Search

Item does not contain fulltext OBJECTIVE: Antirheumatic treatment is frequently not appropriately modified, according to American College of Rheumatology guidelines, in patients with active rheumatoid arthritis (RA) as defined by a Disease Activity Score in 28 joints (DAS28) score greater than 3.2. The objective of this study was to determine which factors most strongly influence patients' and rheumatologists' decisions to escalate care. METHODS: We administered a Maximum Difference Scaling survey to 106 rheumatologists and 213 patients with RA. The survey included 58 factors related to the decision to escalate care in RA. Participants answered 24 choice tasks. In each task, participants were asked to choose the most important factor from a set of 5. We used hierarchical Bayes modeling to generate the mean relative importance score (RIS) for each factor. RESULTS: For rheumatologists, the 5 most influential factors were number of swollen joints (mean +/- SD RIS 5.2 +/- 0.4), DAS28 score (mean +/- SD RIS 5.2 +/- 0.5), physician global assessment of disease activity (mean +/- SD RIS 5.2 +/- 0.6), worsening erosions over the last year (mean +/- SD RIS 5.2 +/- 0.5), and RA disease activity now compared to 3 months ago (mean +/- SD RIS 5.1 +/- 0.6). For patients, the 5 most important factors were current level of physical functioning (mean +/- SD RIS 4.3 +/- 1.1), motivation to get better (mean +/- SD RIS 3.5 +/- 1.4), trust in their rheumatologist (mean +/- SD RIS 3.5 +/- 1.6), satisfaction with current disease-modifying antirheumatic drugs (mean +/- SD RIS 3.4 +/- 1.4), and current number of painful joints (mean +/- SD RIS 3.4 +/- 1.4). CONCLUSION: Factors influencing the decision to escalate care differ between rheumatologists and patients. Better communication between patients and their physicians may improve treatment planning in RA patients with active disease.

Item does not contain fulltext OBJECTIVES: Evidence suggests that doxycycline might have disease-modifying properties in osteoarthritis. However, the clinically relevant question as to whether doxycycline also modifies symptoms in knee osteoarthritis is unanswered. The objective of this study was to investigate the effectiveness of doxycycline on pain and daily functioning in symptomatic knee osteoarthritis. METHODS: A 24-week, randomised, triple-blind, placebo controlled trial on the symptomatic effectiveness of doxycycline twice a day 100 mg in knee osteoarthritis patients according to the clinical and radiological American College of Rheumatology classification criteria. The primary endpoint was the difference in the proportion of participants in both study groups achieving a clinical response defined by the OMERACT-OARSI set of responder criteria. Secondary endpoints included pain, stiffness, daily functioning, patient global assessment, quality of life, osteoarthritis-related medication and side effects. RESULTS: 232 patients were randomly assigned. At study end, 31% of participants met the primary endpoint in both groups. Except for more adverse events in the doxycycline group, no differences were also found on the secondary endpoints. CONCLUSIONS: Doxycycline is not effective in reducing symptoms in knee osteoarthritis patients over a 24-week study period, but is associated with an increased risk of adverse events. Although a possible structure-modifying effect of doxycycline was previously suggested, this is not accompanied by symptom relief in the short and medium term. Dutch Trial Register no NTR1111.

BACKGROUND. Generalised osteoporosis is often described in patients with rheumatoid arthritis (RA). The aim of this study was to evaluate disease related determinants of bone mineral density (BMD) in patients with RA. METHODS. Subjects were selected from a group of 147 patients with recent onset RA. Disease activity and functional capacity were studied prospectively in this cohort. Activity of the disease was assessed once every three months by various parameters, and functional capacity was measured with a health assessment questionnaire once every six months. Ninety seven patients consented to participate in the study. Bone mineral density was assessed with dual energy x ray absorptiometry in the lumbar spine, in a combined region of interest in the hips, and in Ward's triangle. Multiple linear regression procedures were used to analyse the data. RESULTS. Duration of RA was negatively associated with BMD at all three sites of measurement. The mean erythrocyte sedimentation rate in the six months before BMD measurement was negatively associated with BMD in the hip and in Ward's triangle. Other parameters of disease activity were not related to BMD. The mean health assessment questionnaire score in the 18 months before BMD measurement was negatively associated with BMD in the combined hip region only. Bone mineral density tended to be decreased when patients were compared with a normal reference group, especially in the femoral regions of interest. CONCLUSIONS. It is concluded that BMD may be affected in patients with recent onset RA by disease dependent mechanisms. Several factors have been suggested elsewhere as determinants of BMD in RA. The results of this study show that disease duration, disease activity, and functional impairment may, independently of each other, contribute to bone loss, especially in the proximal femur.

Background The data on how to optimally retreat patients with RA with rituximab (RTX) have been limited so far. Objectives The aim of this analysis was to compare two common retreatment strategies: A fixed retreatment approach and retreatment when a flare occurs. Methods Pooled data from the Collaborating European Registries for Rituximab in RA (CERERRA) project were used. We identified RA patients who had received at least 2 retreatments (3 courses) with RTX and who had available information about the strategy for retreatment (according to the physician9s opinion). The two retreatment strategies were compared by applying an adjusted mixed model analysis with DAS28 improvement as the dependent variable. Results A total of 800 patients were retreated at least twice: 616 patients retreated because of a flare (442 at 1st and 174 at 2nd retreatment) and 184 receiving fixed retreatment (128 at 1st and 56 at 2nd retreatment). Baseline characteristics (incl. age, sex, seropositivity, disease duration, number of prior DMARDs and biologics) at first course of RTX did not differ significantly between the two groups. However, patients retreated on flare had, as expected, a significantly higher DAS28-ESR at the time of 1st retreatment (5.1±1.3 vs. 4.1±1.4, p The baseline (=start of each cycle) deltaDAS28 (compared to the DAS28 at the time of RTX start) for the two groups is shown in figure 1. Patients receiving fixed retreatment had a significantly higher (in absolute number) deltaDAS28 (p Conclusions A fixed RTX retreatment strategy in RA seems to be more effective than the retreatment “on-flare” strategy. Disclosure of Interest K. Chatzidionysiou: None declared, E. Lie: None declared, E. Nasonov: None declared, G. Lukina: None declared, M. Hetland: None declared, U. Tarp: None declared, K. Pavelka: None declared, C. Gabay: None declared, D. Nordstrom: None declared, H. Canhao: None declared, M. Tomsic: None declared, P. van Riel: None declared, J. Gomez-Reino: None declared, I. Ancuta: None declared, T. Kvien Grant/research support: research funding to the Diakonhjemmet Hospital from AbbVie, BMS, MSD/Schering-Plough, Pfizer/Wyeth, Roche and UCB, Consultant for: AbbVie, BMS, Celltrion, Eli Lilly, Hospira, MSD/Schering-Plough, Orion Pharma, Pfizer/Wyeth, Roche, UCB, R. van Vollenhoven: None declared DOI 10.1136/annrheumdis-2014-eular.2571

ObjectiveTo investigate the interplay between IL-32 and tumour necrosis factor alpha (TNFα) during the chronic inflammation of rheumatoid arthritis (RA) and to assess whether anti-TNFα treatment of RA patients modulates synovial IL-32 expression.MethodsInduction of IL-32γ by Pam3Cys, lipopolysaccharide, IL-1β or TNFα was investigated in human fibroblast-like synoviocytes (FLS). Stimulation of TNFα production by IL-32γ was studied by adenoviral overexpression of IL-32γ (AdIL-32γ) and lipopolysaccharide stimulation of THP1 cells. Silencing of endogenous IL-32 was employed to study cytokine regulation in FLS. AdIL-32γ followed by TNFα stimulation was performed in FLS to investigate cytokine induction. Immunohistochemistry was applied to study IL-32 expression in synovial biopsies from RA patients.ResultsTNFα potently induced IL-32γ expression in FLS. Increased TNFα, IL-1β, IL-6 and CXCL8 production was observed after IL-32γ overexpression and lipopolysaccharide stimulation of THP1 cells. TNFα stimulation of FLS after silencing IL-32γ resulted in diminished IL-6 and CXCL8 production, whereas IL-32γ overexpression resulted in enhanced IL-6 and CXCL8 levels. Remarkably, the mechanism through which IL-32γ overexpression induced TNFα, IL-1β and CXCL8 was by counteracting messenger RNA decay. Importantly, treatment of RA patients with anti-TNFα resulted in significant reduction of IL-32 protein in synovial tissue.ConclusionsTNFα is a potent inducer of endogenous IL-32 expression and IL-32 itself contributes to prolonged TNFα production, thus inducing an important auto-inflammatory loop. Treatment of RA patients with anti-TNFα antibodies diminished IL-32 expression in synovial tissue. The potent anti-inflammatory effect of TNFα blockade in RA patients may be partly due to the reduction of synovial IL-32 expression.

