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R H W M Derksen

Publications and source records attributed to R H W M Derksen.

At least 19 recordsLinked to original sources
PubMed2006

Platelet adhesion to dimeric beta-glycoprotein I under conditions of flow is mediated by at least two receptors: glycoprotein Ibalpha and apolipoprotein E receptor 2'.

BACKGROUND: The major antigen implicated in the antiphospholipid syndrome is beta2-glycoprotein I (beta2GPI). Dimerized beta2GPI binds to apolipoprotein E receptor 2' (apoER2') on platelets and increases platelet adhesion to collagen under conditions of flow. AIM: To investigate whether the interaction between dimerized beta2GPI and platelets is sufficiently strong to resist shear stresses. METHODS: We studied the interaction of platelets with immobilized dimerized beta2GPI under conditions of flow, and further analyzed the interaction using surface plasmon resonance and solid phase immunoassays. RESULTS: We found that dimerized beta2GPI supports platelet adhesion and aggregate formation under venous flow conditions. Adhesion of platelets to dimerized beta2GPI was completely inhibited by the addition of soluble forms of both apoER2' and GPIbalpha, and the addition of receptor-associated protein and the removal of GPIbalpha from the platelet surface. GPIbalpha co-precipitated with apoER2', suggesting the presence of complexes between GPIbalpha and apoER2' on platelet membranes. The interaction between GPIbalpha and dimeric beta2GPI was of intermediate affinity (Kd = 180 nM) and Zn2+, but not Ca2+-dependent. Deletion of domain V from dimeric beta2GPI strongly reduced its binding to both GPIbalpha and apoER2'. Antibodies that inhibit the binding of thrombin to GPIbalpha inhibited platelet adhesion to dimeric beta2GPI completely, while antibodies blocking the binding of von Willebrand factor to GPIbalpha had no effect. Dimeric beta2GPI showed reduced binding to low-sulfated GPIbalpha compared to the fully sulfated form. CONCLUSION: We show that platelets adhere to dimeric beta2GPI under both arterial and venous shear stresses. Platelets adhere via two receptors: GPIbalpha and apoER2'. These receptors are present in a complex on the platelet surface.

Blood Platelets↗
PubMed2006

Azathioprine/methylprednisolone versus cyclophosphamide in proliferative lupus nephritis. A randomized controlled trial.

Until recently, intravenous cyclophosphamide pulses with oral corticosteroids were regarded standard therapy for proliferative lupus nephritis (LN). Azathioprine, a less toxic alternative, was never proven to be inferior. In the first Dutch lupus nephritis study (enrollment between 1995 and 2001), we randomized 87 proliferative LN patients to either cyclophosphamide pulses (750 mg/m(2), 13 pulses in 2 years) combined with oral prednisone (CY) or to azathioprine (2 mg/kg/day in 2 years) combined with intravenous pulses of methylprednisolone (3 x 3 pulses of 1000 mg) and oral prednisone (AZA). After a median follow-up of 5.7 years (interquartile range 4.1-7.2 years), doubling of serum creatinine was more frequent in the AZA group, although not statistically significant (relative risk (RR): 4.1, with 95% confidence interval (95% CI): 0.8-20.4). Relapses occurred more often in the AZA group (RR: 8.8, 95% CI: 1.5-31.8). Creatinine and proteinuria at last visit did not differ between the two treatment arms. Moreover, 88.4% of the patients in the AZA arm were still free of cyclophosphamide treatment. During the first 2 years, the frequency of remission was not different, but infections, especially herpes zoster virus infections (HZV) were more frequent in the AZA group. Parameters for ovarian function did not differ between the two groups. In conclusion, in this open-label randomized controlled trial, cyclophosphamide was superior to azathioprine with regard to renal relapses and HZV. At last follow-up, there were no differences in serum creatinine or proteinuria between the two groups. However, since our study lacked sufficient power, longer follow-up is needed to reveal putative differences.

