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Treating systemic lupus erythematosus.

Systemic lupus erythematosus is one of the more common rheumatic complaints, affecting mainly women of child-bearing age. It is a life-threatening condition that affects the immune system and causes damage to the main organs of the body. To coincide with Lupus Awareness Week (10-17 April), this article reviews the symptoms, causes, diagnosis and treatment of systemic lupus erythematosus and examines ways in which research is improving management of the condition.

Female↗

PubMed2004

Age-related changes in serum growth hormone, insulin-like growth factor-1 and somatostatin in system lupus erythematosus.

BACKGROUND: Systemic lupus erythematosus is an age- and gender-associated autoimmune disorder. Previous studies suggested that defects in the hypothalamic/pituitary axis contributed to systemic lupus erythematosus disease progression which could also involve growth hormone, insulin-like growth factor-1 and somatostatin function. This study was designed to compare basal serum growth hormone, insulin-like growth factor-1 and somatostatin levels in female systemic lupus erythematosus patients to a group of normal female subjects. METHODS: Basal serum growth hormone, insulin-like growth factor-1 and somatostatin levels were measured by standard radioimmunoassay. RESULTS: Serum growth hormone levels failed to correlate with age (r2 = 3.03) in the entire group of normal subjects (i.e. 20 - 80 years). In contrast, serum insulin-like growth factor-1 levels were inversely correlated with age (adjusted r2 = 0.092). Of note, serum growth hormone was positively correlated with age (adjusted r2 = 0.269) in the 20 - 46 year range which overlapped with the age range of patients in the systemic lupus erythematosus group. In that regard, serum growth hormone levels were not significantly higher compared to either the entire group of normal subjects (20 - 80 yrs) or to normal subjects age-matched to the systemic lupus erythematosus patients. Serum insulin-like growth factor-1 levels were significantly elevated (p < 0.001) in systemic lupus erythematosus patients, but only when compared to the entire group of normal subjects. Serum somatostatin levels differed from normal subjects only in older (i.e. >55 yrs) systemic lupus erythematosus patients. CONCLUSIONS: These results indicated that systemic lupus erythematosus was not characterized by a modulation of the growth hormone/insulin-like growth factor-1 paracrine axis when serum samples from systemic lupus erythematosus patients were compared to age- matched normal female subjects. These results in systemic lupus erythematosus differ from those previously reported in other musculoskeletal disorders such as rheumatoid arthritis, osteoarthritis, fibromyalgia, diffuse idiopathic skeletal hyperostosis and hypermobility syndrome where significantly higher serum growth hormone levels were found. Somatostatin levels in elderly systemic lupus erythematosus patients may provide a clinical marker of disease activity in these patients.

Adult↗

PubMed1999

Anti-DNA autoantibodies and systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that affects most of the organs and tissues of the body, causing glomerulonephritis, arthritis, and cerebritis. SLE can be fatal with nephritis, in particular, predicting a poor outcome for patients. In this review, we highlight what has been learned about SLE from the study of mouse models, and pay particular attention to anti-DNA autoantibodies, both as pathological agents of lupus nephritis and as DNA-binding proteins. We summarize the current approaches used to treat SLE and discuss the targeting of anti-DNA autoantibodies as a new treatment for lupus nephritis.

Animals↗

PubMed2004

Gene expression profiling in the study of the pathogenesis of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with a complex pathogenesis involving multiple genetic and environmental contributions. DNA microarray technology has recently been applied to unravel some of this complexity through genomewide profiling. Early studies using microarray analysis of peripheral blood mononuclear cells (PBMCs) from SLE patients revealed dysregulation of inflammatory cytokines, chemokines, and immune response-related genes, as well as genes involved in apoptosis, signal transduction, and the cell cycle. More recently, using arrays containing many more genes, 4 independent research groups have found that interferon (IFN)-regulated genes are highly overexpressed in the peripheral blood and kidney glomeruli of SLE patients, supporting a crucial role for interferon in SLE. Future studies focusing on target tissues or organs in lupus, including the kidney, may further contribute to our understanding of lupus pathogenesis while providing new targets for therapy.

