Autoantibodies in systemic lupus erythematosus: spectrum and clinical associations

We have analysed the clinical features and autoantibody profile of 84 tunisian patients with newly diagnosed systemic lupus erythematosus (SLE). Antinuclear antibodies (ANA) were detected by an immunofluorescence method, anti-dsDNA and anti-cardiolipin (aCL) antibodies by ELISA, antinucleosome and anti-extractible nuclear antigens (or anti-ENA: anti-Sm, anti-RNP, anti-SSA and anti-SSB) by immunodot. The mean age of the patients was 29,9 years and the sex-ratio F/M was 6. The most common initial features were haematological (80%), rheumatological (78%) and cutaneous (75%) disorders. 59% of the patients had glomerular nephropathy. ANA were detected in 97.6%, antinucleosome in 78.6%, anti-dsDNA in 75%, anti-histones in 44%, anti-Sm in 36.9%, anti-RNP in 32.1%, anti-SSA in 54.8% and anti-SSB in 14.3% of patients. IgG and IgM aCL were detected in 45 and 40% of the patients respectively. The significant clinical associations were those of nephropathy and disease activity with anti-dsDNA and antinucleosome antibodies. Our results confirm the clinical polymorphism of SLE, the high frequency of antinucleosome antibodies at time of diagnosis and the predominance of anti-SSA among anti-ENA antibodies.     

HLA and systemic lupus erythematosus in Chinese

Seventy-five unrelated Chinese SLE patients were HLA typed and subdivided into mild and severe disease The HLA-B13 was associated with mild disease Fourteen of 30 (46.7%) mild disease patients had B13 compared to 63/330 (19.1%) normal subjects (p < 0 0005, corrected p < 0 013, RR = 3 7) The HLA-B17 on the other hand was observed in 29% of 45 severe disease patients compared to 13 9% of 330 normal subjects (p < 0 01, RR = 2.5). The frequency of HLA-B17 in 11 patients who died was even higher (45 5%).     

中国人群系统性红斑狼疮患者OAZ基因多态性研究

目的　研究 OL F1/EBF相关锌指蛋白 (OL F1/EBF associated zinc finger protein,OAZ)基因单核苷酸多态性 (single nucleotide polymorphism,SNP)与系统性红斑狼疮 (systemic lupus erythematosus,SL E)的关联性。方法　选择经过验证、杂合度较高的 SNP对 2 4 4个 SL E家系进行等位基因分型 ,以Genehunter软件分析单个位点及单倍型传递情况。检测 OAZ基因表达水平 ,比较患者中不同单倍型对基因表达的影响。结果　未发现单个 OAZ SNP位点在 SL E患病子代中优势传递。单倍型分析显示 ,由rs1344 5 31- rs2 0 80 35 3- rs9335 6 4 - rs1345 4 31构成的单倍型 T- A- G- G与疾病连锁性较弱 (P=0 .0 4 ) ,而Rs9335 6 4 - D16 s5 17构成的单倍型 G- 2 71bp、Rs2 0 80 35 3- rs9335 6 4 - D16 s5 17构成的单倍型 A- G- 2 71bp优势传递给患者 (P=0 .0 0 0 0 0 0和 0 .0 0 0 0 0 2 )。 Rs2 0 80 35 3- rs9335 6 4 - D16 s5 17- rs1345 4 31构成的单倍型 A- G-2 71bp- G也优势传递给患者 (P=0 .0 0 84 ) ,且该单倍型与基因表达水平相关。结论　 SL E患者中存在特定的 OAZ基因单倍型 ,OAZ可能提示了狼疮发病的新通路。     

Management of systemic lupus erythematosus in Chinese patients

Systemic lupus erythematosus (SLE) is a worldwide disease with prevalence figures ranging from nine to 130 per 100,000 individuals. SLE appears to be more prevalent in certain ethnic groups, such as the African–Americans, African–Caribbeans and Asians. The prevalence of SLE in Hong Kong Chinese was estimated to be 59 out of 100,000 (104/100,000 among women), which is mid-way between that of the Caucasians and African–Americans. Certain organ manifestations, such as lupus nephritis, are more common in Chinese than Caucasians. A recent prospective study reported that the cumulative incidence of renal disease within 5 years of diagnosis of SLE in Chinese patients was 60%. Despite the improvement in survival of SLE in the past few decades, manifestations that are refractory to conventional therapies and treatment related complications are still major challenges in the management of SLE. Novel-therapeutic modalities for SLE should aim at targeting more specifically the immunopathogenetic pathways to achieve higher efficacy and reduce short- and long-term therapy-related toxicities. This review summarizes the management strategies and novel therapeutic modalities in SLE.     

