A framework for remission in SLE: consensus findings from a large international task force on definitions of remission in SLE (DORIS).

OBJECTIVES: Treat-to-target recommendations have identified 'remission' as a target in systemic lupus erythematosus (SLE), but recognise that there is no universally accepted definition for this. Therefore, we initiated a process to achieve consensus on potential definitions for remission in SLE. METHODS: An international task force of 60 specialists and patient representatives participated in preparatory exercises, a face-to-face meeting and follow-up electronic voting. The level for agreement was set at 90%. RESULTS: The task force agreed on eight key statements regarding remission in SLE and three principles to guide the further development of remission definitions:1. Definitions of remission will be worded as follows: remission in SLE is a durable state characterised by …………………. (reference to symptoms, signs, routine labs).2. For defining remission, a validated index must be used, for example, clinical systemic lupus erythematosus disease activity index (SLEDAI)=0, British Isles lupus assessment group (BILAG) 2004 D/E only, clinical European consensus lupus outcome measure (ECLAM)=0; with routine laboratory assessments included, and supplemented with physician's global assessment.3. Distinction is made between remission off and on therapy: remission off therapy requires the patient to be on no other treatment for SLE than maintenance antimalarials; and remission on therapy allows patients to be on stable maintenance antimalarials, low-dose corticosteroids (prednisone ≤5 mg/day), maintenance immunosuppressives and/or maintenance biologics.The task force also agreed that the most appropriate outcomes (dependent variables) for testing the prognostic value (construct validity) of potential remission definitions are: death, damage, flares and measures of health-related quality of life. CONCLUSIONS: The work of this international task force provides a framework for testing different definitions of remission against long-term outcomes.

Measurement of antinuclear antibodies and their fine specificities: time for a change in strategy?

OBJECTIVES: The current strategy for antinuclear antibody (ANA) analysis involves screening for presence with a subsequent detailed analysis of their specificity. The aim of this study is to compare the clinical and financial efficacy of this strategy between different commercial tests in a large cohort of unselected patients. METHODS: In all consecutive 1030 patients associations were defined between results from different ANA test systems and the pre-test probability for connective tissue disease (CTDs). Test systems were used for screening (ANA-IIF vs. CTD screen) and definition of their fine specificity (profile 3 line blot vs. CTD single analytes). RESULTS: Positive ANA-IIF and/or CTD screen results were found in 304 sera. Further analysis for ANA-specificity by profile 3 line blot and CTD single analytes showed 86 discrepant results of which more than a third are clinically relevant, with the CTD single analyte assay performing better than the line blot in supporting or confirming the presence of a CTD. Autoantigens present in one test but absent in the other were of minor practical use. The ANA screening and identification strategies currently employed are not cost-effective as 83% of tests were performed in order to find specific autoantibodies in patients without the fitting clinical signs or symptoms. This causes many unexpected positive results and subsequent confusion with regard to interpretation. CONCLUSIONS: We advocate that some autoantigens should be excluded from the line blot and CTD assays and propose the use of a cost-effective and selective ANA specificity testing purely based on clinical guidance.

Fc-gamma receptor polymorphisms differentially influence susceptibility to systemic lupus erythematosus and lupus nephritis.

OBJECTIVE: To determine relevant Fc-gamma receptor (FcγR) polymorphisms in relation to susceptibility to SLE and LN, and to determine the functional consequences of genetic associations found. METHODS: Using multiplex ligation-dependent probe amplification, copy number regions (CNRs) and relevant known functional single nucleotide polymorphisms of FcγRII and FcγRIII were determined in a LN-enriched cohort of 266 Dutch Caucasian SLE patients and 919 healthy Caucasian controls. Expression of FcγRs on leukocytes was assessed using flow cytometry. RESULTS: In multivariable analysis, low copy number of CNR1 (including FCGR3B; odds ratio (OR) 2.04; 95% CI: 1.29, 3.23), FCGR2A-131RR (OR 2.00; 95% CI: 1.33, 2.99), and the 2B.4 haplotype of FCGR2B (OR 1.59; 95% CI: 1.13, 2.24), but not FCGR2C open reading frame, were significantly (all P < 0.01) and independently associated with susceptibility to SLE. The 2B.4 haplotype was negatively associated with LN and led to surface expression of FcγRIIb on neutrophils and monocytes. CONCLUSION: This study is the first to investigate the most relevant and functional single nucleotide polymorphisms and copy number variations of FcγRII and FcγRIII polymorphisms in one study population, enabling the determination of the individual contribution of each polymorphism in multivariable analysis. Three polymorphisms were shown to be independently associated with susceptibility to SLE. The novel findings of a negative association of the 2B.4 haplotype with LN, and increased expression of FcγRIIb on neutrophils and monocytes as a result of this 2B.4 haplotype warrant future research in the role of these cells and FcγRs in the pathogenesis of SLE and LN.

