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IntroductionThe use of proton therapy increases globally despite a lack of randomised controlled trials demonstrating its efficacy and safety. Proton therapy enables sparing of non-neoplastic tissue from radiation. This is principally beneficial and holds promise of reduced long-term side effects. However, the sparing of seemingly non-cancerous tissue is not necessarily positive for isocitrate dehydrogenase (IDH)-mutated diffuse gliomas grade 2–3, which have a diffuse growth pattern. With their relatively good prognosis, yet incurable nature, therapy needs to be delicately balanced to achieve a maximal survival benefit combined with an optimised quality of life.Methods and analysisPRO-GLIO (PROton versus photon therapy inIDH-mutated diffuse grade 2 and 3 GLIOmas) is an open-label, multicentre, randomised phase III non-inferiority study. 224 patients aged 18–65 years withIDH-mutated diffuse gliomas grade 2–3 from Norway and Sweden will be randomised 1:1 to radiotherapy delivered with protons (experimental arm) or photons (standard arm). First intervention-free survival at 2 years is the primary endpoint. Key secondary endpoints are fatigue and cognitive impairment, both at 2 years. Additional secondary outcomes include several survival measures, health-related quality of life parameters and health economy endpoints.Ethics and disseminationTo implement proton therapy as part of standard of care for patients withIDH-mutated diffuse gliomas grade 2–3, it should be deemed safe. With its randomised controlled design testing proton versus photon therapy, PRO-GLIO will provide important information for this patient population concerning safety, cognition, fatigue and other quality of life parameters. As proton therapy is considerably more costly than its photon counterpart, cost-effectiveness will also be evaluated. PRO-GLIO is approved by ethical committees in Norway (Regional Committee for Medical & Health Research Ethics) and Sweden (The Swedish Ethical Review Authority) and patient inclusion has commenced. Trial results will be published in international peer-reviewed journals, relevant conferences, national and international meetings and expert forums.Trial registration numberClinicalTrials.gov Registry (NCT05190172).

Tender joint count is part of most composite disease activity scores and treatment targets in rheumatoid arthritis (RA).1 Joint tenderness could represent not only synovial inflammation in the absence of clinical swelling but also factors such as erosive damage and pain sensitisation.2 Ultrasound examination can add information to the clinical evaluation of inflammation. Joint tenderness did not reflect inflammatory activity when assessed by ultrasound in patients with established RA3 but might be more related to inflammation in early arthritis.4 5 We aimed to explore joint tenderness in DMARD-naive patients with early RA and assess whether this finding was associated with ultrasound inflammation in the absence of swelling. The analyses were performed using baseline data from the ARCTIC trial,6 which included assessment of joint tenderness by Ritchie Articular Index and a 44-swollen joint count. The Ritchie Articular Index grades joint tenderness 0–3, with certain joints being treated as a single unit, for example, the metacarpal-phalangeal (MCP) joints. In the ultrasound examination, 32 joints were all dorsally scored semiquantitatively 0–3 for power Doppler (PD), with an ultrasound atlas for reference.6 The wrists were predefined as the joint area of interest since they are commonly involved in RA and were assessed both clinically and by ultrasound. Additionally, in these joints, scoring of tenderness by Ritchie Articular Index could correspond to the more commonly used tender joint count. The presence of ultrasound inflammation was defined as …

ObjectiveAlthough COVID-19 is primarily a respiratory infection, mounting evidence suggests that the GI tract is involved in the disease, with gut barrier dysfunction and gut microbiota alterations being related to disease severity. Whether these alterations persist and could be related to long-term respiratory dysfunction is unknown.DesignFrom the NOR-Solidarity trial (n=181), plasma was collected during hospital admission and after three months, and analyzed for markers of gut barrier dysfunction and inflammation. At the three-month follow-up, pulmonary function was assessed by measuring diffusing capacity of the lungs for carbon monoxide (DLCO), and rectal swabs for gut microbiota analyses were collected (n= 97) and analysed by sequencing of the 16S rRNA gene.ResultsGut microbiota diversity was reduced in COVID-19 patients with persistent respiratory dysfunction, defined as DLCO below lower limit of normal three months after hospitalization. These patients also had an altered global gut microbiota composition, with reduced abundance of Erysipelotrichaceae UCG-003 and increased abundance of Flavonifractor and Veillonella, the latter potentially being linked to fibrosis. During hospitalization, increased plasma levels of lipopolysaccharide-binding protein (LBP) were strongly associated with respiratory failure, defined as pO2/fiO2-(P/F-ratio)ConclusionPersistent respiratory dysfunction after COVID-19 is associated with reduced biodiversity and gut microbiota alterations, along with persistently elevated LBP levels. Our results point to a potential gut-lung axis that should be further investigated in relation to long-term pulmonary dysfunction and long COVID.Summary boxWhat is already known about this subject?Mounting evidence suggests that the gastrointestinal tract is involved in the pathogenesis of COVID-19, with the putative SARS-CoV-2 receptor ACE 2 ubiquitously expressed in the gut.In severe COVID-19, the gut-blood barrier is compromised, and leakage of microbial products, such as lipopolysaccharides (LPS), could affect the host’s response to COVID-19 infection.COVID-19 patients exhibit an altered gut microbiota composition, which has been related to disease severity. However, it is currently not known whether dysbiosis or gut barrier dysfunction persist long-term after hospitalization, or whether microbiota-related mechanisms could be related to persistent pulmonary dysfunction.What are the new findings?COVID-19 patients with persistent respiratory dysfunction after three months had a lower microbial diversity and an altered gut microbiota composition at the same time point.The microbiota alterations included reduced abundance of Erysipelotrichaceae UCG-003 and increased abundance of Veillonella and Flavonifractor.During hospitalization, increased plasma levels of LBP were strongly associated with respiratory failure.LBP levels remained elevated during and after hospitalization, and associated significantly with persistent respiratory dysfunction at three-month follow-up.How might it impact on clinical practice in the foreseeable future?Our findings point to a potential gut-lung axis in relation not only to respiratory failure during hospitalization, but also to long-term COVID-19 morbidity. Further studies on gut microbiota composition and gut barrier dysfunction as potential treatment targets and/or disease severity biomarkers in relation to long-term pulmonary dysfunction and long COVID are warranted.

IntroductionIn the multisystem inflammatory disorder systemic sclerosis (SSc), gastrointestinal tract (GIT) affliction is highly prevalent. There are no known disease modifying therapies and the negative impact is substantial. Aiming for a new therapeutic principle, and inspired by recent work showing associations between gut microbiota changes and GIT symptoms in SSc, we performed a pilot study on faecal microbiota transplantation (FMT) with the single-donor bacterial culture ‘Anaerobic Cultivated Human Intestinal Microbiome (ACHIM)’. Motivated by positive pilot study signals, we designed the ReSScue trial as a phase II multicentre, placebo-controlled, randomised 20-week trial to evaluate safety and efficacy on lower GIT symptoms of FMT by ACHIM in SSc.Methods and analysesWe aim to include 70 SSc participants with moderate to severe lower GIT symptoms, defined by the validated patient-reported University of California Los Angeles Scleroderma Clinical Trial Consortium GIT 2.0 2.0 questionnaire. The trial includes three parts. In part A1 (induction phase) lasting from week 0 to week 12, participants will be randomised 1:1 to repeat infusions of 30 mL ACHIM or placebo at week 0 and 2 by gastroduodenoscopy. In part A2, which is an 8-week subsequent maintenance phase, all study participants will receive 30 mL ACHIM at week 12 and followed until week 20 on continued blind. In part B, which will last until the last participant completes part A2, the participants will be followed through a maximum 16-week extended monitoring period, for longer-term data on safety and intervention effects. Primary endpoint is change from baseline to week 12 in UCLA GIT subscale scores of diarrhoea or bloating, depending on the worst symptom at baseline evaluated separately for each patient. Secondary endpoints are safety measures and changes in UCLA GIT scores (total, diarrhoea and bloating).Ethics and disseminationThis protocol was approved by the Northern Norwegian Committee for Medical Ethics. Study findings will be published.Trial registration numberNCT04300426; Pre-results.Protocol versionV.3.1.

This randomized trial compares the effects of half-dose conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) vs stable-dose csDMARDs on the risk of flares in patients with rheumatoid arthritis in sustained remission.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.Question In patients with rheumatoid arthritis in remission taking conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), is reducing the csDMARDs to half dose noninferior to stable csDMARD dosage for the outcome of rheumatoid arthritis flares? Findings In this randomized clinical trial that included 160 patients with rheumatoid arthritis in remission taking csDMARD therapy, treatment with half-dose vs stable-dose csDMARDs resulted in disease flares in 25% vs 6% over 12 months; this did not meet the noninferiority criterion of a 20% difference. There were significantly fewer patients with flares in the stable-dose group. Meaning These findings do not support the use of half-dose treatment in patients with rheumatoid arthritis in remission taking csDMARDs.

BACKGROUND AND OBJECTIVES: The 52-week, randomized, double-blind, noninferiority, government-funded NOR-SWITCH trial demonstrated that switching from infliximab originator to less expensive biosimilar CT-P13 was not inferior to continued treatment with infliximab originator. The NOR-SWITCH extension trial aimed to assess efficacy, safety and immunogenicity in patients on CT-P13 throughout the 78-week study period (maintenance group) versus patients switched to CT-P13 at week 52 (switch group). The primary outcome was disease worsening during follow-up based on disease-specific composite measures. METHODS: Patients were recruited from 24 Norwegian hospitals, 380 of 438 patients who completed the main study: 197 in the maintenance group and 183 in the switch group. In the full analysis set, 127 (33%) had Crohn's disease, 80 (21%) ulcerative colitis, 67 (18%) spondyloarthritis, 55 (15%) rheumatoid arthritis, 20 (5%) psoriatic arthritis and 31 (8%) chronic plaque psoriasis. RESULTS: Baseline characteristics were similar in the two groups at the time of switching (week 52). Disease worsening occurred in 32 (16.8%) patients in the maintenance group vs. 20 (11.6%) in the switch group (per-protocol set). Adjusted risk difference was 5.9% (95% CI -1.1 to 12.9). Frequency of adverse events, anti-drug antibodies, changes in generic disease variables and disease-specific composite measures were comparable between arms. The study was inadequately powered to detect noninferiority within individual diseases. CONCLUSION: The NOR-SWITCH extension showed no difference in safety and efficacy between patients who maintained CT-P13 and patients who switched from originator infliximab to CT-P13, supporting that switching from originator infliximab to CT-P13 is safe and efficacious. Ministry of Health and Care services, Norway

Objective To describe the outcomes of MTX and biologic DMARD (bDMARD) treatment in patients with RA and assess unmet needs in patients who fail treatment, using real-world data from the Norwegian DMARD (NOR-DMARD) registry. Methods Data included RA treatment courses from January 2007 until July 2016. Patients received MTX monotherapy (in MTX-naïve patients), bDMARD monotherapy, bDMARDs + MTX, or bDMARDs + other conventional synthetic DMARDs (csDMARDs). DAS28-4(ESR) was used to measure remission (3.2) across all groups at Months 6 and 12. Estimated ACR20/50/70 and EULAR good and good/moderate response rates (based on DAS28-4[ESR] score) for bDMARDs were modelled at Months 6 and 12 using logistic mixed regression. DAS28-4(ESR) scores and changes from baseline, and rates and reasons for discontinuation, were evaluated for all groups over 24 months. Results The 2778 treatment courses in this analysis included 714 MTX monotherapy, 396 bDMARD monotherapy, 1460 bDMARDs + MTX and 208 bDMARDs + other csDMARDs. Of patients with DAS28-4(ESR) data at Months 6 and 12 (25.0–34.1%), 33.9–47.2% did not switch treatment and were inadequate-responders at Month 12. There were no significant differences in efficacy between bDMARD groups (bDMARD monotherapy, or bDMARDs + MTX or other csDMARDs). Lack of efficacy was the most common reason for stopping treatment across all groups (13.7–22.1% over 24 months). Conclusion An unmet treatment need exists for patients still experiencing inadequate response to MTX monotherapy and bDMARDs as monotherapy or in combination with MTX/other csDMARDs after 12 months. Trial registration ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT01581294.

The association between pulmonary sequelae and markers of disease severity, as well as pro-fibrotic mediators, were studied in 108 patients 3 months after hospital admission for COVID-19. The COPD assessment test (CAT-score), spirometry, diffusion capacity of the lungs (DLCO), and chest-CT were performed at 23 Norwegian hospitals included in the NOR-SOLIDARITY trial, an open-labelled, randomised clinical trial, investigating the efficacy of remdesivir and hydroxychloroquine (HCQ). Thirty-eight percent had a CAT-score ≥ 10. DLCO was below the lower limit of normal in 29.6%. Ground-glass opacities were present in 39.8% on chest-CT, parenchymal bands were found in 41.7%. At admission, low pO2/FiO2 ratio, ICU treatment, high viral load, and low antibody levels, were predictors of a poorer pulmonary outcome after 3 months. High levels of matrix metalloproteinase (MMP)-9 during hospitalisation and at 3 months were associated with persistent CT-findings. Except for a negative effect of remdesivir on CAT-score, we found no effect of remdesivir or HCQ on long-term pulmonary outcomes. Three months after hospital admission for COVID-19, a high prevalence of respiratory symptoms, reduced DLCO, and persistent CT-findings was observed. Low pO2/FiO2 ratio, ICU-admission, high viral load, low antibody levels, and high levels of MMP-9 were associated with a worse pulmonary outcome.

Background: There is an urgent need for new treatment modalities in COVID-19 patients. Recently, the WHO Solidarity trial showed no effects of remdesivir or hydroxychloroquine (HCQ) on mortality. However, the antiviral effects of these drugs and the possible relation to clinical characteristics at admission is not known. Methods: NOR-Solidarity is an independent add-on study to the WHO Solidarity trial, including biobanking, and a clinical three-month follow-up. Eligible patients were adults (≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection. Patients were randomly assigned to receive remdesivir, HCQ or standard of care (SoC). In-hospital mortality, admission to intensive care unit and initiation of mechanical ventilation were primary and secondary clinical endpoints shared with WHO Solidarity. Secondary endpoints were impact of remdesivir or HCQ on SARS-CoV-2 clearance in the oropharynx, as well as their effects on systemic inflammation and the degree of respiratory failure (ClinicalTrials.gov: NCT04321616). Findings: Between March 28 and October 4, 185 patients from 23 hospitals in Norway were randomized and 181 included in the full analysis set: remdesivir (n=42), HCQ (n=52) and SoC (n=87). No significant differences in mortality during hospitalisation, ICU admission or occurrence of mechanical ventilation between the treatment groups and SoC were observed. There was a marked decrease in SARS-CoV-2 load in oropharynx during the first week with similar decrease and 10-day levels between remdesivir, HCQ and their respective SoC. Remdesivir and HCQ did not exert any effect on the degree of respiratory failure or on inflammatory parameters in peripheral blood. Notably, the lack of anti-viral effect was not associated with symptom duration, level of viral load or presence of antibodies against SARS-CoV-2 at hospital admittance. Interpretation: We found no effect on viral clearance by either remdesivir or HCQ in hospitalised COVID-19 patients. Trial Registration: (ClinicalTrials.gov: NCT04321616) Funding: National Clinical Therapy Research in the Specialist Health Services, Norway. Declaration of Interests: All authors declare no competing interest. Ethics Approval Statement: The trial protocol was approved by the Regional Ethic Committee (118684) and by the Norwegian Medicines Agency (20/04950-23) and was overseen by an independent data and safety monitoring board.

