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

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

Assessments of the unmet need in the management of patients with rheumatoid arthritis: analyses from the NOR-DMARD registry.

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 (<2.6) and inadequate response (>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.

Switching from originator infliximab to biosimilar CT-P13 compared with maintained treatment with originator infliximab (NOR-SWITCH): a 52-week, randomised, double-blind, non-inferiority trial.

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.

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

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

Tumour necrosis factor inhibitor treatment and occurrence of anterior uveitis in ankylosing spondylitis: results from the Swedish biologics register.

OBJECTIVES: Tumour 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. METHODS: Patients 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. RESULTS: 1365 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. CONCLUSIONS: The results suggest differences in effect on AU risk between ADA, ETN and IFX, with a clear advantage for ADA/IFX over ETN.

The association of hypertension with asymptomatic cardiovascular organ damage in rheumatoid arthritis.

BACKGROUND: The association of hypertension with asymptomatic cardiovascular organ damage in patients with rheumatoid arthritis (RA) has been little studied by echocardiography. METHODS: Echocardiography was done in 134 RA patients and 102 healthy controls. Left ventricular (LV) geometry was considered abnormal if LV mass index or relative wall thickness was increased. LV diastolic dysfunction was considered present if septal early diastolic tissue velocity <8 cm/s. Systemic arterial compliance (SAC) was assessed from stroke volume index/pulse pressure ratio. RESULTS: The hypertensive RA patients (n = 72) had higher inflammatory activity, older age and more diabetes than the normotensive RA patients (n = 62) (all p < 0.05). Rates of abnormal LV geometry, LV diastolic dysfunction and lower SAC were higher among the hypertensive RA patients (p < 0.05), but similar between normotensive RA patients and controls. Hypertension was associated with a 3-fold higher prevalence both for abnormal LV geometry (odds ratio 2.89 [95% confidence interval 1.09-7.63], p = 0.03) and for diastolic LV dysfunction (odds ratio 2.92 [95% confidence interval 1.14-7.46], p = 0.03) as well as lower SAC (ß = 0.31, p = 0.001) independent of age, gender, diabetes and inflammatory activity measured by erythrocyte sedimentation rate. CONCLUSION: The presence of asymptomatic cardiovascular organ damage in RA patients is closely associated with hypertension independent of inflammatory activity.

CRP and ASDAS are associated with future elevated arterial stiffness, a risk marker of cardiovascular disease, in patients with ankylosing spondylitis: results after 5-year follow-up.

OBJECTIVE: To identify factors associated with elevated arterial stiffness in a 5-year follow-up of patients with ankylosing spondylitis (AS). METHODS: C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), Bath AS disease activity index (BASDAI) and AS disease activity score (ASDAS) were recorded in 2003, and arterial stiffness (Augmentation Index (AIx) and pulse wave velocity (PWV)) in 2008/2009. Patients were grouped into quartiles according to baseline CRP, ESR and BASDAI and four ASDAS groups. Trend analyses were performed using ANCOVA (AIx/PWV as dependent variable) with separate models for CRP, ESR, BASDAI and ASDAS (age and gender adjusted). Independent predictors of future AIx and PWV levels were identified in multivariate linear regression models. RESULTS: In total, 85 patients participated. Increasing baseline values of CRP, ESR and ASDAS were associated with elevated AIx on follow-up (p(trend) 0.01, 0.05 and 0.04, respectively). Similar non-significant patterns were seen for PWV. In the multivariate analyses, baseline CRP and ASDAS were independently associated with future elevated AIx (p=0.03 and0.02, respectively). In the multivariate PWV model, results for CRP and ASDAS were non-significant. CONCLUSIONS: Baseline CRP and ASDAS were associated with future elevated arterial stiffness measured as AIx, supporting that disease activity is related to future risk of cardiovascular disease in patients with AS.

Genetic risk scores and number of autoantibodies in patients with rheumatoid arthritis.

OBJECTIVE: Certain HLA-DRB1 alleles and single-nucleotide polymorphisms (SNPs) are associated with rheumatoid arthritis (RA). Our objective was to examine the combined effect of these associated variants, calculated as a cumulative genetic risk score (GRS) on RA predisposition, as well as the number of autoantibodies (none, one or two present). METHOD: We calculated four GRSs in 4956 patients and 4983 controls from four European countries. All four scores contained data on 22 non-HLA-risk SNPs, and three scores also contained HLA-DRB1 genotypes but had different HLA typing resolution. Most patients had data on both rheumatoid factor (RF) and anti-citrullinated proteins antibodies (ACPA). The GRSs were standardised (std.GRS) to account for population heterogeneity. Discrimination between patients and controls was examined by receiveroperating characteristics curves, and the four std.GRSs were compared across subgroups according to autoantibody status. RESULTS: The std.GRS improved its discriminatory ability between patients and controls when HLA-DRB1 data of higher resolution were added to the combined score. Patients had higher mean std.GRS than controls (p=7.9×10(-156)), and this score was significantly higher in patients with autoantibodies (shown for both RF and ACPA). Mean std.GRS was also higher in those with two versus one autoantibody (p=3.7×10(-23)) but was similar in patients without autoantibodies and controls (p=0.12). CONCLUSIONS: The GRS was associated with the number of autoantibodies and to both RF and ACPA positivity. ACPA play a more important role than RF with regards to the genetic risk profile, but stratification of patients according to both RF and ACPA may optimise future genetic studies.

