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Objectives To investigate whether baseline disease activity levels and responses in patients with rheumatoid arthritis (RA) changed during the period 2000–2010. Methods Data were provided by the Norwegian disease-modifying antirheumatic drug (NOR-DMARD) study. Patients with inflammatory joint diseases starting new treatment with disease-modifying antirheumatic drugs (DMARDs) were consecutively included and followed longitudinally. Time trend analyses were performed in methotrexate (MTX)-naïve RA patients starting MTX monotherapy (MTX mono) and biologic DMARD (bDMARD)-naïve RA patients starting tumour necrosis factor inhibitors+MTX (TNFi+MTX). Results A total of 2573 patients were included in the analyses: MTX mono n=1866 (69.9% female, 62.0% RF+, mean (SD) age 56.0 (13.7) years, median (25–75 percentile) time from diagnosis 0.2 (0.01–2.8) years); TNFi+MTX n=707 (70.3% female, 75.0% RF+, mean (SD) age 52.1 (13.2) years, median (25–75 percentile) time from diagnosis 5.7 (2.0–13.7) years). Significant time trends towards lower baseline disease activity score 28 (DAS28) as well as other disease activity measures were found in both groups (DAS28 from 5.17 to 4.75 in MTX mono and from 5.88 to 4.64 in TNFi+MTX), and disease duration became shorter. Six-month DAS28 remission rates increased significantly over the years (from 17.8 to 37.6 in MTX mono and from 16.9 to 46.3 in TNFi+MTX). Conclusions During the last decade, baseline RA disease activity level at the time of starting MTX as well as TNFi+MTX decreased from high to moderate. A more than twofold increase in 6-month remission rates was observed in both groups. Our findings indicate that clinicians have implemented modern, more aggressive treatment strategies, which hopefully will lead to better long-term disease outcomes.

Objectives To explore the frequency and predictors of flares over 2 years during a treat-to-target strategy with urate-lowering therapy (ULT) in patients with gout. Methods In the treat-to-target, tight control NOR-Gout study patients started ULT with escalating doses of allopurinol. Flares were recorded over 2 years. Baseline predictors of flares during months 9–12 in year 1 and during year 2 were analyzed by multivariable logistic regression. Results Of 211 patients included (mean age 56.4 years, disease duration 7.8 years, 95% males), 81% (150/186) of patients experienced at least one gout flare during the first year and 26% (45/173) during the second year. The highest frequency of flares in the first year was seen during months 3–6 (46.8% of patients). Baseline crystal depositions detected by ultrasound and by dual-energy computed tomography (DECT) were the only variables which predicted flares both during the first period of interest at months 9–12 (OR 1.033; 95% CI 1.010–1.057, and OR 1.056; 95% CI 1.007–1.108) and also in year 2. Baseline subcutaneous tophi (OR 2.42, 95% CI 1.50–5.59) and prior use of colchicine at baseline (OR 2.48, 95% CI 1.28-4.79) were independent predictors of flares during months 9–12, whereas self-efficacy for pain was a protective predictor (OR 0.98 per unit, 95% CI 0.964–0.996). Conclusions In patients with gout, flares remain frequent during the first year of a treat-to-target ULT strategy, especially during months 3–6, but are much less frequent during year 2. Baseline crystal depositions predict flares over 2 years, supporting ULT early during disease course. Trial registration ACTRN12618001372279

