Ronald H. W. M. Derksen

Anti-inflammatory and immunosuppressive drugs and reproduction

Rheumatic diseases in women of childbearing years may necessitate drug treatment during a pregnancy, to control maternal disease activity and to ensure a successful pregnancy outcome. This survey is based on a consensus workshop of international experts discussing effects of anti-inflammatory, immunosuppressive and biological drugs during pregnancy and lactation. In addition, effects of these drugs on male and female fertility and possible long-term effects on infants exposed to drugs antenatally are discussed where data were available. Recommendations for drug treatment during pregnancy and lactation are given.

Morbidity and mortality in the antiphospholipid syndrome during a 10-year period: a multicentre prospective study of 1000 patients

Objectives To assess the prevalence of the main causes of morbi-mortality in the antiphospholipid syndrome (APS) during a 10-year-follow-up period and to compare the frequency of early manifestations with those that appeared later. Methods In 1999, we started an observational study of 1000 APS patients from 13 European countries. All had medical histories documented when entered into the study and were followed prospectively during the ensuing 10 years. Results 53.1% of the patients had primary APS, 36.2% had APS associated with systemic lupus erythematosus and 10.7% APS associated with other diseases. Thrombotic events appeared in 166 (16.6%) patients during the first 5-year period and in 115 (14.4%) during the second 5-year period. The most common events were strokes, transient ischaemic attacks, deep vein thromboses and pulmonary embolism. 127 (15.5%) women became pregnant (188 pregnancies) and 72.9% of pregnancies succeeded in having one or more live births. The most common obstetric complication was early pregnancy loss (16.5% of the pregnancies). Intrauterine growth restriction (26.3% of the total live births) and prematurity (48.2%) were the most frequent fetal morbidities. 93 (9.3%) patients died and the most frequent causes of death were severe thrombosis (36.5%) and infections (26.9%). Nine (0.9%) cases of catastrophic APS occurred and 5 (55.6%) of them died. The survival probability at 10 years was 90.7%. Conclusions Patients with APS still develop significant morbidity and mortality despite current treatment. It is imperative to increase the efforts in determining optimal prognostic markers and therapeutic measures to prevent these complications.

Adhesion mechanism of human beta 2-glycoprotein I to phospholipids based on its crystal structure

Human β2‐glycoprotein I is a heavily glycosylated five‐domain plasma membrane‐adhesion protein, which has been implicated in blood coagulation and clearance of apoptotic bodies from the circulation. It is also the key antigen in the autoimmune disease anti‐phospholipid syndrome. The crystal structure of β2‐glycoprotein I isolated from human plasma reveals an elongated fish‐hook‐like arrangement of the globular short consensus repeat domains. Half of the C‐terminal fifth domain deviates strongly from the standard fold, as observed in domains one to four. This aberrant half forms a specific phospholipid‐binding site. A large patch of 14 positively charged residues provides electrostatic interactions with anionic phospholipid headgroups and an exposed membrane‐insertion loop yields specificity for lipid layers. The observed spatial arrangement of the five domains suggests a functional partitioning of protein adhesion and membrane adhesion over the N‐ and C‐terminal domains, respectively, separated by glycosylated bridging domains. Coordinates are in the Protein Data Bank (accession No. 1QUB).

Dimers of beta 2-glycoprotein I increase platelet deposition to collagen via interaction with phospholipids and the apolipoprotein E receptor 2'.

Patients with prolonged clotting times caused by lupus anticoagulant (LAC) are at risk for thrombosis. This paradoxal association is not understood. LAC is frequently caused by anti-β2-glycoprotein I (β2GPI) antibodies. Antibody-induced dimerization of β2GPI increases the affinity of β2GPI for phospholipids, explaining the observed prolonged clotting times. We constructed dimers of β2GPI that mimic effects of β2GPI-anti-β2GPI antibody complexes, and we studied their effects on platelet adhesion and thrombus formation in a flow system. Dimeric β2GPI increased platelet adhesion to collagen by 150% and increased the number of large aggregates. We also observed increased platelet adhesion to collagen when whole blood was spiked with patient-derived polyclonal anti-β2GPI or some, but not all, monoclonal anti-β2GPI antibodies with LAC activity. These effects could be abrogated by inhibition of thromboxane synthesis. A LAC-positive monoclonal anti-β2GPI antibody, which did not affect platelet adhesion, prevented the induced increase in platelet adhesion by β2GPI dimers. Furthermore, increased platelet adhesion disappeared after preincubation with receptor-associated protein, a universal inhibitor of interaction of ligands with members of the low density lipoprotein receptor family. Using co-immunoprecipitation, it was shown that dimeric β2GPI can interact with apolipoprotein E receptor 2 (apoER2′), a member of the low density lipoprotein receptor family present on platelets. These results demonstrate that dimeric β2GPI induces increased platelet adhesion and thrombus formation, which depends on activation via apoER2′.

