INTRODUÇÃO: A periodontite é uma doença infecciosa associada à inflamação crônica dos tecidos do dente. Os mediadores inflamatórios e citocinas podem influenciar o curso de doenças reumáticas. O objetivo deste trabalho foi verificar se o tratamento da doença periodontal (DP) possue correlação com a atividade do lúpus eritematoso sistêmico (LES). MÉTODOS: Foram avaliados 42 pacientes com LES (ACR, 1997) e consecutivamente randomizados em dois grupos. Os critérios de exclusão foram SLEDAI < 2 e/ou Índice de Sangramento Sulcular (ISS) igual a zero, obtendo-se o grupo TRATADO com 19 pacientes e o CONTROLE com 17 pacientes. Todos os pacientes estavam sob tratamento com ciclofosfamida endovenosa. Estes grupos foram pareados para idade, sexo, e raça. Foram determinados a velocidade de hemossedimentação (VHS), a proteína C reativa (PCR) e o SLEDAI. A graduação da doença periodontal foi aferida através da profundidade da bolsa periodontal (PB), do ISS e do nível de inserção (NI). O tratamento odontológico objetivou a desinfecção oral completa. O grupo TRATADO iniciou o tratamento odontológico imediatamente após a visita inicial e foram reavaliados após três meses. O grupo CONTROLE iniciou o tratamento odontológico após três meses de observação. Assim, todos os pacientes com SLEDAI ? 2 e/ou ISS ? zero, passaram a pertencer ao grupo TRATADO (n=32). Esses pacientes foram reavaliados após três meses do término do tratamento odontológico. RESULTADOS: Os grupos foram similares na visita inicial para o ISS (40,75 ± 30,98 vs. 40,72 ± 36,19%, p=0,89), PB (1,73 ± 1,80 vs. 1,48 ± 0,59mm, p=0,80) e NI (2,47 ± 1,9 vs. 1,91 ± 1,34mm, p=0,18) e para a VHS (20,69 ± 23,88 vs. 23,41 ± 21,92 mm/h, p=0,80), a PCR (4,7 ± 4,61 vs. 4,21 ± 5,86mg/dl, p=0,34) e o SLEDAI (5,94 ± 4,24 vs. 6,29 ± 4,35, p=0,73). A eficácia do tratamento odontológico foi atestada pela redução dos índices periodontais no grupo TRATADO: ISS (40,75 ± 30,98 vs. 15,19 ± 17,22%, p<0,01), PB (1,73 ± 1,80 vs. 1,10 ± 0,29 mm, p<0,01) e NI (2,47 ± 1,96 vs. 1,68 ± 0,90 mm, p<0,01). Os níveis de VHS e PCR não se alteraram ao longo do tratamento para os grupos. O grupo TRATADO apresentou redução do SLEDAI (5,94 ± 4,24 vs. 3,38 ± 3,30, p=0,04). O grupo CONTROLE não alterou os parâmetros odontológicos e nem clínicos nos 3 meses em observação. CONCLUSÃO: O tratamento odontológico propiciou a melhora da doença periodontal nos pacientes com lúpus eritematoso sistêmico, associada a uma redução significativa na atividade da doença aferida pelo SLEDAI. / INTRODUCTION: Periodontal disease is an infectious disease associated to a chronic inflammation of dental tissues. Inflammatory mediators and cytokines determine the course of rheumatic diseases. The aim of this study is to evaluate if periodontal disease (PD) treatment influences systemic lupus erythematosus (SLE) activity. METHODS: Forty-two SLE patients (ACR, 1997) were evaluated and consecutively randomized in two groups. Exclusion criteria were SLEDAI < 2 and/or bleeding gingival index (BGI) of zero, resulting in TREATED group with 19 patients and CONTROL with 17 patients. All SLE patients were under IV cyclophosphamide therapy. Both groups were matched for age, gender, and race. Erythrocyte sedimentation rate (ESR), C- reactive protein (CRP) and SLEDAI were determined. Periodontal disease graduation was defined according to probing depth (PD), bleeding gingival index (BGI) and probing attachment level (PAL). Odontological treatment focused a complete mouth desinfection. TREATED group have odontologial treatment immediately at entry and evaluated after three months. CONTROL started odontological treatment after 3 months of observation period. At the end, all SLE patients with SLEDAI ³ 2 and/or BGI > zero, entered in the TREATED group (n=32). These patients were evaluated 3 months after the end of odontological treatment. RESULTS: At entry, both groups had similar BGI (40.75 ± 30.98 vs. 40.72 ± 36.19%, p=0.89), PD (1.73 ± 1.80 vs. 1.48 ± 0.59mm, p=0.80), and PAL (2.47 ± 1.9 vs. 1.91 ± 1.34mm, p=0.18) and also for ESR (20.69 ± 23.88 vs. 23.41 ± 21.92 mm/h, p=0.80), CRP (4.7 ± 4.61 vs. 4.21 ± 5.86mg/dl, p=0.34) and SLEDAI (5.94 ± 4.24 vs. 6.29 ± 4.35, p=0.73). Efficacy of odontological treatment was identified in the reduction of all indexes of TREATED group: BGI (40.75 ± 30.98 vs. 15.19 ± 17.22%, p<0.01), PD (1.73 ± 1.80 vs. 1.10 ± 0.29 mm, p<0.01) and PAL (2.47 ± 1.96 vs. 1.68 ± 0.90 mm, p<0.01). ESR and CRP did not alter during treatment in both groups. TREATED group had a significant reduction in SLEDAI (5.94 ± 4.24 vs. 3.38 ± 3.30, p=0.04) after odontological treatment whereas CONTROL had similar odontological and clinical parameters during the 3 months of observation. CONCLUSION: SLE patients after odontological treatment had a significant reduction of SLEDAI with a better control of the inflammation of the disease.

