bluuebunny/crossref_metadata_2025 huggingface dataset:
Morphologic capillary changes and manifestations of connective tissue diseases in patients with primary biliary cirrhosis
Authors: Fonollosa V , Simeón C P , Castells L , Garcia F , Castro A , Solans R , Lima J , Vargas V , Guardia J , Vilardell M
Published: November 2003

The objective of this study was to investigate the presence of nailfold capillary abnormalities and extrahepatic signs of connective tissue disease in patients with primary biliary cirrhosis (PBC), as compared to patients with other chronic liver diseases.

We evaluated 22 patients with PBC and 15 patients with other chronic liver diseases as a control group. Nailfold capillaroscopy was performed by two observers blinded to clinical findings using a Wild M3 stereomicroscope with an Intralux 5000 Volpi cold light lamp.

We detected nailfold capillary abnormalities in 20 out of 22 (91%) PBC patients. Twelve of these 20 patients (54%) showed capillary alterations characteristic of systemic sclerosis. In the control group only two out of 15 patients (13%) presented alterations and in both cases they were a nonspecific type. The presence of nailfold capillary abnormalities was significantly greater in PBC patients than in the control group (P < 0.001). Eleven out of the 22 PBC patients (50%) had extrahepatic signs of connective tissue disease and most of them were related to systemic sclerosis; patients with other chronic liver diseases did not present rheumatic manifestations (P < 0.001). In PBC patients there was a significant association between systemic sclerosis capillary pattern and rheumatic manifestations (P < 0.03).

The high prevalence of nailfold capillary abnormalities characteristic of systemic sclerosis in patients with PBC and the correlation with sclerodermal manifestations suggests that this capillaroscopic finding could be a useful indicator to investigate rheumatic manifestations in these patients.
Titration emulation: a computer-assisted technique that simplifies the quantification of anti-dsDNA antibodies using the Crithidia luciliae assay
Authors: Satoh M , Behney K M , Mizutani A , Richards H B , Hutson A D , Reeves W H
Published: November 2003

Titers of anti-double-stranded (ds) DNA antibodies in sera from patients with systemic lupus erythematosus (SLE) using the Crithidia luciliae assay method were compared by conventional titration vs the titration emulation method (ImageTiter1) to evaluate whether the latter assay can replace manual titration. Titers by the two methods were identical or within one dilution in 98% (41=42) of samples. A single sample showed a two-dilution difference. Titration emulation showed a tendency to under-estimate the titer of high titer anti-dsDNA samples, although the difference was small. Titration emulation is a suitable alternative to the conventional titration method, offering an accurate and cost-effective approach to quantification of anti-dsDNA antibodies.
CTLA-4 gene polymorphism in promoter and exon-1 regions in Chinese patients with systemic lupus erythematosus
Authors: Liu M-F , Wang C-R , Lin L-C , Wu C-R
Published: November 2003

Cytotoxic T lymphocyte associated antigen 4 (CTLA-4), a structural homologue of CD28, has been reported to be an important negative regulator of autoimmune diseases. Recent studies showed that CTLA-4 gene polymorphism was associated with several kinds of human autoimmune diseases, suggesting that CTLA-4 gene is probably a general susceptibility gene to autoimmune disease. The present study was conducted in Chinese to determine whether there is any association of the CTLA-4 gene polymorphism with the development of systemic lupus erythematosus (SLE). CTLA-4 gene polymorphism in promoter and exon 1 was detected by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) method in 81 patients with SLE and 81 normal controls. The results showed that there were no statistically significant differences in both exon 1 and promoter gene polymorphism between SLE patients and normal controls. The preliminary study does not suggest an association of the known polymorphism in exon 1 and promoter of CTLA-4 gene with Chinese SLE. However, SLE is a very heterogeneous syndrome and CTLA-4 gene polymorphism might correlate with some specific clinical features. To exploring this possibility, subgroup analysis in more patients needs to be performed.
Ulcerating plantar keratoderma in association with systemic lupus erythematosus
Authors: Grossberg E B , Scherschun L , Fivenson D P
Published: November 2003

This report highlights the finding of ulcerative plantar keratoderma in two patients with systemic lupus erythematosus (SLE). Both patients suffered from painful plantar ulcerations and fissures; in one patient there was diffuse desquamation over the entire plantar surface, while the other patient's lesions were focal and accentuated over weight-bearing surfaces. Other etiologies for keratoderma including papulosquamoua disease, contact dermatitis, tinea and primary keratodermas were excluded. Both patients were resistant to multiple topical therapies including super-potent topical corticosteroids, vitamin D analogues and retinoids, but did report moderate relief with hydrocolloid dressings applied over super-potent topical corticosteroids and pressure off-loading measures. Lupus-associated keratoderma can be recurrent and recalcitrant to treatment, often necessitating aggressive therapy and particular attention to advanced wound care methodologies. While not a specific cutaneous sign of lupus, it should be recognized as a cause for considerable morbidity.
Grand Rounds from International Lupus Centres Protein-losing enteropathy in a young African-American woman with abdominal pain, diarrhea and hydronephrosis
Authors: Gornisiewicz M , Rodriguez M , Smith J K , Saag K , Alarcón G S
Published: November 2003

The case ofa 21-year-old African-American woman who presented with abdominal pain, diarrhea and hydronephrosis and who proved to have protein-losing enteropathy secondary to systemic lupus erythematosus is discussed. This is an unusual complication oflupus.
Dual binding capabilities of anti-double-stranded DNA antibodies and anti-ribosomal phosphoprotein (P) antibodies
Authors: Takeda I , Rayno K , Movafagh F B , Wolfson-Reichlin M , Reichlin M
Published: November 2003

The aimof this study is to identify distinctive properties of pathogenic anti-double stranded DNA antibodies and anti-ribosomal P antibodies.