Item does not contain fulltext OBJECTIVES: We have developed an instrument that provides the physician structured information about medication use and patients' (non-)adherence. This study aimed to determine the effectiveness of this instrument on adherence and medication beliefs in outpatients with rheumatoid arthritis (RA). METHODS: In this within-subject controlled prospective cohort study, 50 outpatients were assessed during three consecutive visits to their rheumatologist. At these three points in time, patients' adherence, medication beliefs, satisfaction about information about medication, and physical functioning were measured using validated self-report questionnaires. An intervention was scheduled during the second visit. The intervention consisted of a written report informing the physician about medication use and adherence to medication for each patient. The effectiveness of the intervention was evaluated by comparing outcome measures at the third visit to the same measures assessed prior to the intervention. RESULTS: At baseline, 30% of the patients (n = 50) were non-adherent. No significant changes in adherence were found between the first and second visit prior to the intervention. Adherence did not change after the intervention, compared to both of the adherence assessments prior to the intervention. Beliefs about medication, patients' satisfaction about information on medication, and physical functioning were also not significantly altered. CONCLUSION: Supplying the rheumatologist a report with information about medication use and adherence did not change adherence or patients' beliefs about medication. Further research is necessary to ensure effective support for adherence for individual patients with RA.

Contains fulltext : 88611.pdf (Publisher’s version ) (Closed access) OBJECTIVE: To evaluate the implementation of an intensive group exercise program in patients with rheumatoid arthritis (RA). METHODS: In 4 regions in The Netherlands, the Rheumatoid Arthritis Patients In Training exercise program was implemented on a limited scale. Evaluation using the RE-AIM model included: Reach, the proportion of the target population participating; Efficacy, effects on muscle strength, aerobic capacity, functional ability, and psychological functioning; Adoption, program adoption by stakeholders; Implementation, intervention quality (quality audits); and Maintenance, stakeholders' willingness to continue the program in the future. RESULTS: Twenty-five physical therapists from 14 practices were trained to provide the program. In total, 150 RA patients were recruited (by estimation, 2% of the target population). Of the 81 patients who had finished the 12-month intervention and were available for followup directly after the intervention, 62 patients provided clinical data. Muscle strength improved significantly, whereas aerobic capacity, functional ability, psychological functioning, and disease activity did not change. All 9 informed local patient organizations facilitated patient recruitment, and 35 of 51 rheumatologists involved referred one or more patients. All 10 approached health insurance companies funded the program for 12 months. The quality audits showed sufficient quality in 9 of 12 practices. All of the providers of the program were willing to provide the program in the future, whereas future reimbursement by health insurance companies remained unclear. CONCLUSION: The implementation of an intensive exercise program for RA patients on a limited scale can be considered successful regarding its reach, adoption, and implementation. The limited effectiveness and the limited data regarding maintenance warrant additional research. 01 juni 2010

Contains fulltext : 88657.pdf (Publisher’s version ) (Closed access) OBJECTIVE: To investigate mortality rates, causes of death, time trends in mortality, prognostic factors for mortality, and the relationship between disease activity and mortality over a 23-year period in an inception cohort of rheumatoid arthritis (RA) patients. METHODS: A prospective inception cohort of RA patients diagnosed between January 1985 and October 2007 was followed for up to 23 years after diagnosis. Excess mortality was analyzed by comparing the observed mortality in the RA cohort with the expected mortality based on the general population of The Netherlands, matched for age, sex, and calendar year. Period analysis was used to examine time trends in survival across calendar time. Prognostic factors for mortality and the influence of the time-varying Disease Activity Score in 28 joints (DAS28) on mortality were analyzed using multivariable Cox proportional hazards models. Causes of death were analyzed. RESULTS: Of the 1,049 patients in the cohort, 207 patients died. Differences in observed and expected mortality emerged after 10 years of followup. No improvement in survival was noted over calendar time. Significant baseline predictors of survival were sex, age, rheumatoid factor, disability, and comorbidity. Higher levels of DAS28 over time, adjusted for age, were associated with lower survival rates, more so in men (hazard ratio [HR] 1.58, 95% confidence interval [95% CI] 1.35-1.85) than in women (HR 1.21, 95% CI 1.04-1.42). CONCLUSION: Excess mortality in RA emerged after 10 years of disease duration. Absolute survival rates have not improved in the last 23 years and a trend toward a widening mortality gap between RA patients and the general population was visible. Higher disease activity levels contribute to premature death in RA patients. 01 maart 2010

There is no agreement as to which variable best mirrors disease activity in rheumatoid arthritis (RA) and no studies have been performed on the validity of disease activity variables. In this study the validity of 10 commonly used single variables and three composite indices was tested. All patients participated in a large follow up study in two clinics. The patients (n = 233) had classical or definite RA and a disease duration of less than one year at entry. The mean follow up time was 30 months; the follow up frequency was once every four weeks; 6011 records were used in the analysis. The validation criteria included correlations with the other variables (correlational validity), with the physical disability (criterion validity I), and with the radiographically determined damage of hands and feet (construct validity). The judgment of a group of rheumatologists in clinical practice was also used as a model of criterion validity (II). In this comparison the disease activity score and Mallya index showed the best validity. The best single variable was the number of swollen joints. The validity of most single variables was poor and these variables were not suitable as single endpoint measures in clinical trials.

The long-term use of second-line antirheumatic drugs was prospectively studied in a consecutive sample of 245 patients with recently diagnosed rheumatoid arthritis. A survival analysis was done in which treatment termination due to side-effects and to insufficient therapeutic effect were used as index causes. Cumulative drug 'survival' of aurothioglucose with treatment termination due to toxicity was significantly less compared with hydroxychloroquine. With regard to lack of efficacy as index cause, the administration time of hydroxychloroquine was significantly less than that of either aurothioglucose or sulphasalazine. Treatment termination due to lack of efficacy or combined insufficient therapeutic response and toxicity proved to be influenced by the initial disease activity and by the rank order of prescription.

We studied the influence of demographic, clinical, laboratory and genetic features and radiographic damage at onset on the outcome after 2 years in a prospective study of 147 patients with classical or definite RA with disease duration shorter than 1 year at entry. Outcome was determined by physical disability and by radiographic damage of hands and feet. By means of multiple regression analysis and discriminant analysis outcome was explained from variables at the start and during the first 6 months. No clinically relevant conclusions could be made for physical disability due to the low explained variance and small number of patients with bad physical disability. Radiographic damage after 2 years was predicted by high disease activity at the start (measured as erythrocyte sedimentation rate, C-reactive protein or Disease Activity Score) combined with DR4 or DR2 (as a prognostically favourable factor) and rheumatoid factor positivity. Radiographic damage could be better predicted if disease activity during the first 6 months was included. Absence or presence of progression of radiographic damage could be correctly predicted in 83% of the patients.

