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Rheumatoid Arthritis: HELP
Articles by Ben A. C. Dijkmans
Based on 100 articles published since 2009
(Why 100 articles?)

Between 2009 and 2019, B. Dijkmans wrote the following 100 articles about Arthritis, Rheumatoid.
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4
1 Guideline EULAR evidence-based recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthritis. 2010

Peters, M J L / Symmons, D P M / McCarey, D / Dijkmans, B A C / Nicola, P / Kvien, T K / McInnes, I B / Haentzschel, H / Gonzalez-Gay, M A / Provan, S / Semb, A / Sidiropoulos, P / Kitas, G / Smulders, Y M / Soubrier, M / Szekanecz, Z / Sattar, N / Nurmohamed, M T. ·Department of Rheumatology, VU University Medical Centre, Amsterdam, The Netherlands. ·Ann Rheum Dis · Pubmed #19773290.

ABSTRACT: OBJECTIVES: To develop evidence-based EULAR recommendations for cardiovascular (CV) risk management in patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA). METHODS: A multidisciplinary expert committee was convened as a task force of the EULAR Standing Committee for Clinical Affairs (ESCCA), comprising 18 members including rheumatologists, cardiologists, internists and epidemiologists, representing nine European countries. Problem areas and related keywords for systematic literature research were identified. A systematic literature research was performed using MedLine, Embase and the Cochrane library through to May 2008. Based on this literature review and in accordance with the EULAR's "standardised operating procedures", the multidisciplinary steering committee formulated evidence-based and expert opinion-based recommendations for CV risk screening and management in patients with inflammatory arthritis. RESULTS: Annual CV risk assessment using national guidelines is recommended for all patients with RA and should be considered for all patients with AS and PsA. Any CV risk factors identified should be managed according to local guidelines. If no local guidelines are available, CV risk management should be carried out according to the SCORE function. In addition to appropriate CV risk management, aggressive suppression of the inflammatory process is recommended to further lower the CV risk. CONCLUSIONS: Ten recommendations were made for CV risk management in patients with RA, AS and PsA. The strength of the recommendations differed between RA on the one hand, and AS and PsA, on the other, as evidence for an increased CV risk is most compelling for RA.

2 Editorial A welcome address for the new criteria. 2010

van Schaardenburg, Dirkjan / Dijkmans, Ben A C. · ·Ann Rheum Dis · Pubmed #20699240.

ABSTRACT: -- No abstract --

3 Editorial Dyslipidaemia, statins and rheumatoid arthritis. 2009

Nurmohamed, Michael T / Dijkmans, Ben A C. · ·Ann Rheum Dis · Pubmed #19286903.

ABSTRACT: -- No abstract --

4 Review [From splint to smart syringe: the changing perspective of rheumatology]. 2011

Dijkmans, Ben A C. ·VU medisch centrum, afd. Reumatologie, Amsterdam, the Netherlands. secr.reumatologie@vumc.nl ·Ned Tijdschr Geneeskd · Pubmed #22085511.

ABSTRACT: Over the course of the past 30 years the outlook for patients with rheumatic arthritis (RA) has changed substantially. The careful "wait-and-see" attitude of rheumatologists of the past has been replaced by early and intensive intervention in patients with early RA. These days it is possible to bring about remission in half of all patients with, among others, the new medicines-- the "biologicals". Auto-antibodies are now detectable in the pre-clinical phase of RA; this means that in the future it will be possible to trace people with a raised risk of developing RA.

5 Review Drug-free remission: is it already possible? 2011

van den Broek, Marianne / Huizinga, Tom W J / Dijkmans, Ben A C / Allaart, Cornelia F. ·Leiden University Medical Center, Leiden, The Netherlands. m.van_den_broek@lumc.nl ·Curr Opin Rheumatol · Pubmed #21427578.

ABSTRACT: 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.

6 Review Carotid intima media thickness in rheumatoid arthritis as compared to control subjects: a meta-analysis. 2011

van Sijl, Alper M / Peters, Mike J / Knol, Dirk K / de Vet, Henrica C / Gonzalez-Gay, Miguel A / Smulders, Yvo M / Dijkmans, Ben A / Nurmohamed, Michael T. ·Department of Rheumatology, VU University Medical Center, Amsterdam, the Netherlands. ·Semin Arthritis Rheum · Pubmed #20889191.

ABSTRACT: OBJECTIVES: Rheumatoid arthritis (RA) is associated with increased risk of cardiovascular disease. Carotid intima media thickness (cIMT) is frequently used to identify populations at elevated cardiovascular risk. A systematic literature search and meta-analysis were performed to evaluate cIMT difference between RA and controls. METHODS: The literature was screened to identify all available studies comparing cIMT in RA patients and controls. Random effects meta-analysis was performed to estimate the overall mean cIMT difference between both groups. Meta-regression was performed to assess the influence of age and the degree of comparability regarding established cardiovascular risk factors on cIMT difference. Potential publication bias was examined by a funnel plot and Egger test. RESULTS: From 22 studies, cIMT data were available from 1384 RA patients and 1147 controls. In 17 of the studies, RA patients had a statistically significantly greater cIMT. The overall mean cIMT difference was 0.09 mm (95%CI: 0.07-0.11 mm). Heterogeneity was observed (I(2) 72.5%, P < 0.001). A likely source of heterogeneity was the difference in cardiovascular risk factors between RA patients and controls at baseline, but not age. The funnel plot did not show a skewed or asymmetrical shape, which was supported by the Egger's test (P = 0.87). CONCLUSIONS: Our observations support the current evidence base for an increased cardiovascular burden in RA and support the use of cIMT in observational studies in RA patients. The next step is to determine its utility as a surrogate cardiovascular risk marker in RA in prospective studies.