Administration, Oral↗
PubMed2006

Annexin A5 polymorphism (-1C-->T) and the presence of anti-annexin A5 antibodies in the antiphospholipid syndrome.

BACKGROUND: Annexin A5 is thought to have a role in the pathophysiology of the antiphospholipid syndrome (APS)-a syndrome characterised by recurrent thrombosis and pregnancy morbidity. OBJECTIVE: To investigate whether anti-annexin A5 immunoglobulin (Ig)M or IgG antibodies, or the -1C-->T polymorphism of annexin A5, is a risk factor for thrombosis or miscarriage, and whether the -1C-->T polymorphism is correlated with APS. METHODS: A cohort study was carried out with a population of 198 patients with primary APS, systemic lupus erythematosus or lupus-like disease. For the detection of anti-annexin A5 antibodies and the measurement of annexin A5 plasma levels, ELISA-type methods were used. The annexin A5 -1C-->T mutation was detected by restriction fragment length polymorphism. RESULTS: 71 patients were positive for annexin A5 IgM or IgG antibodies, of whom 53 patients were positive for anti-annexin A5 IgG antibodies and 27 of 198 patients were positive for anti-annexin A5 IgM antibodies. The prevalence of IgM or IgG anti-annexin A5 antibodies was not significantly associated with thrombosis or miscarriage on multivariate analysis. The prevalence of the -1C-->T mutation in the annexin A5 gene (46/198 patients) was significantly associated with miscarriage (odds ratio 2.7, 95% confidence interval 1.1 to 6.7, independent risk factor). CONCLUSION: The detection of anti-annexin A5 antibodies does not seem relevant for estimating the risk for thrombosis or miscarriage in APS. The -1C-->T mutation was an independent risk factor for miscarriage, which is independent of APS.

Abortion, Spontaneous↗
PubMed2006

International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS).

New clinical, laboratory and experimental insights, since the 1999 publication of the Sapporo preliminary classification criteria for antiphospholipid syndrome (APS), had been addressed at a workshop in Sydney, Australia, before the Eleventh International Congress on antiphospholipid antibodies. In this document, we appraise the existing evidence on clinical and laboratory features of APS addressed during the forum. Based on this, we propose amendments to the Sapporo criteria. We also provide definitions on features of APS that were not included in the updated criteria.

Antibodies, Antiphospholipid↗
PubMed2006

Interaction of beta2-glycoprotein I with members of the low density lipoprotein receptor family.

The antiphospholipid syndrome (APS) is a non-inflammatory autoimmune disease characterized by arterial and/or venous thrombosis and/or pregnancy morbidity in the presence of autoantibodies that recognize beta2-glycoprotein I (beta2GPI) bound to phospholipids. We have previously demonstrated that dimerization of beta2GPI by autoantibodies induces platelet activation, involving the platelet receptor apolipoprotein E receptor 2' (apoER2') a receptor belonging to the low-density lipoprotein receptor (LDL-R) family. Here, we show that dimeric beta2GPI, but not monomeric beta2GPI, interacts with four other LDL-R family members: the LDL-R related protein (LRP), megalin, the LDL-R and the very-low density lipoprotein receptor (VLDL-R). Interaction between dimeric beta2GPI and LDL-R, apoER2' and VLDL-R was best described with a one-site binding model (half-maximal binding; approximately 20 nm for apoER2' and VLDL-R and approximately 300 nm for LDL-R), whereas the interaction between dimeric beta2GPI and LRP or megalin was best described with a two-site binding model, representing a high- (approximately 3 nm) and a low-affinity site (approximately 0.2 microm). Binding to all receptors tested was unaffected by a tryptophane to serine (W316S) substitution in domain V of beta2GPI, which is known to disrupt the phospholipid binding site of beta2GPI. Also deletion of domain I or II left the interaction with the receptors unaffected. Deletion of domain V, however, significantly decreased the affinity for the receptors. In conclusion, our data show that dimeric beta2GPI can interact with different LDL-R family members. This interaction is dependent on a binding site within domain V of beta2GPI, which does not overlap with the phospholipid-binding site within domain V.