The binding activity of anti-dsDNA and anti-ribosomal P antibodies to their cognate antigens in 0.15 M and 1.5 M NaCl solutions on ELISA was examined. All anti-dsDNA and anti-ribosomal P antibodies exhibited a loss of their binding activity from37.5 to 100% and from2.3 to 97.4% in high ionic strength buffers, respectively. In contrast, anti-U1RNP antibodies and anti-Ro/SSA antibodies lost from0 to 32.7% and from0 to 40.1% of their binding activity, respectively. Anti-dsDNA and anti-ribosomal P antibodies from patients with nephropathy showed significantly higher binding activity in high ionic strength buffers than those frompatients without nephropathy. Study of paired sera fromlupus nephritis patients revealed that anti-dsDNA and anti-ribosomal P antibodies frompatients during disease flare show stronger binding activity in high ionic strength buffer than those during remission. Most anti-dsDNA and anti-ribosomal P antibodies bind their antigens by ionic interactions that are sensitive to high salt. Such dual binding capability of anti-dsDNA and anti-ribosomal P antibodies may underlie their multiple cross reactivities to various epitopes and help elucidate the pathogenic potential of autoantibody subsets.
Fas expression on peripheral blood lymphocytes in systemic lupus erythematosus (SLE): relation to lymphocyte activation and disease activity
Authors: Bijl M , Horst G , Limburg P C , Kallenberg C GM
Published: November 2003

Levels of apoptotic lymphocytes have been found to be increased in SLE and persistence of apoptotic cells has been associated with autoantibody production. Increased lymphocyte Fas (CD95) expression due to lymphocyte activation may account for increased susceptibility to Fasmediated apoptosis in SLE.

Flowcytometry was performed to evaluate membrane expression of Fas in combination with the activation markers CD25, HLA-DR and CD38 on, respectively, CD4+, CD8+ and CD19+ lymphocytes of SLE patients with inactive (n = 20) and with active disease (n = 13). SLEDAI-scores were calculated. Healthy volunteers (n = 14) served as controls.

Percentages of CD4+ T-cells expressing CD25 and CD19+ B-cells expressing CD38 were increased in patients with active disease compared to controls (P = 0.03, P = 0.04, respectively). In contrast to CD4+ and CD8+ cells, percentages of CD19+ cells expressing Fas were increased in SLE patients with active disease (P = 0.0002 vs controls). In these patients percentages of cells double positive for both CD38 and Fas were increased compared to patients with inactive disease (P = 0.006) and controls (P = 0.0007). Percentages of CD19+ cells expressing Fas correlated with SLEDAI-scores.

In SLE patients, percentages of Fas-expressing B-lymphocytes are increased, are related to the state of lymphocyte activation, and correlate to disease activity. Increased Fas expression results in a higher susceptibility for Fas-mediated apoptosis, which might contribute to the increased levels of apoptoticlymphocytes in SLE patients.
Anticardiolipin antibodies are not associated with rheumatic heart disease
Authors: Ilarraza H , Márquez M F , Alcocer A , Bañales J L , Nava A H , Reyes P A
Published: November 2003

The aim of this study was to examine the prevalence of anticardiolipin antibodies in rheumatic valve heart disease.

Serum samples of 31 consecutive patients with rheumaticheart disease and documented valve involvement, as well assix patients with acute rheumatic fever were tested for IgGanticardiolipin antibodies by a validated ELISA. No anticardiolipin antibodies were found when a cut-off point set at mean 5 s.d. was applied.

We can conclude that anticardiolipin antibodies are notpresent in rheumatic heart disease patients and, as suggested by several observations, these antibodies do not appear to have a pathogenic role in this particular disease.
Spontaneous rupture of the spleen: an unusual complication of systemic lupus erythematosus
Authors: Karassa F B , Isenberg D A
Published: November 2003

Although splenicabnormalities are widely recognised in patients with lupus, spontaneous rupture of the spleen is rare. We describe a patient whose spleen ruptured spontaneously 19 years after the onset of her disease, and comparethis case with four others that have been described in theprevious literature. Possible contributing factors to this rupture are discussed.
Chorioretinopathy and discoid plaque-like lesions of the eyelids as useful indicators of systemic lupus erythematosus (SLE) progression
Authors: Paroli M P , Riso D , Pinca M , Pivetti-Pezzi P
Published: November 2003

Choroidal involvement in systemic lupus erythematosus (SLE) occurs infrequently. We report a 45-y-old woman with bilateral chorioretinopathy associated with SLE. Diagnosis was performed using indirect ophthalmoscopy, retinal fluorescein angiography (FA) and green indocianin angiography (ICG). In this patient chorioretinopathy and discoid-like plaque of the lids represented the only signs of SLE progression after 15 y of apparent remission of systemic disease.
Association of b2-glycoprotein I IgG and IgM antibodies with thrombosis and thrombocytopenia
Authors: Voss A , Jacobsen S , Heegaard N HH
Published: November 2003