Treat-to-target in systemic lupus erythematosus: recommendations from an international task force

The principle of treating-to-target has been successfully applied to many diseases outside rheumatology and more recently to rheumatoid arthritis. Identifying appropriate therapeutic targets and pursuing these systematically has led to improved care for patients with these diseases and useful guidance for healthcare providers and administrators. Thus, an initiative to evaluate possible therapeutic targets and develop treat-to-target guidance was believed to be highly appropriate in the management of systemic lupus erythematosus (SLE) patients as well. Specialists in rheumatology, nephrology, dermatology, internal medicine and clinical immunology, and a patient representative, contributed to this initiative. The majority convened on three occasions in 2012–2013. Twelve topics of critical importance were identified and a systematic literature review was performed. The results were condensed and reformulated as recommendations, discussed, modified and voted upon. The finalised bullet points were analysed for degree of agreement among the task force. The Oxford Centre level of evidence (LoE, corresponding to the research questions) and grade of recommendation (GoR) were determined for each recommendation. The 12 systematic literature searches and their summaries led to 11 recommendations. Prominent features of these recommendations are targeting remission, preventing damage and improving quality of life. LoE and GoR of the recommendations were variable but agreement was >0.9 in each case. An extensive research agenda was identified, and four overarching principles were also agreed upon. Treat-to-target-in-SLE (T2T/SLE) recommendations were developed by a large task force of multispecialty experts and a patient representative. It is anticipated that ‘treating-to-target’ can and will be applicable to the care of patients with SLE.

A prospective, controlled multicenter study on the obstetric risks of pregnant women with antiphospholipid antibodies

OBJECTIVES A prospective, controlled multicenter study was performed to estimate the obstetric risks of antiphospholipid antibodies (the lupus anticoagulant and anticardiolipin antibodies). In addition, the risks of prior thrombosis, obstetric history, systemic lupus erythematosus, and high-dose prednisone treatment were evaluated. STUDY DESIGN After screening for antiphospholipid antibodies in patients with lupus erythematosus or women with prior fetal loss(es), 59 subsequent pregnancies with and 54 without these antibodies were followed. RESULTS The presence of the lupus anticoagulant and a history of at least three spontaneous abortions could predict fetal loss (p = 0.032 and 0.001, respectively). In live born infants, a low birth weight could be predicted by the presence of anticardiolipin antibodies (p = 0.034), prior intrauterine fetal death (p = 0.025), and treatment with high-dose prednisone (p = 0.002). No relationships were seen between antiphospholipid antibodies and small-for-gestational-age newborns and pregnancy-induced hypertension or preeclampsia. The disappearance of antiphospholipid antibodies during pregnancy was not correlated with live birth. CONCLUSION It is concluded that the presence of antiphospholipid antibodies is a risk factor for adverse pregnancy outcome.

Fcγ receptor polymorphisms in systemic lupus erythematosus: Association with disease and in vivo clearance of immune complexes

OBJECTIVE Fc receptors for IgG (FcgammaR) play a prominent role in the clearance of immune complexes in systemic lupus erythematosus (SLE). Polymorphisms of FcgammaR have been proposed as genetic factors that influence susceptibility to SLE. We analyzed 3 functional FcgammaR polymorphisms in a strictly Caucasian population of SLE patients, and determined the influence of these polymorphisms on the clearance of immune complexes in vivo. METHODS Genomic DNA was isolated from 230 Caucasian patients with SLE and 154 controls. Amplification of FcgammaR-genomic regions in allotype-specific polymerase chain reactions was used to distinguish the genotypes. In addition, we analyzed the FcgammaR genotypes of 13 patients with SLE who participated in a study determining the half-life of IgG-coated erythrocytes in the blood. RESULTS We found a strong trend toward skewing of FcgammaRIIa, with an enrichment of the homozygous FcgammaRIIa-R/R131 genotype in patients compared with controls. We did not find a correlation between this genotype and the development of lupus nephritis. However, we established that the half-life of IgG-coated erythrocytes in the blood was prolonged in patients expressing the FcgammaRIIa-R/R131 genotype. The homozygous FcgammaRIIIa-F/F158 genotype was found more frequently in patients with arthritis and/or serositis. CONCLUSION In Caucasian populations, the R/H polymorphism of FcgammaRIIa is a minor determinant in susceptibility to SLE, whereas the V/F polymorphism of FcgammaRIIIa is associated with a set of disease manifestations. Notably, the R/H polymorphism of FcgammaRIIa affects the clearance of immune complexes in vivo, which may influence the course of a disease such as SLE.

