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1.  Adalimumab alone and in combination with disease‐modifying antirheumatic drugs for the treatment of rheumatoid arthritis in clinical practice: the Research in Active Rheumatoid Arthritis (ReAct) trial 
Annals of the Rheumatic Diseases  2007;66(6):732-739.
To evaluate the safety and effectiveness of adalimumab alone or in combination with standard disease‐modifying antirheumatic drugs (DMARDs) for the treatment of rheumatoid arthritis (RA).
Patients with active RA despite treatment with DMARDs or prior treatment with a tumour necrosis factor antagonist participated in a multicentre, open‐label clinical study of adalimumab 40 mg every other week for 12 weeks with an optional extension phase. Patients were allowed to continue with pre‐existing traditional DMARDs. Long‐term safety results are reported for all patients (4210 patient‐years (PYs) of adalimumab exposure). The observed effectiveness results at week 12 are reported using American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) response criteria.
Among the 6610 treated patients, adalimumab was generally well tolerated. Serious infections occurred in 3.1% of patients (5.5/100 PYs, including active tuberculosis, 0.5/100 PYs). Demyelinating disease (0.06%) and systemic lupus erythematosus (0.03%) were rare serious adverse events. The standardised incidence ratio of malignancy was 0.71 (95% CI 0.49 to 1.01). The standardised mortality ratio was 1.07 (95% CI 0.75 to 1.49). At week 12, 69% of patients achieved an ACR20 response, 83% a moderate, and 33% a good EULAR response. Adalimumab was effective in combination with a variety of DMARDs. The addition of adalimumab to antimalarials was comparably effective to the combination of adalimumab and methotrexate.
Considering the limitations of an open‐label study, adalimumab alone or in combination with standard DMARDs appeared to be well tolerated and effective in 6610 difficult‐to‐treat patients with active RA treated in clinical practice.
PMCID: PMC1954645  PMID: 17329305
adalimumab; rheumatoid arthritis; tumour necrosis factor; monoclonal antibody; antirheumatic agents
2.  Persistence of interleukin 7 activity and levels on tumour necrosis factor α blockade in patients with rheumatoid arthritis 
Annals of the Rheumatic Diseases  2006;66(5):664-669.
To identify the mechanism of interleukin (IL)7‐stimulated tumour necrosis factor α (TNFα) production and to determine the relationship between intra‐articular IL7 and TNFα expression levels in patients with rheumatoid arthritis (RA). In addition, the effect of TNFα blockade on IL7 activity and on IL7 levels was studied.
The effect of IL7 on isolated CD4 T cells and CD14 monocytes/macrophages was studied. IL7 and TNFα levels were measured in the synovial fluid of patients with RA. In RA synovial tissue, IL7 and TNFα expression was assessed in addition to IL1β, numbers of inflammatory cells and adhesion molecule expression. The extent to which TNFα blockade could prevent IL7‐induced lymphocyte responses was studied in vitro. In addition, regulation of serum IL7 levels on anti‐TNFα therapy (adalimumab) was studied.
IL7 induced cell contact‐dependent TNFα production by cocultures of T cells and monocytes, but not by T cells and monocytes cultured separately. IL7 and TNFα levels in RA synovial fluid and synovial tissue significantly correlated. IL7‐stimulated lymphocyte responses were not inhibited by TNFα blockade. Circulating IL7 levels were significantly reduced in patients who successfully responded to anti‐TNFα treatment. However, IL7 levels persisted in non‐responders.
The present data suggest that IL7 is an important inducer of T cell‐dependent TNFα production in RA joints. This may contribute to the correlation of intra‐articular IL7 and TNFα in these joints. Furthermore, the persistence of IL7‐induced inflammatory activity on TNFα blockade in vitro and persistence of IL7 levels and disease activity in anti‐TNFα non‐responders suggest that IL7 might additionally promote TNFα‐independent inflammation.
PMCID: PMC1954618  PMID: 17185327
4.  Patient benefit–risk in arthritis—a rheumatologist’s perspective 
Rheumatology (Oxford, England)  2010;49(Suppl 2):ii11-ii17.