7 Review Recent advances in the management of rheumatoid arthritis. 2010

Klarenbeek, Naomi B / Kerstens, Pit J S M / Huizinga, Tom W J / Dijkmans, Ben A C / Allaart, Cornelia F. ·Department of Rheumatology, Leiden University Medical Centre, Albinusdreef 6, 2333 ZA, Leiden, Netherlands. n.b.klarenbeek@lumc.nl ·BMJ · Pubmed #21177351.

ABSTRACT: -- No abstract --

8 Review The BeSt story: on strategy trials in rheumatoid arthritis. 2009

Klarenbeek, Naomi B / Allaart, Cornelia F / Kerstens, Pit J S M / Huizinga, Tom W J / Dijkmans, Ben A C. ·Department of Rheumatology, C-01-R, Leiden University Medical Center, PO Box 9600, Leiden 2300 RC, The Netherlands. N.B.Klarenbeek@lumc.nl ·Curr Opin Rheumatol · Pubmed #19318946.

ABSTRACT: PURPOSE OF REVIEW: To give an overview of recent strategy trials for the treatment of rheumatoid arthritis. RECENT FINDINGS: Strategy studies showed a clear benefit of dynamic result-driven treatment towards tight control of disease activity compared with 'usual care' in rheumatoid arthritis patients. In addition, treatment given after short symptom duration gives better outcomes than later initiation of treatment. In many trials, combination therapies, especially combinations with prednisolone or biologicals, were superior to monotherapies. Moreover, combination therapies were more effective if given early in the disease as compared with a delayed introduction, giving support to the window of opportunity hypothesis. In the BeSt study, initial combination therapy could be successfully discontinued in half of the patients, emphasizing that 'initial' would mean 'temporary'. Less evidence is available about initial combination in comparison with combination therapy with a shorter delay. Larger tight-controlled, goal-steered, dynamic strategy trials comparing initial combination therapy with a short-delay combination therapy will help to translate the use of initial (temporary) combination therapy into normal daily practice. SUMMARY: Treatment strategy trials have demonstrated that in the majority of patients with rheumatoid arthritis, the following approach is the most beneficial: goal-steered, dynamic treatment towards tight control of disease activity, including early introduction of (an) effective disease-modifying antirheumatic drug(s) in combination with prednisone or antitumor necrosis factor, which includes tapering of the medication if remission or low disease activity is achieved.

9 Clinical Trial HDL protein composition alters from proatherogenic into less atherogenic and proinflammatory in rheumatoid arthritis patients responding to rituximab. 2013

Raterman, Hennie G / Levels, Han / Voskuyl, Alexandre E / Lems, Willem F / Dijkmans, Ben A / Nurmohamed, Michael T. ·Department of Rheumatology and Internal Medicine, VU University Medical Centre, PO Box 7057, 1007 MB Amsterdam, The Netherlands. ·Ann Rheum Dis · Pubmed #22589377.

ABSTRACT: OBJECTIVE: An atherogenic lipid profile is an established risk factor for cardiovascular (CV) diseases. Interestingly, high inflammatory states as present in rheumatoid arthritis (RA) are associated with unfavourable lipid profile. Data about effects of novel immunomodulating agents as rituximab (RTX) on lipid profile are limited. Therefore, changes in lipids in RTX treated RA patients were evaluated. METHODS: In 49 consecutive RTX treated RA patients, serum and EDTA plasma samples were collected at baseline, 1, 3 and 6 months. In these samples, lipid and levels were assessed to determine changes in time. Surface-enhanced laser desorption/ionisation time-of-flight (SELDI-TOF) MS analysis was performed in six good and six non-responding RA patients to study functional high density lipoprotein (HDL) protein composition changes in time. RESULTS: In the total group (n=49), the atherogenic index decreased from 4.3 to 3.9 (∼9%) after 6 months. Testing for effect modification revealed a difference in the effect on lipid levels between responders and non-responders upon RTX (p<0.001). ApoB to ApoA-I ratios decreased significantly (∼9%) in good responding (n=32) patients. SELDI-TOF MS analysis revealed a significant decrease in density of mass charge (m/z) marker 11743, representing a decrease in serum amyloid A, in good responding patients. CONCLUSION: This study indicates beneficial effects on cholesterol profile upon RTX treatment along with improvement of disease activity. Proteomic analysis of the HDL particle reveals composition changes from proatherogenic to a less proatherogenic composition during 6 months RTX treatment. Whether these HDL particle alterations during immunotherapies result in a lower CV event rate remains to be established.

10 Clinical Trial Patients non-responding to etanercept obtain lower etanercept concentrations compared with responding patients. 2012

Jamnitski, A / Krieckaert, C L / Nurmohamed, M T / Hart, M H / Dijkmans, B A / Aarden, L / Voskuyl, A E / Wolbink, G J. ·Jan van Breemen Research Institute/Reade, Amsterdam, The Netherlands. ·Ann Rheum Dis · Pubmed #21914626.