In order to classify gout without identification of monosodium urate (MSU) crystals, the American College of Rheumatology (ACR) formulated criteria in 1977.1 Of the 11 criteria, ≥6 have to be present to classify patients as having gout. The criteria were not developed with reference to MSU crystals, nor were they tested properly afterwards against this gold standard.1,–,3 However, as they are widely used and cited, testing their validity is critical to our ability to understand and treat gout.4 Many studies of gout include patients with ‘self-reported gout’, provided they fulfil the ACR criteria. Most self-reported diagnoses of gout will originate from a diagnosis made by a family physician as most patients presenting with acute gout are managed by them.2 5 This makes the primary care setting particularly relevant to test the ACR criteria. We designed a prospective study in a Dutch primary care population (∼200 000 subjects) to estimate the validity of the ACR criteria (patient recruitment 2004–6). We used identified MSU …

Contains fulltext : 80771.pdf (Publisher’s version ) (Closed access) Background: It has been suggested that the T-cell attracting and profibrotic chemokine CCL18 might play a role in the pathogenesis of systemic sclerosis (SSc). However, it is unclear what underlies the higher CCL18 levels in SSc. The aim of our study was to determine whether Toll-like receptor (TLR)-mediated stimulation of monocytes and dendritic cells (DCs) contributes to the higher levels of CCL18 in SSc. Methods: CCL18 levels were measured in 40 patients with SSc, primary Raynaud's phenomenon (RP) and healthy controls. The presence of TLR4 agonists in the circulation of SSc patients was investigated using TLR4 transgenic Chinese hamster ovary (CHO) cells. CCL18 and interleukin (IL)-10 secretion by monocytes/macrophages and monocyte-derived DCs (moDCs) was measured in the supernatant. The indirect effect of lipopolysaccharide (LPS)-stimulated moDCs on CCL18 secretion by monocytes/macrophages was investigated using a transwell system. Results: CCL18 levels were significantly elevated in SSc patients compared to patients with RP and healthy controls. SSc sera strongly induced CD25 expression on CHO cells genetically modified to express TLR4 but not on those expressing CD14 only. By contrast, serum from systemic lupus erythematosus (SLE) patients or healthy individuals did not have an effect. Neither monocytes/macrophages nor moDCs from SSc patients secreted higher levels of CCL18 compared to healthy controls. However, moDCs matured with the TLR4 ligand LPS from patients with SSc did secrete significantly higher amounts of IL-10 compared to those from healthy counterparts, which were IL-10 dependent. Conclusions: Our results suggest that elevated CCL18 levels in SSc are not caused by an intrinsically enhanced CCL18 secretion by monocytes/macrophages but are, at least partly, orchestrated by an enhanced IL-10 secretion by TLR4-stimulated DCs. These observations suggest a role for TLR4 ligands and DCs in the pathogenesis of SSc, a topic that warrants further investigation.

Contains fulltext : 80677.pdf (Publisher’s version ) (Closed access)

Objective:To investigate the influence of age on the effectiveness and tolerance of antitumour necrosis factor alpha (TNFα) therapy in rheumatoid arthritis (RA).Methods:730 patients of the Dutch Rheumatoid Arthritis Monitoring (DREAM) register were categorised into three groups according to their age at initiation of anti-TNFα therapy (65 years). Effectiveness of anti-TNFα therapy was primarily assessed by longitudinal analysis of the DAS28 during the first 12 months of treatment.Results:Improvement in disease activity and physical functioning was significantly less in elderly patients, correcting for relevant confounders. Elderly patients reached the EULAR categories of good responders and remission less often than younger patients. Drug survival, co-medication use and tolerance were comparable between the three age groups.Conclusion:Anti-TNFα therapy significantly reduced disease activity in all age groups of patients; however, it appeared less effective in elderly compared with younger RA patients.

Contains fulltext : 80642.pdf (Publisher’s version ) (Closed access) BACKGROUND: Tumour necrosis factor alpha (TNFalpha) neutralising antibody constructs are increasingly being used to treat rheumatoid arthritis (RA). OBJECTIVE: To determine potential differences in clinical responses, soluble drug levels and antibody formation between patients with RA receiving infliximab and adalimumab. METHODS: 69 patients with RA fulfilling the 1987 American College of Rheumatology criteria and about to start treatment with infliximab or adalimumab, were enrolled consecutively. All patients had active disease (28-joint count Disease Activity Score >3.2). Infliximab was given intravenously at 3 mg/kg at baseline and after 2, 6 and 14 weeks. Adalimumab was administered as 40 mg biweekly subcutaneously. Concomitant drug treatment was monitored and continued at constant dosage during the study. All serum samples were tested for infliximab/adalimumab levels and anti-infliximab/anti-adalimumab antibodies. RESULTS: 35 patients received infliximab, 34 received adalimumab. At 6 months, 15 (43%), 6 (17%) and 14 (40%) of the infliximab-treated patients fulfilled the EULAR criteria for good, moderate and non-responders, respectively, whereas the corresponding figures for adalimumab-treated patients were 16 (47%), 8 (24%) and 10 (29%). Clinical responses correlated with the levels of S-infliximab/adalimumab and the formation of anti-infliximab/anti-adalimumab antibodies. CONCLUSION: The clinical response to two anti-TNFalpha biological agents closely follows the trough drug levels and the presence of antibodies directed against the drugs. Further studies that focus on the underlying pathways leading to antibody formation are warranted to predict immunogenicity of these expensive biological agents and treatment outcomes.

To the Editor: Excess levels of TNF-α have been associated with certain autoimmune diseases. Prolonged administration of TNF-α antibody is used to effectively treat chronic inflammatory diseases such as rheumatic diseases and Crohn’s disease [1]. Anti-TNF-α drugs have clearly been shown to suppress disease activity in rheumatoid arthritis, and are a candidate therapy for immune intervention in type 1 diabetes. We report a case of a patient with juvenile idiopathic arthritis, who developed type 1 diabetes while receiving anti-TNF-α therapy.

Contains fulltext : 80638.pdf (Publisher’s version ) (Closed access) OBJECTIVE: Patients with rheumatoid arthritis (RA) are at greater risk of developing coronary heart disease than the general population. Systemic inflammation may contribute to this risk. This study investigated whether the level of disease activity is associated with the risk of developing myocardial infarction (MI) in patients with RA. METHODS: A case-control study was performed within a large prospective cohort of patients with RA. Cases were patients who developed their first MI after the diagnosis of RA, controls were patients with RA without MI. Cases and controls had similar RA disease duration. Traditional and disease-specific risk factors for MI were collected and a time-averaged disease activity score (DAS28) was calculated. The data were analysed using conditional logistic regression analysis. RESULTS: Cases of MI were significantly older, were more often male, with higher body mass index (BMI) and total cholesterol and lower high-density lipoprotein (HDL) serum levels than controls. Time-averaged disease activity was similar for cases and controls. The raw odds ratio for MI in patients with a "high" (>4.0) versus a "low" (

Objective.Adipocytokines, including leptin and adiponectin, may play an important role in the pathogenesis of rheumatoid arthritis (RA). We investigated the effects of longterm therapeutic tumor necrosis factor (TNF) blockade on adipocytokine concentrations in patients with RA.Methods.We studied 58 RA patients starting anti-TNF therapy and 58 healthy controls matched for age, sex, and body mass index (BMI). Fasting blood samples were drawn at baseline, 2 weeks, and 6 months after the start of anti-TNF therapy and serum levels of leptin and adiponectin were measured.Results.Patients with RA had increased adiponectin (p < 0.001) and similar leptin concentrations compared with the controls. Leptin concentrations were significantly higher in patients with high BMI (p < 0.001) and correlated positively with BMI at all timepoints (r > 0.75). In contrast, serum adiponectin tended to be higher in lean RA patients and did not correlate with BMI at any timepoint. There were no clear correlations between serum concentrations of adipocytokines and disease activity (Disease Activity Score 28). Short or longterm TNF blockade alone had no influence on circulating leptin and adiponectin concentrations. Patients treated with anti-TNF and concomitant corticosteroids on a stable basis showed a significant decrease in adiponectin levels after 6 months of therapy (p < 0.025).Conclusion.In patients with RA, chronic inflammation and its suppression during anti-TNF therapy have limited influence on plasma leptin concentrations, while significantly decreasing circulating adiponectin levels. Our findings question the suggested key role of inflammatory markers in regulating adipocytokine patterns in RA.

Background:Rheumatoid arthritis (RA) has been associated with an increased risk of infections, but the underlying pathways have not yet been identified. Toll-like receptors (TLR) probably play a role in synovial inflammation and may also contribute to the understanding of the role of infections in RA.Objectives:To investigate if the synovial expression of TLR3 and TLR7 in RA correlates with that of inflammatory cytokines, and to assess whether this has functional consequences for local cytokine production and to study potential links between the TLR3/7 axis and TLR4 in RA synovium.Methods:Immunohistochemistry was used to study the expression of TLR3, TLR7, interferon α (IFNα), tumour necrosis factor α (TNFα) and interleukins IL1β, IL12, IL17 and IL18 in RA synovium obtained by arthroscopy from 34 patients with RA. Monocytes, monocyte-derived dendritic cells (MoDCs) and RA synovial fibroblasts were stimulated via TLR3 (poly-IC) and TLR7 (loxorubin), after which IL1β, IL6 and TNFα were measured by Luminex bead array technology. Following preincubation with IFNα, IL1β and IL18, TLR3 and TLR7 mRNA expression was assessed using real-time PCR. Cytokine production after preincubation with IFNα and subsequent TLR stimulation was measured.Results:Synovial TLR3/7 expression was co-expressed with IFNα, IL1β and IL18, but not with TNFα, IL12 and IL17. Stimulation of TLR3/TLR7 on monocytes, MoDCs or synovial fibroblasts led to secretion of type I IFN but no biologically active IL1β or IL18 could be detected. Type I IFNα increased TLR3/7 mRNA expression whereas IL1β and IL18 did not. In spite of the fact that the mRNA level of TLR4 remained unchanged, IFNα enhanced the response to TLR4 agonists, a phenomenon that was clearly more marked in patients with RA.Conclusion:Type I interferons are highly co-expressed with TLR3/TLR7 in RA synovium. They enhance TLR3/TLR7-mediated cytokine production and also TLR4-mediated responses.