ObjectiveThe associations between fatigue and disease activity in patients with rheumatoid arthritis (RA) have not been defined. The present objectives were to explore in RA patients the cross-sectional and longitudinal relation of fatigue with subjective as well as objective assessments of disease activity.MethodsRA patients were consecutively included when initiating biologic disease-modifying anti-rheumatic drugs (DMARDs) and assessed at baseline, 1, 2, 3, 6, and 12 months with investigation of fatigue, patient-reported outcome measures (PROMs; joint pain and patient’s global disease activity, MHAQ, pain catastrophizing, Mental Health score), clinical examinations (examiner’s global disease activity, 28 tender and swollen joint counts), and laboratory variables (ESR, CRP, calprotectin). Ultrasound examinations (semi-quantitative scoring (0–3)) with grey scale and power Doppler were performed of 36 joints and 4 tendons. Statistics included one-way analysis of variance, Pearson’s correlations, and multiple linear and logistic regression analysis.ResultsA total of 208 RA patients (mean (SD) age 53.2 (13.2) years, disease duration 9.8 (8.5) years) were included. Fatigue levels diminished during follow-up (mean (SD) baseline/12 months; 4.8 (2.8)/3.0 (2.5) (p < 0.001)). Substantial correlations were cross-sectionally found between fatigue and PROMs (median (IQR) r=0.61 (0.52-0.71)) but not with the objective inflammatory assessments. During follow-up, baseline fatigue was associated with PROMs (p < 0.001) but not with objective inflammatory assessments. However, change of fatigue was associated with change in all variables. Higher baseline fatigue levels were associated with lower clinical composite score remission rates.ConclusionFatigue was cross-sectionally associated to subjective but not to objective disease assessments. However, change of fatigue during treatment was associated to all assessments of disease activity.Trial registration numberAnzctr.org.au identifier ACTRN12610000284066, Norwegian Regional Committee for Medical and Health Research Ethics South East reference number 2009/1254Key Points• In this longitudinal study of patients with established RA, fatigue was associated with patient reported outcome measures at each visit, but not with objective assessments of inflammation including calprotectin and comprehensive ultrasound examinations.• Changes in fatigue during biological treatment were associated with changes in patient reported outcome measures, clinical, laboratory and ultrasound assessments.• Baseline fatigue was associated with all patient reported outcome measures, but not objective assessments of inflammation at all the prospective visits.• Higher baseline fatigue levels were associated with lower remission rates as assessed by clinical composite scores.

Background The type I interferon (IFN) gene signature is present in a subgroup of patients with early rheumatoid arthritis (RA). Protein levels of IFNα have not been measured in RA and it is unknown whether they associate with clinical characteristics or treatment effect. Methods Patients with early untreated RA (n = 347) were randomized to methotrexate combined with prednisone, certolizumab-pegol, abatacept, or tocilizumab. Plasma IFNα protein levels were determined by single molecular array (Simoa) before and 24 weeks after treatment initiation and were related to demographic and clinical factors including clinical disease activity index, disease activity score in 28 joints, swollen and tender joint counts, and patient global assessment. Results IFNα protein positivity was found in 26% of the patients, and of these, 92% were double-positive for rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA). IFNα protein levels were reduced 24 weeks after treatment initiation, and the absolute change was similar irrespective of treatment. IFNα protein positivity was associated neither with disease activity nor with achievement of CDAI remission 24 weeks after randomization. Conclusion IFNα protein positivity is present in a subgroup of patients with early RA and associates with double-positivity for autoantibodies but not with disease activity. Pre-treatment IFNα positivity did not predict remission in any of the treatment arms, suggesting that the IFNα system is distinct from the pathways of TNF, IL-6, and T-cell activation in early RA. A spin-off study of the NORD-STAR randomized clinical trial, NCT01491815 (ClinicalTrials), registered 12/08/2011, https://clinicaltrials.gov/ct2/show/NCT01491815 .

Background The variability in treatment response in people with rheumatoid arthritis (RA) warrants the prediction of patients at high risk of treatment failure. Identification of biomarkers linked to clinical remission in RA is currently a challenge. Metabolomics may help to identify such biomarkers as it allows for a comprehensive exploration of disease-related variations that extends beyond the genome and proteome. This hypothesis-free exploratory metabolomics study aimed to profile serum metabolic alterations in early RA to understand the metabolic changes associated with disease activity and therapeutic response. Methods The study included 220 early RA participants from the NORD-STAR study, randomized at baseline into four arms, ranging from conventional anti-rheumatic treatment to biological drugs: methotrexate combined with prednisolone (1), certolizumab (2), abatacept (3), or tocilizumab (4). Untargeted metabolomics was performed in serum samples at baseline and 24-week follow-up. Participants achieving clinical disease activity index remission at 24 weeks were defined as responders. Machine learning models for treatment response were constructed using random forest, logistic regression, support vector machine and extreme gradient boosting algorithms based on selected features. Results We identified 278 metabolites, of which 39 were associated with baseline disease activity, including several acylcarnitines and amino acids. We also found 17 baseline metabolites associated with remission at 24 weeks in the overall cohort, including malic acid (β=-0.4), cytidine (β = 0.4), arginine (β = 0.3), and citrulline (β = 0.2), as well as specific metabolites and metabolic pathways associated with remission in the four treatment arms. Fifteen features were identified using machine learning-based multivariable selection. The best predictive model using logistic regression achieved AUC of 0.75 in training and 0.73 in the test set. Conclusions Our study has identified several baseline metabolites and metabolic pathways associated with disease activity and response to different treatments in early RA. By integrating metabolomics and clinical data, we developed predictive models for response to treatment in early RA, though their predictive performance remains limited.

