Karina de Oliveira Peliçari

Th1/Th2 cytokine profile in childhood-onset systemic lupus erythematosus

OBJECTIVE To determine the serum levels of Th1 (IL-12, IFN-γ,TNF-α) and Th2 (IL-5, IL-6 and IL-10) cytokines in childhood-onset SLE, first-degree relatives and healthy controls. To elucidate their association with disease activity, laboratory and treatment features. METHODS We included 60 consecutive childhood-onset SLE patients [median age 18 years (range 10-37)], 64 first-degree relatives [median 40 (range 28-52)] and 57 healthy [median age 19 years (range 6-30 years)] controls. Controls were age and sex-matched to SLE patients. SLE patients were assessed for clinical and laboratory SLE manifestations, disease activity (SLEDAI), damage (SDI) and current drug exposures. Mood and anxiety disorders were determined through Becks Depression (BDI) and Anxiety Inventory (BAI). Th1 (IL-12, IFN-γ,TNF-α) and Th2 (IL-5, IL-6 and IL-10) cytokines levels were measured by ELISA and compared by non-parametric tests. RESULTS Serum TNF-α (p=0.004), IL-6 (p=0.007) and IL-10 (p=0.03) levels were increased in childhood-onset SLE patients when compared to first-degree relatives and healthy controls. TNF-α levels were significantly increased in patients with active disease (p=0.014) and correlated directly with SLEDAI scores (r=0.39; p=0.002). IL-12 (p=0.042) and TNF-α (p=0.009) levels were significantly increased in patients with nephritis and TNF-α in patients with depression (p=0.001). No association between cytokine levels and SDI scores or medication was observed. CONCLUSION Th1 cytokines may play a role in the pathogenesis of neuropsychiatric and renal manifestations in childhood-onset SLE. The correlation with SLEDAI suggests that TNF-α may be a useful biomarker for disease activity in childhood-onset SLE, however longitudinal studies are necessary to determine if increase of this cytokine may predict flares in childhood-onset SLE.

Obesity and Cytokines in Childhood-Onset Systemic Lupus Erythematosus

Background. In systemic lupus erythematosus (SLE), atherosclerosis is attributed to traditional and lupus related risk factors, including metabolic syndrome (MetS), obesity, and inflammation. Objective. To evaluate the association between obesity, measures of body fat content, serum tumor necrosis factor alpha (TNF-α), and interleukin (IL)-6 and -10 levels in childhood-onset SLE (cSLE). Methods. We screened consecutive cSLE patients followed up in the Pediatric Rheumatology Outpatient Clinic of the State University of Campinas. cSLE patients were assessed for disease and damage. Obesity was definite as body mass index (BMI) ≥30 kg/m2. Serum TNF-α, IL-6, and IL-10 levels were measured by ELISA. Dual-energy X-ray absorptiometry was used to determine total fat mass, lean mass, and percent of body fat. Results. We included 52 cSLE patients and 52 controls. cSLE patients had higher serum TNF-α  (P = 0.004), IL-6 (P = 0.002), and IL-10 (P < 0.001) levels compared to controls. We observed higher serum TNF-α  (P = 0.036) levels in cSLE patients with obesity. An association between serum TNF-α levels and body fat percent (P = 0.046) and total fat mass on trunk region (P = 0.035) was observed. Conclusion. Serum TNF-α levels were associated with obesity and body fat content in cSLE. Our finding suggests that obesity may contribute to the increase of serum TNF-α levels in cSLE.

Clinical and serological manifestations associated with interferon-α levels in childhood-onset systemic lupus erythematosus

