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Objective This study aimed to explore the risk factors for ‘severe’ neuropsychiatric (NP) flare in patients with systemic lupus erythematosus (SLE). Methods This retrospective study comprised newly diagnosed 184 adult SLE patients who visited Hokkaido University Hospital between 2006 and 2017. In this study, severe NP flare was defined as the occurrence of at least one newly developed British Isles Lupus Assessment Group A score in the neurological domain. Overall severe NP flare-free survival was estimated by Kaplan–Meier analysis. Clinical and demographic profiles at SLE diagnosis were assessed as potential risk items in the adjusted multivariate Cox regression model. Results The median follow-up period was 7.9 years (interquartile range (IQR) 4.6–12.3) years. A total of 28 (15.2%) patients had one or more severe NP flares during the observation period. The median time from patient enrolment date to severe NP flare occurrence was 3.1 years (IQR 0.9–6.3 year). The 2- and 10-year severe NP flare-free survival rates were 92.7% and 86.0%, respectively. Among the manifestations of severe NP flare, psychosis was the most frequent (19.1%). In the multivariate model, low serum levels of C4 (hazard ratio (HR) = 3.67, p = 0.013) and severe NP manifestations at SLE diagnosis (HR = 7.11, p Conclusion The first severe NP flare presented early in the course of SLE. Low C4 level and severe NP manifestations at SLE diagnosis could predict the development of severe NP flare.

The objective of this study is to identify the effects of statins and risk factors for thrombosis in patients with new onset of systemic lupus erythematosus (SLE) with or without antiphospholipid antibodies (aPL). Consecutive patients with SLE without history of thrombotic events were retrospectively enrolled from April 1997 to February 2014. The development of first thrombosis and death caused by thrombosis were defined as the study endpoint. Risk and protective factors for developing thrombosis were analyzed. A total of 152 patients, 80 positive and 72 negative for aPL, were included. In aPL-positive patients, 15 developed arterial ( n = 6) and venous ( n = 9) thrombosis (median follow-up period 69 months). Cox's proportional hazards model showed that older age at SLE onset and IgG-anticardiolipin antibodies (aCL) were statistically significant risks for thrombosis. Statin therapy was identified as a statistically significant protective factor against thrombosis (hazard ratio 0.12, 95% confidence interval 0.01-0.98). In aPL-negative patients (median follow-up period 46 months), seven patients developed thrombosis (five arterial and two venous). No risk factors for thrombosis were found in this group. In aPL-positive patients with SLE, the late disease onset and the presence of IgG-aCL represented additional risk factors for thrombosis. Statin treatment appeared as a protective factor for thrombosis.

Objective The objective of this study was to clarify the efficacy and safety of factor Xa inhibitors for antiphospholipid syndrome patients in real world utilization. Methods This is a retrospective cohort study comprised of all consecutive patients with antiphospholipid syndrome in our department over a period of 28 years. Patients treated with factor Xa inhibitors were extracted from the cohort. As a control group, patients treated with warfarin were selected from the same cohort with matched age, gender, coexistence of systemic lupus erythematosus, and the presence of antiplatelet therapy, after which we used a propensity score for each of the risk factors as an additional covariate in multivariate Cox proportional hazard regression. The primary endpoint was set as thrombotic and hemorrhagic event-free survival for five years. Results Among 206 patients with antiphospholipid syndrome, 18 had a history of anti-Xa therapy (five rivaroxaban, 12 edoxaban, one apixaban). Fourteen out of 18 patients on anti-Xa therapy had switched to factor Xa inhibitors from warfarin. Event-free survival was significantly shorter during anti-Xa therapy than that during warfarin therapy (hazard ratio: 12.1, 95% confidence interval: 1.73–248, p = 0.01) ( Figure 1(a) ). Similarly, event-free survival in patients treated with factor Xa inhibitors was significantly shorter compared with controls (hazard ratio: 4.62, 95% confidence interval: 1.54–13.6, p = 0.0075). In the multivariate Cox proportional hazard model, event-free survival in patients with anti-Xa therapy remained significantly shorter (hazard ratio: 11.9, 95% confidence interval: 2.93–56.0, p = 0.0005). Conclusions Factor Xa inhibitors may not be recommended for antiphospholipid syndrome.

