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Serum levels of IL-33 and soluble ST2 and their association with disease activity in systemic lupus erythematosus

OBJECTIVE IL-33 has recently been found to be the specific ligand of ST2, an IL-1 receptor family member that is selectively expressed in Th2 cells and mediates Th2 response. This study aims to measure the serum levels of soluble ST2 (sST2) and IL-33 in patients with SLE and to examine their association with disease activity. METHODS Seventy SLE patients were evaluated for disease activity, determined by SLEDAI, levels of anti-dsDNA antibody, C3 and C4. Fifty-seven patients were evaluated longitudinally on a second occasion. IL-33 and sST2 were measured by sandwich ELISA in the 127 SLE serum samples and compared with 28 age- and sex-matched healthy controls. RESULTS Serum sST2 level was significantly higher in active SLE patients [0.51 (0.18) ng/ml] compared with inactive patients [0.42 (0.08) ng/ml] (P = 0.006) and normal controls [0.36 (0.13) ng/ml] (P < 0.001). sST2 level correlated significantly with SLEDAI, anti-dsDNA antibody and prednisolone dosage, and negatively with C3. Linear regression analysis showed that serum sST2 level was an independent predictive factor for modified SLEDAI, excluding anti-dsDNA and complement score after controlling for age, sex, glomerular filtration rate and prednisolone dosage (regression coefficient: 8.5; 95% CI 2.6, 14.3) (P = 0.005). Serum sST2 level was sensitive to change in disease activity longitudinally, with an effect size of 0.29. Elevated serum IL-33 was comparable in frequency (4.3 vs 7.1%; P = 0.62) and levels (P = 0.53) between SLE patients and controls. CONCLUSIONS Elevated serum sST2 level in SLE patients was found to correlate with disease activity and was sensitive to change, suggesting a potential role as a surrogate marker of disease activity.

The relation of interleukin 17 (IL-17) and IL-23 to Th1/Th2 cytokines and disease activity in systemic lupus erythematosus.

Objective. Interleukin 17 (IL-17) was recently linked to pathogenesis of systemic lupus erythematosus (SLE), but its relation to disease activity has not been well characterized. We examined the relation between serum levels of Th17 (IL-17, IL-23), Th1 (IL-12, interferon-γ), Th2 (IL-10, IL-6, IL-4) cytokines and disease activity in patients with SLE. Methods. Serum cytokines were measured by enzyme linked immunosorbent assays. Disease activity was determined by SLE disease activity index (SLEDAI), anti-dsDNA antibody, and C3 and C4 levels. Results. Serum levels of IL-17 (p < 0.001), IL-6 (p = 0.006) and IL-10 (p < 0.001) were higher in SLE patients (n = 70) compared to healthy controls (n = 36). Higher serum IL-23 level was found in patients with active disease with cutaneous manifestations (p = 0.004) and serositis (p = 0.04) compared to those without. Serum IL-17 level above the detection limit was more frequently found in patients who had active lupus nephritis (11/23, 47.8%) (p = 0.002), nonrenal active disease (9/15, 60%) (p = 0.001), and inactive lupus (21/32, 65.6%) (p < 0.001) compared to healthy controls (0%). Serum IL-17 levels were otherwise comparable between these 3 groups of patients and were not related to SLEDAI, glomerular filtration rate, activity or chronicity score and ISN/RPS criteria class among patients with active lupus nephritis. There was no significant correlation between serum IL-17/IL-23 and Th1 or Th2 cytokine levels. Conclusion. SLE patients had higher serum IL-17 levels than healthy controls. Elevated serum IL-23 was found in patients with inflammatory manifestations including cutaneous involvement and serositis. The lack of correlation between Th17, Th1, and Th2 cytokines suggested independent regulatory mechanisms for these cytokines.