Objetivos: Determinar a incidência de perda de massa óssea em um ano em pacientes com lúpus na pré-menopausa e o valor preditor dos marcadores do metabolismo ósseo para essa complicação. Métodos: Sessenta e três pacientes foram avaliadas à entrada no estudo e após um ano de seguimento. Variações na densidade mineral óssea (DXA) acima da mínima variação significativa (MVS) foram consideradas significativas, como recomendado pela Sociedade Internacional de Densitometria Clínica (International Society for Clinical Densitometry). Os níveis séricos dos marcadores do metabolismo ósseo foram determinados no início do estudo: propeptídeo N-terminal do pro-colágeno tipo 1 (P1NP) e telopeptídeo C-terminal do colágeno tipo 1 (CTX) por eletroquimioluminescência; osteoprotegerina (OPG) e ligante do receptor ativador do fator nuclear kB (RANKL) por ELISA. Resultados: 36,5% dos pacientes apresentaram perda de massa óssea e 17,5% ganho de massa óssea na coluna lombar e/ou fêmur. Os pacientes foram divididos em três grupos: perda de massa óssea (P), massa óssea estável (E) e ganho de massa óssea (G). Pacientes com P e E tomaram doses cumulativa, média e máxima de glicocorticoide semelhantes durante o estudo, mas pacientes com G receberam doses menores (G vs. P e G vs. E, p < 0,05). Os níveis séricos basais de P1NP foram diferentes nos três grupos (P: 36,95 ± 23,37 vs. E: 54,63 ± 30,82 vs. G: 84,09 ± 43,85 ng/ml, p=0,001). Análises de múltiplas comparações demonstraram diferenças significativas nos níveis de P1NP entre P vs. E, p=0,031; P vs. G, p < 0,001 e E vs. G, p=0,039. Não houve diferença entre os grupos com relação aos níveis de CTX, OPG/RANKL, fatores de risco para osteoporose ou parâmetros relacionados à doença. Após análise multivariada, apenas níveis baixos de P1NP permaneceram como fator de risco independente para perda de massa óssea (p < 0,013). Conclusão: Este estudo fornece evidência original que níveis mais baixos de P1NP, o marcador de formação óssea mais específico, são preditores de perda de massa óssea em um ano em mulheres com lúpus na pré-menopausa / Objective: To determine the one-year incidence of bone loss in premenopausal lupus patients and the value of bone markers as predictors of this complication. Methods: Sixty-three premenopausal SLE patients were evaluated at baseline and after one-year of follow-up. Bone mineral density changes (DXA) above the least significant change (LSC) were considered significant, as recommended by International Society for Clinical Densitometry. Serum levels of bone markers were determined at baseline: N-terminal propeptide of type 1 collagen (P1NP) and C-terminal telopeptide of type 1 collagen (CTX) by electrochemiluminescence; osteoprotegerin (OPG) and receptor activator of nuclear factor kB ligand (RANKL) by ELISA. Results: 36.5% of patients presented bone loss and 17.5% bone gain at lumbar spine and/or femur. Patients were divided in three groups: bone mass loss (BL), no bone mass change (NC) and bone mass gain (BG). Patients with BL e NC took similar cumulative, mean and maximum GC doses during the study, but patients with BG took lower doses (BG vs. BL and BG vs. NC, p < 0.05). Baseline P1NP levels were different in the three groups (BL: 36.95 ± 23.37 vs. NC: 54.63 ± 30.82 vs. BG: 84.09 ± 43.85 ng/ml, p=0.001). Further multiple comparison analysis demonstrated significant differences in P1NP between BL vs. NC, p=0.031; BL vs. BG, p < 0.001 and NC vs. BG, p=0.039. No difference was observed concerning the levels of CTX, OPG/RANKL, risk factors for osteoporosis or disease related parameters. After multivariate analysis only lower P1NP levels remained as an independent risk factor for bone loss (p < 0.013). Conclusion: This study provides original evidence that lower levels of P1NP, the most specific bone formation marker, are predictive of bone loss in the next year in premenopausal SLE patients

INTRODUÇÃO. A síndrome antifiosfolípide (SAF) é uma condição trombofílica autoimune associada a títulos elevados e persistentes de anticorpos antifosfolípides. Caracteriza-se por tromboses em diversos órgãos, incluindo os testículos. OBJETIVO. Realizar uma avaliação global da função gonadal em pacientes masculinos com SAF primária (SAFP) e SAF associada ao lúpus eritematoso sistêmico (SAF-LES). MÉTODOS. Estudo transversal realizado em 22 pacientes (12 com SAFP e 10 com SAF-LES) e 20 controles saudáveis pareados por sexo e idade. Os pacientes foram avaliados em relação a dados demográficos, exame urológico, ultrassonografia testicular, perfil hormonal, análise do sêmen, anticorpos antiespermatozóides e características clínicas e laboratoriais. RESULTADOS. A mediana da idade atual foi semelhante nos pacientes com SAFP e controles (p=0,27), assim