Objective Obstetric complications are common in patients with antiphospholipid syndrome. However, the impact of antiphosholipid antibodies (aPL) in the pregnancy outcomes of asymptomatic aPL carriers is uncertain. The aim of this systematic review is to assess whether primary prophylaxis is beneficial to prevent obstetric complications during pregnancy in asymptomatic women positive for aPL who have no history of recurrent pregnancy loss or intrauterine fetal death. Methods Studies evaluating the effect of prophylactic treatment versus no treatment in asymptomatic pregnant aPL carriers were identified in an electronic database search. Design, population and outcome homogeneity of studies was assessed and meta-analysis was performed. The pooled Mantel–Haenszel relative risk of specific pregnancy outcomes was obtained using random effects models. Heterogeneity was measured with the I2 statistic. All analyses were conducted using Review Manager 5.3. Results Data from five studies involving 154 pregnancies were included and three studies were meta-analysed. The risk ratio and 95% confidence interval (CI) of live birth rates, preterm birth, low birth weight and overall pregnancy complications in treated and untreated pregnancies were 1.14 (0.18–7.31); 1.71 (0.32–8.98); 0.98 (0.07–13.54) and 2.15 (0.63–7.33),respectively. Results from the meta-analysis revealed that prophylactic treatment with aspirin is not superior to placebo to prevent pregnancy complications in asymptomatic aPL carriers. Conclusion This systematic review did not find evidence of the superiority of prophylactic treatment with aspirin compared to placebo or usual care to prevent unfavourable obstetric outcomes in otherwise healthy women with aPL during the first pregnancy.

Recently our group introduced the “antiphospholipid score” (aPL-S), a quantitative marker that represents aPL profile. We have validated its efficacy for the diagnosis of antiphospholipid syndrome (APS) and predictive value for thrombosis. The study comprised two independent sets of patients with autoimmune diseases. In the first set of patients ( n = 233), the aPL-S was established by analyzing aPL profiles. In the second set of patients ( n = 411), the predictive value of the aPL-S for thrombosis was evaluated. To define aPL-S, we calculated the relative risks (approximated by odds ratios (ORs)) of having APS manifestations (thrombosis and/or pregnancy morbidity) for each of the aPL tests and devised an original formula in which aPL-S was determined by OR: aPL-S = 5 × exp ([OR] −5)/4. The receiver operating characteristic (ROC) curve showed a hyperbolic pattern and the area under the ROC curve value was 0.752 (0.686 for revised Sapporo criteria), implying that aPL-S is a potential quantitative marker for APS diagnosis. The OR for thrombosis in patients with a high aPL-S (≥30) was 5.27 (95% confidence interval (95% CI) 2.32–11.95, p

Background CD36, known as a scavenger receptor, is a transmembrane glycoprotein expressed on monocytes, platelets and endothelial cells, recognizes multiple ligands, including phosphatidylserine, and regulates atherogenesis and thrombosis. The objective of this study is to investigate the possible involvement of CD36 in the pathophysiology of thrombosis in patients with antiphospholipid syndrome (APS). Methods First, rs3765187, a missense mutation linked to CD36 deficiency, was investigated by TaqMan polymerase chain reaction (PCR) genotyping method in 819 Japanese, including 132 patients with APS, 265 with systemic lupus erythematosus (SLE) in the absence of APS, and 422 healthy subjects. Then, the involvement of CD36 in antiphospholipid antibody (aPL)-induced tissue factor (TF) expression was examined using CD36-null mice or anti-CD36. Purified IgG from patients with APS and a monoclonal phosphatidylserine-dependent antiprothrombin antibody were used in these experiments. TF expression was tested by real-time PCR and flow cytometry. Results Minor allele carrier of rs3765187 was less frequent in patients with APS (3.8% p = 0.032), but not in patients with SLE in the absence of APS (7.9% p = 0.32), compared with healthy subjects (10.2%). The aPL-induced TF expression was significantly suppressed on peritoneal macrophages from CD36-null mice compared to wild type and significantly inhibited by anti-CD36 on human monocytes. Conclusions The gene mutation linked to CD36 deficiency was less frequent in patients with APS. The deficient or suppressed CD36 function significantly reduced aPL-induced TF expression in vitro. Taken together, in a susceptible background CD36 scavenger receptor function may be involved in the thrombotic pathophysiology in patients with APS.

Objective The objective of this paper is to elucidate the not yet known plasma molecule candidates involved in the induction of tissue factor (TF) expression mediated by β2GPI-dependent anticardiolipin antibody (aCL/β2GPI) on monocytes. Methods Human serum incubated with FLAG-β2GPI was applied for affinity chromatography with anti- FLAG antibody. Immunopurified proteins were analyzed by a liquid chromatography coupled with mass spectrometry (LC-MS). TF mRNA induced by the identified molecules on monocytes was also analyzed. Results Apolipoprotein B100 (APOB) was the only identified serum molecule in the MS search. Oxidized LDL, containing APOB as well as ox-Lig1 (a known ligand of β2GPI), was revealed as a β2GPI-binding molecule in the immunoprecipitation assay. TF mRNA was markedly induced by oxidized LDL/β2GPI complexes with either WBCAL-1 (monoclonal aCL/β2GPI) or purified IgG from APS patients. The activities of lipoprotein-associated phospholipase A2, one of the component molecules of oxidized LDL, were significantly higher in serum from APS patients than in those from controls. Conclusion APOB (or oxidized LDL) was detected as a major β2GPI binding serum molecule by LC-MS search. Oxidized LDL/aCL/β2GPI complexes significantly induced TF expressions on monocytes. These data suggest that complexes of oxidized LDL and aCL/β2GPI may have a crucial role in the pathophysiology of APS.

