An update on genetic studies of systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a complex, multifactorial autoimmune disease. Genetic factors are thought to contribute to its pathogenesis. There have been numerous recent advances in the study of murine and human lupus genetics. In well-defined experimental transgenic or gene-knockout mouse models, the development of lupus-like disease has implicated specific genes and pathways in the disease pathogenesis. Linkage analyses have mapped multiple susceptibility loci and disease suppressive loci using inbred strains of mice that spontaneously develop lupus-like disease. Elegant genetic dissection and function studies have led to the recent identification of two murine candidate susceptibility genes, Ifi202 (encoding an interferon-inducible protein) and Cr2 (encoding complement receptors 1 and 2). In human lupus, casecontrol studies have established associations of SLE with certain major histocompatibility class II alleles, complement deficiencies, and polymorphisms of Fcψ receptor genes, a complement-related gene, and cytokine genes. During the past several years, linkage analyses using SLE multiplex families have provided many chromosomal regions for further exploration of susceptibility genes. Six regions exhibiting significant linkage to SLE are promising. Studies are underway to fine map these linked regions and to identify the genes in the susceptibility regions. An understanding of the genes involved in the development of lupus should provide targets for more focused therapy in lupus.     

Whipple’s Disease: Neurological Relapse Presenting as Headache for Two Years

Whipple’s disease is a rare, chronic, multi-systemic infectious disorder caused by the bacterium, Tropheryma whipplei. Relapses are commonly associated with neurological symptoms. We report a case of a 55-year-old man who presented with symptoms of progressive headache, 13 years after apparent complete recovery from intestinal Whipple’s disease. Studies showed hydrocephalus with obstruction of the aqueduct and cerebrospinal fluid findings consistent with chronic meningitis. Diagnosis of central nervous system Whipple’s disease was confirmed by analysis of the cerebrospinal fluid using polymerase chain reaction. After one year of antibiotic therapy, symptoms resolved and cerebrospinal fluid pleocytosis had improved. This case illustrates that Whipple’s disease should be included in the differential diagnosis of central nervous system disorders as it is a potentially treatable cause of chronic meningitis. Failure to recognize this presentation can lead to misdiagnosis or a significant delay in diagnosis and treatment.     

Drug-induced vasculitis

PURPOSE OF REVIEW: This review aims to draw attention to the features that distinguish drug-induced vasculitis and drug-induced lupus-like disease from those of idiopathic autoimmune syndromes, first and foremost primary vasculitides and systemic lupus erythematosus. Drug-induced vasculitis and drug-induced lupus-like disease are seen in patients treated long term with a drug, and close to 100 drugs representing all pharmacologic classes have been assumed capable of inducing such syndromes. The clinical phenotypes vary from single tissue or organ involvement to severe systemic inflammatory disease dominated by vasculitis and sometimes organ failure. RECENT FINDINGS: The recent discovery of antineutrophil cytoplasm antibodies in a large serological subset of drug-induced vasculitis/drug-induced lupus-like disease caused by long-term antithyroid drug treatment has opened new avenues for differential diagnostics. Antineutrophil cytoplasm antibodies with specificity to more than one lysosomal antigen, combined with presence of antibodies to histones and beta-2 glycoprotein 1 constitute a unique serological profile for drug-induced vasculitis/drug-induced lupus-like disease. SUMMARY: Rational use of laboratory marker profiles is likely to aid in distinguishing drug-induced from idiopathic syndromes. Hence, the use of antineutrophil cytoplasm antibodies and other autoantibodies as biomarkers of different phenotypes of drug-induced vasculitis/drug-induced lupus-like disease is the main focus of this review.     

Pegylated interferon alfa-2B induced lupus in a patient with chronic hepatitis B virus infection: case report

Drug-induced lupus is defined as a lupus-like syndrome temporally related to continuous drug exposure which resolves after discontinuation of the offending drug. Newer biological agents such as interferons (IFN) and anti-tumor necrosis factor-α therapies have been involved in the induction of lupus-like syndromes. Prompt recognition and discontinuation of the suspected drug are associated with excellent outcomes in most cases. In this article, we present the case who developed lupus during therapy with pegylated-IFN α-2b for chronic hepatitis B virus infection after 8 months.     

Castleman's disease with coagulation defect

Summary The case of a young man with the plasmacell type of Castleman's disease is described. Beyond the well known systemic manifestations the coagulation tests showed a decrease in the activity of factors V, VIII and X due to the presence of lupus-like circulating anticoagulants. After surgical excision of the mediastinal mass both hematochemical pathological data and the coagulation defect desappeared. It is suggested that the lupus-like anticoagulant was secreted by the tumor.Supported in part by Consiglio Nazionale delle Ricerche, Grant CT 82.02224.04     

Lupus-like syndrome caused by 5-aminosalicylic acid in patients with inflammatory bowel disease.

