Opportunistic treatment of hepatitis C virus infection (OPPORTUNI-C): study protocol for a pragmatic stepped wedge cluster randomized trial of immediate versus outpatient treatment initiation among hospitalized people who inject drugs.

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.

Long-term efficacy and safety of biosimilar infliximab (CT-P13) after switching from originator infliximab: open-label extension of the NOR-SWITCH trial.

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.

Sleep disturbance in patients with rheumatoid arthritis is related to fatigue, disease activity, and other patient-reported outcomes.

OBJECTIVES: To explore factors related to sleep disturbance in patients with rheumatoid arthritis (RA). METHOD: 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. RESULTS: 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 (r2 = 0.71-0.78). Sleep disturbance was moderately correlated to pain (r2 = 0.41-0.61), fatigue (r2 = 0.44-0.58), physical function (r2 = 0.33-0.48), RADAI (r2 = 0.42-0.55), and utility (r2 = 0.49-0.61). RAID sleep demonstrated the highest correlation with other PROs. RADAI, fatigue, the mental component score of SF-36, physical function, body mass index (BMI), and use of Z-drugs/benzodiazepines were independently associated with two or more measures of sleep problems (all p < 0.001). CONCLUSIONS: Sleep disturbance measured by four different measures was independently related to other PROs including fatigue, pain, and disease activity in RA patients.

4ß-Hydroxycholesterol Level in Patients With Rheumatoid Arthritis Before vs. After Initiation of bDMARDs and Correlation With Inflammatory State.

Systemic inflammation has been linked to suppressed CYP3A(4) activity. We determined 4ß-hydroxycholesterol (4ßOHC), an endogenous CYP3A4 metabolite, in patients with rheumatoid arthritis (RA) before and after treatment with biological disease-modifying antirheumatic drugs (bDMARDs). The 4ßOHC was compared in 41 patients before and 2-5 months after initiating TNFα inhibitors (n = 31), IL-6 inhibitors (n = 5), or B-cell inhibitors (n = 5). Correlations between 4ßOHC and inflammatory markers (C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)) were also tested before and after bDMARDs. 4ßOHC did not differ following bDMARD treatment (P = 0.6), nor in patients who started with IL-6 inhibitors (median 51.6 vs. 50.6 nmol/L). The 4ßOHC and CRP/ESR did not correlate before treatment (P > 0.5), but correlated significantly after bDMARDs (CRP = Spearman r -0.40; P < 0.01; ESR = r -0.34; P = 0.028) suggesting that mainly non-CYP3A4-suppressive cytokines were reduced during treatment. Thus, this study does not support a generally regained CYP3A4 phenotype in patients with RA following initiation of bDMARDs.

Exploring cardiovascular disease risk evaluation in patients with inflammatory joint diseases.

OBJECTIVES: 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. METHODS: CVD risk evaluation was performed in patients with IJD using SCORE and ACC/AHA risk calculators to predict CVD events. RESULTS: 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/AHA <5%, 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. CONCLUSION: 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.

Rosuvastatin-Induced Carotid Plaque Regression in Patients With Inflammatory Joint Diseases: The Rosuvastatin in Rheumatoid Arthritis, Ankylosing Spondylitis and Other Inflammatory Joint Diseases Study.

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.

Circulating levels of inflammatory cytokines and cytokine receptors in patients with ankylosing spondylitis: a cross-sectional comparative study.

OBJECTIVES: 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. METHOD: 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). RESULTS: 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, p < 0.01] 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. CONTROLS: More AS patients had a high level of sTNF-R2 than controls (22 vs. 1, p < 0.01). 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. CONCLUSION: 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.

Health status has improved more in women than in men with rheumatoid arthritis from 1994 to 2009: results from the Oslo rheumatoid arthritis register.

OBJECTIVE: To examine changes in patient reported outcome measures (PROs) over 15 years in a representative population of patients with rheumatoid arthritis (RA), with a particular focus on gender differences. PATIENTS AND METHODS: Patients in the Oslo RA register filled in questionnaires including the Modified Health Assessment Questionnaire (MHAQ), the Short-Form 36 (SF-36) with physical (PCS) and mental component summaries and derived utility (SF-6D), visual analogue scales (VAS) for pain, patient global assessment of disease (PtGA) and fatigue, and checklists of medication commonly used in the treatment of RA. Data were collected at five time points during a 15-year period from 1994. Mixed model analyses were used to analyse longitudinal changes in PROs from 1994 to 1996, 2001, 2004 and 2009. RESULTS: Data were available from 829-1025 RA patients at each time point. PROs were statistically significantly improved from 1994 to 2009 (MHAQ, SF-36 PCS, SF-6D, pain VAS, PtGA VAS and fatigue VAS; all p<0.001), and also with clinically important improvement. Men reported significantly better health status than women in 1994, but women improved significantly more than men over 15 years with a reduction of the gender gap in 2009. Antirheumatic medication was increasingly used over 15 years with no gender differences. CONCLUSIONS: RA patients reported statistically significantly improved health status for most PROs from 1994 to 2009. Women improved most, and although they still reported higher disease impact than men, the gender differences were small at the final data collection in 2009.

NOR-DMARD data management: implementation of data capture from electronic health records.