como naqueles com SAF-LES e controles (p=0,31). Disfunção erétil foi significantemente maior nos pacientes com SAFP comparado aos controles (25% vs. 0%, p=0,044), e nos SAF-LES comparado aos controles (30% vs. 0%, p=0,029). Com relação à antropometria do pênis, a análise dos subgrupos de pacientes com (n=7) e sem (n=5) tromboses arteriais prévias demonstrou que a mediana da circunferência do pênis foi significantemente menor em SAFP com trombose arterial versus sem trombose arterial [8,1 (6-10) vs. 10,2 (10-11) cm, p=0,007], bem como também observado em pacientes com SAF-LES com (n=2) e sem (n=8) eventos arteriais prévios [7,5 (7-8) vs. 9,18 (8-10,5) cm, p=0,039]. A mediana da circunferência do pênis foi significantemente menor nos pacientes com SAFP com disfunção erétil versus sem essa alteração [7,5 (6-9,5) vs. 9,5 (7,5-11) cm, p=0,039], assim como no grupo de SAF-LES [8,17 (8-8,5) vs. 9,14 (7-10,5) cm, p=0,0397]. Com relação à avaliação da função testicular, todos os parâmetros foram semelhantes nos pacientes com SAFP e controles (p>0,05). Por sua vez, as medianas de concentração e de mobilidade dos espermatozóides foram significantemente menores nos pacientes com SAF-LES comparado aos controles [41,1 (0-145) vs. 120,06 (34,5-329) x 106/mL, p=0,003; 47,25 (0-87,5) vs. 65,42 (43-82)%, p=0,047; respectivamente], assim como a frequência de oligo/azoopermia (40% vs. 0%, p=0,007). A análise dos pacientes com SAF-LES mostrou que as medianas da concentração e da contagem total de espermatozóides foram significantemente menores nos que usaram ciclofosfamida endovenosa versus os que não usaram tal medicação [6,87 (0-23,5) vs. 63,9 (7,5-145) x 106/mL, p=0,04; 16,12 (0-55,5) vs. 226,25 (8,5-471) x 106, p=0,035; respectivamente]. CONCLUSÕES. Diminuição do tamanho peniano nos pacientes com SAFP e SAF-LES com disfunção erétil associada foi evidenciada, além de disfunção testicular secundária ao uso de agentes alquilantes nos pacientes com SAF-LES / INTRODUCTION. Antiphospholipid syndrome (APS) is an autoimmune thrombophilic condition associated with persistent high titers of antiphospholipid antibodies. It is characterized by thrombosis in various organs including the testes. OBJECTIVE. To perform a global testicular assessment in male primary antiphospholipid syndrome (PAPS) and secondary systemic lupus erythematosus-APS (SLE-APS) patients, and healthy controls. METHODS. A cross-sectional study was conducted in 22 APS (12 PAPS and 10 SLE-APS) male patients, and 20 healthy controls. They were assessed by demographic data, systematic urological examination, testicular ultrasound, hormone profile, sperm analysis, antisperm antibodies, clinical features and treatment. RESULTS. The median of current age was similar in PAPS patients and controls (p=0.27), likewise in SLE-APS and controls (p=0.31). Erectile dysfunction was significantly higher in PAPS patients compared than controls (25% vs. 0%, p=0.044), and in SLE-APS and controls (30% vs. 0%, p=0.029). Regarding the penile anthropometry, the analysis of subgroups of PAPS patients with (n=7) and without (n=5) previous arterial thrombosis demonstrated that the median circumference penis was significantly lower in PAPS with arterial thrombosis versus without [8.1 (6-10) vs. 10.2 (10-11) cm, p=0.007], as also observed in SLE-APS patients with (n=2) and without (n=8) previous arterial events [7.5 (7-8) vs. 9.18 (8-10.5) cm, p=0.039]. In addition, the median penis circumference was significantly lower in PAPS patients with erectile dysfunction versus without this alteration [7.5 (6-9.5) vs. 9.5 (7.5-11) cm, p=0.039], likewise in SLE-APS patients [8.17 (8-8.5) vs. 9.14 (7-10.5) cm, p=0.0397]. Regarding gonadal evaluation, these parameters were uniformly normal in PAPS versus controls (p>0.05). In contrast, the median of sperm concentration and sperm motility were significantly lower in SLE-APS patients compared to controls [41.1 (0-145) vs. 120.06 (34.5-329) x 106/mL, p=0.003; 47.25 (0-87.5) vs. 65.42 (43-82)%, p=0.047; respectively], likewise the frequency of oligo/azoopermia (40% vs. 0%, p=0.007).The analysis of SLE-APS patients showed that the median of sperm concentration and total sperm count were significantly lower in SLE-APS patients treated with intravenous cyclophosphamide versus untreated [6.87 (0-23.5) vs. 63.9 (7.5-145) x 106/mL, p=0.04; 16.12 (0-55.5) vs. 226.25 (8.5-471) x 106, p=0.035; respectively]. CONCLUSIONS. We have identified reduced penile size in PAPS and SLE-APS patients with deleterious erectile function, and testicular dysfunction due to alkylating agents in SLE-APS patients

