Rheumatoid Arthritis: Voskuyl AE

Voskuyl AE, Boers M. · No affiliation provided · J Rheumatol. · Pubmed #12734879 No free full text.

This publication has no abstract.

Voskuyl AE, Dijkmans BA. · VU University Medical Center, Amsterdam, The Netherlands. · Clin Exp Rheumatol. · Pubmed #17083761 No free full text.

Abstract: Complete remission, defined as the presence of clinical as well as radiographic remission, is the ultimate goal of treatment of rheumatoid arthritis (RA). Functional disability in patients with low disease activity is associated with joint inflammation and joint damage. Despite the methodologic problems of scoring radiographs, studies show that radiographic progression is an important outcome measure, and conventional radiography remains the best available method to assess it. Whether radiographic progression is entirely dependent on the presence of joint inflammation is a matter of debate; some evidence suggests that radiologic progression may continue in patients who appear clinically to be in remission. The potential availability of more effective drugs in the near future presents a need to further define and monitor progression of joint damage by more reliable methods. Better diagnosis of joint damage will assist in our quest to attain and document full remission in RA. Some newer techniques that provide direct assessments of metabolic activity in the inflamed joint appear to predict radiographic progression before it can be detected by conventional methods. Until these techniques are validated and assessed for predictive value, we would advocate that radiographic progression be added to existing criteria for clinical remission, in order to define remission in RA more comprehensively.

Nurmohamed MT, Voskuyl AE, van der Horst-Bruinsma IE, Dijkmans BA. · VU Medisch Centrum, afd. Reumatologie, 4A42, Postbus 7057, 1007 MB Amsterdam. · Ned Tijdschr Geneeskd. · Pubmed #16999275 No free full text.

Abstract: Cardiovascular disease is the leading cause of death in patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS) and systemic lupus erythematosus (SLE). In addition to mortality, cardiovascular morbidity is also markedly increased in these patients, compared with the general population. The increased cardiovascular risk can be explained only partially by an increased prevalence of classical risk factors for cardiovascular disease; it also appears to be related to inflammation. Prospective intervention trials aimed at the modification of cardiovascular risk factors are needed to determine the impact of cardiovascular risk reduction in patients with rheumatic disease. In addition to SLE, RA and AS should be acknowledged as new risk factors for cardiovascular disease.

Voskuyl AE. · Department of Rheumatology, 4-A-42, VU University Medical Center, POB 9057, 1007 MB Amsterdam, The Netherlands. · Rheumatology (Oxford). · Pubmed #16980723 links to  free full text

Abstract: Cardiovascular features in rheumatoid arthritis (RA) are common. Among those are the classical extra-articular features that not only include pericarditis, cardiomyopathy/myocarditis, cardiac amyloidosis, coronary vasculitis, arrhythmia and valve diseases, but also congestive heart failure and ischaemic heart disease which are found more frequently and are associated with an increased mortality compared with the general population. This overview discusses the epidemiological aspects of these cardiovascular diseases and their relevance for diagnosis and treatment of RA.

van Tuyl LH, Lems WF, Voskuyl AE, Kerstens PJ, Garnero P, Dijkmans BA, Boers M. · Department of Clinical Epidemiology & Biostatistics, VU University Medical Center, Amsterdam, The Netherlands. · Ann Rheum Dis. · Pubmed #18625629 No free full text.

Abstract: OBJECTIVE: To investigate the efficacy and feasibility of an intensive combination treatment in early rheumatoid arthritis (RA) combined with monitoring both disease activity and cartilage degradation. METHODS: In a pilot trial, 21 patients with active early RA (mean DAS28 5.3; mean disease duration 3 months) were treated with COBRA treatment comprising sulfasalazine, methotrexate and high-dose step-down prednisolone, intensified by adding hydroxychloroquine and continued low-dose prednisolone. In addition, based on measurements of disease activity or a marker of cartilage degradation (CTX-II), treatment adjustments were possible with methotrexate intensification after 8 or 21 weeks; and with infliximab after 21 weeks. RESULTS: Nineteen of 21 patients (90%) were in remission (DAS28 <2.6) after 40 weeks (8 weeks, 57%; 21 weeks, 76%). American College of Rheumatology (ACR) criteria, ACR20, 50, 70 and 90 improvements rates were 100%, 95%, 71% and 43% respectively. CTX-II excretion decreased by mean (SD) 347(292) ng/mmol creatinine, but only 50% of patients reduced their CTX-II excretion below the cut-off point. The two monitoring groups showed no significant difference in remission according to DAS score or CTX-II excretion, despite a trend towards more intensive treatment in the CTX-II group. Treatment intensification was feasible according to protocol. CONCLUSIONS: This small pilot study suggests that intensified and tightly controlled COBRA treatment is uniquely effective in early RA. TRIAL REGISTRATION NUMBER: ISRCTN96372677.

Vis M, Havaardsholm EA, Haugeberg G, Uhlig T, Voskuyl AE, van de Stadt RJ, Dijkmans BA, Woolf AD, Kvien TK, Lems WF. · Department of Rheumatology, VU University Medical Centre, Amsterdam, The Netherlands. · Ann Rheum Dis. · Pubmed #16606653 No free full text.