OBJECTIVES: The use of electronic health records (EHR) is an essential part of modern health care, and electronic data capture (EDC) has become essential for managing clinical trials. Usually, these two entities are independent of each other, and transfer from one system to another is done manually. Our aim was to develop a method to capture data directly from the EHR system and transfer them into an EDC system for the NORwegian Disease-Modifying Anti-Rheumatic Drugs (NOR-DMARD) registry. METHODS: All rheumatology departments contributing to NOR-DMARD had implemented a structured EHR system. Data are extracted locally and securely transferred to the study data management once a month. The study data management then parse the data into a readable format for the EDC and import the data. Once the data is in the EDC, they are available to all authorized researchers and downloadable in a preferred format. RESULTS: From May 2012 to August 2014 almost 6400 visits in 3400 patients treated with biologics have been successfully registered in the EDC system. Previously, NOR-DMARD used standard paper-based case report forms (CRFs), with a substantial cost for data entry. Setting up and maintaining the EDC system required some investments, but the amount saved from avoiding paper handling has made the shift into EDC profitable. In addition to this, gains have been made in administration and data quality. CONCLUSIONS: The transition from paper and pencil format to a fully electronic data management system in NOR-DMARD has had obvious advantages regarding feasibility, cost, data quality and accessibility of the data.

A large conditioned pain modulation response is not related to a large blood pressure response: a study in healthy men.

BACKGROUND: Endogenous pain modulation has been studied with the conditioned pain modulation (CPM) paradigm with large differences in the magnitude of the CPM effect. We hypothesized that differences in CPM effects might be associated with differences in blood pressure responses to the conditioning stimulus when comparing the CPM effects using two different conditioning stimuli. METHODS: A single-blind repeated-measures design with block-randomization was applied on 25 healthy male subjects. The test stimulus (TS; tonic heat pain for 120 s) was first presented alone, thereafter in parallel with a conditioning stimulus (CS). Conditioning stimuli were either a cold pressor test (CPT) or equally painful ischaemic muscle pain (ISC), both lasting 120 s. Finger blood pressure and heart rate were recorded continuously. Data were analysed in a linear mixed model framework with CS type (CPT or ISC) and conditioning (TS or TS + CS) as independent factors. RESULTS: An inhibitory CPM effect was found for both types of conditioning (p < 0.001). The CPM effect was larger during CPT conditioning compared with ISC conditioning (p = 0.001). No association with the concomitant cardiovascular response (blood pressure and heart rate) was found (p > 0.34). CONCLUSION: Cold pressor pain CS induces larger CPM effects than ischaemic pain CS. The larger CPM effect is, however, not associated with a larger blood pressure response. Other factors related to the CS should be investigated to understand why different CS modalities give different CPM effects.

A 1-year randomized, double-blind, placebo-controlled study of intravenous ibandronate on bone loss following renal transplantation.

The clinical profile of ibandronate as add-on to calcitriol and calcium was studied in this double-blind, placebo-controlled trial of 129 renal transplant recipients with early stable renal function (≤ 28 days posttransplantation, GFR ≥ 30 mL/min). Patients were randomized to receive i.v. ibandronate 3 mg or i.v. placebo every 3 months for 12 months on top of oral calcitriol 0.25 mcg/day and calcium 500 mg b.i.d. At baseline, 10 weeks and 12 months bone mineral density (BMD) and biochemical markers of bone turnover were measured. The primary endpoint, relative change in BMD for the lumbar spine from baseline to 12 months was not different, +1.5% for ibandronate versus +0.5% for placebo (p = 0.28). Ibandronate demonstrated a significant improvement of BMD in total femur, +1.3% versus -0.5% (p = 0.01) and in the ultradistal radius, +0.6% versus -1.9% (p = 0.039). Bone formation markers were reduced by ibandronate, whereas the bone resorption marker, NTX, was reduced in both groups. Calcium and calcitriol supplementation alone showed an excellent efficacy and safety profile, virtually maintaining BMD without any loss over 12 months after renal transplantation, whereas adding ibandronate significantly improved BMD in total femur and ultradistal radius, and also suppressed biomarkers of bone turnover. Ibandronate was also well tolerated.

Consequences of handling missing data for treatment response in osteoarthritis: a simulation study.

OBJECTIVE: To understand how handling of missing data influences the statistical power and bias of treatment effects in randomised controlled trials of painful knee osteoarthritis (OA). METHODS: We simulated trials with missing data (withdrawals) due to lack-of-efficacy. Outcome measures were response/non-response according to the Outcome Measures in Rheumatology-Osteoarthritis Research Society International (OMERACT-OARSI) set of responder criteria, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and physical function from the WOMAC questionnaire, and patient global assessment. We used five methods for managing missing data: ignoring the missing data, last and baseline observation carried forward (LOCF and BOCF), and multiple imputation with two different strategies. The treatment effect was then analysed by appropriate univariate and longitudinal statistical methods, and power, bias and mean squared error (MSE) was assessed by comparing the estimated treatment effect in the trials with missing data with the estimated treatment effect on the trials without missing data. RESULTS: The best imputation method in terms of high power and low bias/MSE was our implementation of regression multiple imputation. The most conservative method was the data augmentation Markov chain Monte Carlo (MCMC) multiple imputation. The LOCF, BOCF and the complete-case methods were not particularly conservative and gave relatively low power and high bias. The analysis on the WOMAC pain scale gave less bias and higher power than the OMERACT-OARSI responder outcome measure. CONCLUSIONS: Multiple imputation of missing data may be used to decrease bias/MSE and increase power in OA trials. These results can guide investigators in the choice of outcome measures and especially how missing data can be handled.