Host-directed-therapy strategies are warranted to fight tuberculosis. Here we assess the safety and immunogenicity of adjunctive vaccination with the H56:IC31 candidate and cyclooxygenase-2-inhibitor treatment (etoricoxib) in pulmonary and extra-pulmonary tuberculosis patients in a randomized open-label phase I/II clinical trial (TBCOX2, NCT02503839). A total of 222 patients were screened, 51 enrolled and randomized; 13 in the etoricoxib-group, 14 in the H56:IC31-group, 12 in the etoricoxib+H56:IC31-group and 12 controls. Three Serious Adverse Events were reported in the etoricoxib-groups; two urticarial rash and one possible disease progression, no Serious Adverse Events were vaccine related. H56:IC31 induces robust expansion of antigen-specific T-cells analyzed by fluorospot and flow cytometry, and higher proportion of seroconversions. Etoricoxib reduced H56:IC31-induced T-cell responses. Here, we show the first clinical data that H56:IC31 vaccination is safe and immunogenic in tuberculosis patients, supporting further studies of H56:IC31 as a host-directed-therapy strategy. Although etoricoxib appears safe, our data do not support therapy with adjunctive cyclooxygenase-2-inhibitors., Modulating the host immune response during tuberculosis is an emerging and critical advance in the therapeutic approach. Here the authors present data from a first-in-human phase I/II randomised trial on the safety and immunogenicity of adjuvant therapy of the H56:IC31 vaccine and cyclooxygenase-2 inhibitors in patients with tuberculosis.

Importance Proactive therapeutic drug monitoring (TDM), defined as individualized drug dosing based on scheduled monitoring of serum drug levels, has been proposed as an alternative to standard therapy to maximize efficacy and safety of infliximab and other biological drugs. However, whether proactive TDM improves clinical outcomes when implemented at the time of drug initiation, compared with standard therapy, remains unclear. Objective To assess whether TDM during initiation of infliximab therapy improves treatment efficacy compared with standard infliximab therapy without TDM. Design, Setting, and Participants Randomized, parallel-group, open-label clinical trial of 411 adults with rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, ulcerative colitis, Crohn disease, or psoriasis initiating infliximab therapy in 21 hospitals in Norway. Patients were recruited from March 1, 2017, to January 10, 2019. Final follow-up occurred on November 5, 2019. Interventions Patients were randomized 1:1 to receive proactive TDM with dose and interval adjustments based on scheduled monitoring of serum drug levels and antidrug antibodies (TDM group; n = 207) or standard infliximab therapy without drug and antibody level monitoring (standard therapy group; n = 204). Main Outcomes and Measures The primary end point was clinical remission at week 30. Results Among 411 randomized patients (mean age, 44.7 [SD, 14.9] years; 209 women [51%]), 398 (198 in the TDM group and 200 in the standard therapy group) received their randomized intervention and were included in the full analysis set. Clinical remission at week 30 was achieved in 100 (50.5%) of 198 and 106 (53.0%) of 200 patients in the TDM and standard therapy groups, respectively (adjusted difference, 1.5%; 95% CI, −8.2% to 11.1%;P = .78). Adverse events were reported in 135 patients (68%) and 139 patients (70%) in the TDM and standard therapy groups, respectively. Conclusions and Relevance Among patients with immune-mediated inflammatory diseases initiating treatment with infliximab, proactive therapeutic drug monitoring, compared with standard therapy, did not significantly improve clinical remission rates over 30 weeks. These findings do not support routine use of therapeutic drug monitoring during infliximab induction for improving disease remission rates. Trial Registration ClinicalTrials.gov Identifier:NCT03074656

BACKGROUND: New treatment modalities are urgently needed for patients with COVID-19. The World Health Organization (WHO) Solidarity trial showed no effect of remdesivir or hydroxychloroquine (HCQ) on mortality, but the antiviral effects of these drugs are not known. OBJECTIVE: To evaluate the effects of remdesivir and HCQ on all-cause, in-hospital mortality; the degree of respiratory failure and inflammation; and viral clearance in the oropharynx. DESIGN: NOR-Solidarity is an independent, add-on, randomized controlled trial to the WHO Solidarity trial that included biobanking and 3 months of clinical follow-up (ClinicalTrials.gov: NCT04321616). SETTING: 23 hospitals in Norway. PATIENTS: Eligible patients were adults hospitalized with confirmed SARS-CoV-2 infection. INTERVENTION: Between 28 March and 4 October 2020, a total of 185 patients were randomly assigned and 181 were included in the full analysis set. Patients received remdesivir (n = 42), HCQ (n = 52), or standard of care (SoC) (n = 87). MEASUREMENTS: In addition to the primary end point of WHO Solidarity, study-specific outcomes were viral clearance in oropharyngeal specimens, the degree of respiratory failure, and inflammatory variables. RESULTS: No significant differences were seen between treatment groups in mortality during hospitalization. There was a marked decrease in SARS-CoV-2 load in the oropharynx during the first week overall, with similar decreases and 10-day viral loads among the remdesivir, HCQ, and SoC groups. Remdesivir and HCQ did not affect the degree of respiratory failure or inflammatory variables in plasma or serum. The lack of antiviral effect was not associated with symptom duration, level of viral load, degree of inflammation, or presence of antibodies against SARS-CoV-2 at hospital admittance. LIMITATION: The trial had no placebo group. CONCLUSION: Neither remdesivir nor HCQ affected viral clearance in hospitalized patients with COVID-19. PRIMARY FUNDING SOURCE: National Clinical Therapy Research in the Specialist Health Services, Norway.

Objective To evaluate and compare benefits and harms of three biological treatments with different modes of action versus active conventional treatment in patients with early rheumatoid arthritis. Design Investigator initiated, randomised, open label, blinded assessor, multiarm, phase IV study. Setting Twenty nine rheumatology departments in Sweden, Denmark, Norway, Finland, the Netherlands, and Iceland between 2012 and 2018. Participants Patients aged 18 years and older with treatment naive rheumatoid arthritis, symptom duration less than 24 months, moderate to severe disease activity, and rheumatoid factor or anti-citrullinated protein antibody positivity, or increased C reactive protein. Interventions Randomised 1:1:1:1, stratified by country, sex, and anti-citrullinated protein antibody status. All participants started methotrexate combined with (a) active conventional treatment (either prednisolone tapered to 5 mg/day, or sulfasalazine combined with hydroxychloroquine and intra-articular corticosteroids), (b) certolizumab pegol, (c) abatacept, or (d) tocilizumab. Main outcome measures The primary outcome was adjusted clinical disease activity index remission (CDAI≤2.8) at 24 weeks with active conventional treatment as the reference. Key secondary outcomes and analyses included CDAI remission at 12 weeks and over time, other remission criteria, a non-inferiority analysis, and harms. Results 812 patients underwent randomisation. The mean age was 54.3 years (standard deviation 14.7) and 68.8% were women. Baseline disease activity score of 28 joints was 5.0 (standard deviation 1.1). Adjusted 24 week CDAI remission rates were 42.7% (95% confidence interval 36.1% to 49.3%) for active conventional treatment, 46.5% (39.9% to 53.1%) for certolizumab pegol, 52.0% (45.5% to 58.6%) for abatacept, and 42.1% (35.3% to 48.8%) for tocilizumab. Corresponding absolute differences were 3.9% (95% confidence interval −5.5% to 13.2%) for certolizumab pegol, 9.4% (0.1% to 18.7%) for abatacept, and −0.6% (−10.1% to 8.9%) for tocilizumab. Key secondary outcomes showed no major differences among the four treatments. Differences in CDAI remission rates for active conventional treatment versus certolizumab pegol and tocilizumab, but not abatacept, remained within the prespecified non-inferiority margin of 15% (per protocol population). The total number of serious adverse events was 13 (percentage of patients who experienced at least one event 5.6%) for active conventional treatment, 20 (8.4%) for certolizumab pegol, 10 (4.9%) for abatacept, and 10 (4.9%) for tocilizumab. Eleven patients treated with abatacept stopped treatment early compared with 20-23 patients in the other arms. Conclusions All four treatments achieved high remission rates. Higher CDAI remission rate was observed for abatacept versus active conventional treatment, but not for certolizumab pegol or tocilizumab versus active conventional treatment. Other remission rates were similar across treatments. Non-inferiority analysis indicated that active conventional treatment was non-inferior to certolizumab pegol and tocilizumab, but not to abatacept. The results highlight the efficacy and safety of active conventional treatment based on methotrexate combined with corticosteroids, with nominally better results for abatacept, in treatment naive early rheumatoid arthritis. Trial registration EudraCT2011-004720-35, NCT01491815 .

Here, we randomized 53 patients hospitalized with coronavirus disease 2019 (COVID-19) to hydroxychloroquine therapy (at a dose of 400 mg twice daily for seven days) in addition to standard care or standard care alone (ClinicalTrials.gov Identifier, NCT04316377). All severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive patients 18 years of age or older were eligible for study inclusion if they had moderately severe COVID-19 at admission. Treatment with hydroxychloroquine did not result in a significantly greater rate of decline in SARS-CoV-2 oropharyngeal viral load compared to standard care alone during the first five days. Our results suggest no important antiviral effect of hydroxychloroquine in humans infected with SARS-CoV-2., The use of hydroxychloroquine therapy for the treatment of Covid-19 is controversial. In this study, Lyngbakken and colleagues present a randomized controlled trial and show that the drug has no antiviral effects in humans infected with SARS-CoV-2.

Objectives The hypothesis of the study is that treatment with hydroxychloroquine sulphate in hospitalised patients with coronavirus disease 2019 (Covid-19) is safe and will accelerate the virological clearance rate for patients with moderately severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) when compared to standard care. Furthermore, we hypothesize that early treatment with hydroxychloroquine sulphate is associated with more rapid resolve of clinical symptoms as assessed by the National Early Warning Score 2 (NEWS2), decreased admission rate to intensive care units and mortality, and improvement in protein biomarker profiles (C-reactive protein, markers of renal and hepatic injury, and established cardiac biomarkers like cardiac troponin and B-type natriuretic peptide). Trial design The study is a two-arm, open label, pragmatic randomised controlled group sequential adaptive trial designed to assess the effect on viral loads and clinical outcome of hydroxychloroquine sulphate therapy in addition to standard care compared to standard care alone in patients with established Covid-19. By utilizing resources already paid for by the hospitals (physicians and nurses in daily clinical practice), this pragmatic trial can include a larger number of patients over a short period of time and at a lower cost than studies utilizing traditional randomized controlled trial designs with an external study organization. The pragmatic approach will enable swift initiation of randomisation and allocation to treatment. Participants Patients will be recruited from all inpatients at Akershus University Hospital, Lørenskog, Norway. Electronic real-time surveillance of laboratory reports from the Department of Microbiology will be examined regularly for SARS-CoV-2 positive subjects. All of the following conditions must apply to the prospective patient at screening prior to inclusion: (1) Hospitalisation; (2) Adults 18 years or older; (3) Moderately severe Covid-19 disease (NEWS2 of 6 or less); (4) SARS-CoV-2 positive nasopharyngeal swab; (5) Expected time of hospitalisation > 48 hours; and (6) Signed informed consent must be obtained and documented according to Good Clinical Practice guidelines of the International Conference on Harmonization, and national/local regulations. Patients will be excluded from participation in the study if they meet any of the following criteria: (1) Requiring intensive care unit admission at screening; (2) History of psoriasis; (3) Known adverse reaction to hydroxychloroquine sulphate; (4) Pregnancy; or (5) Prolonged corrected QT interval (>450 ms). Clinical data, including standard hospital biochemistry, medical therapy, vital signs, NEWS2, and microbiology results (including blood culture results and reverse transcriptase polymerase chain reaction [RT-PCR] for other upper airway viruses), will be automatically extracted from the hospital electronic records and merged with the study specific database. Intervention and comparator Included patients will be randomised in a 1:1 ratio to (1) standard care with the addition of 400 mg hydroxychloroquine sulphate (PlaquenilTM) twice daily for seven days or (2) standard care alone. Main outcomes The primary endpoint of the study is the rate of decline in SARS-CoV-2 viral load in oropharyngeal samples as assessed by RT-PCR in samples collected at baseline, 48 and 96 hours after randomization and administration of drug for the intervention arm. Secondary endpoints include change in NEWS2 at 96 hours after randomisation, admission to intensive care unit, mortality (in-hospital, and at 30 and 90 days), duration of hospital admission, clinical status on a 7-point ordinal scale 14 days after randomization ([1] Death [2] Hospitalised, on invasive mechanical ventilation or extracorporeal membrane oxygenation [3] Hospitalised, on non-invasive ventilation or high flow oxygen devices [4] Hospitalized, requiring supplemental oxygen [5] Hospitalised, not requiring supplemental oxygen [6] Not hospitalized, but unable to resume normal activities [7] Not hospitalised, with resumption of normal activities), and improvement in protein biomarker profiles (C-reactive protein, markers of renal and hepatic injury, and established cardiac biomarkers like cardiac troponin and B-type natriuretic peptide) at 96 hours after randomization. Randomisation Eligible patients will be allocated in a 1:1 ratio, using a computer randomisation procedure. The allocation sequence has been prepared by an independent statistician. Blinding (masking) Open label randomised controlled pragmatic trial without blinding, no active or placebo control. The virologist assessing viral load in the oropharyngeal samples and the statistician responsible for analysis of the data will be blinded to the treatment allocation for the statistical analyses. Numbers to be randomized (sample size) This is a group sequential adaptive trial where analyses are planned after 51, 101, 151 and 202 completed patients, with a maximum sample size of 202 patients (101 patients allocated to intervention and standard care and 101 patients allocated to standard care alone). Trial Status Protocol version 1.3 (March 26, 2020). Recruitment of first patient on March 26, 2020, and 51 patients were included as per April 28, 2020. Study recruitment is anticipated to be completed by July 2020. Trial registration ClinicalTrials.gov number, NCT04316377. Trial registered March 20, 2020. Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Background: TNF-alpha inhibitors have improved treatment of chronic immune-mediated inflammatory disorders. The NOR-SWITCH main and extension trial addressed switching from infliximab originator (IFX) to CT-P13 across six diseases. Here we present the exploratory post-hoc analyses in Crohn's disease (CD) and ulcerative colitis (UC). Methods: The 52-week, randomized, non-inferiority, double blind, multicenter, phase 4 NOR-SWITCH study was followed by a 26-week open extension trial where all patients received treatment with CT-P13. Treatment efficacy, safety and immunogenicity were assessed throughout the 78-week study period. The primary endpoint was disease worsening. Findings: The main and extension trials included 155 and 93 patients with CD and 93 and 80 patients with UC, respectively. The baseline characteristics were comparable between treatment arms in both diseases. Disease worsening in the main trial occurred in 14 (21%) of CD patients in the IFX group and 23 (37%) in the CT-P13 group (risk difference -14⋅3%, CI -29⋅3 to 0⋅7). In the extension study, disease worsening occurred in 13 (21%) patients in the CT-P13 maintenance group and 8 (13%) in the IFX/CT-P13 switch group (risk difference 7⋅9%, CI -5⋅2 to 21). The corresponding results in UC were 3 (9%) and 5 (12%) patients (risk difference -2⋅6%, CI -15⋅2 to 10⋅0) in the main trial, and 6 (15%) and 1 (3%) patients (risk difference 12⋅4%, CI -0⋅1 to 25⋅0) in the extension trial. In both diseases, the treatment groups were similar across disease activity measures, drug levels and immunogenicity. Interpretation: The subgroup analyses of IBD in the NOR-SWITCH main and extension trials support switching from originator infliximab to CT-P13 for non-medical reasons. Trial Registration: ClinicalTrials.gov NCT-02148640, EudraCT Number: 2014-002056-40. Funding Statement: This work was supported by the Norwegian Ministry of Health and Care Services. Declaration of Interests: KKJ reports personal fees from Intercept, Norgine and Celltrion. GLG reports personal fees from AbbVie, Biogen, Eli Lilly, MSD, Novartis, Pfizer, Roche, Sandoz, Orion Pharma, Celltrion and Boehringer Ingelheim. NB reports personal fees received from Orion Pharma, Roche, Napp Pharmaceuticals, Pfizer, and Takeda. ICO reports grants from Norwegian Ministry of Health and Care Services during the conduct of the study, and personal fees from Pfizer. EAH reports grants from AbbVie, Pfizer, UCB, Roche, and MSD. IPB reports personal fees from AbbVie, MSD, Takeda, Hospira, and Ferring. KEAL reports grants from MSD, personal fees from Takeda, Orion, Abbvie, Pfizer, and MSD. JJ reports personal fees from MSD, AbbVie, Celltrion, Orion Pharma, Takeda, Napp Pharm, AstroPharma, Hikma and Pfizer. TKK reports reports grants from Norwegian Ministry of Health and Care Services during the conduct of the study and personal fees from AbbVie, Biogen, BMS, Boehringer Ingelheim, Celltrion, Eli Lilly, Epirus, Janssen, Merck-Serono, MSD, Mundipharma, Novartis, Oktal, Orion Pharma, Hospira/Pfizer, Roche, Sandoz, and UCB Pharma. SOF reports personal fees from Takeda, Pharmacosmos, Tillotts, Janssen, Intercept and Pfizer. Ethics Approval Statement: The study was conducted in compliance with the Declaration of Helsinki and the International Conference on Harmonization Guidelines for Good Clinical Practice. The study protocol and consent documents were approved by an independent ethics committee (Regional Committees for Medical and Health Research Ethics South East; reference number 2014/848), by appropriate institutional review boards and by the Norwegian Medicines Agency (reference number 14/07192-11).