Abstract: OBJECTIVES: To examine whether treatment with anti-tumour necrosis factor (TNF) alpha prevents loss of bone mineral density (BMD) at the spine and hip (generalised) and in the hands (local) of patients with rheumatoid arthritis, and to study the changes in markers of bone metabolism, including receptor activator of the NFkappaB ligand (RANKL) and osteoprotegerin (OPG), during anti-TNF treatment. PATIENTS AND METHODS: 102 patients with active rheumatoid arthritis, who were treated with infliximab during 1 year, were included in this open cohort study. The BMD of the spine and hip (dual x ray absorptiometry) and hands dual x ray radiogrammetry was measured before the start of treatment and after 1 year. Changes in osteocalcin formation, beta-isomerised carboxy terminal telopeptide of type 1 collagen (beta-CTx, resorption), RANKL and OPG were determined at 0, 14, 30 and 46 weeks. RESULTS: The BMD of the spine and hip was unchanged during treatment with infliximab, whereas BMD of the hand decreased significantly by 0.8% (p<0.01). The BMD of the hip in patients with a good European League Against Rheumatism response showed a favourable change compared with patients not achieving such a response. Serum beta-CTx and RANKL were both considerably decreased compared with baseline at all time points. The decrease in beta-CTx was associated with the decrease in Disease Activity Score of 28 joints and C reactive protein during the 0-14 weeks interval. CONCLUSION: In patients with rheumatoid arthritis treated with infliximab, spine and hip bone loss is arrested, whereas metacarpal cortical hand bone loss is not stopped. The outcome of the study also supports a relationship between clinical response, in terms of reduced inflammatory activity, and changes in bone loss of the spine, hip and hands.

van Tuyl LH, Plass AM, Lems WF, Voskuyl AE, Kerstens PJ, Dijkmans BA, Boers M. · Department of Rheumatology, EMGO Institute, and the Department of Epidemiology and Biostatistics, VU University Medical Center, 1081 HV Amsterdam, The Netherlands. · J Rheumatol. · Pubmed #19487259 No free full text.

Abstract: OBJECTIVE: COBRA combination therapy is well known and has uncontested efficacy in the treatment of rheumatoid arthritis (RA). However, it is infrequently applied in Dutch clinical practice. Based on qualitative research on opinions of physicians and patients towards COBRA therapy, our study describes the development and pilot testing of an implementation package to facilitate prescription and use of COBRA therapy in early RA. METHODS: The implementation package was developed to address specific barriers towards prescription of COBRA therapy and comprised informational handouts (an information booklet and leaflet for patients), preprinted prescription orders, and background information on COBRA therapy for the rheumatologists. Twenty-two rheumatologists agreed to participate, including the arthritis nurse where available. Rheumatologists, nurses, and patients were asked to record their experience. All Dutch arthritis nurses were invited to an educational session on COBRA therapy. RESULTS: Sixteen rheumatologists accompanied by 10 arthritis nurses used the material to prescribe COBRA therapy to a total of 27 patients. Rheumatologists and nurses both gave high marks to the supplied materials. Eighty-eight percent of rheumatologists reported that the material sped up the prescription process, and 65% indicated they would prescribe COBRA therapy more frequently if these materials were available routinely. Patients expressed great satisfaction with the information handouts, rating it 2.8 (standard deviation 0.5) on a scale of -3 (very negative) to +3 (very positive). Most patients (89%) planned to keep the information booklet as a reference and 70% used it as a tool to remember the correct intake of medication. The attitude and perceived capability of nurses towards the guidance of patients with RA receiving COBRA therapy was improved through a brief educational intervention. CONCLUSION: Rheumatologists, patients, and arthritis nurses all highly appreciated the implementation package and indicated that its availability would increase uptake of COBRA therapy.

Levitus M, Pelliccia A, van de Stadt RJ, Voskuyl AE, Bouman AA. · Department of Clinical Chemistry, VU University Medical Center, De Boelelaan 1118, 1081 HV Amsterdam, The Netherlands. · Clin Rheumatol. · Pubmed #19165556 No free full text.

Abstract: Treatment of rheumatoid arthritis (RA) is monitored with the disease activity score (DAS28), for which the erythrocyte sedimentation rate (ESR) is needed. Apart from the original gold standard method, other methods like the Alifax Test-1TH apparatus are widely used in laboratory worldwide. We compared ESR values obtained by the Alifax Test-1Th apparatus and the gold standard method for 218 RA patients. We found a good correlation (r=0.87) between the Alifax Test-1TH results and the gold standard method. A good correlation (r=0.96) was also found for the DAS28 results obtained with both methods. The number of patients that were misclassified when the Alifax Test-1TH is used is reasonable for both the ESR (14.7%) and the DAS28 (10.6%). These results suggest that it may be useful to determine the ESR by the Alifax Test-1TH, with a DAS28 misclassification in less than 11% of the patients.

