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Systemic lupus erythematosus in children and adolescents is a multisystem autoimmune disease with a great variability in disease presentation and course. This article summarizes available epidemiologic data, clinical patterns, approaches to investigation and treatment, and recent outcome data.
Systemic lupus erythematosus is a challenging disease with varied manifestations resulting from widespread immune complex deposition. It may present in the general pediatric office as an acute illness with fever, rash, and hematuria, or as chronic fatigue and malaise that might be mistaken for "school phobia". Although SLE remains an infrequent disease in general pediatric practice, mild cases are more frequent than was previously recognized. These children benefit from therapy if the physician is alert to their occurrence and makes the appropriate diagnosis. The understanding of the role of genetics and environmental agents in the pathogenesis of SLE has improved over the past 10 years. In addition, the past 10 years have seen refinements in the use of immunosuppressive regimens, such as cyclophosphamide, that have led to both improved quality of life and improved survival for children with active SLE unresponsive to corticosteroids. Although long-term concerns regarding the safety and efficacy of immunosuppressive drug regimens persist, the future is increasingly bright for children with SLE who receive appropriate care in a timely fashion.
Systemic lupus erythematosus (SLE) is a multisystem disorder with cardiac involvement in about 50% of cases, yet clinically significant lesions are less common. SLE with pancarditis at initial presentation has so far not been reported. We present a rare case of SLE with culture negative endocarditis, reversible left ventricular (LV) dysfunction and mild pericardial effusion. Treatment with steroids showed improvement in cardiac contractile function and mitral valve vegetations disappeared over 3 months. In a case of pancarditis with culture negative endocarditis, SLE as a possibility must be explored. After excluding infective endocarditis, a short trial of high dose corticosteroids effects overall improvement in carditis of SLE.
Systemic Lupus Erythematosus (SLE) remains a challenging autoimmune disease in term of etiology, pathogenesis and treatment. It is estimated that 10-17% of lupus patients present before the age of 16. SLE in children appears to have more severe organ involvement than in adults. The outcome of childhood SLE has improved during the last decade, but the morbidity remains high.
Systemic lupus erythematosus (SLE) is the most common of the connective tissue disorders and can involve virtually any organ in the body. It is associated with pleuropulmonary manifestations in well over 50% of cases. Pleuritis with or without pleural effusion is the most common manifestation and can be particularly troublesome to manage but is rarely life-threatening. More serious manifestations in the lung include acute lupus pneumonitis with or without alveolar haemorrhage, chronic lupus pneumonitis and pulmonary hypertension. These all contribute significantly to overall mortality in SLE. The association between SLE and the antiphospholipid syndrome, leading to venous thrombosis and pulmonary embolism, is well recognized. Up to 20% of all cases of SLE present in childhood and many of these have pulmonary features at presentation or during the course of their illness. Sepsis is one of the main causes of death in SLE and pulmonary sepsis in these often immunocompromised patients contributes a significant proportion. Several drugs can produce a clinical syndrome that has many of the clinical and immunological features of SLE. Pleuritis may be seen in up to half of these cases of drug induced SLE. The development of SLE and conditions such as sarcoidosis or asbestosis in the same patient may represent a simple coincidence but there is some evidence for a closer association between these disorders.
Systemic lupus erythematosus (SLE) is an autoimmune disease that occurs primarily in women (9:1 compared to men). Estrogen is a female sex hormone that acts on target cells through specific receptor proteins and alters the rate of transcription of target genes. Experiments in our laboratory have shown that calcineurin steady-state mRNA levels and phosphatase activity increase when estrogen is cultured with SLE T cells. This estrogen-dependent increase is dose-dependent, hormone-specific and temporally regulated. Estrogen receptor antagonism by ICI 182,780 inhibits the increase in calcineurin mRNA and phosphatase activity, while cycloheximide has no effect suggesting that new protein synthesis is not required. Reverse transcription and polymerase chain amplification indicate that estrogen receptor-alpha and estrogen-beta are expressed in human T cells. However, calcineurin does not respond to estrogen stimulation in T cells from normal females, males and lupus males. Taken together, these results indicate a differential function of the estrogen receptor in women with lupus. A model is proposed that suggests estrogen, acting through the estrogen receptor, enhances T cell activation in women with lupus resulting in amplified T-B cells interactions, B cell activation and autoantibody production.
Systemic lupus erythematosus (SLE) is a complex autoimmune disease that exhibits extensive clinical heterogeneity. Several studies have suggested a role for tumor necrosis factor alpha (TNFalpha) in SLE and recently, the locus encompassing the TNF receptor II (TNFRII), which is a mediator of TNF effect, was amongst the candidate loci suggested by genetic linkage studies of multi-case SLE families. Komata et al. reported an association between a polymorphism at position 196 (R allele) of TNFR II and SLE in Japanese patients. We have typed SLE patients from two different ethnic populations, Spanish and UK Caucasoids, for this polymorphism using a polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP)-based technique. No significant differences in allele or genotype frequencies were found between cases and matched controls in either population. The TNFRII 196R allele does not appear to be associated with SLE susceptibility in either Spanish or UK populations.
