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Greisen S.R.,University of Aarhus | Greisen S.R.,Aarhus University Hospital | Rasmussen T.K.,University of Aarhus | Rasmussen T.K.,Aarhus University Hospital | And 6 more authors.
Scandinavian Journal of Rheumatology | Year: 2014

Objectives: Programmed death-1 (PD-1) is an immunoregulatory molecule functioning by down-regulating immune responses. PD-1 is present on follicular helper T cells (TFH) and is important in the formation of plasma cells. PD-1 exists in a bioactive soluble form (sPD-1) and is thought to be implicated in disease activity in chronic rheumatoid arthritis (RA). Method: We measured sPD-1 at baseline and 9 months after treatment initiation in plasma from early RA patients (n = 34). We tested for correlations with the Disease Activity Score using 28 joint counts (DAS28), the Health Assessment Questionnaire (HAQ) score, immunoglobulin M rheumatoid factor (IgM-RF), anti-cyclic citrullinated peptide (anti-CCP) antibodies, C-reactive protein (CRP), interleukin-21 (IL-21), and total Sharp score (TSS). We also measured sPD-1 in plasma from healthy volunteers (HV) (n = 20) and in plasma and synovial fluid (SF) from patients with chronic RA (> 8 years of disease, n = 30). We further investigated the cellular expression of PD-1 and its ligand PD-L1. Results: sPD-1 concentrations in early [median 0.421 ng/mL, interquartile range (IQR) 0.04-2.560 ng/mL] and chronic (median 0.239 ng/mL, IQR 0.184-0.584 ng/mL) RA were increased compared with HV (median 0.04 ng/mL, IQR 0.04-0.04 ng/mL) (all p < 0.005). In early RA the change in sPD-1 was associated with DAS28 (r = 0.363, p < 0.05) and HAQ score (r = 0.554, p < 0.05) and inversely with TSS at 3-5 years (r = -0.468, p < 0.05). sPD-1 concentration correlated with IgM-RF, anti-CCP antibodies, and IL-21 (all p < 0.05). PD-1 was primarily expressed by synovial memory T cells whereas PD-L1 was mainly expressed by synovial monocytes. Conclusions: The significantly elevated plasma levels of sPD-1 in early RA, the association with core disease parameters, and the inverse correlation with TSS suggest that sPD-1 is an important mediator in inflammatory and radiographic disease progression. © 2014 Taylor & Francis on license from Scandinavian Rheumatology Research Foundation.

Ostergaard M.,Copenhagen Center for Arthritis Research | Ostergaard M.,Copenhagen University | Keystone E.C.,University of Toronto | Florentinus S.,Abbvie Inc. | And 2 more authors.
Arthritis Care and Research | Year: 2015

Objective. A longitudinal integration approach evaluated all radiographic scores assessed over 10 years, rather than only completer data, from 2 studies of adalimumab (ADA) for rheumatoid arthritis (RA). Methods. The DE019 (methotrexate [MTX]-inadequate responders, longstanding RA) and PREMIER (MTX-naive, early RA) studies, respectively, had 1- or 2-year double-blind periods followed by 9- or 8-year open-label extensions (OLEs). Patients received ADA ± MTX in both OLEs. Radiographic progression was assessed using change from baseline in modified total Sharp score (ΔmTSS). A mixed-effects model was used post hoc to evaluate repeated measurements of different data campaigns and to estimate ΔmTSS through up to 10 years of treatment based on original randomization groups (placebo [PBO] + MTX or standard dose ADA + MTX). Results. Data from patients with baseline and ≥1 postbaseline radiograph were included (n = 327 for DE019; n = 452 for PREMIER). Integrated and 10-year completer ΔmTSS progression curves differed slightly. In DE019, for patients originally assigned PBO + MTX, accrued ΔmTSS at year 10 was 6.6 units (integrated model) and 6.2 units (completers). For patients originally assigned ADA + MTX, accrued ΔmTSS was 0.9 units by integrated analysis and 0.7 units in completers. In PREMIER, for patients originally assigned PBO + MTX, accrued ΔmTSS at year 10 was 11.2 units (integrated analysis) and 11.0 units (completers). For patients originally assigned ADA + MTX, accrued ΔmTSS was 5.1 units (integrated analysis) and 4.0 units (completers). A higher radiographic progression rate was observed in patients who received delayed versus immediate ADA + MTX treatment. Conclusions. Longitudinal integrated analysis provided robust estimates of radiographic progression that only slightly differed from completers-only scores and confirmed the effects. © 2015, American College of Rheumatology.