Kropholler MA, Boellaard R, Elzinga EH, van der Laken CJ, Maruyama K, Kloet RW, Voskuyl AE, Dijkmans BA, Lammertsma AA. · Department of Nuclear Medicine & PET Research, VU University Medical Centre, Amsterdam, The Netherlands. · Eur J Nucl Med Mol Imaging. · Pubmed #19043704 No free full text.

Abstract: PURPOSE: Rheumatoid arthritis (RA) involves migration of macrophages into inflamed areas. (R)-[(11)C]PK11195 binds to peripheral benzodiazepine receptors, expressed on macrophages, and may be used to quantify inflammation using positron emission tomography (PET). This study evaluated methods for the quantification of (R)-[(11)C]PK11195 binding in the knee joints of RA patients. METHODS: Data from six patients with RA were analysed. Dynamic PET scans were acquired in 3-D mode following (R)-[(11)C]PK11195 injection. During scanning arterial radioactivity concentrations were measured to determine the plasma (R)-[(11)C]PK11195 concentrations. Data were analysed using irreversible and reversible one-tissue and two-tissue compartment models and input functions with various types of metabolite correction. Model preferences according to the Akaike information criterion (AIC) and correlations between measures were evaluated. Correlations between distribution volume (V(d)) and standardized uptake values (SUV) were evaluated. RESULTS: AIC indicated optimal performance for a one-tissue reversible compartment model including blood volume. High correlations were observed between V(d) obtained using different input functions (R(2)=0.80-1.00) and between V(d) obtained with one- and two-tissue reversible compartment models (R(2)=0.75-0.94). A high correlation was observed between optimal V(d) and SUV after injection (R(2)=0.73). CONCLUSION: (R)-[(11)C]PK11195 kinetics in the knee were best described by a reversible single-tissue compartment model including blood volume. Applying metabolite corrections did not increase sensitivity. Due to the high correlation with V(d), SUV is a practical alternative for clinical use.

van der Laken CJ, Elzinga EH, Kropholler MA, Molthoff CF, van der Heijden JW, Maruyama K, Boellaard R, Dijkmans BA, Lammertsma AA, Voskuyl AE. · VU University Medical Center, Amsterdam, The Netherlands. · Arthritis Rheum. · Pubmed #18975347 No free full text.

Abstract: OBJECTIVE: Noninvasive imaging by positron emission tomography (PET) of macrophages in inflamed joints of patients with rheumatoid arthritis (RA) may allow early detection of disease activity. We undertook this study to investigate whether rheumatoid synovitis can be visualized by PET using the tracer 11C-(R)-PK11195, which binds to peripheral benzodiazepine receptors (PBRs) on macrophages. METHODS: Knee joints of 11 RA patients with active arthritis of at least 1 knee joint were imaged with 11C-(R)-PK11195 PET. Tissue uptake of 11C-(R)-PK11195 was quantified. PET was followed by arthroscopy of the most inflamed knee joint of each RA patient. Synovial tissue samples were subjected to immunohistochemical staining. RESULTS: 11C-(R)-PK11195 uptake on the PET scans was significantly higher in severely inflamed joints than in joints with moderate or mild signs of inflammation. In addition, tracer uptake in contralateral uninflamed knee joints of RA patients was significantly higher than in uninflamed joints of control patients without inflammatory joint disease, suggesting the presence of subclinical disease activity. PET tracer uptake in joints correlated significantly with PBR staining in the sublining of synovial tissue. PBR staining correlated significantly with CD68 staining of macrophages. CONCLUSION: 11C-(R)-PK11195 PET imaging allows noninvasive in vivo imaging of macrophages in rheumatoid synovitis and possibly even in subclinical synovitis. Noninvasive visualization of macrophages may be useful both for detecting early synovitis and for monitoring synovitis activity during treatment.

van der Laken CJ, Voskuyl AE, Roos JC, Stigter van Walsum M, de Groot ER, Wolbink GJ, Dijkmans BA, Aarden LA. · Afd. Reumatologie, VU Medisch Centrum, Amsterdam. · Ned Tijdschr Geneeskd. · Pubmed #18714521 No free full text.

Abstract: OBJECTIVE: To investigate the in vivo mechanism of non-responding to infliximab treatment of patients with rheumatoid arthritis (RA) and the role of anti-infliximab antibodies by using radiolabeled infliximab. DESIGN: Descriptive and comparative study. METHOD: Two responding and two non-responding RA patients were infused with radiolabeled infliximab. Subsequently imaging investigations and serum analysis were performed at set times. RESULTS: The scintigrams showed that the labelled infliximab was mainly present in the blood until 24 h after infusion. There was a trend of faster blood clearance and higher liver and spleen uptake of 99mTc-infliximab in one non-responding patient. Labelled infliximab was taken up by inflamed joints. The anti-infliximab level was high (1008 and 1641 U/ml) in the non-responders and low or not detectable in the responders. Sucrose gradients of serum revealed antibody complexes in both non-responders. Various sizes of antibody complexes, including very large ones, were observed in one non-responder who developed a serious infusion reaction. CONCLUSION: Infliximab-anti-infliximab immune complexes were found to form in RA non-responders due to the presence of significant quantities of anti-infliximab. This finding may partly explain the failure of the infliximab treatment.

van Tuyl LH, Plass AM, Lems WF, Voskuyl AE, Kerstens PJ, Dijkmans BA, Boers M. · Department of Clinical Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, The Netherlands. · Rheumatology (Oxford). · Pubmed #18710900 No free full text.