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.

Apolipoprotein E receptor 2 is involved in the thrombotic complications in a murine model of the antiphospholipid syndrome.

Antiphospholipid (aPL)/anti-ß(2) glycoprotein I (anti-ß(2)GPI) antibodies stimulates tissue factor (TF) expression within vasculature and in blood cells, thereby leading to increased thrombosis. Several cellular receptors have been proposed to mediate these effects, but no convincing evidence for the involvement of a specific one has been provided. We investigated the role of Apolipoprotein E receptor 2 (ApoER2') on the pathogenic effects of a patient-derived polyclonal aPL IgG preparation (IgG-APS), a murine anti-ß(2)GPI monoclonal antibody (E7) and of a constructed dimeric ß(2)GPI I (dimer), which in vitro mimics ß(2)GPI-antibody immune complexes, using an animal model of thrombosis, and ApoER2-deficient (-/-) mice. In wild type mice, IgG-APS, E7 and the dimer increased thrombus formation, carotid artery TF activity as well as peritoneal macrophage TF activity/expression. Those pathogenic effects were significantly reduced in ApoER2 (-/-) mice. In addition, those effects induced by the IgG-APS, by E7 and by the dimer were inhibited by treatment of wild-type mice with soluble binding domain 1 of ApoER2 (sBD1). Altogether these data show that ApoER2 is involved in pathogenesis of antiphospholipids antibodies.

Long-term follow-up of a randomised controlled trial of azathioprine/methylprednisolone versus cyclophosphamide in patients with proliferative lupus nephritis.

OBJECTIVES: The objectives of this study are to analyse the long-term follow-up of a randomised controlled trial of induction treatment with azathioprine/methylprednisolone (AZA/MP) versus high-dose intravenous cyclophosphamide (ivCY) in patients with proliferative lupus nephritis (LN) and to evaluate the predictive value of clinical, laboratory and renal biopsy parameters regarding renal outcome. METHODS: 87 patients with biopsy-proven proliferative LN were treated with either AZA/MP (n=37) or ivCY (n=50), both with oral prednisone. After 2 years, renal biopsy was repeated, and all patients continued with AZA/oral prednisone. The primary study end point was sustained doubling of serum creatinine. Secondary end points included renal relapse, end-stage renal disease and mortality. RESULTS: After a median follow-up of 9.6 years, no significant differences between AZA/MP versus ivCY groups were found in the proportion of patients with sustained doubling of serum creatinine (n=6 (16%) vs n=4 (8%); p=0.313), end-stage renal disease (n=2 (5%) vs n=2 (4%); p=1.000) or mortality (n=6 (16%) vs n=5 (10%); p=0.388). Renal relapses occurred more often in the AZA/MP group (n=14 (38%) vs n=5 (10%); p=0.002, HR: 4.5). Serum creatinine, proteinuria and immunosuppressive treatment regimens at the last follow-up were comparable. Clinical and laboratory parameters at baseline and after 2 years, and renal biopsy parameters (only) at baseline predicted renal outcome. CONCLUSION: Induction treatment with ivCY was superior to AZA/MP in preventing renal relapses, but other parameters for renal function did not differ. AZA/MP can therefore serve as an alternative in patients with proliferative LN who wish to avoid gonadal toxicity of CY. Several prognostic factors of long-term renal outcome were identified.

Beta2-glycoprotein I can exist in 2 conformations: implications for our understanding of the antiphospholipid syndrome.

The antiphospholipid syndrome is defined by the presence of antiphospholipid antibodies in blood of patients with thrombosis or fetal loss. There is ample evidence that beta(2)-glycoprotein I (beta(2)GPI) is the major antigen for antiphospholipid antibodies. The autoantibodies recognize beta(2)GPI when bound to anionic surfaces and not in solution. We showed that beta(2)GPI can exist in at least 2 different conformations: a circular plasma conformation and an "activated" open conformation. We also showed that the closed, circular conformation is maintained by interaction between the first and fifth domain of beta(2)GPI. By changing pH and salt concentration, we were able to convert the conformation of beta(2)GPI from the closed to the open conformation and back. In the activated open conformation, a cryptic epitope in the first domain becomes exposed that enables patient antibodies to bind and form an antibody-beta(2)GPI complex. We also demonstrate that the open conformation of beta(2)GPI prolonged the activated partial thromboplastin time when added to normal plasma, whereas the activated partial thromboplastin time is further prolonged by addition of anti-beta(2)GPI antibodies. The conformational change of beta(2)GPI, and the influence of the autoantibodies may have important consequences for our understanding of the antiphospholipid syndrome.

