well controlled RA patients. Objectives: To test the ability of the MBDA score to identify rheumatoid arthritis patients who will relapse following continuation or tapering of TNF blocker (TNFb) treatment in the STRASS study Methods: MBDA scores were determined in a central laboratory (Crescendo Biosciences, San Francisco, USA) for available archived serum samples that had been obtained at baseline from patients in STRASS (N=133). The ability of the MBDA score to predict relapse (defined as DAS28 >2.6 and increased >0.6 from previous study visit) in each arm of the 18-month STRASS trial was assessed by: 1) comparing MDBA scores in relapsing vs. non-relapsing patients by Wilcoxon rank sum or Fisher's test, and 2) determining the ability of the MBDA score to discriminate relapse, based on receiver operating characteristic (ROC) analysis summarized by C-statistic (i.e., area under the ROC curve [AUC]), and its 95% confidence interval (CI). Analyses were performed for intention-to-treat (ITT) and completer populations Results: At 18 months, 48% and 77% of the patients relapsed in the full dose maintenance and the spacing arms, respectively. In each study arm, mean MBDA scores and the percentages of patients with low, moderate or high MBDA scores at baseline were not significantly different in relapsing vs. non-relapsing patients (Table 1). The ROC analyses displayed no statistically significant discriminating ability for the MBDA score in terms of relapse prediction over the 18-month period of the trial in either arm of the ITT population (Figure 1). However, a significant ROC result was obtained in the maintenance group in the completer analysis (AUC 0.638 [95% CI: 0.502, 0.774], p=0.01). Conclusion: The MBDA score did not display quantification of the risk of relapse in RA patients in remission, when assessed, in the context of the DAS28-driven TNFb tapering strategy in STRASS.
OBJECTIVES: The aim was to evaluate the ability of baseline multi-biomarker disease activity (MBDA) score to discriminate between patients with rheumatoid arthritis (RA) in remission who are at high risk versus low risk of relapse after TNF-inhibitor (TNFi) tapering.
METHODS: The study is a post-hoc analysis of patients who completed the Spacing of TNFi injections in Rheumatoid ArthritiS Study (STRASS), a multicentre 18-month equivalence randomised controlled study, of TNFi tapering in RA patients in remission, and had baseline serum samples available for MBDA testing. The primary endpoint of this study was the ability of the baseline MBDA score to predict relapse at any time during the 18 months following initiation of TNFi tapering. Secondary endpoints were the ability of baseline MBDA score to predict TNFi discontinuation at Month 18, and structural damage progression on x-rays assessed by the change in total van der Heijde-modified Sharp score from baseline to month 18.
RESULTS: 64 and 73 patients were included in the spacing (S)-arm and maintenance (M)-arm, respectively. In the M-arm, the mean MBDA score at baseline was higher among patients who relapsed during the 18-month follow-up than those who did not relapse: 32.5 compared to 27.2 (p=0.053) whereas no difference in the MBDA score was observed in the S-arm between patients who relapsed or not 27 compared to 26.2 (p=0.57) 13 patients (21.3%) of the S-arm were able to discontinue TNFi, for which the predictive value of the MBDA score was low (AUC=0.560). Radiographic progression in both arms, although low (n=9) was not correlated with the MBDA score at baseline with a poor discriminative value in both arms (AUC=0.558).
CONCLUSIONS: In our study MBDA score in baseline was not predictive of relapse, discontinuation of TNFi in patients with long-standing RA patients tapering TNFi.
