Urinary biomarkers for lupus nephritis: the role of the vascular cell adhesion molecule-1.

Renal involvement is one of the main complications of systemic lupus erythematosus, causing a significant impact on patients' morbidity and mortality. Renal biopsy is still the gold standard of diagnosis, but it has many limitations. In this sense, several recent studies aim to identify biomarkers that not only predict disease activity and renal histology, but also lead to earlier treatment. In previous studies, the soluble vascular cell adhesion molecule-1 measured in urine showed a strong association with the presence of lupus nephritis, with clinical and histological activity indexes of the disease and with more severe renal lesions. This paper reviews the main urinary biomarkers of lupus nephritis that have been studied, with special emphasis on vascular cell adhesion molecule-1 results.

Evaluation of polymorphic variants in apoptotic genes and their role in susceptibility and clinical progression to systemic lupus erythematosus.

Background Systemic lupus erythematosus (SLE) is an autoimmune disease marked by the disruption of the immune homeostasis. Patients exhibit a wide range of clinical manifestations, and environmental and genetic factors are involved in SLE pathogenesis. Evidence suggests that abnormalities in the cellular and molecular events that coordinate apoptosis may favour the generation of autoantigens involved in autoimmunity. In this way, the apoptotic deregulation may be affected by polymorphic variants in apoptotic-related genes. Methods We analyzed FAS, FASL, BCL-2 and BAX polymorphisms in order to correlate to SLE susceptibility and clinical features. A total of 427 SLE patients from the Hospital de Clínicas de Porto Alegre and 543 controls from southern Brazil were evaluated. Results We observed higher frequencies of the FASL -844CC genotype and -844C allele, as well as of the FASL-844C/IVS2nt-124A haplotype in African-derived SLE patients when compared to controls ( P < 0.001). FASL -844C, which is related to high FasL expression, could contribute to increased apoptosis and to the breakdown of immunological tolerance, favouring autoantibody production and inflammation. On the other hand, the BAX -248GA genotype and the -248A allele , related to low protein expression, were observed as a protective factor against SLE in this same population. The rate of apoptosis and cell death was evaluated in peripheral lymphocytes, and SLE patients presented a higher percentage of dead lymphocytes (CD3+Annexin V+ 7-AAD+) compared to the control group. Conclusion Our data support a role for apoptosis in SLE susceptibility.

Wernicke's encephalopathy mimicking neuropsychiatric symptoms in patients with systemic lupus erythematosus: a report of three cases and literature review.

Systemic lupus erythematosus (SLE) is a chronic inflammatory disease that involves many organs and systems. Nervous system involvement in SLE encompasses neurological and psychiatric disorders, and remains a diagnostic and therapeutic challenge. Wernicke's encephalopathy (WE) is a neurological disorder that occurs as a consequence of thiamine deficiency, and its clinical presentation resembles the neuropsychiatric events attributed to SLE (NPSLE). Differentiation between these two entities is crucial because their treatment differs greatly and can change prognosis. We describe three cases of patients with SLE who presented with initial clinical findings suggestive of NPSLE that, at the end of a thorough clinical investigation, were actually found to represent WE. In all of these cases, treatment with thiamine resulted in significant improvement. WE should be considered as a differential diagnosis in SLE patients with neuropsychiatric signs and symptoms, especially when risk factors for thiamine deficiency are present.

Assessment of anti-Müllerian hormone levels in premenopausal patients with systemic lupus erythematosus.

OBJECTIVE: The ovarian reserve of patients with systemic lupus erythematosus (SLE) may be affected by disease activity and medication use. Studies have found that patients with SLE have similar fertility rates as healthy women of the same age. The goal of the present study was to investigate the ovarian reserve of patients with SLE by measuring anti-Müllerian hormone (AMH) levels, and compare it to that of healthy controls. METHOD: This was a case-control study performed on 80 premenopausal women, of whom 40 fulfilled the 1997 American College of Rheumatology (ACR) criteria for SLE and 40 healthy controls paired by oral contraceptive use. Serum concentrations of AMH in peripheral venous blood were measured using a human AMH ELISA kit (CUSABIO, Wuhan, China). RESULTS: AMH serum levels did not differ between patients with SLE and controls (22.79 ± 17.32 ng/ml versus 21.41 ± 16.22 ng/ml, respectively, p = 0.7), even after adjusting for age (21.03 ± 2.074 ng/ml versus 23.97 ± 2.71 ng/ml; p = 0.5). AHM levels were not significantly correlated with disease duration (r = 0.2; p = 0.3), body mass index (r = 0.2; p = 0.2) and disease activity (SLEDAI (r = 0.1; p = 0.7)) and damage indices (SLICC (r = 0.1; p = 0.7)). No associations were found between AMH and ethnicity, current smoking, as well as current or prior use of cyclophosphamide and other immunosuppressants. CONCLUSION: In this cross-sectional study, women with SLE demonstrated similar AMH levels as healthy controls, suggesting preserved ovarian reserve in this population.