Abstract: OBJECTIVE: The COBRA therapy (combination therapy in early rheumatoid arthritis) has proven to be an effective treatment for early RA, but is rarely prescribed. A survey showed reluctance of Dutch reumatologists to apply COBRA therapy in early RA. The present qualitative study was carried out to further explore the reservation of Dutch rheumatologists towards prescribing COBRA therapy and include patients' view on (components of) COBRA therapy. METHODS: Two focus group discussions were undertaken for rheumatologists (n(1) = 8, n(2) = 7) and two for patients (n(1) = 4, n(2) = 8). In addition, in-depth interviews were conducted with 11 rheumatologists and 1 patient. These were taped and transcribed. Two independent researchers identified themes and these were discussed with three other researchers. RESULTS: Rheumatologists were positive concerning effectiveness of COBRA therapy, but highly concerned about their patients' possible negative reaction to the large amount of pills to be prescribed. In addition, rheumatologists perceived lack of time explaining and prescribing COBRA therapy and felt uncomfortable prescribing high doses of prednisolone. Patients were positive about an aggressive combination therapy such as COBRA, and they had no qualms taking many pills if this could improve their prognosis. Patients associated prednisolone with negative side-effects, but were also aware of the benefits and the need of prednisolone in rough times. A decrease in the amount of pills after intensive treatment was highly appreciated. CONCLUSION: Rheumatologists and patients differed in opinion about the use of COBRA therapy. Rheumatologists were particularly concerned about their patients' reaction towards them prescribing such an aggressive and complex therapy, whereas patients, while aware of the side-effects, were most interested in suppressing illness symptoms and reducing future damage regardless of the amount of pills.

Peters MJ, van Halm VP, Nurmohamed MT, Damoiseaux J, Tervaert JW, Twisk JW, Dijkmans BA, Voskuyl AE. · Department of Rheumatology, VU University Medical Center, Amsterdam, The Netherlands. · J Rheumatol. · Pubmed #18597411 No free full text.

Abstract: OBJECTIVE: Rheumatoid arthritis (RA) is associated with an unexplained increased cardiovascular risk. Autoantibodies recognizing oxidized low-density lipoprotein (oxLDL-ab) are associated with atherosclerosis in the general population and have been reported in several autoimmune diseases. We investigated relations between oxLDL-ab, inflammation, subclinical atherosclerosis, and cardiovascular disease (CVD) in patients with RA. METHODS: In a nested case-control study, serum concentrations of oxLDL-ab were measured in 140 RA patients. Ultrasound examination of the carotid artery [i.e., carotid intima-media thickness (CIMT)] was performed in a third of these patients. Correlations were calculated for oxLDL-ab, C-reactive protein (CRP), and high-density lipoprotein (HDL) cholesterol. Regression analyses were used to examine associations between oxLDL-ab and prevalent CVD, and oxLDL-ab and CIMT. RESULTS: OxLDL-ab were positively correlated with CRP (r = 0.33, p < 0.001) and negatively correlated with HDL cholesterol (r = -0.28, p = 0.001). An indication for interaction was found (p = 0.09), suggesting that inflammation modifies the relation between HDL cholesterol and oxLDL-ab. OxLDL-ab were independently associated with intimal thickening, but not associated with prevalent CVD. CONCLUSION: OxLDL-ab were strongly related with the degree of inflammation and may predispose to a higher risk for CVD, as they were independently associated with subclinical atherosclerosis in patients with RA.

Vis M, Bos WH, Wolbink G, Voskuyl AE, Twisk JW, Van de Stadt R, Hamann D, Dijkmans BA, Lems WF. · VU University Medical Center, Sanquin Research, and Jan van Breemen Institute, Amsterdam, The Netherlands. · J Rheumatol. · Pubmed #18322974 No free full text.

Abstract: OBJECTIVE: To investigate the effect of treatment with infliximab on serum levels of rheumatoid factor (IgM-RF), antibodies against cyclic citrullinated peptide (anti-CCP), and antibodies against deiminated human fibrinogen, a specific citrullinated peptide (ACF), and their association with disease activity and disease duration in patients with rheumatoid arthritis (RA). METHODS: The study sample included 62 consecutive patients who were treated with infliximab for at least one year. IgM-RF, anti-CCP, and ACF were measured at 0, 14, 30, and 46 weeks. RESULTS: Patients had a mean age of 54 years and median disease duration of 10 years and were predominantly female (81%). At baseline 63%, 77%, and 82% of patients were positive for IgM-RF, anti-CCP, and ACF, respectively. In terms of percentages, the levels of IgM-RF were reduced by 64% at 46 weeks, while anti-CCP and ACF levels were reduced by roughly 25%. The decrease in serum levels of these autoantibodies was not associated with the decrease in disease activity. The change in ACF was significantly related to disease duration, while the changes in IgM-RF or anti-CCP were not. CONCLUSION: In a cohort of patients with RA who responded to infliximab therapy, all autoantibodies decreased significantly, but IgM-RF showed a larger decrease than anti-CCP or ACF. These changes in levels of autoantibodies are not directly related to the change in disease activity. Early in the disease, ACF levels were best influenced by treatment with infliximab.