The pathogenesis of thrombocytopenia in patients with antiphospholipid syndrome (APS) is heterogeneous. Patients with antiphospholipid antibodies (aPL) and thrombocytopenia in the absence of clinical manifestations of APS will be diagnosed and treated as idiopathic thrombocytopenic purpura. However, the presence of aPL places those individuals at particular risk for developing both bleeding and thrombotic complications. Therefore, we propose the inclusion of such patients in the subgroup ‘aPL-associated thrombocytopenia’. More attention should be devoted to this subgroup of patients to elucidate the role of aPL in the development of thrombocytopenia and to facilitate the adequate monitoring of its potential thrombotic risk.

Interstitial lung disease (ILD) in patients with polymyositis (PM) and dermatomyositis (DM) is often resistant to treatment and life threatening, being recognized as one of the severest complication in these autoimmune disorders. Patients with clinically amyopathic dermatomyositis (CADM) or those with anti-CADM140/MDA5 antibody are especially prone to develop rapidly progressive interstitial pneumonia. We retrospectively analyzed 46 patients with PM/DM admitted to our hospital and identified DM, rapidly progressive disease, honeycomb lung, CADM and extensive ILD as risk factors for recurrence or death. In the presence of two or more risk factors, the sensitivity and specificity for the prediction of death or relapse were 81.3% and 76.7%, respectively. Calcineurin inhibitors have been widely used as induction and maintenance therapy for PM/DM-associated ILD. Recently we reported the benefit of tacrolimus on the disease-free survival and event-free survival of the patients with PM/DM-associated ILD. Among those patients treated with tacrolimus, poor prognostic factors for death, recurrence or severe adverse event were identified as acute progression of the disease, honeycomb lung, forced vital capacity (FVC) less than 80% and having DM. The potential effectiveness of an intensive therapy protocol with triple therapy that comprises high-dose corticosteroids, calcineurin inhibitors and cyclophosphamide has been reported.

Objective: To study the clinical and immunological manifestations of antiphospholipid syndrome (APS) in the Japanese population by a single-centre registration. Methods: In this retrospective cohort study, 141 consecutive patients with APS, fulfilling the Sydney revised Sapporo criteria for definite APS, who visited our autoimmune clinic from 1988 to 2010, were recruited and followed up. All the patients were interviewed and underwent a general physical examination by qualified rheumatologists on the day of blood sampling. Results: The population comprised 119 woman and 22 men with a mean age at diagnosis of 44 years (range 9–79 years). Seventy patients (49.6%) had primary APS, and 71 (50.4%) had systemic lupus erythematosus. The prevalence of thrombosis was 85.8 per cent, arterial thrombosis was found in 93 patients (66.0%) and venous thrombosis was found in 46 patients (32.6%). The most common thrombosis was cerebral infarction [86/141 (61.0%)] followed by deep vein thrombosis [33/141 (23.4%)]. Among 70 pregnant women, 45 (64.3%) had obstetric complications. Lupus anticoagulant was detected in 116 patients (82.3%), anticardiolipin antibodies in 83 (58.9%), anti-β2 glycoprotein I antibodies in 73 (51.8%) and phosphatidylserine-dependent antiprothrombin antibodies in 98 (69.5%). Conclusion: High prevalence of arterial thrombosis was noted in Japanese patients with APS. The profile of heterogeneous and complex clinical manifestations was substantiated in Japanese patients with APS.

Abstract: Current classification criteria for definite APS recommend the use of one or more of three positive standardized laboratory assays, including anticardiolipin antibodies (aCL), lupus anticoagulant (LA), and antibodies directed to β2glycoprotein I (anti-β2GPI) to detect antiphospholipid antibodies (aPL) in the presence of at least one of the two major clinical manifestations (i.e., thrombosis or pregnancy morbidity) of the syndrome. Several other autoantibodies shown to be directed to phospholipids and/or their complexes with phospholipids and/or to proteins of the coagulation cascade, as well as a mechanistic test for resistance to annexin A5 anticoagulant activity, have been proposed to be relevant to APS. A task force of worldwide scientists in the field discussed and analyzed critical questions related to ‘non-criteria’ aPL tests in an evidence-based manner during the 13th International Congress on Antiphospholipid Antibodies (APLA 2010, 13–16 April 2010, Galveston, Texas, USA). This report summarizes the findings, conclusions, and recommendations of this task force.