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PubMed2004

Update on the management of cutaneous lupus erythematosus.

This paper reviews the latest treatments for cutaneous lupus erythematosus. It focuses on evidence-based guidance for the management of cutaneous lupus erythematosus, with identification of the strength of evidence available at this time. In addition, I have briefly reviewed the epidemiological aspects, diagnosis and evaluation of patients with cutaneous lupus erythematosus. This review reflects data available from the Cochrane Library, Medline, literature searches, and the experience of the author managing patients with cutaneous lupus erythematosus for over 25 years.

Adrenal Cortex Hormones↗

PubMed1988

Autoantibodies to the heat-shock protein hsp90 in systemic lupus erythematosus.

Patients with systemic lupus erythematosus (SLE) develop multiple autoantibodies to self-antigens. Analysis of autoantibody systems in this and related autoimmune disorders can provide information of etiologic and pathogenetic significance. We report here a previously unrecognized autoantibody to the 90,000-D heat-shock protein, hsp90, a molecule thought to have important functions in the cellular response to stress, virus-induced transformation, steroid hormone receptor action, and cellular activation. Autoantibodies to hsp90 were exclusively of the IgG class, and were detected in approximately 50% of unselected patients with SLE and 2/6 patients with idiopathic polymyositis. Anti-hsp90 antibodies were not detected in sera from 10 normal subjects, 10 patients with rheumatoid arthritis, or 7 patients with scleroderma. The identity of this major intracytoplasmic antigen was established by its specific removal from nonionic detergent cell lysates following immunoabsorption with monospecific rabbit anti-hsp90, and by demonstration of increased synthesis following a 10-min 45 degrees C heat shock. These data define the frequent occurrence of a novel autoantibody to a major heat-shock protein in patients with SLE.

Autoantibodies↗

PubMed1987

Family study of the major histocompatibility complex in HLA DR3 negative patients with systemic lupus erythematosus.

Susceptibility to systemic lupus erythematosus (SLE) is known to be governed by genes in the HLA region of the 6th chromosome. From previous studies it has not been possible to distinguish between the effects of null genes for the complement component C4 and HLA-DR3, because of the marked linkage disequilibrium between DR3 and a null allele of C4A (C4A QO) in caucasoid populations. We report here an immunogenetic study of 44 cases of SLE, selected because they were DR3 negative. Eighteen of the 30 Caucasoid cases (60%) had extended HLA haplotypes with a C4 null allele, compared with 22 of 60 (37%) of a control panel of 60 DR3 negative normal Caucasoid subjects. This difference is significant (chi 2 = 4.41; 0.05 greater than P greater than 0.01). Of 14 non-caucasoid patients analysed, 10 had a C4 null allele. It is concluded that the null alleles of the C4 A and B genes are themselves directly responsible for conferring susceptibility to SLE.

Alleles↗

PubMed2005

Environment and systemic lupus erythematosus: an overview.

Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown etiology that manifests as a pleomorphic systemic disease mainly affecting females. The variety of autoantibodies found in the serum of patients indicate that SLE is an autoimmune disease, but the mechanisms leading to the aberrant responses are not clearly understood although it is thought that a number of genetic and environmental factors may be involved. Environmental (or non-genetic) exposures could include infectious agents, chemicals or other compounds capable of modulating immune responses such as occupational/environmental pollutants or drugs, and behavioural factors such as smoking and diet. Environmental exposures may lead to the production of autoreactive T cells and autoantibodies, the stimulation of pro- and antiinflammatory cytokines, and target end-organ damage, but are not so convincing as agents causing SLE. Exposure to viruses increases antibody titres, but these may be the result of polyclonal B cell activation. The amount and timing of exposure to different environmental factors may play a significant and complex role in the pathogenesis of SLE and other autoimmune diseases. A better understanding of the etiopathogenetic mechanism of SLE is required in order to clarify the multiple interactions between environmental exposures and genetic factors.

Animals↗

PubMed2003

Gender differences in a cohort of Puerto Ricans with systemic lupus erythematosus.

