Longitudinal comparison of IL-6, IL-10, and IL-12 cytokine profiles in adult and childhood-onset systemic lupus erythematosus.

Objective: To compare the levels of Th1 (IL-12) and Th2 (IL-6 and IL10) cytokines over a two-year period among systemic lupus erythematosus patients with childhood-onset (cSLE), adult-onset (sSLE), and healthy controls, and correlate with their clinical, laboratory, and treatment manifestations. Methods: The study included 63 patients with cSLE [57 (90%) women; mean age 19.7 ± 4.3 years (range = 10-29); mean disease duration 7.3 ± 4.2 years (range 2-15)], 67 patients with aSLE [65 (97%) women; mean age of 39.9 ± 11.8 years (range 21-68); disease duration 7.7 ± 3.1 years (range 4-16)], and 40 healthy controls [36 (90%) women; mean age of 29.6 ± 10 years (range 12-49)]. cSLE and aSLE patients were paired by disease duration. Clinical and laboratory manifestations, disease activity (SLEDAI), cumulative damage (SDI), and current drug exposures were evaluated. Symptoms of anxiety and depression were evaluated by the Beck inventory (BAI and BDI, respectively). Th1 (IL-12) and Th2 (IL-6 and IL-10) cytokines were measured by the ELISA test. Data were collected at four different time points (TI, TII, TIII, and TIV) and compared by non-parametric tests. Results: IL-6 levels were significantly higher in aSLE patients compared to healthy controls at times I, II, and III (TI p = 0.013, TII p = 0.015, TIII p = 0.004, and TIV p = 0.634). However, no difference was observed between cSLE patients and healthy controls (TI p = 0.223, TII p = 0.613, TIII p = 0.341, and TIV p = 0.977). In addition, no difference was observed between aSLE and cSLE patients (TI p = 0.377, TII p = 0.123, TIII p = 0.105, and TIV p = 0.591). The levels of IL-12 were significantly higher in cSLE patients compared to healthy controls at all time points (TI p = 0.04, TII p < 0.001, TIII p = 0.015, and TIV p = 0.021). aSLE patients showed significantly elevated levels when compared to healthy controls at time III and IV (TI p = 0.752, TII p = 0.827, TIII p = 0.011*, and TIV p < 0.001*). cSLE patients showed significantly higher levels than aSLE patients at times I and II (TI p = 0.07*, TII p < 0.001*, TIII p = 0.998, and TIV p = 0.140). In aSLE patients, IL-6 was associated with headache (p = 0.006), arthritis (p = 0.044), and nephritis (p = 0.012); IL-10 was associated with nephritis (p = 0.043), hypocomplementemia (p = 0.001), and disease activity (p = 0.001); in these patients, IL-12 was associated with alopecia (p = 0.025) and leukopenia (p = 0.044). In cSLE patients, IL-6 was associated with arthritis (p = 0.022) and malar rash (p = 0.012). Conclusion: aSLE and cSLE patients with long disease duration present similar levels of cytokines, despite differences in clinical activity patterns over time.

Axonal dysfunction is associated with interferon-γ levels in childhood-onset systemic lupus erythematosus: a multivoxel magnetic resonance spectroscopy study.

OBJECTIVE: Axonal/neuronal damage has been shown to be a pathological finding that precedes neuropsychiatric manifestations in SLE. The objective of this study was to determine the presence of axonal dysfunction in childhood-onset SLE patients (cSLE) and to determine clinical, immunological and treatment features associated with its occurrence. METHODS: We included 86 consecutive cSLE patients [median age 17 (range 5-28) years] and 71 controls [median age 18 (5-28) years]. We performed proton magnetic resonance spectroscopic imaging using point resolved spectroscopy sequence over the superior-posterior region of the corpus callosum and signals from N-acetylaspartate (NAA), choline-based (CHO), creatine-containing (Cr), myo-inositol (mI), glutamate, glutamine and lactate were measured and metabolites/Cr ratios were determined. Complete clinical, laboratory and neurological evaluations were performed in all subjects. Serum IL-4, IL-5, IL-6, IL-10, IL-12, IL-17, TNF-α and INF-γ cytokine levels, antiribosomal P protein antibodies (anti-P) and S100ß were measured by ELISA using commercial kits. Data were compared by non-parametric tests. RESULTS: NAA/Cr ratios (P = 0.035) and lactate/Cr ratios (P = 0.019) were significantly decreased in cSLE patients when compared with controls. In multivariate analysis, IFN-γ levels [odds ratio (OR) = 4.1; 95% CI: 2.01, 7.9] and depressive symptoms (OR = 1.9; 95% CI: 1.1, 3.2) were associated with NAA/Cr ratio. Increased CHO/Cr was associated with the presence of cognitive impairment (OR = 3.4; 95% CI: 2.034, 5.078; P < 0.001). mI/Cr ratio correlated with cumulative glucocorticoids dosage (r = 0.361, P = 0.014). CONCLUSION: NAA and CHO ratios may be useful as biomarkers in neuropsychiatric cSLE. Longitudinal studies are necessary to determine whether they predict structural damage.