Turkstra F, Rinkel RN, Biermann H, van der Valk P, Voskuyl AE. · Department of Rheumatology, VU University Medical Center, Amsterdam, the Netherlands. · Clin Rheumatol. · Pubmed #18204872 links to  free full text

Abstract: In this case report, we describe a patient with longstanding rheumatoid arthritis who developed tracheobronchomalacia with fatal outcome. Despite negative antemortem biopsies of abdominal fat and tongue, amyloid was found postmortem in the trachea and appeared to be associated with tracheobronchomalacia.

van der Pouw Kraan TC, van Baarsen LG, Wijbrandts CA, Voskuyl AE, Rustenburg F, Baggen JM, Dijkmans BA, Tak PP, Verweij CL. · Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands. · Genes Immun. · Pubmed #17928867 No free full text.

Abstract: Rheumatoid arthritis (RA) is a heterogeneous disease with unknown etiology. Here we aimed to distinguish RA subtypes based on peripheral blood (PB) gene expression profiles in comparison with a pathogen-response transcriptional program. PB was obtained from 35 RA patients and 15 healthy individuals. For expression profiling we used DNA microarrays. A combined cluster analysis of RA and control samples together with samples from a viral infection model revealed that the gene expression profile of a subgroup of RA patients (RA(A)) was reminiscent to that of poxvirus-infected macaques. Statistical analysis, followed by Gene Ontology analysis of the RA(A) patients confirmed that these patients form a distinct group, with activation of several host defense mechanisms that resemble a common host-pathogen response. Analysis of the promoter region of genes that were overexpressed in the RA(A) patients, revealed an enrichment of transcription factor binding sites for NF kappaB and interferon-activated transcription factors. Moreover, this subgroup of RA patients expressed significantly increased titers of anti-cyclic citrullinated peptide antibodies. We conclude that activation of a host-pathogen response defines a subgroup of RA patients characterized by increased autoreactivity against citrullinated proteins.

Elzinga EH, van der Laken CJ, Comans EF, Lammertsma AA, Dijkmans BA, Voskuyl AE. · Department of Rheumatology, VU University Medical Centre, Amsterdam, The Netherlands. · Mol Imaging Biol. · Pubmed #17902022 links to  free full text

Abstract: PURPOSE: Previous positron emission tomography (PET) studies have shown increased 2-deoxy-2-[18F]fluoro-D-glucose (FDG) uptake in joints of patients with osteoarthritis (OA) and inflamed joints of patients with rheumatoid arthritis (RA). This study compares FDG uptake in joints of RA and OA patients and FDG-uptake with clinical signs of inflammation. PROCEDURES: FDG-PET scans of hands and wrists were performed in patients with RA and primary OA. PET data were compared with clinical data. RESULTS: 29% of RA joints and 6% of OA joints showed elevated FDG-uptake. The level of uptake in PET-positive OA joints was not significantly different from that in RA joints. The majority of PET results of RA joints corresponded with clinical findings. Clinical synovitis was found some OA joints with FDG-uptake. CONCLUSIONS: FDG-uptake was observed in the majority of clinically inflamed RA joints and in a few OA joints with no significant difference in uptake level. The latter may be due to secondary synovitis.

Raterman HG, van Halm VP, Voskuyl AE, Simsek S, Dijkmans BA, Nurmohamed MT. · Department of Rheumatology, VU University Medical Center, Amsterdam, The Netherlands. · Ann Rheum Dis. · Pubmed #17557891 No free full text.

Abstract: OBJECTIVE: Rheumatoid arthritis (RA) patients have an increased risk of developing cardiovascular diseases (CVD). Other autoimmune diseases such as hypothyroidism are also associated with an enhanced risk for CVD. Our objective was to determine first, the prevalence of hypothyroid disorders in RA patients, and second, the risk of CVD in RA patients with hypothyroid abnormalities. METHODS: SUBJECTS: were RA patients who participated in an ongoing prospective cohort study of cardiovascular mortality and morbidity (n = 358) in which hypothyroid abnormalities were assessed. CVD was defined as a verified medical history of coronary, cerebral or peripheral arterial disease. RESULTS: Clinical hypothyroidism was observed in 16 of 236 female RA patients (6.8%), which is significantly higher than in the general population of The Netherlands. Subclinical hypothyroidism was detected in 6 out of 236 RA women (2.5%). In female RA patients, CVD was present in 6 out of 16 (37.5%) of all hypothyroid women. The odds ratio for CVD comparing female hypothyroid RA patients with female euthyroid RA patients was 4.1 (95% CI 1.2-14.3) after adjustment for sex, age, diabetes, smoking (ever), hypertension and statin use. CONCLUSIONS: Clinical hypothyroidism was observed three times more often in female RA patients than females in the general population. In female RA patients, clinical hypothyroidism was associated with a fourfold higher risk of CVD in comparison with euthyroid female RA patients independently of the traditional risk factors.

van Tuyl LH, Plass AM, Lems WF, Voskuyl AE, Dijkmans BA, Boers M. · Department of Clinical Epidemiology & Biostatistics, VU University Medical Center, PO Box 7057, 1053 MB Amsterdam, The Netherlands. · Ann Rheum Dis. · Pubmed #17392349 No free full text.