There is a range of pharmacological options available to the rheumatologist for treating arthritis. Non-selective NSAIDs or Cox-2 selective inhibitors are widely prescribed to reduce inflammation and alleviate pain; however, they must be used with caution in individuals with an increased cardiovascular, renal or gastrointestinal (GI) risk. The potential cardiovascular risks of Cox-2 selective inhibitors came to light over a decade ago. The conflicting nature of the study data reflects some context dependency, but the evidence shows a varying degree of cardiovascular risk with both Cox-2 selective inhibitors and non-selective NSAIDs. This risk appears to be dose dependent, which may have important ramifications for arthritis patients who require long-term treatment with high doses of anti-inflammatory drugs. The renal effects of non-selective NSAIDs have been well characterized. An increased risk of adverse renal events was found with rofecoxib but not celecoxib, suggesting that this is not a class effect of Cox-2 selective inhibitors. Upper GI effects of non-selective NSAID treatment, ranging from abdominal pain to ulceration and bleeding are extensively documented. Concomitant prescription of a proton pump inhibitor can help in the upper GI tract, but probably not in the lower. Evidence suggests that Cox-2 selective inhibitors are better tolerated in the entire GI tract. More evidence is required, and a composite end-point is being evaluated. Appropriate treatment strategies are needed depending on the level of upper and lower GI risk. Rheumatologists must be vigilant in assessing benefit–risk when prescribing a Cox-2 selective inhibitor or non-selective NSAID and should choose appropriate agents for each individual patient.
PMCID: PMC2857791  PMID: 20407136
Gastrointestinal bleeding; Cox-2 selective inhibitors; NSAID; Celecoxib; Diclofenac; Ibuprofen; Cardiovascular risk; Renal risk; Ulcers; Proton pump inhibitors
5.  The cost effectiveness of behavioural graded activity in patients with osteoarthritis of hip and/or knee 
Annals of the Rheumatic Diseases  2006;66(2):215-221.
To evaluate whether exercise treatment based on behavioural graded activity comprising booster sessions is a cost‐effective treatment for patients with osteoarthritis of the hip and/or knee compared with usual care.
An economic evaluation from a societal perspective was carried out alongside a randomised trial involving 200 patients with osteoarthritis of the hip and/or knee. Outcome measures were pain, physical functioning, self‐perceived change and quality of life, assessed at baseline, 13, 39 and 65 weeks. Costs were measured using cost diaries for the entire follow‐up period of 65 weeks. Cost and effect differences were estimated using multilevel analysis. Uncertainty around the cost‐effectiveness ratios was estimated by bootstrapping and graphically represented on cost‐effectiveness planes.
97 patients received behavioural graded activity, and 103 patients received usual care. At 65 weeks, no differences were found between the two groups in improvement with respect to baseline on any of the outcome measures. The mean (95% confidence interval) difference in total costs between the groups was −€773 (−€2360 to €772)—that is, behavioural graded activity resulted in less cost but this difference was non‐significant. As effect differences were small, a large incremental cost‐effectiveness ratio of €51 385 per quality adjusted life year was found for graded activity versus usual care.
This study provides no evidence that behavioural graded activity is either more effective or less costly than usual care. Yielding similar results to usual care, behavioural graded activity seems an acceptable method for treating patients with osteoarthritis of the hip and/or knee.
PMCID: PMC1798485  PMID: 16880195
6.  Disease activity guided dose reduction and withdrawal of adalimumab or etanercept compared with usual care in rheumatoid arthritis: open label, randomised controlled, non-inferiority trial  
Objective To evaluate whether a disease activity guided strategy of dose reduction of two tumour necrosis factor (TNF) inhibitors, adalimumab or etanercept, is non-inferior in maintaining disease control in patients with rheumatoid arthritis compared with usual care.
Design Randomised controlled, open label, non-inferiority strategy trial.
Setting Two rheumatology outpatient clinics in the Netherlands, from December 2011 to May 2014.
Participants 180 patients with rheumatoid arthritis and low disease activity using adalimumab or etanercept; 121 allocated to the dose reduction strategy, 59 to usual care.
