Ryo Hisada

Post-steroid neuropsychiatric manifestations are significantly more frequent in SLE compared with other systemic autoimmune diseases and predict better prognosis compared with de novo neuropsychiatric SLE ☆

In patients with systemic lupus erythematosus (SLE), neuropsychiatric (NP) symptoms sometimes occur after administration of corticosteroids, making differential diagnosis between NPSLE and steroid-induced psychosis challenging for clinicians. The aim of this study was to clarify the characteristics of post-steroid NP disease (PSNP) in patients with SLE. Clinical courses of 146 patients with SLE and 162 with other systemic autoimmune diseases, all in the absence of NP manifestations on admission, were retrospectively analyzed. Forty-three NPSLE patients on admission (de novo NPSLE) were also investigated. All patients were consecutively recruited and treated with 40mg/day or more of prednisolone in Hokkaido University Hospital between April 2002 and March 2015. The prevalence of PSNP was strikingly higher in SLE patients than other systemic autoimmune diseases (24.7% vs. 7.4%, OR 4.09, 95% CI 2.04-8.22). As independent risk factors to develop PSNP in SLE patients, past history of mental disorder and the presence of antiphospholipid syndrome were identified using multiple logistic regression analysis. In patients with PSNP-SLE, mood disorder was significantly more frequent than in de novo NPSLE (47.2% vs. 20.9%, OR 3.38, 95% CI 1.26-9.04). Of PSNP-SLE patients, two-thirds were with one or more abnormal findings in cerebrospinal fluid, electroencephalogram, MRI or SPECT. Majority of our PSNP-SLE patients received intensified immunosuppressive treatments and experienced improvement in most cases. PSNP-SLE had better relapse-free survival than de novo NPSLE (p<0.05, log rank test). In conclusion, PSNP frequently occurred in patients with SLE and treated successfully with immunosuppressive therapy, indicating that NPSLE is likely to harbor patients with PSNP-SLE.

Thrombotic risk stratification by platelet count in patients with antiphospholipid antibodies: a longitudinal study.

Essentials Thrombotic risk stratification is an unmet need in antiphospholipid antibody carriers. Platelet count and antiphospholipid score (aPL‐S) were combined to predict thrombotic events. Patients with high aPL‐S are at high thrombotic risk regardless of platelet count. If platelet count is low, patients with low aPL‐S are also on high thrombotic risk.

Autoantibodies against a complement component 1 q subcomponent contribute to complement activation and recurrent thrombosis/pregnancy morbidity in anti-phospholipid syndrome

OBJECTIVE To investigate the prevalence and significance of the autoantibodies against complement component 1 q subcomponent (C1q) in patients with APS. METHODS In all, 40 consecutive primary APS patients, 42 patients with non-SLE CTDs and 20 SLE patients negative for aPL were enrolled in this retrospective analysis. Refractory APS was defined as a clinical status of recurring thrombosis or pregnancy morbidity during adequate secondary prophylaxis. An ELISA was used to measure serum levels of anti-C1q antibodies and anaphylatoxins (C3a, C4a). RESULTS Anti-C1q antibodies were found in 36% (15/42) and 2.5% (1/40) of primary APS patients and controls, respectively. Among primary APS patients, anti-C1q antibody titres were significantly correlated with serum C4a levels (P = 0.013). Neither the prevalence nor the titre of anti-C1q antibodies was associated with any specific clinical manifestations of APS, nor titres of aPL. Refractory APS patients (n = 10) had a higher prevalence of anti-C1q antibodies (9/10 vs 6/32, P = 0.01) than APS patients without recurrence (n = 32). CONCLUSION Anti-C1q antibodies are associated with complement activation in APS and may contribute to the pathogenesis, particularly in refractory cases.

Treatment of Vasodilator-resistant Mixed Connective Tissue Disease-associated Pulmonary Arterial Hypertension with Glucocorticoid and Cyclophosphamide

Pulmonary arterial hypertension (PAH) associated with systemic lupus erythematosus (SLE) or mixed connective tissue disease (MTCD), in contrast to other types of PAH, may respond to immunosuppressive therapy. Most PAH cases with an immunosuppressant response were in the early stages of the disease (WHO functional class III or less). The present case was a 34-year-old woman with MCTD-associated PAH (WHO functional class IV) who was resistant to a combination of three vasodilators. Afterwards, she was treated with glucocorticoid and cyclophosphamide. This case suggested the potential benefit of immunosuppressants in patients with severe MCTD-associated PAH.

