Effects of tapering conventional synthetic disease-modifying antirheumatic drugs to drug-free remission versus stable treatment in rheumatoid arthritis (ARCTIC REWIND): 3-year results from an open-label, randomised controlled, non-inferiority trial.

BACKGROUND: Tapering of disease-modifying antirheumatic drugs (DMARDs) to drug-free remission is an attractive treatment goal for patients with rheumatoid arthritis, although long-term effects of tapering and withdrawal remain unclear. We compared 3-year risks of flare between three conventional synthetic DMARD treatment strategies in patients with rheumatoid arthritis in sustained remission. METHODS: In this open-label, randomised controlled, non-inferiority trial, we enrolled patients aged 18-80 years with rheumatoid arthritis who had been in sustained remission for at least 1 year on stable conventional synthetic DMARD therapy. Patients from ten hospitals in Norway were randomly assigned (2:1:1) with centre stratification to receive stable conventional synthetic DMARDs, half-dose conventional synthetic DMARDs, or half-dose conventional synthetic DMARDs for 1 year followed by withdrawal of all conventional synthetic DMARDs. The primary endpoint of this part of the study was disease flare over 3 years, analysed as flare-free survival and risk difference in the per-protocol population with a non-inferiority margin of 20%. This trial is registered with ClinicalTrials.gov (NCT01881308) and is completed. FINDINGS: Between June 17, 2013, and June 18, 2018, 160 patients were enrolled and randomly assigned to receive stable-dose conventional synthetic DMARDs (n=80), half-dose conventional synthetic DMARDs (n=42), or half-dose conventional synthetic DMARDs tapering to withdrawal (n=38). Four patients did not receive the intervention and 156 patients received the allocated treatment strategy. One patient was excluded due to major protocol violation and 155 patients were included in the per-protocol analysis. 104 (67%) of 156 patients were women and 52 (33%) were men. 139 patients completed 3-years follow-up without major protocol violation; 68 (87%) of 78 patients in the stable-dose group, 36 (88%) of 41 patients in the half-dose group and 35 (95%) of 37 patients in the half-dose tapering to withdrawal group. During the 3-year study period, 80% (95% CI 69-88%) were flare-free in the stable-dose group, compared with 57% (41-71%) in the half-dose group and 38% (22-53%) in the half-dose tapering to withdrawal group. Compared with stable-dose conventional synthetic DMARDs, the risk difference of flare was 23% (95% CI 6-41%, p=0·010) in the half-dose group and 40% (22-58%, p<0·0001) in the half-dose tapering to withdrawal group, non-inferiority was therefore not shown. Adverse events were reported in 65 (83%) of 78 patients in the stable-dose group, 36 (90%) of 40 patients in the half-dose group, and 36 (97%) of 37 patients in the half-dose tapering to withdrawal group. One death occurred in the stable-dose conventional synthetic DMARD group (sudden death considered unlikely related to the study medication). INTERPRETATION: Two conventional synthetic DMARD tapering strategies were associated with significantly lower rates of flare-free survival compared with stable conventional synthetic DMARD treatment, and the data do not support non-inferiority. However, drug-free remission was achiveable for a significant subgroup of patients. This trial provides information on risk and benefits of different treatment strategies important for shared decision making. FUNDING: Research Council of Norway and South-Eastern Norway Regional Health Authority.

Effectiveness and Persistence in SB4- and Reference Etanercept-Treated Rheumatoid Arthritis Patients in Ordinary Clinical Practice in Norway.

OBJECTIVE: Biosimilars represent cost-effective alternatives to reference biologic disease-modifying antirheumatic drugs. Our objective was to compare drug effectiveness and drug persistence in the treatment of rheumatoid arthritis (RA), assessing the etanercept biosimilar SB4 in efficacy and safety compared with reference etanercept in a Phase III, randomized controlled trial. We applied EULAR Points to Consider for Comparative Effectiveness Research in a retrospective database study of etanercept and SB4 in patients treated in clinical practice in Norway. METHODS: Patients with RA (n = 1,455) treated with etanercept or SB4 between 2010 and 2018 at 5 centers in Norway with ≥1 year of follow-up were included. Disease outcomes (Disease Activity Score in 28 joints [DAS28] at week 52) and drug persistence were compared between unmatched etanercept (n = 575) and SB4 (n = 299) cohorts and matched analyses (n = 172, both cohorts) using propensity score (PS) matching to adjust for confounders. RESULTS: In unmatched analyses, the difference in change from baseline between etanercept (n = 221) and SB4 (n = 106) for DAS28 at week 52 was mean -0.02 (95% confidence interval [95% CI] -0.32, 0.27), demonstrating equivalence by the predetermined equivalence margin (±0.6). In PS-matched analyses, the difference between etanercept (n = 49) and SB4 (n = 49) was 0.03 (95% CI -0.46, 0.52), within the predefined equivalence margin. Persistence using the drug at week 52 was similar between etanercept (0.62 [95% CI 0.57, 0.65]) and SB4 (0.66 [95% CI 0.60, 0.71]) cohorts in the unmatched analysis; in PS-matched cohorts, persistence at week 52 was 0.52 (95% CI 0.44, 0.59) for etanercept and 0.68 (95% CI 0.61, 0.75) for SB4. CONCLUSION: Outcomes for disease status/drug persistence at week 52 were similar between patients with RA treated with etanercept or SB4.

