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Annals of the rheumatic diseases 05/2012; 71(11):1915-6. · 8.11 Impact Factor
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P Suwannalai,
L A van de Stadt,
H Radner,
G Steiner,
H S El-Gabalawy,
C M Jol-van der Zijde,
M J van Tol, D van Schaardenburg,
T W J Huizinga,
R E M Toes,
L A Trouw
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ABSTRACT: Anti-citrullinated protein antibodies (ACPAs) are highly specific for rheumatoid arthritis (RA) and are present years before the onset of symptoms. The avidity of autoantibodies can have a strong impact on their effector potency. This study was undertaken to analyze the avidity of ACPAs in serum samples obtained from ACPA-positive healthy individuals (predisease), patients with early disease, and patients with established RA as well as the avidity maturation over time in samples from healthy subjects who later developed RA.
We measured ACPA avidity in serum samples from ACPA-positive healthy individuals, symptomatic individuals, and patients with established RA in 5 collections from The Netherlands, Canada, and Austria. We determined the dynamics of avidity maturation of ACPAs from the predisease stage to established disease in 1 case from the native North American population and in 10 cases from a Dutch blood donor cohort.
The overall ACPA response was characterized by low-avidity antibodies. Higher-avidity ACPAs were observed in symptomatic patients only, while low-avidity ACPAs were observed in both healthy subjects and patients. In longitudinal samples obtained from subjects prior to disease onset, ACPA avidity increased over time until disease onset. No further avidity maturation was observed after disease onset.
Our findings indicate that avidity maturation of the ACPA response takes place prior to disease onset.
Arthritis & Rheumatism 11/2011; 64(5):1323-8. · 7.87 Impact Factor
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ABSTRACT: To describe the disease course after the cessation of infliximab in early rheumatoid arthritis patients with disease activity score (DAS)-steered treatment and to identify predictors of persistent low disease activity.
In a post-hoc analysis of the BeSt study, disease activity and joint damage progression were observed in patients treated with methotrexate plus infliximab, who discontinued infliximab after achieving low disease activity (DAS ≤2.4) for 6 months. Predictors were identified using Cox regression analysis.
104 patients discontinued infliximab, of whom 77 had received infliximab plus methotrexate as initial treatment. Mean DAS at the time of infliximab cessation was 1.3, median symptom duration was 23 months and median Sharp/van derHeijde score was 5.5. The median follow-up was 7.2 years. Infliximab was re-introduced after loss of low disease activity in 48%, after a median of 17 months. The joint damage progression rate did not increase in the year after cessation, regardless of flare. After re-introduction of infliximab, 84% of these patients again achieved a DAS ≤2.4. In the multivariable model, smoking, infliximab treatment duration ≥18 months and shared epitope (SE) were independently associated with the re-introduction of infliximab: 6% of the non-smoking, SE-negative patients treated <18 months needed infliximab re-introduction.
Cessation of infliximab was successful in 52%, with numerically higher success rates in patients initially treated with infliximab. Of the 48% who flared, 84% regained low disease activity. The joint damage progression rate did not increase in the year after cessation. Smoking, long infliximab treatment duration and SE were independently associated with re-introduction of infliximab.
Annals of the rheumatic diseases 04/2011; 70(8):1389-94. · 8.11 Impact Factor
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L A Korswagen,
G M Bartelds,
C L M Krieckaert,
F Turkstra,
M T Nurmohamed, D van Schaardenburg,
C A Wijbrandts,
P P Tak,
W F Lems,
B A C Dijkmans,
R M van Vugt,
G J Wolbink
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ABSTRACT: We observed 3 patients who developed severe venous and arterial thromboembolic events during treatment with adalimumab, 2 of whom had rheumatoid arthritis (RA) and 1 of whom had psoriatic arthritis. Antiadalimumab antibodies were detected in all 3 patients. We undertook this study to determine whether the development of antiadalimumab antibodies was associated with thromboembolic events during adalimumab treatment.
A retrospective search (with blinding with regard to antiadalimumab antibody status) for thromboembolic events was performed in a prospective cohort of 272 consecutively included adalimumab-treated RA patients. Incidence rates were calculated and hazard ratios (HRs) were estimated using Cox regression. None of the index patients were part of the cohort.