Animals↗

PubMed2006

Anti-interleukin-6 monoclonal antibody inhibits autoimmune responses in a murine model of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease resulting from dysregulation of the immune system. Interleukin-6 (IL-6) is a multifunctional cytokine produced by macrophages, monocytes and T and B cells. It stimulates B-cell differentiation/maturation, immunoglobulin secretion, and T-cell functions. Elevated levels of IL-6 in serum, urine and renal glomeruli were detected in patients with active SLE and in murine models of SLE. Our study investigated the role of IL-6 in an SLE-like disease in New Zealand Black/White (NZB/W) F1 mice by administration of an anti-murine IL-6 monoclonal antibody (mAb). Intraperitoneal administration of the anti-IL-6 mAb suppressed the production of anti-dsDNA autoantibody. B-cell proliferation induced by anti-IgM and anti-CD40 was lower in the anti-IL-6 mAb-treated mice, ex vivo studies demonstrated that anti-IL-6 mAb treatment inhibited anti-dsDNA production. Anti-CD3-induced T-cell proliferation and mixed lymphocyte reactions were inhibited by anti-IL-6 mAb treatment, indicating a partial down-regulation of T cells. Histological analysis showed that treatment with anti-IL-6 mAb prevented the development of severe kidney disease. These results suggest that treatment with anti-IL-6 mAb has a beneficial effect on autoimmunity in murine SLE and that autoreactive B cells may be the primary target for anti-IL-6 mAb treatment; its effect on autoreactive T cells is also indicated.

Animals↗

PubMed2006

Roles of genetic variations in signalling/immunoregulatory molecules in susceptibility to systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with a complex genetic basis that includes many susceptibility genes on multiple chromosomes. As complex human diseases like SLE involve multiple, interacting genetic and environmental determinants, identifying genes for complex traits is challenging and has had limited success so far. However, recent advances in genetic resources and technology have been providing new tools to identify the novel pathways or the sequence variants that contribute to autoimmune diseases. During the past several years, several new candidate genes have been implicated in development of SLE though association studies. In this article we describe an overview of the latest findings in the genetics of SLE, especially focusing on the genetic variations in the signalling or immunoregulatory molecules including CD28 and IRF family members.

Animals↗

PubMed2006

Haplotype analysis of tumour necrosis factor receptor genes in 1p36: no evidence for association with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with partially understood aetiology. The 1p36 region has been previously linked with SLE and harbours tumour necrosis factor receptor (TNFR) genes. Functional and genetic data implicate their gene products in SLE and other autoimmune diseases. In all, single-nucleotide polymorphisms (SNPs) across TNFRSF14 (HVEM), and 43 SNPs across the TNFRSF8 (CD30) and TNFRSF1B (CD120B) locus were investigated for linkage disequilibrium (LD) and haplotype analysis in European-Caucasians. Strong LD was observed across HVEM and CD120B, and little LD and recombination across CD30. We also examined the association of SNPs and haplotypes in HVEM, CD30 and CD120B with SLE in European-Caucasians. There was no evidence of association for these genes in 456 European-Caucasian families with SLE from UK. Haplotype tagging SNPs are made known across areas of strong LD, which will facilitate analysis for susceptibility in other diseases.

