bluuebunny/crossref_metadata_2025 huggingface dataset:
Anti-endothelial cell antibodies in the sera of hyperprolactinemic women
Authors: Krause I , Blumenfeld Z , Malchinsky M , Cohen S , Blank M , Eldor A , Weksler B , Schweitzer K , Shoenfeld Y
Published: November 2003

Prolactin (PRL) is closely associated with autoimmune diseases in animal models and humans, and several disease-related autoantibodies were reported in increased titers in patients with hyperprolactinemia (HPRL). We studied the presence of anti-endothelial cell antibodies (AECA) and other autoantibodies in sera of female patients with HPRL. Sera from 25 HPRL patients and 10 healthy female controls were tested for AECA (against both macrovascular and microvascular endothelial cell antigens), anti-dsDNA, and anti-cardiolipin (anti-CL) using ELISA. Sera were considered positive for the autoantibody when the optical density (OD) value was more than 3 s.d. above the mean of the OD in normal controls. Sera from 13 patients were obtained repeatedly during dopaminergic anti-PRL treatment, to relate PRL level or anti-PRL treatment with the autoantibody levels. Elevated micro and/or macrovascular AECA were observed in sera from 19=25 patients (76%). Elevated titers of anti-CL Abs, all b2-GPI-dependent, and low levels of anti-dsDNA antibodies (Abs) were also observed in the HPRL patients. Inhibition studies showed that the affinity purified AECAs bound the endothelial cell (EC) antigens in a dose-dependent manner. Titers of AECA as well as anti-DNA and anti-CL autoantibodies did not correlate with PRL level nor with the use or duration of anti-PRL treatment. None of the HPRL patients presented clinical manifestations of autoimmune disease. We conclude that elevated levels of AECA as well as anti-DNA and anti-CL autoantibodies are frequent in hyperprolactinemia. Our results further support the association of PRL and autoimmunity, and may point to a relationship between AECA-associated diseases and HRPL. The presence of autoantibodies in patients with HPRL might portend an increased risk for future development of autoimmune disease.
The hypothalamic-pituitary response in SLE. Regulation of prolactin, growth hormone and cortisol release
Authors: Rovenský J , Blažíĉková S , Rauovaá L , Ježová D , Koŝka J , Lukáĉ J , Vigaŝ M
Published: November 2003

It has been suggested that neuroendocrine regulation plays an important role in the pathogenesis and activation of autoimmune diseases. The aim of this investigation was to clarify the hypothalamic-pituitary response to a well-defined stimulus under standardised conditions in patients with SLE. Plasma concentrations of prolactin (PRL), growth hormone (GH) and cortisol were determined in venous blood drawn through an indwelling cannula during insulin-induced hypoglycaemia (0.1 U/kg b.w., i.v.) in ten patients and in 12 age-, gender-and weight-matched healthy subjects. Basal PRL concentrations were higher in patients vs healthy controls (12 vs 6ng/ml, P < 0.01), though still within the physiological range. Insulin-induced plasma PRL and GH were significantly increased both in patients and healthy subjects; however, the increments or areas under the curves were not different in the two groups. Plasma cortisol response showed moderate attenuation in patients. Sensitivity of pituitary lactotrothrops to thyrotropin-releasing hormone (TRH) administration (200 mg, i.v.) was the same in patients and control subjects. In SLE patients with low activity of the disease the sensitivity of pituitary PRL release to TRH administration remained unchanged. The hypothalamic response to stress stimulus (hypoglycaemia) was comparable in patients and healthy subjects.
Prolactin levels in patients with systemic lupus erythematosus: a case controlled study
Authors: Jimena P , Aguirre M A , López-Curbelo A , de Andrés M , Garcia-Courtay C , Cuadrado M J
Published: November 2003

Recent accumulated evidence suggests that prolactin (PRL) is an important immunomodulator and might have a role in the pathogenesis of systemic lupus erythematosus (SLE). Our aim was to assess the frequency of hyperprolactinemia in women with SLE and to evaluate its correlation with disease activity. PRL plasma levels were measured in 36 women with SLE and 20 age-matched healthy controls. We excluded patients with renal and/or hepatic failure, pregnant patients and patients taking drugs which could increase PRL levels. Disease activity was assessed using the SLE disease activity index (SLEDAI). Patients with a score > 10 were considered active. In patients and controls, PRL levels were determined by radioimmunoassay (RIA) during the first part of the menstrual cycle (between the 5th and 8th day) (normal value < 20 ng/ml). Ten of 36 (27.7%) SLE patients had high PRL levels (> 20 ng/ml). The mean PRL level was higher in SLE than in the control group (17.1=12.9 s.d. vs 9.= 3.5, P < 0.01). Patients with active disease had a trend to higher mean PRL levels than inactive patients although this difference was not statistically significant (21.1=4.8 vs 14.8= 6.9, P = 0.09). No correlation was found between PRL levels and SLEDAI score. Furthermore, no significant correlation was found between PRL levels and any clinical or serological finding.
Systemic lupus erythematosus in Kuwait—hospital based study
Authors: Al-Jarallah K , Al-Awadi A , Siddiqui H , Al-Salim I , Shehab D , Umamaheswaran I , Gaurer S , Al-Saied K , Kumar R , Malaviya A N
Published: November 2003