Vitamin D levels and cytokine profiles in patients with systemic lupus erythematosus.

OBJECTIVES: To evaluate the expression of Th1, Th2, and Th17 cytokines in patients with systemic lupus erythematosus (SLE), and verify the association between serum cytokine levels and vitamin D concentration. METHODS: The sample consisted of 172 patients with SLE. 25-Hydroxyvitamin D (25(OH)D) levels were measured by chemiluminescence and 25(OH)D levels <20 ng/mL were considered to reflect vitamin D deficiency. Serum cytokine levels were measured in once-thawed samples, using a Th1/Th2/Th17 CBA (cytometric beads array) kit. RESULTS: One hundred and sixty-one (93.6%) patients were women and 128 (74.4%) were of European descent. Mean patient age was 40.5 ± 13.8 years, and mean age at diagnosis was 31.5 ± 13.4 years. At the time of study entry, patients had a median (IQR) SLEDAI of 2 (1-4) and SLICC of 0 (0-1). Mean 25(OH)D concentration was 25.4 ± 11.04 ng/mL. Fifty-nine (34.3%) patients had a vitamin D deficiency. No statistically significant associations were identified between cytokine and vitamin D levels. The most significant finding was a positive correlation between INF-α levels and SLEDAI (r(s) = 0.22, p = 0.04). CONCLUSION: Although vitamin D deficiencies are highly prevalent in patients with SLE, vitamin D levels were not significantly associated with patient cytokine profiles. The positive correlation between IFN-α levels and SLEDAI showed in this study corroborates other findings in the literature. The present results did not replicate those of in vitro studies of the effect of vitamin D levels on cytokine profiles. Placebo-controlled intervention trials of the effect of vitamin D on cytokine profiles are still required before any definitive conclusions can be drawn regarding the association between these variables.

Electroconvulsive therapy as a treatment for refractory neuropsychiatric lupus with catatonia: three case studies and literature review.

Neuropsychiatric disorders associated with systemic lupus erythematosus are very common. Treatment generally consists of glucocorticoids and immunosuppressive therapy; however, some cases are unresponsive. Electroconvulsive therapy (ECT) is a recognized treatment modality in psychiatry and is an option for refractory cases of neuropsychiatric lupus. This report describes three cases of neuropsychiatric lupus that improved with ECT after failure of antipsychotics and immunosuppressive therapy. All cases met DSM-5 criteria for catatonia (case 1: agitation, stereotypies, and grimacing; case 2: stupor, mutism, and grimacing; case 3: agitation, mutism, and stereotypies); therefore, ECT was indicated. This case series shows that ECT can be a therapeutic option in patients with neuropsychiatric lupus, especially when associated with catatonia and unresponsive to conventional treatment.

CCR5delta32 in systemic lupus erythematosus: implications for disease susceptibility and outcome in a Brazilian population.

The aim of this study was to analyze the allelic and genotypic frequencies of the CCR5delta32 polymorphism in systemic lupus erythematosus (SLE) patients and to investigate a possible association of this allele with SLE susceptibility and clinical outcome. A total of 367 SLE patients and 435 healthy controls were genotyped for the CCR5delta32 polymorphism. We observed that, in European-derived individuals, the frequency of the CCR5delta32 allele was smaller in patients than in controls (2.7% vs. 7.5%, OR 0.34, 95% CI 0.17-0.65, p Bonf=0.002), suggesting that this allele could be considered a protective factor for the disease. Regarding clinical manifestations, we observed that CCR5delta32 female African-derived carrier patients presented a higher predisposition to class IV nephritis when compared with absent nephritis/other class group (13.8% vs. 3.8%, OR 37.1, 95% CI 2.8-1854.7, p Bonf=0.030). A multivariate analysis including all female patients and controlling for the presence or absence of anti-dsDNA antibodies, ethnicity and age at diagnosis showed an increased relative risk of 3.9 times for patients carrying the CCR5delta32 allele to develop class IV nephritis as compared with noncarriers. Our data suggest that the CCR5delta32 allele is a protective factor for the disease in European-derived patients and a susceptibility factor to class IV nephritis in African-derived female patients.

