MBL2 gene polymorphisms and its relation to infection in Brazilian systemic lupus erythematosus patients: A 10-years follow-up study.

INTRODUCTION: Systemic lupus erythematosus (SLE) is a multifactorial disease and MBL2 genetic variants, which are associated to differential peripheral MBL levels, potentially affect its etiology and increase infection risk in this population. OBJECTIVE: To evaluate the potential association of MBL2 polymorphisms of the coding and promoter gene region and haplotypes on hospitalization, number of admission and days of admission for major infection causes in Brazilian SLE patients. Methods: 325 SLE patients from a southern Brazilian outpatient SLE clinic were genotyped in 2006 for MBL2 gene polymorphisms from coding and promoter region (rs1800450, rs1800451, rs5030737, rs11003125, and rs7096206) and followed until 2016. Clinical and laboratory data from each patient were obtained and information regarding the need for hospitalization, the number of admissions and number of days admitted for infection treatment were compiled and compared with MBL2 gene polymorphisms and haplotypes. A linear regression analysis was constructed considering the variables of bivariate which demonstrated an association (p<0.05) and variables which had a theoretical basement. RESULTS: No difference was found in polymorphism prevalence when comparing the group that was admitted for infection treatment and the group who did not. Allele C, and haplotypes LY and HY correlated with more infection hospitalizations [wild-type homozygosis for C: 2 (IQR 1-3), heterozygosis for C: 3 (IQR 2-6) p=0.038; LY 2 (IQR 1-3) p=0.049; HY 2 (IQR 1-3) p=0.005] and haplotype HY carriers stayed fewer days in hospital for infection treatment: 18 (IQR 10-38) p=0.041. When linear regression was applied HY associated with shorter admission time for infections (-18.11 days, p=0.021) and HY (-1.52 admission, p 0.001) carriers with older age at diagnosis had less admissions for infection (HY regression model: -0.42, p=0.006; LY regression model -0.04, p=0.010; -0.04, p=0.013). CONCLUSION: The presence of the HY promoter haplotype associated to fewer in hospital care for infection treatment probably due to higher MBL plasma levels. Also, HY haplotype and older age at SLE diagnosis is related to less admissions for infection. This factor should be taken into consideration, since infection is a very import cause of mortality in SLE patients being also related to aggressive immunosuppressive treatment.

T-cell specific upregulation of Sema4A as risk factor for autoimmunity in systemic lupus erythematosus and rheumatoid arthritis.

The aim of the present study was to evaluate the impact of SEMA4A genetic variants on expression of sema4A protein and its relation to autoimmunity development in Systemic Lupus Erythematosus and Rheumatoid Arthritis patients. A total of 541 SLE patients, 390 RA patients and 607 healthy individuals were genotyped. We also assessed SEMA4A mRNA expression from whole blood cells and the in vitro protein production from resting and activated T lymphocytes as well as mature dendritic cells from healthy individuals stratified according to their genotypes for SLE/RA associated SEMA4A variants. Our results showed that T/T genotype for rs3738581 SNP is associated with both RA and SLE development (p = .000053, OR = 2.35; p = .0019, OR = 2.07, respectively; statistical power = 100%) and also to an increased in vitro sema4A production in active T lymphocytes. Our findings are indicative of a T cell-specific upregulation of sema4A in the presence of T/T genotype, being a risk factor for SLE and RA.

Treating psoriatic arthritis to target: discordance between physicians and patients' assessment, non-adherence, and restricted access to drugs precluded therapy escalation in a real-world cohort.

The treat-to-target strategy (T2T) was associated with better outcomes in psoriatic arthritis (PsA) compared to standard care in clinical trials. This study aimed to analyze factors precluding treatment optimization in a T2T strategy conducted in a real-world cohort of PsA patients. A retrospective cross-sectional study nested in a cohort was conducted. Medical records of patients ≥ 18 years old, fulfilling CASPAR criteria and with at least one visit in the PsA clinic, were reviewed. Demographic data, current medication, and minimal disease activity (MDA) criteria were recorded. Reasons for the non-escalation of therapy in patients who were not classified as MDA were reported as absolute and relative frequencies. In the 8-month period, 131 visits (corresponding to 74 patients) were conducted. The MDA criteria were available in 113 visits (86.3%) and patients were classified as MDA in 31.0% of the visits (N = 35/113). Although in 69.0% of the visits patients were not in MDA, (N = 78/113), therapy was adjusted in only 42.3% (N = 33/78). Reasons precluding treatment escalation in non-MDA subjects were physician's impression of remission (57.7%, N = 26), non-adherence to previous prescription (17.8%, N = 8), restricted access to drugs (17.8%, N = 8), adverse events (11.1%, N = 5), poor understanding of medication instructions (6.7%, N = 3), patient's refusal to escalate therapy (4.4%, N = 2), and recent change in therapy (2.2%, N = 1). Discordance between the physician's clinical evaluation and the MDA criteria, non-adherence to prescription, and poor access to drugs were the main factors precluding escalation of therapy in a T2T strategy in a real-world PsA cohort.