Introdução: A ativação do eixo hormônio liberador de corticotropina (CRH) e da pró-opiomelanocortina (POMC) leva a produção de vários derivados bioativos que incluem o hormônio adrenocorticotrófico (ACTH) e o hormônio estimulador de melanócito alfa (alfa-MSH). Estudos avaliando a participação desse eixo no lúpus eritematoso sistêmico (LES) são escassos, particularmente no envolvimento cutâneo da doença. Objetivo: Avaliar a participação do CRH e das melanocortinas (MCs) na fisiopatologia do lúpus eritematoso sistêmico com envolvimento cutâneo. Métodos: Dezessete pacientes com LES com envolvimento cutâneo foram avaliados clinicamente e biópsias da pele afetada e não afetada e do sangue periférico foram obtidas. Dezessete indivíduos saudáveis foram pareados por idade e gênero. Os fragmentos de pele foram submetidos à análise imuno-histoquímica para avaliação da expressão de CRH, ACTH, alfaMSH, e receptor de melanocortina tipo 1 (MC-1R). Os níveis séricos de alfa-MSH, IL-1, IL-1ra, IL-6, IL-10, IL-12p70, IL-17, TNF-alfa, e IFN-y foram determinados pelo método Multiplex. Resultados: A pele afetada de pacientes com LES apresentaram maior expressão CRH na derme profunda quando comparada à pele não afetada dos mesmos doentes e a pele saudável dos controles (p = 0,024). Níveis séricos de alfa-MSH foram similares entre LES e controles. Dentre as citocinas avaliadas, IFN-y, TNF-alfa e IL-6 foram mais elevadas nos pacientes com LES em relação aos controles (p = 0,041, p = 0,001 e p = 0,049, respectivamente). Embora não significativamente, os níveis de IL-17 também foram mais altos nos pacientes (p = 0,099). A expressão tecidual de ACTH, cortisol, alfa-MSH e seu receptor MC-1R foram semelhantes entre os pacientes e controles. Conclusões: Nossos resultados mostram, pela primeira vez a participação do eixo CRH-POMC na patogênese das lesões cutâneas do LES / Introduction: Corticotropin-releasing hormone (CRH) and pro-opiomelanocortin (POMC) axis activation leads to the production of several bioactive hormones including adrenocorticotrophic hormone (ACTH) and the neuropeptide alfa-melanocyte stimulating hormone (alfa-MSH). There are scarce data regarding their role in systemic lupus erythematosus (SLE) particularly in cutaneous involvement of this disease. Objective: To evaluate the role of CRH and melanocortins (MCs) in the pathophysiology of systemic lupus erythematosus with skin involvement. Methods: Seventeen patients with SLE with skin involvement were evaluated clinically and biopsies of affected and unaffected skin and peripheral blood were obtained. Seventeen healthy subjects were matched for age and gender. The skin fragments were subjected to immunohistochemical analysis for the expression of CRH, ACTH, alfa-MSH and melanocortin receptor type 1 (MC-1R). Serum levels of alfa-MSH, IL-1, IL-1ra, IL-6, IL-10, IL-12p70, IL-17, TNF-alfa and IFN-y were determined by multiplex. Results: The affected skin of SLE patients exhibited greater CRH expression in the deep dermis compared to unaffected skin of the same patients and the control\'s healthy skin (p = 0.024). alfa-MSH were similar between SLE and controls. Among the evaluated cytokines, IFN-y, TNF-alfa and IL-6 were significantly higher in SLE patients compared to controls (p = 0.041, p = 0.001 and p = 0.049, respectively). Although not significant, levels of IL-17 were also higher in patients (p = 0.099). Tissue expression of ACTH, cortisol, alfa-MSH and its receptor MC-1R were similar between patients and controls. Conclusions: Our results show for the first time the involvement of CRH-POMC axis in the pathogenesis of SLE cutaneous lesions through interactions between the brain-skin axis

Introdução: A sobrevida dos pacientes com lúpus eritematoso sistêmico juvenil (LESJ) tem melhorado progressivamente nas últimas décadas. Sendo assim, novos aspectos devem ser considerados no acompanhamento destes pacientes, tais como comprometimento da massa óssea e doenças periodontais. Objetivos: 1- Avaliar parâmetros do metabolismo ósseo e saúde oral em pacientes com LESJ comparando com grupo controle saudável; 2 - Avaliar possíveis associações entre parâmetros do remodelamento ósseo e densidade mineral óssea com alterações orais, assim como com: dados demográficos, manifestações clínicas, índices de atividade e dano cumulativo da doença, terapias utilizadas e qualidade de vida relacionada à saúde em pacientes com diagnóstico de LESJ. Métodos: Foram avaliadas 24 adolescentes púberes do sexo feminino com diagnóstico de LESJ e 29 adolescentes púberes saudáveis do sexo feminino quanto aos dados demográficos, antropométricos, clínicos e hábitos de vida.. Nos pacientes também foram determinados os índices de atividade da doença, de dano cumulativo e de qualidade de vida e a terapêutica utilizada. A avaliação do metabolismo ósseo incluiu a medida dos níveis de osteoprotegerina sérica (OPG), soluble receptor activator of nuclear factor kappa B ligand (sRANKL), propeptídeo N-terminal do prócolágeno tipo I (P1NP), telopeptídeo carboxiterminal do colágeno tipo I (CTX), 25-hidroxivitamina D, paratormônio (PTH) e densidade mineral óssea (DMO). Pacientes e controles foram submetidas à avaliação clínica oral, incluindo características clínicas, avaliação dentária e periodontal. Resultados: Pacientes com LESJ apresentaram Z-Score da coluna lombar (p < 0,001), fêmur total (p=0,027), colo do fêmur (p=0,015) e corpo total (p < 0,001) significantemente menores quando comparados aos controles saudáveis. Apresentaram também níveis significantemente mais baixos de P1NP (p=0,007), CTX (p < 0,001) e de PTH (p=0,009) quando comparados ao grupo controle. Foi encontrada correlação negativa estatisticamente significante entre dose cumulativa de glicocorticoides (GC) e o Z-Score do colo do fêmur (r= -0,491 p=0,024). Pacientes com Z-Score <= -2 no fêmur total tinham idade ao diagnóstico significantemente maior quando comparados àquelas com Z-Score > -2 [14,5 anos vs 11 anos (p=0,038)]. A mediana do número de dentes cariados, perdidos e obturados (CPO-D) foi significativamente maior em pacientes com LESJ (p=0,010) comparados aos controles e maiores doses cumulativas de GC estiveram correlacionadas com maiores índices de CPO-D (r= +0,435 p=0,048). Conclusão: Pacientes com LESJ tem redução da massa mineral óssea e do remodelamento ósseo quando comparados a controles saudáveis. Maiores doses cumulativas de GC foram correlacionadas a maior número de CPO-D e a baixa densidade mineral óssea. A DMO do fêmur total é menor em pacientes com idade maior ao diagnóstico, sugerindo que o processo inflamatório e o uso de GC durante as fases de maior formação óssea acarretam maior impacto na massa óssea. Não foi encontrada associação entre densidade ou parâmetros de metabolismo ósseo e alterações orais / Introduction: The survival of Juvenile systemic lupus erythematosus (JSLE) patients has improved progressively. Thus, new aspects must be considered in the monitoring of these patients, such as impairment of bone mass and periodontal disease. Objective: 1- To assess bone mineral density, bone turnover parameters and oral health in patients with JSLE; 2- To evaluate possible associations between parameters of bone remodeling and bone mineral density with oral amendments, as well as demographic data, clinical manifestations, activity rates and cumulative damage, therapy and quality of life related to health in patients with JSLE. Methods: Twenty-four female adolescent JSLE patients were studied and compared to 29 female adolescent healthy controls regarding demographic, anthropometric and clinical data, and habits of life. In patients also were determined indices of quality of life, activity and cumulative damage of disease and therapy used. Evaluation parameters of bone metabolism included serum levels of osteoprotegerin (OPG), soluble receptor activator of nuclear factor KB ligand (sRANKL), propeptídeo N-terminal of type I collagen (P1NP), telopeptide of type I collagen (CTX), 25 hydroxyvitamin D, parathyroid hormone (PTH) and bone mineral density (BMD). Orofacial evaluation included clinical features, dental and periodontal assessment in patients and health controls. Results: Patients with JSLE presented lower Z-score in lumbar spine (p < 0.001), total femur (p=0.027), femoral neck (p=0.015) and total body (p < 0.001) when compared to healthy controls. They also presented lower levels of P1NP (p=0.007), CTX (p < 0.001), and PTH (p=0.009) when compared to the later group. It was found a negative correlation between the cumulative dose of glucocorticoids (GC) and the femoral neck Z-score (r= -0,491 p=0.024). Patients with Z- score <= -2 in total femur had significantly higher age at diagnosis compared to those with Z- score > -2 [14,5 years vs 11 years (p= 0,038)]. Median of decayed, missing and filled teeth (DMFT) was significantly greater in JSLE patients (p=0.010) than controls. Higher cumulative doses of GC were correlated with higher indices of DMFT (r= +0.435 p=0.048). Conclusion: JSLE patients have decreased bone mineral density and bone turnover when compared to healthy controls. Furthermore, they have a larger number of DMFT. Cumulative doses of GC were correlated to the number of DMFT and low BMD. Total femur BMD was lower in patients that were older at diagnosis, suggesting that the inflammatory process and the use of GC during the greatest bone formation period constitute the major impact factors on bone mass. No association was found between BMD, bone metabolism and oral abnormalities