Variations in systemic lupus erythematosus (SLE) clinical manifestations, serologies and outcomes have been related to gender differences. However, these associations have not been evaluated in Puerto Ricans. A cross-sectional study was performed in a cohort of 235 Puerto Rican SLE patients. Clinical variables, autoantibodies, SLICC/ACR damage index and mortality rate were determined. Of the 235 SLE patients, 12 (5%) were males. Male and female patients were similar with respect to age, disease duration and follow up. Men were more likely to have pericardial effusion (41% vs 5%, p<0.01), pleural effusion (58% vs 10%, p<0.01), proteinuria (>0.5 g/24 hr) (58% vs 24%, p=0.02), renal insufficiency (42% vs 11%, p<0.01) and end-stage renal disease (33% vs 6%, p<0.01) than women. Anti-Sm antibodies (60.0% vs 13%, p<0.01) and anti-snRNP antibodies (56% vs 21%, p=0.03) were more prevalent in men. SLICC/ACR mean damage index (2.7 +/- 2.7 vs 1.0 +/- 1.6, p<0.01) and mortality rate (25% vs 4.5%, p=0.02) were higher in men. In conclusion, male SLE patients of this cohort had higher prevalence of serositis and renal involvement than women. They also had a poorer outcome, presenting higher disease damage and mortality.

Adolescent↗

PubMed1992

[Systematic lupus erythematosus and pregnancy].

Systemic lupus erythematosus (SLE) is an autoimmune disease that affects primarily women of childbearing age. 20-30 years ago it was common belief that SLE is exacerbated during pregnancy. Recent studies, however, could not support this notion. The likelihood of an increase in clinical activity of SLE is similar during pregnancy and in nonpregnant patients. It correlates directly with the activity of disease at the time of conception. The pregnancy outcome in patients with SLE has improved considerably in recent years. The frequency of fetal loss, however, still remains higher in SLE patients than in healthy women. In most of the cases fetal loss is due to habitual abortions, intrauterine death and premature labors. The main reasons are anti-phospholipid antibodies and the activity of SLE at the onset of pregnancy, respectively during the pregnancy. For monitoring disease activity and especially for distinguishing between the development of eclampsia and exacerbation of SLE, periodic determinations of complement proteins CH50, C3, C4 and C3d are helpful. A prophylactic therapy e.g. with prednisone in pregnant SLE patients is not justified. However, when SLE is exacerbating immunosuppressive therapy with prednisone and, if needed in combination with azathioprine, should be administered. In cases with high antiphospholipid antibody titers and prior fetal loss a treatment with low-dose acetylsalicylic acid can be considered.

Female↗

PubMed2004

Intravenous cyclophosphamide--resistant systemic lupus erythematosus in Arizona.

Systemic lupus erythematosus (SLE) tends to be severe and to have a variable response in childhood. We undertook this retrospective study to assess response rates and outcome in 14 children with SLE. Mean age at onset was 12.8+/-3.1 years. Ten patients were female and 4 were male, and 12 patients (86%) were Hispanic. Creatinine clearance prior to therapy was 104+/-36 ml/min. All had hematuria and proteinuria with a protein/creatinine ratio of 3.9+/-4.8. WHO classification of renal biopsies revealed class IV in 64%, class III in 21%, and class V in 14%. Patients were treated with 6-monthly pulses of intravenous cyclophosphamide (IVCY) followed by longer-duration pulses. The mean duration of follow-up was 3.7+/-3.3 years. Of the 14 patients, 3 (21%) achieved systemic remission but all relapsed subsequently; 7 of 14 achieved renal remission, although 6 relapsed. Six (42%) had adverse outcomes, defined by death, dialysis, or need for bone marrow transplant. All 6 had failed 6 months of IVCY, suggesting that patients who demonstrate resistance to initial IVCY therapy have an unfavorable outcome and a high likelihood of complications. In summary, we report a poor response to standard therapeutic protocols with higher relapse rates, as well as significant adverse outcomes.

Adolescent↗

PubMed1999

The role of sex hormones in systemic lupus erythematosus.