Abstract: BACKGROUND: The Combinatietherapie Bij Reumatoide Artritis (COBRA) trial has proved that combination therapy with prednisolone, methotrexate and sulphasalazine is superior to sulphasalazine monotherapy in suppressing disease activity and radiological progression of early rheumatoid arthritis (RA). In addition, 5 years of follow-up proved that COBRA therapy results in sustained reduction of the rate of radiological progression. Despite this evidence, Dutch rheumatologists seem reluctant to prescribe COBRA therapy. OBJECTIVE: To explore the reasons for the reluctance in Dutch rheumatologists to prescribe COBRA therapy. METHODS: A short structured questionnaire based on social-psychological theories of behaviour was sent to all Dutch rheumatologists (n = 230). RESULTS: The response rate was 50%. COBRA therapy was perceived as both effective and safe, but complex to administer. Furthermore, rheumatologists expressed their concern about the large number of pills that had to be taken, the side effects of high-dose prednisolone and the low dose of methotrexate. Although the average attitude towards the COBRA therapy was slightly positive (above the neutral point), the majority of responding rheumatologists had a negative intention (below the neutral point) to prescribe COBRA therapy in the near future. CONCLUSION: The reluctance of Dutch rheumatologists to prescribe effective COBRA therapy may be due to perceptions of complexity of the treatment schedule and negative patient-related consequences of the therapy.

Peters MJ, Vis M, van Halm VP, Wolbink GJ, Voskuyl AE, Lems WF, Dijkmans BA, Twisk JW, de Koning MH, van de Stadt RJ, Nurmohamed MT. · Department of Rheumatology, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands. · Ann Rheum Dis. · Pubmed #17314120 No free full text.

Abstract: OBJECTIVE: To evaluate the effects of infliximab and corticosteroid treatment on the lipid profile in patients with active rheumatoid arthritis (RA). METHODS: Infliximab infusions were given at weeks 0, 2, 6 and then every 8 weeks. Before each infusion, disease activity parameters (Disease Activity Index 28-Joint Score (DAS28)) C reactive protein (CRP) and lipid levels (total cholesterol, high-density lipoprotein (HDL)-cholesterol, triglycerides, apolipoprotein A1 (apo A1) and apolipoprotein B) were measured in 80 consecutive patients with RA, who completed the study period of 48 weeks. Longitudinal analyses were used to investigate (1) the course of lipid levels over a period of time and (2) the relationship between lipids, prednisone dose and disease activity. RESULTS: Infliximab treatment causes a significant reduction in disease activity and a concomitant decrease in prednisone dose. Although they initially improved significantly, all lipid levels had returned to baseline levels after 48 weeks, except for apo A1. Longitudinal analyses revealed significant yet opposite associations between lipid levels and disease activity and between lipid levels and prednisone dose. DAS28 improvement by 1 point was associated with an increase of 0.016 mmol/l (0.618 mg/dl) total cholesterol and 0.045 mmol/l (1.737 mg/dl) HDL-cholesterol. Reduction of 10 mg prednisone was associated with a decrease of 0.04 mmol/l (1.544 mg/dl) total cholesterol and 0.16 mmol/l (6.177 mg/dl) HDL-cholesterol. CONCLUSION: Overall, no changes in serum lipid levels were observed after 48 weeks of infliximab treatment. The initial beneficial effects of infliximab on the lipid profile, by means of a reduction of disease activity, are attenuated by a concomitant decrease in prednisone dose.

Gazi H, Pope JE, Clements P, Medsger TA, Martin RW, Merkel PA, Kahaleh B, Wollheim FA, Baron M, Csuka ME, Emery P, Belch JF, Hayat S, Lally EV, Korn JH, Czirjak L, Herrick A, Voskuyl AE, Bruehlmann P, Inanc M, Furst DE, Black C, Ellman MH, Moreland LW, Rothfield NF, Hsu V, Mayes M, McKown KM, Krieg T, Siebold JR. · Division of Rheumatology, Department of Medicine, The University of Western Ontario, London, Ontario, Canada. · J Rheumatol. · Pubmed #17299843 No free full text.