Contains fulltext : 71181.pdf (Publisher’s version ) (Closed access) OBJECTIVE: To make recommendations on how to report disease activity in clinical trials of rheumatoid arthritis (RA) endorsed by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR). METHODS: The project followed the EULAR standardised operating procedures, which use a three-step approach: (1) expert-based definition of relevant research questions (November 2006); (2) systematic literature search (November 2006 to May 2007); and (3) expert consensus on recommendations based on the literature search results (May 2007). In addition, since this is the first joint EULAR/ACR publication on recommendations, an extra step included a meeting with an ACR panel to approve the recommendations elaborated by the expert group (August 2007). RESULTS: Eleven relevant questions were identified for the literature search. Based on the evidence from the literature the expert panel recommended that each trial should report the following items: (1) disease activity response and disease activity states; (2) appropriate descriptive statistics of the baseline, the endpoints and change of the single variables included in the core set; (3) baseline disease activity levels (in general); (4) the percentage of patients achieving a low disease activity state and remission; (5) time to onset of the primary outcome; (6) sustainability of the primary outcome; (7) fatigue. CONCLUSIONS: These recommendations endorsed by EULAR and ACR will help harmonise the presentations of results from clinical trials. Adherence to these recommendations will provide the readership of clinical trials with more details of important outcomes, while the higher level of homogeneity may facilitate the comparison of outcomes across different trials and pooling of trial results, such as in meta-analyses.

Contains fulltext : 71274.pdf (Publisher’s version ) (Closed access) BACKGROUND: Systemic sclerosis (SSc) is a generalised autoimmune disease that causes morbidity and reduced life expectancy. Recently, evidence has been accumulating that immunosuppressive treatment in an early stage of the disease could improve survival, enhancing the need for early diagnosis and regular evaluation of organ involvement. Among others, a high-resolution computer tomography (HRCT) scan of the chest is performed for the assessment of pulmonary involvement in SSc. The objective of this study is to evaluate the predictive value of oesophageal dilatation on the HRCT scan for the diagnosis of SSc. METHODS: In total, 105 consecutive patients with scleroderma and 107 consecutive controls were included in this study. The first available scan for each patient and control was evaluated in random order and blinded for the diagnosis, by two independent radiologists, for oesophageal dilatation and interstitial lung disease. RESULTS: The positive predictive value of oesophageal dilatation for the diagnosis of SSc was 83%. No significant correlation of oesophageal dilatation and interstitial lung disease was found in the patients with scleroderma or controls. CONCLUSION: Oesophageal dilatation as visible on an HRCT scan of the chest may alert doctors to look for other signs or symptoms of SSc in these patients, enabling early diagnosis and specific treatment.

Contains fulltext : 71315_p41.pdf (Publisher’s version ) (Closed access) OBJECTIVES: To examine the psychometric properties of the self-administered Dutch Rheumatoid Arthritis Disease Activity Index (RADAI) and its short form (RADAI-SF) in patients with rheumatoid arthritis starting anti-tumour necrosis factor treatment. METHOD: Internal consistency was assessed with Cronbach's alpha. A confirmatory factor analysis (CFA) was carried out to test the single-factor structure. Construct validity was examined by correlating RADAI and RADAI-SF scores with Disease Activity Score in 28 joints (DAS28). Internal responsiveness was evaluated with the paired t test and the standardised response mean (SRM). External responsiveness was assessed with receiver operating characteristic analysis and the SRM, using the EULAR response criterion as external criterion. Change scores were correlated with changes in DAS28. RESULTS: At baseline and after 3 months' treatment, respectively, 191 and 171 patients completed the RADAI. The internal consistency of the RADAI and the RADAI-SF was satisfactory. CFAs confirmed the single-factor structure of both RADAI versions, but the short form provided the best model fit. Moderate correlations were found with the DAS28. SRMs of the RADAI and the RADAI-SF were, respectively, 0.76 and 0.80. Both versions had moderate accuracy to distinguish responders from non-responders. Changes scores were moderately correlated with DAS28 change scores. CONCLUSIONS: This study showed satisfactory psychometric properties of the Dutch version of the RADAI. Omission of the tender joint count (RADAI-SF) produced comparable results and is justified for research purposes. The tender joint count might be useful as additional clinical information in patient management.

Contains fulltext : 70760.pdf (Publisher’s version ) (Closed access) Aim: to evaluate the effects of adalimumab, etanercept and infliximab on disease activity, functional ability and quality of life and the medication costs in a naturalistic design. METHODS: All patients from the Dutch Rheumatoid Arthritis Monitoring (DREAM) register starting on tumour necrosis factor (TNF)alpha-blocking agents for the first time were monitored and assessed by trained research nurses every 3 months. The primary outcome was the Disease Activity Score (DAS28) course over the 12 months follow-up, analysed by linear mixed models. Secondary outcomes were the Health Assessment Questionnaire (HAQ), EuroQol five dimensions (EQ-5D) and the Short-Form 36 items (SF36) scores, and medication-related total costs. RESULTS: The DAS28 and SF-36 physical component scale decreased in all three medication groups over 12 months, but the decrease was larger for adalimumab and etanercept in comparison to infliximab (p

Contains fulltext : 70860.pdf (Publisher’s version ) (Closed access) OBJECTIVE: To illustrate a multidisciplinary group treatment for patients with fibromyalgia (FM) tailored to the patient's cognitive-behavioral pattern. METHOD: In a case-study design the tailored treatment approaches of two FM patients were described. One patient characterized by avoidance behavior (pain-avoidance pattern) participated in a group treatment aimed at changing pain-avoidance mechanisms and one patient characterized by continuing with activities in spite of pain (pain-persistence pattern) participated in a group treatment aimed at changing pain-persistence mechanisms. Assessments were made at baseline, post-treatment and at 6-months follow-up. RESULTS: Comparison of the pretest, post-test and follow-up scores on pain, functional disability, fatigue and psychological distress showed clinically significant improvements for both patients. CONCLUSION: The heterogeneity of patients regarding pain-related cognitive-behavioral mechanisms has been proposed to underlie varying treatment outcomes in FM patients. These results demonstrate that a group treatment tailored to pain-avoidance and pain-persistence patterns is feasible and can result in clinically significant changes for FM patients. PRACTICE IMPLICATIONS: FM offers a great challenge for clinicians due to the lack of effective treatment options. These case studies suggests that tailored CBT and exercise training directed at specific patient patterns can contribute to the improvement of the care of FM patients.

Contains fulltext : 70629.pdf (Publisher’s version ) (Closed access) OBJECTIVE: To assess the effect of a functional polymorphism (676T>G, M196R) in the tumour necrosis factor receptor super family 1b (TNFSF1b) gene on disease activity, radiological joint damage and response to infliximab and adalimumab treatment in patients with rheumatoid arthritis (RA). METHODS: Two cohorts of patients with RA were genotyped for the 676T>G polymorphism (rs1061622) in exon 6 of the TNFSF1b gene by restriction fragment length polymorphism analysis. One cohort (n = 234) included patients from the Dutch Rheumatoid Arthritis Monitoring register with detailed information on their response to anti-TNF therapy (infliximab and adalimumab), the other cohort comprised patients from a long-term observational early inception cohort at our centre (n = 248). RESULTS: The 676T>G polymorphism was not associated with anti-TNF response after 3 or 6 months of treatment. Linear regression analysis showed no significant difference in the progression of radiological joint damage during the first 3 and 6 years of disease between the three genotype groups (TT, TG and GG). Additionally, no difference in mean disease activity between genotypes was seen after 3 and 6 years of disease. CONCLUSION: Despite its demonstrated functionality, the 676T>G polymorphism in the TNFSF1b gene does not have a major role in either the response to anti-TNF therapy or in the disease severity or radiological progression in RA.