ObjectiveTo explore associations between remission, based on clinical and ultrasound definitions, and future good radiographic and physical outcome in early rheumatoid arthritis (RA).MethodsNewly diagnosed patients with RA followed a treat-to-target strategy incorporating ultrasound information in the Aiming for Remission in rheumatoid arthritis: a randomised trial examining the benefit of ultrasound in a Clinical TIght Control regimen (ARCTIC) trial. We defined 6-month remission according to Disease Activity Score, Disease Activity Score in 28 joints-erythrocyte sedimentation rate, American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Boolean criteria, Simplified Disease Activity Index, Clinical Disease Activity Index and two ultrasound definitions (no power Doppler signal, grey scale score ≤2). Two outcomes were defined: no radiographic progression and good outcome (no radiographic progression+physical function≥general population median), both sustained 12–24 months. We calculated the ORs of these outcomes for the remission definitions.ResultsOf 103 patients, 42%–82% reached remission at 6 months, dependent on definition. Seventy-one per cent of patients had no radiographic progression and 37% had good outcome. An association between 6-month remission and no radiographic progression was observed for ACR/EULAR Boolean remission (44 joints, OR 3.2, 95% CI 1.2 to 8.4), ultrasound power Doppler (OR 3.6, 95% CI 1.3 to 10.0) and grey scale remission (OR 3.2, 95% CI 1.2 to 8.0). All clinical, but not ultrasound remission criteria were associated with achievement of a good outcome.ConclusionsOur data support ACR/EULAR Boolean remission based on 44 joints as the preferred treatment target in early RA. Absence of ultrasound inflammation was associated with no radiographic progression.Trial registration number NCT01205854; Post-results.

Background Disease-modifying antirheumatic drugs (DMARDs) are widely used for treating rheumatoid arthritis (RA). However, there are no established biomarkers to predict a patient’s response to these therapies. Prostanoids, encompassing prostaglandins, prostacyclins, and thromboxanes, are potent lipid mediators implicated in RA progression. Nevertheless, the influence of DMARDs on prostanoid biosynthesis in RA patients remains poorly understood. This study aims to assess the impact of various DMARDs on urinary prostanoids levels and to explore whether urinary prostanoid profiles correlate with disease activity or response to therapy. Methods This study included 152 Swedish female patients with early RA, all rheumatoid factor (RF) positive, enrolled in the NORD-STAR trial (registration number: NCT01491815). Participants were randomized into four therapeutic regimes: methotrexate (MTX) combined with (i) prednisolone (arm ACT), (ii) TNF-α blocker certolizumab pegol (arm CZP), (iii) CTLA-4Ig abatacept (arm ABA), or (iv) IL-6R blocker tocilizumab (arm TCZ). Urine samples, collected before start of treatment and at 24 weeks post-treatment, were analyzed for tetranor-prostaglandin E metabolite (tPGEM), tetranor-prostaglandin D metabolite (tPGDM), 2,3-dinor thromboxane B 2 (TXBM), 2,3-dinor-6-keto prostaglandin F 1a (PGIM), leukotriene E 4 (LTE 4 ) and 12-hydroxyeicosatetraenoic acid (12-HETE) using liquid chromatography–mass spectrometry (LC–MS). Generalized estimating equation (GEE) models were used to analyze the change in urinary eicosanoids and their correlations to clinical outcomes. Results Patients receiving MTX combined with CZP or TCZ exhibited significant elevations in urinary tPGEM and TXBM levels after 24 weeks of treatment. Other eicosanoids did not show significant alterations in response to any treatment. Baseline urinary eicosanoid levels did not correlate with baseline clinical disease activity index (CDAI) levels, nor with changes in CDAI from baseline to week 24. Their levels were also similar between patients who achieved CDAI remission and those with active disease at week 24. Conclusions Treatment with anti-TNF or anti-IL6R agents in early RA patients leads to an increased systemic production of proinflammatory and prothrombotic prostanoids. However, urinary eicosanoid levels do not appear to be predictive of the response to DMARDs therapy.

