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 firstdegree 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 firstdegree 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

Depressive Symptoms Are Associated With Tumor Necrosis Factor Alpha In Systemic Lupus Erythematosus

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Background: Tumor necrosis factor alpha (TNF-alpha) is deeply related to pathogenesis of neurodevelopmental disorders, especially depression. The aim of this study was to explore potential relationships between sera TNF-alpha 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-alpha 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-alpha 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-alpha levels (r = 0.22; p = 0.003) was observed. TNF-alpha levels were significantly increased in patients with active disease (p = 0.012). In addition, we observed a correlation between sera TNF-alpha levels and disease activity (r = 0.28; p = 0.008). In the multivariate analysis, sera TNF-alpha levels were independently associated with depressive symptoms (t = 3.28; 95 % CI 1.08-2.2; p = 0.002). Conclusions: Sera TNF-alpha levels are increased in SLE patients with mood and anxiety disorders. In SLE, sera TNF-alpha 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.13Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)FAPESP [2008/02917-0, 2009/06049-6, 2009/15286-1, 2011/03788-2]CNPq [300447/2009-4, 471343/2011-0, 302205/2012-8, 473328/2013-5, 406054/2013-4

Serum Interleukin-17 levels are associated with nephritis in childhood-onset systemic Lupus Erythematosus

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. 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. 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). 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 erythematosus705313317CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP300447/2009-4; 471343/2011-0; 302205/2012-8; 473328/2013-52008/02917-0; 2010/13636-2; 2012/21071-

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

Influence of glutathione s-transferase on the ototoxicity caused by aminoglycosides

The process of hair cell damage and death as a result of exposure to noise and ototoxins seems to be mediated by reactive oxygen species. AIM: To investigate the relationship between genetic polymorphisms in the Glutathione S-transferase and the susceptibility to hearing loss induced by aminoglycosides. MATERIALS AND METHODS: Null genotypes were analyzed by multiplex-PCR in the DNA samples from 50 patients and 72 controls. The patients were divided into 3 groups, 10 with hearing loss using aminoglycosides (group A), 20 with hearing loss without exposure to the drug (group B) and 20 hearing individuals who used the antibiotic (group C). STUDY DESIGN: Experimental. RESULTS: Polymorphisms in the GSTM1 and GSTT1 genes were found in 16% and 42% of patients and in 18% and 53% of the control group, respectively. After statistical analysis no significant difference was observed between the control groups and A (p=0.86) and (p=0.41), controls and B (p=0.27) and (p=0.24), controls and C (p=0.07) and (p=0.47), controls and A + C (p=0.09) and (p=0.47), C and A (p=0.32) and (p=0.75), GSTT1 and GSTM1, respectively. CONCLUSION: Our data show that polymorphisms in GSTM1 and GSTT1 genes have no influence on the ototoxicity of aminoglycosides.O processo de morte e danos em células ciliadas devido à exposição ao ruído e ototoxinas parece ser mediado por espécies reativas de oxigênio. OBJETIVO: Investigar a relação entre polimorfismos gênicos na Glutationa S-transferase e a susceptibilidade à deficiência auditiva induzida pelos aminoglicosídeos. CASUÍSTICA E MÉTODO: Genótipos nulos foram analisados por PCR-multiplex em amostras de DNA de 50 pacientes e 72 controles. Os pacientes foram divididos em três grupos, sendo 10 com deficiência auditiva e uso de aminoglicosídeos (grupo A), 20 com deficiência auditiva sem exposição à droga (grupo B), e 20 ouvintes que utilizaram o antibiótico (grupo C). FORMA DE ESTUDO: Experimental. RESULTADOS: Polimorfismos nos genes GSTT1 e GSTM1 foram encontrados em 16% e 42% dos pacientes e em 18% e 53% do grupo controle, respectivamente. Após a análise estatística nenhuma diferença significativa foi observada entre os grupos controle e A (p=0,86) e (p=0,41), controle e B (p=0,27) e (p=0,24), controle e C (p=0,07) e (p=0,47), controle e A+C (p=0,09) e (p=0,47), C e A (p=0,32) e (p=0,75), GSTT1 e GSTM1, respectivamente. CONCLUSÃO: Nossos dados demonstram que polimorfismos na GSTT1 e GSTM1 não exercem influência sobre a ototoxicidade dos aminoglicosídeos.30630