Abstract: OBJECTIVE: To obtain a consensus on the minimal clinically relevant treatment effect in various scleroderma disease outcome measures to be used in future clinical trials. METHODS: A Delphi consensus building exercise using a survey was sent out to members of the Scleroderma Clinical Trials Consortium (SCTC). The 65 SCTC members were divided into 2 groups. Group 1 was informed, in a cover letter, of the usual American College of Rheumatology 20% response results in randomized trials using effective biologic treatments for rheumatoid arthritis, while Group 2 was not. The first round of the exercise presented the scleroderma experts with a survey composed of 95 questions/clinical scenarios divided into 8 categories. These included situations where the treatment group improved, or worsened, or where some outcome measures improved, while others worsened. From the responses of this first round, a mean, mode, median, and range of responses for each of the 95 questions was obtained. This information was sent out, in the second round of the Delphi exercise, only to those respondents who answered the first round. The respondent's previous answer and the mean and range from the first round were provided for each question. It gave respondents the option to change any of their initial responses. The median of their responses in the second round was used to calculate the values for the minimal clinically relevant treatment effect. RESULTS: Thirty-two of the 65 SCTC members returned the first round of the Delphi exercise. Twenty-eight members returned the second round. Intraclass correlation coefficients between responses to round 1 and 2 were calculated for the questions. These varied from 0.99 (excellent agreement) to 0.02 (poor agreement). The p value was under 0.09 for 9 questions and under 0.19 for 20 questions. Standard deviations (SD) were calculated and were found to be lesser for each of the questions in round 2 when compared to the SD in responses from round 1, thus indicating a movement towards a consensus by the second round. An average of 33% of the responses were changed by the respondents in the second round of the Delphi exercise to a value closer to the median/average of the first round's responses. A range in required values for the minimal clinically relevant treatment effect for Modified Rodnan skin score is 3 to 7.5 units, Health Assessment Questionnaire Disability Index (HAQ-DI) 0.2 to 0.25 units, HAQ pain 0.2 to 0.3 units, MD global (100 mm visual analog scale) 8 to 13, patient global assessment 10 to 12, and diffusing capacity (percentage predicted) 9 to 10. The scenarios were especially weighted towards overall disease modification, thus organ-specific measures, such as 6 minute walk time (which has been used in many pulmonary artery hypertension trials), forced vital capacity, and a dyspnea rating (which may be important in scleroderma lung trials), were not included in the survey. CONCLUSION: Our study begins to address the current deficiency in our knowledge of appropriate values for the minimal clinically relevant treatment effect in various scleroderma disease outcome measures. A consensus could be achieved, or at least a range of minimal clinically relevant treatment effect values could be found for several outcome measurements. Of course, this consensus statement will be modified by evidence as it accrues in each consensus area.

van der Pouw Kraan TC, Wijbrandts CA, van Baarsen LG, Voskuyl AE, Rustenburg F, Baggen JM, Ibrahim SM, Fero M, Dijkmans BA, Tak PP, Verweij CL. · Department of Molecular and Cellular Biology & Immunology, VU Medical Centre, J295, PO Box 7057, 1007 MB Amsterdam, The Netherlands. · Ann Rheum Dis. · Pubmed #17223656 No free full text.

Abstract: BACKGROUND: Rheumatoid arthritis (RA) is a heterogeneous disease with unknown cause. AIM: To identify peripheral blood (PB) gene expression profiles that may distinguish RA subtypes. METHODS: Large-scale expression profiling by cDNA microarrays was performed on PB from 35 patients and 15 healthy individuals. Differential gene expression was analysed by significance analysis of microarrays (SAM), followed by gene ontology analysis of the significant genes. Gene set enrichment analysis was applied to identify pathways relevant to disease. RESULTS: A substantially raised expression of a spectrum of genes involved in immune defence was found in the PB of patients with RA compared with healthy individuals. SAM analysis revealed a highly significant elevated expression of interferon (IFN) type I regulated genes in patients with RA compared with healthy individuals, which was confirmed by gene ontology and pathway analysis, suggesting that this pathway was activated systemically in RA. A quantitative analysis revealed that increased expression of IFN-response genes was characteristic of approximately half of the patients (IFN(high) patients). Application of pathway analysis revealed that the IFN(high) group was largely different from the controls, with evidence for upregulated pathways involved in coagulation and complement cascades, and fatty acid metabolism, while the IFN(low) group was similar to the controls. CONCLUSION: The IFN type I signature defines a subgroup of patients with RA, with a distinct biomolecular phenotype, characterised by increased activity of the innate defence system, coagulation and complement cascades, and fatty acid metabolism.

van Halm VP, Nurmohamed MT, Twisk JW, Dijkmans BA, Voskuyl AE. · Department of Rheumatology, VU University Medical Center, Boelelaan 1117, Amsterdam, 1085 HV, The Netherlands. · Arthritis Res Ther. · Pubmed #16984661 links to  free full text