Background Infliximab (INX) and other tumour necrosis factor inhibitors (TNFi) have revolutionised the treatment of several immune mediated inflammatory diseases. Still, many patients do not respond sufficiently to therapy or lose efficacy over time. The large interindividual variation in serum drug concentrations on standard doses and the development of anti-drug antibodies are thought to be major reasons for treatment failures. Therapeutic drug monitoring (TDM), an individualised treatment strategy based on systematic assessments of serum drug concentrations, has been proposed as a clinical tool to optimise efficacy of INX treatment. TDM seems reasonable both from a clinical and an economical point of view, but the effectiveness of this treatment strategy has not yet been demonstrated in randomised clinical trials. The NORwegian DRUg Monitoring study (NOR-DRUM) aims to assess the effectiveness of TDM, both with regard to the achievement of remission in patients starting INX treatment (part A) as well as to maintain disease control in patients on INX treatment (part B). Methods The NOR-DRUM study is a randomised, open, controlled, parallel-group, comparative, multi-centre, national, superiority, phase IV study with two separate parts, NOR-DRUM A and NOR-DRUM B. Patients with rheumatoid arthritis, psoriatic arthritis, spondyloarthritis, ulcerative colitis, Crohn’s disease and psoriasis are included. In both study parts participants are randomised 1:1 to either TDM of infliximab (intervention group) or to standard treatment with infliximab without knowledge of drug levels or ADAb status (control group). NOR-DRUM A will include 400 patients starting INX therapy. The primary outcome is remission at 30 weeks. In NOR-DRUM B, 450 patients on maintenance treatment with INX will be included. The primary endpoint is occurrence of disease worsening during the 52-week study period. Discussion As the first trial to assess the effectiveness, safety and cost-effectiveness of TDM in patients receiving TNFi for a range of immune mediated inflammatory diseases, we hope that the NOR-DRUM study will contribute to the advancement of evidence based personalised treatment with biological medicines. Trial registration Clinicaltrials.gov, NCT03074656. Registered on 090317.

Background Scaled-up direct-acting antiviral (DAA) treatment of hepatitis C virus (HCV) infection among people who inject drugs (PWID) is crucial to reach the World Health Organization HCV elimination targets within 2030. One of the critical obstacles to HCV care in this population is the lack of treatment models within specialist healthcare adapted to marginalized individuals. Methods OPPORTUNI-C is a pragmatic stepped wedge cluster randomized trial comparing the efficacy of immediate initiation of HCV treatment with the current standard of care among PWID admitted for inpatient care. Screening for HCV RNA will be performed as soon as possible after admission. The intervention includes immediate non-invasive liver disease assessment, counseling, and initiation of pan-genotypic DAA treatment with individualized follow-up. Standard of care is a referral to outpatient care at discharge. To mimic usual clinical practice as closely as possible, we will use a pragmatic clinical trial approach utilizing clinical infrastructure, broad eligibility criteria, flexible intervention delivery, clinically relevant outcomes, and collection of data readily available from the electronic patient files. The stepped wedge design involves a sequential rollout of the intervention over 16 months, in which seven participating clusters will be randomized from standard of care to intervention in a stepwise manner. Randomization will be stratified according to cluster size to keep high prevalence clusters separated. The trial will include approximately 220 HCV RNA positive individuals recruited from departments of internal medicine, addiction medicine, and psychiatry at Akershus University Hospital, Oslo University Hospital, and Lovisenberg Diaconal Hospital, Oslo, Norway. Individuals not able or willing to give informed consent and those with ongoing HCV assessment or treatment will be excluded. The primary outcome is treatment completion, defined as dispensing of the final prescribed DAA package from the pharmacy within 6 months after inclusion. Secondary outcomes include treatment uptake, virologic response, reinfection incidence, and resistance-associated substitutions. Discussion Representing a novel model of care suited to reach and engage marginalized PWID in HCV care, this study will inform HCV elimination efforts locally and internationally. If the model proves efficacious and feasible, it should be considered for broader implementation, replacing the current standard of care. Trial registration ClinicalTrials.gov, NCT04220645. Registered on 7 January 2020.

Summary Background Skin emollients applied during early infancy could prevent atopic dermatitis, and early complementary food introduction might reduce food allergy in high-risk infants. The study aimed to determine if either regular skin emollients applied from 2 weeks of age, or early complementary feeding introduced between 12 and 16 weeks of age, reduced development of atopic dermatitis by age 12 months in the general infant population. Methods This population-based 2×2 factorial, randomised clinical trial was done at Oslo University Hospital and Ostfold Hospital Trust, Oslo, Norway; and Karolinska University Hospital, Stockholm, Sweden. Infants of women recruited antenatally at the routine ultrasound pregnancy screening at 18 weeks were cluster-randomised at birth from 2015 to 2017 to the following groups: (1) controls with no specific advice on skin care while advised to follow national guidelines on infant nutrition (no intervention group); (2) skin emollients (bath additives and facial cream; skin intervention group); (3) early complementary feeding of peanut, cow's milk, wheat, and egg (food intervention group); or (4) combined skin and food interventions (combined intervention group). Participants were randomly assigned (1:1:1:1) using computer- generated cluster randomisation based on 92 geographical living area blocks as well as eight 3-month time blocks. Carers were instructed to apply the interventions on at least 4 days per week. Atopic dermatitis by age 12 months was the primary outcome, based on clinical investigations at 3, 6 and 12 months by investigators masked to group allocation. Atopic dermatitis was assessed after completing the 12-month investigations and diagnosed if either of the UK Working Party and Hanifin and Rajka (12 months only) diagnostic criteria were fulfilled. The primary efficacy analyses was done by intention-to-treat analysis on all randomly assigned participants. Food allergy results will be reported once all investigations at age 3 years are completed in 2020. This was a study performed within ORAACLE (the Oslo Research Group of Asthma and Allergy in Childhood; the Lung and Environment). The study is registered at clinicaltrials.gov , NCT02449850 . Findings 2697 women were recruited between Dec 9, 2014, and Oct 31, 2016, from whom 2397 newborn infants were enrolled from April 14, 2015, to April 11, 2017. Atopic dermatitis was observed in 48 (8%) of 596 infants in the no intervention group, 64 (11%) of 575 in the skin intervention group, 58 (9%) of 642 in the food intervention group, and 31 (5%) of 583 in the combined intervention group. Neither skin emollients nor early complementary feeding reduced development of atopic dermatitis, with a risk difference of 3·1% (95% CI –0·3 to 6·5) for skin intervention and 1·0% (–2·1 to 4·1) for food intervention, in favour of control. No safety concerns with the interventions were identified. Reported skin symptoms and signs (including itching, oedema, exanthema, dry skin, and urticaria) were no more frequent in the skin, food, and combined intervention groups than in the no intervention group. Interpretation Neither early skin emollients nor early complementary feeding reduced development of atopic dermatitis by age 12 months. Our study does not support the use of these interventions to prevent atopic dermatitis by 12 months of age in infants. Funding The study was funded by several public and private funding bodies: The Regional Health Board South East, The Norwegian Research Council, Health and Rehabilitation Norway, The Foundation for Healthcare and Allergy Research in Sweden-Vardalstiftelsen, Swedish Asthma and Allergy Association's Research Foundation, Swedish Research Council—the Initiative for Clinical Therapy Research, The Swedish Heart-Lung Foundation, SFO-V at the Karolinska Institute, Freemason Child House Foundation in Stockholm, Swedish Research Council for Health, Working Life and Welfare—FORTE, Oslo University Hospital, the University of Oslo, and Ostfold Hospital Trust.

Objective The European guidelines on cardiovascular disease (CVD) prevention advise use of relative risk and risk age algorithms for estimating CVD risk in patients with low estimated absolute risk. Patients with inflammatory joint diseases (IJD) are associated with increased risk of CVD. We aimed to estimate relative risk and risk age across IJD entities and evaluate the agreement between ‘cardiovascular risk age' and ‘vascular age models'. Methods Using cross-sectional data from a nationwide project on CVD risk assessment in IJD, risk age estimations were performed in patients with low/moderate absolute risk of fatal CVD. Risk age was calculated according to the cardiovascular risk age and vascular age model, and risk age estimations were compared using regression analysis and calculating percentage of risk age estimations differing ≥5years. Results Relative risk was increased in 53% and 20% had three times or higher risk compared to individuals with optimal CVD risk factor levels. Furthermore, 20–42% had a risk age ≥5years higher than their actual age, according to the specific risk age model. There were only minor differences between IJD entities regarding relative risk and risk age. Discrepancies ≥5years in estimated risk age were observed in 14–43% of patients. The largest observed difference in calculated risk age was 24years. Conclusion In patients with low estimated absolute risk, estimation of relative CVD risk and risk age may identify additional patients at need of intensive CVD preventive efforts. However, there is a substantial discrepancy between the risk age models.

Background:Gastro-intestinal tract (GIT) symptoms is highly prevalent in patients with systemic sclerosis (SSc). The GIT-symptoms impact on the quality of life is significant, and available treatment alternatives are limited. Recently published articles show associations between gut microbiota changes and GIT-symptoms in SSc. We, therefore, performed a successful feasibility trial on faecal microbiota transplantation (FMT) in SSc patients using the single-donor bacterial culture “Anaerobic Cultivated Human Intestinal Microbiome (ACHIM)”. Based on the promising results from the feasibility trial, we aim to evaluate the safety and efficacy of FMT by ACHIM in SSc patients. (NCT04300426)Objectives:To design a clinical trial that explores the safety and efficacy of FMT in SSc patients.Methods:The ReSScue trial is a phase II, placebo-controlled, randomised 20-week, multicentre trial. The trial comprises three parts. In the induction phase (A1) lasting from week 0 to week 12, participants are randomised 1:1 to repeat infusions of 30 ml ACHIM or placebo at week 0 and 2 by gastro-duodenoscopy. In the maintenance phase (A2), all study participants will receive 30 ml ACHIM at week 12 and are followed continued blinded until week 20.For longer-term data on intervention effects and safety, the participant will be followed for a maximum extended monitoring period of 16 weeks (part B).The primary endpoint is change from baseline to week 12 in UCLA GIT scores on bloating or diarrhoea, depending on the worst symptom at baseline evaluated separately for each patient. Secondary endpoints are changes in UCLA GIT scores (bloating, diarrhoea and total) and safety measures.Results:We aim to enrol 70 SSc patients based on the power calculations for the primary endpoint “change in worst symptom from baseline to week 12”, with a considered drop out rate of 10%. This number of patients is expected to give a power of 80% of detecting a change in mean (p=0.05, two-sided) of -5.0 (or higher) if the relating standard deviation is 0.70 or lower. The patient screening started in September 2020, and we expect the study to be completed in May 2022.Conclusion:The ReSScue-study is to our knowledge the first FMT-study in SSc. This trial will assess the safety and efficacy of FMT in SSc patients with lower GI-symptoms, possibly leading to a novel treatment approach in SSc patients.Disclosure of Interests:Håvard Fretheim Grant/research support from: Received travel bursaries from Actelion, and remuneration from Bayer., Imon Barua: None declared, Vikas Sarna: None declared, Maylen N Carstens: None declared, Oliver Distler Speakers bureau: Below, Consultant of: Below, Grant/research support from: OD has/had consultancy relationship and/or has received research funding in the area of potential treatments for systemic sclerosis and its complications from (last three years): Abbvie, Acceleron Pharma, Amgen, AnaMar, Arxx, Baecon Discovery, Blade, Bayer, Boehringer Ingelheim, ChemomAb, Corbus, CSL Behring, Galapagos NV, Glenmark, GSK, Horizon (Curzion), Inventiva, iQvia, Italfarmaco, iQone, Kymera, Lilly, Medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Novartis, Pfizer, Roche, Sanofi, Serodapharm, Topadur, Target Bioscience and UCB. Patent issued “mir-29 for the treatment of systemic sclerosis” (US8247389, EP2331143)., Dinesh Khanna Consultant of: Abbvie, Actelion/Janssen, Acceleron Pharma, Amgen, Bayer, Boehringer Ingelheim, CSL Behring, GSK, Horizon Pharmaceuticals, Mitsubishi Tanabe Pharma, Pfizer, Roche, Sanofi, United Therapeutics. DK is chief medical officer of Eicos Sciences, Inc., Grant/research support from: Abbvie, Actelion/Janssen, Acceleron Pharma, Amgen, Bayer, Boehringer Ingelheim, CSL Behring, GSK, Horizon Pharmaceuticals, Mitsubishi Tanabe Pharma, Pfizer, Roche, Sanofi, United Therapeutics. DK is chief medical officer of Eicos Sciences, Inc., Elizabeth Volkmann Consultant of: Boehringer Ingelheim, Grant/research support from: Corbus, Forbius, Boehringer Ingelheim, Øyvind Midtvedt Shareholder of: Son of owner of ACHIM., Henriette Didriksen Speakers bureau: Travel bursary - GSK, Alvilde Dhainaut: None declared, Anna-Kristine H Halse: None declared, Gunnstein Bakland: None declared, Inge Christoffer Olsen: None declared, Maiju E Pesonen: None declared, Øyvind Molberg: None declared, Anna-Maria Hoffmann-Vold Consultant of: Actelion, ARXX, Bayer, Boehringer Ingelheim, Medscape, Merck Sharp & Dohme, Lilly and Roche., Grant/research support from: Actelion, ARXX, Bayer, Boehringer Ingelheim, Medscape, Merck Sharp & Dohme, Lilly and Roche.