Chromosomes, Human, Pair 1↗

PubMed2004

Reduced complement receptor 1 (CR1, CD35) transcription in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease characterized by the production of a broad spectrum of autoantibodies against nuclear, cytoplasmic and cell surface antigens and immune complex overload. Complement receptor 1 (CR1, CD 35), a transmembrane glycoprotein found on the surface of erythrocytes, leukocytes and glomerular podocytes plays a key role in the clearance of immune complexes and regulation of complement cascade. A drastic decline in the level of cell surface CR1 appears to be an important event in pathology of SLE. However, the etiology of lower than normal expression of cell surface CR1 in this disease is poorly understood. We studied the level of leukocyte CR1 transcription in 30 patients with active SLE and 30 controls by reverse transcriptase-polymerase chain reaction (RT-PCR) and related the same with the level of CR1 protein expression monitored by Western blotting. For RT-PCR, ratio of CR1/beta-actin was considered for semiquantitation of the level of CR1 transcription. Despite individual variation at the level of transcription, 70% (21 out of 30) of the patients expressed CR1 transcript at the lowest range of 0-15% as compared to the controls wherein only 30% (9 out of 30 individuals) demonstrated CR1 transcript in this range. Majority of the controls (70%) expressed CR1 transcript at the level above 15%. Mean level of CR1 transcript in patients (mean +/- S.D. = 21.09 +/- 14.3) was significantly lower than the controls (mean +/- S.D. = 48.91 +/- 26.34) (P < 0.001). The level of CR1 transcription correlated inversely with circulating immune complexes (CIC) (r = 0.52, P < 0.01). This may suggest that although erythrocyte CR1 is the chief vehicle for CIC clearance, drastic decline in leukocyte CR1 expression may impair the phagocyte mediated immune complex clearance and contribute to increased complement consumption in SLE. Total leukocyte CR1 protein expression was also significantly reduced in patients (P < 0.001) as compared to controls. This decline at the protein level gave a very significant positive correlation with CR1 transcript (r = 0.67, P < 0.01). A marginal increase in soluble CR1 (sCR1) was observed in the plasma (ELISA) of SLE patients compared to the controls but was insignificant. This paper for the first time brings evidence to suggest that reduced synthesis of CR1 contributes substantially to the low cell surface CR1 expression in SLE. Our findings also suggest increased proteolytic cleavage of leukocyte cell surface CR1 in these patients. However, evidence for the latter is indirect.

Adult↗

PubMed1996

The development and initial validation of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index for systemic lupus erythematosus.

OBJECTIVE: To develop and perform an initial validation of a damage index for systemic lupus erythematosus (SLE). METHODS: A list of items considered to reflect damage in SLE was generated through a nominal group process. A consensus as to which items to be included in an index was reached, together with rules for ascertainment. Each center submitted 2 assessments, 5 years apart, on 2 patients with active and 2 with inactive disease, of whom 1 had increased damage and the other had stable disease. Analysis of variance was used to test the factors physician, time, amount of damage, and activity status. RESULTS: Nineteen physicians completed the damage index on 42 case scenarios. The analysis revealed that the damage index could identify changes in damage seen in patients with both active and inactive disease. Patients who had active disease at both time points had a higher increase in damage. There was good agreement among the physicians on the assessment of damage in these patients. CONCLUSION: This damage index for SLE records damage occurring in patients with SLE regardless of its cause. The index was demonstrated to have content, face, criterion, and discriminant validity.

Health Status Indicators↗

PubMed1994

[Changes in thyroid function in systemic lupus erythematosus, progressive systemic sclerosis and rheumatoid arthritis].

According to frequent thyroid function disorders in systemic connective tissue diseases a group of 380 patients were analysed - 70 with systemic erythematous lupus (SLE), 31 with progressive systemic scleris (PSS) and 270 with rheumatoid arthritis (RA). Thyroxine (T4) and triodothyronine (T3) were measured by radioimmunoassay technique and thyroid stimulating hormone (TSH) chronologically by monoclonal antibody technique and thereafter by fluoroimmunoassay. Thyreopahty was found at 15 patients with SLE (21.43%), 11 patients with PSS (35.48%) and 35 patients with RA (12.54%). Our results pointed out the significant frequency of thyroid function disorders in these diseases and imply the necessity of the routine thyroid function follow up, therefore to take adequate cure in due time.