Antiphospholipid antibodies (APA) have been known for decades. Their relation to clinical manifestations, primarily thromboses and thrombocytopenia, was recognised in the 1980s. In this clinical study two cohorts of patients, a population-based (84 patients with systemic lupus erythematosus (SLE)) and a hospital-based (87 patients with SLE and 53 with other connective tissue diseases) were investigated for APA and associated clinical manifestations. Anticardiolipin antibodies (ACA) of IgG and IgM classes were found in 13 and 38% of the population-based patients and in 29 and 58% of the hospital-based patients, respectively. The corresponding figures for antibodies against b2-glycoprotein I (anti-b2GPI) were 15 and 10% in the population-based patients and 14 and 8% in the hospital-based cohort. Anti-b2GPI antibodies were always found in association with the corresponding immunoglobulin class of ACA. In both cohorts anti-b2GPI of the IgG class were associated with arterial/venous occlusion, a result concordant with other studies. A novel finding in both cohorts, however, was an association between thrombocytopenia and IgM anti-b2GPI.
Autoreactive murine Th1 and Th2 cells kill syngeneic macrophages and induce autoantibodies
Authors: Yung R , Kaplan M , Ray D , Schneider K , Mo R-R , Johnson K , Richardson B
Published: November 2003

D10 cells, a cloned Th2 line, become autoreactive following treatment with DNA methylation inhibitors like 5-azacytidine (5-azaC), and induce anti-DNA antibodies if injected into unirradiated syngenic mice. The mechanism by which the autoreactive cells break tolerance is unknown. To further define effector functions required, we asked if 5-azaC-treated Th1 cells could also induce autoimmunity. AE7 cells, a cloned Th1 line, were treated with 5-azaC and shown to become autoreactive and induce anti-DNA antibodies in vivo. Comparison of effector mechanisms demonstrated that the two cell lines secreted a distinct repertoire of cytokines, and that only killing of syngeneic Mù was common to both AE7 and D10 cells. This suggests that Mù killing may be an early step in the induction of anti-DNA antibodies, providing antigenic nucleosomes and decreasing clearance of apoptotic material. Secretion of cytokines promoting B cell differentiation may play a role, but no one cytokine is required.
Can B cell epitopes of 60 kDa Ro distinguish systemic lupus erythematosus from Sjögren's syndrome?
Authors: Scofield A N , Kurien B T , Gordon T P , Scofield R H
Published: November 2003

Antibodies binding components of the Ro/La (or SSA/SSB) ribonucleoprotein particle are found in the sera of patients with systemic lupus erythematosus (SLE) and Sjögren's syndrome (SS) as well as mothers who give birth to babies with neonatal lupus. Anti-La occurs in a subset of sera that contain anti-Ro, and anti-La is found more commonly in sera of patients with SS than in sera from SLE patients. The fine specificity of autoantibodies binding 60 kDa has been studied extensively. Recent data have suggested that there are disease-specific epitopes which identify patients with either SLE or SS. Alternatively, other data suggest that the B cell epitopes of 60 kDa Ro vary according to the presence of anti-La. The present study was undertaken to determine whether binding of putative disease-specific 60 kDa Ro epitopes is associated with the diagnosis of SLE vs SS, or instead associated with the presence of anti-La. Anti-60 kDa Ro positive sera from 24 SLE patients and 44 SS patients were studied for antibodies binding two epitopes of 60 kDa Ro. We find the epitope defined by residues 171–190 is associated with anti-60 kDa Ro without anti-La, regardless of diagnosis. Meanwhile, binding of the epitope defined by residues 215–232 is not commonly found in anti-60 kDa Ro sera, especially in those sera with both anti-60 kDa Ro and anti-La. Thus, the fine specificity of antibody binding to 60 kDa Ro varies according to the presence of anti-La, not to the diagnosis of either SLE or SS.
Suppression of renal disease and mortality in the female NZBNZW F1 mouse model of systemic lupus erythematosus (SLE) by chenodeoxycholic acid
Authors: Suwannaroj S , Lagoo A , McMurray R W
Published: November 2003

The objective of this study was to examine the effects of ursodeoxycholic (UDCA) and chenodeoxycholic acid (CDCA) on autoimmune disease in the NZBNZW F1(B =W) mouse model of systemic lupus erythematosus (SLE).

The development of murine lupus was assessed in female B/W mice given UDCA or CDCA. At 6 week intervals mice were examined for weight change, albuminuria, anti-DNA antibody and total IgG levels. Morbidity and mortality were assessed daily. UDCA-and CDCA-treated mice were examined at 24 weeks of age for serum cytokines, lymphocyte phenotype, and in vitro cytokine production after immunization with DNP-KLH. Liver and kidneys were examined histopathologically.

The administration of UDCA and CDCA was tolerated without side effects. Weight gain in UDCA-or CDCA-treated and control mice was identical through 24 weeks of age. CDCA, but not UDCA, suppressed the development of renal disease. CDCA-treated B/W mice also had improved survival compared to UDCA-treated or control B/W mice. There were no significant effects of CDCA on anti-DNA antibodies, serum total IgG, or other immunologic parameters. CDCA-treated mice had lower serum IFN-g concentrations compared to control and UDCA-treated mice.