Haplotype associations define target regions for susceptibility loci in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by diverse and variable clinical manifestations. The etiology of SLE is still unknown, but both environmental and genetic factors are involved. Recent genome-wide scans and candidate genes studies in different ethnic groups have already suggested susceptibility loci for SLE, but most of the genetic component remains unexplained. We have previously conducted a genome-wide scan in 35 Finnish families multiply affected with SLE. With 417 microsatellite markers, we detected suggestive linkage in regions on chromosomes 6q and 14q as well as HLA on 6p. The 14q locus has also been implicated in three previous genome scans on SLE, whereas a partially overlapping region on 6q was implicated in one previous study. In an effort to obtain additional evidence for susceptibility loci on 6q and 14q and in order to refine their positions, we performed fine mapping at 1 cM density across the suggestive regions of linkage. Our results show evidence for excess sharing of a haplotype on 14q and excess transmission of a haplotype on 6q. Our results are compatible with the idea of a founder effect for susceptibility genes in SLE in central eastern Finland and suggest a path to the isolation of the putative susceptibility genes.     

Current and novel therapeutics in the treatment of systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with significant clinical heterogeneity. Recent advances in our understanding of the genetic, molecular, and cellular bases of autoimmune diseases and especially SLE have led to the application of novel and targeted treatments. Although many treatment modalities are effective in lupus-prone mice, the situation is more complex in human subjects. This article reviews the general approach to the therapy of SLE, focusing on current approved therapies and novel approaches that might be used in the future.     

Identification of a novel HLA-A allele HLA-A*2451 in a Chinese donor

A novel human leucocyte antigen-A (HLA-A) allele, A*2451, has been identified during routine sequence-specific oligonucleotide typing and sequence-based typing of a sample from a registered donor of the Chinese Marrow Donor Program. The A*2451 allele differs from the closest matching allele A*2415 by one nucleotide substitution in exon 3, nt 363 G-->A, resulting in an amino acid change from M ATG to I ATA at codon 121.     

Tuberculosis in patients with systemic lupus erythematosus

In a retrospective analysis of 146 systemic lupus erythematosus (SLE) patients seen over a 5 year period, 17 patients of tuberculosis (TB) were identified yielding a prevalence rate of 11.6%. The median duration of SLE was 12 months (range 2-96 months) and 12/17 patients had disease activity score of more than five. The median duration of steroid treatment was 12 months (range 0-96 months) and the median cummulative dose of steroid was 7.75 gms (range 0-22.1 gms). Pulmonary TB (miliary-5, nonmiliary infiltrates-7 and pleural effusion-2) was the commonest type and there was an average diagnostic delay of approximately 1 month. While, majority of the patients responded adequately to treatment, 1 patient had a relapse and 1 expired due to a combination of active lupus and disseminated TB. Only 1 patient had received prophylactic isoniazid.     

Immunogenetics in systemic lupus erythematosus: Transitioning from genetic associations to cellular effects

Systemic lupus erythematosus (SLE) is a heterogeneous rheumatic autoimmune disease. Genetic studies have identified up to 100 SLE risk loci. Many of these encode proteins of importance in the immune system, but the cellular and molecular mechanisms underlying these associations are still elusive. In this review, we will highlight some of the SLE risk loci where mechanistic insights have been achieved recently by linking genetic risk polymorphisms to cellular or molecular phenotypes important for the disease process.     

Neonatal lupus erythematosus in offspring of mothers with experimental systemic lupus erythematosus.

Neonatal lupus erythematosus (NLE) syndrome is a result of the transfer of autoantibodies produced by the mother, across the placenta, to the fetus. NLE is characterized by a transient dermatitis, a variety of systemic and hematological abnormalities, and isolated cases of congenital heart block. The latter has been reported to be due to the presence of autoantibodies specific to La (SS-B) and/or Ro (SS-A). As female mice with experimental SLE, induced by immunization with the monoclonal anti-DNA 16/6 Id, produce a variety of autoantibodies including anti-Ro and anti-La antibodies, we examined the relevance of NLE in the murine system. Offspring of SLE-afflicted BALB/c mothers possessed antibody titers to the 16/6 Id, ssDNA, and nuclear extract, which gradually declined until reduced to normal levels by day 60 after delivery. Antibody titers in the sera of the mothers remained elevated throughout this period. Electrocardiograms were recorded from groups of neonates from mothers with experimental SLE. The results indicated that a high percentage of the offspring had defects in their conduction system including first, second, and third degree heart block; significant bradycardia; and wide QRS complex. Normal patterns were observed in offspring of healthy mothers. Experiments done with mice that were exposed to SLE-related autoantibodies early in their development indicated that offspring to mothers with experimental SLE were neither protected nor more susceptible to disease induction by the 16/6 Id.     