Background:Immunogenicity is related to loss of efficacy and safety to TNFα inhibitors and is frequently observed early in the treatment course. The highest rate of anti-drug antibody (ADAb) formation has been reported for infliximab (IFX). 1 Knowledge about risk factors for immunogenicity might contribute to better handling of this problem in clinical practice.Objectives:To identify risk factors for ADAb formation during the early phase of IFX treatment.Methods:411 patients with immune-mediated inflammatory diseases (84 rheumatoid arthritis (RA), 119 spondyloarthritis (SpA), 45 psoriatic arthritis, 83 ulcerative colitis, 58 Crohn’s disease and 22 psoriasis) initiating IFX treatment were included in the 38-week NOR-DRUM A trial and randomised 1:1 to therapeutic drug monitoring or standard IFX therapy.2 The primary endpoint was clinical remission at week 30. Serum (s) IFX levels and ADAb were measured at each infusion by in-house assays; time-resolved fluorometric assay for sIFX and inhibition assay for ADAb.2 In this sub-study, possible risk factors for ADAb formation including demographic variables, diagnosis, comedication, disease activity, IFX dose, sIFX and drug holidays, were assessed using logistic regression. Variables with a p-value Results:410 of 411 patients had at least one measurement of sIFX and were included in the present analyses. 76% of patients were biologic-naive and 45% (18% of RA patients) used IFX as monotherapy. Patients received a mean IFX dose of 3.2-5.9 mg/kg (RA 3.2 mg/kg). ADAb were detected in 78 (19%) patients. The Table 1 shows variables with a significant association to ADAb development. Analyses revealed an increased risk of ADAb development in patients with RA (Odds ratio (OR) 2.1, 95% confidence interval (CI) 1.1-3.9), while SpA had a lower risk (OR 0.5, CI 0.2-0.9) compared to the other diagnoses. These findings were consistent in both univariate- and multivariate analyses (Table 1). Figure 1 shows the cumulative hazard for ADAb development according to diagnosis. Other risk factors for ADAb (Table 1) were smoking (OR 1.8, CI 1.0-3.3) and drug holidays of more than 12 weeks (OR 4.7, CI 1.2-18.3). Additionally, the risk of ADAb increased with higher disease activity (OR 1.5, CI 1.0-2.3) and lower sIFX levels (0.7, 0.6-0.8). Patients co-treated with methotrexate (OR 0.4, CI 0.2-0.9) or thiopurines (OR 0.3, CI 0.1-0.8), or having one or more IFX dose increments (OR 0.4, CI 0.3-0.8), had a reduced risk of immunogenicity.Table 1.Risk factors for ADAb. Results from logistic regression analysesUnivariate analysesMultivariate analyses (Adjusted for diagnosis, disease activity, age and gender)ORCIORCIRA2.2**[1.3,3.8]2.1*[1.1,3.9]SpA0.4**[0.2,0.8]0.5*[0.2,0.9]Methotrexate1.1[0.7,1.9]0.4*[0.2,0.9]Thiopurine0.3*[0.1,0.9]0.3*[0.1,0.8]Current or former smoking2.2**[1.3,3.8]1.8*[1.0,3.3]Mean sIFX0.7***[0.6,0.8]0.7***[0.6,0.8]>12 weeks between infusions4.5*[1.3,16.0]4.7*[1.2,18.3]IFX dose increment0.5*[0.3,0.9]0.4**[0.3,0.8]Mean DAS28 (RA and PsA)1.5*[1.0,2.1]1.5*[1.0,2.3]Mean ESR1.1***[1.0,1.1]1.1***[1.0,1.1]Mean CRP1.1**[1.0,1.1]1.1**[1.0,1.1]* pOnly variables with a p-value Conclusion:This study identified smoking, drug holidays, high disease activity, IFX monotherapy and low sIFX levels as risk factors for ADAb development. Of particular interest, we found that RA patients had significantly increased risk of ADAb compared to the other immune-mediated inflammatory diseases. Whether this novel finding reflects different underlying disease mechanisms or the fact that RA patients receive a lower IFX dose, is not known and needs to be further explored.References:[1]Thomas SS et al. BioDrugs 2015;29(4):241-58 2 Syversen SW et al. Trials 2020 6;21(1):13Disclosure of Interests:Marthe Kirksæther Brun: None declared, Guro Løvik Goll Speakers bureau: Pfizer, AbbVie, Boehringer Ingelheim, Roche, Orion pharma, Sandoz and Novartis, Kristin Kaasen Jørgensen Speakers bureau: Celltrion, AOP Orphan Pharmaceuticals and Norgine, Joe Sexton: None declared, Johanna Elin Gehin Speakers bureau: Roche, Øystein Sandanger: None declared, Inge Olsen: None declared, Rolf Anton Klaasen: None declared, David J Warren: None declared, Cato Mørk Speakers bureau: Novartis Norge AS, LEO Pharma AS, ACO Hud Norge AS, Cellgene AS, Abbvie, Galderma Nordic and UCB, Tore K. Kvien Speakers bureau: TAmgen, Celltrion, Egis, Evapharma, Ewopharma, Hikma, Oktal, Sandoz and Sanofi, Consultant of: AbbVie, Amgen, Biogen, Celltrion, Eli Lilly, Gilead, Mylan, Novartis, Pfizer, Sandoz and Sanofi, Grant/research support from: Research funding to Diakonhjemmet Hospital from AbbVie, Amgen, BMS, MSD, Pfizer and UCB, Jørgen Jahnsen: None declared, Nils Bolstad Speakers bureau: Roche Pharmaceuticals and Novartis, Consultant of: Janssen, Espen A Haavardsholm Speakers bureau: Pfizer, AbbVie, Celgene, Novartis, Janssen, Gilead, Eli-Lilly and UCB, Silje Watterdal Syversen Speakers bureau: Thermo Fisher.

Summary Background TNF inhibitors have improved treatment of Crohn's disease, ulcerative colitis, spondyloarthritis, rheumatoid arthritis, psoriatic arthritis, and chronic plaque psoriasis, but are expensive therapies. The aim of NOR-SWITCH was to examine switching from originator infliximab to the less expensive biosimilar CT-P13 regarding efficacy, safety, and immunogenicity. Methods The study is a randomised, non-inferiority, double-blind, phase 4 trial with 52 weeks of follow-up. Adult patients on stable treatment with infliximab originator treated in a hospital setting for at least 6 months were eligible for participation. Patients with informed consent were randomised in a 1:1 ratio to either continued infliximab originator or to switch to CT-P13 treatment, with unchanged dosing regimen. Data were collected at infusion visits in 40 Norwegian study centres. Patients, assessors, and patient care providers were masked to treatment allocation. The primary endpoint was disease worsening during 52-week follow-up. 394 patients in the primary per-protocol set were needed to show a non-inferiority margin of 15%, assuming 30% disease worsening in each group. This trial is registered with ClinicalTrials.gov, number NCT02148640. Findings Between Oct 24, 2014, and July 8, 2015, 482 patients were enrolled and randomised (241 to infliximab originator, 241 to CT-P13 group; one patient was excluded from the full analysis and safety set for CT-P13) and 408 were included in the per-protocol set (202 in the infliximab originator group and 206 in the CT-P13 group). 155 (32%) patients in the full analysis set had Crohn's disease, 93 (19%) had ulcerative colitis, 91 (19%) had spondyloarthritis, 77 (16%) had rheumatoid arthritis, 30 (6%) had psoriatic arthritis, and 35 (7%) had chronic plaque psoriasis. Disease worsening occurred in 53 (26%) patients in the infliximab originator group and 61 (30%) patients in the CT-P13 group (per-protocol set; adjusted treatment difference −4·4%, 95% CI −12·7 to 3·9). The frequency of adverse events was similar between groups (for serious adverse events, 24 [10%] for infliximab originator vs 21 [9%] for CT-P13; for overall adverse events, 168 [70%] vs 164 [68%]; and for adverse events leading to discontinuation, nine [4%] vs eight [3%], respectively). Interpretation The NOR-SWITCH trial showed that switching from infliximab originator to CT-P13 was not inferior to continued treatment with infliximab originator according to a prespecified non-inferiority margin of 15%. The study was not powered to show non-inferiority in individual diseases. Funding Norwegian Ministry of Health and Care Services.

ObjectivesTumour necrosis factor-α inhibitor (TNFi) treatment has been shown to reduce the rates of anterior uveitis (AU) in patients with ankylosing spondylitis (AS). Our objective was to compare the effect of adalimumab (ADA), etanercept (ETN) and infliximab (IFX) on AU occurrence in AS, using real-world data.MethodsPatients with AS starting ADA, ETN or IFX as their first TNFi from January 2003 to December 2010 were extracted from the Swedish Rheumatology Quality Register. AU rates, based on visits to an ophthalmologist with International Classification of Diseases 10 codes for AU, were obtained by linkage to the Swedish National Patient Register. For each TNFi, AU rates 2 years before TNFi start and for the first 2 years on TNFi treatment were compared. In the subgroup of patients who were AU-free during the 2 years before TNFi start, we also compared the risk of a first AU event.Results1365 patients with AS were included (406 ADA, 354 ETN, 605 IFX). Compared with pretreatment rates, we noted a reduction in overall AU rates for ADA and IFX, and an increase for ETN. The adjusted HRs for AU in 1127 patients who were free of AU in the last 2 years before TNFi start were significantly higher for ETN versus ADA (HR: 3.86 95% CI 1.85 to 8.06) and ETN versus IFX (HR: 1.99, 95% CI 1.23 to 3.22), while the HR for IFX versus ADA was not statistically significant.ConclusionsThe results suggest differences in effect on AU risk between ADA, ETN and IFX, with a clear advantage for ADA/IFX over ETN.

Background:Remission is the preferred treatment target in rheumatoid arthritis (RA), and many patients require biologic DMARDs to reach this state. It is debated whether tapering of tumor necrosis factor inhibitor (TNFi) treatment to discontinuation should be considered in RA patients who sustain remission on treatment (1).Objectives:The primary study objective was to assess the effect of tapering and withdrawal of TNFi on the risk of flares in RA patients in clinical remission.Methods:In the non-inferiority ARCTIC REWIND trial, RA patients in remission for at least 12 months on stable TNFi therapy were randomly assigned to continued stable TNFi or tapering (half-dose TNFi for 4 months, thereafter withdrawal of TNFi), with visits every four months. csDMARD co-medication was kept stable in both arms. Patients had to be in DAS remission at inclusion with 0/44 swollen joints. The primary endpoint was the proportion of patients with disease flare during the 12-month study period (defined as DAS>1.6, change in DAS>0.6 and 2 or more swollen joints, or the physician and patient agreed that a clinically significant flare had occurred). Full-dose TNFi was reinstated in case of flares in the tapering arm. The non-inferiority margin was 20%, with a predefined superiority test if non-inferiority was not shown. The inferiority null-hypothesis was tested in the per-protocol population by mixed effect logistic regression. Radiographs were scored by van der Heijde modified Sharp score (0 and 12 months, average of two readers, progression: ≥1 unit change). ClinicaltrialsNCT01881308.Results:We randomised 99 patients, 92 received the allocated treatment strategy, 84 were included in the per-protocol population. Baseline characteristics, clinical and ultrasound disease activity were balanced (Table). csDMARD co-medication was used by 93% in the stable and 88% in the tapering arm. In the primary analysis, 5% of patients in the stable TNFi arm experienced a flare during 12 months, compared to 63% in the tapering TNFi arm. The risk difference (95% CI) was 58% (42% to 74%, Fig 1), with stable treatment being deemed superior to tapering. 90% in the stable and 81% in the tapering arm did not show progression of radiographic joint damage, difference (95% CI) -9% (-24%, 6%). At 12 months, DAS scores, DAS remission and function were similar between groups (Fig 2). The numbers of adverse events (AE)/serious AE in the stable and tapering arm were 57/2 and 50/3, respectively, with 26 and 15 infections.Conclusion:In a randomised clinical trial assessing patients in prolonged and deep RA remission, we observed a large increase in the flare rate in patients who tapered and discontinued TNFi. Patients responded well to reinstated treatment and remission rates in the two study arms were comparable at 12 months.References:[1]Smolen et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. ARD 2020Table 1.Baseline values – n (%), mean (SD), or median (IQR)Stable, n=45Tapering, n=47Age, yrs57 (11)58 (13)Female30 (67%)25 (53%)ACPA+35 (78%)36 (77%)Symptom duration, yrs10 (7)12 (7)DAS0.9 (0.4)0.8 (0.3)CRP mg/L1 (1 – 2)1 (1 – 3)No ulttrasound power Doppler signal in any of 32 joints42 (96%)44 (94%)Disclosure of Interests:Siri Lillegraven: None declared, Nina Paulshus Sundlisæter: None declared, Anna-Birgitte Aga: None declared, Joe Sexton: None declared, Inge Olsen: None declared, Åse Lexberg: None declared, Tor Magne Madland: None declared, Hallvard Fremstad: None declared, Christian A. Høili Consultant of: Novartis, Gunnstein Bakland Consultant of: Novartis, UCB, Cristina Spada: None declared, Hilde Haukeland Consultant of: Novartis, Inger M. Hansen: None declared, Ellen Moholt: None declared, Till Uhlig Consultant of: Lilly, Pfizer, Speakers bureau: Grünenthal, Novartis, Daniel Solomon Grant/research support from: Funding from Abbvie and Amgen unrelated to this work, Désirée van der Heijde Consultant of: AbbVie, Amgen, Astellas, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Cyxone, Daiichi, Eisai, Eli-Lilly, Galapagos, Gilead Sciences, Inc., Glaxo-Smith-Kline, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda, UCB Pharma; Director of Imaging Rheumatology BV, Tore K. Kvien Grant/research support from: Received grants from Abbvie, Hospira/Pfizer, MSD and Roche (not relevant for this abstract)., Consultant of: Have received personal fees from Abbvie, Biogen, BMS, Celltrion, Eli Lily, Hospira/Pfizer, MSD, Novartis, Orion Pharma, Roche, Sandoz, UCB, Sanofi and Mylan (not relevant for this abstract)., Paid instructor for: Have received personal fees from Abbvie, Biogen, BMS, Celltrion, Eli Lily, Hospira/Pfizer, MSD, Novartis, Orion Pharma, Roche, Sandoz, UCB, Sanofi and Mylan (not relevant for this abstract)., Speakers bureau: Have received personal fees from Abbvie, Biogen, BMS, Celltrion, Eli Lily, Hospira/Pfizer, MSD, Novartis, Orion Pharma, Roche, Sandoz, UCB, Sanofi and Mylan (not relevant for this abstract)., Espen A Haavardsholm Grant/research support from: AbbVie, UCB Pharma, Pfizer Inc, MSD Norway, Roche Norway, Consultant of: Pfizer, AbbVie, Janssen-Cilag, Gilead, UCB Pharma, Celgene, Lilly, Paid instructor for: UCB Pharma, Speakers bureau: Pfizer, AbbVie, UCB Pharma, Celgene, Lilly, Roche, MSD