The bile acid, CDCA, significantly inhibited the development of renal disease and modestly prolonged lifespan in the female B/W mouse model of SLE. Suppression of glomerulonephritis was associated with lower serum IFNg concentrations. Further investigation is needed to verify potential mechanisms of action, but these findings suggest that bile acids may alter the development or progression of autoimmunity.
Antiphospholipid antibody levels in intravenous immunoglobulin (IVIg) preparations
Authors: Sherer Y , Wu R , Krause I , Peter J B , Shoenfeld Y
Published: November 2003

The antiphospholipid syndrome (APS) is characterized by various clinical manifestations and by elevated levels of antiphospholipid antibodies. Passive induction of APS by infusion of these antibodies has been demonstrated in animal models. Intravenous immunoglobulin (IVIg) is one of the therapeutic options in APS. In this study, five commercially used preparations of IVIg were tested for the presence of elevated levels of cardiolipin,β-glycoprotein-I, phosphatidylserine, antinuclear, and double-stranded DNA autoantibodies, as well as for lupus anticoagulant activity. The absence of abnormal elevated levels of any of these autoantibodies in five different IVIg preparations provides additional evidence for the safety of IVIg use in APS.
Polymorphisms of the human prolactin gene—implications for production of lymphocyte prolactin and systemic lupus erythematosus
Authors: Stevens A , Ray D W , Worthington J , Davis J RE
Published: November 2003

Hyperprolactinaemia is associated with systemic lupus erythematosus (SLE) but the mechanism is unknown. Prolactin is expressed not only by pituitary lactotrophic cells but also by T-lymphocytes under the control of an alternative upstream promoter region. T-lymphocytes from SLE patients have been shown to secrete more prolactin than controls, thus implying a possible underlying difference in regulation. This may be due to genetic polymorphism that can be determined by scanning for mutations and using a variety of methods to determine their function. A polymorphism may also be used in disease association studies as it may be in linkage disequilibrium with a disease gene on the same haplotype. Single nucleotide polymorphisms (SNPs) have been found across the prolactin gene region including the extrapituitary and the pituitary promoter regions. These SNPs have been examined for genetic association with SLE and potential effects upon the function of the gene.

One SNP in the lymphocyte specific upstream promoter affects prolactin transcription and disease association studies in a cohort of SLE cases demonstrated an increased frequency of the PRL-1149 G allele compared to control subjects. This indicates a possible mechanism for the association of prolactin with SLE. Although prolactin is likely to be one of several predisposing factors in the pathogenesis and progression of SLE, this suggests that manipulation of lymphocyte prolactin production (rather than pituitary production) might be a useful therapeutic approach.
Prolactin, a lymphocyte growth and survival factor
Authors: Buckley A R
Published: November 2003

Evidence accumulated over the past 20 y indicates that the anterior pituitary hormone, prolactin (PRL), is a critical, physiologically relevant immunomodulator. Results from early hormone-ablation studies in animals implicated PRL as a factor that contributes to maintenance of immunocompetence. However, the discovery of PRL receptors on T and B lymphocytes and the observation that these cells synthesize and secrete PRL spurred intensive investigation into the actions and underlying mechanisms triggered by the hormone in the immune system. In numerous cell culture systems, PRL was found to act as a co-mitogen, enhancing the efficacy of plant lectins and cytokines in the stimulation of lymphocyte proliferation. In addition, results from more recent studies suggest that PRL may promote survival of certain lymphocyte subsets presumably due to its capacity to augment expression of anti-apoptotic genes. In this review, we focus on the proliferative actions of PRL and its survival promoting properties in immune cells.
Effects of prolactin on hematopoiesis
Authors: Welniak La , Richards Sm , Murphy Wj
Published: November 2003

The presence of extra-pituitary prolactin and its cognitive receptors in the hematopoietic micro-environment raises the question of whether prolactin plays a role in lympho-hematopoiesis and under what conditions. Current studies suggest that endogenous prolactin does not play a signifycant role under normal steady-state conditions. Rather, prolactin has been implicated as a `stress hormone', functioning to restore hematopoietic homeostasis under conditions of dysregulation. The stress response of prolactin as well as its complex relationship with other hormones and factors has resulted in confiicting reports in the literature regarding prolactin's role in lympho-hematopoiesis. A review of this literature is provided as well as discussion of conditions under which lymphohematopoietic activity of prolactin may be evident. Lupus (2001) 10, 700±705.
Prolactin receptor signal transduction
Authors: Clevenger C V , Kline J B
Published: November 2003

Within the immune system, multiple isoforms of the human prolactin receptor (PRLr) serve to mediate the effects of its ligand (PRL). Now numbering four, these isoforms are structurally and functionally distinct, demonstrating significant differences in ligand affinities, kinetics of transduction and the transduction proteins activated. The proximal transduction pathways activated during PRLr-associated signaling include the tyrosine kinases Jak2, Fyn and Tec, the phosphatase SHP-2, the guanine nucleotide exchange factor Vav, and the signaling suppressor SOCS. Differential activation of these pathways may contribute to the pleiotropism of PRL action in tissues of the immune system.
Effects of prolactin on signal transduction and gene expression: possible relevance for systemic lupus erythematosus
Authors: Hooghe R , Dogusan Z , Martens N , Velkeniers B , Hooghe-Peters E L
Published: November 2003

Receptors for prolactin (PRL-R) are expressed in normal leukocytes from rat and man. PRL signals through PRL-R associated Janus tyrosine kinase (Jak)-2 and signal transducers and activators of transcription (Stat). In addition, in human leukocytes PRL also activates the p38 MAP kinase pathway. PRL, at physiological concentrations, stimulates the expression of the interferon regulatory factor (IRF)-1 gene in rat spleen and bone marrow cells. In man, genes induced by PRL include several members of the `suppressors of cytokine signaling' (SOCS) family and inducible nitric oxide synthase (iNOS; in mononuclear cells and in granulocytes) and IRF-1 (in granulocytes). Thus, in normal leukocytes, PRL induces the expression of several genes relevant to innate and acquired immune responses.

