Systemic lupus erythematosus in the elderly: antimalarials in disease remission

To analyze the long-term antimalarials (AM) usage on elderly systemic lupus erythematosus (SLE) patients from 2002 to 2008. Fifty-seven consecutive SLE patients, a parts per thousand yen65 years, were enrolled. The patients were divided into groups A (disease remission) and B (disease activity: with clinical and/or laboratory alterations attributed to SLE activity, and/or using steroid and immunosuppressors). Forty-three patients (75.4%) were in group A. The mean age in groups A and B was, respectively, 69.8 +/- A 4.5 versus 67.8 +/- A 4.8 years (P = 0.210), with similar disease onset (46.9 +/- A 11.2 vs. 42.3 +/- A 11.6 years; P = 0.220). There was no difference in gender, ethnicity, and clinical previous manifestations. In 21 out of 57 cases (10 from group A and 11, group B, P < 0.001), AM had been suspended after 5.2 +/- A 1.3 years, because of its side effects (maculopathy). The disease remission was strongly associated to AM usage (OR 12.91; 95% CI 2.87-58.13). In summary, SLE remission was significantly associated with the long-term AM usage.

Anti-Ro antibody and cutaneous vasculitis in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a complex systemic autoimmune disease with various clinical and serological manifestations. Previous studies have shown the association of SLE and anti-Ro antibody with a series of clinical manifestations. We investigated this association in Brazilian patients with SLE. Five hundred and nine consecutive patients who fulfilled the revised American College of Rheumatology criteria for the SLE were enrolled in the study from June to December 2007. All patients were from our Service of Rheumatology, School of Medicine, University of Sao Paulo, Brazil. Frequencies of a series of laboratorial and clinical manifestations were calculated. Anti-Ro antibody was associated to anti-La antibody, female, and cutaneous vasculitis. In multivariate analysis, patients with anti-Ro antibody has 1.63 (95% CI 1.07-2.50) more risk to develop cutaneous vasculitis than patients without this antibody. Our data have demonstrated that anti-Ro antibody is an independent useful serologic marker for cutaneous vasculitis.

Chronic autoimmune urticaria as the first manifestation of juvenile systemic lupus erythematosus

Chronic urticaria (daily or almost daily symptoms lasting for more than six weeks) is characterized by wheals and erythema, with or without itching. A few case reports have shown chronic autoimmune urticaria at the beginning of systemic lupus erythematosus (SLE), particularly in adults. However, the prevalence of this manifestation in a lupus paediatric population was not studied. During 27 consecutive years, 5419 patients were followed up at our University Hospital and 271 (5%) had juvenile SLE (American College of Rheumatology criteria). Two of them (0.7%) had chronic and painless autoimmune urticaria as the first manifestation of juvenile SLE, and were reported herein. One case was a five-year old female with continuous widespread urticaria (duration 120 days), antinuclear antibodies (ANA) 1:640 (dense fine speckled pattern) and elevated complement levels. The juvenile SLE diagnosis was established after one year. The other case was a 13-year old female who had chronic widespread urticaria (lasting 45 days), ANA 1:160 (fine speckled pattern) and normal complement levels. The juvenile SLE diagnosis was established after three years. In conclusion, chronic autoimmune urticaria is very rare and may be the first lupus manifestation, particularly associated with the presence of autoantibodies. This study reinforces the importance of a rigorous follow-up in children and adolescents suffering from autoimmune urticaria due to the possibility of connective tissue disorders, such as paediatric lupus. Lupus (2011) 20, 763-766.

Discoid lupus erythematosus in children - A retrospective study of 34 patients

Discoid lupus erythematosus is much less frequent and studied in children. We undertook a retrospective study of 34 children less than 16 years of age with this disease, seen over a period of 9 years. A female predominance of 2:1 was found. An association between discoid lupus erythematosus and systemic lupus erythematosus was observed in 23.5% of patients, a higher proportion compared to adult discoid lupus erythematosus. Disseminated lesions were much more frequent in patients with criteria for systemic lupus erythematosus (87.5% vs 34%), suggesting that it could be associated with a worse prognosis. Histologic findings were similar to those observed in adult discoid lupus erythematosus.