Rheumatoid arthritis seems to have DMARD treatment decision influenced by fibromyalgia.

OBJECTIVE: To compare DMARD use in patients with and without FM over time, including overtreatment and undertreatment rates in both groups. METHODS: A prospective cohort study with patients attending an RA outpatient clinic was conducted. Participants were consecutively recruited between March 2006 and June 2007 and were followed through December 2013. Data on DMARD use (prevalences, doses and escalation rates), DAS28, HAQ and radiographic progression were compared among RA patients with FM and without FM. Mistreatment clinical scenarios were allegedly identified and compared between groups. RESULTS: 256 RA patients (32 with FM) were followed for 6.2±2.0 (mean±SD) years comprising 2986 visits. At baseline, RA duration was 11.1±7.4 years. DAS28 and HAQ were greater in RA with FM group, and were closer to RA without FM group towards the end. RA patients with FM used higher doses of tricyclic antidepressants, leflunomide and prednisone, and lower doses of methotrexate. When compared to RA patients without FM, participants with RA and FM used more often tricyclic antidepressants, leflunomide, prednisone, continuous analgesics and less often methotrexate. Groups presented similar 7-year biologic-free survival, and radiographic progression-free survival in Cox regression. RA patients with FM had greater proportions of visits in mistreatment scenarios when compared to RA patients without FM (28.4 vs. 19.8%, p<0.001). CONCLUSIONS: RA patients with FM used more leflunomide and prednisone, and RA mistreatment was more frequent in FM patients. Certainly, RA patients with FM will benefit from a personalized T2T strategy, including ultrasound (when suitable) and proper FM treatment.

Rheumatoid arthritis seems to have DMARD treatment decision influenced by fibromyalgia / As decisões de tratamento com DMARD na artrite reumatoide parecem ser influenciadas pela fibromialgia

Abstract Objective: To compare DMARD use in patients with and without FM over time, including overtreatment and undertreatment rates in both groups. Methods: A prospective cohort study with patients attending an RA outpatient clinic was conducted. Participants were consecutively recruited between March 2006 and June 2007 and were followed through December 2013. Data on DMARD use (prevalences, doses and escalation rates), DAS28, HAQ and radiographic progression were compared among RA patients with FM and without FM. Mistreatment clinical scenarios were allegedly identified and compared between groups. Results: 256 RA patients (32 with FM) were followed for 6.2 ± 2.0 (mean ± SD) years comprising 2986 visits. At baseline, RA duration was 11.1 ± 7.4 years. DAS28 and HAQ were greater in RA with FM group, and were closer to RA without FM group towards the end. RA patients with FM used higher doses of tricyclic antidepressants, leflunomide and prednisone, and lower doses of methotrexate. When compared to RA patients without FM, participants with RA and FM used more often tricyclic antidepressants, leflunomide, prednisone, continuous analgesics and less often methotrexate. Groups presented similar 7-year biologic-free survival, and radiographic progression-free survival in Cox regression. RA patients with FM had greater proportions of visits in mistreatment scenarios when compared to RA patients without FM (28.4 vs. 19.8%, p < 0.001). Conclusions: RA patients with FM used more leflunomide and prednisone, and RA mistreatment was more frequent in FM patients. Certainly, RA patients with FM will benefit from a personalized T2T strategy, including ultrasound (when suitable) and proper FM treatment.