Disease activity and left ventricular structure in patients with rheumatoid arthritis.

OBJECTIVE: Increased left ventricular (LV) wall thickness/internal diameter ratio (relative wall thickness) was recently reported in RA patients. The aim of this study was to assess the association between LV relative wall thickness and RA disease activity. METHODS: Clinical and echocardiographic data from 129 RA patients without established cardiovascular disease and 102 controls were used. RA disease activity was assessed by different composite scores and active RA defined by the Simplified Disease Activity Index (SDAI) level exceeding the cut-off for remission (SDAI >3.3). RESULTS: The RA patients were on average 61.3 years old, 77% were women and 67% had active RA (SDAI >3.3). Patients with active RA had greater LV relative wall thickness and included more patients with treated hypertension (all P < 0.05), but had LV mass index and blood pressure comparable to patients in remission. Having active RA by the SDAI score (ß = 0.20, P = 0.008) was also independently associated with greater LV relative wall thickness after adjusting for systolic blood pressure, wall stress, age and sex in a multivariate model. This association was robust also in secondary models including other disease activity composite scores such as the Clinical Disease Activity Index and 28-joint DAS. CONCLUSION: Among RA patients, higher disease activity was independently associated with greater LV relative wall thickness, reflecting subclinical heart disease. The findings point to the importance of disease activity control in RA patients to prevent progression to clinical heart disease.

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

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

Investigating survival, quality of life and cognition in PROton versus photon therapy for IDH-mutated diffuse grade 2 and 3 GLIOmas (PRO-GLIO): a randomised controlled trial in Norway and Sweden.

INTRODUCTION: The 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 ANALYSIS: PRO-GLIO (PROton versus photon therapy in IDH-mutated diffuse grade 2 and 3 GLIOmas) is an open-label, multicentre, randomised phase III non-inferiority study. 224 patients aged 18-65 years with IDH-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 DISSEMINATION: To implement proton therapy as part of standard of care for patients with IDH-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 NUMBER: ClinicalTrials.gov Registry (NCT05190172).

An approach to combining parallel and cross-over trials with and without run-in periods using individual patient data.

BACKGROUND: In active run-in trials, where patients may be excluded after a run-in period based on their response to the treatment, it is implicitly assumed that patients have individual treatment effects. If individual patient data are available, active run-in trials can be modelled using patient-specific random effects. With more than one trial on the same medication available, one can obtain a more precise overall treatment effect estimate. METHODS: We present a model for joint analysis of a two-sequence, four-period cross-over trial (AABB/BBAA) and a three-sequence, two-period active run-in trial (AB/AA/A), where the aim is to investigate the effect of a new treatment for patients with pain due to osteoarthritis. RESULTS: Our approach enables us to separately estimate the direct treatment effect for all patients, for the patients excluded after the active run-in trial prior to randomisation, and for the patients who completed the active run-in trial. A similar model approach can be used to analyse other types of run-in trials, but this depends on the data and type of other trials available. LIMITATIONS: We assume equality of the various carry-over effects over time. CONCLUSIONS: The proposed approach is flexible and can be modified to handle other designs. Our results should be encouraging for those responsible for planning cost-efficient clinical development programmes.

Therapeutic drug monitoring of infliximab compared to standard clinical treatment with infliximab: study protocol for a randomised, controlled, open, parallel-group, phase IV study (the NOR-DRUM study).

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.

Efficacy and Safety of CT-P13 in Inflammatory Bowel Disease after Switching from Originator Infliximab: Exploratory Analyses from the NOR-SWITCH Main and Extension Trials.