Anti-nucleosome and anti-chromatin antibodies are present in active systemic lupus erythematosus but not in the cutaneous form of the disease

The objective of this study is to investigate the presence of anti-nucleosome (anti-NCS) and anti-chromatin (anti-CRT) antibodies in patients with cutaneous lupus erythematosus (CLE) compared with active and inactive systemic lupus erythematosus (SLE). A total of 154 subjects were evaluated: 54 patients presenting CLE, 66 patients with active SLE and 34 with inactive SLE. Lupus activity was assessed using the disease activity index (SLEDAI). Anti-NCS and anti-CRT antibodies were detected by enzyme-linked immunosorbent assay ( ELISA). Only one of 54 patients with CLE tested positive for both anti-NCS and anti-CRT antibodies. The prevalence of anti-CRT antibodies was significantly higher in active SLE (84.8%) when compared with inactive SLE (26.4%) and CLE (1.8%) ( P < 0.001). Anti-NCS antibodies were also more prevalent in active SLE patients (74.2%) than inactive SLE (11.7%) and CLE patients ( 1.8%) ( P < 0.001). The presence of anti-CRT and anti-NCS antibodies was correlated to disease activity in patients with SLE (r = 0.4937, r = 0.5621, respectively). Furthermore, the detection of both antibodies was correlated with disease activity in patients with SLE who tested negative for anti-dsDNA antibodies ( r = 0.4754 for anti-NCS and r = 0.4281 for anti-CRT). The presence of these two auto-antibodies was strongly associated with renal damage in patients with SLE ( OR = 13.1, for anti-CRT antibodies and OR = 25.83, for anti-NCS antibodies). The anti-NCS and anti-CRT antibodies were not found in CLE. In patients with SLE, there is a correlation of these antibodies with disease activity and active nephritis. When compared with anti-dsDNA antibodies, anti-NCS and anti-CRT antibodies were more sensitive in detecting disease activity and kidney damage in lupus patients. Lupus (2009) 18, 223-229.

Shared and Unique Gene Expression in Systemic Lupus Erythematosus Depending on Disease Activity

Patients presenting with active Systemic lupus erythematosus (SLE) manifestations may exhibit distinct pathogenetic features in relation to inactive SLE. Also, cDNA microarrays may potentially discriminate the gene expression profile of a disease or disease variant. Therefore, we evaluated the expression profile of 4500 genes in peripheral blood lymphocytes (PBL) of SLE patients. We studied 11 patients with SLE (seven with active SLE and four with inactive SLE) and eight healthy controls. Total RNA was isolated from PBL, reverse transcribed into cDNA, and postlabeled with Cy3 fluorochrome. These probes were then hybridized to a glass slide cDNA microarray containing 4500 human IMAGE cDNA target sequences. An equimolar amount of total RNA from human cell lines served as reference. The microarray images were quantified, normalized, and analyzed using the R environment (ANOVA, significant analysis of microarrays, and cluster-tree view algorithms). Disease activity was assessed by the SLE disease activity index. Compared to the healthy controls, 104 genes in active SLE patients (80 repressed and 24 induced) and 52 genes in nonactive SLE patients (31 induced and 21 repressed) were differentially expressed. The modulation of 12 genes, either induced or repressed, was found in both disease variants; however, each disease variant had differential expression of different genes. Taken together, these results indicate that the two lupus variants studied have common and unique differentially expressed genes. Although the biological significance of the differentially expressed genes discussed above has not been completely understood, they may serve as a platform to further explore the molecular basis of immune deregulation in SLE.

Mannose binding lectin gene (MBL2) functional polymorphisms are associated with systemic lupus erythematosus in southern Brazilians

Susceptibility to systemic lupus erythematosus (SLE) has been associated with immunologic, environmental, and genetic factors. To uncover a possible association between MBL2 gene polymorphisms and SLE, we analyzed functional polymorphisms in the promoter and first exon of the MBL2 gene in 134 Brazilian SLE patients and 101 healthy controls. Genotype and allele frequencies of MBL2 A/O polymorphism were significantly different between patients and controls, and the 0 allele was associated with an increased risk of SLE. An association between low mannose binding lectin (MBL) producer combined genotypes and increased risk for SLE was also reported. Furthermore, when stratifying SLE patients according to clinical and laboratory data, an association between the A/O genotype and nephritic disorders and between the X/Y genotype and antiphospholipid syndrome was evident. Combined genotypes responsible for low MBL production were more frequently observed in SLE patients with nephritis. Our results indicate MBL2 polymorphisms as possible risk factors for SLE development and disease-related clinical manifestations. (C) 2011 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