Resumo Objetivo: Comparar o uso de fármacos antirreumáticos modificadores da doença (DMARD) em pacientes com e sem fibromialgia (FM) ao longo do tempo, incluindo as taxas de tratamento excessivo e subtratamento em ambos os grupos. Métodos: Estudo de coorte prospectiva com pacientes atendidos em um ambulatório de artrite reumatoide (AR). Os participantes foram recrutados consecutivamente entre março de 2006 e junho de 2007 e foram seguidos até dezembro de 2013. Compararam-se os dados de uso de DMARD (prevalências, doses e taxas de escalonamento), 28-Joint Disease Activity Score (DAS28), Health Assessment Questionnaire (HAQ) e progressão radiográfica entre pacientes com e sem FM. Os cenários clínicos de tratamento supostamente incorreto foram identificados e comparados entre os grupos. Resultados: Seguiram-se 256 pacientes com AR (32 com FM) por 6,2 ± 2,0 (média ± DP) anos, período que abrangeu 2.986 consultas. No início do estudo, a duração da AR era de 11,1 ± 7,4 anos. O DAS28 e o HAQ foram maiores no grupo AR com FM e estavam mais próximos do grupo AR sem FM no fim do estudo. Os pacientes com AR com FM usaram doses mais altas de antidepressivos tricíclicos, leflunomida e prednisona e doses mais baixas de metotrexato. Quando comparados com os pacientes com AR sem FM, os participantes com AR e FM usaram mais frequentemente antidepressivos tricíclicos, leflunomida, prednisona e analgésicos contínuos e menos frequentemente metotrexato. Os grupos apresentaram sobrevida em sete anos sem agentes biológicos e livres de progressão radiográfica semelhantes na regressão Cox. Os pacientes com AR com FM apresentaram uma maior proporção de consultas em cenários de tratamento supostamente incorreto quando comparados com os pacientes com AR sem FM (28,4 vs. 19,8%, p < 0,001). Conclusões: Os pacientes com AR e FM usaram mais leflunomida e prednisona e o tratamento supostamente incorreto na AR foi mais frequente em pacientes com FM. Os pacientes com AR com FM certamente se beneficiarão de uma estratégia personalizada de tratamento por metas (T2 T), incluindo ultrassonografia (quando apropriado) e controle da FM.

Survival analysis of patients with systemic lupus erythematosus in a tertiary hospital in southern Brazil.

Systemic lupus erythematosus (SLE) treatments progress over the years. However, the mortality remains higher than in the general population. Few studies have examined SLE patients' survival in Brazil. This study aims to identify the main characteristics and risk factors to predict mortality and recognize the main causes of death in Brazilian patients with SLE. We retrospectively assessed clinical, demographic, and serological characteristics from 600 patients followed since 2001 in SLE outpatient clinic from Hospital de Clínicas de Porto Alegre. Risk factors for mortality were examined by univariate and multivariate Cox proportional hazards regression analyses. A p < 0.05 was considered significant. There were 527 survivors (87.83%). The main causes of death were cardiovascular disease (17%), infection (17%), and infection and SLE activity (17%). Risk factors for death were age at diagnosis (HR 1.065, CI 95% 1.039-10.092), SLICC damage index (HR 1.299, CI 95% 1.076-1569), antiphospholip syndrome (HR 3.021, CI 95% 1.307-6.985), and metilprednisolone pulse (HR 2.628, CI 95% 1.283-5.383). Antimalarials was a protective factor for death (HR 0.191, CI 95% 0.064-0.570). Cardiovascular disease, infection, and SLE activity associated with infection were the main known causes of deaths in our SLE patients. Secondary antiphospolipid syndrome, highest score in SLICC damage index, advanced age at diagnosis, and high dose of corticosteroids were risk factors for mortality. Antimalarials was an important protective factor.

Age of onset influences on clinical and laboratory profile of patients with systemic lupus erythematosus.

The present study aims to evaluate differences in clinical and laboratory manifestations and medication use in the different ages of disease onset in patients with systemic lupus erythematosus (SLE). This cross-sectional study consisted of 598 SLE patients (550 female and 48 male), who attended the Rheumatology Clinic of the Hospital de Clínicas de Porto Alegre between 2003 and 2015. Demographic, clinical and laboratory data were collected. The patients were classified into three groups according to their ages at disease diagnosis. Mean age of diagnosis was 33.6 ± 14.3 years, and the median (25th-75th percentile) disease duration was 13 (7-20) years. Among the patients studied, 419 (70%) were adult-onset (aSLE), 90 (14.8%) were late-onset (lSLE) and 89 (14.8%) were childhood-onset (cSLE). The female to male ratio was higher in aSLE (18:1) compared to the other groups (p = 0.001). Arthritis was predominantly found in aSLE (78.5%) when compared with lSLE (57.7%) (p < 0.001). Nephritis was more common in cSLE (60.6%) than in lSLE (26.6%) (p < 0.001). Median (25th-75th percentile) of SLE disease activity index (SLEDAI) was higher in the cSLE group [2 (0-5)] when compared to the lSLE group [0 (0-4)] (p = 0.045). Childhood-onset SLE showed a more severe disease due to the higher incidence of nephritis and needed a more aggressive treatment with immunosuppressive drugs.

Rheumatoid arthritis seems to have DMARD treatment decision influenced by fibromyalgia. / As decisões de tratamento com DMARD na artrite reumatoide parecem ser influenciadas pela fibromialgia.