The disease systemic lupus erythematosus (SLE) is a complex one. One major clinical manifestation that relates to both cause and pathogenesis of all autoimmune diseases but specifically SLE is the sexual predilection for females. A consideration of mechanisms for this manifestation is the subject of this paper. The cytokine network is a major aspect of immune regulation and directly affected by sex steroids. The sexual dimorphism of the immune system relates to both organ-specific and general synthesis of sex steroids that are affected by and in turn affect cytokine profiles of T helper cells. There are also specific responses in cells from diseased patients that support the molecular activities of sex hormones on cells. Among these is the rise of calcineurin mRNA in SLE T cells in response to estrogen. Clinical research provides support for a more estrogenic environment in patients with SLE of both sexes. A preferential hydroxylation of estrone and increased oxidation of testosterone in patients with SLE maximizes the effects of estrogens on T cell functions. The effects of gonadotrophins like prolactin are discussed as stimulants of immune functions when elevated in SLE. Last, while the roles of exogenous estrogens on immune functions are known, the effects of such steroids alone or in combination with progestogens on SLE are not known. Investigation of both hormone replacement therapy and premenopausal hormone use are in progress.

Female↗

PubMed1999

Regional cerebral blood flow in patients with systemic lupus erythematosus.

Patients with systemic lupus erythematosus (SLE) with or without definite neuropsychiatric symptoms/signs were studied. Technetium-99m (Tc-99m) hexamethylpropylenamine (HMPAO) brain images were used to detect basal ganglion and cerebral cortex regional cerebral blood flow (rCBF) in patients with SLE with brain involvement. One hundred nine female patients with SLE were investigated using Tc-99m HMPAO brain images with fan-beam single-photon emission computed tomography (SPECT) and surface three-dimensional (3D) display. These patients were separated into 2 subgroups: group 1, 74 cases with definite neuropsychiatric symptoms/signs; and group 2, 35 cases without any neuropsychiatric symptoms/signs. Fan-beam SPECT demonstrated unilateral or bilateral hypoperfusion of basal ganglia or thalamus in 22% and 9% of patients in groups 1 and 2, respectively. Local hypoactivity anomalies were found in the brain cortex of 89% and 20% of patients in groups 1 and 2, respectively, using surface 3D display of the brain. In either group 1 or group 2 patients, parietal and frontal lobes are the most common areas and cerebellum and thalamus are the least common areas of brain involvement, respectively. This study suggests that in comparison with traditional brain imaging techniques, Tc-99m HMPAO brain imaging with fan-beam SPECT in combination with surface 3D display may provide objective information for detection of anomalies of rCBF in patients with SLE.

Adult↗

PubMed2006

Using cDNA microarrays to identify human CD19(+) B cell gene products (ESTs) originated from systemic lupus erythematosus susceptibility loci.

Systemic lupus erythematosus (SLE) is a prototype of autoimmune disease which arises from interactions between susceptibility genes and environmental factors. Despite the heterogeneous manifestations in this disease, all SLE patients present plasma autoantibodies recognizing nuclear components. Thus, auto reactive B cells represent key effectors to be investigated. Human linkage analysis is providing the localization of susceptibility loci distributed in chromosomes contributing to elucidate the manner in which interactions between these loci mediate SLE pathogenesis. We associate the cDNA microarray technology to investigate the differential gene expression of CD19(+) B cells with genetic linkage data. Bioinformatics programs served to evidentiate the differentially expressed sequences and the design of the microarray allowed hierarchical clustering of patients and controls. Sequencing allowed the identification of 8 new gene products differentially expressed (ESTs) that were co-localized in SLE or other autoimmune diseases susceptibility loci on chromosome 1p21, 2q21, 13q33, 16p12.1 and 16q12.1. These findings strongly suggest that chromosomal regions previously identified as SLE susceptibility loci are in fact transcribed in CD19(+) B cells of patients. In this review, we delineate a new possibility for the use of cDNA microarrays in studies focusing the control of gene expression of disease susceptibility loci identified by genetic linkage.

Antigens, CD19↗

PubMed1997

Association between IgM anticardiolipin antibodies and deep venous thrombosis in patients without systemic lupus erythematosus.