Corrigendum to "Maternal and Perinatal Outcome in Women with Systemic Lupus Erythematosus: A Retrospective Bicenter Cohort Study".

[This corrects the article DOI: 10.1155/2017/8245879.].

Association between beta2-glycoprotein I plasma levels and the risk of myocardial infarction in older men.

von Willebrand factor (VWF) serves as adhesive surface for platelets to adhere to the vessel wall. We have recently found that beta2-glycoprotein I is able to inhibit platelet binding to VWF, indicating a role in the pathophysiology of arterial thrombosis. In the present study, we investigated whether differences in beta2-glycoprotein I plasma levels influence the risk of myocardial infarction. We have measured beta2-glycoprotein I and VWF antigen levels in 539 men with a first myocardial infarction and in 611 control subjects. Although we did not find a profound effect of beta2-glycoprotein I plasma levels on myocardial infarction in the overall population, we found a dose-dependent protective effect of increasing beta2-glycoprotein I plasma levels on myocardial infarction in men 60 years and older. In this age group, we found an odds ratio of 0.41 (95% confidence interval, 0.22-0.74) for high beta2-glycoprotein I levels compared with low levels. High plasma levels of beta2-glycoprotein I remained protective for myocardial infarction despite high levels of VWF. To conclude, high circulating levels of beta2-glycoprotein I appeared to be associated with a reduced risk of myocardial infarction in elderly men. In vivo experiments are needed to investigate the exact contribution of beta2-glycoprotein I on the pathophysiology of myocardial infarction.

Current insight into diagnostics and pathophysiology of the antiphospolipid syndrome.

The diagnosis of the antiphospholipid syndrome, a non-inflammatory autoimmune disease characterized by thrombosis or pregnancy morbidity in the presence of antiphospholipid antibodies, depends greatly upon laboratory diagnostics. The diagnostic value of all available assays to detect antiphospholipid antibodies and the anticardiolipin assay in particular, is a matter of ongoing debate. Although the presence of lupus anticoagulant correlates best with thrombosis, accurate determination is not always possible due to anticoagulant treatment. Data on the predictive value of alternatives such as the anti-beta2-glycoprotein I and the anti-prothrombin antibody assay are insufficient and prospective cohort studies are needed. Determining antiphospholipid antibody profiles seems to increase diagnostic specificity. Substantial progress has been made in unravelling the pathophysiological mechanisms underlying the antiphospholipid syndrome. Several cellular receptors for antibody-beta2-glycoprotein I complexes have been identified and their roles in cellular activation are being investigated. In vivo data should provide more insight into the importance of the interaction with individual receptors.

Twenty-two years of failure to set up undisputed assays to detect patients with the antiphospholipid syndrome.

The antiphospholipid syndrome is defined by the persistent presence of antiphospholipid antibodies in plasma of patients with a history of thrombosis and/or pregnancy morbidity. From the definition in 1985 onwards, confusion has arisen concerning who has the syndrome and who has not. Although the clinical criteria are well defined, there is ongoing discussion regarding serologic criteria. Lack of standardization of the assays that define the serologic criteria, notably phospholipids-dependent coagulation assays, and enzyme-linked immunosorbent assays (ELISAs) for anticardiolipin and anti-beta2 glycoprotein I, have led to heated arguments regarding which population(s) of antibodies should be measured to detect a patient at risk for (recurrent) thrombosis or pregnancy complications. Everybody agrees on the need to better standardize the assays, but different views are held on how this should be achieved, and commercial interests have hampered consensus on which assays should be applied, how they should be performed, and the cutoff values that discriminate between pathologic and nonpathologic results. New prospective cohort studies to reevaluate the clinical significance of the available assays are essential, but the lack of sufficient patient numbers visiting single hospital facilities frustrates progress. This review discusses shortcomings of the current serologic assays, provides strategies to solve these shortcomings, and discusses new developments/assays to improve the specificity of such assays for thrombosis and pregnancy complications.