Abstract: Rheumatoid arthritis (RA) is characterized by inflammation and an increased risk for cardiovascular disease (CVD). This study investigates possible associations between CVD and the use of conventional disease-modifying antirheumatic drugs (DMARDs) in RA. Using a case control design, 613 RA patients (5,649 patient-years) were studied, 72 with CVD and 541 without CVD. Data on RA, CVD and drug treatment were evaluated from time of RA diagnosis up to the first cardiovascular event or the end of the follow-up period. The dataset was categorized according to DMARD use: sulfasalazine (SSZ), hydroxychloroquine (HCQ) or methotrexate (MTX). Odds ratios (ORs) for CVD, corrected for age, gender, smoking and RA duration, were calculated per DMARD group. Patients who never used SSZ, HCQ or MTX were used as a reference group. MTX treatment was associated with a significant CVD risk reduction, with ORs (95% CI): 'MTX only', 0.16 (0.04 to 0.66); 'MTX and SSZ ever', 0.20 (0.08 to 0.51); and 'MTX, SSZ and HCQ ever', 0.20 (0.08 to 0.54). The risk reductions remained significant after additional correction for the presence of rheumatoid factor and erosions. After correction for hypertension, diabetes and hypercholesterolemia, 'MTX or SSZ ever' and 'MTX, SSZ and HCQ ever' showed significant CVD risk reduction. Rheumatoid factor positivity and erosions both increased CVD risk, with ORs of 2.04 (1.02 to 4.07) and 2.36 (0.92 to 6.08), respectively. MTX and, to a lesser extent, SSZ were associated with significantly lower CVD risk compared to RA patients who never used SSZ, HCQ or MTX. We hypothesize that DMARD use, in particular MTX use, results in powerful suppression of inflammation, thereby reducing the development of atherosclerosis and subsequently clinically overt CVD.

van der Laken CJ, Voskuyl AE, Roos JC, Stigter van Walsum M, de Groot ER, Wolbink G, Dijkmans BA, Aarden LA. · Department of Rheumatology, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands. · Ann Rheum Dis. · Pubmed #16793840 No free full text.

Abstract: BACKGROUND: Many patients with rheumatoid arthritis are currently successfully treated with infliximab (anti-tumour necrosis factor); however, about 30% of the patients do not respond to infliximab. One of the postulated hypotheses of not responding is the fast clearance of infliximab due to the development of infliximab-anti-infliximab complexes. OBJECTIVE: To investigate the in vivo mechanism of not responding and the role of human anti-chimeric antibodies (HACAs) by using radiolabelled infliximab. METHODS: Two responding and two non-responding patients with rheumatoid arthritis, infused with radiolabelled infliximab, were investigated by both imaging and serum analysis. RESULTS: Images showed predominant presence of infliximab in blood up to 24 h, with a trend of faster blood clearance and of higher liver/spleen uptake in a non-responding patient. Clinically inflamed joints showed uptake of the drug. The HACA level in the non-responders was high (1641 and 1008 U/ml), but low or not detectable in responders. Sucrose gradients of serum showed antibody complexes in both non-responders. Various sizes of antibody complexes, including very large ones, were observed in a non-responder who developed a serious infusion reaction. CONCLUSION: Formation of infliximab-anti-infliximab complexes were found in non-responders due to the presence of large amounts of HACA. This finding, supported by both imaging and serum analysis data, may explain failure of infliximab treatment.

van Halm VP, Nielen MM, Nurmohamed MT, van Schaardenburg D, Reesink HW, Voskuyl AE, Twisk JW, van de Stadt RJ, de Koning MH, Habibuw MR, van der Horst-Bruinsma IE, Dijkmans BA. · Departments of Internal Medicine and Rheumatology, VU University Medical Centre, PO Box 7057, 1007 MB Amsterdam, The Netherlands. · Ann Rheum Dis. · Pubmed #16760255 No free full text.

Abstract: BACKGROUND: Rheumatoid arthritis is characterised by inflammation and an increased cardiovascular risk. It was recently shown that active early rheumatoid arthritis is associated with dyslipidaemia, which may partially explain the enhanced cardiovascular risk. However, it is unknown when this dyslipidaemia starts. OBJECTIVE: To investigate the progression of the lipid profile over time and the influence of inflammatory parameters on this lipid profile, in people who later developed rheumatoid arthritis. METHODS: Levels of total cholesterol, high-density lipoprotein cholesterol (HDLc), triglycerides, apolipoprotein AI (apo AI), apolipoprotein B (apo B) and lipoprotein(a) (Lp(a)) were determined in 1078 stored, deep-frozen, serial blood bank samples, collected between 1984 and 1999, of 79 blood donors who later developed rheumatoid arthritis. These samples were compared with 1071 control samples of unselected blood donors, matched for age, sex and storage time. RESULTS: Samples of patients who later developed rheumatoid arthritis showed, on average, 4% higher total cholesterol, 9% lower HDLc, 17% higher triglyceride and 6% higher apo B levels than matched controls (p< or =0.05). The magnitude of the differences in lipid levels between groups, explained by C reactive protein (CRP), was limited. For example, only 3.6% of the difference in HDLc levels between the groups was explained by the CRP concentrations. CONCLUSION: Patients who later develop rheumatoid arthritis have a considerably more atherogenic lipid profile than matched blood donors at least 10 years before onset of symptoms. As inflammation only marginally explains the differences between the two groups, a modulating effect of lipids on inflammatory processes is hypothesised.