OBJECTIVE: To compare DMARD use in patients with and without FM over time, including overtreatment and undertreatment rates in both groups. METHODS: A prospective cohort study with patients attending an RA outpatient clinic was conducted. Participants were consecutively recruited between March 2006 and June 2007 and were followed through December 2013. Data on DMARD use (prevalences, doses and escalation rates), DAS28, HAQ and radiographic progression were compared among RA patients with FM and without FM. Mistreatment clinical scenarios were allegedly identified and compared between groups. RESULTS: 256 RA patients (32 with FM) were followed for 6.2±2.0 (mean±SD) years comprising 2,986 visits. At baseline, RA duration was 11.1±7.4 years. DAS28 and HAQ were greater in RA with FM group, and were closer to RA without FM group towards the end. RA patients with FM used higher doses of tricyclic antidepressants, leflunomide and prednisone, and lower doses of methotrexate. When compared to RA patients without FM, participants with RA and FM used more often tricyclic antidepressants, leflunomide, prednisone, continuous analgesics and less often methotrexate. Groups presented similar 7-year biologic-free survival, and radiographic progression-free survival in Cox regression. RA patients with FM had greater proportions of visits in mistreatment scenarios when compared to RA patients without FM (28.4 vs. 19.8%, p<0.001). CONCLUSIONS: RA patients with FM used more leflunomide and prednisone, and RA mistreatment was more frequent in FM patients. Certainly, RA patients with FM will benefit from a personalized T2T strategy, including ultrasound (when suitable) and proper FM treatment.

Ficolin Gene Polymorphisms in Systemic Lupus Erythematosus and Rheumatoid Arthritis.

Systemic lupus erythemathosus (SLE) and rheumatoid arthritis (RA) are complex autoimmune diseases characterized by an immune balance breakdown and by chronic inflammation. Several findings link SLE and RA development with the complement system and ficolin components have emerged as candidates for disease development. Since genetic association studies with ficolin genes in SLE and RA have not yet been conducted in a Brazilian population, the aim of this study was to determine whether polymorphisms of ficolin-1(FCN1) and ficolin-2 (FCN2) genes are associated with SLE and RA susceptibility as well as disease manifestation. Two SNPs within FCN1 (rs2989727 and 1071583) and three in FCN2 (rs17514136, rs3124954, and rs7851696) were studied in 208 SLE and184 RA patients as well as 264 healthy individuals in a Southeast Brazilian population. For SLE patients, the FCN2 rs17514136 SNP was associated with a more severe disease (SLICC) (p = 0.0067). Furthermore, an association between the occurrence of nephritis and the T/T genotype for FCN2 rs3124954 SNP (p = 0.047, OR = 3.17, 95%CI = 1.34-7.5) was observed. No association was observed between the studied polymorphisms and RA development. Thus, our data support involvement of the FCN2 gene in the SLE phenotype.

Vitamin D receptor polymorphisms and expression profile in rheumatoid arthritis Brazilian patients.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation and important joint commitment, being the most common systemic autoimmune disease worldwide. RA displays important genetic background with a variety of genes contributing to the immune balance breakdown. Recent studies have demonstrated that vitamin D, through its receptor (VDR), is able to regulate the immune balance and suppress the autoimmunity process, being a potential target in autoimmune diseases. In the present genetic association study, we assessed 5 Tag single nucleotide polymorphisms (SNPs) (rs11168268, rs2248098, rs1540339, rs4760648 and rs3890733), which cover most of the VDR gene, in three different Brazilian populations (from Northeast, Southeast and South Brazil). We also evaluated the VDR expression profile in whole blood and monocytes from RA patients. For genotyping study, 428 RA patients and 616 healthy controls were genotyped with fluorogenic allele specific probes on an ABI7500 platform. For gene expression study, VDR mRNA levels of 15 RA patients and 26 healthy individuals were assessed by RT-PCR. Our results showed that SNPs rs4760648 and rs3890733 are associated to RA susceptibility (p value = 0.0026, OR 1.31 and p value = 0.0091, OR 1.28 with statistical power = 0.999 and 0.993, respectively). Regarding RA clinical features, the studied SNPs did not show significant associations. The gene expression assays showed that VDR mRNA levels were down regulated in both whole blood (-3.3 fold) and monocytes (-3.2 fold) of RA patients when compared to healthy controls. Our results, the first reported for distinct Brazilian populations, support a role of the VDR gene in the susceptibility to RA.