Animals↗
PubMed2005

Cost-effective detection of non-antidouble-stranded DNA antinuclear antibody specificities in daily clinical practice.

OBJECTIVES: To compare the utility of indirect immunofluorescence for the detection of antinuclear antibodies (ANA-IIF) and a fully automated test (ELiA Symphony) that detects antibodies against a mixture of nuclear and cytoplasmic antigens (ENA), to select sera that should be tested for non-antidouble-stranded DNA (dsDNA) antinuclear antibodies in a relatively expensive automated line immunoassay (INNO-LIA ANA update, Lineblot). METHODS: All 328 sera sent to the laboratory for ANA or anti-ENA tests, over a 4 month period were evaluated in all three assays. Results were related to signs and symptoms of systemic autoimmune disease (AID) that patients had before or at the time of blood sampling. RESULTS: Overall, 72 (22%) sera were Lineblot positive. Of 198 patients without clinical manifestations of AID, 7% were Lineblot positive. Limiting Lineblot to sera positive in either ANA-IIF or Symphony tests failed to detect 26 (ANA-IIF) and 22 (Symphony) Lineblot-reactive sera, with 15 sera being negative in both assays. From a clinical point of view, failure to detect these reactivities was not important in most cases. CONCLUSIONS: Restriction of performance of Lineblot to patients with at least one criterion for AID is an ideal and cost-effective strategy. In ignorance of clinical signs and symptoms, screening of sera by ANA-IIF or Symphony strongly reduces the costs of anti-ENA detection, with minimal loss in diagnostic capacity. Based on small differences, including the fact that anti-dsDNA antibodies give a positive ANA-IIF, we prefer screening with ANA-IIF over Symphony.

Adolescent↗
PubMed2005

[Polymyalgia rheumatica and temporal arteritis].

Polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) are closely related and frequently occurring inflammatory diseases with an incidence of 50 and 18 per 100,000 per year, respectively, in people aged 50 years or over. The most frequent symptom of PMR is aching and morning stiffness lasting more than 1 month and exacerbated by movement, occurring in the shoulder and pelvic girdles and in the neck region. GCA is vasculitis of the large and medium-sized arteries that originate from the aortic arch, causing new and marked headache localised over the temporal or occipital areas, jaw claudication, visual impairment or claudication of the arms. GCA is characterised by histopathological panarteritis with a predominantly lymphohistiocytic cell infiltrate. Activation of macrophages is central to the arteritis. Standard treatment for PMR and GCA is glucocorticoids, which may consist of prednisone 10-20 mg/day or its equivalent for PMR patients and prednisone 30-40 mg to 1 mg/kg body weight for GCA patients. For GCA patients with recently impaired vision, treatment should start with high doses of intravenously administered glucocorticoids, such as methylprednisolone 1 g/day for 3 consecutive days. A treatment duration of 1-2 years is often required for patients with PMR or GCA; because of the side effects associated with long-term use of glucocorticoids, osteoporosis prophylaxis with oral calcium supplementation, vitamin D and bisphosphonates is appropriate.

Age Factors↗
PubMed2005

Pathophysiology of the antiphospholipid syndrome.

Antiphospholipid syndrome is a distinct disorder with the clinical features of recurrent thrombosis in the venous or arterial circulation and fetal losses. Its serological marker is the presence of antiphospholipid antibodies in the blood of these patients. The relation between the presence of antibodies against anionic phospholipids and thromboembolic complications is well established over the last 25 years but the pathophysiology of the syndrome is largely unclear. Even after all these years, there is a persisting debate about the specificity and sensitivity of the assays for the detection of antiphospholipid antibodies. We now accept that antibodies to beta2-glycoprotein I rather than to anionic phospholipids are the major pathological antibodies, although there is no clear consensus on how the presence of these antibodies correlates with the different clinical manifestations of the syndrome. In this review, we discuss the current methods of detection of the antibodies and our insight into the pathobiology of the syndrome. We propose a mechanism for describing how the presence of anti-beta2-glycoprotein I antibodies relates to the different clinical manifestations observed.

