Effect of tapered versus stable treatment with tumour necrosis factor inhibitors on disease flares in patients with rheumatoid arthritis in remission: a randomised, open label, non-inferiority trial.

OBJECTIVES: Many patients with rheumatoid arthritis (RA) require treatment with tumour necrosis factor inhibitor (TNFi) to reach remission. It is debated whether tapering of TNFi to discontinuation should be considered in sustained remission. The aim of ARCTIC REWIND TNFi was to assess the effect of tapering TNFi to withdrawal compared with stable treatment on the risk of disease activity flares in patients with RA in remission ≥1 year. METHODS: This randomised, open-label, non-inferiority trial was undertaken at nine Norwegian rheumatology departments. Patients with RA in remission ≥12 months on stable TNFi therapy were allocated by computer-based block-randomisation to tapering to discontinuation of TNFi or stable TNFi. Conventional synthetic disease-modifying antirheumatic co-medication was unchanged. The primary endpoint was disease flare during the 12-month study period (non-inferiority margin 20%), assessed in the per-protocol population. RESULTS: Between June 2013 and January 2019, 99 patients were enrolled and 92 received the allocated treatment strategy. Eighty-four patients were included in the per-protocol population. In the tapering TNFi group, 27/43 (63%) experienced a flare during 12 months, compared with 2/41 (5%) in the stable TNFi group; risk difference (95% CI) 58% (42% to 74%). The tapering strategy was not non-inferior to continued stable treatment. The number of total/serious adverse events was 49/3 in the tapering group, 57/2 in the stable group. CONCLUSION: In patients with RA in remission for more than 1 year while using TNFi, an increase in flare rate was reported in those who tapered TNFi to discontinuation. However, most regained remission after reinstatement of full-dose treatment. TRIAL REGISTRATION NUMBERS: EudraCT: 2012-005275-14 and clinicaltrials.gov: NCT01881308.

Effect of Half-Dose vs Stable-Dose Conventional Synthetic Disease-Modifying Antirheumatic Drugs on Disease Flares in Patients With Rheumatoid Arthritis in Remission: The ARCTIC REWIND Randomized Clinical Trial.

Importance: Sustained remission has become an achievable goal for patients with rheumatoid arthritis (RA) receiving conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), but how to best treat patients in clinical remission remains unclear. Objective: To assess the effect of tapering of csDMARDs, compared with continuing csDMARDs without tapering, on the risk of flares in patients with RA in sustained remission. Design, Setting, and Participants: ARCTIC REWIND was a multicenter, randomized, parallel, open-label noninferiority study conducted in 10 Norwegian hospital-based rheumatology practices. A total of 160 patients with RA in remission for 12 months who were receiving stable csDMARD therapy were enrolled between June 2013 and June 2018, and the final visit occurred in June 2019. Interventions: Patients were randomly assigned to half-dose csDMARDs (n = 80) or stable-dose csDMARDs (n = 80). Main Outcomes and Measures: The primary end point was the proportion of patients with a disease flare between baseline and the 12-month follow-up, defined as a combination of Disease Activity Score (DAS) greater than 1.6 (threshold for RA remission), an increase in DAS score of 0.6 units or more, and at least 2 swollen joints. A disease flare could also be recorded if both the patient and investigator agreed that a clinically significant flare had occurred. A risk difference of 20% was defined as the noninferiority margin. Results: Of 160 enrolled patients (mean [SD] age, 55.1 [11.9] years; 66% female), 156 received the allocated therapy, of which 155 without any major protocol violations were included in the primary analysis population (77 receiving half-dose and 78 receiving stable-dose csDMARDs). Flare occurred in 19 patients (25%) in the half-dose csDMARD group compared with 5 (6%) in the stable-dose csDMARD group (risk difference, 18% [95% CI, 7%-29%]). Adverse events occurred in 34 patients (44%) in the half-dose group and 42 (54%) in the stable-dose group, none leading to study discontinuation. No deaths occurred. Conclusions and Relevance: Among patients with RA in remission taking csDMARD therapy, treatment with half-dose vs stable-dose csDMARDs did not demonstrate noninferiority for the percentage of patients with disease flares over 12 months, and there were significantly fewer flares in the stable-dose group. These findings do not support treatment with half-dose therapy. Trial Registration: ClinicalTrials.gov Identifier: NCT01881308.

Clinical and ultrasound remission after 6 months of treat-to-target therapy in early rheumatoid arthritis: associations to future good radiographic and physical outcomes.