Interventions Disease activity guided dose reduction (advice to stepwise increase the injection interval every three months, until flare of disease activity or discontinuation) or usual care (no dose reduction advice). Flare was defined as increase in DAS28-CRP (a composite score measuring disease activity) greater than 1.2, or increase greater than 0.6 and current score of at least 3.2. In the case of flare, TNF inhibitor use was restarted or escalated.
Main outcome measures Difference in proportions of patients with major flare (DAS28-CRP based flare longer than three months) between the two groups at 18 months, compared against a non-inferiority margin of 20%. Secondary outcomes included TNF inhibitor use at study end, functioning, quality of life, radiographic progression, and adverse events.
Results Dose reduction of adalimumab or etanercept was non-inferior to usual care (proportion of patients with major flare at 18 months, 12% v 10%; difference 2%, 95% confidence interval −12% to 12%). In the dose reduction group, TNF inhibitor use could successfully be stopped in 20% (95% confidence interval 13% to 28%), the injection interval successfully increased in 43% (34% to 53%), but no dose reduction was possible in 37% (28% to 46%). Functional status, quality of life, relevant radiographic progression, and adverse events did not differ between the groups, although short lived flares (73% v 27%) and minimal radiographic progression (32% v 15%) were more frequent in dose reduction than usual care.
Conclusions A disease activity guided, dose reduction strategy of adalimumab or etanercept to treat rheumatoid arthritis is non-inferior to usual care with regard to major flaring, while resulting in the successful dose reduction or stopping in two thirds of patients.
Trial registration Dutch trial register (, NTR 3216.
PMCID: PMC4391970  PMID: 25858265
7.  T cell recognition of naturally presented epitopes of self-heat shock protein 70 
Cell Stress & Chaperones  2014;19(4):569-578.
Self-reactive T cells have shown to have a potential role as regulators of the immune system preventing or even suppressing autoimmunity. One of the most abundant proteins that can be eluted from human HLA molecules is heat shock protein 70 (HSP70). The aims of the current study are to identify HSP70 epitopes based on published HLA elution studies and to investigate whether T cells from healthy individuals may respond to such self-epitopes. A literature search and subsequent in silico binding prediction based on theoretical MHC binding motifs resulted in the identification of seven HSP70 epitopes. PBMCs of healthy controls proliferated after incubation with two of the seven peptides (H167 and H290). Furthermore H161, H290, and H443 induced CD69 expression or production of cytokines IFNγ or TNFα in healthy controls. The identification of these naturally presented epitopes and the response they elicit in the normal immune system make them potential candidates to study during inflammatory conditions as well as in autoimmune diseases.
Electronic supplementary material
The online version of this article (doi:10.1007/s12192-013-0484-1) contains supplementary material, which is available to authorized users.
PMCID: PMC4041940  PMID: 24425585
Heat shock protein 70; HSP70; Naturally processed T cell epitopes; Human HSP70 peptides; Autoreactive T cells
8.  EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update 
Annals of the Rheumatic Diseases  2013;73(3):492-509.
In this article, the 2010 European League against Rheumatism (EULAR) recommendations for the management of rheumatoid arthritis (RA) with synthetic and biological disease-modifying antirheumatic drugs (sDMARDs and bDMARDs, respectively) have been updated. The 2013 update has been developed by an international task force, which based its decisions mostly on evidence from three systematic literature reviews (one each on sDMARDs, including glucocorticoids, bDMARDs and safety aspects of DMARD therapy); treatment strategies were also covered by the searches. The evidence presented was discussed and summarised by the experts in the course of a consensus finding and voting process. Levels of evidence and grades of recommendations were derived and levels of agreement (strengths of recommendations) were determined. Fourteen recommendations were developed (instead of 15 in 2010). Some of the 2010 recommendations were deleted, and others were amended or split. The recommendations cover general aspects, such as attainment of remission or low disease activity using a treat-to-target approach, and the need for shared decision-making between rheumatologists and patients. The more specific items relate to starting DMARD therapy using a conventional sDMARD (csDMARD) strategy in combination with glucocorticoids, followed by the addition of a bDMARD or another csDMARD strategy (after stratification by presence or absence of adverse risk factors) if the treatment target is not reached within 6 months (or improvement not seen at 3 months). Tumour necrosis factor inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab, biosimilars), abatacept, tocilizumab and, under certain circumstances, rituximab are essentially considered to have similar efficacy and safety. If the first bDMARD strategy fails, any other bDMARD may be used. The recommendations also address tofacitinib as a targeted sDMARD (tsDMARD), which is recommended, where licensed, after use of at least one bDMARD. Biosimilars are also addressed. These recommendations are intended to inform rheumatologists, patients, national rheumatology societies and other stakeholders about EULAR's most recent consensus on the management of RA with sDMARDs, glucocorticoids and bDMARDs. They are based on evidence and expert opinion and intended to improve outcome in patients with RA.