The present study describes the clinical characteristics of patients with systemic lupus erythematosus (SLE), from the rheumatology service of the two main teaching hospitals in Kuwait. It was a retrospective-cum-prospective clinical study of 108 SLE patients. There were 98 females and 10 males, with a median age of 31.5 y. Kuwaitis constituted 69%, while 31% were expatriates. The mean disease duration was 62 months. The main clinical features were: musculoskeletal involvement (87%), photosensitivity (48%), malar rash (43%), discoid lesions (10%), oral ulcers (33%), vasculitic skin lesions (10%), haematological features (53%), constitutional symptoms (51.4%), neuropsychiatric manifestations (23%), renal involvement (37%), serositis (29%), clinical manifestations of antiphospholipid syndrome (21%), cardiac involvement (10%) and pulmonary manifestations (19%). In conclusion, the clinical features of SLE in Kuwait were similar to most major studies from developed countries. Main differences included prominent haematological and mucocutaneous manifestations and possibly a low prevalence of anti-Sm antibodies. Whether these differences are due to the environment or genetic factors, remains to be studied.
Immunomodulation of murine experimental SLE-like disease by interferon-γ
Authors: Amital H , Levi Y , Blank M , Barak V , Langevitz P , Afek A , Nicoletti F , Kopolovic J , Gilburd B , Meroni P L , Shoenfeld Y
Published: November 2003

The objective of this study was to assess the impact of murine recombinant IFN-γ and anti-IFN-γ monoclonal antibody on the BALB/c mice experimental model of lupus. BALB/c female mice were immunized with a human anti-DNA antibody that carries the 16=6 idiotype. These mice were divided into several therapeutic groups according to different treatment strategies; injection with mouse recombinant IFN-γ, anti-IFN-γ mAb, phosphate-buffered saline (PBS), irrelevant mouse IgG and control groups that were neither treated nor immunized with the human anti-DNA antibody.

The administration of IFN-γ intensified the degree of clinical, histological and serological parameters in this model of BALB/c murine lupus. This immunomanipulation decreased the mice longevity. All the laboratory parameters reflected acceleration of the disease in the IFN-γ treated group as an elevated sedimentation rate, decreased white blood cell count and the development of massive proteinuria. One month after the boost injection, all the mice that were immunized with the anti-DNA antibody, developed high titers of autoantibodies; however, following an additional month, their levels declined in the IFN-γ treated group. These findings were in concordance with an increased glomerular deposition of immune complexes in the IFN-γ treated mice. IFN-γ upregulated the levels of IL-4 and increased the number of IL-4 and IL-6 secreting splenocytes.

In conclusion IFN-γ administration can aggravate the clinical and laboratory outcome of 16=6id induced lupus in BALB/c mice.
Apoptosis and expression of soluble Fas mRNA in systemic lupus erythematosus
Authors: Papo T , Parizot C , Ortova M , Piette J-C , Frances C , Debre P , Godeau P , Gorochov G
Published: November 2003

Our objective was to measure the relative proportions of messenger RNAs coding for soluble and membrane-bound Fas in peripheral blood mononuclear cells (PBMCs) and to quantify lymphocyte apoptosis in vitro in systemic lupus erythematosus (SLE).

A RT-PCR (soluble/membrane Fas mRNA) ratio was calculated in 16 SLE, 11 RA and 16 healthy subjects' PBMCs. Apoptosis was quantitated in vitro using nick-end labeling and flowcytometry analysis immediately and after overnight T cell activation.

The mean soluble/membrane Fas ratio was 1.219–0.424 in the SLE group, significantly higher than in healthy subjects, 0.516–0.180 (P = 0.0001). There was no significant difference between inactive and active SLE groups whereas Fas ratio was higher in SLE patients with nephritis (1.460–0.365) compared to those without nephritis (1.031–0.380) (P = 0.039). Mean soluble/membrane Fas ratio in RA patients (0.975–0.37) was higher than in healthy subjects (P = 0.0003) and lower than lupus nephritis patients (P = 0.015). A significantly higher proportion of mononuclear cells engaged apoptosis after T cell activation in active lupus patients, compared to control subjects.