Clinical significance of plasma presepsin levels in patients with systemic lupus erythematosus

Abstract Objectives: Presepsin (PSEP: soluble CD14 subtype) is produced from bacteria-stimulated monocytes or neutrophils, thus recognized as a biomarker of sepsis. Aberrant functions in monocyte or neutrophils are increasingly recognized in systemic lupus erythematosus (SLE). We investigated whether plasma PSEP reflects disease activity in patients with SLE. Methods: This retrospective study comprised 35 patients with SLE and 72 with non-SLE autoimmune diseases who visited our facility during the period from August 2012 to September 2015. Plasma PSEP levels and laboratory data were compared between SLE and non-SLE. Clinical markers of SLE disease activity, including SLE disease activity index 2000 (SLEDAI-2K), serum complement concentrations and serum anti-ds-DNA antibodies were assessed in correlation with plasma PSEP levels. Results: Plasma PSEP levels in SLE were higher than those in non-SLE. This phenomenon holds true when comparing SLE and non-SLE patients in the absence of infection (p = .0008). Plasma PSEP levels in SLE patients negatively correlated with C3 (r = –0.4454, p = .0430), CH50 (r = –0.4502, p = .0406) and positively with SLEDAI-2K (r = 0.4801, p = .0237). Conclusion: Elevated plasma PSEP levels were correlated with disease activity of SLE, suggesting inappropriate monocyte or neutrophil activation in the pathophysiology of SLE exacerbation.

Diversity of borderline pulmonary arterial pressure associated with systemic sclerosis: 3 case series

Abstract Mean pulmonary arterial pressure of 21 to 24 mmHg, called borderline pulmonary arterial pressure (BoPAP), may represent a pre-pulmonary arterial hypertension (PAH) condition but has not so far been indicated for specific PAH therapy. Despite the recent progress in PAH-targeted therapy, the prognosis of patients with systemic sclerosis (SSc)-associated PAH still remains poor. One of the possible strategies to improve the prognosis of those patients is the early detection and therapeutic intervention of pre-PAH conditions. We present three different clinical courses of BoPAP associated with SSc, which include successful treatment with bosentan and tocilizumab, an improvement following the treatment of interstitial lung disease, and spontaneous progression to fatal PAH, and suggest the efficacy of frequent follow-up examinations and therapeutic intervention for BoPAP in SSc patients.

OP0356 Plasmablast proliferation is associated with toll like receptor 7 polymorphisms and upregulation of type i interferon, contributing to the antibody production in antiphospholipid syndrome