BACKGROUND: The NOR-SWITCH main and extension trials demonstrated that switching from originator to biosimilar infliximab (CT-P13) is efficacious and safe across six diseases. However, a subgroup analysis of Crohn's disease (CD) in the main trial displayed a close to significant difference favouring originator infliximab, and more scientific data have therefore been requested. OBJECTIVE: The aim was to assess treatment efficacy, safety, and immunogenicity in an explorative subgroup analysis in CD and ulcerative colitis (UC) in the NOR-SWITCH trials. PATIENTS AND METHODS: The 52-week, randomised, non-inferiority, double-blind, multicentre, 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 in CD and UC were assessed throughout the 78-week study period. RESULTS: The main and extension trials included 155 and 93 patients with CD and 93 and 80 patients with UC, respectively. Demographic and baseline characteristics were comparable in both treatment arms within patient groups. There were no differences in the main and extension trials regarding changes in activity indices, C-reactive protein, faecal calprotectin, patient's and physician's global assessment of disease activity and patient-reported outcome measures in CD and UC. Moreover, comparable results were also demonstrated for trough serum levels, presence of anti-drug antibodies, and reported adverse events. CONCLUSION: Efficacy, safety, and immunogenicity of both the originator and biosimilar infliximab were comparable in CD and UC in the NOR-SWITCH main and extension trials. These explorative subgroup analyses confirm that there are no significant concerns related to switching from originator infliximab to CT-P13 in CD and UC. TRIAL REGISTRATION: ClinicalTrials.gov, number NCT02148640.

Active conventional treatment and three different biological treatments in early rheumatoid arthritis: phase IV investigator initiated, randomised, observer blinded clinical trial.

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.

Effect of oxcarbazepine in the treatment of agitation and aggression in severe dementia.

BACKGROUND/AIMS: To evaluate the efficacy of oxcarbazepine (OXC) in the treatment of agitation and aggression in patients with Alzheimer's disease, vascular dementia or both. METHODS: This is an 8-week, multicenter, randomized, double-blind, placebo-controlled trial carried out independently of the pharmaceutical industry. Changes in the agitation and aggression subscore of the Neuropsychiatric Inventory (NPI) were the primary outcomes. The secondary out- comes were the changes in the caregivers' total burden scores (measured by the NPI) and changes in the Brief Agitation Rating Scale (BARS). RESULTS: In total, 103 institutionalized patients at 35 sites were randomized to the trial. After 8 weeks, no statistically significant differences were found between the 2 groups for all outcomes. A trend was observed in favor of the OXC group in the reduction in the scores on the BARS (p = 0.07). CONCLUSION: This study found no significant effect of OXC in treatment of agitation and aggression in patients with dementia.

Guideline recommended treatment to targets of cardiovascular risk is inadequate in patients with inflammatory joint diseases.

OBJECTIVES: 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. METHODS: 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 were <2.6 mmol/L in case of diabetes, total cholesterol > 8 mmol/L or a SCORE estimate ≥ 5%, and <1.8 mmol/L for those with established CVD or SCORE ≥ 10%. Comparisons across IJD entities were performed using age and sex adjusted logistic regression. RESULTS: 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. CONCLUSIONS: 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.

The Impact of Ultrasound on the Use and Efficacy of Intraarticular Glucocorticoid Injections in Early Rheumatoid Arthritis: Secondary Analyses From a Randomized Trial Examining the Benefit of Ultrasound in a Clinical Tight Control Regimen.

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.

Feasibility of cardiovascular disease risk assessments in rheumatology outpatient clinics: experiences from the nationwide NOCAR project.

OBJECTIVE: The European League Against Rheumatism recommends implementing cardiovascular disease (CVD) risk assessments for patients with inflammatory joint diseases (IJDs) into clinical practice. Our goal was to design a structured programme for CVD risk assessments to be implemented into routine rheumatology outpatient clinic visits. METHODS: The NOrwegian Collaboration on Atherosclerosis in patients with Rheumatic joint diseases (NOCAR) started in April 2014 as a quality assurance project including 11 Norwegian rheumatology clinics. CVD risk factors were recorded by adding lipids to routine laboratory tests, self-reporting of CVD risk factors and blood pressure measurements along with the clinical joint examination. The patients' CVD risks, calculated by the European CVD risk equation SCORE, were evaluated by the rheumatologist. Patients with high or very high CVD risk were referred to their primary care physician for initiation of CVD preventive measures. RESULTS: Data collection (autumn 2015) showed that five of the NOCAR centres had implemented CVD risk assessments. There were 8789 patients eligible for CVD risk evaluation (rheumatoid arthritis (RA), 4483; ankylosing spondylitis (AS), 1663; psoriatic arthritis (PsA), 1928; unspecified and other forms of spondyloarthropathies (SpA), 715) of whom 41.4 % received a CVD risk assessment (RA, 44.7%; AS, 43.4%; PsA, 36.3%; SpA, 30.6%). Considerable differences existed in the proportions of patients receiving CVD risk evaluations across the NOCAR centres. CONCLUSION: Patients with IJD represent a patient group with a high CVD burden that seldom undergoes CVD risk assessments. The NOCAR project lifted the offer of CVD risk evaluation to over 40% in this high-risk patient population.