OBJECTIVE: To determine the serum levels of interferon alpha in childhood-onset systemic lupus erythematosus patients, their first-degree relatives and healthy controls and to evaluate the associations between serum interferon alpha and disease activity, laboratory findings and treatment features. METHODS: We screened consecutive childhood-onset systemic lupus erythematosus patients in a longitudinal cohort at the pediatric rheumatology unit of the State University of Campinas between 2009 and 2010. All patients demonstrated disease onset before the age of 16. Disease status was assessed according to the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). Interferon alpha levels were measured using an enzyme-linked immunoabsorbent assay. RESULTS: We included 57 childhood-onset systemic lupus erythematosus patients (mean age 17.33±4.50), 64 first-degree relatives (mean age 39.95±5.66), and 57 healthy (mean age 19.30±4.97) controls. Serum interferon alpha levels were significantly increased in childhood-onset systemic lupus erythematosus patients compared to their first-degree relatives and healthy controls. Interferon alpha levels were significantly increased in patients with positive dsDNA antibodies, patients with cutaneous vasculitis, patients with new malar rash and patients who were not receiving medication. Interferon alpha levels correlated with C3 levels and systemic lupus erythematosus Disease Activity Index scores. In addition, we observed an inverse correlation between patient age and interferon alpha levels. CONCLUSION: Interferon alpha may play a role in the pathogenesis of childhood-onset systemic lupus erythematosus, especially in cutaneous manifestations and dsDNA antibody formation. The observation that interferon alpha levels are increased in patients who are not taking medication should be investigated in longitudinal studies to determine whether elevated interferon alpha levels may predict systemic lupus erythematosus flares.

Serum interleukin-17 levels are associated with nephritis in childhood-onset systemic lupus erythematosus

OBJECTIVES: To determine the serum interleukin-17 (IL-17) levels in childhood-onset systemic lupus erythematosus patients and to evaluate the association between IL-17 and clinical manifestations, disease activity, laboratory findings and treatment. METHODS: We included 67 consecutive childhood-onset systemic lupus erythematosus patients [61 women; median age 18 years (range 11-31)], 55 first-degree relatives [50 women; median age 40 years (range 29-52)] and 47 age- and sex-matched healthy controls [42 women; median age 19 years (range 6-30)]. The childhood-onset systemic lupus erythematosus patients were assessed for clinical and laboratory systemic lupus erythematosus manifestations, disease activity [Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)], cumulative damage [Systemic Lupus International Collaborating Clinics/American College of Rheumatology (ACR) Damage Index] and current drug use. Serum IL-17 levels were measured by an enzyme-linked immunosorbent assay using commercial kits. RESULTS: The median serum IL-17 level was 36.3 (range 17.36-105.92) pg/mL in childhood-onset systemic lupus erythematosus patients and 29.47 (15.16-62.17) pg/mL in healthy controls (p=0.009). We observed an association between serum IL-17 levels and active nephritis (p=0.01) and migraines (p=0.03). Serum IL-17 levels were not associated with disease activity (p=0.32), cumulative damage (p=0.34), or medication use (p=0.63). CONCLUSION: IL-17 is increased in childhood-onset systemic lupus erythematosus and may play a role in the pathogenesis of neuropsychiatric and renal manifestations. Longitudinal studies are necessary to determine the role of IL-17 in childhood-onset systemic lupus erythematosus.

Association between academic performance and cognitive dysfunction in patients with juvenile systemic lupus erythematosus

OBJECTIVE To determine whether there is an association between the profile of cognitive dysfunction and academic outcomes in patients with juvenile systemic lupus erythematosus (JSLE). METHODS Patients aged ≤18 years at the onset of the disease and education level at or above the fifth grade of elementary school were selected. Cognitive evaluation was performed according to the American College of Rheumatology (ACR) recommendations. Symptoms of anxiety and depression were assessed by Beck scales; disease activity was assessed by Systemic Lupus Erythematosus Disease Activity Index (SLEDAI); and cumulative damage was assessed by Systemic Lupus International Collaborating Clinics (SLICC). The presence of autoantibodies and medication use were also assessed. A significance level of 5% (p<0.05) was adopted. RESULTS 41 patients with a mean age of 14.5±2.84 years were included. Cognitive dysfunction was noted in 17 (41.46%) patients. There was a significant worsening in mathematical performance in patients with cognitive dysfunction (p=0.039). Anxiety symptoms were observed in 8 patients (19.51%) and were associated with visual perception (p=0.037) and symptoms of depression were observed in 1 patient (2.43%). CONCLUSION Patients with JSLE concomitantly with cognitive dysfunction showed worse academic performance in mathematics compared to patients without cognitive impairment.

Low-Density Lipoprotein Cholesterol Is Associated With Asymptomatic Sensorineural Hearing Loss in Patients With Systemic Lupus Erythematosus.