Patients with systemic lupus erythematosus (SLE) are at risk of developing deep venous thrombosis (DVT). Should anticardiolipin antibodies (aCL) be detectable, this risk is significantly raised, particularly when these autoanti-bodies are cofactor-dependent. We conducted a cross-sectional study of consecutive unselected outpatients referred for clinical suspicion of DVT, as an attempt to address the following questions: firstly, were aCL antibodies associated with DVT in non-SLE patients? Secondly, was this association related to the cofactor dependence? From March 1992 to February 1994, 208 patients were enrolled in the study. Venography was positive in 110 patients (DVT patients), while the diagnosis of DVT could not be confirmed in the remaining 98 (referred to as disease controls). ACL was measured by ELISA, for IgG and IgM isotypes in two ways: fetal calf serum or bovine serum albumin were used as blocking agents to distinguish between cofactor-dependent and cofactor-independent antibodies. Positive aCL was defined as optical density (OD) values greater than the 95th percentile of OD distribution of 60 healthy controls. We found a high frequency of positive IgG aCL antibodies in both DVT patients and in disease controls (25.5 vs 23.5%). We suggest an association between IgM aCL and DVT. This association was, however, not dependent on the cofactor requirement.

Aged↗

PubMed1979

Antibodies to small nuclear RNAs complexed with proteins are produced by patients with systemic lupus erythematosus.

Patients with systemic lupus erythematosus often possess antibodies against two nuclear antigens called Sm and RNP (ribonucleoprotein). We have established the molecular identity of these antigens by analyzing immune precipitates of nuclear extracts from mouse Ehrlich ascites cells labeled with (32)P and (35)S. Anti-Sm serum selectively precipitates six small nuclear RNA molecules (snRNAs); anti-RNP serum reacts with only two of these; and a third serum, characterized as mostly anti-RNP, precipitates a subset of three snRNA bands. Three of the six RNAs are identified by fingerprint analysis as the previously characterized and highly abundant nucleoplasmic snRNA species U1a (171 nucleotides), U1b, and U2 (196 nucleotides). The other three RNAs (U4, U5, and U6) likewise are uridine rich and contain modified nucleotides, but they are smaller, with lengths of about 145, 120, and 95 residues, respectively. Each of the six snRNAs is complexed with and apparently antigenic by virtue of association with specific proteins. All three sera precipitate an identical complement of seven different polypeptides ranging in molecular weight from 12,000 to 35,000; these proteins are abundant in nuclear extracts, but are neither histones nor the major polypeptides comprising the 30S heterogeneous nuclear RNP particles of mammalian nuclei. Our data argue that each of the six snRNAs exists in a separate small nuclear ribonucleoprotein (snRNP) complex with a total molecular weight of about 175,000. We find that human antisera also precipitate snRNAs from a wide range of vertebrate species and from arthropods. We discuss the antigenic snRNPs in relation to the published literature on snRNAs and nuclear RNPs and consider possible functions of snRNPs in nuclear processes.

Antibodies, Antinuclear↗

PubMed1995

Characterization of in vivo mutated T cell clones from patients with systemic lupus erythematosus.

Patients with systemic lupus erythematosus (SLE) have increased percentages of activated T cells and increased numbers of cells with mutations in their hypoxanthineguanine phosphoribosyltransferase (hprt) gene, as judged by growth in the presence of 6-thioguanine. To study the relevance of these mutant T cells to disease pathogenesis, we have assessed the phenotype and functional capabilities of such cells from 21 patients with SLE who never had received cytotoxic drugs. The frequency of T cells with mutations in hprt in the blood of these patients ranged from normal to 25 times normal (mean +/- SEM [21.1 +/- 6.1] x 10(-6) versus [4.8 +/- 0.8] x 10(-6), in 15 age-matched normal individuals, P < 0.001) and correlated significantly with disease duration. CD4+ and CD8+ phenotypes were comparable among mutated and nonmutated clones from both patients and normals. Although the frequency of CD3+CD4-CD8- cells was low, it was increased among SLE-derived T cells (mutated and wild-type) compared with clones derived from normals (5% for SLE vs 1% for normals). A substantial percentage of all clones were able to help autologous B cells to produce anti-ssDNA, 11 of 68 (16%) selected clones and 3 of 28 (11%) nonselected clones. Help for autoantibody production was confined to CD4+ SLE-derived T cell clones. It could be blocked using an anti-HLA-DR mAb, suggesting that classical cognate help was operative. This represents the first estimate of the frequency of T cells able to drive autoantibody production in SLE.