Tore Kristian Kvien View author publications You can also search for this author in PubMed Google Scholar 6. [...]Uhlig View author publications You can also search for this author in PubMed Google Scholar 7. Validity and diagnostic performance of fluorescence optical imaging measuring synovitis in hand osteoarthritis: baseline results from the Nor-Hand cohort [RAW_REF_TEXT] Øystein Maugesten 1,2 , [/RAW_REF_TEXT] [RAW_REF_TEXT] Alexander Mathiessen1 , [/RAW_REF_TEXT] [RAW_REF_TEXT] Hilde Berner Hammer1,2 , [/RAW_REF_TEXT] [RAW_REF_TEXT] Sigrid Valen Hestetun1 , [/RAW_REF_TEXT] [RAW_REF_TEXT] Tore Kristian Kvien1,2 , [/RAW_REF_TEXT] [RAW_REF_TEXT] Till Uhlig1,2 , [/RAW_REF_TEXT] [RAW_REF_TEXT] Sarah Ohrndorf3 & [/RAW_REF_TEXT] [RAW_REF_TEXT] Ida Kristin Haugen1 [/RAW_REF_TEXT] Arthritis Research & Therapy volume 23, Article number: 87 (2021) Cite this article [RAW_REF_TEXT] 10 Accesses [/RAW_REF_TEXT] [RAW_REF_TEXT] Metrics details [/RAW_REF_TEXT] The Original Article was published on 01 May 2020 Correction to: Validity and diagnostic performance of fluorescence optical imaging measuring synovitis in hand osteoarthritis: baseline results from the Nor-Hand cohort [RAW_REF_TEXT] Øystein Maugesten 1,2 , Alexander Mathiessen1 , Hilde Berner Hammer1,2 , Sigrid Valen Hestetun1 , Tore Kristian Kvien1,2 , Till Uhlig1,2 , Sarah Ohrndorf3 & Ida Kristin Haugen1 [/RAW_REF_TEXT] Arthritis Research & Therapy volume 23, Article number: 87 (2021) Cite this article [RAW_REF_TEXT] 10 Accesses Metrics details

Objective Fluorescence optical imaging (FOI) demonstrates enhanced microcirculation in finger joints as a sign of inflammation. We wanted to assess the validity and diagnostic performance of FOI measuring synovitis in persons with hand OA, comparing it with magnetic resonance imaging (MRI)- and ultrasound-detected synovitis. Methods Two hundred and twenty-one participants with hand OA underwent FOI and ultrasound (gray-scale synovitis and power Doppler activity) of the bilateral hands and contrast-enhanced MRI examination of the dominant hand. Fifteen joints in each hand were scored on semi-quantitative scales (grade 0–3) for all modalities. Four FOI images were evaluated: one composite image (Prima Vista Mode (PVM)) and three images representing phases of fluorescent dye distribution. Spearman’s correlation coefficients were calculated between sum scores of FOI, MRI, and ultrasound. Sensitivity, specificity, and area under the curve (AUC) were calculated for FOI using MRI or ultrasound as reference. Results FOI did not demonstrate enhancement in the thumb base, and the joint was excluded from further analyses. FOI sum scores showed poor to fair correlations with MRI (rho 0.01–0.24) and GS synovitis sum scores (rho 0.12–0.25). None of the FOI images demonstrated both good sensitivity and specificity, and the AUC ranged from 0.50–0.61 and 0.51–0.63 with MRI and GS synovitis as reference, respectively. FOI demonstrated similar diagnostic performance with PD activity and GS synovitis as reference. Conclusion FOI enhancement correlated poorly with synovitis assessed by more established imaging modalities, questioning the value of FOI for the evaluation of synovitis in hand OA.