RATIONALE Chronic obstructive pulmonary disease patients and in particular smokers are more susceptible to respiratory infections contributing to acute exacerbations of disease. The... Show moreRATIONALE Chronic obstructive pulmonary disease patients and in particular smokers are more susceptible to respiratory infections contributing to acute exacerbations of disease. The immunoproteasome is a specialized type of proteasome destined to improve major histocompatibility complex (MHC) class I-mediated antigen presentation for the resolution of intracellular infections. OBJECTIVES To characterize immunoproteasome function in COPD and its regulation by cigarette smoke. METHODS Immunoproteasome expression and activity were determined in bronchoalveolar lavage (BAL) and lungs of human donors, COPD, and IPF patients, as well as in cigarette smoke-exposed mice. Smoke-mediated alteration of immunoproteasome activity and MHC I surface expression were analysed in human blood-derived macrophages. Immunoproteasome-specific MHC I antigen presentation was evaluated in spleen and lung immune cells that had been smoke-exposed in vitro or in vivo. MEASUREMENTS AND MAIN RESULTS Immunoproteasome and MHC I mRNA expression was reduced in BAL cells of COPD patients and in isolated alveolar macrophages of COPD and IPF patients. Exposure of immune cells to cigarette smoke extract in vitro reduced immunoproteasome activity and impaired immunoproteasome-specific MHC I antigen presentation. In vivo, acute cigarette smoke exposure dynamically regulated immunoproteasome function and MHC I antigen presentation in mouse BAL cells. End-stage COPD lungs showed markedly impaired immunoproteasome activities. CONCLUSIONS We here show for the first time that the activity of the immunoproteasome is impaired by cigarette smoke resulting in reduced MHC I antigen presentation. Regulation of immunoproteasome function by cigarette smoke may thus alter adaptive immune responses and add to prolonged infections and exacerbations in COPD and IPF. Show less
Heijde, D. van der; Helm-van Mil, A.H.M. van der; Aletaha, D.; Bingham, C.O.; Burmester, G.R.; Dougados, M.; ... ; Combe, B. 2013
The development of outcome measures in the field of rheumatology has shown a rapid and constructive advance in the last decades. It has been achieved to obtain more uniformity in the evaluation of... Show moreThe development of outcome measures in the field of rheumatology has shown a rapid and constructive advance in the last decades. It has been achieved to obtain more uniformity in the evaluation of inflammatory rheumatic disorders, especially concerning long-term outcomes and disease activity assessments. In the field of rheumatoid arthritis, clinical experts and researchers have done a lot of work under the umbrella of OMERACT (Outcome Measures in Rheumatology Clinical Trials). In the field of ankylosing spondylitis, major advances in the outcome and therapeutic advances in the last years have been possible because of projects piloted within ASAS (the Assessment of Spondyloarthritis international Society). The analyses and studies presented in this thesis were part of this process, with most of the work performed in international working groups under auspices of either OMERACT or ASAS or both. In rheumatoid arthritis, a detailed insight into radiographic scores was conducted (Sharp van der Heijde score, SENS). Performances of automated methods for measuring measurement of joint space narrowing were assessed. The delay to first specific treatment in early rheumatoid arthritis was also analyzed, and its impact on radiographic outcome was evaluated. In ankylosing spondylitis, three different methods aiming at scoring activity of the disease on MRI of the spine were compared, and a new disease activity score was developed (ASDAS). Show less
Lukas, C.; Knevel, R.; Helm-Van Mil, A.H.M. van der; Rincheval, N.; Heijde, D. van der; Combe, B.G. 2011
Objective. While there is consensus that treatment with disease-modifying antirheumatic drugs (DMARDs) should be started early in patients with inflammatory arthritis, confirmation that... Show moreObjective. While there is consensus that treatment with disease-modifying antirheumatic drugs (DMARDs) should be started early in patients with inflammatory arthritis, confirmation that radiographic progression is inhibited with early treatment start is scarce. This study was undertaken to compare radiographic progression in patients treated with a DMARD very early in the course of their disease (within 3 months of diagnosis) and those who began DMARD treatment later. Methods. Patients included in the French observational ESPOIR (Etude et Suivi des Polyarthrites Indifferenciees Recentes [Study and Followup of Early Undifferentiated Polyarthritis]) cohort were followed up, and radiographic progression after 12 months was assessed. Propensity scores, reflecting the indication to start a DMARD, were obtained by modeling the start of DMARD therapy by disease-specific and demographic variables obtained at baseline, using logistic regression analysis. The influence of very early versus delayed DMARD start on radiographic progression