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.

Increasing Risk of Hospital-Treated Infections and Community-Based Antibiotic Use After Hip Fracture Surgery: A Nationwide Study 2005-2016.

We aimed to examine trends in the incidence of treated infections following hip fracture surgery in Denmark from 2005 to 2016. We conducted a nationwide cohort study using individual-level linked data from Danish population-based registries. We calculated cumulative incidence considering death as competing risk and, based on the pseudo-observation method, risk ratios (RRs) with 95% confidence interval (CI) using the period 2005-2006 as a reference. RRs were adjusted for age, sex, and comorbidity. A total of 74,771 patients aged 65 years or older with first-time hip fracture surgery were included. The risk of postoperative (at 15, 30, 90, and 365 days) infections increased during 2005-2016. The 30-day cumulative incidence of all hospital-treated infections increased from 10.8% (95% CI, 10.2% to 11.3%) in 2005-2006 to 14.3% (95% CI, 13.7% to 15.0%) in 2015-2016 (adjusted RR 1.32; 95% CI, 1.23 to 1.42). Adjusted RR for 30-day hospital-treated pneumonia was 1.70 (95% CI, 1.49 to 1.92). The 30-day cumulative incidence of redeeming community-based antibiotic prescriptions increased from 17.5% (95% CI, 16.8% to 18.2%) in 2005-2006 to 27.1% (95% CI, 26.3% to 27.9%) in 2015-2016 (adjusted RR 1.54; 95% CI, 1.47 to 1.62). The largest increase was observed for broad-spectrum antibiotic use (adjusted RR 1.79; 95% CI, 1.68 to 1.90). During 2005-2016, risk of infections was substantially higher in hip fracture patients than in the general population. The risk of hospital-treated pneumonia and antibiotic prescriptions increased more over time among hip fracture patients. We found increased risks of postoperative treated infections following hip fracture surgery during the 12-year study period, which could not entirely be explained by similar infection trends in the general population. Given the high mortality following infections in the elderly, further research is needed to identify patients at increased risk to target preventive treatment and potentially reduce complications and mortality in hip fracture patients. © 2018 American Society for Bone and Mineral Research.