Background Antiphospholipid antibodies (aPL) as pathogenic autoantibodies in systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) are supported by a number of clinical, ex vivo and animal studies. Nevertheless, aPL are not eliminated by corticosteroid administration or immunosuppression. Novel therapy targeting aPL production is currently unmet needs, in contrast, little is known on its pathological mechanism. Objectives This study aimed to clarify the mechanism of aPL production by lymphocyte subset analysis, genomic analysis and ex vivo experiments. Methods B cell and T cell subsets, a total of 21 subsets, were evaluated in peripheral blood mononuclear cells (PBMC) of 26 primary APS (PAPS), 18 SLE-associated APS (SLE/APS) patients and 10 healthy controls by flow cytometry. Twenty-one single nucleotide polymorphisms (SNP), which were shown to be associated with autoimmune or thrombotic diseases, were analysed in genomic DNA of those patients by TaqMan genotyping assay. Interferon (IFN) score was calculated based on the mRNA expression of Ly6e, Mx1, IFIT1 and IFIT3 in PBMC. To evaluate the aPL-producing capability of plasmablasts, PBMC obtained from APS patients were cultured following depletion of CD19 +CD20+or CD19+CD20 cells and the culture supernatants were applied to aPL measurements by enzyme-linked immunosorbent assay and cell assay using β2GPI/HLA-DR7 overexpressing HEK293T cells.1 Results In PAPS and SLE/APS patients, plasmablasts, Th2 cells and Th17 cells were increased while pre- and post- switched memory B cells, regulatory B cells and regulatory T cells were decreased compared to healthy controls. Genomic analysis revealed that the increase of plasmablasts (p=0.032) and the decrease of memory B cells (p=0.013) were more pronounced in patients with a risk allele of SNP in toll like receptor 7 (TLR7) gene (rs3853839). IFN score was significantly higher in the TLR7 SNP risk allele carriers, confirming the downstream signalling of TLR7 (p=0.029). Ex vivo experiments showed that aPL, including anti-cardiolipin/β2-glycoprotein I-HLA class II complexes -IgG and -IgM, were present in the culture supernatant of CD19 +CD20+depleted PBMC from APS patients, but not in that of CD19 +CD20 depleted cells. Conclusions Our data indicate an important role of plasmablasts in the production of aPL. Furthermore, plasmablast proliferation was associated with TLR 7 and type I IFN, suggesting a common pathophysiology in SLE and APS. Targeting plasmablasts might be a novel, immunological therapeutic approach in the treatment of APS. Reference [1] Tanimura K, et al. β2-Glycoprotein I/HLA class II complexes are novel autoantigens in antiphospholipid syndrome. Blood2015. Disclosure of Interest None declared

29 Antiphospholipid score is a novel risk factor for idiopathic osteonecrosis

Background and Aims Our group introduced a quantitative marker of antiphospholipid antibodies (aPL) ‘‘antiphospholipid score (aPL-S)’’, which well reflected the risk of developing thrombosis (Otomo K, et al. Arthritis Rheum 2012). Idiopathic osteonecrosis (ION) has been shown to occur as a result of ischemia, however, the involvement of aPL in its pathophysiology remains to be elucidated. In this study, we aimed to identify the impact of aPL on the development of ION using aPL-S. Methods A single centre retrospective study comprising 75 consecutive patients with systemic lupus erythematosus who underwent magnetic resonance imaging of hip joints from January 2000 to March 2016. aPL-S, as well as classical risk factors for ION, were evaluated in all the enrolled patients. Results ION of the femoral head was observed in 33 out of 75 patients(44%). High aPL-S (p=0.009), aPL positivity (p=0.009), male (p=0.007), malar rash (p=0.010)and high dose (>0.8 mg/kg/day) glucocorticoids(p<0.001) were identified as risk factors for ION at univariate analysis. Multivariate analysis confirmed high aPL-S, male, malar rash and high dose glucocorticoids as independent variables. Six out of 8 patients(75%) with very high aPL-S (>30), developed ION. Conversely, systemic lupus erythematosus disease activity index and pulse methylprednisolone therapy were not identified as risk factors for ION. Conclusions We newly identified aPL-S as a risk factor for ION. ION should be considered as one of the antiphosholipid antibody-associated-disease.

FRI0364 Usefulness of serum haptoglobin levels as a novel marker for pulmonary arterial hypertension complicated with connective tissue disease