ABSTRACT: OBJECTIVE: To investigate the relationship between serum etanercept levels and clinical response. METHODS: In 292 etanercept-treated patients with rheumatoid arthritis clinical and pharmacological data were determined at baseline and after 1, 4 and 6 months of etanercept treatment. Differences in etanercept levels between good, moderate and European League Against Rheumatism (EULAR) non-responders were assessed after 6 months of therapy. RESULTS: After 6 months of therapy etanercept levels were significantly higher in good responders (median (IQR) 3.78 (2.53-5.17)) compared with both moderate 3.10 (2.12-4.47) and EULAR non-responders 2.80 (1.27-3.93) (all p<0.05). There was a significant association between clinical response and serum etanercept levels (regression coefficient 0.54, 95% CI 0.21 to 0.86, p=0.001). When patients were categorised into quartiles according to the height of etanercept levels, the lowest quartile (etanercept level <2.1 mg/l) comprised 40% of all non-responders. The highest quartile (etanercept level >4.7 mg/l) comprised 35% of all good EULAR responders. Anti-etanercept antibodies were detected in none of the sera. CONCLUSION: The authors demonstrated that lower etanercept levels were associated with non-response. Therapeutic drug monitoring and the possibility of the adjusted dosing regimes in the selected groups of patients should be investigated further as a possible tool to optimise treatment with etanercept.

11 Clinical Trial Pharmacological induction of interferon type I activity following treatment with rituximab determines clinical response in rheumatoid arthritis. 2011

Vosslamber, Saskia / Raterman, Hennie G / van der Pouw Kraan, Tineke C T M / Schreurs, Marco W J / von Blomberg, B Mary E / Nurmohamed, Michael T / Lems, Willem F / Dijkmans, Ben A C / Voskuyl, Alexandre E / Verweij, Cornelis L. ·Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands. ·Ann Rheum Dis · Pubmed #21444302.

ABSTRACT: OBJECTIVE: Despite the fact that rituximab depletes B cells in all treated patients with RA, not all patients show a favourable clinical response. The goal of this study was to provide insight into pharmacological changes in peripheral blood that are associated with clinical response to rituximab. METHODS: Gene expression profiling was performed on peripheral blood RNA of 13 patients with RA (test group) using Illumina HumanHT beadchip microarrays. An independent group of nine patients was used for validation using TaqMan quantitative PCR. Clinical responder status was determined after 6 months using change in 28-joint Disease Activity Score (ΔDAS28) and European League Against Rheumatism (EULAR) response criteria. Significance analysis of microarrays and ontology analysis were used for data analysis and interpretation. RESULTS: Pharmacogenomic analyses demonstrated marked interindividual differences in the pharmacological responses at 3 and 6 months after start of treatment with rituximab. Interestingly, only differences in the regulation of type I interferon (IFN)-response genes after 3 months correlated with the ΔDAS28 response. Good responders (DAS>1.2; n=7) exhibited a selective increase in the expression of type I IFN-response genes, whereas this activity was unchanged or hardly changed in non-responders (DAS<1.2; n=6) (p=0.0040 at a cut-off of 1.1-fold induction). Similar results were obtained using EULAR response criteria. These results were validated in an independent cohort of nine patients (five non-responders and four responders, p=0.0317). CONCLUSIONS: A good clinical response to rituximab in RA is associated with a selective drug-induced increase in type I IFN-response activity in patients with RA. This finding may provide insight in the biological mechanism underlying the therapeutic response to rituximab.

12 Clinical Trial The presence or absence of antibodies to infliximab or adalimumab determines the outcome of switching to etanercept. 2011

Jamnitski, Anna / Bartelds, Geertje M / Nurmohamed, Michael T / van Schouwenburg, Pauline A / van Schaardenburg, Dirkjan / Stapel, Steven O / Dijkmans, Ben A C / Aarden, Lucien / Wolbink, Gerrit Jan. ·Jan van Breemen Institute, Amsterdam, The Netherlands. g.wolbink@janvanbreemen.nl ·Ann Rheum Dis · Pubmed #21068090.

ABSTRACT: OBJECTIVE: The aim of this study was to test the hypothesis that the reason for non-response (caused by immunogenicity or not) to a first tumour necrosis factor (TNF) inhibitor defines whether a second TNF inhibitor will be effective. METHODS: This cohort study consisted of 292 consecutive patients with rheumatoid arthritis (RA), all treated with etanercept. A total of 89 patients (30%) were treated previously with infliximab or adalimumab ('switchers'), and the remaining 203 (70%) were anti-TNF naive. All switchers were divided into two groups: with and without antibodies against the previous biological. Differences in clinical response to etanercept between switchers with and without antibodies and patients who were anti-TNF naive were assessed after 28 weeks of treatment using changes in Disease Activity Score in 28 joints (DAS28). RESULTS: After 28 weeks of treatment, response to etanercept did not differ between patients who were anti-TNF naive and switchers with anti-drug antibodies (ΔDAS28=2.1 ± 1.3 vs ΔDAS28=2.0 ± 1.3; p = 0.743). In contrast, switchers without anti-drug antibodies had a diminished response to etanercept treatment compared to patients who were TNF naive (ΔDAS28 =1.2±1.3 vs ΔDAS28 = 2.1 ± 1.3; p = 0.001) and switchers with antibodies (ΔDAS28 =1.2±1.3 vs ΔDAS28 = 2.0 ± 1.3; p = 0.017). CONCLUSION: Patients with RA with an immunogenic response against a first TNF-blocking agent had a better clinical response to a subsequent TNF blocker compared to patients with RA without anti-drug antibodies. Hence, determining immunogenicity can be helpful in deciding in which patient switching could be beneficial and can be part of a personalised treatment regimen.

13 Clinical Trial Vitamin D deficiency is common in patients with RA and linked to disease activity, but circulating levels are unaffected by TNFα blockade: results from a prospective cohort study. 2011

Welsh, Paul / Peters, Mike J L / McInnes, Iain B / Lems, Willem F / Lips, Paul T / McKellar, Gayle / Knox, Susan / Michael Wallace, A / Dijkmans, Ben A C / Nurmohamed, Michael T / Sattar, Naveed. · ·Ann Rheum Dis · Pubmed #21047908.