Background:The optimal first-line treatment of patients (pts) with early rheumatoid arthritis (RA) is yet to be established.Objectives:The primary aim was to assess and compare the proportion of pts who achieved remission with active conventional therapy (ACT) and with three different biologic therapies after 24 wks. Secondary aims were to assess and compare other efficacy measures.Methods:The investigator-initiated NORD-STAR trial (NCT01491815) was conducted in the Nordic countries and Netherlands. In this multicenter, randomized, open-label, blinded-assessor study pts with treatment-naïve, early RA with DAS28>3.2, and positive RF or ACPA, or CRP >10mg/L were randomized 1:1:1:1. Methotrexate (25 mg/week after one month) was combined with: 1) (ACT): oral prednisolone (tapered quickly);or: sulphasalazine, hydroxychloroquine and mandatory intra-articular (IA) glucocorticoid (GC) injections in swollen joints Results:812 pts were randomized. Age was 54.3±14.7 yrs (mean±SD), 31.2% were male, DAS28 5.0±1.1, 74.9% were RF and 81.9% ACPA positive. Fig 1 shows the adjusted CDAI remission rates over time with 95% CI. Table shows crude remission and response rates and absolute differences in adjusted remission and response rates (superiority analysis). Differences in remission and response rates with CZP and TCZ, but not with ABA, remained within the pre-defined non-inferiority margin versus ACT, Fig 2.Figure 1.CDAI remission over time (adj. estimates with 95% CI)Figure 2.Non-inferiority analysis of protocol population. Estimated differences in CDAI remission rates between Arm 1 (active conventional therapy) and Arms 2, 3, and 4 (biologic arms) as reference with 95% confidence intervals, adjusted for gender, ACPA status, country, age, body-mass index and baseline DAS28-CRP. ABA, abatacept; CZP, certolizumab-pegol; MTX, methotrexate; TCZ, tocilizumab.Conclusion:High remission rates were found across all four treatment arms at 24 wks. Higher CDAI remission rate was observed for ABA versus ACT (+9%) and for CZP (+4%), but not for TCZ (-1%). With the predefined 15% margin, ACT was non-inferior to CZP and TCZ, but not to ABA. This underscores the efficacy of active conventional therapy based on MTX combined with glucocorticoids and may guide future treatment strategies for early RA.Table.Primary and key secondary outcomes at 24 weeks (ITT)Active conventional therapy (ACT)Certolizumab+MTXAbatacept+MTXTocilizumab+MTXNo of pts (ITT)200203204188§Crude remission and response ratesCDAI remission42.0%47.8%52.5%41.0%ACR/EULAR Boolean remission34.0%38.4%37.3%31.4%DAS28 remission63.5%68.5%69.6%63.3%SDAI remission41.5%49.8%51.5%42.6%EULAR good response71.5%76.9%79.9%71.3%Difference (95% CI) in rates with Arm 1 as reference (adjusted)CDAI remissionRef4% (-5 to 13%)9% (0.1 to 19%)-1% (-10 to 9%)ACR/EULAR Boolean remissionRef4% (-6 to 13%)5% (-5 to 14%)-4% (-13 to 6%)DAS28 remissionRef3% (-6 to 11%)5% (-4 to 13%)-1% (-10 to 8%)SDAI remissionRef6% (-3 to 18%)9% (-0.3 to 18%)1% (-8 to 11%)EULAR good responseRef4% (-4 to 14%)8% (-2 to 18%)0.4% (-10 to 11%)§17 patients allocated to Tocilizumab did not receive it due to its unavailability and were excluded from ITT.Acknowledgments:Manufacturers provided CZP and ABA.Disclosure of Interests:Merete L. Hetland Grant/research support from: BMS, MSD, AbbVie, Roche, Novartis, Biogen and Pfizer, Consultant of: Eli Lilly, Speakers bureau: Orion Pharma, Biogen, Pfizer, CellTrion, Merck and Samsung Bioepis, Espen A Haavardsholm Grant/research support from: AbbVie, UCB Pharma, Pfizer Inc, MSD Norway, Roche Norway, Consultant of: Pfizer, AbbVie, Janssen-Cilag, Gilead, UCB Pharma, Celgene, Lilly, Paid instructor for: UCB Pharma, Speakers bureau: Pfizer, AbbVie, UCB Pharma, Celgene, Lilly, Roche, MSD, Anna Rudin Consultant of: Astra/Zeneca, Dan Nordström Consultant of: Abbvie, Celgene, Lilly, Novartis, Pfizer, Roche and UCB., Speakers bureau: Abbvie, Celgene, Lilly, Novartis, Pfizer, Roche and UCB., Michael Nurmohamed Grant/research support from: Not related to this research, Consultant of: Not related to this research, Speakers bureau: Not related to this research, Björn Gudbjornsson Speakers bureau: Novartis and Amgen, Jon Lampa Speakers bureau: Pfizer, Janssen, Novartis, Kim Hørslev-Petersen: None declared, Till Uhlig Consultant of: Lilly, Pfizer, Speakers bureau: Grünenthal, Novartis, Gerdur Gröndal: None declared, Mikkel Ǿstergaard Grant/research support from: AbbVie, Bristol-Myers Squibb, Celgene, Merck, and Novartis, Consultant of: AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Hospira, Janssen, Merck, Novartis, Novo Nordisk, Orion, Pfizer, Regeneron, Roche, Sandoz, Sanofi, and UCB, Speakers bureau: AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Hospira, Janssen, Merck, Novartis, Novo Nordisk, Orion, Pfizer, Regeneron, Roche, Sandoz, Sanofi, and UCB, Marte Heiberg: None declared, Jos Twisk: None declared, Simon Krabbe: None declared, Kristina Lend: None declared, Inge Olsen: None declared, Joakim Lindqvist: None declared, Anna-Karin H Ekwall Consultant of: AbbVie, Pfizer, Kathrine L. Grøn Grant/research support from: BMS, Meliha C Kapetanovic: None declared, Francesca Faustini: None declared, Riitta Tuompo: None declared, Tove Lorenzen: None declared, Giovanni Cagnotto: None declared, Eva Baecklund: None declared, Oliver Hendricks Grant/research support from: Pfizer, MSD, Daisy Vedder: None declared, Tuulikki Sokka-Isler: None declared, Tomas Husmark: None declared, Maud-Kristine A Ljosa: None declared, Eli Brodin: None declared, Torkell Ellingsen: None declared, Annika Soderbergh: None declared, Milad Rizk Speakers bureau: AbbVie, Åsa Reckner: None declared, Per Larsson: None declared, Line Uhrenholt Speakers bureau: Abbvie, Eli Lilly and Novartis (not related to the submitted work), Søren Andreas Just: None declared, David Stevens: None declared, Trine Bay Laurberg Consultant of: UCB Pharma (Advisory Board), Gunnstein Bakland Consultant of: Novartis, UCB, Ronald van Vollenhoven Grant/research support from: BMS, GSK, Lilly, UCB, Pfizer, Roche, Consultant of: AbbVie, AstraZeneca, Biogen, Biotest, Celgene, Gilead, Janssen, Pfizer, Servier, UCB, Speakers bureau: AbbVie, Pfizer, UCB

Cardiovascular disease (CVD) risk calculators developed for the general population have been shown to inaccurately predict CVD events in patients with inflammatory joint disease (IJD). European guidelines for CVD prevention recognize the presence of carotid plaques (CP) as a very high CVD risk factor, equivalent of coronary artery disease. Patients with IJD have a high prevalence of CP. We evaluated if CP resulted in reclassification of patients with IJD into a more appropriate CVD risk class and recommended lipid lowering treatment.CVD risk evaluation was performed in patients with IJD using SCORE and ACC/AHA risk calculators to predict CVD events.Of the 335 IJD patients evaluated (including rheumatoid arthritis n=201, ankylosing spondylitis n=85 and psoriatic arthritis n=49), 183 and 159 IJD patients had a calculated CVD risk by SCORE and ACC/AHA5%, indicating no need of lipid lowering treatment (LLT). However, of patients with low to moderate risk calculated by SCORE and ACC/AHA, 67 (36.6%) and 48 (30.2%) had CP and should according to guidelines receive intensive LLT. For patients with high risk, in the LLT considered group, 54.9% and 58.1% were reclassified to correct treatment when adding information on the presence of CP. Our results reveal a considerable reclassification into correct CVD risk category when adding CP in female patients.The high frequency of asymptomatic atherosclerosis in patients with IJD has a notable impact on CVD risk stratification. Identification of CP will reclassify patients into recommended CVD preventive treatment group, which may be clinically important.

Introduction: This study aims to investigate the use of oxytocin augmentation during labor in nulliparous women following Zhang’s guideline or the WHO partograph. Material and methods: This is a secondary analysis of a cluster randomized controlled trial in 14 birth care units in Norway, randomly assigned to either the intervention group, which followed Zhang’s guideline, or to the control group, which followed the WHO partograph, for labor progression. The participants were nulliparous women who had a singleton full-term fetus in a cephalic presentation and spontaneous onset of labor, denoted as group 1 in the Ten Group Classification System. Results: Between December 2014 and January 2017, 7277 participants were included. A total of 3219 women (44%) were augmented with oxytocin during labor. Oxytocin was used in 1658 (42%) women in the Zhang group compared with 1561 (47%) women in the WHO group. The adjusted relative risk for augmentation with oxytocin was 0.98, 95% CI; 0.84 to 1.15; P=0.8 in the Zhang versus WHO group, with an adjusted risk difference of −0.8 %, 95% CI; −7.8 to 6.1. The participants in the Zhang group were less likely to be augmented with oxytocin prior to 6 centimeters of cervical dilatation (24%) compared with participants in the WHO group (28%), with an adjusted relative risk of 0.84, 95% CI; 0.75 to 0.94; P=0.003. Oxytocin was administrated almost 20 minutes longer in the Zhang group than in the WHO group, with an adjusted mean difference of 17.9, 95% CI; 2.7 to 33.1; P=0.021 minutes. In addition, 19% of the women in the Zhang group and 23% in the WHO group were augmented with oxytocin without being diagnosed with labor dystocia. Conclusions: Although no significant difference in the proportion of oxytocin augmentation was observed between the two study groups, there were differences in how oxytocin was used. Women in the Zhang group were less likely to be augmented with oxytocin prior to 6 centimeters of cervical dilatation. The duration of augmentation with oxytocin was longer in the Zhang group than in the WHO group. This study was funded by the Research Department, Østfold Hospital Trust, Norway and the Faculty of Health Sciences, Department of Nursing and Health Promotion, OsloMet – Oslo Metropolitan University, Oslo, Norway.

Objective: To investigate labour duration in different phases of labour when adhering to Zhang’s guideline for labour progression compared with the WHO partograph. Design: A secondary analysis of a cluster randomised controlled trial. Setting: Fourteen Norwegian birth care units, each with more than 500 deliveries per year constituted the clusters. Participants: A total of 7277 nulliparous women with singleton foetus in a cephalic presentation and spontaneous onset of labour at term were included. Intervention: Seven clusters were randomised to the intervention group that adhered to Zhang’s guideline (n = 3972) and seven to the control group that adhered to the WHO partograph (n = 3305) for labour progression. Measurements: The duration of labour from the first registration of cervical dilatation (≥ 4 cm) to the delivery of the baby and the duration of the first and second stages of labour; the time-to-event analysis was used to compare the duration of labour between the two groups after adjusting for baseline covariates. Findings: The adjusted median duration of labour was 7.0 h in the Zhang group, compared with 6.2 h in the WHO group; the median difference was 0.84 h with 95% confidence interval [CI] (0.2–1.5). The adjusted median duration of the first stage was 5.6 h in the Zhang group compared with 4.9 h in the WHO group; the median difference was 0.66 h with 95% CI (0.1–1.2). The corresponding adjusted median duration of the second stage was 88 and 77 min; the median difference was 0.18 h with 95% CI (0.1–0.3). Key Conclusions: The women who adhered to Zhang’s guideline had longer overall duration and duration of the first and second stages of labour than women who adhered to the WHO partograph. Implications for practice: : Understanding the variations in the duration of labour is of great importance, and the results offer useful insights into the different labour progression guidelines, which can inform clinical practice. This study was funded by the Research Department, Østfold Hospital Trust, Norway and the Faculty of Health Sciences, Department of Nursing and Health Promotion, OsloMet – Oslo Metropolitan University, Oslo, Norway.

ObjectivesRecent studies suggest that implementation of the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for rheumatoid arthritis (RA) leads to higher inflammatory activity in seronegative compared with seropositive patients at time of diagnosis. Our aim was to compare the disease course in seronegative and seropositive patients classified according to the 2010 criteria.MethodsDMARD-naïve patients with RA fulfilling the 2010 criteria were included in the treat-to-target ARCTIC trial and followed for 24 months. We stratified patients as seropositive (rheumatoid factor (RF)+, anticitrullinated protein antibodies (ACPA)+ or both) or seronegative (RF– and ACPA–) and compared disease activity, radiographic progression, treatment response and remission rates across groups.Results230 patients were included with mean (SD) age 51.4 (13.7) years, and 61% were female. 34 patients (15%) were seronegative. At 24 months, disease activity measures, radiographic progression and remission rates were similar between groups, despite more inflammatory activity in seronegative patients at baseline. Treatment response was slower in seronegative compared with seropositive patients. The groups received similar treatment.ConclusionOur findings suggest that among patients with RA classified according to the 2010 ACR/EULAR criteria, seronegative patients respond well to modern treatment strategies. However, treatment response was somewhat slower in seronegative patients and radiographic progression was similar in seronegative and seropositive patients. Our results indicate that seronegative RA is not a mild form of the disease and requires intensive treat-to-target therapy similar to treatment of seropositive RA.