Antiadalimumab antibodies were detected in 76 of 272 patients (28%). Eight thromboembolic events were found, 4 of which had occurred in patients with antiadalimumab antibodies. The incidence rate was 26.9/1,000 person-years for patients with antiadalimumab antibodies and 8.4/1,000 person-years for patients without those antibodies (HR 3.8 [95% confidence interval 0.9-15.3], P = 0.064). After adjustment for duration of followup, age, body mass index, erythrocyte sedimentation rate, and prior thromboembolic events, the HR was 7.6 (95% confidence interval 1.3-45.1) (P = 0.025).
These findings suggest that the occurrence of venous and arterial thromboembolic events during adalimumab treatment is higher in patients with antiadalimumab antibodies than in those without antiadalimumab antibodies. Patient numbers were relatively small; therefore, validation in other cohorts is mandatory.
Arthritis & Rheumatism 04/2011; 63(4):877-83. · 7.87 Impact Factor
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M G H van de Sande,
M J H de Hair,
C van der Leij,
P L Klarenbeek,
W H Bos,
M D Smith,
M Maas,
N de Vries, D van Schaardenburg,
B A C Dijkmans,
D M Gerlag,
P P Tak
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ABSTRACT: The aetiology of rheumatoid arthritis (RA), a prototype immune-mediated inflammatory disorder, is poorly understood. It is currently unknown whether the disease process starts in the synovium, the primary target of RA, or at other sites in the body.
To examine, in a prospective study, the presence of synovitis in people with an increased risk of developing RA.
Thirteen people without evidence of arthritis, who were positive for IgM rheumatoid factor and/or anticitrullinated protein antibodies, were included in the study. To evaluate synovial inflammatory changes, all participants underwent dynamic contrast-enhanced MRI and arthroscopic synovial biopsy sampling of a knee joint at inclusion. Results were compared with knee MRI data and synovial biopsy data of 6 and 10 healthy controls, respectively.
MRI findings evaluated by measurement of maximal enhancement, rate of enhancement, synovial volume and enhancement shape curve distribution were similar between the autoantibody-positive subjects and the healthy controls. Consistent with these findings, all but one autoantibody-positive subject showed very low scores for phenotypic markers, adhesion molecules and vascularity, all in the same range as those in normal controls. The one person with higher scores had patellofemoral joint space narrowing.
Subclinical inflammation of the synovium does not coincide with the appearance of serum autoantibodies during the pre-RA stage. Thus, systemic autoimmunity precedes the development of synovitis, suggesting that a 'second hit' is involved. This study supports the rationale for exploring preventive strategies aimed at interfering with the humoral immune response before synovial inflammation develops.
Annals of the rheumatic diseases 12/2010; 70(5):772-7. · 8.11 Impact Factor
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M Güler-Yüksel,
C F Allaart,
I Watt,
Y P M Goekoop-Ruiterman,
J K de Vries-Bouwstra, D van Schaardenburg,
M V van Krugten,
B A C Dijkmans,
T W J Huizinga,
W F Lems,
M Kloppenburg
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ABSTRACT: To investigate the association between systemic and local inflammation and incident and progressive radiographic secondary osteoarthritis (OA) in interphalangeal joints (IPJs) over 3 years in rheumatoid arthritis (RA) patients and the effect of tumor necrosis factor alpha (TNF-α) inhibitor infliximab on secondary OA in IPJs.
In the present observational longitudinal study baseline and 3-year hand X-rays of 416 recent-onset RA patients were scored for osteophytes and erosions in IPJs, blinded for time, using Osteoarthritis Research Society International atlas and Sharp-van der Heijde score. The associations between inflammatory factors and incident and progressive secondary OA in distal IPJs (DIPJs) and proximal IPJs (PIPJs) and the effect of infliximab compared to disease-modifying anti-rheumatic drug treatment on secondary OA were analyzed by multivariable regression and generalised estimating equations analyses.
Sixty-seven percent of the patients were female with, at baseline, a mean age of 54 years and OA present in DIPJs and PIPJs in 37% and 13%. Three years later, new secondary OA in DIPJs and PIPJs was seen in 11% and 10%, and progressive secondary OA in 36% and 35%. High erythrocyte sedimentation rate over 3 years and progressive erosive damage were risk factors for incident secondary OA in DIPJs, but not in PIPJs. At joint level, progression of erosions was associated with both incident and progressive secondary OA, only in DIPJs. Infliximab treatment was associated with lower incident secondary OA in PIPJs [relative risk 0.5 (95% confidence interval 0.2, 1.0)], independent of decrease in inflammation.