ObjectiveThe aims of this study were to determine the frequency of asymptomatic sensorineural hearing loss (SNHL) in systemic lupus erythematosus (SLE) and to determine the association between SNHL and demographic, clinical, and laboratory features and cardiovascular risk factors. MethodsWe conducted a cross-sectional study including consecutive female SLE patients. We performed audiometry and clinical and laboratory evaluation and determined cardiovascular risk factors in all patients. Statistical analysis included principal component analysis and logistic regression. ResultsEighty-nine women were included with mean age of 38.98 (SD, 7.77) years and mean disease duration of 10.29 (SD, 9.19) years. Asymptomatic SNHL was observed in 14 patients (16%). In logistic regression model, only low-density lipoprotein levels (z = 2.64; P = 0.008) were associated with SNHL. ConclusionsWe observed asymptomatic SNHL in 16% of SLE and an association with low-density lipoprotein levels suggesting atherosclerosis as a mechanism. Follow-up is needed to determine clinical implications.

AB1022 Validation of Sledai-2K Modified in Patients with Childhood-Onset Systemic Lupus Erythematosus

Background Over the past 4 decades, the prognosis of patients with systemic lupus erythematosus (SLE) has improved because of advances in the recognition from the softest to the most severe forms of the disease. The assessment of global disease activity over time can be an important predictor of mortality. Objectives Validate SLEDAI-2K modified in childhood-onset systemic lupus erythematosus (cSLE). Methods We included consecutive patients with cSLE at the Hospital of Clinics/UNICAMP. All included patients had disease diagnosis ≤18 years age. Disease activity was assessed using the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), SLEDAI-2K, Modified SLEDAI-2K (SLEDAI-2K modified), Mexican version of SLEDAI (MEX-SLEDAI), the European Consensus Lupus Activity Measurement Index (ECLAM) and Systemic Lupus Erythematosus Disease Activity Index Modification SELENA (SELENA-SLEDAI). We evaluated 4 visits for each patient. Results We included 58 consecutive patients with cSLE (mean age 19.08±4.13). The mean follow-up time of patients was 390 patient-years. The correlation coefficients between SLEDAI, SLEDAI-2K and SELENA-SLEDAI were 1 (p<0.001). Among SLEDAI and MEX-SLEDAI (r =0.83, p<0.001), modified SLEDAI-2K (r =0.96, p<0.001) ECLAM and (r =0.84, p<0.001). Among MEX-SLEDAI and modified SLEDAI-2K (r =0.87, p<0.001) and ECLAM (r =0.71, p<0.001). Finally, between modified SLEDAI-2K and ECLAM the correlation coefficient was 0.78; p<0.001. This direct correlation was observed in all tested visits. Conclusions The results show high correlation between the different indices, showing that the SLEDAI 2K-modified can also be used in patients with cSLE. Acknowledgements Grants: Research Support Foundation of São Paulo –FAPESP (Simone 2008/02917-0, Mariana 2011/03788-2, Aline 2013/09480-5, Nailú 2010/13637-9) CNPQ (300447/2009-4 and 471343/2011-0; 302205/2012-8; 473328/2013-5) Disclosure of Interest None declared

AB0616 Biomarkers for Neuropsychiatric Manifestations in Systemic Lupus Erythematosus