Contains fulltext : 69269.pdf (Publisher’s version ) (Closed access) OBJECTIVE: To use an evidence-based and consensus-based approach to elaborate recommendations on how to report disease activity in clinical trials of patients with rheumatoid arthritis (RA) endorsed by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR). METHODS: After an initial expert meeting, during which relevant research questions were identified, a systematic literature search was performed using Medline, Embase and the Cochrane Library as sources. To ensure literature retrieved was comprehensive, we emphasised search algorithms that were sensitive rather than specific. The results of the literature search were discussed by the expert panel, modified and expanded, and were used as the basis for the elaboration of the recommendation in the consensus process. Finally, an independent ACR panel approved these items with some minor modifications. RESULTS: The following pieces of evidence were obtained from the literature search: (1) timing and the sustaining of a response is relevant to achieve better outcomes; (2) composite disease activity indices have been used to define low disease activity and remission and these definitions have been validated as has the American Rheumatism Association (ARA) remission criteria. The "patient-reported symptom state" (PASS) is not yet well validated; (3) evidence was obtained to identify those measures, scales and patient-reported instruments, for which there is a documented association with relevant outcomes; (4) baseline disease activity is associated with disease activity levels at the end of follow-up; and (5) there was not sufficient evidence relating the added benefit of MRI or ultrasound over clinical assessments. Most data stemmed from observational studies rather than clinical trials and literature review was supplemented by input from experts. The results served as the basis for the elaboration of the seven recommendations by the experts. CONCLUSIONS: The approach based on scientific evidence from the literature as well as on expert input provided sufficient information to derive recommendations on reporting disease activity in RA clinical trials. The methodology, results and conclusions of this project were endorsed by EULAR and the ACR.

To measure health status in Dutch rheumatoid arthritis patients, we have translated and revised the Health Assessment Questionnaire (HAQ) and added questions about psychosocial status from the Arthritis Impact Measurement Scales (AIMS). The resultant questionnaire turned out to be reproducible and valid. In a double-blind trial comparing Hydroxychloroquine and Sulphasalazine, after 48 weeks the Physical Disability score showed a significant difference in favour of the Sulphasalazine group, reflecting the smaller deterioration in radiographic damage in this group. Thus the Physical Disability part of the questionnaire is sensitive to difference between two slow-acting anti-rheumatic drugs.

In the last decade it became apparent that patients with rheumatoid arthritis (RA) have an increased risk of cardiovascular disease (CVD) leading to an excess mortality of approximately 25%.1–3 Nowadays a substantial body of evidence indicates that atherosclerosis shares many features with inflammatory disease, such as RA, and that the involved inflammatory mediators are likely to be similar. More recently, evidence has emerged for the involvement of macrophage migration inhibitory factor (MIF) both in RA and atherosclerosis suggesting that MIF might form the link between RA and the increased incidence of CVD in this condition. Two known single nucleotide polymorphisms in the MIF gene have been …

Contains fulltext : 53447.pdf (Publisher’s version ) (Closed access) BACKGROUND: Physicians are frequently confronted with patients reporting severe itch and pain. Particularly in patients suffering from persistent itch and pain, central and peripheral sensitization processes are assumed to be involved in the long-term maintenance and aggravation of the symptoms. The present study explores generalized and symptom-specific sensitization processes in patients suffering from persistent itch and pain. Specifically, it examines whether patients with chronic itch and pain are more sensitive to somatosensory stimuli (generalized sensitization) and simultaneously perceive somatosensory stimuli as a symptom of their main physical complaint, e.g. pain in chronic pain patients (symptom-specific sensitization). METHODS: Thresholds for different mechanical and electrical sensory stimuli of Quantitative Sensory Testing were determined in 15 female patients suffering from chronic itch associated with atopic dermatitis, 15 female chronic pain patients diagnosed with fibromyalgia, and 19 female healthy controls. Intensities of itch and pain sensations were rated on a visual analogue scale. RESULTS: As expected, the patient groups had significantly lower tolerance thresholds for the somatosensory stimuli applied than the healthy controls, supporting generalized sensitization. Moreover, patients with chronic itch consistently reported more itch, while patients with chronic pain partly reported more pain in response to analogous somatosensory stimuli than the healthy controls and the other patient group, indicating symptom-specific sensitization. CONCLUSION: The present study provides preliminary support that both generalized and symptom-specific sensitization processes play a role in the regulation and processing of somatosensory stimulation of patients with chronic itch and pain.

Contains fulltext : 51458.pdf (Publisher’s version ) (Closed access) BACKGROUND: Randomised controlled trials (RCTs) evaluating the efficacy of antagonists to tumour necrosis factor alpha (TNFalpha) showed high response percentages in the groups treated with active drugs. OBJECTIVE: To compare the efficacy of anti-TNF treatments for rheumatoid arthritis (RA) patients in RCTs and in daily clinical practice, with an emphasis on the efficacy for patients eligible and not eligible for RCTs of anti-TNF treatments. METHODS: First, randomised placebo-controlled trials written in English for etanercept, infliximab and adalimumab for patients with RA were selected by a systematic review. Second, the DREAM (Dutch Rheumatoid Arthritis Monitoring) register with patients starting for the first time on one of the TNF-blocking agents was used. Patient characteristics, doses of medication and co-medication as well as the ACR20 response percentages were compared between RCTs and DREAM data, stratified for trial eligibility. RESULTS: In 10 of 11 comparisons, the ACR20 response percentages were lower in daily clinical practice than in the RCT active drug group, which was significant in five of 11 comparisons. Only 34-79% of DREAM patients fulfilled the selection criteria for disease activity in the several RCTs examined. DREAM patients eligible for RCTs had higher response percentages than ineligible DREAM patients. ACR20 response percentages of eligible DREAM patients were comparable with the ACR20 response percentages of the RCT active drug group in 10 of 11 comparisons. CONCLUSION: The efficacy of TNF-blocking agents in RCTs exceeded the efficacy of these drugs in clinical practice. However, in clinical practice more patients with lower disease activity were treated with TNF-blocking agents compared with those treated in RCTs. For daily practice patients who were eligible for RCTs, responses were more similar to responses reached in RCTs.

Contains fulltext : 53567.pdf (Publisher’s version ) (Closed access) The goals for the management of established rheumatoid arthritis (RA) differ slightly from the goals for the management of early RA. In established RA, in most cases, joint damage will be present, therefore the main goals are aimed at keeping the disease activity as low as possible to prevent joint damage progression. Furthermore, patients with RA have a reduced life expectancy, mainly due to co-morbid conditions such as cardiovascular disease. As in early disease, pharmacotherapy is the cornerstone of the management of patients with established RA. In this article we will discuss the characteristic manifestations of established RA, the pharmacological treatment strategies available for reaching the management goals of established RA, the role of prognostic factors and the measurements available for evaluating the outcomes of the management of individual patients with established RA in daily clinical practice.

Contains fulltext : 51750.pdf (Publisher’s version ) (Closed access) OBJECTIVE: To assess the accuracy of echocardiography for predicting pulmonary arterial hypertension (PAH) in a cohort of patients with systemic sclerosis and other connective tissue diseases, and to evaluate whether addition of the right ventricular (RV) Tei-index contributes to the non-invasive diagnosis of PAH in this patient group. PATIENTS AND METHODS: Ninety-eight patients with systemic sclerosis and other connective tissue diseases in whom an echocardiography was performed in the period from January 1st 2004 to July 1st 2005 were included. Echocardiographic systolic pulmonary arterial pressure (PAP), end-diastolic PAP and RV Tei-index were calculated. In cases with a high suspicion of PAH right heart catheterization was performed and systolic, diastolic and mean PAP as well as pulmonary wedge pressure, cardiac output and pulmonary vascular resistance were obtained. These results were compared to the echocardiographic measurements. RESULTS: The average RV Tei-index of our patients was substantially above normal values. In 35 (36%) patients a right heart catheterization was performed and PAH was confirmed in 28 patients. In 6 of 7 patients without PAH, the RV Tei-index was below the upper limit of normal. A significant correlation was found between the RV Tei-index and the catheterization parameters such as systolic PAP, diastolic PAP and mean PAP. CONCLUSION: The accuracy of echocardiography for the detection of PAH increases when the echocardiographic systolic PAP is combined with an elevated RV Tei-index. As a result, by applying the Tei-index, the number of negative catheterizations can be minimized.