The role of BsmI and FokI vitamin D receptor gene polymorphisms and serum 25-hydroxyvitamin D in Brazilian patients with systemic lupus erythematosus.

Vitamin D deficiency has been described in systemic lupus erythematosus (SLE). BsmI VDR (vitamin D receptor) gene polymorphism was associated with SLE in Asian patients. Studies in Brazilian populations have not been realized. A case-control study with 195 SLE patients and 201 healthy controls was conducted to investigate the influence of BsmI and FokI VDR gene polymorphisms on susceptibility to SLE. In addition, 25-hydroxyvitamin D [25(OH)D] was measured in SLE patients to evaluate possible associations with VDR polymorphic variants and clinical and laboratory expressions of disease. Genotyping was performed by RFLP-PCR. The measurement of 25(OH)D was performed by chemiluminescence. There was no statistically significant difference in genotype and allelic frequencies of BsmI and FokI polymorphisms between European-derived cases and controls. The mean serum levels of 25(OH)D were 25.51 ± 11.43 ng/ml in SLE patients. According to genotype distribution, 25(OH)D concentrations were significantly higher in patients carrying the FokI f/f genotype compared with patients carrying the F/F genotype (31.6 ± 14.1 ng/ml versus 23.0 ± 9.2 ng/ml, p = 0.004), reinforcing its role in the functional activity of VDR. This feature may be considered in future clinical and experimental studies involving vitamin D measurements. Therefore, genetic-specific definitions of ideal levels of vitamin D in SLE need to be established in future studies.

TLR7/8/9 polymorphisms and their associations in systemic lupus erythematosus patients from southern Brazil.

Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease and can affect several organs and systems. It is characterized by high production of autoantibodies against nuclear compounds. TLR7/8/9 are responsible for nucleic acid recognition and they trigger proinflammatory responses through activation of NK-kappaB and Type I IFN production, making a bridge between the innate and the adaptative immune systems. We analyzed the frequency of TLR7 rs179008, TLR8 rs3764880, TLR9 rs5743836 and rs352140 in 370 patients with SLE and 415 healthy controls from southern Brazil. All analyses were conducted with regard to gender and ethnicity. Genotypic and allelic frequencies were different for TLR7 rs179008 (0.253 vs. 0.163, p = 0.020 and p = 0.003, OR for T allele: 1.74 CI 95% 1.12-2.70) and TLR9 rs5743836 (0.174 vs. 0.112, p = 0.045 and p = 0.017, OR for C allele: 1.59, CI 95% 0.99-2.57) between European-derived female groups. A higher frequency was observed for the presence of Anti-SSa/Ro for TRL9 rs5743836 C allele carriers (0.228 vs 0.126, Bonferroni corrected p = 0.06). No statistical differences were found for TLR9 haplotypic analyses. We suggest that TLR7 rs179008 and TLR9 rs5743836 can be considered SLE susceptibility factors for women of European descent in our population.

Association of the HLA-G gene +3142C>G polymorphism with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disease that affects several organs and systems. Its etiology remains unknown, although it is probably multifactorial. The human leukocyte antigen G (HLA-G) is a nonclassic major histocompatibility complex I molecule characterized by restricted expression and low DNA polymorphism. HLA-G plays a role in immunosuppression through different mechanisms. In inflammatory diseases, it has been postulated that HLA-G expression may be a possible mechanism of tissue protection against exacerbated inflammatory response. On the 3' untranslated region (3' UTR) of the HLA-G gene, there is an insertion/deletion polymorphism of 14 bp (rs1704) that was shown to influence the mRNA stability. The influence of this polymorphism in disease susceptibility is controversial. Also in the 3' UTR there is a single nucleotide polymorphism C/G (rs1063320) on the position +3142, at a possible binding site for microRNAs (miRNAs) and having an influence on miRNA affinity. In this study, we analyzed the +3142C>G and the 14 bp polymorphisms in 195 SLE European-derived female patients. Our findings show a significant increase of the +3142G allele frequency among patients as compared with controls (0.58 vs 0.47, P = 0.011). Also, patients presented a higher frequency of the GG genotype (OR = 1.90, 95% CI: 1.08-3.42). Double heterozygotes for the two polymorphisms presented a milder mean systemic lupus erythematosus disease activity index (SLEDAI) than heterozygotes for only one of the variants or non-heterozygous individuals (1.56 vs 3.15 and 3.26, respectively, corrected P = 0.044). These results suggest the involvement of the HLA-G molecule on SLE susceptibility and outcome.