INTRODUÇÃO: Com a melhora do prognóstico nos pacientes com lúpus eritematoso sistêmico juvenil novas recomendações são necessárias na reumatologia pediátrica, como avaliação da saúde bucal e do sistema mastigatório. O objetivo deste estudo é avaliar o comprometimento orofacial nos pacientes com lúpus eritematoso sistêmico juvenil e grupo controle, e avaliar possíveis associações entre o comprometimento orofacial e manifestações clínicas, exames laboratoriais e terapias da doença. MÉTODOS: Entre março de 2004 e julho de 2005 foram avaliados 48 pacientes com diagnóstico de lúpus eritematoso sistêmico juvenil, atendidos na Unidade de Reumatologia Pediátrica do ICr-HC-FMUSP. O grupo controle incluiu 48 crianças e adolescentes saudáveis atendidos na Divisão de Odontologia do HC-FMUSP. A pesquisa incluiu avaliação de dados sócio-demográficos, manifestações clínicas, exames laboratoriais, atividade da doença (SLEDAI), dano cumulativo (SLICC/ACR-DI) e terapias da doença. A avaliação orofacial incluiu questionário de anamnese, índice CPO-D, índice de placa, índice de sangramento gengival, relação dentária, perfil facial, índice de Helkimo e avaliação da articulação temporomandibular através da radiografia panorâmica de face em todos os pacientes e tomografia computadorizada apenas nos casos com achatamento e/ou destruição dos côndilos mandibulares. RESULTADOS: Os dois grupos foram homogêneos com relação à faixa etária, distribuição por gênero e classe sócio-econômica. A idade dos pacientes com lúpus eritematoso sistêmico juvenil variou de 87 a 218 meses (média de 161,9±38,4) e do grupo controle de 78 a 254 meses (média de 154,4±45,8; p=0,384). As medianas dos índices de placa e de sangramento gengival nos pacientes com lúpus eritematoso sistêmico juvenil foram superiores em relação aos controles (61,5X38,1; p=0,003 e 26,0X15,95; p=0,014). O índice de disfunção clínica e o índice de mobilidade mandibular mostraram-se mais alterados nos pacientes com LESJ versus controles (p=0,002, p=0,025). Correlação linear estatística foi evidenciada entre: tempo de doença e índice de sangramento gengival (p=0,017; r=0,11), dose cumulativa de prednisona e índice de placa (p=0,010, r=0,385) e dose cumulativa de prednisona e índice de sangramento gengival (p=0,001, r=0,02). A mediana do índice de mobilidade mandibular foi superior nos pacientes com lúpus eritematoso sistêmico juvenil em uso de um ou mais imunossupressores em relação aos que não utilizaram estas drogas (p=0). Apenas dois pacientes apresentaram radiografia panorâmica com achatamento e/ou destruição dos côndilos mandibulares e na tomografia computadorizada de ATM os achados foram: redução do espaço articular bilateralmente, erosões dos platôs articulares com aplainamento dos côndilos sugestivo de necrose avascular da articulação temporomandibular. CONCLUSÕES: Os pacientes com lúpus eritematoso sistêmico juvenil apresentaram uma precária higiene oral, maior freqüência de gengivite e disfunção da articulação temporomandibular em relação ao grupo controle. Os pacientes com maior tempo de doença e maior dose cumulativa de prednisona tiveram maior freqüência de gengivite e os que utilizaram imunossupressores apresentaram disfunção da articulação temporomandibular / INTRODUCTION: Given the enhanced prognosis of patients with juvenile systemic lupus erythematosus, new recommendations are necessary in pediatric rheumatology, such as the analysis of oral health and the masticatory system. The aim of this study was to compare dental and facial conditions of patients with juvenile systemic lupus erythematosus and a control group, and to evaluate a potential relationship between dental and facial endangering and clinical manifestations, laboratory tests and therapies for the disease. PATIENTS AND METHODS: A total of 48 children and adolescents with juvenile systemic lupus erythematosus attending the Pediatric Rheumatology Unit of the Children\'s Institute of our University Hospital were studied between January 2004 and July 2005. The control group included 48 healthy children and adolescents that were selected from the Odontology Division of our University Hospital. The search included the analysis of social and demographic data, clinical manifestations, laboratory tests, juvenile systemic lupus erythematosus disease activity and cumulative damage (using the SLEDAI and the SLICC/ACR-DI), and therapies. The dental and facial examination included the anamnesis questionnaire, DMFT index, plaque and gengival bleeding index, dental relationship, facial profile, Helkimo\'s index and evaluation of the temporomandibular joint through a radiographic panoramic examination of all patients and a computer tomography on those with flattening and/or destruction of the mandibular condyles. RESULTS: The two groups were homogeneous regarding age, gender and