PMCID: PMC3933074  PMID: 24161836
Rheumatoid Arthritis; DMARDs (synthetic); DMARDs (biologic); Treatment; Early Rheumatoid Arthritis
9.  Modulation of monocyte/macrophage function by human CD4+CD25+ regulatory T cells 
Human immunology  2005;66(3):222-230.
The suppressive effects of CD4+CD25+ regulatory T cells (Tregs) on T cells have been well documented. Here we investigated whether human CD4+CD25+ Tregs can inhibit the pro-inflammatory properties of monocytes/macrophages. Monocytes and T cells were isolated from peripheral blood of healthy volunteers by magnetic cell separation, and co-cultured for 40 hours. Monocytes were analyzed directly for cytokine production and phenotypic changes, or re-purified and used in T cell stimulation and LPS challenge assays. Co-culture with CD4+CD25+ Tregs induced minimal cytokine production in monocytes, whereas co-culture with CD4+CD25− T cells resulted in large amounts of pro-inflammatory (TNF-α, IFN-γ IL-6) and regulatory (IL-10) cytokines. Importantly, when these CD4+CD25+ Treg-treated monocytes were re-purified after co-culture and challenged with LPS, they were severely inhibited in their capacity to produce TNF-α and IL-6 compared to control-treated monocytes. In addition, monocytes that were pre-cultured with CD4+CD25+ Tregs displayed limited up-regulation of HLA class II, CD40 and CD80, and down-regulation of CD86 compared to control-treated monocytes. This altered phenotype had functional consequences, as shown by the reduction in T cell-stimulatory capacity of Treg-treated monocytes. Together these data demonstrate that CD4+CD25+ Tregs can exert direct suppressive effects on monocytes/macrophages, thereby affecting subsequent innate and adaptive immune responses.
PMCID: PMC3904343  PMID: 15784460
Suppression; antigen-presenting cell; rheumatoid arthritis
10.  Performance of a multi-biomarker score measuring rheumatoid arthritis disease activity in the CAMERA tight control study 
Annals of the Rheumatic Diseases  2012;71(10):1692-1697.
To evaluate the performance of individual biomarkers and a multi-biomarker disease activity (MBDA) score in the early rheumatoid arthritis (RA) patient population from the computer assisted management in early rheumatoid arthritis (CAMERA) study.
Twenty biomarkers were measured in the CAMERA cohort, in which patients were treated with either intensive or conventional methotrexate-based treatment strategies. The MBDA score was calculated using the concentrations of 12 biomarkers (SAA, IL-6, TNF-RI, VEGF-A, MMP-1, YKL-40, MMP-3, EGF, VCAM-1, leptin, resistin and CRP) according to a previously trained algorithm. The performance of the scores was evaluated relative to clinical disease activity assessments. Change in MBDA score over time was assessed by paired Wilcoxon rank sum test. Logistic regression was used to evaluate the ability of disease activity measures to predict radiographic progression.
The MBDA score had a significant correlation with the disease activity score based on 28 joints-C reactive protein (DAS28-CRP) (r=0.72; p<0.001) and an area under the receiver operating characteristic curve for distinguishing remission/low from moderate/high disease activity of 0.86 (p<0.001) using a DAS28-CRP cut-off of 2.7. In multivariate analysis the MBDA score, but not CRP, was an independent predictor of disease activity measures. Additionally, mean (SD) MBDA score decreased from 53 (18) at baseline to 39 (16) at 6 months in response to study therapy (p<0.0001). Neither MBDA score nor clinical variables were predictive of radiographic progression.