ABSTRACT: -- No abstract --

14 Clinical Trial Stable bone mineral density in lumbar spine and hip in contrast to bone loss in the hands during long-term treatment with infliximab in patients with rheumatoid arthritis. 2011

Eekman, Danielle A / Vis, Marijn / Bultink, Irene E M / Kuik, Dirk J / Voskuyl, Alexandre E / Dijkmans, Ben A C / Lems, Willem F. · ·Ann Rheum Dis · Pubmed #20447956.

ABSTRACT: -- No abstract --

15 Clinical Trial Beneficial effect of 1-year etanercept treatment on the lipid profile in responding patients with rheumatoid arthritis: the ETRA study. 2010

Jamnitski, A / Visman, I M / Peters, M J L / Dijkmans, B A C / Voskuyl, A E / Nurmohamed, M T. ·Jan van Breemen Institute, Amsterdam, The Netherlands. ·Ann Rheum Dis · Pubmed #20498216.

ABSTRACT: BACKGROUND: Effective anti-inflammatory treatment with tumour necrosis factor α (TNFα) inhibitors may have favourable effects on the lipid profile. Available evidence is derived from short-term studies, and it is not clear whether TNFα inhibitors have a similar effect on the lipid profile in responders and non-responders to the treatment. OBJECTIVES: To investigate the effect of long-term etanercept treatment on the lipid profile in a large sample of patients with rheumatoid arthritis (RA), stratified for European League Against Rheumatism (EULAR) response. METHODS: Between 2004 and 2008, 292 consecutive patients with active RA (DAS28 >3.2) and a new etanercept prescription were included in an observational cohort. Clinical response variables and lipid samples were collected at baseline and after 4 months and 1 year of etanercept treatment. Generalised estimating equation analyses were used to investigate the longitudinal course of lipid levels in relation to clinical response variables. RESULTS: According to the EULAR response criteria, 76% of the patients were good or moderate responders at 4 months, and 85% of the remainder at 1 year. Significant changes in apoA-I (increased by 3.5% (p=0.002) at 4 months and 3.1% (p=0.005) at 1 year) and apoB/apoA-I ratio (decreased by 6.2% (p<0.001) at 4 months and 3.6% (p=0.025) at 1 year) were observed in EULAR responders. No significant differences were observed in EULAR non-responders at all time points. CONCLUSIONS: Treatment with etanercept resulted in a significant and sustained decrease in the apoB/apoA-I ratio in patients with good or moderate EULAR response. This may have a beneficial effect on the cardiovascular risk in patients with RA.

16 Clinical Trial The selective estrogen receptor alpha agonist Org 37663 induces estrogenic effects but lacks antirheumatic activity: a phase IIa trial investigating efficacy and safety of Org 37663 in postmenopausal female rheumatoid arthritis patients receiving stable background methotrexate or sulfasalazine. 2010

van Vollenhoven, Ronald F / Houbiers, Jos G A / Buttgereit, Frank / In 't Hout, Joanna / Boers, Maarten / Leij, Susanne / Kvien, Tore K / Dijkmans, Ben A C / Szczepański, Leszek / Szombati, Istvan / Sierakowski, Stanislaw / Miltenburg, André M M. ·Karolinska Institute, Stockholm, Sweden. ·Arthritis Rheum · Pubmed #20112368.

ABSTRACT: OBJECTIVE: Multiple lines of evidence suggest that sex hormones may play a role in the pathogenesis or clinical expression of rheumatoid arthritis (RA). Studies on the effects of exogenous estrogens in RA patients have yielded contradictory results. We undertook this study to determine the effects of the selective estrogen receptor alpha (ERalpha) agonist Org 37663 in patients with RA, in terms of both its estrogenic effects and its ability to ameliorate disease activity. METHODS: A 10-week, multicenter, randomized, double-blind, placebo-controlled, parallel group, dose-finding, proof-of-concept trial was initiated to obtain data on the efficacy and safety of Org 37663 in postmenopausal female patients with RA who were receiving background treatment with either methotrexate or sulfasalazine. Patients were randomized to receive placebo or Org 37663 at doses of 4 mg/day, 15 mg/day, or 50 mg/week. The primary efficacy variable was the Disease Activity Score in 28 joints (DAS28). RESULTS: Org 37663 induced a clear biologic, estrogenic response in several organ systems, including a dose-related increase in levels of sex hormone binding globulin. However, the DAS28 decreased similarly for all treatment groups including placebo, indicating lack of clinical efficacy of Org 37663 in this trial. CONCLUSION: The observed lack of clinical benefit in RA patients treated with an ERalpha agonist, in association with a clear biologic response to the study drug, provides evidence that a biologically relevant ERalpha-mediated estrogenic effect is not associated with a clinically relevant effect on RA symptoms and signs.

17 Clinical Trial Tumour necrosis factor {alpha} blockade reduces circulating N-terminal pro-brain natriuretic peptide levels in patients with active rheumatoid arthritis: results from a prospective cohort study. 2010

Peters, Mike J L / Welsh, Paul / McInnes, Iain B / Wolbink, Gertjan / Dijkmans, Ben A C / Sattar, Naveed / Nurmohamed, Michael T. ·Correspondence to Dr Mike Peters, VU University Medical Centre, P O Box 7057, 1007 MB Amsterdam, The Netherlands. mjl.peters@vumc.nl ·Ann Rheum Dis · Pubmed #19934107.

