Irene E. M. Bultink

The association between circulating antibodies against domain I of beta2-glycoprotein I and thrombosis: an international multicenter study

Summary.  Background: Diagnosis of the antiphospholipid syndrome (APS) is difficult as a result of limited specificity of existing assays for detecting clinically relevant antiphospholipid antibodies. Anti‐beta2‐glycoprotein I (beta2GPI) antibodies play a central role in the disease process of APS. Objectives: We have investigated the relation between antiphospholipid antibodies with specificity for domain I of beta2GPI and thrombosis/pregnancy morbidity in an international multicenter study. Patients/methods: Four hundred and seventy‐seven patients derived from nine different centres met the inclusion criterion of having anti‐beta2GPI antibodies in their plasma/serum. Clinical data and results of tests for lupus anticoagulant, anti‐cardiolipin antibodies and anti‐beta2GPI antibodies were established at the different centres of inclusion. After being re‐tested for the presence of IgG and/or IgM anti‐beta2GPI antibodies, the samples were tested for the presence of IgG‐directed against domain I of beta2GPI and results were correlated with the thrombotic and obstetric history. Results: Re‐testing for the presence of anti‐beta2GPI antibodies resulted in inclusion of 442/477 patients. IgG class anti‐domain I antibodies were present in plasma of 243/442 patients (55%). 201/243 (83%) had a history of thrombosis. This resulted in an odds ratio of 3.5 (2.3–5.4, 95% confidence interval) for thrombosis. Anti‐domain I IgG antibodies were also significantly correlated with obstetric complications [odds ratio: 2.4 (1.4–4.3, 95% confidence interval)]. Conclusion: In this multicenter study, the detection of IgG antibodies that are directed against domain I of beta2GPI proved to be more strongly associated with thrombosis and obstetric complications than those detected using the standard anti‐beta2GPI antibody assay.

Glucocorticoid-induced Osteoporosis

Glucocorticoid-induced osteoporosis is one of the most important side-effects of glucocorticoid use, leading to an increased fracture risk. In this review, recent advances in the understanding of the mechanisms of glucocorticoid-induced osteoporosis are summarised. Methods to identify persons at risk for fractures are discussed, as well as the new ACR recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis (2010). Different treatment options are summarised considering the pathogenesis of glucocorticoid-induced osteoporosis. Improved insights into pathogenesis might result in development of new treatment possibilities.

Osteoporosis and fractures in systemic lupus erythematosus

Introduction Osteoporosis and fractures contribute to damage in one of the most frequently involved organ systems in patients with systemic lupus erythematosus (SLE): the musculoskeletal system. In recent studies, a high frequency of low bone mineral density (BMD) and both peripheral and vertebral fractures has been demonstrated in patients with SLE. Moreover, a relative high frequency of undertreatment of SLE patients with manifest osteoporosis or at high risk of the development of osteoporosis has been reported. These findings highlight the need to develop better strategies for the prevention and treatment of osteoporosis and fractures as important disease complications in SLE. SLE is a chronic autoimmune disease that usually affects women. Because survival of SLE patients has improved over the last decades, attention is now focused on complications that contribute to increased morbidity and mortality. The etiology of bone loss and the occurrence of fractures in SLE is supposed to be multifactorial, involving both non–disease-related and disease-related factors. Importantly, several risk factors associated with reduced BMD and fractures in SLE are modifiable by lifestyle measures or medication. This review discusses the etiology of osteoporosis and fractures in patients with SLE and proposes measures for the prevention and treatment of these complications.

Advances in Glucocorticoid-Induced Osteoporosis

Glucocorticoid-induced osteoporosis (GIOP) is one of the most important side effects of glucocorticoid use, as it leads to an increased risk of fractures. Recently, many published studies have focused on the cellular and molecular mechanisms of bone metabolism, the pathophysiology of GIOP, and the intervention options to prevent GIOP. In this review, recent advances in GIOP are summarized, particularly recent progress in our understanding of the mechanisms of GIOP resulting in improved insight that might result in the development of new treatment options in the near future.