BACKGROUND: Although 5-aminosalicylic acid (5-ASA) preparations used to treat inflammatory bowel disease are reported to have fewer side effects than sulphasalazine, increased clinical use of these compounds has resulted in increased reports of significant side effects. OBJECTIVE: To report four patients with antinuclear antibody-positive migratory arthralgias and acute inflammation unrelated to the underlying inflammatory bowel disease, fulfilling the criteria of a drug-induced lupus-like syndrome. SETTING: A university-affiliated teaching hospital. INTERVENTION: Cessation of treatment with 5-ASA compounds. RESULTS: The cases described constitute a drug-induced lupus-like syndrome. All patients improved rapidly after discontinuation of 5-ASA compounds. CONCLUSIONS: Reversible lupus-like syndrome appears to be a rare but significant side effect of 5-ASA compounds. Patients treated with 5-ASA compounds who experience acute inflammatory symptoms or clinical deterioration not related to their gastrointestinal disease should be screened to rule out a lupus-like reaction.     

Anti-tubulin-alpha-1c antibody as a marker of value in Behçet syndrome

Clinical Rheumatology - Behçet’s syndrome (BS) is a multi-systemic vasculitis characterized by recurrent oral ulcers, genital ulcers, ocular lesions, and other systemic manifestations....     

Antigen-specific immature dendritic cell vaccine ameliorates anti-dsDNA antibody-induced renal damage in a mouse model

OBJECTIVES: Dendritic cells (DCs) can inhibit immune response by clonal anergy when immature. Recent studies have shown that immature DCs (iDCs) may serve as a live cell vaccine after specific antigen pulse based on its potential of blocking antibody production. In this study, we aimed to investigate the effects of nuclear antigen-pulsed iDCs in the treatment of lupus-like renal damages induced by anti-dsDNA antibodies. METHODS: iDCs were generated from haemopoietic stem cells in bone marrow and then pulsed in vitro with nuclear antigen. The iDC vaccine and corresponding controls were injected into mice with lupus-like renal damages. The evaluation of disease was monitored by biochemical parameters and histological scores. Anti-dsDNA antibody isotypes and T-lymphocyte-produced cytokines were analysed for elucidating therapeutic mechanisms. RESULTS; The mice treated with antigen-pulsed iDCs had a sustained remission of renal damage compared with those injected with non-pulsed iDCs or other controls, including decreased anti-dsDNA antibody level, less proteinuria, lower blood urea nitrogen and serum creatinine values, and improved histological evaluation. Analysis on isotypes of anti-dsDNA antibody showed that iDC vaccine preferentially inhibited the production of IgG3, IgG2b and IgG2a. Furthermore, administration of antigen-treated iDCs to mice resulted in significantly reduced IL-2, IL-4 and IL-12 and IFN-γ produced by T-memory cells. Conversely, the vaccination of antigen-pulsed mature DCs led to increased anti-dsDNA antibody production and an aggravation of lupus-like disease in the model. CONCLUSIONS; These results suggested the high potency of iDC vaccine in preventing lupus-like renal injuries induced by pathogenic autoantibodies.     

A lupus-like syndrome associated with infliximab therapy

Infliximab, a chimeric monoclonal antibody targeting tumor necrosis factor alpha (TNF-alpha), is efficacious in the treatment of rheumatoid arthritis and Crohn's disease. We report in detail an unusual adverse reaction to infliximab therapy, a drug-induced lupus-like clinical syndrome. A 45-year-old woman with steroid-dependent Crohn's colitis, successfully managed with maintenance infliximab infusions and methotrexate, developed a lupus-like syndrome eight months after her initial infusion. This was characterized by inflammatory arthritis and an urticarial and papulosquamous rash and was accompanied by high titers of antinuclear, double-stranded DNA, glomerular-binding, and histone antibodies and by reduced levels of the C4 component of complement. After discontinuance of infliximab infusions and treatment of symptoms with intermittent courses of prednisone, the patient's arthritis progressively improved, with accompanying decrements in autoantibody titers. One year later, she has minimal joint discomfort and no rash or gastrointestinal symptoms despite also discontinuing prednisone and methotrexate. Infliximab therapy may cause a lupus-like syndrome that is reversible upon discontinuing this agent. These findings support recent evidence identifying TNF-alpha as an inhibitor of autoantibody formation.     

Hearing loss in patients with scleroderma: associations with clinical manifestations and capillaroscopy

Clinical Rheumatology - Systemic sclerosis is a multi-systemic disease with widespread small-vessel vasculopathy and fibrosis. Involvement of the middle and inner ear and hearing loss has been...     

An overview of controlled studies of adolescent substance abuse treatment.