Background New treatment options and strategies have dramatically reduced the severity and impact of rheumatoid arthritis (RA) and especially early intensive combination therapy, aimed at achieving remission, has shown good clinical outcomes. The reason for early identification and treatment of RA is to control progression of the disease. Since there is no cure for RA, the current most important goal is to reach remission as soon as possible, which should be sustained during the course of the disease. Objectives Despite wide implementation of treat-to-target (T2T) strategies in RA, a proportion of patients still fail to achieve early remission. This study aimed to identify baseline predictors of reaching remission in Dutch patients with early RA following a T2T strategy. Methods Baseline demographic, clinical and patient-reported outcome measures and one-year follow-up data were used from patients with early RA included in the DREAM remission induction cohort II study. Survival analyses and simple and multivariable logistic regression analyses were used to examine remission rates and significant predictors of achieving remission. Results A total number of 137 patients was included. 77.2% of the patients reached remission at least once in 12 months follow-up, and median time to first remission was 17 weeks. None of the examined baseline variables were significantly associated with achieving remission within 1 year. Lower ESR (p=0.007), male gender (p=0.057), better physical health status (p=0.062) and fewer tender joints (p=0.175) were significantly or marginally associated with achieving remission within 17 weeks. In multivariable analysis, however, only ESR remained significantly predictive (p=0.023). Conclusions The results indicate that baseline characteristics were not predictive of early remission. Together with the high proportion of responders, this provides additional evidence for the general applicability of T2T strategies in patients with early RA. Disclosure of Interest None declared

Background Besides pain, patients with rheumatoid arthritis (RA) mention fatigue as the most important complaint. Many RA patients experience fatigue, which may be caused by their disease. However, many people in the general population are also fatigued; it is unclear whether fatigue indeed is more severe in RA patients than in the general population. Fatigue may be related to the level of physical activity (PA); while RA patients may be less physically active compared to the general population, it is useful to estimate the size of the “gap”. Objectives 1) to compare the level of PA and the level of fatigue between RA patients and the general Dutch population and 2) to investigate the relation between the level of PA and fatigue in both groups. Methods Data representative of the general Dutch population were obtained as part of the Nijmegen Biomedical Study (NBS) in 2012, a population-based survey among randomly selected inhabitants of the municipality of Nijmegen (n=3764). 740 RA patients across the Netherlands filled in an online survey in 2013 and 2014. Self-reported PA was assessed using the Short Questionnaire to Assess Health (SQUASH) Enhancing PA. This Dutch questionnaire contains questions about PA divided over four categories. Total amount of PA in minutes per week was calculated. Fatigue was assessed using the Dutch ‘Shortened fatigue questionnaire’ (SFQ), whereby a higher score indicates a more severe level of fatigue. Results RA patients on average had 1642±1167 (Mean ± SD) minutes of PA per week which was lower (p Conclusions In comparison with the general Dutch population, RA patients showed higher levels of fatigue and were less physically active; less PA was associated with a higher level of fatigue, and this association was more than twice as strong in RA patients compared with the general Dutch population. Disclosure of Interest None declared

Background Smoking is a negative predictor of response to antirheumatic therapy. Objectives To assess whether smoking influence the response to rituximab (RTX) in Rheumatoid Arthritis (RA). Methods Pooled data from the Collaborating European Registries for RTX in RA (CERERRA) were used. Patients who received at least 1 cycle with RTX were included. Smoking status was defined as smokers (current smokers) and non-smokers (never and ex-smokers). Analysis of co-variance (ANCOVA) was performed with DeltaDAS28 at 6 months as the dependent variable and smoking status as well as other baseline variables (age, sex, disease duration, number of prior biologic DMARDs) as covariates. Separate analyses were made for anti-CCP positive and negative patients. Results A total of 2274 patients were included - 1815 (80%) non-smokers and 459 (20%) smokers. 81% were female and 80% (out of 1199 patients with available anti-CCP) were anti-CCP positive. Smokers had shorter disease duration than non-smokers (median (IQR) 8 (4-13) years vs. 10 (5-16), p Smokers had less improvement in disease activity than non-smokers at 6 months (mean ± SD DeltaDAS28 -1.5±1.7 vs. -1.8±1.7, respectively, p=0.04). However, the difference was no longer significant after adjustment for baseline differences (p=0.40). When the analysis was stratified by anti-CCP status, smoking did not influence the response to therapy in the anti-CCP negative subset (p=0.39) but there was a trend in the anti-CCP positive subset (p=0.06, figure 1). For the anti-CCP negative patients, 67% of non-smokers and 69% of smokers achieved EULAR response (p=0.6), while in the anti-CCP positive the respective response rates were 76% among non-smokers and 70% among smokers (p=0.09). Conclusions Smoking was negatively associated with the response to rituximab therapy in RA patients who were anti-CCP positive. References Khan A. et al. Smoking, rheumatoid factor status and responses to rituximab. Ann Rheum Dis 2012;71:1587-1588 doi:10.1136/annrheumdis-2012-201758 Saevarsdottir S. et al. Patients with early rheumatoid arthritis who smoke are less likely to respond to treatment with methotrexate and tumor necrosis factor inhibitors: observations from the Epidemiological Investigation of Rheumatoid Arthritis and the Swedis Reumatology register cohorts. Arthritis Rheum 2011;63:26–36. Chatzidionysiou K. et al. Highest clinical effectiveness of rituximab in autoantibody-positive patients with rheumatoid arthritis and in those for whom no more than one previous TNF antagonist has failed. Pooled data from 10 European registries. Ann Rheum Dis 2011;70:1575–80. Disclosure of Interest K. Chatzidionysiou: None declared, E. Lie: None declared, E. Nasonov: None declared, G. Lukina: None declared, M. Hetland: None declared, E. Hauge: None declared, K. Pavelka Consultant for: MSD, AbbVie, Pfizer, Roche, BMS, C. Gabay Grant/research support from: Roche, Merck, Abbvie, Consultant for: Roche, Abbvie, Pfizer, BMS, Sanofi-Aventis, Merck, AB2 Bio, D. Nordstrom Consultant for: AbbVie, BMS, MSD, Pfizer, Roche, UCB, H. Canhao: None declared, M. Tomsic: None declared, P. van Riel: None declared, J. Gomez-Reino: None declared, I. Ancuta: None declared, T. Kvien: None declared, R. van Vollenhoven Grant/research support from: AbbVie, BMS, GSK, Pfizer, Roche, UCB, Consultant for: AbbVie, Biotest, BMS, GSK, Janssen, Lilly, Merck, Pfizer, Roche, UCB, Vertex, S. Saevarsdottir: None declared

Background Nowadays the focus is on tapering or stopping biological treatment in patients with rheumatoid arthritis (RA) because of the cost reduction. However, the use of methotrexate (MTX) can cause considerable burden for patients, therefore the quality of life of patients would increase if the MTX could be tapered or stopped. Objectives The objective of this study was: 1. to analyse if patients taper or stop MTX in daily practice while they are using Tumor Necrosis Factor inhibitor (TNFi) treatment and 2. the effect of taper or stop MTX on the effectiveness and the long term TNFi drug survival. Methods Data was obtained from the DREAM registry. Patients with RA started TNFi treatment in combination with MTX were included in this study. Drug survival of the TNFi was analysed using Cox proportional hazard model with taper or stop MTX as time-dependent covariate. Treatment effectiveness before and after taper or stop MTX was analysed using DAS28. Linear mixed models was used to analyse the difference of DAS28 over time (variable time) between taper and not taper (interaction term = no taper*time) and stop and not stop MTX. Analyses were corrected for possible confounders. Results Of the 1331 patients starting TNFi with MTX, 487 (36.6%) patients tapered their MTX and 177 of the 1331 (13.3%) stopped their MTX treatment. On average the DAS28 scores decrease after tapering (-0.39, -0.45) and after stopping MTX (-0.26, -0.06) at 6 and 12 month respectively. About 61% of the patients shows an improvement in DAS28 (DAS28 0.6. On average patients that taper or stop have both stable DAS28 scores over time, the same course over time was showed, compared to patients that do not taper or stop MTX (Interaction no taper*time: B=0.00; CI=-0.01:0.00; p=0.339 and interaction no stop*time: B=0.00; CI=-0.01:0.01; p=0.647 respectively). Moreover, the long term drug survival of TNFi is even better in patients tapering MTX and the same in patients stopping MTX, see Table. Conclusions In daily practice, patients with RA do taper or stop their MTX dose when using TNFi treatment. This does not seem to influence the average DAS28 over time or the long term TNFi drug survival. This indicates that the right/correct patients are chosen to taper or stop MTX treatment in daily practice which could increase the quality of life in these patients. Disclosure of Interest None declared