ABSTRACT: BACKGROUND: Patients with rheumatoid arthritis (RA) are at increased risk of heart failure and vascular events. Small increases in circulating N-terminal pro-brain natriuretic peptide (NT-proBNP) are associated with an increased risk of a cardiovascular event, and high levels signal left ventricular dysfunction. Data on the effects of tumour necrosis factor alpha(TNFalpha) blocking agents on circulating NT-proBNP levels in patients with active RA are lacking but may be informative. METHODS: 171 consecutive patients with RA (28-joint disease activity score >3.2) without congestive heart failure (NYHA class III or IV) were scheduled to receive adalimumab once every 2 weeks. Serum NT-proBNP concentrations were measured simultaneously on stored baseline and 16-week samples. Paired sample t tests were used to observe differences in biomarkers before and after adalimumab administration. Correlations between the biomarkers and changes in circulating log NT-proBNP levels were evaluated with the Pearson test and multivariable linear regression analyses of correlates were performed (forward selection procedure). RESULTS: Circulating levels of NT-proBNP decreased significantly after 16 weeks of adalimumab administration (median NT-proBNP 83.0 pg/ml vs 69.5 pg/ml, p=0.004). Changes in NT-proBNP levels were associated with changes in pulse pressure (r=0.18, p=0.02), systolic blood pressure (r=0.16, p=0.04) and erythrocyte sedimentation rate (r=0.18, p=0.02). On multivariable analysis, changes in pulse pressure and erythrocyte sedimentation rate remained independently associated with changes in circulating NT-proBNP levels. CONCLUSIONS: These observations show that blocking TNFalpha in patients with RA without evident heart failure decreases NT-proBNP levels by about 18%. This suggests no treatment-induced deterioration in cardiac function and a potential cardiovascular risk benefit.

18 Article Cardiovascular risk management in rheumatoid arthritis patients still suboptimal: the Implementation of Cardiovascular Risk Management in Rheumatoid Arthritis project. 2017

van den Oever, Inge A M / Heslinga, Maaike / Griep, Ed N / Griep-Wentink, Hanneke R M / Schotsman, Rob / Cambach, Walter / Dijkmans, Ben A C / Smulders, Yvo M / Lems, Willem F / Boers, Maarten / Voskuyl, Alexandre E / Peters, Mike J L / van Schaardenburg, Dirkjan / Nurmohamed, Micheal T. ·Department of Rheumatology, Amsterdam Rheumatology and Immunology Center, Reade, Amsterdam. · Department of Rheumatology, Antonius Hospital Zuidwest Friesland, Sneek. · Department of General Practice and Geriatric Medicine, VU University Medical Center, Amsterdam. · Dutch Institute for Rational Use of Medicine, Utrecht. · Department of Internal Medicine. · Department of Rheumatology VU University Medical Center. · Department of Rheumatology, Amsterdam Rheumatology and Immunology Center, AMC, Amsterdam, The Netherlands. ·Rheumatology (Oxford) · Pubmed #28199724.

ABSTRACT: Objective: To assess the 10-year cardiovascular (CV) risk score and to identify treatment and undertreatment of CV risk factors in patients with established RA. Methods: Demographics, CV risk factors and prevalence of cardiovascular disease (CVD) were assessed by questionnaire. To calculate the 10-year CV risk score according to the Dutch CV risk management guideline, systolic blood pressure was measured and cholesterol levels were determined from fasting blood samples. Patients were categorized into four groups: indication for treatment but not treated; inadequately treated, so not meeting goals (systolic blood pressure ⩽140 mmHg and/or low-density lipoprotein ⩽2.5 mmol/l); adequately treated; or no treatment necessary. Results: A total of 720 consecutive RA patients were included, 375 from Reade and 345 from the Antonius Hospital. The mean age of patients was 59 years (s.d. 12) and 73% were female. Seventeen per cent of the patients had a low 10-year CV risk (<10%), 21% had an intermediate risk (10-19%), 53% a high risk (⩾20%) and 9% had CVD. In total, 69% had an indication for preventive treatment (cholesterol-lowering or antihypertensive drugs). Of those, 42% received inadequate treatment and 40% received no treatment at all. Conclusion: Optimal CV risk management remains a major challenge and better awareness and management are urgently needed to reduce the high risk of CVD in the RA population.

19 Article A genome-wide association study of rheumatoid arthritis without antibodies against citrullinated peptides. 2015