Type I interferon in the pathogenesis of systemic lupus erythematosus.

Type I interferon (IFN) is a primary pathogenic factor in systemic lupus erythematosus (SLE). Gain-of-function genetic variants in the type I IFN pathway have been associated with risk of disease. Common polygenic as well as rare monogenic influences on type I IFN have been demonstrated, supporting a complex genetic basis for high IFN in many SLE patients. Both SLE-associated autoantibodies and high type I IFN can be observed in the pre-disease state. Patients with SLE and evidence of high type I IFN have more active disease and a greater propensity to nephritis and other severe manifestations. Despite the well-established association between type I IFN and SLE, the specific triggers of type I IFN production, the mechanisms by which IFNs help perpetuate the cycle of autoreactive cells and autoantibody production are not completely clear. This review provides an updated overview of type I IFN in SLE pathogenesis, clinical manifestations, and current therapeutic strategies targeting this pathway.

Familial Aggregation of Childhood- and Adulthood-Onset Systemic Lupus Erythematosus.

OBJECTIVE: To assess the familial occurrence of systemic lupus erythematosus (SLE) in a large Brazilian cohort. METHODS: Consecutive patients with SLE were recruited and stratified according to age at disease onset into childhood-onset SLE or adult-onset SLE. Each patient was personally interviewed regarding the history of SLE across 3 generations (first-, second-, and third-degree relatives). Recurrence rates were analyzed for each degree of relation. RESULTS: We included 392 patients with SLE (112 with childhood-onset SLE and 280 with adult-onset SLE). We identified 2,574 first-degree relatives, 5,490 second-degree relatives, and 6,805 third-degree relatives. In the combined overall SLE cohort, we observed a familial SLE recurrence rate of 19.4 in first-degree relatives, 5.4 in second-degree relatives, and 3.0 in third-degree relatives. Recurrence rates were higher for first- and second-degree relatives of patients with childhood-onset SLE than for first- and second-degree relatives of patients with adult-onset SLE (25.2 versus 18.4 for first-degree, and 8.5 versus 4.5 for second-degree), while in third-degree relatives, recurrence rates were higher in adult-onset SLE than in childhood-onset SLE (P = 2.2 × 10-4 for differences in recurrence proportions between childhood-onset SLE and adult-onset SLE). There were no phenotypic differences in patients from multicase versus single-case families, and there was no sex-skewing observed in the offspring of patients with SLE. CONCLUSION: The greater decline in SLE recurrence rate by generation in childhood-onset SLE versus adult-onset SLE suggests a more polygenic and epistatic inheritance and suggests that adult-onset SLE may be characterized by fewer risk factors that are individually stronger. This finding suggests a higher genetic load in childhood-onset SLE versus adult-onset SLE and a difference in the genetic architecture of the disease based on age at onset.

Epidemiology, characterization, and diagnosis of neuropsychiatric events in systemic lupus erythematosus.

INTRODUCTION: Neuropsychiatric systemic lupus erythematosus (NPSLE) is characterized by a heterogeneity of clinical manifestations. The absence of diagnostic criteria and the lack of clinical trials is a challenge in clinical practice. Areas covered: A literature review was performed to describe epidemiology, characterization (clinical, immunological, and imaging), diagnosis and treatment of NPSLE. Classification criteria have been the first step towards a uniform definition. More recently, different attribution models have been developed to help to determine if the NP event is due to SLE. Disease activity is a major risk factor for NP events. Cytokines and autoantibodies are associated with NP events, however, only a few studies have identified risk factors for individual NP events. Expert opinion: Further research needs to search for and validate biomarkers for NPSLE and individual NP events, including neuroimaging findings, attribution models, and serologic markers. This will be a fundamental step in planning randomized control trials in the treatment of NPSLE to improve outcome.

Defining biological subsets in systemic lupus erythematosus: progress toward personalized therapy.