Inflammatory Rheumatic Disorders and Bone

Inflammatory joint diseases such as rheumatoid arthritis, as well as other rheumatic conditions, such as systemic lupus erythematosus (SLE) and ankylosing spondylitis, comprise a heterogeneous group of joint disorders that are all associated with extra-articular side effects, including bone loss and fractures. The concept of osteoimmunology is based on growing insights into the links between the immune system and bone. The pathogenesis of osteoporosis in these patients is multifactorial. We have, more or less as an example, described this extensively for patients with SLE. High disease activity (inflammation) and immobility are common factors that substantially increase fracture risk in these patients, on top of the background fracture risk based on, among other factors, age, body mass index, and gender. Although no fracture reduction has been shown in intervention studies in patients with inflammatory rheumatic diseases, we present treatment options that might be useful for clinicians who are treating these patients.

Sensing of latent EBV infection through exosomal transfer of 5′pppRNA

Significance Increasing evidence suggests that the exosomal messenger pathway warns neighboring cells against cellular stress and infection. Recent studies have shown that viruses and cancer cells exploit exosomes to transmit functional RNAs. Our studies reveal that a viral small RNA signal for innate immunity Epstein–Barr virus (EBV)-EBER1 is produced by latent EBV-infected B cells and recognized by noninfected dendritic cells activating an inflammatory response. We detected high amounts of EBV-EBER1 transcripts and EBV-microRNAs in inflamed skin lesions of autoimmune patients that are infiltrated with dendritic cells. Importantly, we found virtually no EBV-DNA present in these tissues, suggesting that continuous cell–cell EBER1 transmission via exosomes occurs in humans. We propose that innate sensing of latent EBV in predisposed individuals may be more harmful than previously thought. Complex interactions between DNA herpesviruses and host factors determine the establishment of a life-long asymptomatic latent infection. The lymphotropic Epstein–Barr virus (EBV) seems to avoid recognition by innate sensors despite massive transcription of immunostimulatory small RNAs (EBV-EBERs). Here we demonstrate that in latently infected B cells, EBER1 transcripts interact with the lupus antigen (La) ribonucleoprotein, avoiding cytoplasmic RNA sensors. However, in coculture experiments we observed that latent-infected cells trigger antiviral immunity in dendritic cells (DCs) through selective release and transfer of RNA via exosomes. In ex vivo tonsillar cultures, we observed that EBER1-loaded exosomes are preferentially captured and internalized by human plasmacytoid DCs (pDCs) that express the TIM1 phosphatidylserine receptor, a known viral- and exosomal target. Using an EBER-deficient EBV strain, enzymatic removal of 5′ppp, in vitro transcripts, and coculture experiments, we established that 5′pppEBER1 transfer via exosomes drives antiviral immunity in nonpermissive DCs. Lupus erythematosus patients suffer from elevated EBV load and activated antiviral immunity, in particular in skin lesions that are infiltrated with pDCs. We detected high levels of EBER1 RNA in such skin lesions, as well as EBV-microRNAs, but no intact EBV-DNA, linking non–cell-autonomous EBER1 presence with skin inflammation in predisposed individuals. Collectively, our studies indicate that virus-modified exosomes have a physiological role in the host–pathogen stand-off and may promote inflammatory disease.