Antibodies, Antiphospholipid↗
PubMed2005

Lupus anticoagulants and the risk of a first episode of deep venous thrombosis.

We have determined lupus anticoagulants, anti-beta2 glycoprotein I (beta2GPI) and antiprothrombin antibodies in the Leiden Thrombophilia Study, a population-based case-control study designed to determine risk factors for deep venous thrombosis (DVT). Lupus anticoagulant (LAC) was measured in 473 patients and 472 control subjects. Four control subjects (0.9%) and 14 patients (3.1%) had a positive LAC, resulting in a 3.6-fold increased risk [odds ratio (OR) 3.6, 95% CI: 1.2-10.9]. Of the total population, 49 were positive for anti-beta2GPI antibodies: 15 controls (3.4%) and 34 patients (7.5%), implying a 2.4-fold increased risk (95% CI: 1.3-4.2). Antiprothrombin antibodies were present in 114 subjects: 48 controls (11.0%) and 66 cases (14.6%) with an OR of 1.4 (95% CI: 1.0-2.1). When LAC was considered in the co-presence of antiprothrombin or anti-beta2GPI antibodies the OR increased to 10.1 (95% CI: 1.3-79.8). A LAC without a positive anti-beta2GPI or antiprothrombin test was not associated with a risk for DVT (OR 1.3, 95% CI: 0.3-6.0). This study demonstrates that the presence of LAC, anti-beta2GPI antibodies and antiprothrombin antibodies are risk factors for DVT in a general population. The strongest association holds for the combination LAC and the presence of anti-beta2GPI or antiprothrombin antibodies.

Adolescent↗
PubMed2004

Prolonged bleeding time and lupus anticoagulant: a second paradox in the antiphospholipid syndrome.

OBJECTIVE: Systemic lupus erythematosus and antiphospholipid syndrome (APS) often appear concomitantly. Lupus nephritis and antiphospholipid antibody-related ischemic nephropathy cannot be distinguished clinically, although their etiology and treatment differ greatly. Examination of a renal biopsy sample is therefore essential in order to provide the correct treatment. We have observed that patients with lupus anticoagulant (LAC), a serologic marker for APS, often have a prolonged bleeding time, which is a contraindication for performing a percutaneous renal biopsy. We undertook this study to evaluate systematically the bleeding time in 27 consecutive patients. METHODS: The bleeding time was measured in 27 patients who were persistently positive for LAC and who were not exposed to aspirin or nonsteroidal antiinflammatory drugs. Platelet function and von Willebrand factor (vWF) parameters were subsequently assessed in patients with a prolonged bleeding time. RESULTS: Twenty-one of 27 patients (78%) had a prolonged bleeding time despite a normal platelet count in the majority of patients (81%). Platelet functioning and vWF parameters in these 21 patients were normal, except for those in 1 patient with a mild storage pool disease. CONCLUSION: With this study, we introduce yet another paradox in the phenomenon of APS. Although a prolonged bleeding time is generally accepted to be a sign of defective primary hemostasis, LAC is associated with thrombosis. Further studies are needed to elucidate the mechanism behind this disturbance of primary hemostasis.

Adult↗
PubMed2004

The effect of dehydroepiandrosterone on lumbar spine bone mineral density in patients with quiescent systemic lupus erythematosus.