In comparison with healthy subjects, Fas alternative splicing was skewed toward the soluble form of Fas in SLE and RA. Apoptosis after T cell activation in vitro was increased in active SLE patients.
The clinical features and prognosis of male lupus in Taiwan
Authors: Chang D-M , Chang C-C , Kuo S-Y , Chu S-J , Chang M-L
Published: November 2003

Our objective was to describe the clinical manifestations, laboratory data, and prognosis in male Chinese lupus patients in Taiwan. Seventy-two male lupus patients, diagnosed and followed in Tri-Service General Hospital between 1983 and 1996, were studied and their clinical data analyzed, retrospectively. The mean age at diagnosis was 34–16 y (mean–s.d., range: 13 – 82 y). The peak incidence of age at diagnosis was between 13 and 40 years. The three most frequent clinical manifestations were renal disease, 75%; malar rash, 61%; and arthritis, 53%. The three most frequent abnormal laboratory findings were anti-nuclear antibodies (ANA), 97%; hypocomplementemia, 76%; and anti-ds DNA, 57%. The 1-, 5-, and 10-year survival rates were 85%, 76%, and 75%, respectively. In summary, a higher frequency of renal disease, malar rash and photosensitivity, but a lower frequency of arthritis and lymphadenopathy were demonstrated in our 72 ethnic Chinese male Taiwanese lupus patients compared to previous reports of Caucasians. The prognosis seems to be similar to that of both Chinese and Caucasian males but seems to be poor when compared to either Chinese or Caucasian female lupus patients.
Identification and characterization of a calreticulin-binding nuclear protein as histone (H1), an autoantigen in systemic lupus erythematosus
Authors: Treves S , Bajocchi G , Zorzato F , Govoni M , Trotta F
Published: November 2003

Our objective was to identify nuclear calreticulin-binding protein(s) and investigate whether there is a correlation between presence of autoantibodies against calreticulin and calreticulin-binding protein(s) in the sera of patients suffering from systemic lupus erythematosus (SLE).

The ligand overlay procedure using digoxigenin-labelled calreticulin was used to identify a calreticulin-binding protein in the nuclear fraction of bovine brain. Fractionation of the nuclear components was used to localize the major positive calreticulin-binding protein. The protein was partially purified using hydroxylapatitie chromatography and subjected to NH2-amino acid sequence analysis. Immunoblots using the sera of SLE patients were then carried out on calreticulin and the calreticulin-binding protein.

The calreticulin-binding protein present in the nucleoplasm was identified as histone H1. Approximately 62% (26=42) patients with SLE had IgG antibodies directed against H1 whereas the sera of healthy individuals did not react with the antigen; 36% of patients with SLE had both anticalreticulin and anti-histone H1 antibodies. Phosphorylation of the latter protein did not alter its immunoreactivity.

These findings demonstrate that the concomitant presence of autoantibodies directed against both calreticulin and histone H1 occurs frequently in patients with SLE and may help shed some light on the mechanisms which bring about the autoimmune response.
Nervous system lupus mimics limbic encephalitis
Authors: Stübgen J-P
Published: November 2003

A 28-year-old woman with systemic lupus erythematosus (SLE) suffered recent onset fever, headache, encephalopathy followed by severe, repeated generalized seizures. Investigations revealed limbic encephalitis. Tests for Herpes simplex encephalitis and paraneoplastic encephalomyelitis were negative. High titers anti-ribosomal-P antibodies in the cerebrospinal fluid (CSF) suggested an association with nervous system lupus. No brain biopsy was performed. Treatment was with anti-seizure, anti-viral, and immunomodulating medication.
Association of an insertion polymorphism of angiotensinconverting enzyme gene with the activity of systemic lupus erythematosus
Authors: Sato H , Akai Y , Iwano M , Kurumatani N , Kurioka H , Kubo A , Yamaguchi T , Fujimoto T , Dohi K
Published: November 2003

Systemic lupus erythematosus (SLE) shows various clinical manifestations, which are characterized by inflammation in many different organ systems. The cause of SLE is still unclear; however, the immunological abnormalities are considered to be responsible for the pathogenesis of SLE. As angiotensin I-converting enzyme (ACE) has been reported to be associated with various immunological phenomena, we investigated the correlation between insertion (I)/deletion (D) polymorphism of the ACE gene and the disease activity of SLE. Ninety-three patients with newly diagnosed SLE were enrolled in this study. ACE genotype was determined by the polymerase chain reaction (PCR). We measured serum levels of anti-double-stranded (ds) DNA antibody (Ab) and serum levels of total complements (CH50) as the parameter for lupus activity. Moreover, we evaluated the clinical disease activity by calculating SLE disease activity index (SLEDAI).

