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.

Serious infections in systemic lupus erythematosus with a focus on pneumococcal infections.

BACKGROUND: Infections are important denominators of morbidity and mortality in patients with systemic lupus erythematosus (SLE). Pneumococcus pneumoniae has been identified as a relatively frequent cause of serious infections in SLE and vaccination against this pathogen is possible. We analysed the incidence of serious infections in a cohort of SLE patients, focussing on Streptococcus pneumoniae. METHODS: We retrospectively screened the medical records of all SLE patients who were regularly seen in the outpatient clinic of our department between January 2010 and December 2012. We registered all infections that necessitated admission to the hospital (serious infection) and compared relevant clinical and laboratory parameters and immunomodulating/immunosuppressive treatment in patients with and without serious infections. RESULTS: In the total cohort of 260 patients, there were 132 episodes of serious infection in 70 patients, with a median follow-up per patient of 11.4 years (range 0 to 50.2 years). S. pneumoniae accounted for 11/132 (8.3%) serious infection episodes and eight of 11 episodes were invasive. With a follow-up of 3970.6 years for the total cohort, this leads to an incidence of 201/100.000 patient-years. In the multivariate analysis neither clinical parameters nor use of immunosuppressive drugs correlated with occurrence of serious infections. CONCLUSIONS: Compared to the incidence of invasive pneumococcal infections in the Dutch population (15.6/100.000 patient years), the incidence in SLE patients is 13 times higher. This, in combination with the absence of a relation to use of immunosuppressive drugs, is a strong argument to recommend vaccination against S. pneumoniae in all SLE patients.

Pathophysiology of thrombotic APS: where do we stand?

The antiphospholipid syndrome (APS) is diagnosed when patients with thrombotic complications or foetal losses have elevated levels of antiphospholipid antibodies in their plasmas. The term APS is confusing, because the pathogenic auto-antibodies are not directed against phospholipids but towards a plasma protein, ß(2)-glycoprotein I. For many years the reason why auto-antibodies against ß(2)-glycoprotein I were pro-thrombotic was unclear, because man and mice deficient in ß(2)-glycoprotein I do not express a clear phenotype. Animal models in which passive transfer of patient antibodies into mice resulted in an increased thrombotic response have provided novel insights in the importance of this protein in the pathology of APS.

Fatigue in patients with systemic lupus erythematosus: the role of dehydroepiandrosterone sulphate.

Fatigue is a major problem in systemic lupus erythematosus (SLE), but the physiological substrate of this fatigue is largely unclear. To examine if low levels of dehydroepiandrosterone (DHEA) and its sulphate DHEAS play a role in SLE fatigue, we compared: 1) DHEAS levels and fatigue between 60 female patients with SLE with low disease activity (31 using, 29 not using prednisone) and 60 age-matched healthy women, and 2) fatigue between patients with SLE with low and normal DHEAS levels. Serum DHEAS levels were determined with an Advantage Chemiluminescense System. The Multidimensional Fatigue Inventory (MFI) was used to assess fatigue. Patients were more fatigued (p ≤ 0.001) than healthy women and more often had below-normal DHEAS levels (p < 0.001). Patients using prednisone with low and normal DHEAS levels reported a similar level of fatigue (p ≥ 0.39). Patients with low DHEAS levels not using prednisone reported less fatigue than those with normal DHEAS levels (p ≤ 0.03). Thus, our results indicate that low DHEAS levels in SLE are not - or even inversely - related to fatigue. After our previous finding that DHEA administration does not reduce fatigue, this result further indicates that low serum DHEA(S) levels alone do not offer an explanation for SLE fatigue.

Receptor for advanced glycation end products (RAGE) polymorphisms are associated with systemic lupus erythematosus and disease severity in lupus nephritis.

OBJECTIVE: Interaction of advanced glycation end products (AGEs) with their receptors (RAGE) plays an important role in inflammation in auto-immune diseases. Several functional polymorphisms of RAGE have been described. In this study we analysed the role of RAGE polymorphisms in disease susceptibility for systemic lupus erythematosus (SLE). In addition, we investigated whether these polymorphisms in SLE are associated with serum levels of soluble RAGE (sRAGE), renal involvement (lupus nephritis (LN)) and its outcome. METHODS: For this cross-sectional study DNA samples of 97 SLE patients, 114 LN patients and 429 healthy controls (HC) were genotyped for four RAGE polymorphisms: -429 T/C, -374 T/A, 2184 A/G and Gly82Ser. Differences in genotype frequencies and allele frequencies were tested between patients and HCs. In SLE patients, sRAGE was measured by enzyme-linked immunosorbent assay (ELISA). In addition, association of genotypes with sRAGE and disease severity in LN was analysed. RESULTS: The C allele of -429 T/C, the T allele of -374 T/A and the G allele of 2184 A/G were significantly more prevalent in SLE and LN compared with HC. In LN, the C allele of RAGE -429 T/C, the A allele of -374 T/A and the G allele of RAGE 2184 A/G polymorphism were significantly associated with more proteinuria and worse renal function during the first two years of treatment. No association of genotype with sRAGE was found. CONCLUSION: RAGE polymorphisms are associated with susceptibility to SLE and LN. In addition, some of these polymorphisms are likely to be associated with disease severity and initial response to treatment in LN.