Prognosis in systemic lupus erythematosus

Conclusions In SLE, morbidity is universal and fatality is significant. One cannot learn too much about the prognostic markers for this disorder. The identification by means of renal biopsy of subclasses of lupus nephritis spurred the development of new treatment regimens that have improved outcomes. While proliferative nephritis remains a marker of serious renal involvement, the newer indices that attempt to quantify the activity and chronicity of the renal lesion, as well as greater awareness of the importance of tubulointerstitial involvement and improvement in the amount of subendothelial electron-dense deposits with therapy, will likely permit further fine-tuning of the treatment of individual patients with lupus nephritis.Neuropsychiatric involvement in SLE is another major determinant of financial costs, morbidity and death. Unfortunately, our knowledge of the prognostic markers for this more heterogeneous group of manifestations is less advanced than for lupus renal involvement. Additional studies are needed urgently to determine the factors that predict the subsequent development of the different forms of neuropsychiatric lupus. The determinants will likely differ among the various forms of neuropsychiatric lupus, thereby permitting different preventative or treatment regimens to be developed.The role of social factors, particularly socioeconomic status, has attracted attention in the United States. The lessons are likely applicable elsewhere. Additional studies to identify social factors that can be modified may bring tangible benefits to SLE patients in this decade.Although not universally accepted, it does appear that as more SLE patients survive the acute disease, there is an inordinately high risk of developing vascular diseases, including coronary artery disease, stroke and peripheral vascular disease. As with neuropsychiatric lupus, the determinants may differ depending on the specific vascular disease. Better knowledge of these determinants will permit a further improvement in the overall prognosis for patients with SLE.     

Atherosclerosis in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune rheumatic disease that has a late mortality phase owing mainly to cardiovascular manifestations. Atherosclerosis itself is characterized by inflammatory components, fulfilling the criteria of Witebsky and Rose for an autoimmune disease. SLE patients have increased risk for cardiovascular events, and these are the result of both atherosclerosis and thromboembolic events. Risk factors for atherosclerosis in SLE include “traditional” risk factors (mainly the Framingham risk factors), as well as disease-related factors including disease duration, steroid therapy, and renal disease, and inflammatory mechanisms that specifically contribute to enhanced atherosclerosis in SLE. These include specific antibodies to β2GPI; anticardiolipin antibodies; anti-oxidized low-density lipoprotein; and antibodies to heat shock proteins, complement activation, impaired ability to activate TGF-β1, and elevated levels of CRP. These findings stress the importance of surveillance and preventive strategies to control atherosclerosis in SLE.     

Prolactin and systemic lupus erythematosus

Immunologic Research -     

Amyloidosis and systemic lupus erythematosus

A 59 year old man with systemic lupus erythematosus developed proteinuria and renal insufficiency. Renal biopsy revealed both crescentic glomerulonephritis and amyloid in glomeruli and blood vessels. The amyloid was characterized as secondary because of its sensitivity to potassium permanganate pretreatment of Congo red stained sections. Amyloidosis is very uncommon in systemic lupus erythematosus but may be a cause of steroid unresponsive proteinuria and renal insufficiency.     

Dyslipidemia in systemic lupus erythematosus

Cardiovascular disease is one of the major causes of morbidity and mortality in patients with systemic lupus erythematosus (SLE). Accelerated atherosclerosis is related to traditional (age, hypertension, diabetes mellitus, dyslipidemia, obesity, smoking, and positive family history) and non-traditional, disease-related factors. Traditional risk factors are still more prominent in patients with lupus, as both hypertension and hypercholesterinemia were independently associated with premature atherosclerosis in several SLE cohorts. In this work, the authors summarize the epidemiology of dyslipidemia in lupus patients and review the latest results in the pathogenesis of lipid abnormalities. The prevalence of dyslipidemia, with elevations in total cholesterol (TC), low-density lipoprotein (LDL), triglyceride (TG), and apolipoprotein B (ApoB), and a reduction in low-density lipoprotein (LDL) levels are about 30% at the diagnosis of SLE rising to 60% after 3 years. Multiple pathogenetic mechanism is included, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) can suppress HDL and increase TG, auto-antibodies can cause the injury of the endothelium, lipoprotein lipase (LPL) activity can be reduced by circulating inflammatory mediators and antibodies, and increased oxidative stress may trigger a wide range of pro-atherogenic lipid modifications. As a major risk factor, dyslipidemia should be treated aggressively to minimize the risk of atherosclerosis and cardiovascular events. Randomized controlled trials with statins are controversial in the detention of atherosclerosis progression, but can be favorable by inhibiting immune activation that is the arterial wall and by decreasing lupus activity.