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.

Ten years of follow-up data in psoriatic arthritis: results based on standardized monitoring of patients in an ordinary outpatient clinic in southern Norway.

BACKGROUND: Over the last decade, a treat-to-target (T2T) strategy has been recommended for psoriatic arthritis (PsA) and new treatment options have become available. There is a lack of data on PsA regarding any changes that may have occurred over these past years. Thus, the main aim of this study was to look for changes in clinical disease status and treatment in a PsA outpatient clinic population monitored over the period 2008 to 2017. METHODS: Annual data collection included demographic data, laboratory (erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)) and clinic measures of disease activity (e.g., 28 and 32 joint count Disease Activity Score (DAS28), Clinical Disease Activity Index (CDAI), and modified Disease Activity index for Psoriatic arthritis (DAPSA)), evaluator's global assessment, and patient-reported outcomes (PROs), including for example measures of physical function, pain, and patient global assessment. Disease-modifying antirheumatic drug (DMARD) use was also registered. RESULTS: In the PsA outpatient clinic population over the 10-year period (annual mean number of patients, 331) the mean (standard deviation) age was 58.4 (12.4) years, disease duration was 9.6 (7.9) years, 49.4% were female, and 17.6% were current smokers. From 2008 to 2017, no statistically significant increase in remission rates was seen for DAPSA (13.5% and 22.0%) or Boolean remission (6.6% and 8.9%), whereas a statistically significant increase was seen for DAS28-ESR (36.8% and 50.6%) and CDAI (20.0% and 29.6%), but not for the last 5 years (DAS28-ESR, 42.3% and 50.6%; CDAI, 27.9% and 29.6%). Furthermore, over the 10-year period no significant improvement for PROs and no significant change in the use of synthetic (annual mean 53.0%) and biologic DMARDs (annual mean 29.9%) was found. CONCLUSION: Our data suggest that even in the biologic treatment era there is an unmet need for treating PsA patients to target remission. New treatment options and the development of more feasible and valid outcome measures for use in a T2T strategy in ordinary clinical practice may in the future to further improve clinical outcomes in PsA.

Ultrasound in management of rheumatoid arthritis: ARCTIC randomised controlled strategy trial.

OBJECTIVE:  To determine whether a treatment strategy based on structured ultrasound assessment would lead to improved outcomes in rheumatoid arthritis, compared with a conventional strategy. DESIGN:  Multicentre, open label, two arm, parallel group, randomised controlled strategy trial. SETTING:  Ten rheumatology departments and one specialist centre in Norway, from September 2010 to September 2015. PARTICIPANTS:  238 patients were recruited between September 2010 and April 2013, of which 230 (141 (61%) female) received the allocated intervention and were analysed for the primary outcome. The main inclusion criteria were age 18-75 years, fulfilment of the 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for rheumatoid arthritis, disease modifying anti-rheumatic drug naivety with indication for disease modifying drug therapy, and time from first patient reported swollen joint less than two years. Patients with abnormal kidney or liver function or major comorbidities were excluded. INTERVENTIONS:  122 patients were randomised to an ultrasound tight control strategy targeting clinical and imaging remission, and 116 patients were randomised to a conventional tight control strategy targeting clinical remission. Patients in both arms were treated according to the same disease modifying anti-rheumatic drug escalation strategy, with 13 visits over two years. MAIN OUTCOME MEASURES:  The primary endpoint was the proportion of patients with a combination between 16 and 24 months of clinical remission, no swollen joints, and non-progression of radiographic joint damage. Secondary outcomes included measures of disease activity, radiographic progression, functioning, quality of life, and adverse events. All participants who attended at least one follow-up visit were included in the full analysis set. RESULTS:  26 (22%) of the 118 analysed patients in the ultrasound tight control arm and 21 (19%) of the 112 analysed patients in the clinical tight control arm reached the primary endpoint (mean difference 3.3%, 95% confidence interval -7.1% to 13.7%). Secondary endpoints (disease activity, physical function, and joint damage) were similar between the two groups. Six (5%) patients in the ultrasound tight control arm and seven (6%) patients in the conventional arm had serious adverse events. CONCLUSIONS:  The systematic use of ultrasound in the follow-up of patients with early rheumatoid arthritis treated according to current recommendations is not justified on the basis of the ARCTIC results. The findings highlight the need for randomised trials assessing the clinical application of medical technology.Trial registration Clinical trials NCT01205854.

