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Bos W.H.,Jan Van Breemen Institute | Wolbink G.J.J.,Jan Van Breemen Institute and Sanquin Research | Van Schaardenburg D.,VU University Amsterdam
Arthritis and Rheumatism | Year: 2010

Objective. To identify molecular features associated with the development of rheumatoid arthritis (RA), to understand the pathophysiology of preclinical development of RA, and to assign predictive biomarkers. Methods. The study group comprised 109 anti-citrullinated protein antibody (ACPA)- and/or rheumatoid factor-positive patients with arthralgia who did not have arthritis but were at risk of RA, and 25 patients with RA. The gene expression profiles of blood samples obtained from these patients were determined by DNA microarray analysis and quantitative polymerase chain reaction. Results. In 20 of the 109 patients with arthralgia who were at risk of RA, arthritis developed after a median of 7 months. Gene expression profiling of blood cells revealed heterogeneity among the at-risk patients, based on differential expression of immune-related genes. This report is the first to describe gene signatures relevant to the development of arthritis. Signatures significantly associated with arthritis development were involved in interferon (IFN)-mediated immunity, hematopoiesis, and chemokine/cytokine activity. Logistic regression analysis revealed that the odds ratio (OR) for developing arthritis within 12 months was 21.0 (95% confidence interval [95% CI] 2.8-156.1 [P = 0.003]) for the subgroup characterized by increased expression of genes involved in IFN-mediated immunity and/or cytokine/chemokine-activity. Genes involved in B cell immunology were associated with protection against progression to arthritis (OR 0.38, 95% CI 0.21-0.70 [P = 0.002]). These processes were reminiscent of those in patients with RA, implying that the preclinical phase of disease is associated with features of established disease. Conclusion. The results of this study indicate that IFN-mediated immunity, hematopoiesis, and cell trafficking specify processes relevant to the progression of arthritis independent of ACPA positivity. These findings strongly suggest that certain gene signatures have value for predicting the progression to arthritis, which will pave the way to preventive medicine. © 2010, American College of Rheumatology.


Van Den Broek M.,Leiden University | Klarenbeek N.B.,Leiden University | Dirven L.,Leiden University | Van Schaardenburg D.,Jan Van Breemen Institute | And 6 more authors.
Annals of the Rheumatic Diseases | Year: 2011

Objective: To describe the disease course after the cessation of infliximab in early rheumatoid arthritis patients with disease activity score (DAS)-steered treatment and to identify predictors of persistent low disease activity. Methods: In a post-hoc analysis of the BeSt study, disease activity and joint damage progression were observed in patients treated with methotrexate plus infliximab, who discontinued infliximab after achieving low disease activity (DAS ≤2.4) for 6 months. Predictors were identified using Cox regression analysis. Results: 104 patients discontinued infliximab, of whom 77 had received infliximab plus methotrexate as initial treatment. Mean DAS at the time of infliximab cessation was 1.3, median symptom duration was 23 months and median Sharp/van derHeijde score was 5.5. The median follow-up was 7.2 years. Infliximab was re-introduced after loss of low disease activity in 48%, after a median of 17 months. The joint damage progression rate did not increase in the year after cessation, regardless of flare. After re-introduction of infliximab, 84% of these patients again achieved a DAS ≤2.4. In the multivariable model, smoking, infliximab treatment duration ≥18 months and shared epitope (SE) were independently associated with the re-introduction of infliximab: 6% of the non-smoking, SE-negative patients treated <18 months needed infliximab re-introduction. Conclusion: Cessation of infliximab was successful in 52%, with numerically higher success rates in patients initially treated with infliximab. Of the 48% who flared, 84% regained low disease activity. The joint damage progression rate did not increase in the year after cessation. Smoking, long infliximab treatment duration and SE were independently associated with re-introduction of infliximab.


Klarenbeek N.B.,Leiden University | Van Der Kooij S.M.,Leiden University | Gler-Yuksel M.,Leiden University | Van Groenendael J.H.L.M.,Sint Franciscus Hospital | And 5 more authors.
Annals of the Rheumatic Diseases | Year: 2011

Objectives: To determine the relapse rate after discontinuing treatment in patients with rheumatoid arthritis (RA) in sustained clinical remission, to identify predictors of a relapse and to evaluate treatment response after restarting treatment. Methods: Five-year data from the BeSt study were used, in which 508 patients with recent-onset RA were randomised into four dynamic treatment strategies, aiming at a disease activity score (DAS) ≤2.4. When DAS was <1.6 for ≥6 months, the last disease-modifying antirheumatic drug (DMARD) was tapered and discontinued. If DAS increased to ≥1.6, the last DMARD was immediately reintroduced. Results: During a 5-year period, 115/508 patients (23%) achieved drug-free remission. Of these, 53 patients (46%) restarted treatment because the DAS was ≥1.6 after a median of 5 months, 59 patients (51%) remained in drug-free remission for a median duration of 23 months and 3 (3%) were lost to follow-up. In those who restarted treatment, mean (SD) DAS increased from 1.13 (0.73) at remission before tapering to 2.18 (0.65) at restart, reflecting an increase in all four components of DAS. Multivariable predictors for restarting treatment were anti-cyclic citrullinated peptide (anti-CCP), last DMARD sulfasalazine, low baseline Health Assessment Questionnaire score and high mean DAS until remission. Of the 53 patients who restarted treatment, 39 (74%) again achieved remission 3-6 months after the restart. The median (IQR) damage progression in those who restarted treatment during the year of DAS increase was 0 (0-1) Sharp-van der Heijde units. Conclusion During 5 years DAS steered treatment, nearly 25% of patients with RA achieved drug-free remission;46% restarted DMARD monotherapy because of a relapse, the majority of whom again achieved clinical remission within 3-6 months without showing radiological progression during the relapse.