Systemic lupus erythematosus (SLE) is a heterogeneous disease with respect to disease severity, response to treatment, and organ damage. The pathogenesis of SLE includes immunological mechanisms which are driven by both genetic and environmental factors. There are clear differences in the pathogenesis of SLE between patients of different ancestral backgrounds, including differences in genetic risk factors, immunological parameters, and clinical manifestations. Patients with high vs. low levels of type I interferon (IFN) in circulation represents one major biological subset within SLE, and these two groups of patients are present in all ancestral backgrounds. Genetic factors, autoantibodies, and levels of other cytokines all differ between high and low IFN patients. This distinction has also been important in predicting response to treatment with anti-type I IFN therapies, providing a precedent in SLE for biological subsets predicting treatment response. This review will highlight some recent developments in defining biological subsets of SLE based on disease pathophysiology, and the idea that improved knowledge of disease heterogeneity will inform our efforts to personalize therapy in this disease.

Interferon-γ Is Associated with Cerebral Atrophy in Systemic Lupus Erythematosus.

OBJECTIVE: We evaluated the cerebrospinal fluid (CSF) cytokine profile and magnetic resonance imaging (MRI) findings in systemic lupus erythematosus (SLE) patients with central nervous system (CNS) involvement. METHODS: Consecutive SLE patients followed at the rheumatology unit were enrolled into this study. Neurologically asymptomatic controls were matched for age and sex and recruited during myelography. SLE patients were assessed for disease activity (Systemic Lupus Erythematosus Disease Activity Index; SLEDAI) and cumulative damage (Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index; SDI). All subjects underwent MRI scans and blood and CSF withdrawal. Immunoglobulin G (IgG) and albumin were measured by nephelometry and link indexes were calculated according to the literature. Interleukin (IL)-12 p40/p70, interferon (IFN)-γ, tumor necrosis factor (TNF)-α, and IL-10 were measured by enzyme-linked immunosorbent assay. RESULTS: We included 20 SLE patients (18 women, mean age 30.2 ± 9.2 years, range 19-45) with CNS manifestations. Increased IL-12 p40/p70, IFN-γ, TNF-α, and IL-10 CSF levels were observed in SLE patients. Mild pleocytosis was observed in 8 (66%) SLE patients and intrathecal production of IgG was observed in 2 (10%) SLE patients. Three (15%) SLE patients had demyelinating lesions, 5 (25%) patients had cerebral atrophy, and 12 (60%) patients had ischemic lesions on MRI. We observed that the cerebral lesion count was associated with CNS manifestations and SDI scores. We observed a significant cerebral volume reduction in SLE patients compared to controls (p < 0.001). Moreover, a direct correlation between cerebral volume reduction and CSF IFN-γ levels was observed (r = 0.5, p = 0.01). CONCLUSIONS: IL-12 p40/p70, IFN-γ, TNF-α, and IL-10 CSF levels were increased in SLE patients with CNS manifestations, but only IFN-γ was associated with a cerebral volume reduction in SLE, suggesting an immunological basis for global atrophy in SLE.

Prevalence and features of metabolic syndrome in childhood-onset systemic lupus erythematosus.

To estimate the prevalence and features of metabolic syndrome (MetS) in childhood-onset systemic lupus erythematosus (cSLE), we performed a cross-sectional study of 76 consecutive cSLE patients and 54 healthy controls, age and sex matched. All individuals were assessed for anthropometric and MetS features according to World Health Organization (WHO), NCEP Adult Treatment Panel III (NCEP-ATP III), and International Diabetes Federation (IDF) criteria. The cSLE patients were further assessed for clinical and laboratory manifestations, disease activity (Systemic Lupus Erythematosus Disease Activity Index), cumulative damage (Systemic Lupus International Collaborating Clinics (SLICC)), and current and cumulative drug exposures. Sixty-nine (90.8%) patients were female with mean age of 16.8 years [standard deviation (SD) ±4.0 years]. Mean disease duration was 4.8 years (SD ± 4.1). Based on the WHO MetS criteria, MetS was observed in two (2.6%) cSLE patients. We observed high prevalence of the MetS in cSLE patients according to NCEP-ATP III MetS criteria (18.4%) (p = 0.002) and according to IDF MetS criteria (17.1%) (p = 0.003). We did not observe MetS in the control group. No difference in cSLE patients <18 and ≥18 years was observed. We observed an association between the presence of MetS and SLICC scores in cSLE <18 years and cumulative corticosteroid dose adjusted by weight in cSLE ≥18 years. This study showed that MetS is frequently observed in cSLE using NCEP-ATP III MetS criteria and IDF MetS criteria. The identification of MetS is important to indicate cardiovascular morbidity and mortality in cSLE.