Arthritis, Rheumatoid↗

PubMed2026

Mapping the plasma proteomic architecture of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a heterogeneous systemic autoimmune disease, yet the molecular basis underlying this variability remains incompletely understood. We profiled the plasma proteome in 260 SLE patients and 86 healthy volunteers (HVs) using the SomaScan v4.1 platform, quantifying 7,288 analytes corresponding to 6,595 unique proteins. We identified 215 proteins that were robustly differentially abundant between SLE patients and HVs in both discovery (n = 207 SLE, n = 45 HVs) and validation sets (n = 53 SLE, n = 41 HVs). Within-cases analyses identified 421 proteins associated with disease activity. Network-based clustering delineated correlated protein modules, including an interferon-associated (IFN-associated) module and a kidney-associated module. Autoantibody-stratified analyses further uncovered distinct proteomic endotypes; positivity for antibodies targeting RNA-binding proteins (anti-Sm, anti-Ro-60, anti-RNP68, anti-RNP-A) was associated with increased IFN-stimulated protein levels (e.g., MX1, ISG15, and CXCL10), independent of disease activity. Anti-Sm, anti-RNP-A, and anti-Ro52 antibodies were associated with reduced plasma levels of their respective autoantigens. Anti-dsDNA antibodies were associated with elevated levels of CD40 ligand (CD40LG) and the neutrophil protease, proteinase-3. Moreover, we identified an association between CD40LG and disease activity specific to the anti-dsDNA-positive subgroup. Together, these data define plasma protein signatures of SLE and disease activity, highlight autoantibody-specific molecular phenotypes, and provide a basis for precision medicine.

Humans↗

PubMed2005

Polymorphisms in the tyrosine kinase 2 and interferon regulatory factor 5 genes are associated with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a complex systemic autoimmune disease caused by both genetic and environmental factors. Genome scans in families with SLE point to multiple potential chromosomal regions that harbor SLE susceptibility genes, and association studies in different populations have suggested several susceptibility alleles for SLE. Increased production of type I interferon (IFN) and expression of IFN-inducible genes is commonly observed in SLE and may be pivotal in the molecular pathogenesis of the disease. We analyzed 44 single-nucleotide polymorphisms (SNPs) in 13 genes from the type I IFN pathway in 679 Swedish, Finnish, and Icelandic patients with SLE, in 798 unaffected family members, and in 438 unrelated control individuals for joint linkage and association with SLE. In two of the genes--the tyrosine kinase 2 (TYK2) and IFN regulatory factor 5 (IRF5) genes--we identified SNPs that displayed strong signals in joint analysis of linkage and association (unadjusted P<10(-7)) with SLE. TYK2 binds to the type I IFN receptor complex and IRF5 is a regulator of type I IFN gene expression. Thus, our results support a disease mechanism in SLE that involves key components of the type I IFN system.

Alleles↗

PubMed1997

Atypical manifestations in a patient with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a chronic systemic inflammatory disease associated with the production of various autoantibodies and involvement of multiple organs. Necropsy findings in a 65 year old woman with SLE who had multiple aortic aneurysms and dissections, as well as other unusual manifestations, are described. The case illustrates the occurrence of and the difficulties encountered in the diagnosis of several diseases, namely aortic aneurysm, aortic dissection, acute pancreatitis, and Penicillium marneffei infection.

Aged↗

PubMed1990

Subdural hematoma presenting as headache in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) affects the nervous system in 75% of cases (1). A female with several neurological manifestations in the case history presented with severe headache, psychiatric disturbances, and increasing paraparesis. She was found to have bilateral subdural hematomas, and after evacuation her neuropsychiatric symptoms, including headache, disappeared. It is speculated that the reported low incidence of subdural hematomas in SLE may be more apparent than real. On the basis of our case, we recommend repeated neuroradiological investigations to uncover this important, treatable and otherwise potentially fatal cause of headache.

Adult↗

PubMed2002

[Recent advance in genetics of systemic lupus erythematosus].

Systemic lupus erythematosus (SLE) is the prototype systemic autoimmune disease and genetic component seems to play an important role in disease susceptibility. Studies from murine models have shown that about 30 loci are related to the disease. Meanwhile, 50 loci have been found in linkage to SLE in human genomic studies, especially 1q23-24, 1q41-42, 2q37, 4p16-15.2, 6p21-11 and 16q13. A lot of candidate genes contribute to the disease susceptibility and different combinations of genes at multiple loci in individual patient may result in the development of diverse clinical features.