Systemic lupus erythematosus (SLE) is a highly prevalent human autoimmune diseases that causes progressive glomerulonephritis, arthritis and an erythematoid rash. Mice deficient in deoxyribonuclease I (Dnase1) develop an SLE-like syndrome. Here we describe two patients with a heterozygous nonsense mutation in exon 2 of DNASE1, decreased DNASE1 activity and an extremely high immunoglobulin G titer against nucleosomal antigens. These data are consistent with the hypothesis that a direct connection exists between low activity of DNASE1 and progression of human SLE.
Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by activation of the type I interferon (IFN) pathway. Here we convincingly replicate association of the IFN regulatory factor 5 (IRF5) rs2004640 T allele with SLE in four independent case-control cohorts (P = 4.4 x 10(-16)) and by family-based transmission disequilibrium test analysis (P = 0.0006). The rs2004640 T allele creates a 5' donor splice site in an alternate exon 1 of IRF5, allowing expression of several unique IRF5 isoforms. We also identify an independent cis-acting variant associated with elevated expression of IRF5 and linked to the exon 1B splice site. Haplotypes carrying the variant associated with elevated expression and lacking the exon 1B donor site do not confer risk of SLE. Thus, a common IRF5 haplotype driving elevated expression of multiple unique isoforms of IRF5 is an important genetic risk factor for SLE, establishing a causal role for type I IFN pathway genes in human autoimmunity.
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.
Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease that is caused by genetic and environmental factors. The tumour necrosis factor (TNF) superfamily of genes play a central role in immune regulation and have been proposed to be involved in the development of SLE. TNFRSF5 (CD40) falls on 20q11-13, a region linked with SLE in three independent genome-wide studies. TNFSF5 (CD40L) falls on Xq26 and is the ligand for TNFRSF5. Seven single-nucleotide polymorphisms (SNPs) in CD40 and eight SNPs in CD40L were looked at for linkage disequilibrium (LD) and haplotype analysis in European-Caucasians. Limited haplotype diversity was observed across CD40 and CD40L, and >97% of the diversity was captured. We also examined the association of SNPs and haplotypes in CD40 and CD40L with SLE in European-Caucasians. There was no evidence of association for CD40 or CD40L in 408 European-Caucasian families with SLE from UK. Haplotype tagging SNPs (htSNPs) are made known, which will facilitate analysis for susceptibility in other autoimmune diseases and risk for infectious disease.
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the activation of autoreactive B lymphocytes, which are supposed to carry aberrant signal transduction after the stimulation of B-cell receptor (BCR). To investigate abnormalities in BCR-mediated signaling pathway in lupus B lymphocytes, we analyzed HS1, a molecule downstream of BCR, in 80 Japanese SLE patients. We identified 37 amino acid deletion of HS1 in a 25-year-old female patient, and the aberrant HS1 lacked a part of a functional motif. Analysis of genomic DNA revealed that the aberrant HS1 was caused by exon skipping. Family study showed that the patient as well as her father and sister are heterozygous for the abnormality. WEHI-231 cell, a mouse B cell line, transfected with the aberrant HS1 displayed a significantly increased cell death upon cross-linking of BCR. Additionally, peripheral B lymphocytes from the patient exerted increased apoptosis after BCR stimulation compared to those from control SLE patients. These data suggest that the aberrant HS1 molecule may transmit an accelerated signal after BCR stimulation and may play a role in the activation of autoreactive B lymphocytes.
Systemic lupus erythematosus is an autoimmune disease in which complex interactions between genes and environmental factors determine the disease phenotype. We have shown that genes from the non-autoimmune strains 129 and C57BL/6 (B6), commonly used for generating gene-targeted animals, can induce a lupus-like disease. Here, we conducted a genome-wide scan analysis of a cohort of (129 x B6)F2 C1q-deficient mice to identify loci outside the C1qa locus contributing to the autoimmune phenotype described in these mice. The results were then confirmed in a larger dataset obtained by combining the data from the C1q-deficient mice with data from previously reported wild-type mice. Both analyses showed that a 129-derived interval on distal chromosome 1 is strongly linked to autoantibody production. The B6 genome contributed to anti-nuclear autoantibody production with an interval on chromosome 3. Two regions were linked to glomerulonephritis: a 129 interval on proximal chromosome 7 and a B6 interval on chromosome 13. These findings demonstrate that interacting loci between 129 and B6 mice can cause the expression of an autoimmune phenotype in gene-targeted animals in the absence of any disrupted gene. They also indicate that some susceptibility genes can be inherited from the genome of non-autoimmune parental strains.