was evaluated by generalized linear regression, with and without adjustment for propensity scores. Results. Six hundred sixty-one patients were analyzed. In an unadjusted analysis, patients starting DMARD therapy within 3 months of diagnosis did not show a significant difference in radiographic progression score as compared to those starting DMARD therapy later (1.2 units versus 1.6 units; P = 0.37). Adjustment for the propensity score revealed a statistically significant difference in mean progression (0.8 units versus 1.7 units; P = 0.033). Analysis by propensity score quintile showed a trend suggesting that early treatment was especially beneficial for patients in the fourth and fifth quintiles (worse prognosis). Conclusion. Our findings indicate that among patients with inflammatory arthritis in daily clinical practice, early initiation of DMARD therapy reduces 12-month radiographic progression. This strengthens the current recommendations for very early initiation of specific therapy in patients with early arthritis. Show less
Lukas, C.; Heijde, D. van der; Fatenajad, S.; Landewe, R. 2010
Background Negative radiographic change scores obtained under blinded time-sequence conditions suggest that repair of joints may indeed occur. It is likely that, if repair truly exists, it would be... Show moreBackground Negative radiographic change scores obtained under blinded time-sequence conditions suggest that repair of joints may indeed occur. It is likely that, if repair truly exists, it would be preferentially seen in clinically inactive joints from patients treated with drugs with well-known structural efficacy. Objective To determine whether repair is associated with both the absence or improvement of swelling and with treatment. Patients and methods Radiographs from patients of the TEMPO trial were scored twice by two readers according to the Sharp-van der Heijde score, blinded to both treatment and true time sequence. Single-joint change scores in erosions were coupled with single-joint swelling scores obtained from clinical examination. Consistency of observed improvement across readers and repeat reads was described, and factors expected to increase the likelihood of occurrence of both worsening and improvement of erosion were tested by generalised estimating equations (GEE) modelling. Results In all of the four independent reads, the mean change in erosion score was statistically significantly negative only in the subgroup of joints with absent or improved swelling, when erosions were present at baseline. Multivariate analysis showed that worsening of the erosion score in a joint was significantly increased if that joint was already damaged at study entry, clinical swelling persisted and methotrexate was used instead of etanercept. Repair was associated with improvement of swelling and use of etanercept (p <= 0.007 for all associations). Conclusion Repair of erosions almost exclusively occurs in joints with improvement or absence of swelling, in patients treated with etanercept. Progression is seen more frequently in joints with persistent swelling, in patients receiving methotrexate monotherapy, primarily if damage is already present. Show less
Landewe, R.B.M.; Gunther, K.P.; Lukas, C.; Braun, J.; Combe, B.; Conaghan, P.G.; ... ; Heijde, D.M.F.M. van der 2010
Objectives: The European League Against Rheumatism (EULAR) and the European Federation of National Associations of Orthopaedics and Traumatology (EFORT) have recognised the importance of variation... Show moreObjectives: The European League Against Rheumatism (EULAR) and the European Federation of National Associations of Orthopaedics and Traumatology (EFORT) have recognised the importance of variation in diagnostic and therapeutic performance across disciplines, have found consensus in starting task forces aiming at achieving diagnostic and therapeutic uniformity, and have identified medical conditions with which representatives of both organisations will frequently be confronted in common clinical practice. The aim of the present work was to establish recommendations for the diagnosis and initial management of patients presenting with acute or recent onset swelling of the knee. Methods: The EULAR standard operating procedures for the elaboration and implementation of evidence-based recommendations were followed. Results: In all, 11 rheumatologists from 11 countries and 12 orthopaedic surgeons from 7 countries met twice under the leadership of 2 conveners, a clinical epidemiologist and a research fellow. After carefully defining the content and procedures of the task force, research questions were developed, a comprehensive literature search was performed and the results were presented to the entire committee. Subsequently, a set of 10 recommendations was formulated based on evidence from the literature if available, and after discussion and consensus building. Conclusions: This is the first combined interdisciplinary project of rheumatologists and orthopaedic surgeons, successfully aiming at achieving consensus in the diagnosis and initial management of patients presenting with acute or recent onset swelling of the knee. Show less