Background The effectiveness of TNF-inhibitors (TNFi) in the treatment of rheumatoid arthritis has been demonstrated in many studies [1]. However, little is known on stopping TNFi in patients with stable low disease activity and the subsequent likelihood of exacerbation of rheumatoid arthritis (RA). In addition, it is not clear whether TNFi can be restarted effectively and safely. Given the costs and risks [2], it is important to examine whether patients in stable low disease activity can effectively stop TNFi. Objectives To assess whether RA-patients in stable remission or low disease activity (DAS28 Methods Multicenter open-label randomized controlled trial. Patients diagnosed with RA according to the ACR 1987 criteria were included. Patients had been treated with a TNFi for at least 1 year and with stable dose DMARDs for at least 6 months. All included patients had low disease activity in the 6 months prior to inclusion, with at least 2 DAS28 scores Results In total 817 patients from 47 centers were included: 531 (65%) patients were randomized to the stop group and 286 (35%) to TNFi continuation. All included patients had low disease activity in the 6 months prior to inclusion, with at least 2 DAS28 scores Conclusions 59% of RA-patients with stable remission or low disease activity (DAS28 References Nam JL, Winthrop KL, van Vollenhoven RF, et al. Current evidence for the management of rheumatoid arthritis with biological disease-modifying antirheumatic drugs: a systematic literature review informing the EULAR recommendations for the management of RA. Ann Rheum Dis 2010;69:976–86. Ramiro S, Gaujoux-Viala C, Nam JL, et al. Safety of synthetic and biological DMARDs – a systematic literature review informing the 2013 update of the EULAR recommendations for management of rheumatoid arthritis. Ann Rheum Dis 2013; submitted. Disclosure of Interest None declared

Background A significant number of rheumatoid arthritis (RA) patients can reach low disease activity (LDA) by using TNF-inhibitors (TNF-i), but this therapy can cause serious side-effects and is expensive. Therefore it could be expedient to stop in case of LDA, especially if relapse can be predicted. Ultrasonography of joints seems to be a predictor in this respect in smaller studies. The Dutch POET (Potential Optimalisation of Expediency of TNF-i (TNF-inhibitor)) study, is a multicenter randomized prospective cohort study investigating if in patients with RA with LDA on TNF-i and conventional DMARD, the TNF-i can be stopped. Patients were randomized to continue or stop TNF-i. Part of this study is the POET-ultrasonography (US) study. Objectives To investigate whether US at the time of stopping TNF-i in RA patients with LDA can predict future flare. Methods Data of patients who stopped TNF-i in the POET study were used for this analysis. Participating patients had RA according to ACR 1987 criteria, >6 months a DAS28 one year next to a conventional DMARD, without dose change in the past six months. Nineteen trained ultrasonographers performed US at baseline of the study, using different US machines, of 20 joints (bilaterally: MCP 1-5 dorsal and volar, wrists and MTP 2-5 dorsal aspect). The joints were graded on grayscale (GS; 0-3) and power doppler (PD; 0-3). US signs of arthritis were defined as GS>1 and/or PD>0. Trial visits were performed every 3 months and when flare was suspected. Flare was defined as DAS28>3.2 and at least >0.6 increase compared to the DAS28 at inclusion. Cox regression was performed to compare TNF-i free LDA between patients with versus those without US signs of arthritis (figure). Results Nine months data were available for 248 patients. Twenty-one percent was lost to follow-up and censored at last observation. Higher age, longer disease duration, anti-CCP and IgM-RF positivity were all related to flare occurrence. Patients with US signs of arthritis in one or more joints had a greater risk of flare (HR 1.77; 95% CI of 1.16 to 2.70) and shorter relapse-free period compared to patients without US signs of arthritis (see figure). The table shows patient- and US-characteristics at inclusion for patients without flare within 9 months versus patients with flare. Conclusions On the group level, US can predict flare in RA patients with LDA in whom TNF-i is stopped. Disclosure of Interest F. Lamers-Karnebeek Grant/research support from: Abbvie, T. Jansen: None declared, P. van Riel: None declared, J. Luime: None declared, J. Jacobs: None declared

During the Symposium on Advances in Targeted Therapies two groups met to discuss issues regarding clinical trials in rheumatoid arthritis. This has been a most eventful time for rheumatology. In the past decade six biological response modifiers have been approved. There has been universal acceptance of earlier intervention to treat this disease and the success of combination therapies. And we have evidence that measuring disease activity quantitatively and adjusting drug therapy based on these measurements can improve the course of the disease, resulting in a better outcome for the patients with regard to, for instance, functional capacity and quality of life. However, despite the significant advances in the treatment of rheumatoid arthritis, remission still is generally not an achievable goal. The discussion during this meeting addressed issues regarding current trial design …

Contains fulltext : 52661.pdf (Publisher’s version ) (Closed access) OBJECTIVES: To observe the course of the disease activity in rheumatoid arthritis (RA) patients treated with the standard infliximab dosing regimen and to adjust treatment guided by the pattern of disease activity. METHODS: All RA patients starting infliximab treatment were included and observed for at least 37 weeks. At infusion 4 (week 14), European League Against Rheumatism response was assessed. In moderate responders the dose was unchanged and the disease activity was carefully observed. In case of stable disease activity, the dose was increased at infusion 5 (week 22). In case of a temporary response the interval was reduced. Paired t-testing was applied to the disease activity score with 28-joint counts (DAS28) at week 22 and study endpoint. RESULTS: A total of 76 patients were included. Response after 14 weeks: good 22 (29%) patients, moderate 26 (34%) patients, and non-response in 21 patients. Seven patients (9%) dropped out before week 14 due to adverse events (5) or patients' initiative (2). In patients with moderate response, the following disease course between infusion 4 and 5 was observed: improvement to good response 6, temporary response 6, stable disease activity 6, drop out 8. In moderate responders, interval reduction and dose increase resulted in a decrease in mean DAS28 from 5.1 to 3.6 [P = 0.005, mean interval 5.6 weeks, mean infliximab dose 4.8 mg/kg/8 week (endpoint)] and from 4.1 to 3.6 [P = 0.04, mean infliximab dose 7.3 mg/kg/8 week (endpoint)], respectively. CONCLUSION: Three different patterns of disease activity were observed in moderate responders after 14 weeks of infliximab treatment, i.e. further improvement, no change in disease activity or a temporary response. Both interval reduction and dose increase significantly reduced disease activity, however, with different mean infliximab dosages. In good responders the response was often sustained over follow-up, whereas non-responders showed modest or no improvement despite dose adjustments.