Sex hormones, such as estrogen and PRL, have been implicated in the pathogenesis of murine and human SLE. Also defective signaling in leukocytes is a feature of the disease. What the origin is of aberrant signaling processes in SLE lymphocytes and how they relate to tolerance breakdown and immunopathology is still unknown. It is not unlikely that PRL is a player at some level. The exact contribution of PRL to immune responses in normal subjects and in SLE patients is not known. Further work should also indicate whether PRL might contribute to the onset or progression of the disease and assess the possible benefits of manipulating PRL concentrations in patients.
Effect of prolactin on the antigen presenting function of monocyte-derived dendritic cells
Authors: Matera L , Mori M , Galetto A
Published: November 2003

Monocyte derived macrophages (Mf) and dendritic cells (DC) play critical roles at the interface between innate and adaptive immunity. Both types of cells can effectively phagocytose exogenous antigens, whereas only DC can process and present them efficiently to antigen-specific T lymphocytes. The hormone PRL is also produced by immune cells and is regarded as a key component of the neuroendocrine–immune loop and a local regulator of lymphocyte response. Its main feature is cooperation with cytokines and hemopoietins. Triggering of monocyte PRL receptors with physiological-to-supraphysiological concentrations of PRL up-regulates the GMCSF receptors, resulting in synergistic PRL-GM-CSF induced maturation of immature (i)DC. Further incubation induces increased antigen-presenting activity at the highest PRL concentrations studied (200 ng/ml). IFN-g release by allogeneic lymphocytes is dependent on T cell-triggered IL-12 release by PRL-preincubated iDC. This, in turn, may be secondary to increased DC expression of CD40 or IFN-g. The permissive action of high PRL concentrations in the antigen presenting process may be of significance in initiation of the response against major histocompatibility complex (MHC)-presented self-antigens and may explain the association of hyperprolactinemia with autoimmune diseases.
Anti-dsDNA antibody avidity determination by a simple reliable ELISA method for SLE diagnosis and monitoring
Authors: Villalta D , Romelli P B , Savina C , Bizzaro N , Tozzoli R , Tonutti E , Ghirardello A , Doria A
Published: November 2003

High avidity anti-dsDNA antibodies are more specific for SLE diagnosis, and more closely associated with renal involvement than intermediate or low-affinity anti-dsDNA antibodies. ELISA methods are largely used to detect anti-dsDNA, but their high sensitivity is inversely related to specificity because they also detect low avidity antibodies.We developed an ELISA assay based on the law of mass action and the competitive binding of dsDNA in solution and coated to microwells with anti-dsDNA antibodies. A simplified Scatchard plot analysis system was used to measure anti-dsDNA antibody avidity which was expressed as apparent affinity constant (Kaa), and quantified in liters per unit (l=U).

We prospectively studied 101 consecutive SLE patients, who were followed for 3 years; three serum samples were sequentially collected from each patient during follow-up for determination of IgG anti-dsDNA antibody concentration, and anti-dsDNA avidity. SLE disease activity was estimated using the European Consensus Lupus Activity Measure (ECLAM) index. Sera from 100 healthy subjects and 133 patients with other connective tissue diseases or infectious diseases were also assayed as controls.

The mean Kaa in SLE patients was 65.2±47.3 l=U, with no variations over time. Anti-dsDNA-positive SLE patients had higher Kaa values (79.1±46.8) than anti-dsDNA negative patients (27.2±20.1; P < 0.001). No correlation emerged between anti-dsDNA avidity and the ECLAM activity index score. Avidity was significantly higher in patients with renal involvement vs patients without this complication (78.2±50 vs 59.9±45.6 l=U; P = 0.0013).

This simple ELISA method could be very useful in the diagnostic phase to differentiate high avidity anti-dsDNA autoantibodiesthat are characteristicallyfound in SLE patients from low avidity antibodies that can also be found in other inflammatory diseases. Moreover, our data confirm the predictive value of high avidity anti-dsDNA antibodies for the development of lupus nephritis.
Anti-β2-glycoprotein I autoantibodies require an antigen density threshold, consistent with divalent binding
Authors: Reddel S W , Wang Y X , Krilis S A
Published: November 2003

Autoantibodies binding β2-glycoprotein I (B2GPI) are an important finding in the antiphospholipid syndrome. While antibodies from mice or rabbits immunized with B2GPI readily bind B2GPI coated on a polystyrene microwell plate, anti-B2GPI autoantibodies only do so when using a modified microwell plate with a negatively charged surface.

This study demonstrates that, for the detection of anti-B2GPI autoantibodies in an ELISA using modified plates, an antigen coating concentration threshold exists, such that minimal or no binding occurs below a certain coating concentrationof antigen, even though antigen is easily demonstrable on the plate. This is consistent with the hypothesis that autoantibodies require divalent binding to B2GPI for detection, as sufficient antigen density for two protein molecules to be sufficiently close to enable divalent binding would only be expected to occur at higher coating concentrations.