Bossini-Castillo, L / de Kovel, C / Kallberg, H / van 't Slot, R / Italiaander, A / Coenen, M / Tak, P P / Posthumus, M D / Wijmenga, C / Huizinga, T / van der Helm-van Mil, A H M / Stoeken-Rijsbergen, G / Rodriguez-Rodriguez, Luis / Balsa, Alejandro / González-Álvaro, Isidoro / González-Gay, Miguel Ángel / Gómez-Vaquero, Carmen / Franke, B / Anonymous670785 / Vermeulen, S / van der Horst-Bruinsma, Ie / Dijkmans, B A C / Wolbink, G J / Ophoff, R A / Maehlen, M T / van Riel, P / Merriman, M / Klareskog, L / Lie, B A / Merriman, T / Crusius, J B A / Brouwer, E / Martin, J / de Vries, N / Toes, R / Padyukov, L / Koeleman, B P C. ·Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas (IPBLN-CSIC), Granada, Spain. · Department of Medical Genetics, UMCU, Utrecht, The Netherlands. · Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden Institute of Environmental Medicine, Karolinska Institutet, Sweden. · Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. · Division of Clinical Immunology and Rheumatology, AMC, University of Amsterdam, Amsterdam, The Netherlands. · Department of Rheumatology, UMCG, Groningen, The Netherlands. · Department of Medical Genetics, UMCG, Groningen, The Netherlands. · Department of Rheumatology, LUMC, Leiden, The Netherlands. · Rheumatology Service, Hospital Clínico San Carlos, Madrid, Spain. · Rheumatology Service, Hospital Universitario La Paz, Madrid, Spain. · Rheumatology Service, Hospital Universitario La Princesa, Instituto de Investigación Sanitaria La Princesa, Madrid, Spain. · Rheumatology Service, Hospital Universitario Marqués de Valdecilla, IFIMAV, Santander, Spain. · Rheumatology Service, Hospital Universitari Bellvitge, Barcelona, Spain. · Department of Rheumatology, VUMC, Amsterdam, The Netherlands. · Jan van Breemen Research Institute, Amsterdam, The Netherlands. · Department of Medical Genetics; University of Oslo and Oslo University, hospital, Oslo, Norway; K. G. Jebsen Inflammation Research Centre, University of Oslo, Oslo, Norway. · Department of Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. · Department of Biochemistry, University of Otago, New Zealand. · Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden. · Laboratory of Immunogenetics, Department of Medical Microbiology and Infection Control, VU University Medical Center, Amsterdam, The Netherlands. ·Ann Rheum Dis · Pubmed #24532677.

ABSTRACT: INTRODUCTION: Rheumatoid arthritis (RA) patients can be classified based on presence or absence of anticitrullinated peptide antibodies (ACPA) in their serum. This heterogeneity among patients may reflect important biological differences underlying the disease process. To date, the majority of genetic studies have focused on the ACPA-positive group. Therefore, our goal was to analyse the genetic risk factors that contribute to ACPA-negative RA. METHODS: We performed a large-scale genome-wide association study (GWAS) in three Caucasian European cohorts comprising 1148 ACPA-negative RA patients and 6008 controls. All patients were screened using the Illumina Human Cyto-12 chip, and controls were genotyped using different genome-wide platforms. Population-independent analyses were carried out by means of logistic regression. Meta-analysis with previously published data was performed as follow-up for selected signals (reaching a total of 1922 ACPA-negative RA patients and 7087 controls). Imputation of classical HLA alleles, amino acid residues and single nucleotide polymorphisms was undertaken. RESULTS: The combined analysis of the studied cohorts resulted in identification of a peak of association in the HLA-region and several suggestive non-HLA associations. Meta-analysis with previous reports confirmed the association of the HLA region with this subset and an observed association in the CLYBL locus remained suggestive. The imputation and deep interrogation of the HLA region led to identification of a two amino acid model (HLA-B at position 9 and HLA-DRB1 at position 11) that accounted for the observed genome-wide associations in this region. CONCLUSIONS: Our study shed light on the influence of the HLA region in ACPA-negative RA and identified a suggestive risk locus for this condition.

20 Article Methotrexate analogues display enhanced inhibition of TNF-α production in whole blood from RA patients. 2014

van der Heijden, J W / Assaraf, Y G / Gerards, A H / Oerlemans, R / Lems, W F / Scheper, R J / Dijkmans, B A C / Jansen, G. ·Department of Rheumatology, VU University Medical Center , Amsterdam , The Netherlands. ·Scand J Rheumatol · Pubmed #23987246.

ABSTRACT: OBJECTIVES: Although methotrexate (MTX) is the anchor drug in the treatment of rheumatoid arthritis (RA), patients experience clinical resistance to MTX upon prolonged treatment. We explored whether new-generation antifolates elicit superior anti-inflammatory properties when compared to MTX, based on their capacity to inhibit tumour necrosis factor (TNF)-α production. METHOD: T cells in whole blood from 18 RA patients (including MTX-naïve, MTX- responsive, and MTX non-responsive patients) and seven healthy volunteers were stimulated with αCD3/αCD28 antibodies and incubated ex vivo for 72 h with MTX and eight novel antifolate drugs with potentially favourable biochemical and pharmacological properties. Drug concentrations exerting 50% inhibition (IC-50) of TNF-α production (by enzyme-linked immunosorbent assay, ELISA) were determined as an estimate for their anti-inflammatory capacity. In addition, induction of T-cell apoptosis was evaluated by flow cytometry. RESULTS: The new-generation antifolates PT523, PT644, raltitrexed, and GW1843 proved to be potent inhibitors of TNF-α production in activated T cells from all three groups of RA patients and from healthy volunteers. Based on IC-50 values, these antifolates were up to 10.3 times more potent than MTX. The anti-inflammatory effects were observed at drug concentrations that provoked suppression of T-cell activation and induction of apoptosis in 20-40% of activated T cells. CONCLUSION: In an ex-vivo setting, novel antifolates elicited marked inhibition of TNF-α production in activated T cells from RA patients. Further clinical evaluation is warranted to investigate whether a low dosage of these antifolates can elicit immunosuppressive effects equivalent to MTX, and whether they are superior to MTX in patients who fail to respond to MTX.

21 Article A non-inferiority trial of an attenuated combination strategy ('COBRA-light') compared to the original COBRA strategy: clinical results after 26 weeks. 2014

den Uyl, Debby / ter Wee, Marieke / Boers, Maarten / Kerstens, Pit / Voskuyl, Alexandre / Nurmohamed, Mike / Raterman, Hennie / van Schaardenburg, Dirkjan / van Dillen, Nancy / Dijkmans, Ben / Lems, Willem. ·Department of Rheumatology, VU University Medical Center, , Amsterdam, The Netherlands. ·Ann Rheum Dis · Pubmed #23606682.