Mannose-binding lectin gene polymorphisms in Brazilian patients with systemic lupus erythematosus.

The mannose-binding lectin gene (MBL-2) has emerged as a candidate for systemic lupus erythematosus susceptibility, but studies in Brazilian population have not been conducted. To examine potential associations of mannose-binding lectin alleles G57E, G54D, IVSnt5, R52C and R52H with susceptibility to and clinical expression of systemic lupus erythematosus in southern Brazilian patients, we conducted a case-control study with 327 consecutive patients with diagnosis of systemic lupus erythematosus and 345 healthy controls. Genotyping was performed by restriction fragment length polymorphism-polymerase chain reaction assay. A statistically significant difference in the frequencies of allele R52C was observed in European-derived systemic lupus erythematosus patients when compared with controls (9.6% vs. 3.3%, p < 0.001, odds ratio: 3.15, 95% confidence interval: 1.76-5.62, p < 0.05). The frequencies of alleles G54D and G57E were not different between European-derived systemic lupus erythematosus patients and controls. There were no differences between clinical and laboratory features in systemic lupus erythematosus patients according to the presence or absence of mannose-binding lectin allelic variants. These results support an increased risk of systemic lupus erythematosus in European-derived individuals carrying allele R52C. Patients carrying this allele have an approximately three-fold higher odds ratio of developing systemic lupus erythematosus when compared with controls. Our data do not support associations between the mannose-binding lectin allelic variants studied and clinical expression of systemic lupus erythematosus.

Association of the HLA-G 14 bp polymorphism with systemic lupus erythematosus.

Human leukocyte antigen-G (HLA-G) is a nonclassical class I major histocompatibility complex molecule which is induced at the course of inflammatory pathologies, and its expression has been suggested as a possible mechanism of tissue protection against autoimmune inflammatory responses, therefore acting as a mechanism of immune surveillance. We investigated the influence of the 14 bp polymorphism of the HLA-G gene on systemic lupus erythematosus (SLE) by analyzing 293 patients with SLE and 460 healthy controls. The patient's group was not in Hardy-Weinberg equilibrium, presenting an excess of heterozygotes (P = 0.014). The heterozygote group exhibited lower systemic lupus erythematosus disease activity indexes than the homozygous deletion group and the homozygous insertion group (mean value = 2.29 against 2.97 and 3.4, respectively, P = 0.035). Photosensitive patients showed a higher frequency of heterozygotes and an equivalent lower frequency of homozygotes for deletion; on the other hand, patients without arthritis presented a higher frequency of heterozygotes than the arthritis group and also a lower frequency of the del/del genotype. Overall, our results support the idea of a role of the HLA-G insertion/deletion polymorphism and therefore a role for the HLA-G molecule, on the pathology of SLE.

Glu298Asp eNOS polymorphism is not associated with SLE.

To examine potential associations of the Glu298Asp polymorphism in the coding region of the endothelial nitric oxide synthase (eNOS) gene with susceptibility to and clinical expression of systemic lupus erythematosus (SLE). One hundred thirteen consecutive patients of European ancestry with diagnosis of SLE, satisfying the American College of Rheumatology criteria, from the outpatient clinic of the Serviço de Reumatologia of the Hospital de Clínicas de Porto Alegre, and 206 healthy controls from the same geographic area were genotyped by polymerase chain reaction for the Glu298Asp polymorphism in the coding region of the eNOS gene. Clinical, demographic, and laboratorial data were collected. Clinical manifestations of SLE and related diseases were evaluated for the association with specific genotypes. The allelic and genotypic distribution of the Glu298Asp did not differ significantly between SLE patients and controls. We found no association of the polymorphism with lupus nephritis, antiphospholipid syndrome, cardiovascular disease (CVD), and risk factors to CVD. The presented results in this study do not provide support for a major role of eNOS Glu298Asp neither in the susceptibility for SLE or clinical manifestations, although there was low statistical power for the latter evaluation.