Klarenbeek N.B.,Leiden University | Guler-Yuksel M.,Leiden University | Van Der Kooij S.M.,Leiden University | Han K.H.,Maasstad Hospital | And 6 more authors.
Annals of the Rheumatic Diseases | Year: 2011

Objective To compare clinical and radiological outcomes of four dynamic treatment strategies in recent-onset rheumatoid arthritis (RA) after 5 years follow-up. Methods 508 patients with recent-onset RA were randomly assigned into four treatment strategies: sequential monotherapy; step-up combination therapy; initial combination with prednisone; initial combination with infliximab. Treatment adjustments were made based on 3-monthly disease activity score (DAS) measurements (if DAS >2.4 next treatment step; if DAS ≤2.4 during ≥6 months taper to maintenance dose; if DAS <1.6 during ≥6 months stop antirheumatic treatment). Primary and secondary outcomes were functional ability, joint damage progression, health-related quality of life and (drug-free) remission percentages. Results After 5 years, 48% of patients were in clinical remission (DAS <1.6) and 14% in drug-free remission, irrespective of initial treatment. After an earlier improvement in functional ability and quality of life with initial combination therapy, from 1 year onwards clinical outcomes were comparable across the groups and stable during 5 years. The initial combination groups showed less joint damage in year 1. In years 2-5 annual progression was comparable across the groups. After 5 years, initial combination therapy resulted in significantly less joint damage progression, reflecting the earlier clinical response. Conclusion Irrespective of initial treatment, an impressive improvement in clinical and radiological outcomes of RA patients can be achieved with dynamic treatment aimed at reducing disease activity, leading to 48% remission, 14% drug-free remission and sustained functional improvement. Starting with combination therapy resulted in earlier clinical improvement and less joint damage without more toxicity.


Simsek S.,VU University Amsterdam | Simsek S.,Medical Center Alkmaar | Van Den Oever I.A.M.,Jan Van Breemen Institute | Raterman H.G.,VU University Amsterdam | And 2 more authors.
Mediators of Inflammation | Year: 2010

Endothelial dysfunction is regarded as an important factor in the pathogenesis of vascular disease in obesity-related type 2 diabetes. The imbalance in repair and injury (hyperglycemia, hypertension, dyslipidemia) results in microvascular changes, including apoptosis of microvascular cells, ultimately leading to diabetes related complications. This review summarizes the mechanisms by which the interplay between endothelial dysfunction, inflammation, and apoptosis may cause (micro)vascular damage in patients with diabetes mellitus. Copyright © 2010 Theodora Boutsikou et al.


Holla J.F.M.,Jan Van Breemen Institute | Steultjens M.P.M.,VU University Amsterdam | Roorda L.D.,Jan Van Breemen Institute | Heymans M.W.,VU University Amsterdam | And 2 more authors.
Arthritis Care and Research | Year: 2010

Objective. To predict the 2-year course of activity limitations in patients with early knee and/or hip osteoarthritis (OA). Methods. The Cohort Hip & Cohort Knee (CHECK) study is a prospective followup study. The CHECK cohort, comprising participants (n = 1,002) with early OA-related knee and/or hip symptoms, was followed for 2 years. Participants completed questionnaires and underwent physical, laboratory, and radiographic examination. Regression models were used to examine whether baseline variables predicted the course of activity limitations as measured with the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Analyses were performed separately for participants with knee symptoms and participants with hip symptoms. Results. After 2 years of followup, activity limitations slightly decreased. Large between-subject variation was observed in WOMAC change scores. In participants with knee symptoms, young age, non-Western ethnicity, bilateral hip pain, morning stiffness in the knee, high comorbidity count, high body mass index, high bodily pain, poor general health perception, and pain coping strategy were associated with a poor 2-year outcome on activity limitations. In participants with hip symptoms, few activity limitations at baseline, bilateral hip pain, morning stiffness in the knee, high comorbidity count, low active hip flexion, poor general health perception, and pain coping strategy were associated with a poor 2-year outcome on activity limitations. Conclusion. After 2 years of followup, large between-subject variation was observed in the course of activity limitations. The course of activity limitations is to some extent already predictable at an early stage of knee and hip OA. © 2010, American College of Rheumatology.