Superoxide anion production by neutrophils is associated with prevalent clinical manifestations in systemic lupus erythematosus

To determine the relation between neutrophil function and the clinical characteristics of systemic lupus erythematosus ( SLE), the superoxide anion (O(2)(-)) production by neutrophils, mediated by Fc gamma R and Fc gamma R/CR cooperation, was studied in 64 SLE patients classified according to their prevalent clinical manifestations. Three clinically distinct patterns were designated: ( 1) manifestations associated with the occurrence of cytotoxic antibodies ( SLE-I group); ( 2) manifestations associated with circulating immune complexes ( IC; SLE-II group), and ( 3) manifestations associated with IC and cytotoxic antibodies ( SLE-III group). O(2)(-) production was evaluated by a lucigenin-dependent chemiluminescent assay in neutrophils stimulated with ICIgG opsonized or not with complement. No difference in O(2)(-) production was observed when neutrophil responses from healthy controls were compared to the unclassified patients. However, when the SLE patient groups were considered, the following differences were observed: ( 1) SLE-I neutrophils showed lower O(2)(-) production mediated by the IgG receptor ( Fc gamma R) with the cooperation of complement receptors ( Fc gamma R/ CR) than observed in the SLE-II, SLE-III, and healthy groups; ( 2) neutrophils from the SLE-II group showed a decreased O(2)(-) production mediated by Fc gamma R/ CR compared to the SLE-III group, ( 3) SLE-III neutrophils produced more O(2)(-) than neutrophils from the SLE-II and control groups, and ( 4) CR showed inefficiency in mediating the O(2)(-) production by neutrophils from the SLE-I group. Comparative experiments on the kinetics of chemiluminescence ( CL; T(max) and CL(max)) disclosed differences only for the SLE- I group. Taken together, these results suggest that differences in oxidative metabolism of neutrophils mediated by Fc gamma R/ CR may reflect an acquired characteristic of disease associated with distinct clinical manifestations.

Efficiency of the DNA repair and polymorphisms of the XRCC1, XRCC3 and XRCC4 DNA repair genes in systemic lupus erythematosus

Impaired DNA repair efficiency in systematic lupus erythematosus (SLE) patients has been reported ill some studies, mainly regarding the repair of oxidative damage, but little is known about repair kinetics towards primarily single-stranded DNA breaks. In the present study, we aimed to investigate: (a) the efficiency of SLE peripheral blood leucocytes in repairing DNA damage induced by ionizing radiation and (b) the association of DNA repair gene (XRCC1 Arg399Gln, XRCC3 Thr241Met and XRCC4 Ile401Thr) polymorphisms in SLE patients, considering the whole group, or stratified sub-groups according to clinical and laboratory features. A total of 163 SLE patients and 125 healthy control were studied. The kinetics of DNA strand break repair was evaluated by the comet assay, and genotyping for DNA repair genes was performed by PCR-RFLP. Compared with controls. SLE leucocytes exhibited decreased efficiency of DNA repair evaluated at 30 min following irradiation. A significant association with DNA repair gene polymorphisms was not observed for the whole group of SLE patients; however, the XRCC1Arg399Gln polymorphism was associated with the presence of anti-dsDNA antibody. The concomitance of two DNA repair polymorphic sites was associated with the presence of neuropsychiatric manifestations and antiphospholipid antibody syndrome. Taken together, these results indicated that SLE leucocytes repair less efficiently the radiation-induced DNA damage, and DNA repair polymorphic sites may predispose to the development of particular clinical and laboratory features. Lupus (2008) 17, 988-995.

The Kinin System in Patients with Systemic Lupus Erythematosus Exhibiting Mucocutaneous Lesions: A Clinical Study

In the present study, we evaluated the kinin system components in the plasma of patients with systemic lupus erythematosus exhibiting mucocutaneous lesions. Fifteen women with active cutaneous lupus (P) and 15 normal healthy women (C) were studied. Low molecular (LKg) and high molecular (HKg) weight kininogen were determined by ELISA (expressed mu g Bk/ml). The activities of tissue kallikrein (TKal), plasma kallikrein (PKal) and kininase II were assayed by their action on selective substrates. Statistical analysis was performed using the Mann-Whitney test. The patients presented increased plasma levels of LKg (P = 2.98, C = 0.79) and HKg (P = 1.78, C = 0.5) associated with the increased activity of PKal (P = 2.50, C = 1.63 U/ml), TKal (P = 1.87, C = 1.30 mu M pNa/ml) and kininase II (P = 1.50, C = 0.51 mu M Hys-Leu/ml), when compared to the values observed in the control group (P < 0.0001 for each comparison). Thus, the increased concentration of all parameters of the kinin system in these patients indicate an overactivity of the kinin system in the acute phase of lupus, corroborating with the participation of these mediators in lupus pathogenesis.