Systemic sclerosis is an independent risk factor for increased coronary artery calcium deposition

OBJECTIVE Endothelial dysfunction and inflammation are pathogenic mechanisms common to systemic sclerosis (SSc) and atherosclerosis. This study was undertaken to examine the relationship between coronary atherosclerosis, as assessed by the coronary artery calcium score (CACS), and conventional cardiovascular and disease-specific risk factors in SSc patients. METHODS The CACS was measured by computed tomography, and cardiovascular risk factors were examined in SSc patients and compared with controls matched for age, sex, and glycemic status. Disease activity score, antiphospholipid antibodies, high-sensitivity C-reactive protein level, and erythrocyte sedimentation rate were measured in SSc patients. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were determined. RESULTS We recruited 53 SSc patients (50 women and 3 men) and 106 controls. The patients had a mean ± SD age of 53.1 ± 12.9 years and a median disease duration of 9 years. Compared to controls, SSc patients had significantly lower low-density lipoprotein (LDL) cholesterol levels (P = 0.001), high-density lipoprotein cholesterol levels (P = 0.01), diastolic blood pressure, waist circumference, and body mass index and were more likely to be receiving vasodilators (all P < 0.001). There was a significantly higher proportion of SSc patients among subjects with more severe coronary calcification (CACS ≥ 101) compared to those with lesser severity (CACS <100) (56.5% versus 29.4%; P = 0.01). Multiple logistic regression analysis revealed SSc to be an independent determinant for a CACS ≥ 101 (OR 10.89 [95% CI 2.21-53.75], P = 0.003) together with age and LDL cholesterol level after adjustment for other cardiovascular risk factors. Among disease-specific factors, only disease duration (OR 1.14 [95% CI 1.02-1.27], P = 0.02) was independently associated with more severe coronary calcification (CACS ≥ 101). CONCLUSION Our findings indicate that SSc is an independent risk factor for coronary calcification, in addition to the conventional risk factors for coronary atherosclerosis, such as age and hypertension.

Alternatively activated dendritic cells derived from systemic lupus erythematosus patients have tolerogenic phenotype and function.

Tolerogenic dendritic cells (DCs) are potential cell-based therapy in autoimmune diseases. In this study, we generated alternatively activated DCs (aaDCs) by treating monocyte-derived DCs from patients with systemic lupus erythematosus (SLE) and healthy subjects with combination of 1,25 dihydroxyvitamin D(3) (vitD3) and dexamethasone followed by lipopolysaccharide-induced maturation. Lupus aaDCs were found to acquire semi-mature phenotype that remained maturation-resistant to immunostimulants. They produced low level of IL-12 but high level of IL-10. They had attenuated allostimulatory effects on T cell activation and proliferation comparable to normal aaDCs and demonstrated differential immunomodulatory effects on naïve and memory T cells. These aaDCs were capable of inducing IL-10 producing regulatory T effectors from naïve T cells whereas they modulated cytokine profile with suppressed production of IFN-γ and IL-17 by co-cultured memory T cells with attenuated proliferation. These aaDCs were shown to be superior to those generated using vitD3 alone in lupus patients.

Coronary atherosclerosis using computed tomography coronary angiography in patients with systemic sclerosis

Background: Impaired coronary artery reserve has previously been demonstrated in patients with systemic sclerosis (SSc). Both micro- and macrovascular factors are probably contributory to the underlying pathogenesis. Objectives: To examine the frequency of coronary atherosclerosis in a series of SSc patients by computed tomography coronary angiography (CTCA), a less invasive method than conventional coronary angiography, the current gold standard in the detection of coronary atherosclerosis, and to explore its clinical associations. Methods: Nineteen consecutive SSc patients [six with diffuse (dSSc) and 13 with limited disease (lSSc)] with disease duration of ≥ 3 years were recruited. Coronary calcium score and contrast angiography were examined by CT scan. Conventional cardiovascular factors and inflammatory markers were measured and correlated with CT findings. Results: The mean±SD age of these patients was 52.5±12.5 years with median disease duration of 12.5 years. Six (31.6%) patients were found to have coronary artery calcification (calcium score 13–2008). Coronary calcium was detected in one dSSc patient but contrast angiography was not performed because of interference from an in situ implantable cardiac device. Some parts of the coronary arteries were not assessable in two patients who had ectopic cardiac rhythm. Five lSSc patients had calcified plaques causing variable coronary luminal stenosis. All patients were asymptomatic. Patients with abnormal CTCA findings were more likely to be older (p < 0.001) and were less likely to have serum anti-Scl70 antibodies (p = 0.003) than those without, after Bonferroni correction. Conclusions: Coronary atherosclerosis is not uncommon in asymptomatic SSc patients. CTCA is a convenient and non-invasive method for studying coronary atherosclerosis.