OBJECTIVE: To explore associations between remission, based on clinical and ultrasound definitions, and future good radiographic and physical outcome in early rheumatoid arthritis (RA). METHODS: Newly diagnosed patients with RA followed a treat-to-target strategy incorporating ultrasound information in the Aiming for Remission in rheumatoid arthritis: a randomised trial examining the benefit of ultrasound in a Clinical TIght Control regimen (ARCTIC) trial. We defined 6-month remission according to Disease Activity Score, Disease Activity Score in 28 joints-erythrocyte sedimentation rate, American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Boolean criteria, Simplified Disease Activity Index, Clinical Disease Activity Index and two ultrasound definitions (no power Doppler signal, grey scale score ≤2). Two outcomes were defined: no radiographic progression and good outcome (no radiographic progression+physical function≥general population median), both sustained 12-24 months. We calculated the ORs of these outcomes for the remission definitions. RESULTS: Of 103 patients, 42%-82% reached remission at 6 months, dependent on definition. Seventy-one per cent of patients had no radiographic progression and 37% had good outcome. An association between 6-month remission and no radiographic progression was observed for ACR/EULAR Boolean remission (44 joints, OR 3.2, 95% CI 1.2 to 8.4), ultrasound power Doppler (OR 3.6, 95% CI 1.3 to 10.0) and grey scale remission (OR 3.2, 95% CI 1.2 to 8.0). All clinical, but not ultrasound remission criteria were associated with achievement of a good outcome. CONCLUSIONS: Our data support ACR/EULAR Boolean remission based on 44 joints as the preferred treatment target in early RA. Absence of ultrasound inflammation was associated with no radiographic progression. TRIAL REGISTRATION NUMBER: NCT01205854; Post-results.

Predictors of sustained remission in patients with early rheumatoid arthritis treated according to an aggressive treat-to-target protocol.

Objectives: To study prognostic factors for achievement of sustained remission in early RA patients receiving semi-personalized tight controlled treatment, and to assess the consistency of potential predictors across definitions of sustained remission. Methods: DMARD-naïve early RA patients with symptom duration <2 years were treated according to a pre-defined algorithm within the Aiming for Remission in rheumatoid arthritis: a randomised trial examining the benefit of ultrasound in a Clinical TIght Control regimen trial. The algorithm allowed treatment adjustments based on established risk factors for a worse outcome. Multivariate logistic regression was used to examine baseline predictors of achieving sustained DAS remission at 16-24 months, and to assess predictors of secondary remission outcomes (all sustained 16-24 months): ACR/EULAR Boolean, Simplified Disease Activity Index (SDAI), no swollen joints and a composite outcome of DAS remission, no swollen joints and no radiographic progression. Results: Of 222 patients, 118 (53%) reached sustained DAS remission, while 53 (24%) reached sustained ACR/EULAR Boolean and 73 (33%) sustained SDAI remission. More joint tenderness, assessed by Ritchie Articular Index, was a negative predictor of reaching sustained DAS remission (odds ratio (OR) = 0.90/U, 95% CI: 0.86, 0.94), sustained ACR/EULAR Boolean remission (OR = 0.92, 95% CI: 0.86, 0.98), sustained SDAI remission (OR = 0.94, 95% CI: 0.90, 1.00) as well as the two alternative definitions of sustained remission. Short symptom duration at baseline predicted sustained Boolean and SDAI remission. Other identified predictors were inconsistent across outcomes. Conclusion: A higher tender joint score at baseline consistently reduced the chance of reaching sustained remission across all definitions. Our results support sustained remission as an achievable goal in early RA, especially when initiating DMARDs within 3 months symptom duration. Trial registration: ClinicalTrials.gov, http://clinicaltrials.gov, NCT01205854.

Discontinuation of Conventional Synthetic Disease-Modifying Antirheumatic Drugs in Patients With Rheumatoid Arthritis and Excellent Disease Control.

This open-label randomized clinical trial assessed the 12-month risk of disease activity flares after discontinuation of conventional synthetic DMARDs (csDMARDs) compared with continuing half-dose csDMARDs in adult Norwegian patients with rheumatoid arthritis and excellent disease control.

Performance of the Rheumatoid Arthritis Impact of Disease (RAID) score in relation to flares in disease activity.