ABSTRACT: BACKGROUND: Early, intensive treatment of rheumatoid arthritis (RA) with the combination of (initially high dose) prednisolone, methotrexate and sulfasalazine (COBRA therapy) considerably lowers disease activity and suppresses radiological progression, but is infrequently prescribed in daily practice. Attenuating the COBRA regimen might lessen concerns about side effects, but the efficacy of such strategies is unknown. OBJECTIVE: To compare the 'COBRA-light' strategy with only two drugs, comprising a lower dose of prednisolone (starting at 30 mg/day, tapered to 7.5 mg/day in 9 weeks) and methotrexate (escalated to 25 mg/week in 9 weeks) to COBRA therapy (prednisolone 60 mg/day, tapered to 7.5 mg/day in 6 weeks, methotrexate 7.5 mg/week and sulfasalazine 2 g/day). METHOD: An open, randomised controlled, non-inferiority trial in 164 patients with early active RA, all treated according to a treat to target strategy. RESULTS: At baseline patients had moderately active disease: mean (SD) 44-joint disease activity score (DAS44) 4.13 (0.81) for COBRA and 3.95 (0.9) for COBRA-light. After 6 months, DAS44 significantly decreased in both groups (-2.50 (1.21) for COBRA and -2.18 (1.10) for COBRA-light). The adjusted difference in DAS44 improvement between the groups, 0.21 (95% CI -0.11 to 0.53), was smaller than the predefined clinically relevant difference of 0.5. Minimal disease activity (DAS44 <1.6) was reached in almost half of patients in both groups (49% and 41% in COBRA and COBRA-light, respectively). CONCLUSIONS: At 6 months COBRA-light therapy is most likely non-inferior to COBRA therapy. CLINICAL TRIAL REGISTRATION NUMBER: 55552928.

22 Article Increased progression of carotid intima media thickness in thyroid peroxidase antibodies-positive rheumatoid arthritis patients. 2013

Raterman, H G / Voskuyl, A E / Simsek, S / Schreurs, M W J / van Hoogstraten, I M W / Peters, M J L / van Halm, V P / Dijkmans, B A C / Lips, P / Lems, W F / Nurmohamed, M T. ·Departments of Rheumatology. ·Eur J Endocrinol · Pubmed #24005313.

ABSTRACT: OBJECTIVE: Autoimmune diseases such as rheumatoid arthritis (RA) and hypothyroidism tend to cluster, and this coexistence amplifies the elevated cardiovascular risk in RA. Whether thyroid peroxidase antibodies (TPOabs) are associated with increased cardiovascular disease (CVD) risk has not been studied extensively. Therefore, this study determined firstly the prevalence of TPOabs in RA and secondly whether TPOabs were associated with CVD. Moreover, this study explored whether TPOabs were related to RA characteristics. DESIGN AND METHODS: Data from the CARRÉ Study, an ongoing study investigating CVDs and its risk factors in RA (n=322), was used to ascertain the prevalence of TPOabs in RA patients. In addition, cardiovascular and RA disease characteristics were compared between TPOabs-positive and -negative patients at baseline and at a second visit after 3 years. RESULTS: TPOabs were present in 47/322 (15%) RA patients and TSH levels were higher in TPOabs-positive patients (1.40 mU/l) compared with TPOabs-negative patients (1.26 mU/l, P=0.048). At baseline and after 3 years no association was observed between TPOabs and (risk factors for) CVD. Regression analyses revealed a significantly larger progression of carotid intima media thickness (cIMT; β=0.13 mm) in TPOabs-positive compared with TPOabs-negative patients independent of risk factors for cIMT progression. RA disease activity scores (DAS28) were higher in TPOabs-positive compared with TPOabs-negative patients (4.4 vs 3.8 P=0.018). CONCLUSIONS: TPOabs were associated with increased cIMT progression. Moreover, an association between TPOabs and DAS28 was observed. Hence, TPOabs seems to have a role in the amplified cardiovascular risk in RA patients.

23 Article Risk of alanine transferase (ALT) elevation in patients with rheumatoid arthritis treated with methotrexate in a DAS-steered strategy. 2013

Dirven, L / Klarenbeek, N B / van den Broek, M / van Groenendael, J H L M / de Sonnaville, P B J / Kerstens, P J S M / Huizinga, T W J / Dijkmans, B A C / Lems, W F / Allaart, C F. ·Department of Rheumatology, Leiden University Medical Center, PO Box 9600, 2300 Leiden, The Netherlands. l.dirven@lumc.nl ·Clin Rheumatol · Pubmed #23224330.

ABSTRACT: OBJECTIVE: To determine incidence of increased levels of alanine transferase (ALT) >2× upper limit of normal (ULN) in patients receiving methotrexate (MTX), treated according to a dynamic strategy, and to identify predictors of ALT of >2× ULN. METHODS: Data of 508 recent-onset rheumatoid arthritis (RA) patients from the BeSt study, randomized to initial monotherapy or combination therapy, were used. Treatment was dynamic, aiming at a disease activity score = ≤ 2.4. ALT was measured every three months. With logistic regression analyses, baseline variables predictive of first ALT of >2× ULN were identified and the association between use of concomitant antirheumatic drugs, the actual and cumulative dose of MTX and ALT of >2× ULN was determined. RESULTS: In total, 498 patients ever initiated MTX, with a total duration on MTX of 1,416 patient-years. In 89 patients, a first incidence of ALT of >2× ULN occurred. Incidence rate was 6.3 per 100 patient-years and cumulative incidence 18 %. ACPA positivity and baseline ALT of >1× ULN were independent predictors of later ALT of >2× ULN (OR 1.8 (95 % CI, 1.1-3.1) and OR 3.1 (95 % CI, 1.6-6.2), respectively). Smoking showed a trend (OR 1.6 (95 % CI, 0.98-2.7)). Mean MTX dosage over time was higher in patients with an ALT of >2× ULN. Patients who did not have an ALT of >2× ULN used more concomitant disease-modifying antirheumatic drugs and longer. CONCLUSIONS: In RA patients treated with MTX according to a dynamic strategy resembling daily clinical practice, incidence of increased ALT of >2× ULN was lower than previously reported, and also without treatment adjustments, persistence was rare. The recommendations for ALT monitoring may be reevaluated.