Tibolone in postmenopausal women with systemic lupus erythematosus: A pilot study

Objective: To determine the influence of the use of tibolone on the frequency of flares of systemic lupus erythematosus (SLE) in postmenopausal patients. Methods: Thirty patients with inactive or controlled SLE were included in the study. Patients were randomized to receive a 12-month course of either tibolona (2.5 mg/day) or placebo. The following were investigated: hypoestrogenism symptoms by Kupperman index, weight; anti-dsDNA antibodies; SLE flares (frequency) assessed by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI); and biochemical profile (total cholesterol, high-density lipoprotein cholesterol [HDL-C], triglycerides, complement components [C3/C4], alpha 1-acid glycoprotein, urea, creatinine, 24-h proteinuria, C-reactive protein and erythrocyte sedimentation rate). Results: The reduction in Kupperman index was greater in the patients using tibolone than in those using placebo. I-lie mean SLEDAI was not different between the groups during the study as well as SLE flare frequency (tibolone: 2/15 [13.3%] vs. placebo: 1/15 [6.7%]; p = 0.54). All cases of flares were considered mild to moderate. Although the groups were similar at the baseline evaluation, after 6 and 12 months of treatment lower values were found in the tibolone group for triglycerides (6 months: 161.6 +/- 30.9 mg/dl vs. 194.4 +/- 46.5: p = 0.04: 12 months 163.7 +/- 29.8 mg/dl vs. 204.1 +/- 49.9 mg/dl; p = 0.02: tibolone vs. placebo group, respectively) and for HDL-C (6 months: 40.7 +/- 10.7 mg/dl vs. 53.4 +/- 16.5; p = 0.02; 12 months: 47.2 +/- 7.9 mg/dl vs. 63.2 +/- 16.3 mg/dl; p < 0.01: tibolone vs. placebo group, respectively). There were no differences between the two groups in any of the remaining variables. Conclusion: In patients with inactive or stable SLE, the short-term use of tibolone did not significantly affect the frequency of flares. In addition, tibolone was well tolerated and effective to control hypoestrogenism related symptoms in SLE patients. (C) 2009 Elsevier Ireland Ltd. All rights reserved.

Systemic lupus erythematosus: Association with KIR and SLC11A1 polymorphisms, ethnic predisposition and influence in clinical manifestations at onset revealed by ancestry genetic markers in an urban Brazilian population

Systemic lupus erythematosus (SLE) is an autoimmune disorder of the connective tissue with a wide and heterogeneous spectrum of manifestations, with renal and neurological involvement usually related to worse prognosis. SLE more frequently affects females of reproductive age, and a high prevalence and renal manifestation seem to be associated with non-European ethnicity. The present study aims to investigate candidate loci to SLE predisposition and evaluate the influence of ethnic ancestry in the disease risk and clinical phenotypic heterogeneity of lupus at onset. Samples represented by 111 patients and 345 controls, originated from the city of Belem, located in the Northern Region of Brazil, were investigated for polymorphisms in HLA-G, HLA-C, SLC11A1, MTHFR, CASP8 and 15 KIR genes, in addition to 89 Amerindian samples genotyped for SLC11A1. We also investigated 48 insertion/deletion ancestry markers to characterize individual African, European and Amerindian ancestry proportions in the samples. Predisposition to SLE was associated with GTGT deletion at the SLC11A1 3`UTR, presence of KIR2DS2 +/KIR2DS5 +/KIR3DS1 + profile, increased number of stimulatory KIR genes, and European and Amerindian ancestries. The ancestry analysis ruled out ethnic differences between controls and patients as the source of the observed associations. Moreover, the African ancestry was associated with renal manifestations. Lupus (2011) 20, 265-273.