Incident and progressive secondary OA in DIPJs over 3 years was associated with high inflammatory activity in RA. Infliximab treatment reduced incident secondary OA in PIPJs independent of decrease in inflammation, suggesting that anti-TNF-α therapy might be effective against secondary hand OA via other pathways than suppression of inflammation. Further studies in populations of primary hand OA are necessary to determine the role of anti-TNF-α in treatment of primary hand OA.
Osteoarthritis and Cartilage 10/2010; 18(10):1256-62. · 3.90 Impact Factor
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Annals of the rheumatic diseases 10/2009; 68(9):1512-3. · 8.11 Impact Factor
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Annals of the rheumatic diseases 12/2008; 67(11):1642. · 8.11 Impact Factor
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Nederlands tijdschrift voor geneeskunde 06/2008; 152(21):1244; author reply 1244-6.
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W H Bos,
J Ursum,
N de Vries,
G M Bartelds,
G J Wolbink,
M T Nurmohamed,
I E van der Horst-Bruinsma,
R J van de Stadt,
J B A Crusius,
P P Tak,
B A C Dijkmans, D van Schaardenburg
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ABSTRACT: Patients presenting with both arthralgia and antibodies to cyclic citrullinated peptide (anti-CCP) have an increased risk of developing rheumatoid arthritis (RA). To further characterise this patient group and shed more light on its relationship with clinically manifest early arthritis and established RA, an immunogenetic and serological analysis was performed.
In a group of 111 patients with anti-CCP-positive arthralgia, anti-CCP levels and shared epitope (SE) status were determined. Data were compared with 125 and 128 patients with anti-CCP-positive early arthritis and established RA respectively.
In patients with anti-CCP-positive arthralgia, the frequency of SE allele positivity is significantly lower when compared with anti-CCP-positive early arthritis and established RA (58% vs 80%, and 58% vs 92%, respectively, both p<0.001). Median anti-CCP levels were higher in the group of patients with SE-positive arthralgia compared with the group of patients with SE-negative arthralgia (p = 0.02). Median anti-CCP levels were similar in the groups of patients with SE-positive arthralgia and arthritis.
The lower frequency of SE positivity in patients with arthralgia compared with patients with RA indicates that, compared with patients who were SE positive, patients who were SE negative as a group go through a longer arthralgia phase, or alternatively have a lower risk for transition from anti-CCP positive arthralgia to RA. Furthermore, the present results suggest that in this early stage the effect of the SE on disease risk may be mediated through higher anti-CCP levels.
Annals of the rheumatic diseases 04/2008; 67(9):1347-50. · 8.11 Impact Factor
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V P van Halm,
M M J Nielen,
M T Nurmohamed, D van Schaardenburg,
H W Reesink,
A E Voskuyl,
J W R Twisk,
R J van de Stadt,
M H M T de Koning,
M R Habibuw,
I E van der Horst-Bruinsma,
B A C Dijkmans
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ABSTRACT: 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.
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.
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.
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.
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.
Annals of the Rheumatic Diseases 02/2007; 66(2):184-8. · 8.73 Impact Factor
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Annals of the Rheumatic Diseases 08/2006; 65(7):973-4. · 8.73 Impact Factor
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ABSTRACT: To investigate the temporal relationship between onset of inflammation (as measured by secretory phospholipase A2 (sPLA2) and C reactive protein (CRP)) and the presence of autoantibodies (IgM rheumatoid factor (IgM RF) and antibodies against citrullinated peptides (anti-CCP)) in the preclinical phase of rheumatoid arthritis (RA).
For 79 patients with RA who had been blood donors before the onset of disease, a median of 13 serum samples per patient was available. sPLA2 was measured in patient and matched control samples and related to previous CRP, IgM RF, and anti-CCP measurements. The temporal relationship between the increased markers of inflammation and autoantibodies was analysed with time lag analysis.
IgM RF and anti-CCP concentrations were significantly associated (p<0.001) with concentrations of sPLA2, CRP, and the combination of sPLA2 and CRP at the same time point. However, we found no stronger association between the two autoantibody tests and the three inflammation measures 1, 2, and 3 years before or after a time point than for measurements at the same time, in the whole group or in subgroups of IgM RF and anti-CCP positive patients.
Both the acute phase response and autoantibody formation often develop years before the first symptoms of RA occur, and these phenomena are probably closely connected in time.
Annals of the Rheumatic Diseases 05/2006; 65(4):535-7. · 8.73 Impact Factor
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ABSTRACT: The anti-cyclic citrullinated peptide (CCP) test has a high sensitivity and specificity for rheumatoid arthritis, although CCP is not the physiological target of the autoantibodies. Citrullinated fibrin is abundant in inflamed synovium
To assess the diagnostic and prognostic value of antibodies against citrullinated fibrinogen (ACF), a soluble precursor of fibrin, in comparison with IgM-rheumatoid factor (IgM-RF) and the second generation anti-CCP test.