Baker J.F.,Philadelphia Veterans Affairs Medical Center | Baker J.F.,University of Pennsylvania | Ostergaard M.,Copenhagen Center for Arthritis Research | Ostergaard M.,Copenhagen University | And 7 more authors.
Annals of the Rheumatic Diseases | Year: 2014

Introduction Greater body mass index (BMI) has been associated with less radiographic progression in rheumatoid arthritis (RA). We evaluated the association between BMI and joint damage progression as measured by X-ray and MRI.Methods 1068 subjects with RA from two clinical trials of golimumab (GO-BEFORE and GO-FORWARD) had radiographs performed at weeks 0, 52 and 104 and evaluated using the van der Heijde-Sharp (vdHS) scoring system. Contrast-enhanced MRIs of the dominant wrist and hand were obtained at weeks 0, 12, 24, 52 and 104. Multivariable logistic regression evaluated the risk of radiographic progression for each BMI category (<25, 25-30, (>30 kg/m2). Within GO-BEFORE, piecewise, robust generalised estimating equations marginal models assessed the probability of MRI erosion progression for each BMI category. Multivariable linear regression models assessed baseline associations between BMI and bone oedema (aprecursor of bone erosion).Results Higher BMI category was associated with a lower probability of progression in vdHS score at weeks 52 and 104 independent of potential confounders. Higher BMI was also independently associated with a lower probability of progression in MRI erosion score over 2 years. Subjects with greater BMI demonstrated less bone oedema independent of differences in other disease severity measures, including MRI synovitis in the same joints.Conclusions Greater BMI is associated with a lower risk of progression on X-ray and MRI over 2 years. Subjects with greater BMI also demonstrate less bone oedema at baseline. Greater BMI may indicate a less aggressive RA phenotype and aid in risk stratification.

Sorensen J.,University of Southern Denmark | Hetland M.L.,Copenhagen Center for Arthritis Research | Hetland M.L.,Copenhagen University
Annals of the Rheumatic Diseases | Year: 2014

Background/purpose: Early diagnosis of inflammatory rheumatic diseases is important in order to improve long-term outcome. We studied whether delay in diagnosis (time between onset of symptoms and establishment of diagnosis) in patients with rheumatoid arthritis (RA), psoriatic arthritis (PSA) and ankylosing spondylitis (AS) changed from year 2000 to 2011. Methods: Month and year of initial symptoms and diagnosis, gender, hospital, year of birth and date of first data entry were obtained for 13 721 patients with RA, PSA or AS who had been registered in the DANBIO registry. Time between symptom onset and diagnosis was modelled using generalised linear regression to predict the average duration for each calendar year of initial symptoms with adjustments for gender, year of birth and date of DANBIO entry. Results: Patients with valid data (RA: 10 416 (73%); PSA: 1970 (68%); AS: 1335 (65%)) did not differ significantly from the whole DANBIO population, except more missing data in early years. The regression model showed that the mean duration from initial symptoms to diagnosis for RA, PSA and AS declined steadily from 30, 53 and 66 months (year 2000), respectively, to 3-4 months (year 2011). Sensitivity analyses including patients who were included after 2005, patients who had received biological treatment or had symptom onset less than 2 and 5 years prior to first entry into DANBIO showed similar results. Conclusion: Since the year 2000, a significant reduction in diagnostic delay was observed in this large cohort of patients with RA, PSA or AS, probably reflecting a stronger awareness of the importance of early diagnosis. © 2014 BMJ Publishing Group Ltd & European League Against Rheumatism.

Baker J.F.,University of Pennsylvania | Conaghan P.G.,University of Leeds | Emery P.,University of Leeds | Baker D.G.,Janssen Research & Development LLC | And 2 more authors.
Annals of the Rheumatic Diseases | Year: 2016

Purpose We assessed whether MRI measures of synovitis, osteitis and bone erosion were associated with patient-reported outcomes (PROs) in a longitudinal clinical trial setting among patients with rheumatoid arthritis (RA). Methods This longitudinal cohort of 291 patients with RA was derived from the MRI substudy of the GOBEFORE randomised controlled trial of golimumab among methotrexate-naïve patients. Correlations between RAMRIS scores (synovitis, osteitis, bone erosion) and physical function (Health Assessment Questionnaire (HAQ)), pain and global patient scores were determined at 0, 12, 24 and 52 weeks. Correlations between interval changes were also assessed. Multivariable regression models using robust generalised estimating equations evaluated associations over all time-points and their relationship to other clinical disease activity measures. Results Greater synovitis, osteitis and bone erosion scores were positively associated with HAQ at all timepoints (all p<0.05) and with pain and patient global scores at 24 and 52 weeks. Over all visits, synovitis was associated with HAQ, pain and patient global scores (p=0.03) independent of clinical disease activity measures. Improvements in synovitis and bone erosion were also associated with improvements in PROs. Less improvement in synovitis and progression in MRI erosion at 52 weeks were both independently associated with worsening in all PROs at 52 weeks while progression on X-ray was not associated. Similar associations were observed across treatment groups. Conclusions MRI measures of inflammation and structural damage correlate independently with physical function, pain and patient global assessments. These observations support the validity of MRI biomarkers. Trial registration number NCT00264537; Postresults. © 2016 BMJ Publishing Group Ltd & European League Against Rheumatism.

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