To explore factors related to sleep disturbance in patients with rheumatoid arthritis (RA).Cross-sectional data from 986 patients in the Oslo RA Register (ORAR) collected in 2009 were included. Sleep problems were assessed by four measures: the Medical Outcomes Study (MOS) sleep disturbance scale, and the sleep components of the Rheumatoid Arthritis Impact of Disease (RAID) score, the Multi-Dimensional Health Assessment Questionnaire (MDHAQ), and the 15-dimensional quality of life questionnaire (15D). Patient-reported outcomes (PROs) were recorded using standard questionnaires for physical and mental function [the HAQ and the MOS 36-item Short-Form Health Survey (SF-36), disease activity (the RA Disease Activity Index, RADAI), utility (SF-6D), and visual analogue scales (VAS) for pain, fatigue, and disease activity]. Demographics including comorbidity were collected. Information on use of medication for RA and sleep disturbance was obtained using checklists. Multivariate analyses were used to identify factors independently associated with sleep problems by four different measures.The mean (standard deviation, SD) age of the patients was 59.4 (12.5) years, 76.9% were females, and the mean (SD) disease duration was 13.7 (10.7) years. The correlation between the various sleep measures was high (rSleep disturbance measured by four different measures was independently related to other PROs including fatigue, pain, and disease activity in RA patients.

Background:Sustained remission is the goal of rheumatoid arthritis (RA) care, and more patients reach and maintain this state on conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs) with treat-to-target strategies. The knowledge about whether csDMARDs can be tapered in RA remission is limited.Objectives:The primary objective of the study was to assess the effect of tapering of csDMARDs on the risk of flares in RA patients in sustained clinical remission.Methods:In the open, phase 4, non-inferiority ARCTIC REWIND trial, RA patients in clinical remission for ≥ 12 months on stable csDMARD therapy were randomised to continued stable csDMARD or half dose csDMARD. Patients had to be in DAS remission at inclusion with no swollen joints (of 44). The primary endpoint was the proportion of patients with a disease flare during 12 months (defined as a combination of DAS >1.6, change in DAS >0.6 and ≥2 swollen joints, or the physician and patient agreed that a clinically significant flare had occurred). Patients attended visits every 4 months, with extra visits in case of flares. The non-inferiority margin was 20%, with a predefined superiority test if non-inferiority was not shown. Mixed effect logistic regression was used to test the inferiority null-hypothesis in the per-protocol population. Radiographs at 0 and 12 months were scored by van der Heijde Sharp score (average score of two readers, progression: ≥1 unit change/year). Clinicaltrials.govNCT01881308.Results:We enrolled 160 patients, 155 received the allocated treatment strategy. Baseline characteristics were overall well balanced (Table). 78% of patients in the stable csDMARD arm and 84% in the half-dose csDMARD arm used methotrexate monotherapy. In the primary analysis, we observed flares in 6% of patients on stable csDMARD, compared to 25% in the half-dose csDMARD arm, giving a risk difference (95% CI) of 18.3% (7.2% to 29.3%, Fig 1). Non-inferiority could not be claimed, with the results showing superiority of the stable arm over the half-dose arm (Fig 1). Similar results were found in methotrexate monotherapy users. In the stable arm, 2/5 (40%) escalated DMARD medication following the flares, compared to 18/19 (95%) in the tapering arm. No progression of radiographic joint damage was observed in 79.5% of patients on stable DMARDs and 62.7% of those tapering, difference (95% CI) -17.7% (-33.0%, -2.3%, Fig 2E). At 12 months, 92% of patients in the stable and 85% of patients in the tapered arm were in DAS remission (Fig 2C). The frequency of adverse events was 75 in the stable arm and 53 in the tapered arm, with serious adverse events in 2 (2.6%) of patients in the stable and 4 (5.1%, including two serious infections) patients in the tapered arm.Conclusion:In RA patients in sustained remission on csDMARDs, continued csDMARD therapy with stable dosage led to significantly fewer disease activity flares and less frequent radiographic joint damage progression than tapered csDMARD treatment.Table.Baseline values; mean (SD), n (%) or median (IQR)Stable, n=78Tapering, n=78Age, yrs55 (12)56 (12)Female50 (64%)54 (69%)ACPA+57 (73%)63 (81%)Symptom dur., yrs3.7 (1.8)3.4 (1.4)DAS0.8 (0.4)0.8 (0.3)CRP mg/L2 (1, 3)2.0 (1,3)MTX monotherapy61 (78%)65 (84%)Disclosure of Interests:Siri Lillegraven: None declared, Nina Paulshus Sundlisæter: None declared, Anna-Birgitte Aga: None declared, Joe Sexton: None declared, Inge Olsen: None declared, Hallvard Fremstad: None declared, Cristina Spada: None declared, Tor Magne Madland: None declared, Christian A. Høili Consultant of: Novartis, Gunnstein Bakland Consultant of: Novartis, UCB, Åse Lexberg: None declared, Inger Johanne Widding Hansen: None declared, Inger M. Hansen: None declared, Hilde Haukeland Consultant of: Novartis, Maud-Kristine A Ljosa: None declared, Ellen Moholt: None declared, Till Uhlig Consultant of: Lilly, Pfizer, Speakers bureau: Grünenthal, Novartis, Daniel Solomon Grant/research support from: Funding from Abbvie and Amgen unrelated to this work, Désirée van der Heijde Consultant of: AbbVie, Amgen, Astellas, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Cyxone, Daiichi, Eisai, Eli-Lilly, Galapagos, Gilead Sciences, Inc., Glaxo-Smith-Kline, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda, UCB Pharma; Director of Imaging Rheumatology BV, Tore K. Kvien Grant/research support from: Received grants from Abbvie, Hospira/Pfizer, MSD and Roche (not relevant for this abstract)., Consultant of: Have received personal fees from Abbvie, Biogen, BMS, Celltrion, Eli Lily, Hospira/Pfizer, MSD, Novartis, Orion Pharma, Roche, Sandoz, UCB, Sanofi and Mylan (not relevant for this abstract)., Paid instructor for: Have received personal fees from Abbvie, Biogen, BMS, Celltrion, Eli Lily, Hospira/Pfizer, MSD, Novartis, Orion Pharma, Roche, Sandoz, UCB, Sanofi and Mylan (not relevant for this abstract)., Speakers bureau: Have received personal fees from Abbvie, Biogen, BMS, Celltrion, Eli Lily, Hospira/Pfizer, MSD, Novartis, Orion Pharma, Roche, Sandoz, UCB, Sanofi and Mylan (not relevant for this abstract)., Espen A Haavardsholm Grant/research support from: AbbVie, UCB Pharma, Pfizer Inc, MSD Norway, Roche Norway, Consultant of: Pfizer, AbbVie, Janssen-Cilag, Gilead, UCB Pharma, Celgene, Lilly, Paid instructor for: UCB Pharma, Speakers bureau: Pfizer, AbbVie, UCB Pharma, Celgene, Lilly, Roche, MSD

Background:A lack or loss of response to TNFα inhibitors (TNFi) has been associated with low serum drug levels and formation of anti-drug antibodies (ADAb). Therapeutic drug monitoring (TDM), an individualised treatment strategy based on regular assessments of serum drug levels, has been suggested to optimise efficacy of TNFi. It is still unclear if TDM improves clinical outcomes, and the value of TDM has recently been included in the research agenda across different specialities. This first randomised controlled trial on the effectiveness of TDM in a range of immune mediated inflammatory diseases including rheumatic diseases, the NORwegian DRUg Monitoring trial part A (NOR-DRUM (A)) focus on the induction period of infliximab (INX) treatment.Objectives:To assess if TDM is superior to standard treatment in order to achieve remission in patients starting INX.Methods:In the investigator-initiated, randomised, open-label, multicentre NOR-DRUM (A) study, adult patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), spondyloarthritis (SpA), ulcerative colitis (UC), Crohn’s disease (CD) and psoriasis (Ps) starting INX therapy were randomly assigned to administration of INX according to a treatment strategy based on TDM (TDM arm) or to standard administration of INX without TDM (control arm). Study visits were conducted at each infusion. The primary endpoint was remission at week 30. In the TDM arm, the dose and interval were adjusted according to INX trough levels to reach the therapeutic range (Figure 1). If the patient developed significant levels of ADAb, INX was terminated. To guide the investigators, the TDM strategy was integrated in an interactive eCRF. The primary endpoint was analysed by mixed effect logistic regression in the full analyses set (FAS), adjusting for diagnoses. Infections and infusion reactions were specified as adverse events (AEs) of special interest.Clinical trial.gov:NCT03074656Results:We enrolled 411 patients at 21 study centres between January 2017 and December 2018. 398 patients (RA 80, PsA 42, SpA 117, UC 80, CD 57, Ps 22) received the allocated strategy and were included in the FAS population. Demographic and baseline characteristics were comparable in both arms. TDM was not found to be superior to standard treatment with regard to the primary outcome. Remission at week 30 was reached in 100 (53%) and 106 (54%) of the patients in the TDM and control arm, respectively (adjusted difference, 1.5%; 95% confidence interval (CI), -8.2 to 11.1, p=0.78) (Figure 2). Consistent results were shown for all the secondary endpoints (Figure 3) and in the sensitivity analyses. Twenty patients (10%) in the TDM arm and 30 patients (15%) in the control arm developed significant levels of ADAb. The number of adverse events (AE) was similar in both groups, however infusion reactions were less frequent (5 patients (2.5%) vs 16 patients (8.0%)) in the TDM arm (difference 5.5% (95% CI 1.1, 9.8%))Conclusion:NOR-DRUM (A) is the first randomised trial to address effectiveness of TDM in the induction period of TNFi treatment, and the first trial to address TDM in rheumatic diseases. In this study, TDM was not superior to standard treatment in order to achieve remission. Although improved safety is indicated by a reduction in infusion reactions, implementation of TDM as a general strategy in the induction period of INX is not supported by the NOR-DRUM (A) study.Disclosure of Interests:Silje Watterdal Syversen Speakers bureau: Roche, Thermo Fisher, Guro Løvik Goll Consultant of: Novartis, Pfizer, Speakers bureau: Abbvie, Biogen, Boehringer Ingelheim, Orion Pharma, Eli Lilly, Novartis, Pfizer, MSD, Roche, UCB, Kristin Kaasen Jørgensen Consultant of: AOP Orphan, Celltrion, Sandoz, Speakers bureau: Norgine, Tillots, Øystein Sandanger: None declared, Joe Sexton: None declared, Inge Olsen: None declared, Johanna Gehin Speakers bureau: Roche, Marthe Kirksæther Brun: None declared, David Warren: None declared, Cato Mørk Consultant of: Abbot, Novartis, Celagene, Almiral, Galderma, ACO, Almiral, ACO, Speakers bureau: Novartis, Abbott, Abbvie, Celegene, LEO, Almiral, Galderma, Tore K. Kvien Grant/research support from: Received grants from Abbvie, Hospira/Pfizer, MSD and Roche (not relevant for this abstract)., Consultant of: Have received personal fees from Abbvie, Biogen, BMS, Celltrion, Eli Lily, Hospira/Pfizer, MSD, Novartis, Orion Pharma, Roche, Sandoz, UCB, Sanofi and Mylan (not relevant for this abstract)., Paid instructor for: Have received personal fees from Abbvie, Biogen, BMS, Celltrion, Eli Lily, Hospira/Pfizer, MSD, Novartis, Orion Pharma, Roche, Sandoz, UCB, Sanofi and Mylan (not relevant for this abstract)., Speakers bureau: Have received personal fees from Abbvie, Biogen, BMS, Celltrion, Eli Lily, Hospira/Pfizer, MSD, Novartis, Orion Pharma, Roche, Sandoz, UCB, Sanofi and Mylan (not relevant for this abstract)., Jørgen Jahnsen Consultant of: AbbVie, Boerhinger Ingelheim, Celltrion, Ferring, Janssen, Meda, MSD, Norgine, Novartis, Orion Pharma, Pfizer, Pharmacosmos, Takeda, and Sandoz., Speakers bureau: AbbVie, Astro Pharma, Boerhinger Ingelheim, BMS, Celltrion, Ferring, Hikma, Janssen, Meda, MSD, Napp Pharma, Orion Pharma, Pfizer, Pharmacosmos, Roche, Takeda, Tillotts and Sandoz, Nils Bolstad Consultant of: Pfizer, Janssen, Speakers bureau: Orion Pharma, Napp Pharmaceuticals, Takeda, Roche, Novartis, Espen A Haavardsholm Grant/research support from: AbbVie, UCB Pharma, Pfizer Inc, MSD Norway, Roche Norway, Consultant of: Pfizer, AbbVie, Janssen-Cilag, Gilead, UCB Pharma, Celgene, Lilly, Paid instructor for: UCB Pharma, Speakers bureau: Pfizer, AbbVie, UCB Pharma, Celgene, Lilly, Roche, MSD

Objective Intraarticular glucocorticoid injections are common in rheumatoid arthritis (RA) treatment. This study was undertaken to investigate whether ultrasound in combination with clinical examination is better than clinical examination alone at identifying joints that will benefit from intraarticular injections, and to compare the efficacy of ultrasound-guided versus palpation-guided procedures. Methods In the treat-to-target Aiming for Remission in Rheumatoid Arthritis: a Randomised Trial Examining the Benefit of Ultrasonography in a Clinical Tight Control Regimen (ARCTIC), patients with early RA were randomized 1:1 to follow-up with or without ultrasound. In addition to disease-modifying antirheumatic drugs, intraarticular glucocorticoids were used to treat inflamed joints. The distribution of injections was assessed in both study groups. The relationship of clinical and ultrasound findings at the time of injection with treatment efficacy was examined, with non-swollen joint at the next visit as the outcome measure. Treatment success was compared across study groups to evaluate ultrasound-guided versus palpation-guided procedures. Results More injections were administered in the ultrasound group than in the conventional strategy group (n = 770 versus 548), especially in intercarpal joints (n = 58 versus 5) and metatarsophalangeal joints (n = 200 versus 104). Injecting clinically swollen joints without power Doppler (PD) activity on ultrasound was not efficacious compared to not injecting (odds ratio [OR] 1.3; P = 0.59). Efficacy was best in swollen joints (OR 9.0; P = 0.001) and non-swollen joints (OR 8.4; P = 0.016) with moderate PD activity. Treatment success was similar for the ultrasound-guided and palpation-guided procedures. Conclusion Our findings indicate that the efficacy of intraarticular glucocorticoid injections varies according to ultrasound findings at the time of injection, supporting the use of ultrasound as a tool to select joints that will benefit from intraarticular injections. However, ultrasound needle guidance was not superior to palpation guidance.

