Effect of using the Simple Erosion Narrowing Score or Sharp/van der Heijde score on power of rheumatoid arthritis clinical trials to detect differences in radiographic progression.

OBJECTIVES: The Simple Erosion Narrowing Score (SENS) is a simplification of the Sharp/van der Heijde score (SHS). Previous studies found SENS and SHS to have very similar measurement properties, but suggest that SENS has a lower discriminative ability that may result in reduced power. Therefore, we aimed to quantify the effect of using SENS rather than SHS on the power to show between-group differences in radiographic progression. METHODS: Using data from two clinical trials in rheumatoid arthritis (DRESS and BeSt), SENS was derived from the SHS. Criterion validity of the SENS in relation to the SHS was assessed by calculating the Spearman correlation. The power of both scores to show a difference between groups was compared using bootstrapping to generate 10.000 replications of each study. Then, the number of replications with a significant difference in progression (using ANCOVA adjusted for baseline scores) were compared. RESULTS: Correlations between SENS and SHS were all >0.9, indicating high criterion validity of SENS compared with SHS as a reference standard. There was one exception, the DRESS study showed a somewhat lower correlation for the change score at 18 months (0.787). The loss in power of SENS over SHS was limited to at most 19% (BeSt year 5). In addition, the difference in power between SENS and SHS is smaller at higher levels of power. CONCLUSION: SENS appears to be a reasonable alternative to SHS, with only a limited loss of power to show between-group differences in radiographic progression.

18F-FDG PET-CT in rheumatoid arthritis patients tapering TNFi: reliability, validity and predictive value.

OBJECTIVES: To investigate the reliability and validity of fluorine-18 fluorodeoxyglucose (18F-FDG) PET-CT scanning (FDG-PET) in RA patients with low disease activity tapering TNF inhibitors (TNFis) and its predictive value for successful tapering or discontinuation. METHODS: Patients in the tapering arm of the Dose REduction Strategies of Subcutaneous TNFi study, a randomized controlled trial of TNFi tapering in RA, underwent FDG-PET before tapering (baseline) and after maximal tapering. A total of 48 joints per scan were scored both visually [FDG-avid joint (FAJ), yes/no] and quantitatively [maximal and mean standardized uptake values (SUVmax and SUVmean)]. Interobserver agreement was calculated in 10 patients at baseline. Quantitative and visual FDG-PET scores were investigated for (multilevel) association with clinical parameters both on a joint and patient level and for the predictive value at baseline and the change between baseline and maximal tapering (Δ) for successful tapering and discontinuation at 18 months. RESULTS: A total of 79 patients underwent FDG-PET. For performance of identification of FAJs on PET, Cohen's κ was 0.49 (range 0.35-0.63). For SUVmax and SUVmean, intraclass correlation coefficients were 0.80 (range 0.77-0.83) and 0.96 (0.9-1.0), respectively. On a joint level, swelling was significantly associated with SUVmax and SUVmean [B coefficients 1.0 (95% CI 0.73, 1.35) and 0.2 (0.08, 0.32), respectively]. On a patient level, only correlation with acute phase reactants was found. FDG-PET scores were not predictive of successful tapering or discontinuation. CONCLUSIONS: Quantitative FDG-PET arthritis scoring in RA patients with low disease activity is reliable and has some construct validity. However, no predictive values were found for FDG-PET parameters for successful tapering and/or discontinuation of TNFi.

A multi-biomarker score measuring disease activity in rheumatoid arthritis patients tapering adalimumab or etanercept: predictive value for clinical and radiographic outcomes.

Objective: The aim was to evaluate the predictive value of the baseline multi-biomarker disease activity (MBDA) score in long-standing RA patients with low disease activity tapering TNF inhibitors (TNFi) for successful tapering or discontinuation, occurrence of flare and major flare, and radiographic progression. Methods: Dose REduction Strategies of Subcutaneous TNF inhibitors (Dutch Trial Register, NTR 3216) is an 18-month non-inferiority randomized controlled trial comparing tapering of TNFi until discontinuation or flaring with usual care (UC) in long-standing RA patients with stable low disease activity. Flare was defined as DAS28-CRP increase >1.2 or >0.6 if current DAS ⩾3.2; major flare was a flare lasting >3 months, despite treatment intervention. MBDA scores were measured at baseline. Radiographs were scored at baseline and 18 months using the Sharp-van der Heijde score. The area under the receiver operating characteristic (AUROC) curve was used to analyse the capability of baseline MBDA score to predict the above-mentioned outcomes. Results: Serum samples and outcomes were available for 171 of 180 patients from Dose REduction Strategies of Subcutaneous TNF inhibitors (115 tapering; 56 UC). AUROC analyses showed that baseline MBDA score was not predictive for the above-mentioned clinical outcomes in the taper group, but did predict major flare in the UC group (AUROC = 0.72, 95% CI: 0.56, 0.88). Radiographic progression was minimal and was not predicted by MDBA score. Conclusion: In this disease activity-guided strategy study of TNFi tapering in RA patients with low disease activity, baseline MBDA score was not predictive for successful tapering, discontinuation, flare, major flare or radiographic progression in patients who tapered TNFi.

Extra-articular findings with FDG-PET/CT in rheumatoid arthritis patients: more harm than benefit.