In 379 patients with early arthritis (258 rheumatoid and 121 undifferentiated), the sensitivity, specificity, and positive predictive value of ACF, anti-CCP, and IgM-RF for diagnosing rheumatoid arthritis were calculated. Multivariate logistic regression analysis was used to assess the diagnostic and prognostic value (radiographic progression after two years) of the tests.
The sensitivities of the ACF, anti-CCP, and IgM-RF tests were 55.8%, 57.8%, and 44.6%, with specificities of 92.6%, 94.2%, and 96.7%, respectively. Approximately 30% of the IgM-RF negative patients were positive for ACF or anti-CCP or both. The ACF and anti-CCP test had a high agreement in early arthritis (kappa = 0.84). Of all baseline characteristics, the ACF test and the anti-CCP test were the best predictors for diagnosing rheumatoid arthritis at one year (odds ratio (OR) = 10.3 and 10.6, respectively) and for radiographic progression after two years (OR = 12.1 and 14.8).
ACF is as sensitive as anti-CCP and more sensitive than IgM-RF in diagnosing rheumatoid arthritis in early arthritis. The ACF test is also a good predictor of radiographic progression, with a performance similar to the anti-CCP test. The ACF test and the anti-CCP test are especially valuable in IgM-RF negative arthritis.
Annals of the Rheumatic Diseases 09/2005; 64(8):1199-204. · 8.73 Impact Factor
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ABSTRACT: In some conditions e.g. osteoporosis, hypertension and hypercholesterolaemia, certain phenomena precede manifestation of the disease and preventive measures can be taken long before the disease presents itself. In the same way systemic lupus erythematosus (SLE) and rheumatoid arthritis can be explored. Recently, studies have been published on healthy blood donors, who later developed SLE or rheumatoid arthritis, and in whom specific autoantibodies could be demonstrated. In SLE the autoantibodies are not specific enough to develop preventive strategies, but in rheumatoid arthritis in particular there are specific antibodies against cyclic citrullinated peptides (anti-CCP-antibodies) which are very specific. A clinical trial has been initiated in which HLA-DR4-positive people with raised autoantibody concentrations are given 1-2 intramuscular injections of dexamethasone with the aim of halving the antibody concentration and in the long term lowering the incidence of rheumatoid arthritis.
Nederlands tijdschrift voor geneeskunde 04/2005; 149(13):688-93.
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ABSTRACT: To identify variables that can predict a progressive outcome after one year of follow up in patients presenting with undifferentiated polyarthritis (UPA) at an early arthritis clinic.
New patients with arthritis in two or more joints of less than three years' duration were categorised at entry as UPA or as rheumatoid arthritis (RA) based on the clinical diagnosis of the rheumatologist. Outcome variables after one year were radiographic damage (Sharp/van der Heijde score) and functional status (Health Assessment Questionnaire: HAQ score). A progressive disease at one year was defined as radiographic progression > or =4, or one year radiographic damage > or =10, or HAQ score > or =1. The baseline variables of patients with UPA with a progressive or mild outcome were compared.
280 patients (70% women; median age 56 years (range 18-90), median duration of symptoms 3.5 months) were included. 203 (72%) patients were clinically diagnosed as having RA and 77 (27%) as having UPA. The group of patients with progressive UPA (n=32 (42%)) had a significantly higher mean age, prevalence of arthritis of the hands, and disease activity (DAS28) at the first visit compared with the patients of the mild UPA group (n=45 (58%)). The RA group had significantly more frequent serum IgM-RF positivity, higher mean disease activity (DAS28) and mean C reactive protein concentration, more frequent symmetric arthritis, and arthritis in more than three joint groups than the progressive UPA group. Six (19%) of the progressive UPA group versus eight (4%) of the RA group did not receive disease modifying antirheumatic drugs during the first year.
After one year of follow up, 32 (42%) of the patients with UPA had a progressive disease. A progressive outcome was associated with older age, higher disease activity, and arthritis of the hands at baseline. To avoid undertreatment of patients with UPA, treatment should be based on severity rather than on diagnosis.
Annals of the Rheumatic Diseases 09/2002; 61(8):700-3. · 8.73 Impact Factor
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ABSTRACT: To determine factors at diagnosis, associated with radiographic damage at diagnosis and after one year, in patients with early rheumatoid arthritis (RA).