24 Article The interferon type I signature towards prediction of non-response to rituximab in rheumatoid arthritis patients. 2012

Raterman, Hennie G / Vosslamber, Saskia / de Ridder, Sander / Nurmohamed, Michael T / Lems, Willem F / Boers, Maarten / van de Wiel, Mark / Dijkmans, Ben A C / Verweij, Cornelis L / Voskuyl, Alexandre E. ·Department of Rheumatology, VU University medical center, de Boelelaan 1117, Amsterdam, 1081HV, the Netherlands. c.verweij@vumc.nl. ·Arthritis Res Ther · Pubmed #22540992.

ABSTRACT: INTRODUCTION: B cell depletion therapy is efficacious in rheumatoid arthritis (RA) patients failing on tumor necrosis factor (TNF) blocking agents. However, approximately 40% to 50% of rituximab (RTX) treated RA patients have a poor response. We investigated whether baseline gene expression levels can discriminate between clinical non-responders and responders to RTX. METHODS: In 14 consecutive RA patients starting on RTX (test cohort), gene expression profiling on whole peripheral blood RNA was performed by Illumina® HumanHT beadchip microarrays. Supervised cluster analysis was used to identify genes expressed differentially at baseline between responders and non-responders based on both a difference in 28 joints disease activity score (ΔDAS28 < 1.2) and European League against Rheumatism (EULAR) response criteria after six months RTX. Genes of interest were measured by quantitative real-time PCR and tested for their predictive value using receiver operating characteristics (ROC) curves in an independent validation cohort (n = 26). RESULTS: Genome-wide microarray analysis revealed a marked variation in the peripheral blood cells between RA patients before the start of RTX treatment. Here, we demonstrated that only a cluster consisting of interferon (IFN) type I network genes, represented by a set of IFN type I response genes (IRGs), that is, LY6E, HERC5, IFI44L, ISG15, MxA, MxB, EPSTI1 and RSAD2, was associated with ΔDAS28 and EULAR response outcome (P = 0.0074 and P = 0.0599, respectively). Based on the eight IRGs an IFN-score was calculated that reached an area under the curve (AUC) of 0.82 to separate non-responders from responders in an independent validation cohort of 26 patients using Receiver Operator Characteristics (ROC) curves analysis according to ΔDAS28 < 1.2 criteria. Advanced classifier analysis yielded a three IRG-set that reached an AUC of 87%. Comparable findings applied to EULAR non-response criteria. CONCLUSIONS: This study demonstrates clinical utility for the use of baseline IRG expression levels as a predictive biomarker for non-response to RTX in RA.

25 Article Sustained drug-free remission in rheumatoid arthritis after DAS-driven or non-DAS-driven therapy: a comparison of two cohort studies. 2012

van der Woude, Diane / Visser, Karen / Klarenbeek, Naomi B / Ronday, H Karel / Peeters, André J / Kerstens, Pit J S M / Dijkmans, Ben A C / Huizinga, Tom W J / van der Helm-van Mil, Annette H M / Allaart, Cornelia F. ·Department of Rheumatology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands. dvanderwoude@lumc.nl ·Rheumatology (Oxford) · Pubmed #22337939.

ABSTRACT: OBJECTIVES: To compare the prevalence of and predictors for sustained drug-free remission in two cohorts of patients with recent-onset RA treated with DAS-driven therapy or non-DAS-driven therapy. METHODS: Sustained drug-free remission was assessed after 5 years of follow-up in 508 patients treated with DAS-driven therapy (DAS ≤ 2.4) in a randomized treatment cohort, and in 424 patients who received non-DAS-driven therapy in a prospective inception cohort. The design of the DAS-driven cohort required systematic joint assessments with DAS-driven restart of therapy. Predictors for remission were identified by univariable and multivariable logistic regression in each cohort separately and in a combined multivariate logistic regression analysis corrected for propensity scores, including a sensitivity analysis on patients receiving initial monotherapy. RESULTS: Patients in the DAS-driven cohort had more active disease at baseline, but the prevalence of sustained drug-free remission was similar after DAS-driven (9.8%) and non-DAS-driven therapy (10.6%). Among patients with ACPA, drug-free remission was more frequently achieved after DAS-driven than after non-DAS-driven therapy (5.4 vs. 2.1%, OR = 2.68, 95% CI 0.97, 7.43). Absence of ACPA and short symptom duration were independent predictors for sustained drug-free remission in both cohorts. Initial treatment choice and inclusion period were not predictive. The sensitivity analysis yielded comparable results. CONCLUSION: Retrospectively comparing a DAS-driven to a non-DAS-driven therapy cohort, the occurrence and predictors of sustained drug-free remission were similar. The DAS-driven cohort had a more unfavourable prognosis. DAS-driven therapy may improve the chance of sustained drug-free remission in ACPA-positive patients with recent-onset RA.