Rel B-modified dendritic cells possess tolerogenic phenotype and functions on lupus splenic lymphocytes in vitro

Systemic lupus erythematosus (SLE) is an autoimmune disease that is characterized by high morbidity and mortality and its treatment remains challenging. Dendritic cells (DCs) have been shown to participate in the initiation and perpetuation of lupus pathogenesis and the DCs that can induce tolerogenicity appear as potential cell‐based therapy in this condition. In this study, we examined the in vitro tolerogenic properties of bone‐marrow derived DCs (BMDCs) in the murine lupus setting. We used lentiviral transduction of RelB‐silencing short hairpin RNA to modify the expression of RelB, a key transcription factor regulating DC maturation, in BMDCs from MRL/MpJ mice. Tolerogenic properties of RelB‐modified DCs were compared with scrambled control (SC) ‐modified DCs. RelB expression was found to be significantly reduced in RelB‐modified DCs derived from MRL/MpJ mice, wild‐type of the same genetic background as MRL/lpr lupus‐prone mice. These MRL/MpJ RelB‐modified DCs displayed semi‐mature phenotype with expression of lower levels of co‐stimulatory molecules compared with SC‐modified DCs. RelB‐modified DCs were found to be low producers of interleukin‐12p70 (IL‐12p70) and could induce hyporesponsiveness of splenic T cells from MRL/MpJ and MRL/lpr mice. Furthermore, they down‐regulated interferon‐γ expression and induced IL‐10‐producing T cells in MRL/MpJ splenocytes, and attenuated interferon‐γ and IL‐17 expression in MRL/lpr splenic CD4+ lymphocytes. Splenocytes primed by RelB‐modified DCs demonstrated antigen‐specific suppressive effects on allogeneic splenocytes. In conclusion, RelB‐silencing in DCs generates DCs of tolerogenic properties with immunomodulatory function and appears as potential option of cell‐targeted therapy.

Symptoms of attention deficit hyperactivity disorder in patients with systemic lupus erythematosus

Objectives Cognitive function and mood disturbance are common in patients with systemic lupus erythematosus (SLE). This study aims to examine whether SLE patients have more features of adult attention deficit hyperactivity disorder (ADHD) and their relation to anxiety and depressive symptoms. Methods Symptoms and clinically significant items of the inattention and hyperactivity/impulsivity domains of ADHD were examined in Part A and Part B by the screening instrument of the ADHD Self-Reported Scale (ASRS), respectively. Anxiety and depressive symptoms were measured by HADS-A and HADS-D, respectively. Results There were no differences in symptom scores of inattention and hyperactivity/impulsivity between inactive SLE patients (n = 117) and age- and sex-matched controls (n = 64). However, SLE patients had more clinically significant items in the inattention domain compared with controls (p = 0.006), particularly among those who had previous cerebral involvement (p = 0.004). Patients who had psychiatric diseases had more clinically significant items in the hyperactivity/impulsivity domain (p = 0.006). Possible ADHD was found in 7.7% of SLE and 6.3% of healthy individuals (p = 1.00) by the screening tool. Patients with higher inattention symptom scores were more likely to be unemployed but not for duration of education and smoking habit. Anxiety and depressive symptoms correlated with ADHD symptoms. HADS-A was an independent predictive factor for clinically significant symptoms of inattention (p < 0.001) and hyperactivity/impulsivity (p = 0.04) by logistic regression. Conclusion Inactive SLE patients, particularly those who had previous cerebral lupus, had more clinically significant symptoms of inattention but not hyperactivity/impulsivity reflecting underlying cognitive impairment. Anxiety and depressive symptoms were common confounders for ADHD-like symptoms.

Cognitive function in systemic lupus erythematosus patients with past history of neuropsychiatric manifestations: a longitudinal study

This free journal suppl. entitled: Special Issue: 2014 ACR/ARHP Annual Meeting Abstract Supplement

348 Dectin-1 on monocytic cells mediates aberrant innate and adaptive immune responses in patients with systemic lupus erythematosus