Trends in systemic lupus erythematosus mortality rates in the state of Sao Paulo, Brazil from 1985 to 2004

Objectives To estimate mortality rates and mortality trends from SLE in the state of Sao Paulo, Brazil. Material and methods The official data bank was used to study all deaths occurred from 1985 to 2004 in which SLE was mentioned as the underlying cause of death. Besides the overall mortality rate, the annual gender- and age-specific mortality rates were estimated for each calendar year by age bracket (0-19 years, 20-39 years, 40-59 years and over 60 years) and for the sub-periods 1985-1995 (first) and 1996-2004 (second), by decades. Chi-square test was used to compare the mortality rates between the two periods, as well the mortality rates according to educational level considering years of study. Pearson correlation coefficient test was used to analyse mortality trends. The crude rates were adjusted for age by the direct method, using the standard Brazilian population in 2000. Results A total of 2,601 deaths (90% female) attributed to SLE were analysed. The mean age at death was significantly higher in the second than in the first sub-period (36.6 +/- 15.6 years vs. 33.9 +/- 14.0 years; p<0.001). The overall adjusted mortality rate was 3.8 deaths/million habitants/year for the entire period and 3.4 deaths/million inhabitants/year for the first and 4.0 deaths/million inhabitants/year for the second sub-period (p<0.001). In each calendar year, the mortality rate was significantly lower for the better educated group. Throughout the period, there was a significant increase in mortality rates only among women over 40. Conclusion SLE patients living in the state of Silo Paulo still die at younger ages than those living in developed countries. Our data do not support the theory that there was an improvement in the SLE mortality rate in the last 20 years in the state of Sao Paulo. Socio-economic factors, such as the difficulty to get medical care and adequate treatment, may be the main factors to explain the worst prognosis for our patients.

QUALITY OF LIFE IN SYSTEMIC LUPUS ERYTHEMATOSUS PATIENTS IN NORTHEASTERN BRAZIL: IS HEALTH-RELATED QUALITY OF LIFE A PREDICTOR OF SURVIVAL FOR THESE PATIENTS?

Objective: To identify social, demographic and clinical characteristics that influence survival of patients with systemic lupus erythematosus (SLE). Methods: Sixty-three patients with a diagnosis of SLE were studied at our medical services in 1999 and then reviewed in 2005. We utilized a protocol to obtain demographic and clinical traits, activity and damage indices, and health-related quality of life via the SF-36. All statistical tests were performed using a significance level of 5%. Results: Out of the 63 patients examined in 1999, six died, four were lost for the follow-up and the previous protocol was applied to the remaining 53 patients. The six patients who died presented the worst recorded health-related quality of fife, in all aspects. The most important observed predictor of death was a mean lower score in the Role-Emotional Domain of the mental health component of the SF-36 (p<0.01). Conclusion: Health-related quality of life may be used as possible predictive factor of mortality among patients with SLE.

Administration of M. leprae Hsp65 Interferes with the Murine Lupus Progression

The heat shock protein [Hsp] family guides several steps during protein synthesis, are abundant in prokaryotic and eukaryotic cells, and are highly conserved during evolution. The Hsp60 family is involved in assembly and transport of proteins, and is expressed at very high levels during autoimmunity or autoinflammatory phenomena. Here, the pathophysiological role of the wild type [WT] and the point mutated K(409)A recombinant Hsp65 of M. leprae in an animal model of Systemic Lupus Erythematosus [SLE] was evaluated in vivo using the genetically homogeneous [NZBxNZW]F(1) mice. Anti-DNA and anti-Hsp65 antibodies responsiveness was individually measured during the animal's life span, and the mean survival time [MST] was determined. The treatment with WT abbreviates the MST in 46%, when compared to non-treated mice [p<0.001]. An increase in the IgG2a/IgG1 anti-DNA antibodies ratio was also observed in animals injected with the WT Hsp65. Incubation of BALB/c macrophages with F1 serum from WT treated mice resulted in acute cell necrosis; treatment of these cells with serum from K(409)A treated mice did not cause any toxic effect. Moreover, the involvement of WT correlates with age and is dose-dependent. Our data suggest that Hsp65 may be a central molecule intervening in the progression of the SLE, and that the point mutated K(409)A recombinant immunogenic molecule, that counteracts the deleterious effect of WT, may act mitigating and delaying the development of SLE in treated mice. This study gives new insights into the general biological role of Hsp and the significant impact of environmental factors during the pathogenesis of this autoimmune process.