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

OBJECTIVE: The 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. METHODS: We 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. RESULTS: Eighty-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. CONCLUSIONS: We 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.

Drugs in early clinical development for Systemic Lupus Erythematosus.

INTRODUCTION: While immunosuppressive therapy has positively impacted the prognosis of systemic lupus erythematosus (SLE), many patients still do not respond to traditional therapy. Thus, active SLE disease remains a significant problem. Furthermore, conventional immunosuppressive treatments for SLE are associated a high risk of side effects. These issues call for improvement in our current therapeutic armamentarium. AREAS COVERED: In this review, the authors highlight the recent developments in therapies for SLE, and present an overview of drugs which are in early clinical development for SLE. There are many new therapeutic approaches being developed, including those focused on B-cell targets, T-cell downregulation, co-stimulatory blockade, anti-cytokine agents, and kinase inhibition, and Toll-like receptor inhibition. They also discuss peptide therapy as a potential method to re-establish immune tolerance, and some of the challenges ahead in developing and testing novel agents for SLE. EXPERT OPINION: Many novel agents are currently in development for SLE, but this encouraging news is tempered by several disappointments in clinical trials and provides a timely moment to reflect on the future of therapeutic development in SLE. It seems likely that biological heterogeneity between patients is a major contributor to difficulty in drug design in SLE.

Reduction of Cerebral and Corpus Callosum Volumes in Childhood-Onset Systemic Lupus Erythematosus: A Volumetric Magnetic Resonance Imaging Analysis.

OBJECTIVE: There have been few studies in which the prevalence of cerebral atrophy in childhood-onset systemic lupus erythematosus (SLE) was evaluated using magnetic resonance imaging (MRI) volumetric measurements. This study was undertaken to determine the prevalence of cerebral and corpus callosum atrophy in childhood-onset SLE and to determine the possible relationships between atrophy and clinical, laboratory, and treatment features of the disease. METHODS: We included 76 patients with childhood-onset SLE (69 female and 7 male; median age 16 years) and 66 age- and sex-matched healthy controls. Neurologic manifestations were analyzed according to the American College of Rheumatology (ACR) criteria. These SLE patients were further assessed for clinical and laboratory manifestations of SLE, disease activity (using the SLE Disease Activity Index), damage (using the Systemic Lupus International Collaborating Clinics/ACR Damage Index), and current and cumulative drug exposures. Scans were performed with a Philips 3.0T MRI scanner using a standardized protocol. RESULTS: Childhood-onset SLE patients had significantly smaller cerebral and corpus callosum volumes than controls (median cerebral volume 1,067.9 cm(3) versus 1,172.7 cm(3) and median corpus callosum volume 11.6 cm(3) versus 13.7 cm(3) ; P < 0.001). The presence of structural abnormalities was observed in 42 patients (55.3%) with childhood-onset SLE. The presence of cerebral atrophy was associated with anticardiolipin antibodies (aCL) (P = 0.02), anti-double-stranded DNA (P = 0.02), and cumulative corticosteroid dose (P = 0.04). The presence of corpus callosum atrophy was associated with low complement level (P = 0.006) and acute confusional state (P = 0.01). Serum levels of S100B or high molecular weight neurofilament and the presence of anti-ribosomal P were not associated with atrophy. CONCLUSION: Structural brain abnormalities were observed in 55.3% of the patients and were associated with neuropsychiatric manifestations, aCL, and corticosteroid use. To determine permanent neurologic damage, longitudinal studies must be conducted in these patients.

Depressive symptoms are associated with tumor necrosis factor alpha in systemic lupus erythematosus.