Pathophysiology of the antiphospholipid syndrome

Summary.  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 β2‐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‐β2‐glycoprotein I antibodies relates to the different clinical manifestations observed.

Platelet activation by dimeric β2‐glycoprotein I requires signaling via both glycoprotein Ibα and apolipoprotein E receptor 2′

Summary.  Background: Dimerization of β2‐glycoprotein I (β2‐GPI) by autoantibodies is thought to trigger the clinical manifestations observed in the antiphospholipid syndrome. Arterial thrombosis, a frequently occurring clinical manifestation of the antiphospholipid syndrome, is a process in which platelets play a crucial role. Previous work has shown that binding of dimeric β2‐GPI to the platelet receptors apolipoprotein E receptor 2′ (ApoER2′) and glycoprotein Ibα (GPIbα) mediates increased platelet activation in an in vitro thrombosis model. Objective: The individual roles of ApoER2′ and GPIbα in mediating platelet activation by dimeric β2‐GPI has hitherto been unclear. In this study, we have determined the roles of either receptor in platelet activation by dimeric β2‐GPI. Methods: Platelet activation by dimeric β2‐GPI was studied under conditions of flow. Intracellular signaling induced by dimeric β2‐GPI was subsequently analyzed by means of sodium dodecylsulfate polyacrylamide gel electrophoresis (SDS‐PAGE) and western blot analysis. Results: The increase in platelet deposition onto a fibronectin surface under conditions of flow by dimeric β2‐GPI was completely abolished by inhibition of the interaction of dimeric β2‐GPI with either GPIbα or ApoER2′. Upon platelet stimulation with dimeric β2‐GPI, GPIbα translocated to the cytoskeleton via the scaffold protein 14‐3‐3ζ. Concomitantly, ApoER2′ dissociated from the adapter protein Disabled1, presumably through phosphorylation of the cytoplasmic tail. Inhibition of one process could not inhibit the other. Conclusion: We show that dimeric β2‐GPI signals via two distinct pathways in platelets, both of which are required for platelet activation. Abrogation of either signal results in loss of activation.

Haematopoietic and endothelial progenitor cells are deficient in quiescent Systemic Lupus Erythematosus

Background: Systemic lupus erythematosus (SLE) is associated with a high prevalence of cardiovascular disease. Circulating endothelial progenitor cells (EPCs) contribute to vascular regeneration and repair, thereby protecting against atherosclerotic disease. EPCs are derived from CD34+ haematopoietic stem cells (HSCs), which have an increased propensity for apoptosis in the bone marrow of patients with SLE. Aim: To determine whether circulating HSCs and EPCs are reduced in SLE, contributing to an increased cardiovascular risk. Methods: Progenitor cells were sampled from 15 female patients with SLE in prolonged clinical remission from their disease and 15 matched healthy controls. HSC and CD34+KDR+ EPCs were quantified by flow cytometry. Annexin V staining was used to identify apoptotic cells. Results: Patients with SLE had reduced levels of circulating CD34+ HSCs and CD34+KDR+ EPCs, associated with increased HSC apoptosis. Compared with controls, the fraction of HSCs that could be identified as EPCs was higher in patients with SLE, consistent with a primary defect of HSCs. EPC outgrowth from mononuclear cells, which depends mainly on CD34− cells, was unaffected. Conclusions: Patients with SLE have lower levels of circulating HSCs and EPCs, even during clinical remission. The data suggest that increased HSC apoptosis is the underlying cause for this depletion. These observations indicate that progenitor cell-mediated endogenous vascular repair is impaired in SLE, which may contribute to the accelerated development of atherosclerosis.