Hormônio anti-Mülleriano como preditor de reserva ovariana em pacientes lúpicas: uma revisão / Anti-Müllerian hormone levels as a predictor of ovarian reserve in systemic lupus erythematosus patients: a review

RESUMOO hormônio anti-Mülleriano (HAM) é secretado a partir das células da granulosa dos folículos ovarianos em crescimento e parece ser o melhor marcador endócrino capaz de estimar a reserva ovariana. O lúpus eritematoso sistêmico (LES) é uma doença autoimune que acomete predominantemente mulheres em idade reprodutiva e pode afetar negativamente sua fertilidade pela atividade da doença, bem como pelos tratamentos usados. Conhecer o real impacto do LES e de seu tratamento na fertilidade vem sendo o objetivo de estudos recentes, os quais têm usado o HAM para esse fim.

ABSTRACTThe anti-Müllerian hormone (AMH) is secreted from granulosa cells of growing ovarian follicles and appears to be the best endocrine marker capable of estimating ovarian reserve. Systemic lupus erythematosus (SLE) is an autoimmune disease that predominantly affects women of reproductive age and may negatively affect their fertility due to disease activity and the treatments used. Recently, several studies assessed AMH levels to understand the real impact of SLE and its treatment on fertility.

The paradox of high availability and low recognition of soluble HLA-G by LILRB1 receptor in rheumatoid arthritis patients.

HLA-G is a regulatory molecule involved in immunologic tolerance. Growing evidence indicates that HLA-G plays a role in the regulation of inflammatory processes and autoimmune diseases. This study aimed at a systematic evaluation of soluble HLA-G (sHLA-G) in plasma of rheumatoid arthritis (RA) patients with long-lasting chronic inflammation. RA patients (n=68) and healthy controls (n=26) had their plasmatic sHLA-G measured by ELISA whereas the binding capability of sHLA-G to its cognate LILRB1 receptor was measured by a Luminex-based assay. All subjects were PCR-genotyped for HLA-G 14 bp polymorphism (rs66554220). Significantly higher sHLA-G levels were observed in patients (p<0.001), however no significant differences were observed in LILRB1 binding capacity between RA patients and controls. Remarkably, the proportion of patients presenting specific binding of sHLA-G to LILRB1 was significantly decreased as compared to controls (56% vs. 81%, p=0.027). Patients without rheumatoid factor (RF-) were significantly overrepresented in the group of patients positive for LILRB1 binding as compared to patients without LILRB1 binding (31% vs 10%, p=0.033). Furthermore, methotrexate treated patients (n=58) revealed significantly lower LILRB1 binding to sHLA-G molecules than non-treated patients (medians: 12.2 vs. 67.7 units/ml, p=0.031). Unlike in controls, no significant differences in sHLA-G levels were observed among patients grouped by 14 pb genotype. Thus, in a substantial number of late RA patients, the circulating sHLA-G molecules are impaired regarding LILRB1 recognition, meaning that although increased levels are observed; these molecules are not qualified to exert their protective functions against inflammation. Our findings offer new insights into the immunopathology of RA patients with long-lasting anti-RA-treatment and highlight the importance to also measure the binding capability of sHLA-G to LILRB1.

Is ultrasound a better target than clinical disease activity scores in rheumatoid arthritis with fibromyalgia? A case-control study.

OBJECTIVES: Our goal is to study the correlations among gray-scale seven-joint ultrasound score (GS-US7), power Doppler seven-joint ultrasound score (PD-US7), disease activity score-28 joints (DAS28), simplified disease activity index (SDAI) and clinical disease activity index (CDAI) in patients with and without fibromyalgia (FM). METHODS: A matched case-control study included all patients consecutively seen in the Rheumatoid Arthritis (RA) Clinic. Participants were allocated into one of two groups: RA with FM and RA without FM. Ultrasound (US) and clinical scoring were blinded for the presence of FM. Medians and proportions were compared by Mann-Whitney's test and McNemar's test, respectively. Spearman's rank correlation coefficients (rs) were calculated among clinical and US scores and differences were tested by r-to-z transformation test. RESULTS: Seventy-two women were included, out of 247 RA patients, mostly white, with median (IQR) age of 57.5 (49.3-66.8) years, with RA symptoms for 13.0 (6.0-19.0) years and FM symptoms for 6.0 (2.0-15.0) years. Disease-modifying antirheumatic drugs, non-steroidal anti-inflammatory drugs and prednisone use was comparable between groups. Objective activity parameters were not different between groups. RA patients with FM had greater DAS28, SDAI and CDAI but similar GS-US7 and PD-US7. GS-US7 correlated with DAS28, SDAI and CDAI in patients with and without FM (rs = 0.36-0.57), while PD-US7 correlated with clinical scores only in patients without FM (rs = 0.35-0.38). CONCLUSION: To our knowledge, this is the first study to demonstrate that ultrasound synovitis scores are not affected by FM in RA patients. PD-US7 performed better than GS-US7 in long-standing RA patients with DAS28, SDAI or CDAI allegedly overestimated due to FM. Since sonographic synovitis predicts erosion better than swollen joint count, C-reactive protein and erythrocyte sedimentation rate, US should be considered a promising treatment target in RA patients with FM.