social-economic class. The age of the juvenile systemic lupus erythematosus patients ranged from 87 to 218 months (mean of 161.9±38.4) and of the control group from 78 a 254 months (mean of 154.4±45.8; p=0.384). The medians of the plaque and gingival bleeding indexes were higher in juvenile systemic lupus erythematosus patients than in the control group (61.5X38.10; p=0.003 and 26.0X15.95; p=0.014). The indexes of clinical dysfunction and mandibular mobility were higher in juvenile systemic lupus erythematosus patients versus the control group (p=0,002, p=0,025). A linear statistical correlation was evidenced between: juvenile systemic lupus erythematosus duration and the gingival bleeding index (p=0.017; r=0.11), cumulative dose of prednisone and the plaque index (p=0,010; r=0.385) and cumulative dose of prednisone and the gingival bleeding index (p=0.001, r=0.02). The median of the mandibular mobility index was higher in juvenile systemic lupus erythematosus patients that used at least one imunossupressive drugs compared with those that didn\'t use this medication (p=0). Only two patients showed a panoramic radiography with flattening and/or destruction of the mandibular condyles. The computer tomography revealed: narrowing of joint spaces bilaterally and erosions of joints plateaus with flattening of condyles that suggested avascular necrosis of temporomandibular joint. CONCLUSIONS: Juvenile systemic lupus erythematosus patients presented poor oral hygiene, higher incidence of gingivitis and temporomandibular joint dysfunction compared to the control group. Patients with longer disease duration and higher cumulative dose of prednisone had a greater incidence of gingivitis, and those who used imunossupressives drugs showed temporomandibular joint dysfunction

Les patients atteints de lupus érythémateux systémique ont une augmentation de la prévalence du syndrome métabolique (MetS) mais les mécanismes sous-jacents ne sont pas connus. Le récepteur de type Toll 7 (TLR7), qui reconnait de l’ARN simple brin, joue un rôle important dans la défense anti-microbienne de l’hôte, mais contribue également au développement et à la progression du lupus. Cependant, l’implication de TLR7 dans le MetS est inconnue. L’objectif de mon projet de thèse était d’explorer l’idée nouvelle que la signalisation de TLR7 peut conduire non seulement au lupus mais aussi à des anomalies métaboliques.Nous avons trouvé que l’obésité induite par un régime riche en gras (régime HFD) a conduit à une exacerbation du lupus et de paramètres métaboliques dans des souris TLR8ko, qui développent spontanément une auto-immunité de type lupique à cause d’une augmentation de la signalisation de TLR7 dans les cellules dendritiques (DCs). Au contraire, sous un régime HFD, les souris TLR7/8ko n’ont pas développé de lupus, et les souris TLR7ko et TLR7/8ko ont été protégées contre les anomalies métaboliques incluant l'augmentation de poids et l’intolérance au glucose. De manière intéressante, dans des souris sauvages (WT) le régime HFD a conduit à une augmentation de l’expression de TLR7 et de la production de TNF par les DCs spléniques et hépatiques, et ce phénotype était plus profond dans les souris TLR8ko. Mon étude montre l’implication de la signalisation de TLR7 dans l’interconnexion entre le lupus et les anomalies métaboliques, donc cibler TLR7 pourrait constituer une nouvelle approche comme thérapie contre le lupus et les maladies métaboliques. / Systemic lupus erythematosus (SLE) patients have increased prevalence of metabolic syndrome but the underlying mechanisms are unknown. Toll-like receptor 7 (TLR7) that detects single stranded-RNA plays a key role in antimicrobial host defence, but also contributes in the initiation and progression of SLE. However, the implication of TLR7 in MetS is unknown. The objective of my PhD project was to explore the novel idea that TLR7 signalling can lead not only to SLE but also to metabolic abnormalities. We found that high fat diet (HFD)-induced obesity led to exacerbation of lupus and metabolic parameters in TLR8ko mice, which develop spontaneous lupus-like disease due to increased TLR7 signalling by dendritic cells (DCs). In contrast, upon HFD TLR7/8ko mice did not develop SLE, and both TLR7ko and TLR7/8ko mice were protected from metabolic abnormalities including body weight gain and glucose intolerance. Interestingly, in wild-type mice HFD led to an increase of TLR7 expression and TNF production by hepatic and splenic DCs, and this phenotype was more profound in TLR8ko mice. My study uncovers the implication of TLR7 signalling in the interconnection of SLE and metabolic abnormalities, thus targeting TLR7 might be a novel approach as a tailored therapy in SLE and metabolic diseases.