Background Pulmonary arterial hypertension (PAH) is of great clinical significance as a life-threatening complication of connective tissue diseases (CTD). Pulmonary artery thrombotic microangiopathy (PATM) is an important pathophysiology of PAH. The concept of PATM refers to localized thrombotic microangiopathy to be defined histologically and should be discriminated from systemic thrombotic microangiopathy characterized by microangiopathic haemolysis and thrombocytopenia. The degree of PATM has been suggested to be associated with vasodilator response, severity, and prognosis of PAH, and anticoagulation therapy might be effective in PAH patients with features of PATM [1]. Haptoglobin (Hp) is a plasma protein mainly produced by hepatocytes, which binds free haemoglobin released from erythrocytes and protects the kidneys from damage induced by haemoglobin. The Hp is measured in clinical setting as a sensitive marker to detect intravascular haemolysis including thrombotic microangiopathy [2]. Objectives We hypothesized that serum Hp levels decreased in patients with PAH due to pulmonary microangiopathic haemolysis. The aim of this study was to investigate the association between serum Hp levels and pulmonary artery systolic pressure estimated by echocardiography (ePASP) in patients with CTD. Methods This study included CTD patients with suspicion of PAH who were attending Rheumatology Department in Hokkaido University Hospital between August 2015 and August 2016 and underwent echocardiography. PAH was diagnosed based on right heart catheter findings. Serum Hp levels were measured by standardised turbidimetric immunoassay in all patients. Demographic data, laboratory results, and echocardiographic findings were extracted from the medical records. Decreased serum Hp levels were defined as below 19 mg/dL based on the 95th-percentile of healthy controls. Results Twenty-four CTD patients with confirmed PAH (CTD-PAH) and 32 CTD patients without PAH (non-PAH) were enrolled. Decreased serum Hp levels were significantly frequent in patients with CTD-PAH compared with non-PAH patients (29% vs 6%, p=0.03). In patients with CTD-PAH, serum Hp levels had a significant negative correlation (r = -0.692, p<0.0001, Figure 1) with ePASP, and serum lactate dehydrogenase (LDH) levels were significantly elevated in patients with decreased Hp levels (233±47 U/L vs 187±42 U/L, p=0.01). Follow up study showed lowering ePASP led to normalizing serum Hp levels. Conclusions Serum Hp levels correlated negatively with ePASP in patients with CTD-PAH, and serum LDH levels were higher in CTD-PAH patients with decreased Hp levels. These findings suggest that decreased Hp levels in CTD-PAH patients may reflect PATM and subsequent subclinical haemolysis. Serum Hp levels are a candidate of additional non-invasive marker of CTD-PAH to assess the degree of PATM. References Johnson SR, et al. Thrombotic arteriopathy and anticoagulation in pulmonary hypertension. Chest. 2006. Barcellini W, et al. Clinical Applications of Hemolytic Markers in the Differential Diagnosis and Management of Hemolytic Anemia. Dis Markers. 2015. Disclosure of Interest None declared

THU0354 Thrombocytopenia in Patients with Antiphospholipid Antibodies: A Paradoxical Thrombotic Risk Factor

Background Thrombocytopenia is a non-criteria manifestation of antiphospholipid syndrome (APS). Antiphospholipid antibodies (aPL) have been shown to activate platelet through multiple mechanisms. In patients with idiopathic/immune thrombocytopenia, aPL have been shown to increase the risk of thrombosis. Conversely, it remains unclear whether thrombocytopenia increases the risk of thrombosis in patients who have aPL. Objectives To evaluate the relationship between thrombocytopenia and thrombosis in patients who have aPL. Methods A single center retrospective study comprising 670 consecutive patients who underwent testing for aPL including lupus anticoagulant, anticardiolipin antibodies (IgG and M), anti-β2-glycoprotein I antibodies (IgG and M), and phosphatidylserine-dependent antiprothrombin antibodies (IgG and M) between January 2004 and December 2006. Excluded were patients who had been followed-up for ≤1 year. Results Of 524 patients included in this study, 187 had systemic lupus erythematosus, 70 rheumatoid arthritis, and 33 primary APS. At least one of aPL was positive in 241 patients. The prevalence of thrombocytopenia was not different in aPL positive and negative patients (24% vs 18%, p=0.11). In aPL positive group, patients with thrombocytopenia experienced arterial thrombosis (46% vs. 17%, p<0.001), venous thrombosis (27% vs. 7%, p<0.001), and recurrent thrombosis (10% vs. 2%, p=0.006) more frequently than patients without thrombocytopenia. Lupus anticoagulant (56% vs. 35%, p=0.006) and phosphatidylserine-dependent antiprothrombin antibodies (57% vs 34%, p=0.001) were more prevalent in patients with thrombocytopenia than in those without. Higher aPL score (Otomo K, et al. Arthritis Rheum 2012), were detected higher (p=0.001) in patients with thrombocytopenia than in those without. In aPL negative group, conversely, patients with and without thrombocytopenia similarly experienced thrombosis (23% vs 16%, p=0.23). Conclusions Our data indicate that thrombocytopenia is associated with the risk of thrombosis in aPL positive patients providing new insight into the pathophysiology of aPL mediated platelet activation. Disclosure of Interest None declared