The development of offspring from mothers with systemic lupus erythematosus. A systematic review.

OBJECTIVE: To analyze published data on the influence of maternal systemic lupus erythematosus (SLE) on different aspects of child development. METHODS: A systematic review was conducted using PubMed and Embase searches for SLE or SLE-related antibodies and physical, neurocognitive, psychiatric or motor development outcomes in children. RESULTS: In total 24 cohort and 4 case-control studies were included after initial screening of 1853 hits. Learning disorders (LD) were reported in 21.4-26% of SLE offspring, exceeding the prevalence in the general population. Four studies reported that dyslexia and reading problems were present in 14.3-21.6% of lupus offspring with a clear male predominance. Furthermore, a twofold increased rate of autism spectrum disorders (ASD) (n=1 study) and a two- to threefold increased risk for speech disorders (n=3 studies) were reported in lupus offspring compared to controls, although the latter was not statistically significant. More divergent results were found for attention deficit (n=5 studies) and behavior disorders (n=3 studies). In two large controlled studies attention disorders were more prevalent and a trend towards more behavior disorders was reported in 2 of 3 studies analyzing this subject. Finally, IQ and motor skills were not affected in respectively 7 and 5 studies. Cardiopulmonary functioning and mood disorders were scarcely investigated (both n=1). Maternal anti-SSA antibodies were associated with LD in offspring in one study. Other SLE-related antibodies were rarely studied. CONCLUSION: This systematic review suggests that maternal SLE is associated with LD (specifically dyslexia), ASD, attention deficit and probably speech problems in offspring. However, over half of the studies were assigned a low or moderate evidence level. Therefore, further research is necessary to substantiate the found evidence and expand the scope to lesser researched areas such as cardiopulmonary functioning.

Maternal and Perinatal Outcome in Women with Systemic Lupus Erythematosus: A Retrospective Bicenter Cohort Study.

OBJECTIVE: To investigate disease activity around and during pregnancy and pregnancy outcome in women with systemic lupus erythematosus (SLE) considering antiphospholipid antibody status. Moreover, differences between first and consecutive pregnancies were examined. METHODS: Pregnancies > 16 weeks gestation of SLE patients receiving joint care from rheumatologists and gynecologists in two tertiary centers in the Netherlands between 2000 and 2015 were included. Disease activity, flare rate, and pregnancy outcomes and complications were assessed. RESULTS: Ninety-six women (84% Caucasian) with 144 pregnancies were included. The median SLE(P)DAI score was 2 before, during, and after pregnancy. Flare rates were 6.3%, 20.1%, and 15.3%, respectively. Severe hypertensive disorder of pregnancy, intrauterine fetal death, preterm birth, and small-for-gestational age infants occurred in 18.1%, 4.1%, 32.7%, and 14.8%, respectively. Complication rates were similar in the first and consecutive pregnancies. Half of the women did not experience any pregnancy complication whereas 42.7% developed a complication during all pregnancies. Mean number of pregnancies was 2.4 and live births 1.7. CONCLUSION: In this SLE population with low disease activity, pregnancy complications were present irrespective of antiphospholipid antibody status. Furthermore, there were no differences in complication rates between the first and consecutive pregnancies as seen in healthy mothers. This information is useful for patient counseling.

Delineating the deranged immune system in the antiphospholipid syndrome.

The antiphospholipid syndrome (APS) is a systemic autoimmune disease that is characterized serologically by the presence of antiphospholipid antibodies (aPL) and clinically by vascular thrombosis and obstetric complications. The protein ß2 glycoprotein I (ß2GPI) is identified as the most important autoantigen in this syndrome. Activation of endothelial cells, thrombocytes and placental tissue by anti-ß2GPI antibodies relates to the clinical manifestations of APS. This review describes genetic and environmental factors in relation to APS and summarizes the current knowledge on abnormalities in components of both the innate and adaptive immune system in APS. The role of dendritic cells, T-cells, B-cells, monocytes, neutrophils and NK-cells as well as the complement system in APS are discussed. Several gaps in our knowledge on the pathophysiology of APS are identified and a plea is made for future extensive immune cell profiling by a systems medicine approach in order to better unravel the pathogenesis of APS, to gain more insight in the role of the immune system in APS as well as having the potential to reveal biomarkers or novel therapeutic targets.

The prevalence of antinuclear antibodies in patients with schizophrenia spectrum disorders: results from a large cohort study.