Although several treatments for adolescents with substance use disorders are available, there are few well-controlled studies in the extant literature that compare these treatments for efficacy. This paper provides an overview of controlled treatment studies for adolescents with substance use disorders. It focuses specifically on five main treatment modalities: family-based and multi-systemic interventions, behavioral therapy, cognitive behavioral therapy, pharmacotherapy, and twelve step approaches. Examples of adolescent-specific standardized assessment instruments are also provided, the inclusion of which may improve future treatment comparison studies. While the results look especially promising for cognitive behavioral therapy and family-based/multi-systemic therapies for adolescents with SUDs, most of the relevant studies fail to utilize validated outcome measures, making it difficult to conclude that one treatment approach is more effective than another.     

Study of three patients with monoclonal gammopathies and ''lupus-like'' anticoagulants

In three patients with monoclonal gammopathies: a case of multiple myeloma, a case of monoclonal gammopathy of uncertain significance (MGUS) and a case of monoclonal gammopathy associated with lymphocytic lymphoma, we found the presence of a circulating lupus-like anticoagulant. Coagulative studies showed that the paraproteins: an IgG3k, an IgG1k and an IgMlambda, were responsible for the anticoagulant activity by interacting with the thromboplastin phospholipids. Using isoelectrofocusing we demonstrated that the three monoclonal immunoglobulins had a strong basic charge which may have contributed to determining their interaction with the acidic thromboplastin phospholipids. The binding of various phospholipids to the monoclonal proteins was assessed by the fluorescence quenching method which showed heterogeneous specificity. In order to establish whether the electrical charge is also relevant in cases with polyclonal lupus anticoagulant, the polyclonal immunoglobulins were fractionated according to their charge. The strongest inhibitor activity was found in the most basic immunoglobulins. Monoclonal lupus-like anticoagulants represent useful tools for investigating the heterogeneous world of polyclonal lupus-like anticoagulants.     

Increased NO production in lysinuric protein intolerance

Summary Lysinuric protein intolerance (LPI) is a disorder of dibasic amino acid transport secondary to mutation of the SLC7A7 gene characterized by renal failure, pulmonary alveolar proteinosis, lupus-like autoimmune symptoms and usually increased plasma citrulline. In order to better understand the underlying mechanism, we studied the plasma and urinary nitrite/nitrate (NO₂ ^-/NO₃ ^-) concentrations in three LPI patients and the in vitro NO₂ ^- production in cultured fibroblasts. Our data show that NO₃ ^- levels are increased in the plasma of patients with LPI. Similarly, NO₂ ^- release in the medium of cultured fibroblasts was increased. On this basis, we hypothesize that some of the poorly understood clinical signs of LPI could be related to the activation of the NO-citrulline pathway.     

Mechanisms of drug-induced lupus. III. Sex-specific differences in T cell homing may explain increased disease severity in female mice

Objective. To determine if sex-specific differences in lymphocyte trafficking could contribute to increased disease severity in female mice. Methods. A lupus-like disease was induced by injecting male and female mice with procainamide-treated T cell clones. Trafficking was examined by labeling the injected cells with ⁵¹Cr or 5-chloromethylfluorescein diacetate. Results. Females developed more autoimmune liver disease and greater titers of anti-DNA antibodies than did males, and 2-7 times more cells accumulated in the female spleens. Splenectomy prevented the development of autoantibodies and renal and liver disease. Oophorectomy decreased the splenic homing, autoantibody titer, and liver disease severity, to levels found in males. Conclusion. T cells traffic differently to the spleen in male and female mice, and the spleen appears to be essential in the disease process. This suggests that differences in T cell homing could contribute to sex-specific disease severity in this murine model, and also possibly in human disease.     

The prevalence and clinical associations of the lupus anticoagulant in systemic lupus erythematosus

To determine the prevalence and clinical associations of the lupus anticoagulant (LAC) in patients with systemic lupus erythematosus (SLE), we studied 74 patients with SLE, 6 with lupus-like disease and a heterogeneous group of 45 patients with various autoimmune diseases. LAC was demonstrated in 19 SLE patients (26%), 5 patients with lupus-like disease (83%) and in none of the other patients. Statistically significant associations were found between LAC and a history of thromboembolic events (p less than 0.001), fetal loss (p less than 0.001), thrombocytopenia (p less than 0.01), biologically false-positive VDRL test (p less than 0.02) and convulsions (p less than 0.05). A negative correlation was found between LAC and a history of butterfly rash (p less than 0.01) and the presence of antibodies against extractable nuclear antigen (p less than 0.01). No significant difference was found between LAC-negative SLE patients and patients with other autoimmune diseases with respect to the prevalence of thromboembolic events or fetal loss. We conclude that LAC is a useful marker to identify a subset of patients with SLE or lupus-like disease at risk of thromboembolic events, fetal wastage, and thrombocytopenia.     