Systemic lupus erythematosus (SLE) is a chronic, multisystem, autoimmune disease in which neuropsychiatric involvement occurs in about 50% of patients and carries a poor prognosis. Despite extensive research, the precise mechanisms of nervous tissue injury remain the least well understood. This article summarizes the important clinical neuropsychiatric features of SLE and, reviewing classical histopathological and more recent experimental studies, discusses theories concerning their presumed pathogenesis. The distinctive production of diverse autoantibodies seems to be related to defective clearance of apoptotic cells. Antibody-mediated neural cell injury and rheological disturbances represent the two principal suggested mechanisms of tissue injury. An interplay between these processes, underlying genetic factors, their modification by hormones, complicated by a number of secondary factors, may explain the wide spectrum of features encountered in this disease.
Systemic lupus erythematosus is a non-organ specific, autoimmune disease characterised by antinuclear antibodies and vasculitis. This may manifest itself with areas of cutaneous necrosis which may require extensive excision and reconstruction. Major areas of skin and soft tissue loss may require coverage with either local or microvascular free tissue transfer. This presents potential difficulties in patients with generalised vasculitis. We present the case of a professional cellist with extensive soft tissue loss in her dominant hand, successfully reconstructed with a free latissimus dorsi muscle flap, treated with peri- and postoperative anticoagulation and corticosteroids.
Systemic lupus erythematosus (SLE) is an autoimmune disease with a complex genetic basis that includes susceptibility gene(s) within the chromosome 1q41-1q42 region. Toll-like receptor 5 (TLR5), the innate immune receptor for bacterial flagellin, maps to chromosome 1q41 and contains a common stop codon polymorphism that abrogates signaling (allele C1174T) and is associated with an increased risk of infection. By using transmission disequilibrium testing in a cohort containing 199 affected patients and their 75 unaffected siblings and 326 parents, we found that allele 1174C, but not 1174T (with the stop codon), was preferentially transmitted to SLE-affected offspring (a 19:6 transmitted/not transmitted ratio, P = 0.009). In contrast, the alleles of the other three TLR5 SNPs did not exhibit preferential transmission. In addition, we found that allele 1174C was not preferentially transmitted to unaffected offspring (3:6 transmitted/not transmitted ratio, P value not significant). The allele frequency of 1174T in the probands was 3.2% compared with 5.8% in unaffected individuals, which was consistent with a protective association (odds ratio, 0.51; 95% confidence interval, 0.26-0.98; P = 0.041). Subjects with the TLR5 stop codon produced significantly lower levels of proinflammatory cytokines in comparison with individuals with the wild-type genotype. Together, these results indicate that the TLR5 stop codon polymorphism is associated with protection from the development of SLE. These data support a role for flagellated bacteria and the innate immune response in the development of SLE with implications for novel immunomodulatory treatment strategies.
Systemic lupus erythematosus (SLE) is an auto-immune disease which can affect multiple organs. It may also involve the pancreas and in rare cases may cause acute pancreatitis. The etiology of acute pancreatitis in SLE is a matter of controversy. We present a case diagnosed with SLE that developed acute pancreatitis while being treated with corticosteroids. During the course of the disease, pancreatic pseudocysts developed and were treated by percutaneous drainage. There are few reports in the literature about the therapy of acute pancreatitis and percutaneous drainage of pseudocysts in SLE. We discuss the pathogenesis and therapy for acute pancreatitis in SLE patients.
Systemic lupus erythematosus (SLE or lupus) is a complex disease with a multifactoral etiology, with genetic, hormonal, and environmental influences. Molecular mimicry as a result of viral infection may contribute to the development of lupus. The pattern of autoantibody development in lupus is consistent with initiation through molecular mimicry, as the initial autoantigenic epitopes that have been observed are limited and cross-reactive with viral proteins. Autoantibody specificity may then later diversify to other autoantigens through B-cell epitope spreading. Epstein-Barr virus (EBV) is an excellent candidate to be involved in molecular mimicry in lupus. EBV infection has been associated with lupus through serological and DNA studies. Infection with EBV results in the production of the viral protein Epstein-Barr virus nuclear antigen-1 (EBNA-1), antibodies against which cross-react with lupus-associated autoantigens, including Ro, Sm B/B', and Sm D1, in lupus patients. The immune response against EBV, and EBNA-1 in particular, differs among lupus patients and healthy controls, with controls maintaining a limited humoral response and failing to produce long-standing cross-reactive antibodies. We hypothesize that the humoral immune response to EBNA-1 in susceptible individuals leads to the generation of cross-reactive antibodies. Through the process of epitope spreading, these cross-reactive antibodies target additional, non-cross reactive autoepitopes, spread to additional autoantigens, and become pathogenic, leading eventually to clinical lupus. This paper reviews some of the current literature supporting roles for EBV exposure and epitope spreading in SLE.