Background: Norway9s government funded the NOR-SWITCH study to investigate switching from originator infliximab (INX) to biosimilar CT-P13 in Crohn’s disease (CD), ulcerative colitis (UC), spondyloarthritis (SpA), rheumatoid arthritis (RA), psoriatic arthritis (PsA) and chronic plaque psoriasis (Ps). Previously, the main analyses have been published1. Immunogenicity is associated with treatment failure and is of particular concern in switching2. Objectives: To evaluate the consistency and fine specificity of anti-drug antibody (ADAb) responses to INX and CT-P13, in arthritis and IBD patients, after switching from INX to CT-P13. Methods: The study included adult patients with CD, UC, SpA, RA, PsA or Ps1. Assays for drug serum levels and ADAb have been described1. ADAb positive sera were tested for cross-reactivity to 5 batches of INX and CT-P13. We quantified IgG4 ADAb, testing for functional inhibition. Infliximab peptides were used to compare epitope recognition of positive sera. Immunogenic infliximab-epitopes were identified by ELISA and sera compared across diseases. Results: We tested 15 controls, 15 arthritis, 21 IBD patients. No Ps patients had ADAbs in our study. All 23 anti-CT-P13 and 13 anti-INX sera cross-reacted with INX and CT-P13, respectively. ADAb concentrations to INX or CT-P13 correlated strongly (r values between 0.92 and 0.99, p Conclusions: ADAbs to INX also recognize CT-P13, with similar epitopes. We found no consistent difference in ADAb epitope specificity between diagnoses. However, two specific minor epitopes are only recognized by IBD patients which might reflect the importance of HLA background for ADAb. References 1. Jorgensen KK, Olsen IC, Goll GL, et al. Switching from originator infliximab to biosimilar CT-P13 compared to maintained treatment with originator infliximab (NOR-SWITCH): a 52-week randomised double-blind non-inferiority trial. Lancet, 2017Jun 10;389(10086):2304–2316. [Epub 2017 May11]. 2. Dorner T, Jay J. Biosimilars in rheumatology: current perspectives and lessons learnt. Nat Rev Rheumatol2015Dec;11(12):713–24. Disclosure of Interest: G. Goll Consultant for: AbbVie, Biogen, Eli Lilly, Novartis, Pfizer, MSD, Roche, UCB, Boehringer Ingelheim, Orion Pharma, N. Bolstad Consultant for: Pfizer, Orion Pharma, Napp Pharmaceuticals, I. Iria: None declared, R. Klaasen: None declared, K. Jorgensen Consultant for: Tillott, Celltrion, Intercept, I. Olsen Consultant for: Pfizer, A. Valido: None declared, M. Saavedra: None declared, J. Fonseca Consultant for: AbbVie, Ache, Amgen, Biogen, BMS, Janssen, Lilly, MSD, Novartis, Pfizer, Roche, UCB, K. Lundin Grant/research support from: MSD, Consultant for: Takeda, Orion, AbbVie, Rfizer, MSD, D. Warren: None declared, E. Haavardsholm Consultant for: AbbVie, Pfizer, MSD, Roche, UCB, J. Jahnsen Consultant for: AbbVie, Takeda, Janssen, Celltrion, Napp, AstroPharma, Hikma, Orion, Pfizer, T. Kvien Consultant for: AbbVie, Biogen, Eli Lilly, Novartis, Pfizer, MSD, Roche, UCB, Boehringer Ingelheim, Orion Pharma, J. Goncalves Consultant for: AbbVie, Amgen, Biogen, MSD, Pfizer

Background: Patient reported outcome measures (PROM) are important for clinical practice and research. Given the unmet need for a comprehensive PROM for systemic sclerosis (SSc), the ScleroID questionnaire was developed by a joint team of patients with SSc and medical experts. This is intended as a brief, specific, patient-derived, disease impact score for research and clinical use in SSc. Objectives: Here, we present the validation and final version of the ScleroID. Methods: This EULAR-endorsed project involves 9 European expert SSc centers. Patients fulfilling the ACR/EULAR 2013 criteria were prospectively included since 05/16 in a large observational cohort study. Patients completed the ScleroID and comparators SHAQ, EQ5D, SF36. They also weighted the 10 dimensions of the ScleroID by distributing 100 points according to the perceived impact on their health. The final score calculation is based on the ranking of the weights. The validation study included a reliability arm and a longitudinal arm, looking at sensitivity to change at follow-up. Results: Of the 472 patients included at baseline, 109 patients also had a reliability visit and 113 patients a follow-up visit. 84.5% of patients were female, 29.8% had diffuse SSc, mean age was 54.6 years, and mean disease duration 9.5 years. The highest weights were assigned by the patients to Raynaud`s phenomenon, fatigue, hand function and pain, confirming our previous results. The total ScleroID score showed good Spearman correlation coefficients with the comparators (SHAQ, 0.73; EQ5D -0.48; Patient’s global assessment, VAS 0.77; HAQ-DI 0.62; SF36 physical score -0.62; each p Conclusion: The EULAR ScleroID is a novel PROM designed for use in clinical practice and clinical trials to reflect the disease impact of SSc, showing good performance in the validation study. Importantly, Raynaud syndrome, impaired hand function, pain and fatigue were the main patient reported drivers of disease impact. Disclosure of Interests: Mike O. Becker: None declared, Rucsandra Dobrota: None declared, Kim Fligelstone: None declared, Annelise Roennow: None declared, Yannick Allanore Grant/research support from: BMS, Inventiva, Roche, Sanofi, Consultant of: Actelion, Bayer AG, BMS, BI, Patricia Carreira Grant/research support from: Actelion, Roche, MSD, Consultant of: GlaxoSmithKline, VivaCell Biotechnology, Emerald Health Pharmaceuticals, Boehringer Ingelheim, Roche, Speakers bureau: Actelion, GlaxoSmithKline, Roche, Laszlo Czirjak Consultant of: Actelion, BI, Roche-Genentech, Lilly, Medac, Novartis, Pfizer, Bayer AG, Christopher Denton Grant/research support from: GlaxoSmithKline, CSL Behring, and Inventiva, Consultant of: Medscape, Roche-Genentech, Actelion, GlaxoSmithKline, Sanofi Aventis, Inventiva, CSL Behring, Boehringer Ingelheim, Corbus Pharmaceuticals, Acceleron, Curzion and Bayer, Roger Hesselstrand: None declared, Gunnel Sandqvist: None declared, Otylia Kowal-Bielecka Consultant of: Bayer, Boehringer Ingelheim, Inventiva, MSD, Medac, Novartis, Roche and Sandoz, Speakers bureau: Bayer, Boehringer Ingelheim, Inventiva, MSD, Medac, Novartis, Roche and Sandoz, Cosimo Bruni Speakers bureau: Actelion, Eli Lilly, Marco Matucci Cerinic: None declared, Carina Mihai: None declared, Ana Maria Gheorghiu: None declared, Ulf Muller-Ladner Speakers bureau: Biogen, Joe Sexton: None declared, Turid Heiberg: None declared, Oliver Distler Grant/research support from: Grants/Research support from Actelion, Bayer, Boehringer Ingelheim, Competitive Drug Development International Ltd. and Mitsubishi Tanabe; he also holds the issued Patent on mir-29 for the treatment of systemic sclerosis (US8247389, EP2331143)., Consultant of: Consultancy fees from Actelion, Acceleron Pharma, AnaMar, Bayer, Baecon Discovery, Blade Therapeutics, Boehringer, CSL Behring, Catenion, ChemomAb, Curzion Pharmaceuticals, Ergonex, Galapagos NV, GSK, Glenmark Pharmaceuticals, Inventiva, Italfarmaco, iQvia, medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Roche, Sanofi and UCB, Speakers bureau: Speaker fees from Actelion, Bayer, Boehringer Ingelheim, Medscape, Pfizer and Roche

Background The NOR-SWITCH study was funded by the Norwegian government to investigate if switching from originator infliximab (INX) to biosimilar CT-P13 is safe in rheumatoid arthritis (RA), spondyloarthritis (SpA), psoriatic arthritis (PsA), Crohn’s disease (CD), ulcerative colitis (UC), and chronic plaque psoriasis (Ps). Objectives Assessing efficacy, safety. immunogenicity at week 78 in patients on CT-P13 for 78 weeks (maintenance group) vs CT-P13 for 26 weeks (switch group). Methods 481 adult patients on stable originator infliximab were randomised 1:1 to continued INX or switch to CT-P13 treatment in the main study1. All extension participants received CT-P13. The primary endpoint was disease worsening, analysed with logistic regression, adjusted for diagnosis and treatment duration. Results 380 patients entered the extension trial. Demographic and baseline (52 w) characteristics of the extension study population are shown (table 1). Disease worsening in the study arms (Per Protocol Set, PPS) and in each diagnosis (explorative analyses) are shown (table 1). Generic disease variables, disease specific composite measures, trough drug levels, anti-drug antibodies and reported adverse events were comparable between groups (data not shown). Conclusions We found no difference between patients switched from INX to CT-P13 vs those on maintained CT-P13 Reference [1] Jorgensen KK, Olsen IC, Goll GL, et al. Switching from originator infliximab to biosimilar CT-P13 compared to maintained treatment with originator infliximab (NOR-SWITCH): A 52-week randomised double-blind non-inferiority trial. Lancet2017Jun 10;389(10086):2304–2316. Disclosure of Interest G. Goll Consultant for: AbbVie, Biogen, Boehrinfer Ingelheim, Orion Pharma, Eli Lilly, Novartis, PfizerMSD, Roche, UCB, K. Jorgensen Consultant for: Tillott, Celltrion, Intercept, J. Sexton: None declared, I. Olsen Consultant for: Pfizer, N. Bolstad Consultant for: Pfizer, Orion Pharma, Napp pharmaceuticals, Takeda, M. Lorentzen: None declared, E. Haavardsholm Consultant for: AbbVie, Pfizer, MSD, Roche, UCB, C. Mork Consultant for: AbbVie, Novartis, LEO Pharma AS, ACI hud Norge, Cellgene AS, Galderma Nordic AB, J. Jahnsen Consultant for: AbbVie, Celltrion, Takeda, Napp Pharm, AstroPharma, Hikma, Orion Pharma, Pfizer, T. Kvien Consultant for: AbbVie, Biogen, Eli Lilly, Novartis, Pfizer, MSD, Roche, UCB, Boehringer Ingelheim, Epirus, JAnssen, Merck-Serono, Mundipharma, Oktal, Orion Pharma

Summary Background There is an ongoing debate concerning which guidelines and monitoring tools are most beneficial for assessing labour progression, to help prevent use of intrapartum caesarean section (ICS). The WHO partograph has been used for decades with the assumption of a linear labour progression; however, in 2010, Zhang introduced a new guideline suggesting a more dynamic labour progression. We aimed to investigate whether the frequency of ICS use differed when adhering to the WHO partograph versus Zhang's guideline for labour progression. Methods We did a multicentre, cluster-randomised controlled trial at obstetric units in Norway, and each site was required to deliver more than 500 fetuses per year to be eligible for inclusion. The participants were nulliparous women who had a singleton, full-term fetus with cephalic presentation, and who entered spontaneous active labour. The obstetric units were treated as clusters, and women treated within these clusters were all given the same treatment. We stratified these clusters by size and number of previous caesarean sections. The clusters containing the obstetric units were then randomly assigned (1:1) to the control group, which adhered to the WHO partograph, or to the intervention group, which adhered to Zhang's guideline. The randomisation was computer-generated and was done in the Unit of Biostatistics and Epidemiology, Oslo University Hospital, Oslo, Norway, and investigators in this unit had no further involvement in the trial. Our study design did not enable masking of participants or health-care providers, but the investigators who were analysing the data were masked to group allocation. The primary outcome was use of ICS during active labour (cervical dilatation of 4–10 cm) in all participating women. The Labour Progression Study (LaPS) is registered with ClinicalTrials.gov, number NCT02221427. Findings Between Aug 1, 2014, and Sept 1, 2014, 14 clusters were enrolled in the LaPS trial, and on Sept 11, 2014, seven obstetric units were randomly assigned to the control group (adhering to the WHO partograph) and seven obstetric units were randomly assigned to the intervention group (adhering to Zhang's guideline). Between Dec 1, 2014, and Jan 31, 2017, 11 615 women were judged to be eligible for recruitment in the trial, which comprised 5421 (46·7%) women in the control group units and 6194 (53·3%) women in the intervention group units. In the control group, 2100 (38·7%) of 5421 women did not give signed consent to participate and 16 (0·3%) women abstained from participation. In the intervention group, 2181 (35·2%) of 6194 women did not give signed consent to participate and 41 (0·7%) women abstained from participation. 7277 (62·7%) of 11 615 eligible women were therefore included in the analysis of the primary endpoint. Of these women, 3305 (45·4%) participants were in an obstetric unit that was randomly assigned to the control group (adhering to the WHO partograph) and 3972 (54·6%) participants were in an obstetric unit that was randomly assigned to the intervention group (adhering to Zhang's guideline). No women dropped out during the trial. Before the start of the trial, ICS was used in 9·5% of deliveries in the control group obstetric units and in 9·3% of intervention group obstetric units. During our trial, there were 196 (5·9%) ICS deliveries in women in the control group (WHO partograph) and 271 (6·8%) ICS deliveries in women in the intervention group (Zhang's guideline), and the frequency of ICS use did not differ between the groups (adjusted relative risk 1·17, 95% CI 0·98–1·40; p=0·08; adjusted risk difference 1·00%, 95% CI −0·1 to 2·1). We identified no maternal or neonatal deaths during our study. Interpretation We did not find any significant difference in the frequency of ICS use between the obstetric units assigned to adhere to the WHO partograph and those assigned to adhere to Zhang's guideline. The overall decrease in ICS use that we observed relative to the previous frequency of ICS use noted in these obstetric units might be explained by the close focus on assessing labour progression more than use of the guidelines. Our results represent an important contribution to the discussion on implementation of the new guideline. Funding Ostfold Hospital Trust.