BACKGROUND: An increased prevalence of autoantibodies has been found in patients with schizophrenia, suggesting a role for autoimmunity in schizophrenia pathogenesis. METHODS: We examined the presence of antinuclear antibodies (ANAs), with further determination of specific antibodies, in 368 patients with a schizophrenia spectrum disorder and 283 healthy controls. RESULTS: No significant difference in prevalence of ANAs between patients (8%) and controls (11%) was found. CONCLUSION: We did not find an association between ANAs and schizophrenia spectrum disorders. We discuss potential reasons for the discrepancy with some previous studies, such as inclusion of patients using chlorpromazine, which can induce ANAs.

Newer drugs for the treatment of lupus nephritis.

This article first reviews the current treatment of lupus nephritis, with a focus on the most serious forms, that is, the proliferative subtypes. Current standards for treatment have been developed empirically. Corticosteroids form the basis of all regimens. Cyclophosphamide given intravenously for prolonged periods is the current gold standard. Azathioprine can be regarded as an effective drug for maintenance treatment of lupus nephritis. Studies on its efficacy in schedules for remission induction are in progress. It has been learned from studies on 'conventional' immunosuppression that randomised, clinical trials should comprise large numbers of patients and a follow-up of many years to elucidate differences between effective strategies. These requirements are not met by any of the 'new' treatments we discuss in this review. There is only limited experience in patients with lupus nephritis with drugs that are currently used for immunosuppression in other autoimmune diseases, such as methotrexate, cyclosporin and high-dose intravenous gammaglobulins, nor with new immunosuppressive drugs that have been developed for immunosuppression in organ transplantation (mycophenolate mofetil, tacrolimus, fludarabine and cladribine). Hormonal therapy with the weak androgen prasterone (dehydroepiandrosterone; DHEA) has no role in treatment of active lupus nephritis. There are interesting experiences with agents that have evolved from progress in immunobiology and in our understanding of immunological processes. These modalities enable more specific immunosuppression and include monoclonal antibodies directed at immune cells, cytokines and components of the complement system, constructs developed to induce tolerance in pathogenic B cells, and gene therapy. Finally, we review data on autologous bone marrow transplantation in patients with systemic lupus erythematosus. We conclude that some strategies (like mycophenolate mofetil) are good candidates for further investigation in large-scale, prospective, randomised trials with prolonged follow-up (which are almost by definition hard to perform). Most new biological agents still are in a pre-clinical phase.

Beta2-glycoprotein I and LDL-receptor family members.

The presence of antiphospholipid antibodies in plasma is a risk factor for thrombo-embolic complications. In vitro, however, the same antibodies can prolong clotting times in coagulation assays, a classic marker for a bleeding tendency. For years this contradiction puzzles many scientists.We now know that the term antiphospholipid antibodies comprises a heterogeneous population of antibodies and there is growing evidence that only subpopulations of antiphospholipid antibodies are relevant for the clinical complication. In combination with new information on the complex interaction between antiphospholipid antibodies, the protein beta2-Glycoprotein I, and cellular surfaces have opened new avenues for the understanding of the pathology of this syndrome.

Optimisation of lupus anticoagulant tests: should test samples always be mixed with normal plasma?

Coagulation factor deficiencies are thought to interfere with the detection of the phospholipid-dependent coagulation inhibitor known as lupus anticoagulant (LA). Treatment with vitamin K antagonists (VKA) in particular, is thought to preclude accurate LA assessment. For this reason, the procedure to detect LA includes a mixing test, in which coagulation factor deficiencies are corrected by mixing samples with an equal volume of normal plasma. Despite these mixing tests, interpretation of LA test results is considered difficult in patients receiving high intensity VKA treatment. As a result, VKA treatment is often temporarily discontinued to allow LA assessment. However, whether coagulation factor deficiencies influence LA test results is unclear. We found that neither deficiency of a single coagulation factor, nor a functional coagulation factor deficiency due to high intensity VKA treatment, resulted in false positive dRVVT- or APTT-based (silica clotting time; SCT) LA test results. LA was readily detected in unmixed samples from VKA-treated LA-positive patients with both dRVVT and SCT reagents. VKA treatment caused an underestimation of the strength of the LA with SCT reagents, but did not lead to misclassification of LA status. Although mixing with normal plasma during both screen and confirm tests allowed more accurate assessment of the strength of the LA with SCT reagents in samples with an international normalised >2.5, the mixing procedure itself lead to misclassification of LA in weakly positive samples from patients not treated with VKA. Based on these findings, we conclude that mixing studies are not necessary during LA-assessment.