Deficiency of functional mannose-binding lectin is not associated with infections in patients with systemic lupus erythematosus

Infection imposes a serious burden on patients with systemic lupus erythematosus (SLE). The increased infection rate in SLE patients has been attributed in part to defects of immune defence. Recently, the lectin pathway of complement activation has also been suggested to play a role in the occurrence of infections in SLE. In previous studies, SLE patients homozygous for mannose-binding lectin (MBL) variant alleles were at an increased risk of acquiring serious infections in comparison with patients who were heterozygous or homozygous for the normal allele. This association suggests a correlation between functional MBL level and occurrence of infections in SLE patients. We therefore investigated the biological activity of MBL and its relationship with the occurrence of infections in patients with SLE. Demographic and clinical data were collected in 103 patients with SLE. Functional MBL serum levels and MBL-induced C4 deposition were measured by enzyme-linked immunosorbent assay using mannan as coat and an MBL- or C4b-specific monoclonal antibody. The complete MBL-dependent pathway activity was determined by using an assay that measures the complete MBL pathway activity in serum, starting with binding of MBL to mannan, and was detected with a specific monoclonal antibody against C5b-9. Charts were systematically reviewed to obtain information on documented infections since diagnosis of SLE. Major infections were defined as infections requiring hospital admission and intravenous administration of antibiotics. In total, 115 infections since diagnosis of lupus, including 42 major infections, were documented in the 103 SLE patients (mean age 41 ± 13 years, mean disease duration 7 ± 4 years). The percentage of SLE patients with severe MBL deficiency was similar to that in 100 healthy controls: 13% versus 14%, respectively. Although deposition of C4 to mannan and MBL pathway activity were reduced in 21% and 43% of 103 SLE patients, respectively, neither functional MBL serum levels nor MBL pathway activity was associated with infections or major infections in regression analyses. In conclusion, SLE patients frequently suffer from infections, but deficiency of functional MBL does not confer additional risk.

Depression in systemic lupus erythematosus, dependent on or independent of severity of disease.

Objectives To estimate the prevalence of depression in subjects with systemic lupus erythematosus (SLE) in relation to the general population and to unravel the relation between depression and SLE disease characteristics. Methods One hundred and two subjects with SLE (mean age 44.4 years) were studied using the Beck Depression Inventory (BDI) score to estimate the prevalence of depression. The BDI scores in subjects with SLE were compared with BDI scores from a pan-European population based study (Outcome in Depression International Network (ODIN) study, n = 7934), i.e. the general population. Results The mean BDI score was higher in SLE subjects (10.1 points) compared with the BDI scores derived from the general population (10.1 versus 5.6 points, respectively, p < 0.001). This corresponds to a prevalence of depression of 16.6% and 6.7%, respectively. There was no association between disease activity or organ damage and BDI scores in subjects with SLE (p > 0.1). Only 7% of SLE subjects with high BDI scores used antidepressants. Conclusion The mean BDI score and prevalence of depression are significantly higher in SLE subjects compared with the general population. No association was found between SLE disease characteristics and BDI scores. The number of depressed SLE subjects treated with antidepressants is low, suggesting inadequate recognition and treatment of depression in SLE.

Glucocorticoid-induced osteoporosis: an update on current pharmacotherapy and future directions

Introduction: Glucocorticoid-induced osteoporosis (GIOP) is one of the most devastating side-effects of glucocorticoid (GC) use, as it is associated with an increased fracture risk. The importance of GIOP as a health problem is underlined by the frequent use of GC treatment in patients with various chronic diseases and by the high rates of osteoporosis found in these patient groups. Areas covered: Recent studies on bone metabolism and the influence of GCs have contributed to a better understanding of the pathogenesis of GIOP. Furthermore, new intervention trials have reported beneficial effects of antiresorptive and anabolic agents on GIOP. This article reviews the epidemiology and pathophysiology of osteoporosis and fractures in GC-treated patients and discusses current pharmacotherapy and possible future treatment options. Expert opinion: Several guidelines for the management of GIOP have been published, using different criteria for bone mineral density (BMD) thresholds and for GC dosages above which anti-osteoporotic therapy should be started. Although alendronate and risedronate are currently first choice, the anabolic agent teriparatide seems to be superior and might be considered as a potential first-line therapy for patients with low BMD on long-term GC treatment. Adherence to anti-osteoporotic drugs is limited, particularly in GIOP patients, due to several factors.

Fusobacterium nucleatum Septicemia and Portal Vein Thrombosis

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