<p>Systemic lupus erythematosus (SLE) is a complex autoimmune disease with unknown etiology. The aim of this thesis was to identify susceptibility regions through genetic mapping, using model-based linkage analysis on nuclear and extended SLE multicase families.</p><p>In the first paper we performed a genome scan on 19 genetically homogenous Icelandic and Swedish families. One region at 2q37 was identified with a significant linkage with contribution from both populations (Z=4.24). Five other regions 2q11, 4p13, 9p22, 9p13 and 9q13 showed suggestive linkage (Z>2.0).</p><p>In the second paper, 87 families from 10 different countries were analysed only for chromosome 1. One region at 1q31 showed significant linkage (Z=3.79) with contribution from families from all populations, including Mexicans and Europeans. Four other regions 1p36, 1p21, 1q23, and 1q25, showed levels of suggestive linkage. Linkage for most regions was highly dependent on what population was used, which indicated strong genetic heterogeneity in the genetic susceptibility for SLE.</p><p>In the two last papers, we used the positional candidate gene strategy, in order to investigate candidate genes in two regions linked to SLE. For the Bcl-2 gene (at 18q21) we could not detect any association with SLE using three different markers. However, when we investigated the tightly linked low-affinity family of FcγR genes (at 1q23), we could find association for two risk alleles in the FcγRIIA and FcγRIIIA genes. The risk alleles were transmitted to SLE patients on one specific haplotype and therefore are not independent risk alleles.</p><p>The results show that model-based linkage analysis is a strong approach in the search for susceptibility genes behind complex diseases like SLE.</p>

<p>Patients with systemic lupus erythematosus (SLE) have elevated levels of interferon (IFN)-α in blood and IFN-α-producing cells in tissues. In the present thesis, we investigate the mechanisms behind the upregulated IFN-α-production in SLE and also show that the IFN-α system is activated in primary Sjögren’s syndrome (pSS), with IFN-α-producing cells in the major affected organ, the salivary glands. The IFN-α is a type I IFN, a family of cytokines counteracting especially viral infections, by acting directly on infected cells, and via many immunomodulatory effects. The latter may also contribute to autoimmune processes.</p><p>The type I IFNs are usually produced upon recognition of microbial structures. In SLE, however, DNA-containing immune complexes (ICs) that induce IFN-α production are found. Many autoantibodies in SLE and pSS are directed to nucleic acids or to DNA/RNA-binding proteins. We show that also RNA in complex with autoantibodies from SLE or pSS patients (RNA-IC) induces IFN-α-production. The RNA could be either in the form of RNA-containing material released from apoptotic or necrotic cells or as a pure RNA-containing autoantigen, the U1 small nuclear ribonucleoprotein particle. </p><p>The IFN-α-production induced by RNA-IC occurred in plasmacytoid dendritic cells (PDCs), also termed natural IFN-producing cells (NIPCs), via binding to Fcγ-receptor IIa, endocytosis and triggering of Toll-like receptors (TLRs), probably TLR7 and TLR9. The RNA-IC may also have other effects, and we found that they induce prostaglandin E2 (PGE2) production in monocytes and tumor necrosis factor (TNF)-α in both monocytes and NIPC/PDC. The PGE2 downregulated the IFN-α induction in NIPC/PDC, and the IFN-α induction was increased in monocyte-depleted cell cultures. </p><p>The findings presented in this thesis aids in the understanding of the mechanisms behind the activated IFN-α system in SLE and other autoimmune diseases, and shows that also pSS is one of these diseases.</p>

<p>The breakdown of self-tolerance is the main driving force behind susceptibility to SLE. When this occurs, T and B cells are activated in an uncontrolled manner and produce autoantibodies against self fragmented DNA, RNA and sometimes other parts of the cell such as cardiolipin, phosphatidylserine, etc.</p><p>The mechanism behind the breakdown of self-tolerance may be genetic factors that are triggered by environmental factors. SLE is not caused by a single gene, but by many genes, and is thus a polygenic disease. So far only a few genes have been found to be associated with SLE including PDCD1, FcγRs, and PTPN22. The main aim of my thesis is to find susceptibility genes responsible for SLE.</p><p>Recently, a gene called IRF5 was found to be associated with SLE. In paper one, we performed a thorough study and confirmed its association to SLE. In addition, we found a few other SNPs in the gene that were associated to the disease. Among them, SNP rs2004640 is very strongly associated and was found to affect the splicing of the gene. Another SNP, rs2280714, correlated with overexpression of the gene, although SNP rs10954213 was much more highly correlated with expression adding to this, in paper two we found a few other SNPs that were associated to SLE and played crucial roles in gene function. An indel in exon 6, though not associated by itself, regulated which isoforms were expressed. Individuals with 2 repeats expressed isoforms V1 and V4, while individuals with 4 repeats expressed isoforms V5 and V6. SNP rs2070197 was also very strongly associated, but did not have a functional role. In paper three, the same polymorphisms were studied in a Mexican population, which showed an even stronger association when compared to a European population.</p><p>It is known that autoimmune diseases share susceptibility genes, therefore we wanted to see if the IRF5 gene is associated with any other autoimmune diseases. In papers four and five, we tested its association to RA (using three sets of patients and controls from Sweden, Argentina and Spain) and psoriasis (using a set of patients and controls from Sweden). Association was not found in either of the diseases. Therefore, we believe that this association may be SLE-specific.</p>