OBJECTIVE: Because dehydroepiandrosterone (DHEA) is an adrenal steroid hormone with weak intrinsic androgenic properties that can be converted in peripheral tissues into more potent sex hormones, one might expect a positive effect of DHEA on bone mineral density (BMD). We evaluated the effects on lumbar BMD of oral DHEA, 200 mg/day, for 1 year in female patients with quiescent systemic lupus erythematosus (SLE). METHODS: The study subjects were 60 women with SLE. All participants gave informed consent to participate in a double-blind, placebo-controlled study on the effects of DHEA on fatigue and general well-being. BMD was measured with dual-energy x-ray absorptiometry (DEXA) at baseline and after 12 months. RESULTS: Fifty-eight patients (mean age 42.6 years) could be evaluated; 2 patients (both in the DHEA group) refused to undergo DEXA a second time. In premenopausal women, DHEA did not influence BMD significantly. There was a significant increase in BMD with use of DHEA in postmenopausal women who were not receiving bisphosphonates or estrogen-containing medications. This increase was not observed in the group receiving placebo. CONCLUSION: In premenopausal women with quiescent SLE, use of DHEA does not have a significant effect on BMD. DHEA may increase BMD in postmenopausal SLE patients if they are not already protected from bone loss by use of estrogens or bisphosphonates. Small numbers, due to the absence of stratification for menopausal status, and the use of antiresorptive agents at randomization preclude firmer conclusions based on the results of this study.

Absorptiometry, Photon↗
PubMed2004

Serum cytokine levels related to multiple dimensions of fatigue in patients with primary Sjogren's syndrome.

OBJECTIVE: To test whether serum levels of selected cytokines relate to different dimensions of fatigue in patients with primary Sjögren's syndrome (pSS). METHODS: Sixty female patients with pSS filled out a questionnaire to assess multiple dimensions of fatigue. Scores were compared with values in a population based control group (n = 139). Levels of interleukin (IL)1beta, IL2, IL6, IL10, and tumour necrosis factor alpha were measured in serum with commercial sandwich ELISAs. The relationship between self reported dimensions of fatigue and these serum cytokine levels was determined. RESULTS: Patients with pSS had high scores at all dimensions of fatigue (p<0.001): general fatigue, physical fatigue, reduced activity, reduced motivation, and mental fatigue. Fatigue levels were not related to serum cytokine levels. The incidental finding that reduced motivation was higher in patients with detectable serum levels of IL10 (p = 0.04) disappeared after correction for multiple testing. CONCLUSION: Fatigue is prominent in patients with pSS and involves all dimensions of fatigue. The findings do not suggest a widespread effect of circulating cytokines on multiple aspects of fatigue.

Adult↗
PubMed2004

Pathophysiology of antiphospholipid antibodies.

The presence of antiphospholipid antibodies in plasma is a risk factor for thromboembolic complications. In vitro, however, the same antibodies can prolong dotting times in coagulation assays, a classic marker for a bleeding tendency. For years this contradiction has puzzled many scientists. Recently new insights into the interaction between antiphospholipid antibodies and their main target, the protein beta-2-glycoprotein I, have opened new avenues for the understanding of the pathology of this syndrome.

Antibodies, Antiphospholipid↗
PubMed2004

Clinical consequences of antiphospholipid antibodies.

Antiphospholipid antibodies (aPL), notably the lupus anticoagulant and anticardiolipin antibodies, are the serological hallmarks of the antiphospholipid syndrome. Thrombosis and pregnancy complications are the most prominent clinical manifestations of this syndrome. This paper provides the clinician with guidelines for ordering and interpreting tests for aPL and discusses consequences for treatment if persistently positive tests are found.

Antibodies, Anticardiolipin↗
PubMed2003

Low dose aspirin after ischemic stroke associated with antiphospholipid syndrome.

The authors describe course and outcome of eight patients with ischemic stroke as the first thrombotic manifestation of antiphospholipid syndrome who received low-dose aspirin as prophylactic treatment. During 8.9 years of follow-up, two patients had a recurrent stroke. Recurrent stroke rate per 100 patient-years on aspirin was 3.5 (95% CI 0.4 to 12.5).

Adult↗