Corrigendum to "Hydroxychloroquine Use in Lupus Patients during Pregnancy Is Associated with Longer Pregnancy Duration in Preterm Births".

[This corrects the article DOI: 10.1155/2017/2810202.].

Serum dehydroepiandrosterone sulphate levels and laboratory and clinical parameters indicating expression of disease are not associated with fatigue, well-being and functioning in patients with primary Sjögren's syndrome.

OBJECTIVES: The aim of this study was to compare serum dehydroepiandrosterone sulphate (DHEAS) levels and clinical and laboratory parameters reflecting expression of disease between female patients with primary Sjögren's syndrome (pSS) and age-matched healthy women and to examine in pSS patients the correlation of these variables with fatigue, well-being, and functioning. METHODS: Comparisons were made between 60 female pSS patients and 60 age-matched healthy women. We assessed questionnaire scores of general fatigue, depressed mood, mental wellbeing, and physical functioning, tear production (Schirmer I test), tender point counts, serum DHEAS level, haemoglobin concentration, erythrocyte sedimentation rate, and serum immunoglobulin G. RESULTS: As compared to healthy participants, patients had more fatigue and depressed mood, reduced well-being and functioning, more dryness and pain, lower serum DHEAS levels, and more expression of disease as reflected by laboratory assessments (p≤0.001). In pSS patients, fatigue, well-being, and functioning correlated with tender point counts, but not with the extent of dryness and also not with laboratory assessments including serum DHEAS levels. CONCLUSIONS: The high prevalence of fatigue and reduced functioning in pSS patients might suggest a mediating role of generalised autoimmune processes. In the present study, clinical observations and laboratory assessments are not correlated with persistent fatigue and reduced functioning. Our results suggest that treatment of fatigue, well-being, and functioning, should target other variables than those examined in this study, preferably psychological variables or perhaps specific immunologic parameters.

Effects of dehydroepiandrosterone on fatigue and well-being in women with quiescent systemic lupus erythematosus: a randomised controlled trial.

OBJECTIVE: Dehydroepiandrosterone (DHEA) has been reported to improve fatigue and reduced well-being. Both are major problems in patients with systemic lupus erythematosus (SLE), even with quiescent disease. Low serum DHEA levels are common in SLE. The present work investigates the effects of DHEA administration on fatigue, well-being and functioning in women with inactive SLE. METHODS: In a double-blind, randomised, placebo-controlled study, 60 female patients with inactive SLE received 200 mg oral DHEA or placebo. Primary outcome measures were general fatigue, depressive mood, mental well-being and physical functioning. Assessments were made before treatment, after 3, 6 and 12 months on medication, and 6 months after cessation of treatment. RESULTS: Patients from the DHEA and placebo group improved on general fatigue (p<0.001) and mental well-being (p=0.04). There was no differential effect of DHEA. The belief that DHEA had been used was a stronger predictor for improvement of general fatigue than the actual use of DHEA (p=0.04). CONCLUSIONS: The trial does not indicate an effect of daily 200 mg oral DHEA on fatigue and well-being, and therefore DHEA treatment is not recommended in unselected female patients with quiescent SLE. Clinical Trials Registration Number NCT00391924.

Towards evidence-based treatment of thrombotic antiphospholipid syndrome.

Thrombosis in the presence of persistently positive tests for antiphospholipid antibodies is termed thrombotic antiphospholipid syndrome (APS). At present, 'standard' secondary thromboprophylaxis in thrombotic APS is treatment with moderate intensity oral anticoagulants for life after a first venous thrombosis and with high intensity oral anticoagulation after non-embolic ischaemic stroke. These recommendations differ from those applied in the general population, where a restricted period of anticoagulation is common practice after venous thrombosis and antiplatelet drugs are the first choice after ischaemic stroke. From an extensive literature review we conclude that the available data are insufficient to apply a different strategy for secondary thromboprophylaxis in patients with thrombotic APS than the one that holds for the general population.