BACKGROUND: Tumor necrosis factor alpha (TNF-α) is deeply related to pathogenesis of neurodevelopmental disorders, especially depression. The aim of this study was to explore potential relationships between sera TNF-α levels and mood and anxiety disorders in systemic lupus erythematosus (SLE) patients. METHODS: We included 153 consecutive SLE patients (women 148; median age 30; range 10-62) and 40 (women 37; mean age 28.5; range 12-59) age- and sex-matched healthy controls. Mood and anxiety disorders were determined through Beck Depression and Beck Anxiety Inventory. SLE patients were further assessed for clinical and laboratory SLE manifestations. TNF-α levels were measured by enzyme-linked immunosorbent assay using commercial kits. RESULTS: Depressive symptoms were identified in 70 (45.7 %) SLE patients and in 10 (25 %) healthy controls (p < 0.001). Anxiety symptoms were identified in 93 (60.7 %) SLE patients and in 16 controls (40 %) (p < 0.001). Sera TNF-α levels were increased in SLE patients with depressive symptoms (p < 0.001) and with anxiety symptoms (p = 0.014). A direct correlation between the severity of depressive symptoms and sera TNF-α levels (r = 0.22; p = 0.003) was observed. TNF-α levels were significantly increased in patients with active disease (p = 0.012). In addition, we observed a correlation between sera TNF-α levels and disease activity (r = 0.28; p = 0.008). In the multivariate analysis, sera TNF-α levels were independently associated with depressive symptoms (t = 3.28; 95 % CI 1.08-2.2; p = 0.002). CONCLUSIONS: Sera TNF-α levels are increased in SLE patients with mood and anxiety disorders. In SLE, sera TNF-α levels are independently associated with mood disorders. The etiology of mood disorders is still debated in SLE, but our findings suggest the presence of immunological basis for depression in SLE.

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.

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. .

The importance of cytokines and autoantibodies in depression.

The relationship between depression and immunity has been widely discussed. Cytokines, such as TNF-α, play an important role in immune system; these cytokines interact with virtually every pathophysiologic domain relevant to depression, including neurotransmitter metabolism, neuroendocrine function, and synaptic plasticity. Antibodies have also been implicated in the pathophysiology of depression. The association between decreased serotonin levels and excessive glutamatergic activity forms the first biochemical basis for cytokine-induced depression. Cytokines and antibodies (anti-ribosomal-P and anti-N-methyl-D-aspartate receptor antibodies) are deeply related to pathogenesis of neurodevelopmental disorders, especially depression. Tumor necrosis factor alpha (TNF-α) may underlie the mechanism of depression by an activation of the hypothalamo-pituitary-adrenocortical (HPA) axis, an activation of neuronal serotonin transporters and the stimulation of the indoleamine 2,3-dioxygenase which leads to tryptophan depletion. In the last 20 years since the initial reports of neural-immune interactions in depression, studies have shown a clear association between activation of the immune system mediated by proinflammatory cytokines. Genes encoding cytokines are highly polymorphic and single nucleotide polymorphisms, associated with increased or reduced cytokine production, have been described. To date, there are only few studies that investigated the relationship between depression and proinflammatory cytokines in patients with autoimmune diseases. Although an associative link between neuroinflammation and mood disorders is widely accepted, further studies are necessary to establish the cause-effect relationship. In this paper, we review the role of cytokines, focusing on TNF-α and antibodies in the depression and hypothesize how TNF-α may underlie and mediate the inflammatory process depression in patients with autoimmune disease.

Dysregulation of antiviral helicase pathways in systemic lupus erythematosus.

In the autoimmune disease systemic lupus erythematosus (SLE), our normal antiviral defenses are inappropriately activated, resulting in over-activity of the type I interferon (IFN) pathway. This increased activity of the type I IFN pathway is an important primary pathogenic factor in the disease. Emerging evidence has implicated the antiviral helicases in this process. The antiviral helicases normally function as nucleic acid receptors in viral immunity. Genetic variations in antiviral helicase genes have been associated with SLE, supporting the idea that helicase pathways are involved in the primary pathogenesis of SLE. Studies have documented functional consequences of these genetic variations within the type I IFN pathway in human cell lines and SLE patients. In this review, we summarize the function of helicases in the anti-viral immune response, and how this response is dysregulated in SLE patients. In particular, we will focus on known functional genetic polymorphisms in the IFIH1 (MDA5) and mitochondrial antiviral signaling protein genes which have been implicated in human SLE. These data provide fascinating evidence for dysregulation of helicase-mediated innate immunity in SLE, and may support novel therapeutic strategies in the disease.

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/m(2). 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.

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.

Biological therapy in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a prototypic inflammatory autoimmune disorder characterized by multisystem involvement and fluctuating disease activity. Symptoms range from rather mild manifestations such as rash or arthritis to life-threatening end-organ manifestations. Despite new and improved therapy having positively impacted the prognosis of SLE, a subgroup of patients do not respond to conventional therapy. Moreover, the risk of fatal outcomes and the damaging side effects of immunosuppressive therapies in SLE call for an improvement in the current therapeutic management. New therapeutic approaches are focused on B-cell targets, T-cell downregulation and costimulatory blockade, cytokine inhibition, and the modulation of complement. Several biological agents have been developed, but this encouraging news is associated with several disappointments in trials and provide a timely moment to reflect on biologic therapy in SLE.

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.