Background Neuropsychiatric manifestations areconsidered to be a serious complication in systemic lupus erythematosus (SLE).The pathogenesis of neuropsychiatric manifestations has been attributed to autoantibody-mediated neural dysfunction. Objectives To investigate the prevalence and associations of neuropsychiatric manifestations and serum biomarkers in SLE. Methods We included consecutive SLE followed at the rheumatology unit of the State University of Campinas. Neurological manifestations were analyzed according to the ACR classification criteria. Mood disorders were determined through Becks Depression and Anxiety Inventory in all participants. SLE patients were further assessed for clinical and laboratory SLE manifestations, disease activity [SLE Disease Activity Index (SLEDAI)], damage [Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI)] and current drug exposures. Total dose of corticosteroids and other immunosuppressant medications used since the onset of disease were calculated by data obtained by careful review of the medical charts.Serum biomarkers (S100β, NF-H and antiribossomal P (Anti-P) and anticardiolipin antibodies levels were measured by enzyme-linked immunosorbent assay using commercial kits from BioVendor, Inc (Czech Republic). Anti-double stranded DNA (dsDNA) antibodies were determined by indirect immunofluorescence using Crithidia as substrate and considered positive if ≥1:20.Precipitating antibodies to extractable nuclear antigens (ENAs),including Ro (SSA), La (SSB), and Sm were detected by a standardizedELISA method, and considered positive if higher than 1:40. Data were compared by non-parametric tests. Results We included 146 SLE patients (138 women; mean age of 26.60±13.42 years; range 9-67). The mean disease duration was 8.13±7.05 years (range 0-39 years). At time of study entry, 50 (34.24%) SLE patients had active disease (mean SLEDAI scores3.68±3.97; range 0-14). Forty (27.39%) cSLE had cumulative damage (mean SDI scores 0.68±1.04; range0-4). We observed neuropsychiatric manifestations in 59 (40.41%) SLE. The most frequent manifestations observed in our cohort were anxiety (43.83%), headache (39.04%), depression (34.24%) and seizure (11.64%). We observed an association between neuropsychiatric manifestations and antiribosomal P protein (p=0.001), aCL (p=0.012) and LA (p<0.001). In the analyses of each individual manifestation, anxiety was associated with antiribosomal P protein (p=0.003) and anti-Smith (p=0.010), headache with antiribosomal P protein (p<0.001) and LA (p=0.006) and depression was associated with antiribosomal P protein (p=0.031). Conclusions Autoantibodies such as antiribosomal P protein antibodies, aCL and LA, anti-Ro, anti-dsDNA and anti-Smith are associated with neuropsychiatric manifestations in SLE, suggesting the autoantibodies pathway in neural dysfunction in SLE. Acknowledgements Grants: Research Support Foundation of São Paulo –FAPESP (Simone 2008/02917-0, Mariana 2011/03788-2, Aline 2013/09480-5) CNPQ (300447/2009-4 and 471343/2011-0; 302205/2012-8; 473328/2013-5) Disclosure of Interest None declared

Interleukin 12 is associated with cerebral atrophy in childhood-onset systemic lupus erythematosus

images were used for semiautomatic volumetric measurements. Volumes smaller 2 standard deviation from the means of controls were considered abnormal. Total dose of corticosteroids and other immunosuppressant medications used since the onset of disease were calculated by data obtained by careful review of the medical charts. Sera samples were obtained from all participants in the absence of infections. Th1 (IL-12, IFN-g ,T NF-a) and Th2 (IL-4, 5, 6 and 10) cytokines sera levels were measured by ELISA using commercial kits. Data were compared by nonparametric tests. Results We included 76 cSLE patients (69 women; median age 16 years; range 9-30) and 66 (women 51; median age of 19 years; range 5-23) age and sex matched healthy controls. The median and range cerebral volume in patients with cSLE was 1067.9 (range 831.1-1449.2) cm 3 ,c ompared with 1172.7 (range 941.9-1477.1) cm 3 in healthy volunteers (p<0.001). Cerebral atrophy was identified in 18 (23.7%) cSLE patients and in 1 (1.5%) control (p<0.001). Significantly increased Th1 [IL-12 (p=0.016), IFN-g (p<0.001), TNF-a (p<0.001)] and Th2 [IL-4 (p=0.046), 5 (p=0.013), 6 (p<0.001) and 10 (p=0.022)] levels were observed in SLE patients compared to controls. We observed an association between cerebral atrophy and IL-12 (p=0.034). We also observed an association between cerebral atrophy and aCL (p=0.023), cumulative corticosteroid dose/kg (p=0.024), dsDNA (p=0.024), anti-Sm antibodies (p=0.049) and depression (p=0.024).

The relation of cytokines TH1, TH2 and TH17 in childhood-onset systemic lupus erythematosus

Serum IL-6 (p=0.001), IL-10 (p=0.006), IL-12 (p=0.027) and IL-17 (p=0.0001) levels were increased in cSLE patients when compared to healthy controls. IL-6 levels were significantly increased in patients whit active disease (p=0.008). IL-6 (p=0.032) and IL-12 (p=0.028) levels were significantly increased in patients with active nephritis. We observed that IL-17 was associated with migraine (p=0.045), IL-6 with thrombocytopenia (p=0.022) and IL-12 with the presence of anxiety (p=0.048). No association between cytokine levels and SDI scores or medication was observed. Conclusion Cytokines play a central role in cSLE, IL-6 is associated with SLEDAI and may be a biomarker of disease activity, Th1 and Th2 responses may play ar ole in lupus nephritis and Th1 and Th17 may play a role in neuropsychiatric symptoms in cSLE. Longitudinal studies are necessary to confirm their ability to predict SLE related manifestations.