This multi-biomarker test performed well in the assessment of disease activity in RA patients in the CAMERA study. Upon further validation, this test could be used to complement currently available disease activity measures and improve patient care and outcomes.
PMCID: PMC3439649  PMID: 22596166
11.  Multinational evidence-based recommendations for pain management by pharmacotherapy in inflammatory arthritis: integrating systematic literature research and expert opinion of a broad panel of rheumatologists in the 3e Initiative 
Rheumatology (Oxford, England)  2012;51(8):1416-1425.
Objective. To develop evidence-based recommendations for pain management by pharmacotherapy in patients with inflammatory arthritis (IA).
Methods. A total of 453 rheumatologists from 17 countries participated in the 2010 3e (Evidence, Expertise, Exchange) Initiative. Using a formal voting process, 89 rheumatologists representing all 17 countries selected 10 clinical questions regarding the use of pain medications in IA. Bibliographic fellows undertook a systematic literature review for each question, using MEDLINE, EMBASE, Cochrane CENTRAL and 2008–09 European League Against Rheumatism (EULAR)/ACR abstracts. Relevant studies were retrieved for data extraction and quality assessment. Rheumatologists from each country used this evidence to develop a set of national recommendations. Multinational recommendations were then formulated and assessed for agreement and the potential impact on clinical practice.
Results. A total of 49 242 references were identified, from which 167 studies were included in the systematic reviews. One clinical question regarding different comorbidities was divided into two separate reviews, resulting in 11 recommendations in total. Oxford levels of evidence were applied to each recommendation. The recommendations related to the efficacy and safety of various analgesic medications, pain measurement scales and pain management in the pre-conception period, pregnancy and lactation. Finally, an algorithm for the pharmacological management of pain in IA was developed. Twenty per cent of rheumatologists reported that the algorithm would change their practice, and 75% felt the algorithm was in accordance with their current practice.
Conclusions. Eleven evidence-based recommendations on the management of pain by pharmacotherapy in IA were developed. They are supported by a large panel of rheumatologists from 17 countries, thus enhancing their utility in clinical practice.
PMCID: PMC3397467  PMID: 22447886
arthritis; evidence-based medicine; analgesics
12.  Tissue structure modification in knee osteoarthritis by use of joint distraction: an open 1-year pilot study 
Annals of the Rheumatic Diseases  2011;70(8):1441-1446.
Modification of joint tissue damage is challenging in late-stage osteoarthritis (OA). Few options are available for treating end-stage knee OA other than joint replacement.
To examine whether joint distraction can effectively modify knee joint tissue damage and has the potential to delay prosthesis surgery.
20 patients (<60 years) with tibiofemoral OA were treated surgically using joint distraction. Distraction (∼5 mm) was applied for 2 months using an external fixation frame. Tissue structure modification at 1 year of follow-up was evaluated radiographically (joint space width (JSW)), by MRI (segmentation of cartilage morphology) and by biochemical markers of collagen type II turnover, with operators blinded to time points. Clinical improvement was evaluated by Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and Visual Analogue Scale (VAS) pain score.
Radiography demonstrated an increase in mean and minimum JSW (2.7 to 3.6 mm and 1.0 to 1.9 mm; p<0.05 and <0.01). MRI revealed an increase in cartilage thickness (2.4 to 3.0 mm; p<0.001) and a decrease of denuded bone areas (22% to 5%; p<0.001). Collagen type II levels showed a trend towards increased synthesis (+103%; p<0.06) and decreased breakdown (−11%; p<0.08). The WOMAC index increased from 45 to 77 points, and VAS pain decreased from 73 to 31 mm (both p<0.001).
Joint distraction can induce tissue structure modification in knee OA and could result in clinical benefit. No current treatment is able to induce such changes. Larger, longer and randomised studies on joint distraction are warranted.
PMCID: PMC3128325  PMID: 21565898
13.  Optimal use of methotrexate: the advantages of tight control 
Annals of the Rheumatic Diseases  2007;66(11):1409-1410.