Daily practice feasibility and effectiveness of treating long-standing rheumatoid arthritis to target with synthetic disease-modifying antirheumatic drugs: a prospective cohort study.

To prospectively study the daily practice feasibility and effectiveness of treat-to-target (T2T) strategy with synthetic drugs aiming to maintain and achieve disease remission or low activity based on DAS28 and CDAI in long-standing rheumatoid (RA) patients. Two hundred and forty-one consecutive RA patients from Hospital de Clínicas de Porto Alegre were followed for 14 (±5.3) months. At follow-up, patients were evaluated by a rheumatologist at least once every 3 to 4 months. Treatment was adjusted following a step-up strategy, based on the disease activity scores (DAS28 and CDAI), aiming at remission (<2.6 or <2.8, respectively) or at least low disease activity (<3.2 or <10). Patients were predominantly women (84.7 %), mean age 54.9 (±11.9) years with 11.1 (±7.4) years of disease duration. At visit 4, T2T intervention significantly reduced DAS28 (4.6 ± 1.6 vs. 4.0 ± 1.5; p < 0.005), CDAI [17.8 (8.2-28.7) vs. 12.6 (5.1-22.5); p < 0.001], and HAQ (1.5 ± 0.9 vs. 1.3 ± 0.8; p = 0.002). At the end of the study, compared to the baseline scores, more patients achieved remission by DAS28 (11.6 vs. 18.6 %; p < 0.001) and CDAI (8.1 vs. 13.6 %; p < 0.001) and also low disease activity by DAS28 (9.8 vs. 13.0 %; p < 0.001) and CDAI (23.9 vs. 28.4 %; p < 0.001). Both average doses of sulfasalazine and methotrexate at visit 4 were higher (1375 vs. 1621 mg, p = 0.024; and 14.5 vs. 16.5 mg, p < 0.001, respectively). More patients were on combination therapy at the end of the follow-up (48.2 vs. 52.3 %; p < 0.001). The implementation of T2T strategy in the treatment of RA was feasible and effective in this outpatient population. The optimization of synthetic DMARDs use with dose adjustments and combinations of drugs seemed to improve disease outcome regarding disease activity and functional status.

Consenso da Sociedade Brasileira de Reumatologia para o diagnóstico, manejo e tratamento da nefrite lúpica / Consensus of the Brazilian Society of Rheumatology for the diagnosis, management and treatment of lupus nephritis

Objetivo Elaborar recomendações para o diagnóstico, manejo e tratamento da nefrite lúpica no Brasil. Método Revisão extensa da literatura com seleção dos artigos com base na força de evidência científica e opinião dos membros da Comissão de Lúpus Eritematoso Sistêmico da Sociedade Brasileira de Reumatologia. Resultados e conclusões 1) A biópsia renal deve ser feita sempre que possível e houver indicação e quando não for possível, o tratamento deve ser orientado com base na inferência da clase histológica. 2) Devem ser implementados medidas e cuidados idealmente antes do início do tratamento, com ênfase na atenção ao risco de infecção. 3) Devem-se compartilhar riscos e benefícios do tratamento com pacientes e familiares. 4) O uso da hidroxicloroquina (preferencialmente) ou difosfato de cloroquina é recomendado para todos os pacientes (exceto contraindicação) durante as fases de indução e manutenção. 5) A avaliação da eficácia do tratamento deve ser feita com critérios objetivos de resposta (remissão completa/remissão parcial/refratariedade). 6) Os IECA e/ou BRA são recomendados como antiproteinúricos para todos os pacientes (exceto contraindicação). 7) A identificação de sinais clínicos e/ou laboratoriais sugestivos de GN laboratoriais sugestivos de glomerulonefrite proliferativa ou membranosa deve indicar início imediato de terapia específica incluindo corticosteroides e agente imunossupressor, mesmo que não seja possível comprovação histológica. 8) O tempo de uso dos imunossupressores deve ser no mínimo de 36 meses, mas eles podem ser mantidos por períodos mais longos. A sua suspensão só deve ser feita quando o paciente atingir e mantiver remissão completa sustentada. 9) Deve-se considerar nefrite lúpica refratária quando a remissão completa ou parcial não for alcançada após 12 meses de tratamento adequado, quando uma nova biópsia renal deve ser considerada para auxiliar na identificação da causa da refratariedade e decisão terapêutica. .