Animals↗

PubMed1997

Recognition and management of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an inflammatory systemic disease that causes organ damage by the deposition of autoantibodies and complement activating immune complexes or by vascular occlusion due to procoagulant states associated with antiphospholipid antibodies. The vast majority of cases occur in women of childbearing age. SLE is diagnosed on the basis of its clinical manifestations and the demonstration of characteristic immunological phenomena, especially anti-nuclear antibodies. The prognosis in SLE has shown a distinct improvement over recent decades, the 5-year survival rate now approaching or exceeding 90%. The 15-year survival rate of 63 to 79%, on the other hand, underscores the need for further advances in diagnosis and treatment of the disease. Management of the disease includes regular monitoring of disease activity, avoidance of predisposing factors and close supervision of therapy. Drug therapy is guided by the activity and severity of the leading organ manifestations and ranges from nonsteroidal antirheumatic drugs to intensive treatment with cytotoxic agents. Corticosteroids remain irreplaceable for the control of acute flares. Antimalarials and azathioprine are important long term drugs for treating mild or moderate disease activity. Intravenous pulse cyclophosphamide is safer than other regimens and at least as effective as oral cyclophosphamide for severe lupus nephritis. It is also effective in the treatment of central nervous disease and of other organ-threatening manifestations. Recently, an intensified protocol which included cyclophosphamide induced long term treatment-free remission in 60% of patients. The toxicity of cyclophosphamide is considerable, but can be ameliorated by various measures. The value of several new immunosuppressants and other compounds remains to be determined.

Adrenal Cortex Hormones↗

PubMed2006

The epigenetic face of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an archetypical systemic, autoimmune inflammatory disease characterized by the production of autoantibodies to multiple nuclear Ags. Apoptotic defects and impaired removal of apoptotic cells contribute to an overload of autoantigens that become available to initiate an autoimmune response. Besides the well-recognized genetic susceptibility to SLE, epigenetic factors are important in the onset of the disease, as even monozygotic twins are usually discordant for the disease. Changes in DNA methylation and histone modifications, the major epigenetic marks, are a hallmark in genes that undergo epigenetic deregulation in disease. In SLE, global and gene-specific DNA methylation changes have been demonstrated to occur. Moreover, histone deacetylase inhibitors reverse the skewed expression of multiple genes involved in SLE. In the present study, we discuss the implications of epigenetic alterations in the development and progression of SLE and how epigenetic drugs constitute a promising source of therapy to treat this disease.

Animals↗

PubMed2001

Reliability and validity of systemic lupus activity measure-revised (SLAM-R) for measuring clinical disease activity in systemic lupus erythematosus.

New clinical scales for semiquantitating disease activity in systemic lupus erythematosus (SLE) are widely used in research. They are reliable and valid measures. One of the original scales, the Systemic Lupus Activity Measure (SLAM), has been modified based on experience with it in multi-observer studies and training of individuals in its use. We tested the psychometric properties of the revised SLAM (SLAM-R). SLAM-R was tested on 30 SLE patients, who fulfilled 1997 revised ACR criteria and were selected to represent a range of disease activity. The patients were evaluated independently by two physicians, who studied the instruction booklet and who had never used SLAM-R, on two occasions 2-4 weeks apart. At the first visit, the physician's global assessment of activity using visual analog scale, anti-dsDNA Ab, C3 and C4 were checked for construct validity. The psychometric properties were analyzed with nested analysis of variance and Pearson's correlation coefficient using SAS. All patients were female, the median age was 31 (15-52) y, and the mean score of SLAM-R was 10.5 +/- 5.3 (3-26). Estimates of reliability were 0.78 of inter-rater, 0.61 of inter-visit, 0.76 of physician 1 between visits, and 0.56 of physician 2 between visits. Among subcategories except 'Eye,' the 'Gastrointestinal' category had the highest (0.96) and the 'Neuromotor' category had the lowest inter-rater reliability (0.50). With respect to construct validity, the correlation of SLAM-R scores with the disease activity variables except C4 was high and statistically significant. In conclusion, the SLAM-R is reliable and valid for measuring clinical disease activity in SLE.

Adolescent↗