Objective: Whole-body PET with CT scanning using 18F-fluorodeoxyglucose (18F-FDG) is used occasionally in RA patients to detect arthritis. FDG-PET/CT might also detect malignancies, but the amount of incidental findings and the number of relevant malignant diseases that could be missed are currently unknown. We aimed to study the malignancy screening performance of whole-body FDG-PET/CT in longstanding RA patients with low disease activity. Methods: FDG-PET/CT scanning was done in the intervention arm of the Dose REduction Strategy of Subcutaneous TNF-inhibitors (DRESS) study, a randomized controlled trial on dose-tapering of biological DMARDs. The reference standard was clinical diagnosis of malignancy during the 3-year follow-up period of the study. Prevalence of extra-articular abnormalities, follow-up and treatments were summarized post hoc. Results: One hundred and twenty-one scans were carried out in 79 patients. Extra-articular abnormalities were found in 59 of 121 (49%) scans, resulting in additional diagnostic procedures in 21 of 79 (26.6%) patients. Nine patients (7.4%) were suspected of malignancy; none turned out to be malignant. Six clinical malignancies that developed during follow-up were all negative on baseline FDG-PET/CT. Conclusion: Whole-body FDG-PET/CT scanning used in RA patients for imaging of arthritis results in frequent incidental extra-articular findings, whereas some who apparently had normal scans also developed malignancies. Trial registration: Netherlands Trial Register, www.trialregister.nl, NL6771.

Abatacept and tocilizumab tapering in rheumatoid arthritis patients: results of SONATA-a retrospective, exploratory cohort study.

OBJECTIVES: As data on disease-activity-guided dose optimization of abatacept and tocilizumab are scarce, we explored the feasibility, effectiveness and safety of dose optimization of these biological DMARDs in RA patients in daily practice. METHODS: RA patients who had been treated with abatacept or tocilizumab for ≥6 months, with DAS28 <3.2, were included. Four groups were identified: abatacept dose reduction (DR) and usual care (UC), and tocilizumab DR and UC. Successful DR and discontinuation entailed being on a lower dose than at baseline or having discontinued abatacept or tocilizumab, while maintaining disease activity score with ESR using 28 joint count (DAS28) <3.2. Proportions of patients with successful DR or discontinuation at 12 months were described. Maintenance of DR was investigated using Kaplan-Meier curves. Between-group differences in mean DAS28 and Health assessment questionnaire disability index (HAQ-DI) change (Δ) over 6 and 12 months were estimated. RESULTS: One hundred and nineteen patients were included. DR was attempted in 13 of 28 (46%; 95% CI: 28, 66%) abatacept and 64 of 91 (70%; 95% CI: 60, 79%) tocilizumab patients. At 12 months, 3 of 11 (27%; 95% CI: 6, 61%) abatacept and 20 of 48 (42%; 95% CI: 28, 57%) tocilizumab patients were successfully tapered. One of 11 (9%; 95% CI: 0, 41%) abatacept and 5 of 48 (10%; 95% CI: 3, 23%) tocilizumab patients were successfully discontinued. Mean ΔDAS28 and ΔHAQ-DI at months 6 and 12 were not significantly different between DR and UC. For tocilizumab, DAS28 was significantly higher in the DR compared with the UC group at 6 months. Adverse events were comparable between groups. CONCLUSION: Abatacept and tocilizumab DR appears to be feasible and safe in clinical practice. No benefits in terms of fewer adverse events in the DR group were observed. Furthermore, DR was suboptimal, because all patients were eligible for DR, but in a substantial number of patients no DR was attempted.

What causes a small increase in radiographic progression in rheumatoid arthritis patients tapering TNF inhibitors?

OBJECTIVE: In a randomised controlled trial investigating tapering of TNF inhibitors (TNFi) compared with usual care (UC) in rheumatoid arthritis patients, minimal radiographic progression was more frequent in patients who attempted tapering. Possible explanations include higher incidence of flaring, higher mean disease activity or lower TNFi use. METHODS: 18 months data from the DRESS study were used. Change in Sharp-van der Heijde (ΔSvdH) score (linear regression) and proportion of patients with >0.5 ΔSvdH (logistic regression) were used as outcomes. The cumulative incidence and number of short-lived and major flares per patient, mean time-weighted disease activity (MTW-DAS28-CRP) and TNFi use were used as independent variables. Regression models were performed stratified per study group and corrected for possible confounders. RESULTS: 175 of 180 patients had 18-month data available. The mean ΔSvdH were 0.75 and 0.15 units with 37 of 116 (32%) and 9 of 59 (15%) patients exceeding 0.5 points in the tapering and UC group, respectively (both p<0.05). MTW-DAS28-CRP, but not incidence or number of short-lived or major flares, or TNFi use, was independently associated with the mean progression score, but only in the tapering group. Additional analyses on DAS28-CRP subcomponents showed that this was mainly caused by MTW swollen joint count. No confounders were identified. CONCLUSIONS: Radiographic progression was associated with higher MTW-DAS28-CRP (and especially swollen joint count), but only in patients who tapered TNFi. This finding stresses the importance of maintaining disease activity as low as possible in patients in whom TNFi is tapered and to check for radiographic progression regularly. TRIAL REGISTRATION NUMBER: NTR 3216; Post-results.