Objective To develop recommendations for the diagnosis, management and treatment of lupus nephritis in Brazil. Method Extensive literature review with a selection of papers based on the strength of scientific evidence and opinion of the Commission on Systemic Lupus Erythematosus members, Brazilian Society of Rheumatology. Results and conclusions (1) Renal biopsy should be performed whenever possible and if this procedure is indicated; and, when the procedure is not possible, the treatment should be guided with the inference of histologic class. (2) Ideally, measures and precautions should be implemented before starting treatment, with emphasis on attention to the risk of infection. (3) Risks and benefits of treatment should be shared with the patient and his/her family. (4) The use of hydroxychloroquine (preferably) or chloroquine diphosphate is recommended for all patients (unless contraindicated) during induction and maintenance phases. (5) The evaluation of the effectiveness of treatment should be made with objective criteria of response (complete remission/partial remission/refractoriness). (6) Angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers are recommended as antiproteinuric agents for all patients (unless contraindicated). (7) The identification of clinical and/or laboratory signs suggestive of proliferative or membranous glomerulonephritis should indicate an immediate implementation of specific therapy, including corticosteroids and an immunosuppressive agent, even though histological confirmation is not possible. (8) Immunosuppressives must be used during at least 36 months, but these medications can be kept for longer periods. Its discontinuation should only be done when the patient could achieve and maintain a sustained and complete remission. (9) Lupus nephritis should be considered as refractory when a full or partial remission is not achieved after 12 months of an appropriate treatment, when ...

[Anti-Müllerian hormone levels as a predictor of ovarian reserve in systemic lupus erythematosus patients: a review]. / Hormônio anti-Mülleriano como preditor de reserva ovariana em pacientes lúpicas: uma revisão.

The anti-Müllerian hormone (AMH) is secreted from granulosa cells of growing ovarian follicles and appears to be the best endocrine marker capable of estimating ovarian reserve. Systemic lupus erythematosus (SLE) is an autoimmune disease that predominantly affects women of reproductive age and may negatively affect their fertility due to disease activity and the treatments used. Recently, several studies assessed AMH levels to understand the real impact of SLE and its treatment on fertility.

[Consensus of the Brazilian Society of Rheumatology for the diagnosis, management and treatment of lupus nephritis]. / Consenso da Sociedade Brasileira de Reumatologia para o diagnóstico, manejo e tratamento da nefrite lúpica.

OBJECTIVE: To develop recommendations for the diagnosis, management and treatment of lupus nephritis in Brazil. METHOD: Extensive literature review with a selection of papers based on the strength of scientific evidence and opinion of the Commission on Systemic Lupus Erythematosus members, Brazilian Society of Rheumatology. RESULTS AND CONCLUSIONS: 1) Renal biopsy should be performed whenever possible and if this procedure is indicated; and, when the procedure is not possible, the treatment should be guided with the inference of histologic class. 2) Ideally, measures and precautions should be implemented before starting treatment, with emphasis on attention to the risk of infection. 3) Risks and benefits of treatment should be shared with the patient and his/her family. 4) The use of hydroxychloroquine (preferably) or chloroquine diphosphate is recommended for all patients (unless contraindicated) during induction and maintenance phases. 5) The evaluation of the effectiveness of treatment should be made with objective criteria of response (complete remission/partial remission/refractoriness). 6) ACE inhibitors and/or ARBs are recommended as antiproteinuric agents for all patients (unless contraindicated). 7) The identification of clinical and/or laboratory signs suggestive of proliferative or membranous glomerulonephritis should indicate an immediate implementation of specific therapy, including steroids and an immunosuppressive agent, even though histological confirmation is not possible. 8) Immunosuppressives must be used during at least 36 months, but these medications can be kept for longer periods. Its discontinuation should only be done when the patient achieve and maintain a sustained and complete remission. 9) Lupus nephritis should be considered as refractory when a full or partial remission is not achieved after 12 months of an appropriate treatment, when a new renal biopsy should be considered to assist in identifying the cause of refractoriness and in the therapeutic decision.

The number of flares patients experience impacts on damage accrual in systemic lupus erythematosus: data from a multiethnic Latin American cohort.