Patients with inflammatory joint diseases (IJD) have an increased risk of cardiovascular disease (CVD). Our goal was to examine indications for, and use of, lipid-lowering therapy (LLT) and antihypertensive treatment (AntiHT) in patients with IJD. Furthermore, to investigate the frequency of low-density lipoprotein cholesterol (LDL-c) and blood pressure (BP) goal attainment among IJD patients.The cohort was derived from the NOrwegian Collaboration on Atherosclerosis in patients with Rheumatic joint diseases (NOCAR). Indications for AntiHT were: systolic/diastolic BP ≥ 140/90 mm Hg, self-reported hypertension or AntiHT. CVD risk was estimated by the systematic coronary risk evaluation (SCORE) algorithm. LDL-c goals were2.6 mmol/L in case of diabetes, total cholesterol 8 mmol/L or a SCORE estimate ≥ 5%, and1.8 mmol/L for those with established CVD or SCORE ≥ 10%. Comparisons across IJD entities were performed using age and sex adjusted logistic regression.In total, 2277 patients (rheumatoid arthritis: 1376, axial spondyloarthritis: 474, psoriatic arthritis: 427) were included. LLT and AntiHT were indicated in 36.1% and 52.6% of the patients, of whom 37.6% and 47.0% were untreated, respectively. LDL-c and BP targets were obtained in 26.2% and 26.3%, respectively. Guideline recommended treatment and/or corresponding treatment targets were not initiated or obtained in approximately 50%. Rheumatoid arthritis patients were particularly likely to be undertreated with LLT, whereas hypertension undertreatment was most common in psoriatic arthritis.Inadequate CVD prevention encompasses all the three major IJD entities. The unmet need for CVD preventive measures is not only prevalent in RA, but exists across all the major IJD entities.

ObjectivesCalprotectin is an inflammatory marker of interest in rheumatoid arthritis (RA). We evaluated whether the level of calprotectin was associated with disease activity, and if it was predictive of treatment response and radiographic progression in patients with early RA.MethodsPlasma from disease-modifying antirheumatic drug (DMARD)-naïve patients with RA fulfilling 2010 American College of Rheumatology/European League Against Rheumatism classification criteria with symptom duration Results215 patients were included: 61% female, 82% anti-citrullinated peptide antibody positive, mean (SD) age 50.9 (13.7) years and median (25, 75 percentile) symptom duration 5.8 (2.8, 10.5) months. Calprotectin was significantly correlated with Clinical Disease Activity Index (r=0.32), ESR (r=0.50) and ultrasonography power Doppler (r=0.42) before treatment onset. After 12 months of treatment, calprotectin, but not ESR and CRP, was significantly correlated with power Doppler (r=0.27). Baseline levels of calprotectin, ESR and CRP were not predictive of treatment response, but high levels of calprotectin were associated with radiographic progression in multivariate models.ConclusionsCalprotectin was correlated with inflammation assessed by ultrasound before and during DMARD treatment, and was also associated with radiographic progression. The data support that calprotectin may be of interest as an inflammatory marker when assessing disease activity in different stages of RA.Trial registration numberNCT01205854; Post-results.

Objective Patients with rheumatoid arthritis (RA) and carotid artery plaques have an increased risk of acute coronary syndromes. Statin treatment with the goal of achieving a low-density lipoprotein (LDL) cholesterol level of ≤1.8 mmoles/liter (≤70 mg/dl) is recommended for individuals in the general population who have carotid plaques. The aim of the ROsuvastatin in Rheumatoid Arthritis, Ankylosing Spondylitis and other inflammatory joint diseases (RORA-AS) study was to evaluate the effect of 18 months of intensive lipid-lowering treatment with rosuvastatin with regard to change in carotid plaque height. Methods Eighty-six patients (60.5% of whom were female) with carotid plaques and inflammatory joint disease (55 with RA, 21 with AS, and 10 with psoriatic arthritis) were treated with rosuvastatin to obtain the LDL cholesterol goal. Carotid plaque height was evaluated by B-mode ultrasonography. Results The mean ± SD age of the patients was 60.8 ± 8.5 years, and the median compliance with rosuvastatin treatment was 97.9% (interquartile range [IQR] 96.0–99.4). At baseline, the median number and height of the carotid plaques were 1.0 (range 1–8) and 1.80 mm (IQR 1.60–2.10), respectively. The mean ± SD change in carotid plaque height after 18 months of treatment with rosuvastatin was −0.19 ± 0.35 mm (P < 0.0001). The mean ± SD baseline LDL cholesterol level was 4.0 ± 0.9 mmoles/liter (154.7 ± 34.8 mg/dl), and the mean reduction in the LDL cholesterol level was −2.3 mmoles/liter (95% confidence interval [95% CI] −2.48, −2.15) (−88.9 mg/dl [95% CI −95.9, −83.1]). The mean ± SD LDL cholesterol level during the 18 months of rosuvastatin treatment was 1.7 ± 0.4 mmoles/liter (area under the curve). After adjustment for age/sex/blood pressure, no linear relationship between a reduction in carotid plaque height and the level of LDL cholesterol exposure during the study period was observed. Attainment of the LDL cholesterol goal of ≤1.8 mmoles/liter (≤70 mg/dl) or the amount of change in the LDL cholesterol level during the study period did not influence the degree of carotid plaque height reduction. Conclusion Intensive lipid-lowering treatment with rosuvastatin induced atherosclerotic regression and reduced the LDL cholesterol level significantly in patients with inflammatory joint disease.

Insight into the most important inflammatory pathways in ankylosing spondylitis (AS) could be of importance in risk stratification and the development of treatment strategies. Therefore, we aimed to compare circulating levels of inflammatory biomarkers between AS patients and controls, and explore associations between these biomarkers and clinical measures of disease activity.In a cross-sectional study, 143 AS patients were compared with 124 population controls. Blood samples were analysed by immunoassays for interleukin (IL)-6, IL-17a, IL-23, soluble tumour necrosis factor receptor 1 (sTNF-R1) and 2 (sTNF-R2), and osteoprotegerin (OPG). Disease activity was measured by the AS Disease Activity Score (ASDAS) and the Bath AS Disease Activity Index (BASDAI).Analysis of covariance (ANCOVA) demonstrated elevated plasma levels of sTNF-R1 [geometrical mean 0.94 (95% CI 0.88-1.00) vs. 0.83 (95% CI 0.78-0.89) ng/mL, p0.01] and OPG (2.3, 95% CI 2.1-2.4 vs. 2.0, 95% CI 1.9-2.2 ng/mL, p = 0.02) and, although not significant, of IL-23 (122, 95% CI 108-139 vs. 106, 95% CI 93-120 pg/mL, p = 0.07) in AS patients vs.More AS patients had a high level of sTNF-R2 than controls (22 vs. 1, p0.01). No differences between the groups were seen for IL-6 and IL-17a. In patients, no significant associations were seen between inflammatory markers and disease activity measures after adjusting for personal characteristics.Significantly higher plasma levels of sTNF-R1, sTNF-R2, and OPG and numerically but non-significantly higher levels of IL-23 were found in AS patients compared to controls, indicating that these cytokines and cytokine receptors are important inflammatory pathways. Clinical measures of disease activity were not significantly correlated with circulating inflammatory markers.

Background The NOR-SWITCH study is a 52-week randomized, double-blind, non-inferiority, phase IV switch trial in patients with Crohn9s disease (CD), ulcerative colitis (UC), spondyloarthritis (SpA), rheumatoid arthritis (RA), psoriatic arthritis (PsA) and plaque psoriasis (Ps) on stable treatment with originator infliximab (Remicade®, INX), funded by the Norwegian government. Previously, primary analyses of the pooled indications have been published 1 . Objectives To investigate efficacy, safety and immunogenicity in SpA patients treated with continuous INX vs patients switched to CT-P13 (biosimilar infliximab, Remsima®) in the NOR-SWITCH study (explorative analyses). Methods Patients were randomized 1:1 to continued INX or switch to CT-P13. Serum drug levels were analyzed by automated in-house assay. The primary endpoint was disease worsening according to disease-specific composite measures and/or consensus between investigator/patient. Exploratory subgroup analyses examined disease worsening and safety in SpA. The primary endpoint was analysed by logistic regression, adjusted for diagnosis and disease duration. Results Demographics, occurrence of disease worsening, change in disease measures and treatment-emergent adverse events (TEAE) were similar (Table), as were serum drug levels for INX and CT-P13 (Figure). Conclusions Explorative analyses in the NOR-SWITCH study showed similar efficacy, drug levels and safety in SpA patients switched to CT-P13 as those on continuous INX. The study was not powered to show non-inferiority within each diagnosis. References Jorgensen KK et al. Switching from originator infliximab to biosimilar CT-P13 compared to maintained treatment with originator infliximab (NOR-SWITCH): a 52-week randomised double-blind non-inferiority trial. The Lancet, in press. Disclosure of Interest G. Goll Consultant for: AbbVie, Boehringer Ingelheim, Orion Pharma, Novartis, Pfizer, I. Olsen: None declared, N. Bolstad: None declared, K. Jorgensen Consultant for: Celltrion, Intercept, AbbVie, Tillott, M. Lorentzen: None declared, C. Mork Consultant for: Cellgene, AbbVie, Galderma Nordic, ACOhud, Novartis, LEOPharma, J. Jahnsen Consultant for: Celltrion, Orion Pharma, Pfizer, MSD, AbbVie, Takeda, Napp Pharma, AstroPharma, E. Haavardsholm Consultant for: AbbVie, UCB, Pfizer, MSD, Roche, T. Kvien Consultant for: Biogen, BMS, Boehringer Ingelheim, Celltrion, Eli Lily, Epirus, Hospira, Merck-Serono, Novartis, Orion Pharma, Pfizer, Sandoz, UCB

Background Psoriatic arthritis (PsA) is a chronic inflammatory disorder associated with skin and joint manifestations, several extra-articular symptoms, various comorbidities, and disability. The emergence of tumour necrosis factor inhibitor (TNFi) therapy has dramatically changed the course of disease. Over the past decade new TNFi therapies have emerged (certolizumab pegol and golimumab), and recently ustekinumab and secukinumab have also become available for PsA. Objectives The objective of this study was to assess the relative use of biological agents (bDMARDs) in PsA from 2006 through 2014, using data from the Nordic Rheumatology registers. Methods Based on data from the observational registers DANBIO, ICEBIO, NOR-DMARD, ROB-FIN, and SRQ registers, PsA patients initiating treatment with bDMARDs as a first or subsequent biological therapy were identified. Adalimumab, etanercept and infliximab were grouped as “first generation TNFi therapies”; certolizumab pegol and golimumab were grouped as “second generation TNFi”. Treatments with ustekinumab during the study period were also identified. Descriptive statistics for prescription patterns of bDMARD therapy were calculated. Results A total of 11,458 treatment initiations were identified (DANBIO 3,068, ICEBIO 357, NOR-DMARD 1,113, ROB-FIN 708, SRQ 6,212). 54% of the patients were female. Overall, 5,695 patients initiated a first generation TNFi, 912 a second generation TNFi, and 16 ustekinumab, as their first course of biological treatment. The corresponding numbers for those initiating a second (or more) biological treatment were 3,606, 1,090 and 139 patients, respectively. The figure displays the annual number of treatment initiations stratified by treatment type. The total yearly number of first course biological treatment increased significantly throughout the period (p Conclusions Across the Nordic countries the prescription pattern for biological therapies for PsA has changed significantly over time. After 2012 initiation of the first generation TNFi is decreasing both as first and second course therapy, whereas second generation TNFi are increasing both as first and second course of biologic intervention. Collaboration across registers will allow for robust assessment of the uptake of newer biological therapies. Acknowledgements This study was partly funded by a grant from NordForsk and Janssen Pharmaceuticals. Disclosure of Interest T. S. Jorgensen Speakers bureau: Abbvie, Roche, Novartis, UCB, Biogen, L. Dreyer Speakers bureau: MSD, UCB and Janssen Pharmaceuticals, B. Guðbjornsson Speakers bureau: Actavis, Celgene, MSD, Pfizer, M. Hetland Speakers bureau: BMS, MSD, AbbVie, Roche, Eli Lilly, Pfizer, Orion, Novartis, B. Glintborg Speakers bureau: Abbvie, J. Askling Grant/research support from: AstraZeneca, UCB, Lilly, Pfizer, Roche, Merck,Samsung, Janssen, K. Chatzidionysiou Speakers bureau: AbbVie, Pfizer, Eli Lilly, UCB, Roche., D. Di Giuseppe: None declared, L. Jacobsson Consultant for: Abbvie, Celegen, MSD, Novartis and UCB, J. Wallman Consultant for: Novartis, Celgene, UCB, E. Kristianslund: None declared, I. Olsen: None declared, K. Fagerli: None declared, E. Lie Speakers bureau: AbbVie, Celgene, Hospira and Pfizer., D. Nordstrom Speakers bureau: AbbVie, BMS, Lilly, MSD, Novartis, Pfizer, Roche, UCB., K. Aaltonen: None declared, J. Joensuu Speakers bureau: Pfizer., T. J. Love: None declared, A. J. Geirsson: None declared, L. E. Kristensen Speakers bureau: Pfizer, AbbVie, Amgen, UCB, Celgene, BMS, MSD

Background Tumour necrosis factor inhibitors (TNFi) are essential in the treatment of psoriatic arthritis (PsA). Whether the effectiveness of the five different TNFi differs is not known, as they have not been directly compared. In Norway the national authorities consider the TNFi to be equivalent, and since 2009 the least expensive drug in an annual national tender has been preferred in the publicly funded healthcare system. This has led to substantial year-to-year differences in chioce of first TNFi, the system has acted as an unbiased factor distributing patients between different agents across years. Objectives Comparing response to TNFi during the first year of treatment of PsA over years with highly varying uptake of different TNFi. Methods From the NOR-DMARD register we included the 715 biologics-naive patients with PsA who started their first TNFi from 2009 through 2015. The preferred TNFi in national recommendations were: 2009 adalimumab, 2010 golimumab, 2011 and 2012 etanercept, 2013 golimumab, 2014 certolizumab, 2015 certolizumab/biosimilar infliximab (CT-P13). The estimated Disease Activity Score 28 joints (DAS28) at 3, 6 and 12 months after treatment start was compared between treatment years using a mixed-model, adjusted for baseline disease activity, age, sex and treatment centre. Results Demographics, choice of TNFi and baseline characteristics are listed for each year 2009–2015 in Table 1. The preferred drug was started in 56–91% of patients. There was a trend towards lower disease activity at baseline over time. There were no significant differences in DAS28 at 3 and 6 months between treatment years, but a difference was found at 1 year (figure). Conclusions The results from this innovative analytic approach indicate similar effectiveness of different TNFi in PsA, and consequently supports the practice of selecting agent based on cost and feasibility of use. However, there are potential differences after 1 year. The interpretation of this is challenging, especially as there is a marked difference in outcomes between the years 2011 and 2012, where the distribution of type of TNFi was similar. Disclosure of Interest E. K. Kristianslund: None declared, K. M. Fagerli: None declared, E. Lie Consultant for: AbbVie, Celgene, Hospira, Pfizer, UCB., A. Wierod: None declared, S. Kalstad: None declared, E. Rodevand: None declared, F. Kroll: None declared, P. Mielnik: None declared, T. K. Kvien Consultant for: AbbVie, Biogen, BMS, Boehringer Ingelheim, Celltrion, Eli Lilly, Epirus, Janssen, Merck-Serono, MSD, Mundipharma, Novartis, Oktal, Orion Pharma, Hospira/Pfizer, Roche, Sandoz, UCB, I. C. Olsen: None declared