Several mutant forms of B2GPI developed for epitope determination experiments are shown to have decreased binding to microtitre plates compared to wild-type. If wild-type and mutants are assayed for antibody binding near the threshold a significant diminution in binding to mutants occurs that is the result of inadequate binding to the plate, but could be misinterpreted as the result of interruption of an epitope by the mutation.
Proposal for a new definition of congenital complete atrioventricular block
Authors: Brucato A , Jonzon A , Friedman D , Allan L D , Vignati G , Gasparini M , Stein J I , Montella S , Michaelsson M , Buyon J
Published: November 2003

The classic old definition of congenital heart block by Yater (1929) is still generally accepted: ‘Heart block establishedin a young patient. There must be some evidenceof the existenceof the slow pulse at a fairly early age and absence of a history of any infection which might cause the condition after birth: notably diphtheria, rheumatic fever, chorea and congenital syphilis’. However, other definitions are used. We systematicallyreviewed 1825 cases from 38 separatestudies. We conclude that complete AV blocks detected in utero in the absence of structural abnormalities differ from blocks detected later in life with respect to pathogenesis (they are generally associated with maternal anti-Ro/SSA antibodies), poorer childhood prognosis, increased risk of developing late-onset dilated cardiomyopathy, different maternal clinical features and increased risk of recurrence in future pregnancies.For these reasons we propose a new modern definition of congenitalcomplete AV block which might be acceptable to cardiologists, rheumatologists, pediatricians and obstetricians: ‘an AV block is defined as congenital if it is diagnosed in utero, at birth or within the neonatal period (0-27 days after birth)’.
Neuronal-binding antibodies from patients with antiphospholipid syndrome induce cognitive deficits following intrathecal passive transfer
Authors: Shoenfeld Y , Nahum A , Korczyn A D , Dano M , Rabinowitz R , Beilin O , Pick C G , Leider-Trejo L , Kalashnikova L , Blank M , Chapman J
Published: November 2003

Antiphospholipid antibodies (aPL) have been suggested to play a role in causing cognitive and behavioral impairments. In the present study we investigated the pathogenic potential of aPL by intracerebro-ventricular (ICV) administration of immunoglobulins (IgG) from patients with antiphospholipid syndrome (APS). IgG, purified from the sera of four APS patients, was tested for binding to normal mouse brain by immunohistological staining. These IgG (7.5 m g) were injected ICV unilaterally to male C3H mice. Mice injected with IgG purified from pooled sera derived from healthy subjects served as controls. The mice were examined neurologically for motor function and coordination, and cognitively in a Morris water maze. The cognitive tests were performed with the experimenterblinded to the treatment. The performance of the mice in four separate experiments was compared by analysis of variance with repeated measures. IgG from one APS patient was found to bind best to neuronal structures in the hippocampus and cerebral cortex. Mice (n 43) injected with this IgG performed worse in the water maze compared to the controls(n 45) with significant effects of the aPL IgG on the overall performance of the mice (treatment, P < 0.03), on learning throughout the experiment (treatment ×day, P < 0.02) and on short term memory (treatment ×day ×trial, P < 0.002). IgG injected from two of the three other patients also bound specifically to mouse brain neurons and produced an impairment in performance of the water maze. These results support the hypothesis that aPL that gain access to the central nervous system may play a direct role in the pathogenesis of neurological manifestations of APS.
Time perspective predicts the progression of permanent organ damage in patients with systemic lupus erythematosus
Authors: Sundaramurthy S , Bush T M , Neuwelt C M , Ward M M
Published: November 2003

Patients whose perspectiveis oriented to the future more than to the present may have better long-term health outcomes. We examined if time perspective predicted future organ damage in patients with systemic lupus erythematosus(SLE). We assessed the time perspectivesof 87 patients with SLE using a questionnaire at a baseline visit. Permanent organ damage was assessed by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) Damage Index during the same visit, and reassessed after a median of 4.6 years. Patients who were oriented more to the futurewere less likely to have an increasein the Damage Index than those oriented more to the present. In a multivariate analysis, each 1-point increase in the degree of orientation to the future (on a scale of 1-6) was associatedwith a 22% decreasein the likelihood that the Damage Index would increase over time (odds ratio 0.78; 95% confidence interval 0.64-0.94; P 0.009). Other measures that predicted an increase in the Damage Index were lower education levels, greater health locus of control attributed to chance and greater health locus of control attributed to powerful others. In conclusion, time perspective is a significant predictor of future organ damage in SLE. Patients who have a greater orientation to the future are less likely to develop permanent organ damage.
TNF-α: a link between hypertriglyceridaemia and inflammation in SLE patients with cardiovascular disease
Authors: Svenungsson E , Fei G-Z , Jensen-Urstad K , de Faire U , Hamsten A , Frostegård J
Published: November 2003

Patients with systemic lupus erythematosus (SLE) are at high risk of cardiovascular disease (CVD). Tumour necrosisfactor-a (TNF-α) has been implicatedin the pathophysiologicalprocessesof both SLE and CVD. This study focuses on the role of TNF-α and its soluble receptors in SLE-related CVD. In summary, 26 women (52 + 8.2 years) with SLE and a history of CVD (SLE cases)were compared with 26 age-matched women with SLE and no clinical manifestations of CVD (SLE controls) and 26 age-matched population-based control women (population controls). Plasma concentrations of circulating TNF-α, TNF-α receptor 1 (sTNFR1) and TNF-α receptor 2 (sTNFR2) were determined by ELISA. TNF-α, sTNFR1 and sTNFR2 were raised in SLE cases as compared to SLE controls ( P = 0.009; P = 0.001; P = 0.001, respectively), and SLE controls had higher levels than population controls ( P = 0.001; P = 0.02; P = 0.001, respectively). Exclusively in the SLE case group there was a striking positivecorrelationbetweenTNF-α and plasma triglycerides( r = 0.57, P < 0.002), VLDL triglycerides ( r = 0.54, P = 0.004) and VLDL cholesterol ( r = 0.58, P = 0.002). Furthermore, TNF-α correlated with the waist-hip ratio but not with estimated insulin resistance. TNF-α may thus be a major factor in SLE-related CVD acting both by contributing to hypertriglyceridaemia and by promoting atherosclerosis-relatedinflammation. sTNFR1 and sTNFR2 are strongly associated with CVD in SLE but their exact roles in disease development remain to be elucidated.
Prospective observational study of antiphospholipid antibodies in acute lung injury and acute respiratory distress syndrome: comparison with catastrophic antiphospholipid syndrome
Authors: Wiedermann F J , Lederer W , Mayr A J , Sepp N , Herold M , Schobersberger W
Published: November 2003