PURPOSE: To determine the association between the number of flares systemic lupus erythematosus (SLE) patients experience and damage accrual, independently of other known risk factors. METHODS: SLE patients (34 centres, nine Latin American countries) with a recent diagnosis (≤2 years) and ≥3 evaluations were studied. Disease activity was ascertained with the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and damage with the SLICC/ACR Damage Index (SDI). Flare was defined as an increase ≥4 points in the SLEDAI between two study visits. An ambidirectional case- crossover design was used to determine the association between the number of flares and damage accrual. RESULTS: 901 patients were eligible for the study; 500 of them (55.5%) experienced at least one flare, being the mean number of flares 0.9 (SD: 1.0). 574 intervals from 251 patients were included in the case-crossover design since they have case and control intervals, whereas, the remaining patients did not. Their mean age at diagnosis was 27.9 years (SD: 11.1), 213 (84.9%) were women. The mean baseline SDI and SLEDAI were 1.3 (1.3) and 13.6 (8.1), respectively. Other features were comparable to those of the entire sample. After adjusting for possible confounding variables, the number of flares, regardless of their severity, was associated with damage accrual (SDI) OR 2.05, 95% CI 1.43 to 2.94, p<0.001 (OR 2.62, 95% CI 1.31 to 5.24, p=0.006 for severe and OR 1.91, 95% CI 1.28 to 2.83, p=0.001 for mild-moderate). CONCLUSIONS: The number of flares patients experience, regardless of their severity, increases the risk of damage accrual, independently of other known risk factors.

Genetic polymorphisms of glutathione S-transferases and cytochrome P450 enzymes as susceptibility factors to systemic lupus erythematosus in southern Brazilian patients.

Systemic lupus erythematosus (SLE) is an autoimmune chronic inflammatory disease that presents several clinical manifestations, affecting multiple organs and systems. Immunological, environmental, hormonal and genetic factors may contribute to disease. Genes and proteins involved in metabolism and detoxification of xenobiotics are often used as susceptibility markers to diseases with environmental risk factors. Cytochrome P450 (CYP) enzymes activate the xenobiotic making it more reactive, while the Glutathione S-transferases (GST) enzymes conjugate the reduced glutathione with electrophilic compounds, facilitating the toxic products excretion. CYP and GST polymorphisms can alter the expression and catalytic activity of enzymes. This study aimed to investigate the role of genetic variants of CYP and GST in susceptibility and clinical expression of SLE, through the analysis of GSTM1 null, GSTT1 null, GSTP1*Ile105Val, CYP1A1*2C and CYP2E1*5B polymorphisms. 371 SLE patients from Hospital de Clínicas de Porto Alegre and 522 healthy blood donors from southern Brazil were evaluated. GSTP1 and CYP variants were genotyped using PCR-RFLP and GSTT1 and GSTM1 variants were analyzed by multiplex PCR. Among European-derived individuals, a lower frequency of GSTP1*Val heterozygous genotypes was found in SLE patients when compared to controls (p = 0.005). In African-derived SLE patients, the CYP2E1*5B allelic frequency was higher in relation to controls (p = 0.054). We did not observe any clinical implication of the CYP and GST polymorphisms in patients with SLE. Our data suggest a protective role of the GSTP1*Ile/Val heterozygous genotype against the SLE in European-derived and a possible influence of the CYP2E1*5B allele in SLE susceptibility among African-derived individuals.

SIRT1 promoter polymorphisms as clinical modifiers on systemic lupus erythematosus.

Silent mating type Information Regulator 2 homolog 1 (SIRT1) is a deacetylase protein that participates in several physiological processes with importance in transcriptional silencing, apoptosis, immune system regulation and inflammation. Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disease in which upregulated expression of SIRT1 on CD4+ T lymphocytes of active patients has been reported. Also, global hypoacetylation of histones H3 and H4, with H3 hypoacetylation was correlated with a higher disease activity index. SIRT1 promoter rs12778366 and rs3758391 may account for differential expression of this molecule and the role of these variants was investigated in SLE susceptibility and morbidity. Genomic DNA was extracted from peripheral blood of 367 SLE patients and 290 healthy controls of a Southern Brazilian population. SIRT1 rs12778366 and rs3758391 were amplified through PCR and genotyped through sequencing. No statistically significant differences were observed between patients and controls for allelic, genotypic or haplotypic frequencies. Nevertheless, SIRT1 rs3758391 was not in Hardy-Weinberg equilibrium, presenting a paucity of CT heterozygous both in patients and controls. SLE patients with TT and CT genotypes displayed a higher chance of developing lupus nephritis (Pc = 0.012, OR = 2.04 95 % CI 1.32-3.14) and presented a higher disease activity index (Mean rank 170.95 vs 137.26, Pc = 0.006) when compared with CC homozygous patients. Our results suggest that SIRT1 rs3758391 modifies SLE morbidity, with rs3758391 T allele being a risk factor for nephritis and a higher SLEDAI. Nevertheless, it remains to be elucidated how SIRT1 rs3758391 functionally influences SLE severity.