Ten years of change in clinical disease status and treatment in rheumatoid arthritis: results based on standardized monitoring of patients in an ordinary outpatient clinic in southern Norway.

INTRODUCTION: In the new millennium, clinical outcomes in patients with rheumatoid arthritis (RA) have improved. Despite a large number of register data, there is a lack of data reflecting the entire outpatient RA population, and in particular long-term data. The main aim of this study was to explore changes in clinical disease status and treatment in an RA outpatient clinic population monitored with recommended outcome measures over a 10-year period. METHODS: Standard data collected included demographic data, erythrocyte sedimentation rate, C-reactive protein, clinical measures of disease activity (Disease Activity Score in 28 joint counts [DAS28], Clinical Disease Activity Index [CDAI], Simplified Disease Activity Index [SDAI] and global assessments) and patient-reported outcomes (measures of physical function, joint pain, fatigue, patient global assessment and morning stiffness). Treatment with disease-modifying antirheumatic drugs (DMARDs) was also recorded, as well as rheumatoid factor (RF) and anti-citrullinated protein antibody (ACPA) status. RESULTS: In the RA population, the mean age was approximately 64 years and disease duration was 10-12 years. About 70 % were females; approximately 20 % were current smokers; and 65-70 % were positive for RF and ACPA. During follow-up, disease activity improved significantly. When we applied the DAS28, CDAI, SDAI and Boolean criteria for remission, the proportions of patients in remission increased from 21.3 %, 8.1 %, 5.8 % and 3.8 %, respectively, in 2004 to 55.5 %, 31.7 %, 31.8 % and 17.7 %, respectively, in 2013. The proportions of patients with DAS28, CDAI and SDAI low disease activity status were 16.0 %, 34.0 %, and 34.9 %, respectively, in 2004 and 17.8 %, 50.4 % and 50.8 %, respectively, in 2013. A significant improvement in patient-reported outcome was seen only for the full 10-years, but not for the last 4 years, of the study period. The proportion of patients taking synthetic (about 60 %) and biologic (approximately 30 %) DMARDs was stable over the last 4 years of the study period, with no significant change observed, whereas the proportion of patients being treated with prednisolone was reduced significantly from 61 % in 2010 to 54 % in 2013. CONCLUSIONS: The encouraging data we present suggest that the vast majority of patients with RA monitored in outpatient clinics in the new millennium can expect to achieve a status of clinical remission or low disease activity.

EULAR task force recommendations on annual cardiovascular risk assessment for patients with rheumatoid arthritis: an audit of the success of implementation in a rheumatology outpatient clinic.

OBJECTIVE: EULAR recommendations for cardiovascular disease (CVD) risk management include annual CVD risk assessments for patients with rheumatoid arthritis (RA). We evaluated the recording of CVD risk factors (CVD-RF) in a rheumatology outpatient clinic, where EULAR recommendations had been implemented. Further, we compared CVD-RF recordings between a regular rheumatology outpatient clinic (RegROC) and a structured arthritis clinic (AC). METHODS: In 2012, 1142 RA patients visited the rheumatology outpatient clinic: 612 attended RegROC and 530 attended AC. We conducted a search in the patient journals to ascertain the rate of CVD-RF recording. RESULTS: The overall CVD-RF recording rate was 40.1% in the rheumatology outpatient clinic, reflecting a recording rate of 59.1% in the AC and 23.6% in the RegROC. The odds ratios for having CVD-RFs recorded for patients attending AC compared to RegROC were as follows: blood pressure: 12.4, lipids: 5.0-6.0, glucose: 9.1, HbA1c: 6.1, smoking: 1.4, and for having all the CVD-RFs needed to calculate the CVD risk by the systematic coronary risk evaluation (SCORE): 21.0. CONCLUSION: The CVD-RF recording rate was low in a rheumatology outpatient clinic. However, a systematic team-based model was superior compared to a RegROC. Further measures are warranted to improve CVD-RF recording in RA patients.