The role of LRP8 (ApoER2') in the pathophysiology of the antiphospholipid syndrome.

One of the greatest enigmas in thrombosis research is the observation that one can diagnose a person with a thrombotic risk with a prolongation of the clotting time. Our textbooks have taught us that prolongation of clotting correlates with a tendency to bleed. To confuse our textbook knowledge further, the same patients often have a prolonged bleeding time, a diagnostic test to detect a dysfunction in primary haemostasis. In this paper we critically review the literature that tries to explain the contradiction that exists between in-vitro diagnostic tests and the observed clinical manifestations and discuss our current opinion on how antiphospholipid antibodies can disturb the haemostatic balance.

Variability of fatigue during the day in patients with primary Sjögren's syndrome, systemic lupus erythematosus, and rheumatoid arthritis.

OBJECTIVES: Fatigue is a common complaint of patients with primary Sjögren's syndrome (pSS), systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA). The aim of this study was to examine and compare in patients with these diseases the course of fatigue within the first hour after awakening and during the day, and to examine sleep disturbance as a potential determinant of fatigue. METHODS: Eight repeated measurements at 5 fatigue dimensions were assessed on 2 consecutive days in the natural environment of female patients with pSS (n=29), SLE (n=23), RA (n=19), and healthy women (n=52). Sleep disturbance of the previous night was assessed. Fatigue levels and the change of fatigue after awakening and during the day were analysed with analyses of variance (adjusted for age). RESULTS: The patients showed significantly elevated levels at all fatigue dimensions as compared to healthy participants. Fatigue levels decreased in the first hour after awakening in patients with SLE and RA, but increased or did not change in patients with pSS. Fatigue progressively increased during the remainder of the day for all patient groups. Sleep disturbance correlated with overall fatigue levels, but hardly with the change of fatigue within the first hour after awakening. CONCLUSIONS: Our study confirms the presence of increased fatigue in patients with pSS, SLE, and RA. Patients with pSS failed to show a decrease in fatigue in the first hour after awakening. Future research should examine the causes of this difference in fatigue after awakening.

Morbidity and mortality in the antiphospholipid syndrome during a 5-year period: a multicentre prospective study of 1000 patients.

OBJECTIVES: To identify the main causes of morbidity and mortality in patients with antiphospholipid syndrome (APS) during a 5-year period and to determine clinical and immunological parameters with prognostic significance. METHODS: The clinical and immunological features of a cohort of 1000 patients with APS from 13 European countries who had been followed up from 1999 to 2004 were analysed. RESULTS: 200 (20%) patients developed APS-related manifestations during the 5-year study period. Recurrent thrombotic events appeared in 166 (16.6%) patients and the most common were strokes (2.4% of the total cohort), transient ischaemic attacks (2.3%), deep vein thromboses (2.1%) and pulmonary embolism (2.1%). When the thrombotic events occurred, 90 patients were receiving oral anticoagulants and 49 were using aspirin. 31/420 (7.4%) patients receiving oral anticoagulants presented with haemorrhage. 3/121 (2.5%) women with only obstetric APS manifestations at the start of the study developed a new thrombotic event. A total of 77 women (9.4% of the female patients) had one or more pregnancies and 63 (81.8% of pregnant patients) had one or more live births. The most common fetal complications were early pregnancy loss (17.1% of pregnancies) and premature birth (35% of live births). 53 (5.3% of the total cohort) patients died. The most common causes of death were bacterial infection (21% of deaths), myocardial infarction (19%) and stroke (13%). No clinical or immunological predictor of thrombotic events, pregnancy morbidity or mortality was detected. CONCLUSION: Patients with APS still develop significant morbidity and mortality despite current treatment (oral anticoagulants or antiaggregants, or both).

Effect of dehydroepiandrosterone administration on fatigue, well-being, and functioning in women with primary Sjögren syndrome: a randomised controlled trial.

OBJECTIVE: Dehydroepiandrosterone (DHEA) administration has been reported to improve fatigue, psychological distress, and physical disability. These are common features of primary Sjögren syndrome (pSS). We investigated the effects of DHEA administration on fatigue, well-being, and functioning in women with pSS. METHODS: In a double-blind, randomised placebo-controlled clinical trial, 60 female patients with pSS received 200 mg oral DHEA or placebo. Primary outcome measures were general fatigue, depressive mood, mental well-being, and physical functioning. In addition, pain, sicca complaints and disease activity parameters were measured. Patients were assessed before treatment, after 3, 6, and 12 months on study medication, and 6 months after cessation of treatment. RESULTS: Patients from both the DHEA- and placebo-treated group improved on general fatigue (p<0.001), mental well-being (p = 0.04), and depressive mood (p = 0.008). Physical functioning did not change (p = 0.44). Of the secondary outcome variables, complaints of a dry mouth diminished during treatment in both groups (p = 0.006), the erythrocyte sedimentation rate showed a decrease for the DHEA group (p = 0.02), and complaints of dry eyes improved in the placebo group (p = 0.01). The belief to have used DHEA was a stronger predictor for improvement of fatigue and well-being than the actual use of DHEA. CONCLUSIONS: Our study does not support a superior effect of DHEA over placebo in female patients with pSS. Both DHEA and placebo induce improvement of fatigue and well-being. This may suggest possibilities for cognitive behavioural interventions.