The CAMERA study shows that using methotrexate in a tight control setting might lead to considerable improvement in disease activity in early rheumatoid arthritisSee linked article p 1443
PMCID: PMC2111621  PMID: 17934080
14.  EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs 
Annals of the Rheumatic Diseases  2010;69(6):964-975.
Treatment of rheumatoid arthritis (RA) may differ among rheumatologists and currently, clear and consensual international recommendations on RA treatment are not available. In this paper recommendations for the treatment of RA with synthetic and biological disease-modifying antirheumatic drugs (DMARDs) and glucocorticoids (GCs) that also account for strategic algorithms and deal with economic aspects, are described. The recommendations are based on evidence from five systematic literature reviews (SLRs) performed for synthetic DMARDs, biological DMARDs, GCs, treatment strategies and economic issues. The SLR-derived evidence was discussed and summarised as an expert opinion in the course of a Delphi-like process. Levels of evidence, strength of recommendations and levels of agreement were derived. Fifteen recommendations were developed covering an area from general aspects such as remission/low disease activity as treatment aim via the preference for methotrexate monotherapy with or without GCs vis-à-vis combination of synthetic DMARDs to the use of biological agents mainly in patients for whom synthetic DMARDs and tumour necrosis factor inhibitors had failed. Cost effectiveness of the treatments was additionally examined. These recommendations are intended to inform rheumatologists, patients and other stakeholders about a European consensus on the management of RA with DMARDs and GCs as well as strategies to reach optimal outcomes of RA, based on evidence and expert opinion.
PMCID: PMC2935329  PMID: 20444750
15.  Evidence for treating rheumatoid arthritis to target: results of a systematic literature search 
Annals of the Rheumatic Diseases  2010;69(4):638-643.
To summarise existing evidence on a target oriented approach for rheumatoid arthritis (RA) treatment.
We conducted a systematic literature search including all clinical trials testing clinical, functional, or structural values of a targeted treatment approach. Our search covered Medline, Embase and Cochrane databases until December 2008 and also conference abstracts (2007, 2008).
The primary search yielded 5881 citations; after the selection process, 76 papers underwent detailed review. Of these, only seven strategic clinical trials were extracted: four studies randomised patients to routine or targeted treatment, two compared two different randomised targets and one compared targeted treatment to a historical control group. Five trials dealt with early RA patients. All identified studies showed significantly better clinical outcomes of targeted approaches than routine approaches. Disability was reported in two studies with no difference between groups. Four studies compared radiographic outcomes, two showing significant benefit of the targeted approach.
Only few studies employed randomised controlled settings to test the value of treatment to a specific target. However, they provided unanimous evidence for benefits of targeted approaches. Nevertheless, more data on radiographic and functional outcomes and on patients with established RA are needed.
PMCID: PMC3015093  PMID: 20237123
16.  Treating rheumatoid arthritis to target: recommendations of an international task force 
Annals of the Rheumatic Diseases  2010;69(4):631-637.
Aiming at therapeutic targets has reduced the risk of organ failure in many diseases such as diabetes or hypertension. Such targets have not been defined for rheumatoid arthritis (RA).
To develop recommendations for achieving optimal therapeutic outcomes in RA.
A task force of rheumatologists and a patient developed a set of recommendations on the basis of evidence derived from a systematic literature review and expert opinion; these were subsequently discussed, amended and voted upon by >60 experts from various regions of the world in a Delphi-like procedure. Levels of evidence, strength of recommendations and levels of agreement were derived.
The treat-to-target activity resulted in 10 recommendations. The treatment aim was defined as remission with low disease activity being an alternative goal in patients with long-standing disease. Regular follow-up (every 1–3 months during active disease) with appropriate therapeutic adaptation to reach the desired state within 3 to a maximum of 6 months was recommended. Follow-up examinations ought to employ composite measures of disease activity which include joint counts. Additional items provide further details for particular aspects of the disease. Levels of agreement were very high for many of these recommendations (≥9/10).
The 10 recommendations are supposed to inform patients, rheumatologists and other stakeholders about strategies to reach optimal outcomes of RA based on evidence and expert opinion.
PMCID: PMC3015099  PMID: 20215140

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