OBJECTIVES: To explore the performance of the EULAR-initiated patient-reported Rheumatoid Arthritis Impact of Disease (RAID) questionnaire in relation to flares in disease activity, including comparison with other disease activity outcomes. METHODS: Patients with rheumatoid arthritis in sustained remission were randomised to continued stable treatment or tapering in the ARCTIC REWIND project. In patients with flares within 12 months, we compared RAID (total score and components) at the flare visit with the visit prior to and the visit following flare, using Wilcoxon signed-rank test. Similar analyses were performed for patient global assessment, Disease Activity Score (DAS) and C reactive protein (CRP). The discriminative accuracies of RAID, patient global assessment, DAS and CRP with respect to disease activity flares were assessed by receiver operating characteristic (ROC) analyses based on logistic regression models. Flare was defined as a combination of DAS >1.6, a DAS increase ≥0.6 and ≥two swollen joints (of 44 examined) or could be recorded if patient and rheumatologist agreed that a clinically significant flare had occurred. RESULTS: In total, 248 patients were included in the analyses, with 56 flares. RAID, patient global assessment, DAS and CRP all changed significantly at the visits related to flare (p<0.001). Area under the curve (95% CI) values indicated that RAID (0.88 (0.83 to 0.93)) was significantly more accurate than CRP (0.76 (0.69 to 0.84)) in discriminating flare, and less accurate than patient global assessment (0.92 (0.87 to 0.97)) and DAS (0.94 (0.90 to 0.98)). The RAID components with highest and lowest discriminative accuracies were pain (0.91 (0.86 to 0.95)) and sleep (0.69 (0.59 to 0.79)). CONCLUSION: Disease activity flares were associated with a significant increase in median RAID, supporting its ability to respond to flare. TRIAL REGISTRATION NUMBER: NCT01881308.

Agreement between patient-reported flares and clinically significant flare status in patients with rheumatoid arthritis in sustained remission: data from the ARCTIC REWIND trials.

OBJECTIVES: To explore the agreement between patient-reported flare status and clinically significant flare status in patients with rheumatoid arthritis (RA) in sustained remission. METHOD: Patients with RA in remission for ≥12 months on stable treatment were included in the ARCTIC REWIND tapering trials and pooled 12-month data used in current analyses. Patient-reported flare status was assessed according to the Outcome Measures in Rheumatology flare questionnaire; 'Are you having a flare of your RA at this time?' (yes/no). A clinically significant flare was defined as a combination of Disease Activity Score (DAS) >1.6, increase in DAS of ≥0.6 and 2 swollen joints, or the rheumatologist and patient agreed that a clinically significant flare had occurred. Agreement coefficient, sensitivity, specificity and predictive values of patient-reported flare status with regard to clinically significant flare status were determined. RESULTS: Of 248 patients, 64% were women, age 56.1 (11.8) years, disease duration 4.1 (2.8-7.4) years, DAS 0.8 (0.3). 35% of patients reported a flare at least once, clinically significant flares were recorded in 21%. 48/53 clinically significant flares (91%) led to an intensification of disease-modifying antirheumatic drugss. In 621/682 (91%) visits, patient-reported and clinically significant flare status were in agreement, agreement coefficient 0.89. Sensitivity and specificity were both 91%, positive predictive value of patient-reported flare status 46% and negative predictive value 99%. CONCLUSION: Among patients in sustained remission, patient-reported flare status was accurate in ruling out a clinically significant flare. About half of the patient-reported flares were assessed to be clinically significant. These findings support a potential for using patient-reported flare status in remote monitoring of patients with RA in sustained remission.

Inflammation and biologic therapy in patients with rheumatoid arthritis achieving versus not achieving ACR/EULAR Boolean remission in a treat-to-target study.

OBJECTIVE: To investigate limiting factors of American College of Rheumatology (ACR)/EULAR Boolean remission in rheumatoid arthritis (RA), and compare patients who fulfil the criteria to patients who only partly fulfil the criteria, with respect to imaging inflammation and biologic disease modifying anti-rheumatic drug (DMARD) usage. METHODS: Patients with DMARD-naïve RA were treated according to current recommendations in the the ARCTIC trial (Aiming for Remission in rheumatoid arthritis: a randomised trial examining the benefit of ultrasound in a Clinical TIght Control regimen). Limiting factors of reaching ACR/EULAR Boolean remission at 2 years were assessed. Imaging inflammation (ultrasound and MRI) in patients in remission was compared with patients failing to fulfil different components of the criteria. The OR of biologic therapy was calculated using logistic regression. RESULTS: Of 203 patients, 112 (55%) reached ACR/EULAR Boolean remission; 49 (24%) fulfilled three of four criteria. The main limiting factors were patient global assessment (PGA) (59%) and tender joints (22%). Imaging inflammation was not significantly different for patients in remission and patients not fulfilling the criteria due to elevated PGA and/or tender joints, but higher odds of using biologics (OR 3.63, 95% CI 1.73 to 7.61) were observed. CONCLUSIONS: PGA and tender joints were the factors most often limiting achievement of ACR/EULAR Boolean remission. The level of imaging inflammation was not elevated in these patients compared with patients in remission, but the odds of using biologic DMARDs were higher.