Adolescent↗

PubMed2004

Endothelial nitric oxide synthase gene polymorphism is associated with systemic lupus erythematosus.

OBJECTIVE: In systemic lupus erythematosus (SLE), endothelial nitric oxide synthase (eNOS) gene locus has been found to be suggestive of linkage with disease, nitric oxide (NO) is produced in significant amounts, and endothelial cell dysfunction is observed. eNOS gene polymorphism may affect both the synthesis of eNOS protein and its enzymatic activity. We examined the influence of eNOS gene polymorphisms on susceptibility to SLE. METHODS: Genomic DNA from 88 Northwestern Colombian women with SLE, as well as 199 controls matched for sex, age, and ethnicity, was genotyped for the -786T -- > C polymorphism in the promoter region, the intron 4 variable number of tandem repeats, and the Glu298Asp polymorphism in exon 7 of the eNOS gene by polymerase chain reaction and restriction fragment length polymorphism techniques. Haplotype and allele frequency comparisons, a Hardy-Weinberg equilibrium test, and linkage disequilibrium (LD) analysis were performed. RESULTS: The intron 4b allele was associated with SLE (OR 2.2, 95% CI 1.29-3.60, pc = 0.005) as was the 4bb genotype (OR 2.9, 95% CI 1.61-5.33, pc = 0.0009), while the 4a allele was protective (OR 0.4, 95% CI 0.26-0.76, pc = 0.005), as was the 4ab genotype (OR 0.29, 95% CI 0.15-0.56, pc < 0.0001). In controls, all loci were in linkage disequilibrium (p < 0.02). In patients, intron 4 was in Hardy-Weinberg disequilibrium, due to an excess of homozygotes (p = 0.01). CONCLUSION: eNOS polymorphism influences SLE predisposition. Since intron 4bb genotype is responsible for higher levels of eNOS synthesis and intron 4 ab genotype is associated with lower synthesis, our results might provide insight into the elevated levels of NO observed in SLE patients.

Adult↗

PubMed2005

Characteristics of patients with late onset systemic lupus erythematosus in Turkey.

Systemic lupus erythematosus (SLE) is a multi-system autoimmune disorder mainly affecting young women. In this study, we aimed at investigating the clinical, laboratory and management characteristics of our SLE patients with an age of onset > or =50. Twenty patients with late onset SLE (> or =50 years) were identified from the records, on the basis of their first SLE-related symptoms (Group I). A hundred consecutive SLE patients with initial symptoms before the age of 50 were also selected as controls (Group II). Clinical, laboratory and management characteristics of the patients were recorded according to pre-defined protocol and compared by chi(2), Student's t-test and Fisher's exact test. Comparison of the demographic findings between the Group I (F/M: 18/2) and the Group II (F/M: 90/10) were as follows: the mean age of disease onset was 53.9 +/- 4.5 years vs. 26.3 +/- 9.2 years, mean time of follow-up was 44.2 +/- 40.5 months vs. 50.1 +/- 47.4 months, mean damage index was 0.6 +/- 0.6 vs. 0.58 +/- 1.4. There was no significant difference between the two groups with regard to clinical, laboratory parameters, damage index and immunosuppressive treatment characteristics. SLE-related manifestations were similar in two groups except fever (10% in the Group I vs. 41% in the Group II; p = 0.01). The only two patients with pulmonary fibrosis were found in the Group I (p = 0.027). The clinical and laboratory characteristics and the disease outcome in SLE patients with an age of onset > or =50 years did not show significant differences from the control SLE patients with a younger age of onset.

Adolescent↗

PubMed1999

Anti-double-stranded DNA antibodies and immunostimulatory plasmid DNA in combination mimic the endogenous IFN-alpha inducer in systemic lupus erythematosus.