Outcome of primary antiphospholipid syndrome in childhood

The objective of this paper is to investigate the long-term outcome of primary antiphospholipid syndrome (APS) in the paediatric age. The features of unselected patients with primary APS who had disease onset before the age of 16 years were retrospectively analysed in three Italian referralcentres. Clinical and laboratory manifestations were assessed to establish whether, at the end of follow-up, the final diagnosis was still primary APS or whether they had developed definite SLE or lupus-like syndrome. Fourteen patients, nine boys and five girls, who had the presenting clinical manifestation of APS between three and 13 years of age (median nine years) and were followed for two to 16 years (median six years). Six patients presented with deep vein thrombosis, five with cerebral stroke, two with peripheral artery occlusion and onewith myocardial infarction. During follow-up, four patients had one or more recurrences of vascular thrombosis. At last observation, 10 patients could still be classified as having primary APS, two had developed SLE, one lupus-like syndrome and one Hodgkin's lymphoma. In conclusion; our analysis suggests that some children who present with the features of primary APS may progress to develop SLE or lupus-like syndrome.     

Severe B cell hyperplasia and autoimmune disease in TALL-1 transgenic mice

TALL-1/Blys/BAFF is a member of the tumor necrosis factor (TNF) ligand superfamily that is functionally involved in B cell proliferation. Here, we describe B cell hyperplasia and autoimmune lupus-like changes in transgenic mice expressing TALL-1 under the control of a beta-actin promoter. The TALL-1 transgenic mice showed severe enlargement of spleen, lymph nodes, and Peyer's patches because of an increased number of B220+ cells. The transgenic mice also had hypergammaglobulinemia contributed by elevations of serum IgM, IgG, IgA, and IgE. In addition, a phenotype similar to autoimmune lupus-like disease was also seen in TALL-1 transgenic mice, characterized by the presence of autoantibodies to nuclear antigens and immune complex deposits in the kidney. Prolonged survival and hyperactivity of transgenic B cells may contribute to the autoimmune lupus-like phenotype in these animals. Our studies further confirm TALL-1 as a stimulator of B cells that affect Ig production. Thus, TALL-1 may be a primary mediator in B cell-associated autoimmune diseases.     

Tocainide-associated neutropenia and lupus-like syndrome

Neutropenia in association with a lupus-like illness that developed after the introduction of tocainide therapy is described. The mechanism of drug-associated neutropenia and the manifestations of drug-associated lupus are briefly discussed.     

Non-invasive diagnosis and follow-up of rare genetic liver diseases

Rare genetic liver diseases can result in multi-systemic damage, which may compromise the patient's prognosis. Wilson's disease and alpha-1 antitrypsin deficiency must be investigated in any patient with unexplained liver disease. Cystic fibrosis screening of new-borns is now implemented in most high-prevalence countries. The diagnosis of these diseases can be strongly suggested with specific non-invasive tests. Molecular analysis gene for these diseases is long and tedious but is recommended to confirm the diagnosis and help for the family screening. Liver biopsy is not systematic and is discussed when it helps diagnosis. Currently, for these three diseases, non-invasive fibrosis markers could identify patients with risk of cirrhosis and complications. Rare genetic liver diseases can result in multi-systemic damage, which may compromise the patient's prognosis. Wilson's disease, must be investigated in any patient with unexplained liver disease and/or unexplained neurological or neuropsychiatric disorders. The diagnosis is based on a combination of clinical, biological features, including copper balance. The exchangeable copper/total copper ratio is a new sensible and specific biological marker, useful for the diagnosis of the disease. Timely diagnosis and treatment will prevent serious complications from the disease. Neurological evaluation and familial screening are essential in patients with Wilson's disease     

Mechanisms of drug-induced lupus. IV. Comparison of procainamide and hydralazine with analogs in vitro and in vivo

Objective. T cells treated with DNA methylation inhibitors overexpress lymphocyte function-associated antigen 1 (LFA-1), which results in autoreactivity, and the autoreactive cells cause a lupus-like disease in vivo, suggesting a mechanism by which some agents may cause drug-induced lupus. This study compared the effects of procainamide (Pca) and hydralazine (Hyd) with those of structural analogs, to determine if the degree of LFA-1 overexpression and T cell autoreactivity correlated with the ability of the agents to induce autoimmunity. Methods. Cloned murine T helper 2 cells were treated with Pca, N-acetylprocainamide, Hyd, Phthalazine, or hydroxyurea (HU). The treated cells were then compared for LFA-1 overexpression, autoreactivity, and the ability to induce autoimmunity in vivo. Results. Pca and Hyd were more potent than their analogs or HU in all 3 assays. Conclusion. The results support a relationship between LFA-1 overexpression, T cell autoreactivity, and autoimmunity, and suggest a mechanism by which Pca and Hyd, but not the analogs, may cause drug-induced lupus.