Background and aims Dectin-1 is a c-type lectin like receptor that signals via syk and is involved in anti-fungal immunity. Dectin-1 was found to trigger experimental inflammatory arthritis, and likely play a role in the pathogenesis of some autoimmune diseases. This study aimed to examine dectin-1 expression and function of circulating CD14+ monocytes and monocyte-derived dendritic cells (MDDCs) in patients with systemic lupus erythematosus (SLE) Methods SLE patients with active and inactive diseases and healthy subjects were recruited. Dectin-1 agonists including curdlan, zymosan and toll-like receptor agonists Pam3CSK4 (TLR2) and LPS (TLR4) were used to stimulate monocytes and/or MDDCs. Dectin-1, ROS and phosphorylated-syk (p-Syk) were measured by flow cytometry. Cytokine profile was measured by and multi-bead immunoassay. Results Dectin-1 expressing monocytes was significantly lower in active SLE patients compared to inactive patients and healthy controls. The absolute count of dectin-1 expressing monocytes correlated significantly and inversely with SLEDAI, anti-dsDNA antibody level and C4. Despite this, ROS production upon stimulation by dectin-1 agonists was comparable. Stimulation of dectin-1 led to activation and maturation of MDDCs. SLE MDDCs showed higher p-Syk activation compared to normal MDDCs upon dectin-1 stimulation. Curdlan-stimulated MDDCs produced higher levels of IL-1β, IL-23 and TNF-α. Adding TLR2 agonist to curdlan, SLE MDDCs produced significantly higher level of IL-1β compared to normal MDDCs. Conclusions Active SLE patients had significantly lower circulating dectin-1 expressing monocytes which produced comparable level of ROS compared to inactive patients and healthy subjects. Dectin-1 agonists led to significantly higher Th17 promoting cytokines upon co-stimulation with TLR2 in SLE MDDCs.

SAT0029 Dectin-1 Mediates Aberrant Innate and Adaptive Immune Response in Patients with Systemic Lupus Erythematosus

Background Dectin-1 is a c-type lectin receptor that signals via syk and is involved in anti-fungal immunity. Dectin-1 was found to trigger experimental inflammatory arthritis, and likely play a role in the pathogenesis of some autoimmune diseases. Objectives To examine (1) dectin-1 expression on circulating CD14+ monocytes in patients with systemic lupus erythematosus (SLE), (2) the effects of dectin-1 stimulation in ROS production by lupus monocytes and (3) syk signaling and cytokine profile of dectin-1 stimulated lupus monocyte-derived dendritic cells (MDDCs). Methods SLE patients with active and inactive diseases and healthy subjects were recruited. MDDCs were derived from peripheral monocytes in the presence of IL-4 and GM-CSF. Dectin-1 agonists including curdlan, zymosan and toll-like receptor agonists Pam3CSK4 (TLR2) and LPS (TLR4) were used to stimulate monocytes and/or MDDCs. Dectin-1, ROS and phosphorylated-syk (p-syk) were measured by flow cytometry. Cytokine profile was measured by and multi-bead immunoassay. Results The percentage of dectin-1 expressing monocytes was significantly lower in active SLE patients (64.5±24.3%) compared to inactive patients (89.6±7.2%) and healthy controls (91.7±9.5%) (both p<0.001). The absolute count of dectin-1 expressing monocytes correlated significantly and inversely with SLEDAI (r=-0.40, p<0.001), anti-dsDNA antibody level (r=-0.29, p=0.004), C3 (r=0.35, p=0.001) and C4 (r=0.24, p=0.02). Despite this, ROS production upon stimulation by dectin-1 agonists was comparable between these 3 groups. Stimulation of dectin-1 led to activation and maturation of MDDCs with upregulation of HLA-DR and CD86 (all p<0.001). SLE MDDCs showed higher p-syk activation compared to normal MDDCs upon dectin-1 stimulation (6.0±2.0 vs 2.8±1.0%, p<0.001). Curdlan-stimulated MDDCs produced higher levels of IL-1β, IL-23 and TNF-α. Adding TLR2 agonist to curdlan, SLE MDDCs produced significantly higher level of IL-1β (327.1±51.5 vs 125.3±88.5, p=0.009) and IL-6 (median 39.8 vs 21.7, p=0.03) compared to normal MDDCs. Combination of TLR4 agonist and curdlan induced IL-12 and TNF-α in normal MDDCs whereas lupus MDDCs produced predominant IL-6 and TNF-α. Conclusions Active SLE patients had significantly lower circulating dectin-1 expressing CD14+ monocytes which produced comparable level of ROS upon stimulation compared to inactive patients and healthy subjects. Dectin-1 agonists led to activation, maturation and higher p-syk activation in SLE MDDCs. Concomitant dectin-1 and TLR2 stimulation induced production of Th17 promoting cytokines, among which IL-1β and IL-6 were significantly higher in SLE compared to normal MDDCs. Disclosure of Interest None declared