Contains fulltext : 50555.pdf (Publisher’s version ) (Closed access) BACKGROUND: Animal studies suggest that the anti-inflammatory effect of methotrexate (MTX) is mediated by increased adenosine concentrations. OBJECTIVE: To assess the effect of MTX on the vasodilator effects of adenosine and the nucleoside uptake inhibitor, dipyridamole, in humans in vivo as a marker for changes in adenosine kinetics. METHODS: Ten patients with active arthritis were treated with MTX (15 mg/week). Measurements were performed before and after 12 weeks of treatment. At these time points, the activity of adenosine deaminase was measured in isolated lymphocytes, and forearm blood flow (FBF) was determined by venous occlusion plethysmography during administration of adenosine and dipyridamole into the brachial artery. RESULTS: The Vmax of adenosine deaminase in lymphocytes was reduced by MTX treatment (p

Contains fulltext : 58079.pdf (Publisher’s version ) (Closed access) BACKGROUND: Tumour necrosis factor (TNF) is known to increase the concentrations of interleukin (IL) 6 and C reactive protein (CRP) and to induce proatherogenic changes in the lipid profile and may increase the cardiovascular risk of patients with rheumatoid arthritis (RA) and other inflammatory disorders. OBJECTIVE: To assess whether anti-TNF therapy modifies the cardiovascular risk profile in patients with RA. METHODS: The lipoprotein spectrum and the inflammation markers CRP and IL6 were investigated in 33 patients with RA treated with human anti-TNF monoclonal antibodies (D2E7, adalimumab, Humira) and 13 patients with RA given placebo, before and after 2 weeks' treatment. RESULTS: In the anti-TNF treated group, the mean (SD) concentrations of HDL-cholesterol were significantly higher after 2 weeks' treatment (0.86 (0.30) mmol/l v 0.98 (0.33) mmol/l, p

Contains fulltext : 47934.pdf (Publisher’s version ) (Closed access) OBJECTIVE: To evaluate the efficacy and safety of adding sulfasalazine to leflunomide treatment compared with switching to sulfasalazine alone in patients with RA with an inadequate response to leflunomide monotherapy. METHODS: Patients with active RA ((DAS28) >3.2) who were enrolled in the first open label phase of the RELIEF study received leflunomide for 24 weeks. Inadequate responders then entered the double blind phase and received a further 24 weeks' treatment with leflunomide (20 mg once daily) plus sulfasalazine (final dose 2 g once daily), or placebo plus sulfasalazine (dose as above). The primary efficacy variable was the DAS28 response rate, and secondary efficacy outcomes were ACR 20%, 50%, and 70% response rates. Adverse events, including standard laboratory tests, were recorded. RESULTS: 106 inadequate responders entered the double blind phase; 56 received leflunomide plus sulfasalazine, and 50 placebo plus sulfasalazine. In the intention to treat population, more patients receiving leflunomide plus sulfasalazine (25/56 (45%)) achieved a DAS28 response than those receiving placebo plus sulfasalazine (17/50 (34%)) (p = 0.179). In week 24 completers, more patients receiving leflunomide plus sulfasalazine (17/56 (30%)) were DAS28 responders than those receiving placebo plus sulfasalazine (10/50 (20%)) (p = 0.081). Comparable numbers in each group were ACR 20% responders; the ACR 50% response rate was significantly higher in the leflunomide plus sulfasalazine group (8.9%) than in the placebo plus sulfasalazine group (0%) (p = 0.038). The safety profiles of both groups were comparable. CONCLUSION: Patient numbers are small and firm conclusions cannot be reached, but a non-significant benefit is indicated for combining leflunomide with sulfasalazine compared with switching to sulfasalazine alone in patients inadequately responding to leflunomide.

Adult onset Still’s disease (AOSD) is an autoimmune disorder characterised by periodic high fever, arthritis, and typical evanescent rashes. Non-steroidal anti-inflammatory drugs (NSAIDs) are the preferred treatment. In severe cases several disease modifying antirheumatic drugs, thalidomide, and intravenous immunoglobulin have been used. More recently, successful treatment with tumour necrosis factor α (TNFα) blocking agents1,2 and interleukin (IL) 1 neutralisation3 has also been reported. Hypersensitivity to NSAIDs, often characterised by urticaria, angio-oedema, and asthma, has been well documented, and several studies indicate that anaphylactic reactions are related to the inhibition of cyclo-oxygenase-1 (COX-1) enzyme4–6 and that selective COX-2 inhibitors can be safe in these patients. Here we report a case of AOSD complicated by coexisting hypersensitivity …

Contains fulltext : 48404.pdf (Publisher’s version ) (Closed access) OBJECTIVE: To investigate the influence of previous and concomitant leflunomide on the efficacy and safety of infliximab therapy in rheumatoid arthritis (RA) and to compare it to infliximab in combination with other disease-modifying anti-rheumatic drugs. METHODS: RA patients starting infliximab therapy were prospectively followed from January 2000. Every 3 months data were collected regarding disease activity (DAS28), adverse events and treatment changes. In the primary analyses all patients were classified into a leflunomide group (LEF group) if they had used leflunomide during infliximab therapy or within 6 months prior to starting infliximab therapy, the latter because of the long half-life of leflunomide. All other patients were considered as controls (non-LEF group). Secondary drug survival analyses were performed with the LEF group consisting only of patients on active leflunomide at the start of infliximab (active LEF group). RESULTS: A total of 162 RA patients started infliximab therapy (57 in the LEF group, 105 in the non-LEF group). No statistically significant differences in baseline characteristics were observed between the groups. Maximum follow-up time was 46 months for both groups. No differences in drug survival, disease activity or adverse events were observed between the groups. In both groups an increase in patients positive for antinuclear antibodies (ANA) was seen. ANA positivity at start did not predict DAS28 or the occurrence of adverse events. Secondary drug survival analyses showed no differences between the active LEF group and the non-LEF group. CONCLUSION: The results indicate that the administration of infliximab after or simultaneously with leflunomide is safe and efficacious in RA patients.

Monitoring disease activity regularly is preferable to classification as remission at one point in time The goal of the management of rheumatoid arthritis (RA) is to suppress disease activity as much as possible, to prevent loss of function, and to prevent or control joint damage.1 As for most chronic diseases, cure—meaning complete disappearance of all signs and symptoms which persist after stopping treatment—occurs only seldomly. Therefore often the term “remission” is used to define a state which approaches cure as closely as possible. However, remission in RA is not clearly defined, and might, alternatively, be understood to be absence of disease activity, absence of measurable disease activity, or very low disease activity, probably without clinical consequences like progressive damage to the joints or functional loss.2 For the assessment of remission of disease activity in RA, disease activity is probably best regarded as a continuum, and remission can be seen as a state at the very end of it. “Disease activity is a continuum with remission a state at the end of it” As no “gold standard” exists for the measurement of disease activity, the Disease Activity Score (DAS) and DAS28 (28 joint count) were developed and validated in the 1990s.3,4 These composite scores express disease activity, ranging from 0 to 9. To facilitate the interpretation of these …

Contains fulltext : 48767.pdf (Publisher’s version ) (Closed access) BACKGROUND: Leptin regulates food intake and modulates immunity and inflammation. A positive feedback mechanism has been described between tumour necrosis factor (TNF) and leptin, and it has been suggested that leptin potentiates inflammation in patients with rheumatoid arthritis (RA). OBJECTIVE: To assess whether inflammation correlates with leptin concentrations in patients with RA, and whether anti-TNF treatment modulates leptin concentrations in these patients. METHODS: Leptin, IL6 and CRP were measured (at baseline and after 2 weeks of treatment) in the blood of 31 patients with RA starting either anti-TNF treatment or placebo, and in 18 healthy controls. RESULTS: In patients with RA, plasma leptin concentrations at baseline correlated inversely with the degree of inflammation as assessed by C reactive protein (CRP; r(s)(2) = 0.21, p

Background: Dendritic cells orchestrate pivotal immunological processes mediated by the production of cytokines and chemokines. Objective: To assess whether neutralisation of tumour necrosis factor α (TNFα) during maturation of dendritic cells affects their phenotype and behaviour, which might explain the beneficial effects of TNFα neutralisation in rheumatoid arthritis. Methods: Immature and fully matured dendritic cells were cultured from blood monocytes from patients with rheumatoid arthritis and healthy controls following standardised protocols. TNFα was neutralised by addition of the p55 soluble TNFα receptor, PEGsTNFRI. The effect of TNFα neutralisation on the phenotype (CD14, CD16, CD32, CD64, CD80, CD83, CD86, and MHC) of dendritic cells was investigated by flow cytometry. Expression of chemokines (CCL17, CCL18, CCL19, CCL22, CCL3, and CXCL8) and production of IL1β and IL6 during dendritic cell differentiation and maturation were examined. Results: Neutralisation of TNFα during the differentiation and maturation of dendritic cells did not result in an altered dendritic cell phenotype in the rheumatoid patients or the healthy controls. In contrast, the expression of CCL17, CCL18, CCL19, CCL22, CCL3, and CXCL8 by dendritic cells was significantly reduced when TNFα activity was inhibited during lipopolysaccharide triggered dendritic cell maturation. The production of IL1β and IL6 by mature dendritic cells was inhibited by PEGsTNFRI. Conclusions: Inhibition of TNFα activity during dendritic cell maturation leads to the development of semi-mature cells. These data suggest a novel pathway by which the neutralisation of TNFα might exert its therapeutic effects.