Patients with systemic lupus erythematosus (SLE) have increased blood levels of IFN-alpha, which correlate to disease activity. We previously identified an IFN-alpha-inducing factor (IIF) in the blood of SLE patients that activated the natural IFN-alpha-producing cells in cultures of normal PBMC. The SLE-IIF contained DNA and IgG, possibly as small immune complexes. In our study, we demonstrated that SLE-IIF correlated to the presence of anti-dsDNA Abs in patients and contained anti-dsDNA Abs as an essential component. Purified anti-DNA Abs or SLE-IgG caused only a weak IFN-alpha production in cultures of normal PBMC in the presence of costimulatory IFN-alpha2b. However, they converted the plasmid pcDNA3, which itself induced no IFN-alpha production in PBMC, into an efficient IFN-alpha inducer. A human monoclonal anti-ss/dsDNA Ab had the same effect. This IFN-alpha-inducing activity of the plasmid was abolished by methylation, suggesting that unmethylated CpG DNA motifs were important. Like IIF in SLE serum, the combination of SLE-IgG and pcDNA3 appeared to stimulate IFN-alpha production in natural IFN-alpha-producing cells, a unique cell population resembling immature dendritic cells. The IFN-alpha production was greatly enhanced by IFN-alpha2b and IFN-beta, and for SLE-IIF it was also enhanced by GM-CSF but inhibited by IL-10. We have therefore identified a new function of DNA-anti-DNA Ab complexes, IFN-alpha induction, that might be important in the pathogenesis of SLE.

Antigen-Antibody Complex↗

PubMed2002

A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans.

Systemic lupus erythematosus (SLE, OMIM 152700) is a complex autoimmune disease that affects 0.05% of the Western population, predominantly women. A number of susceptibility loci for SLE have been suggested in different populations, but the nature of the susceptibility genes and mutations is yet to be identified. We previously reported a susceptibility locus (SLEB2) for Nordic multi-case families. Within this locus, the programmed cell death 1 gene (PDCD1, also called PD-1) was considered the strongest candidate for association with the disease. Here, we analyzed 2,510 individuals, including members of five independent sets of families as well as unrelated individuals affected with SLE, for single-nucleotide polymorphisms (SNPs) that we identified in PDCD1. We show that one intronic SNP in PDCD1 is associated with development of SLE in Europeans (found in 12% of affected individuals versus 5% of controls; P = 0.00001, r.r. (relative risk) = 2.6) and Mexicans (found in 7% of affected individuals versus 2% of controls; P = 0.0009, r.r. = 3.5). The associated allele of this SNP alters a binding site for the runt-related transcription factor 1 (RUNX1, also called AML1) located in an intronic enhancer, suggesting a mechanism through which it can contribute to the development of SLE in humans.

3' Untranslated Regions↗

PubMed2000

Association of deficient type II protein kinase A activity with aberrant nuclear translocation of the RII beta subunit in systemic lupus erythematosus T lymphocytes.

Systemic lupus erythematosus (SLE) is an autoimmune disorder of indeterminate etiology characterized by abnormal T cell signal transduction and altered T cell effector functions. We have previously observed a profound deficiency of total protein kinase A (PKA) phosphotransferase activity in SLE T cells. Here we examined whether reduced total PKA activity in SLE T cells is in part the result of deficient type II PKA (PKA-II) isozyme activity. The mean PKA-II activity in SLE T cells was 61% of normal control T cells. The prevalence of deficient PKA-II activity in 35 SLE subjects was 37%. Deficient isozyme activity was persistent over time and was unrelated to SLE disease activity. Reduced PKA-II activity was associated with spontaneous dissociation of the cytosolic RIIbeta2C2 holoenzyme and translocation of the regulatory (RIIbeta) subunit from the cytosol to the nucleus. Confocal immunofluorescence microscopy revealed that the RIIbeta subunit was present in approximately 60% of SLE T cell nuclei compared with only 2-3% of normal and disease controls. Quantification of nuclear RIIbeta subunit protein content by immunoprecipitation and immunoblotting demonstrated a 54% increase over normal T cell nuclei. Moreover, the RIIbeta subunit was retained in SLE T cell nuclei, failed to relocate to the cytosol, and was associated with a persistent deficiency of PKA-II activity. In conclusion, we describe a novel mechanism of deficient PKA-II isozyme activity due to aberrant nuclear translocation of the RIIbeta subunit and its retention in the nucleus in SLE T cells. Deficient PKA-II activity may contribute to impaired signaling in SLE T cells.

Adolescent↗