Detection of antiphospholipid (aPL) antibodies in bronchoalveolar lavage fluid (BALF) of patients with acute respiratory distress syndrome (ARDS) suggests involvement of autoimmune mechanisms in the pathogenesisof ARDS. We investigated whether aPL antibodies could be detected in the serum as well as BALF of patients with acute lung injury (ALI) and ARDS. IgG anticardiolipin, IgG anti-b2-glycoproteinI, IgG antiphosphatidicacid and IgG antiphosphatidylserineantibodieswere detected by ELISA in low titers within the normal range in the BALF and serum of nine patients with ALI and 17 patients with ARDS. However, one out of 27 patients investigatedhad high levelsof aPL antibodies in both BALF and serum. This patient suffered from severe ARDS due to sepsis. The high aPL antibodylevels in serum possibly triggered by sepsis were associated with high aPL antibody levels in BALF, which can be explained by high capillary-alveolar permeability. Computed tomography scan revealed widespread infarctions in brain, spleen and kidneys, and pulmonary thromboembolism, suggesting the diagnosis of catastrophic antiphospholipid syndrome.
Water intoxication induced by low-dose cyclophosphamide in two patients with systemic lupus erythematosus
Authors: Salido M , Macarron P , Hernández-García C , D’Cruz D P , Khamashta M A , Hughes G RV
Published: November 2003

Cyclophosphamide(CY) is an alkylating agent used to treat a variety of autoimmune disorders.Water intoxication is a well-known complication of high-dose intravenous (i.v.) CY, but is rare in patients treated with low dose i.v. CY. We describe two patients with lupus nephritis and water intoxication following low dose i.v. CY. The first patient was treated with oral prednisolone and azathioprine for eight weeks with inadequate response and persistent renal inflammatory activity. Eight hours after the first i.v. CY pulse she had a grand mal seizure. The second patient had WHO class III lupus nephritis, and after a single i.v. CY pulse developed vomiting, diarrhoeaand grand mal seizures.They were both fluid-restrictedand their serum sodium levels returned to normal. In conclusion, even at low doses i.v. CY may induce hyponatremiarelated to inappropriateantidiuretichormone secretion. This potentially life-threateningcomplication of i.v. CY could be minimized by avoidance of overhydrationfollowing pulse i.v. CY.
Lupus headaches in childhood-onset systemic lupus erythematosus: relationship to disease activity as measured by the systemic lupus erythematosus disease activity index (SLEDAI) and disease damage
Authors: Brunner H I , Jones O Y , Lovell D J , Johnson A M , Alexander P , Klein-Gitelman M S
Published: November 2003

The Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) is the most commonly used measure of disease activity for children with systemic lupus erythematosus(SLE). For headachesto be scored in the SLEDAI as a symptom of active disease, they have to be nonresponsive to narcotic analgesia. This may affect the overall estimation of disease activity, especially because headaches are common among children with SLE and narcotic analgesia is rarely used for headache therapy in paediatrics.Moreover, the importance of headaches for the developmentof damage and their relation to other clinical parameters and outcomes has not been well described for children with SLE. We reviewed the medical charts of an inception cohort of children (n 63) who were newly diagnosed with SLE. Information on headaches and other disease parameters was obtained. Disease activity and damage were measured using the SLEDAI and the Systemic Lupus International Collaboration Clinics/American College of Rheumatology Damage Index (SDI), respectively. It has been shown that the accumulatedburden of active disease as measured by serial SLEDAI scores over time is one of the best predictors of eventual damage to children with SLE. New-onset or significant increase of severe and/or persistent headaches (LHA) were reportedin 43% of the patients during a mean follow-up of 3.6 years. LHA occurred preferentiallyamong patients with elevated levels of antiphospholipid antibodies (aPL) (P < 0.02) and only 6% of all LHA episodes were treated with narcotics and thus considered for the measurement of disease activity in the SLEDAI. LHA were unrelated to proxy-measures of disease activity, such as the need to intensify therapies. When used in children, the insensitivity of the SLEDAI to capture LHA did not seem to decrease the responsiveness of the SLEDAI to detect clinically important worsening of disease, or negatively impact on its ability to predict damage.
Reversible acute gastrointestinal syndrome associated with active systemic lupus erythematosus in patients admitted to hospital
Authors: Lian T-Y , Edwards C J , Chan S-P , Chng H-H
Published: November 2003