Van Den Broek M.,Leiden University | Huizinga T.W.J.,Leiden University | Dijkmans B.A.C.,Jan Van Breemen Institute | Dijkmans B.A.C.,VU University Amsterdam | Allaart C.F.,Leiden University
Current Opinion in Rheumatology | Year: 2011

Purpose of Review: To give an overview of recently published articles covering drug-free remission in rheumatoid arthritis (RA). Recent Findings: Recent studies covering drug-free remission showed differences in numbers studied, remission definition, disease duration and medication used. Drug-free remission was reported in 9-29%. Only two out of four studies reported on patients who restarted medication due to a disease flare or loss of remission, which occurred in 45-46%. In the BeSt study, remission or low disease activity was achieved again after retreatment within 6 months in 96%. In the Finnish Early Rheumatoid Arthritis study, none of the patients achieved remission after retreatment; their mean Disease Activity Score (DAS28) was 3.68. Joint damage progression was not higher in patients who restarted medication when compared to patients in sustained drug-free remission or patients with continued treatment. Anticitrullinated protein antibody, rheumatoid factor or shared epitope negativity and short symptom duration were independent predictors of successful drug-free remission in more than one cohort. Summary: Drug-free remission can be achieved and sustained in a small group of RA patients. In early RA, retreatment is successful in the majority of patients. Disease flare after cessation of medication does not seem to increase joint damage progression. Sustained drug-free remission is predicted by autoantibody and shared epitope negativity and short disease duration before treatment initiation. © 2011 Wolters Kluwer Health | Lippincott Williams and Wilkins.


Van Kuijk A.W.R.,Jan Van Breemen Institute | Van Kuijk A.W.R.,University of Amsterdam | Tak P.P.,University of Amsterdam
Current Rheumatology Reports | Year: 2011

Psoriatic arthritis (PsA) is a chronic inflammatory arthropathy associated with psoriasis that affects the peripheral joints, spine, and entheses. Most patients with PsA present with peripheral synovitis of the oligoarticular or polyarticular subtype. As one of the targets of this disease, studies on the synovium may provide insight into the mechanisms involved in this condition. Key findings from the available studies comparing synovial tissue of PsA and rheumatoid arthritis patients are discussed in this review. Also, changes in the synovial infiltrate, expression of proinflammatory cytokines and adhesion molecules, and vascularity in synovial tissue after treatment with various medications are addressed. Finally, a model for proof-of-principle study design using serial synovial biopsies is described, which could be used to predict clinical (in)efficacy in early clinical trial design in PsA. © 2011 The Author(s).


INTRODUCTION: To investigate whether baseline levels of anti-citrullinated protein antibody (ACPA) or IgM rheumatoid factor (IgM-RF) and changes in the year thereafter are associated with disease activity, functional and radiographic outcome in early arthritis patients, and provide additional information over baseline autoantibody status. METHODS: In 545 early arthritis patients ACPA and IgM-RF levels, disease activity (DAS28), the Health Assessment Questionnaire (HAQ) and Sharp/Van der Heijde Score (SHS) were assessed annually. Baseline status, levels and first-year changes of the autoantibodies were associated with these measures at the two-year follow-up and sub-analysed according to autoantibody status. RESULTS: The mean age was 52.7 years, 69% was female, at baseline 56% was ACPA positive, 47% IgM-RF positive. At the two-year follow-up the mean DAS28 was 2.88, and the median HAQ and SHS were 0.38 and 1, respectively. At one year, ACPA and IgM-RF levels had decreased by 31% and 56%, respectively. A switch from negative to positive occurred in 2% for ACPA and 3% for IgM-RF. Positive ACPA and RF status were both associated with SHS at two years (P < 0.001), but baseline levels only showed a minor correlation of ACPA with DAS28 and HAQ at two years. Level changes were not associated with the outcome parameters. CONCLUSIONS: Baseline levels and first-year changes of ACPA and IgM-RF are hardly associated with outcome after two years. Seroconversion seldom occurs. Therefore, it does not appear useful to repeat ACPA or IgM-RF measurements.


Krieckaert C.L.M.,Jan van Breemen Institute | Bartelds G.M.,Jan van Breemen Institute | Wolbink G.J.,Jan van Breemen Institute
Arthritis Research and Therapy | Year: 2010

Therapeutic monoclonal antibodies have revolutionized the treatment of various inflammatory diseases. Immunogenicity against these antibodies has been shown to be clinically important: it is associated with shorter response duration because of diminishing concentrations in the blood and with infusion reactions. Concomitant immunomodulators in the form of methotrexate or azathioprine reduced the immunogenicity of therapeutic antibodies in rheumatoid arthritis, Crohn disease, and juvenile idiopathic arthritis. The occurrence of adverse events does not increase when immunomodulators are added to therapeutic antibodies. The mechanism whereby methotrexate and azathioprine influence immunogenicity remains unclear. Evidence-based consensus on prescribing concomitant immunomodulators is needed. © 2010 BioMed Central Ltd.

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