The obstetric antiphospholipid syndrome.

The association of persistent presence of circulating antiphospholipid antibodies and thromboembolic events, (recurrent) pregnancy loss or both is termed antiphospholipid syndrome. Pregnancies in women with the syndrome should be regarded as at high-risk for complications. Optimal management consisting of close follow-up and pharmacological treatment can result in about 70-80% live births. Apart from the laboratory diagnosis of the syndrome and pathophysiology, this review will focus on treatment during pregnancy.

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.

Platelets express three different splice variants of ApoER2 that are all involved in signaling.

BACKGROUND: beta2-Glycoprotein I is the most relevant antigen in antiphospholipid syndrome. We have shown that binding of dimerized beta2-GPI to platelets via ApoER2' sensitizes platelets for second activating stimuli. OBJECTIVE: Determine the region of ApoER2 involved in the binding of dimeric beta2-GPI. METHODS: Cultured human megakaryocytes (MK) and three different human megakaryocytic cell lines were used for mRNA isolation to clone and express recombinant soluble platelet ApoER2. Domain deletion mutants of ApoER2 were constructed to identify the binding site for dimeric beta2-GPI. The presence of ApoER2 splice variants in platelets was demonstrated by immuno-blotting. RESULTS: Three different mRNA splice variants were isolated from all four types of megakaryocytic cells used. Sequence analysis identified the splice variants: (i) shApoER2Delta5 lacking low-density lipoprotein (LDL) binding domains 4, 5 and 6; (ii) shApoER2Delta4-5 lacking LDL binding domains 3, 4, 5, 6 and (iii) shApoER2Delta3-4-5 lacking LDL binding domains 3, 4, 5, 6 and 7. The presence of three splice variants of ApoER2 on platelets was confirmed by immuno-blotting, with ApoER2Delta4-5 being the most abundantly expressed splice variant. Upon stimulation with dimeric beta2-GPI, all three splice variants were translocated to the cytosol; however, ApoER2Delta4-5 translocation was most prominent. Dimeric beta2-GPI binds platelet ApoER2 variants via LDL-binding domain 1. CONCLUSIONS: Three different ApoER2 mRNA splice variants were isolated from MK and platelets express all three splice variants. All splice variants were shown to be functional by translocation upon stimulation with dimeric beta2-GPI. All three splice variants express LDL-binding domain 1.

Hydroxychloroquine Use in Lupus Patients during Pregnancy Is Associated with Longer Pregnancy Duration in Preterm Births.

OBJECTIVE: To investigate the effect of hydroxychloroquine (HCQ) in pregnant women with systemic lupus erythematosus (SLE). METHODS: In SLE pregnancies of a single Dutch center (2000-2015), lupus activity and flares before and during pregnancy and postpartum were assessed using the SLE Disease Activity Index (SLEDAI)/SLEPDAI (SLEDAI adjusted for pregnancy). The association between HCQ use and pregnancy outcomes (early spontaneous abortion, fetal death, and preterm and term live birth) was analyzed using generalized estimating equations (GEE) accounting for the occurrence of multiple pregnancies per patient. Analyses were adjusted for antiphospholipid antibody (aPL) status. RESULTS: 110 pregnancies (63 mostly Caucasian patients) were included, of which, in 30, HCQ was used; overall occurrence of flares was low (non-HCQ group: 5 mild (6.4%) and 2 severe (2.6%); HCQ group: 2 mild (6.7%) and no severe flares). The HCQ group showed a trend towards lower dosage of prednisone (OR 0.2 (95% CI 0.0-1.4); p = 0.10). Pregnancy outcomes were comparable between groups. Among preterm live births, pregnancy duration was significantly longer in HCQ users (2.4 weeks (95% CI 1.0-3.8; p ≤ 0.001)). CONCLUSION: HCQ use was associated with longer pregnancy duration in the vulnerable preterm birth population, underscoring the beneficial effect of HCQ use during pregnancy.

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.

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.

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.