New patients with early RA were followed up for one year. Possible prognostic factors were duration of complaints, morning stiffness, disease activity score (DAS28), functional status (Health Assessment Questionnaire (HAQ) score), rheumatoid factor (IgM RF), and C reactive protein (CRP). Outcome was defined as radiographic damage of the hands and feet (Sharp/van der Heijde score). For the statistical analysis, one way analysis of variance and a forward stepwise logistic regression model was used.
130 patients with RA (68% female; median age 64 years, range 21-86) were included. Despite the fact that the median duration of complaints was short (15 weeks, range 2-106) the radiographic damage at diagnosis was significantly correlated with the duration of complaints (p<0.05). Patients with a duration of complaints of >34 weeks had significantly more radiographic joint damage at diagnosis than patients with a shorter duration of complaints. Radiographic progression at one year was correlated with high radiographic joint damage, high CRP level, and a positive IgM RF at entry.
In early RA, the number of radiographic lesions was correlated with a longer duration of complaints at the first visit. Progression of these lesions was predicted by a high baseline joint damage, high CRP level, and a positive IgM RF. Further reduction of the delay in referral and early treatment may further decrease joint damage in patients with recent onset polyarthritis.
Annals of the Rheumatic Diseases 10/2001; 60(10):924-7. · 8.73 Impact Factor
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Journal of Clinical Endocrinology & Metabolism 01/2001; 85(12):4923-4. · 6.50 Impact Factor
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ABSTRACT: A role for sex steroids in the pathogenesis of AS is suggested by the male predominance, the peak age of onset in young adults, the increased number of first manifestations and flares after pregnancy, and the fact that sex steroids may modulate immune functions. There is a theoretic possibility that (normal levels of) androgens are indeed relevant in the male sex skew of AS. It has been reported that men with AS have higher than normal androgen levels; however, the evidence that serum testosterone levels are elevated in patients with AS is not robust. Elevated DHEAS and 17 alpha-hydroxyprogesterone levels have been reported in male AS patients; these may be secondary to inflammation and stress but may theoretically also be causally related to AS. These elevations might result from a partial late onset 11 beta- or 21-hydroxylase deficiency. Current data on sex steroid hormones provide no straightforward explanation for the male predominance in AS. It is fair to say that present data in patients with long-standing AS are too limited to suggest a role for androgens in the perpetuation of the disease, but a role in the initiation and the early stages of AS cannot be excluded. Such information can only be obtained from prospective studies. Cross-sectional studies cannot clearly distinguish causal relation from secondary disease effects, because blood sampling to test these hypotheses only takes place many years after the onset of disease. The impact of sex steroids on these features of AS is still unresolved. There is as yet no rationale for the use of medication that modifies sex steroid hormones in the management of AS. Alternative explanations for the higher male prevalence of AS may be found in the different chromosomal configuration and body composition of men and women.
Rheumatic Disease Clinics of North America 12/2000; 26(4):969-87. · 3.02 Impact Factor
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ABSTRACT: To find disease parameters that can predict the functional capacity of patients with early rheumatoid arthritis (RA) at the first visit to the rheumatologist and one year after entry.
Patients referred to the outpatients clinic between 1995 and 1996, with a symptom duration of less than three years and fulfilling the American Rheumatism Association 1987 revised criteria for RA within one year after entry were included. Assessments of the duration of morning stiffness, the Disease Activity Score (DAS: a composite score based on erythrocyte sedimentation rate (ESR), number of painful and swollen joints and patient global assessment), pain (Visual Analogue Scale), the Arthritis Impact Measurement Scale (AIMS) and the Health Assessment Questionnaire (HAQ) were performed every three months. Possible predictors of the HAQ at entry and after one year were analysed by logistic regression.
133 patients were included in the study. The median duration of complaints was three months (range 0-35) and the median HAQ score at entry was 1.12 (range 0-3). There was no correlation between duration of complaints and the HAQ at entry (r = 0.01). An HAQ score under the 50th percentile at entry could be predicted correctly for 74% of the patients by entry DAS and C reactive protein concentration, and at one year could be predicted correctly for 73% of the patients by entry HAQ and pain score.
Disease activity is strongly correlated with a lower functional capacity at entry, whereas disease duration is not. The functional status at entry is a good predictor for functional status at one year. Severity rather than duration of arthritis prompts referral in this cohort.
Annals of the Rheumatic Diseases 04/2000; 59(3):223-6. · 8.73 Impact Factor