Patients with systemic lupus erythematosus (SLE) frequently have gastrointestinal (GI) symptoms. These are usually self-limiting and related to treatment side-effects or concurrent illness. However, abdominal pain may be due to bowel ischaemia which can lead to infarction and perforation. The likelihood of these serious events is increased in individuals with pain severe enough to require assessment in hospital or a SLEDAI score > 5. This paper describes a group of patients with active SLE and GI symptoms severe enough to require admission to hospital using a retrospectivereview of 52 SLE patients admitted to hospital with acute abdominal symptoms. The results showed that abdominal pain (87%), vomiting (82%) and diarrhoea (67%) had been present for a mean of 4.4 + 6.5 days and SLEDAI score was ≥4 in 83% of patients. CT scanning showed evidence of serositis and bowel involvementin 63% of patients who underwent this investigation.Intravenous(iv) fluids were used in 87%, parenteral steroids in 90% and iv cyclophosphamidein 31%. Most (n 51) were discharged well. Recurrence of GI symptoms occurred in 12 patients. The conclusions are that active SLE may manifest as an acute gastrointestinal syndrome. Early diagnosis, bowel rest, supportive medical therapy and treatment with corticosteroids and/or immunosupressives can result in a good outcome.
The prevalence and clinical significance of autoantibodies to plasminogen activator inhibitor 1 in systemic lupus erythematosus
Authors: Bates R L , Payne S J , Drury S L , Nelson P N , Isenberg D A , Murphy J J , Frampton G
Published: November 2003

We have recently described the novel autoantigen plasminogen activator inhibitor (PAI-1) in systemic lupus erythematosus (SLE). The aim of this study was to determine the prevalence and clinical significance of anti-PAI-1 autoantibodiesin patients with SLE. Autoantibodies to recombinant PAI-1 were measured in retrospective sera of 48 lupus patients by immunoassay in order to assess their clinical significance. This showed that 71% of sera from 48 lupus patients had significantly elevated anti-PAI-1 autoantibodiesas compared with normal control subjects (P < 0.0001). There was a weak but significant (P < 0.043) correlation with anti-dsDNA autoantibodies. In longitudinal studies, autoantibodies against PAI-1 correlated with clinical parameters measured by the BILAG disease activity index including global clinical score. Our study demonstrates the high frequency of novel autoantibodies to PAI-1 in patients with lupus. The serial clinical correlations with anti-PAI-1 autoantibodies also support the hypothesis that these autoantibodies may play a pathogenic role in lupus.
Simultaneous identification of various antinuclear antibodies using an automated multiparameter line immunoassay system
Authors: López-Longo F J , Rodríguez-Mahou M , Escalona-Monge M , González C M , Monteagudo I , Carreño L
Published: November 2003

The objective was to determine the sensitivity and specificity of an automated multiparameter line immunoassay system compared with other techniques for the identification of autoantibodies in rheumatic diseases. We studied sera from 90 patients. Anti-U1RNP, anti-Sm, anti-Ro/SS-A, anti-La/SS-B, anti-Jo 1 and anti-Scl 70 antibodies were identified by counterimmunoelectrophoresis(CIE) techniques, enzyme-linked immunosorbent assay (ELISA), immunoblotting (IB) using extracts of rabbit thymus and human placenta, and an automated multiparameter line immunoassay system (INNO-LIA ANA UPDATE K-1090) that detects nine different antibodies simultaneously (anti-U1RNP, anti-Sm, anti-Ro/SS-A, anti-La/SS-B, anti-Scl 70, anti-Jo 1, anticentromere, antihistone, and antiribosomal P protein). The line immunoassay system equaled or surpassed the other techniques in the identification of anti-Sm, anti-La/SS-B, anti-Jo 1 and anti-Scl 70 antibodies (sensitivity 100%, specificity 94-100%) and was similarly effective in the case of anti-U1RNP (sensitivity 87.5%, specificity 93.9%) and anti-Ro/SS-A (sensitivity 91.4%, specificity 87.2%) antibodies. In addition, this technique detected more 52 and 60 kD anti-Ro/SS-A sera than IB. Nine antibodies can be detected with this method at a cost of 25.38€ per serum sample. In five hours, 19 sera can be studied.The approximatecost of detecting these nine antibodieswith an automatedELISA system would be 28.93€, which allows 10 sera to be studied in four hours. In conclusion, the automated multiparameter line immunoassay system is a valid method for the detection of autoantibodies in rheumatic diseases. Its most notable advantages are automated simultaneous detection of several autoantibodies in the same serum and its lower cost compared with ELISA techniques.
Neonatal lupus: fetal myocarditis progressing to atrioventricular block in triplets
Authors: Fesslova V , Mannarino S , Salice P , Boschetto C , Trespidi L , Acaia B , Mosca F , Cimaz R , Meroni P L
Published: November 2003

We report a case of neonatal lupus syndrome (NLS) in an in vitro fertilization induced triplet pregnancy. Echocardiographicsigns of myocarditiswere evident at the 21st week of gestation(w.g.) in twin I, with a subsequentdevelopmentof a complete atrioventricular(AV) block at the 25th w.g.; twin III also displayed echocardiographic signs of myocarditis at the same time. Treatment with dexamethasone (4mg/day) was started at the 25th w.g. A complete echocardiographicregression of the myocarditis signs was achieved, while AV block was unaffected.Caesarian section was performed at the 31.5 w.g. after a premature rupture of the membranes. Complete AV block was confirmed in twin I with a heart rate of 51beats/min that required a pacemaker implant 40 days after. Twin III developed a first-degree AV block that switched to a periodic second-degreeblock later, while twin II displayed only liver enzyme abnormalities.