Individuals with II genotype showed a significant increase in SLE activity. Patients with the ACE II genotype showed a higher serum level of anti-dsDNA Ab (14.3 IU/ml (5.475, 74.6, median (25th centile, 75th centile)) than those with the DD genotype (4.65 IU/ml (4.05, 6.8)) (P < 0.01). Moreover, patients with the II genotype also showed lower levels of serum CH50 than those with the DD genotype (P < 0.01). Patients with the II or DI genotype had significantly higher SLEDAI score than those with the DD genotype (P < 0.01). These results suggest that the ACE genotype could be associated with the disease activity of SLE. ACE insertion polymorphism might be used as one of predictive factors for the activity of lupus.
Pulmonary involvement in juvenile systemic lupus erythematosus: a study on lung function in patients asymptomatic for respiratory disease
Authors: Trapani S , Camiciottoli G , Ermini M , Castellani W , Falcini F
Published: November 2003

Pleuro-pulmonary involvement has been well recognized in adults affected with systemic lupus erythematosus (SLE), but few studies have been carried out in children. A longitudinal study on a group of 15 children affected with juvenile SLE (JSLE), asymptomatic for lung disease, was performed, and the prevalence and the features of respiratory function alterations, over a period of 12 months, were analysed. Moreover, a possible correlation between any pulmonary function test (PFT) and disease duration, disease activity, visceral involvement and immunological pattern was evaluated. At baseline, a significant functional lung impairment was present in 40% of patients, with a significantly reduced FVC, VA and DLCO in 26% of them; in 60% of patients at 6 months and in 33% of patients at 12 months. At 6 and 12 months, our data did not show any significant modification in PFTs and the restrictive pattern, observed at baseline, remained unchanged. No correlation between altered PFTs and disease duration, activity and/or immunological findings was found. At baseline, the presence of neurological involvement was the only extra-pulmonary feature correlated to reduced FVC
Genetic susceptibility to lupus nephritis
Authors: Tsao B P
Published: November 2003

Although cumulative evidence suggests that a genetic predisposition plays a major role in development of systemic lupus erythematosus (SLE) and/or lupus nephritis (LN), the susceptibility genes are mostly unknown. The difficulty in identifying susceptibility genes is due in part to multiple genes with variable genetic effects and the diverse genetic backgrounds of human populations. In human SLE, genes of early components of complements as well as many polymorphic genes (including the MHC class II and class III, FcγR, mannose-binding protein, IL-6, Bcl-2, and IL-10 genes) have been associated with SLE or LN by population-based case-control or within-case studies. The contribution of some of these disease-associated genes to the presence or absence of clinical manifestations has been further tested in mice with targeted disruption of the specific candidate gene. In addition to SLE susceptibility genes, there may be a separate set of nephropathy susceptibility genes predisposing to LN as suggested by the familial clustering of endstage renal disease in African-Americans with LN.

The availability of densely mapped genetic markers spanning the entire genome has enabled the identification of chromosomal regions linked to disease susceptibility genes without prior knowledge of the gene function. Our group has used known murine lupus susceptibility loci as a guide, and conducted linkage analysis of genetic markers located within a specific, possibly syntenic human chromosomal region. Evidence for linkage of a chromosome 1q41-42 region was observed in SLE-affected sib pairs from multiple ethnic groups. More recently, several groups have reported results of genome scans of SLE-affected sib pairs or pedigrees. These exciting recent developments in delineating the genetic basis of SLE or LN are summarized in this review.
Production of pathogenic antibodies: Cognate interactions between autoimmune T and B cells
Authors: Datta S K
Published: November 2003

A select population of autoimmune T-helper (TH) cells drive the production of pathogenic anti-DNA autoantibodies in SLE. These TH cells recognize nucleosomal peptides that are processed and presented by the anti-DNA B cells that they help. The critical peptide epitopes for the TH cells reside in the core histones of the nucleosome particle. Remarkably, the nucleosomal peptide epitopes do not obey the rule of MHC-restriction; they can be promiscuously presented and recognized in the context of diverse MHC alleles. Such promiscuous antigens, called pantigens, are also recognized by autoimmune T cells, in a degenerate fashion, and this promiscuous recognition is conferred by the lupus TCR a chains. High-affinity interactions between the lupus TCRs and MHC-nucleosomal peptide complex due to reciprocally charged residues probably overcome the requirement for MHC restriction. These studies open up the possibility of developing ‘universally’ tolerogenic epitopes for therapy of lupus in humans despite their diversity of HLA alleles. The results also have profound implications regarding the selection of autoimmune T cells in the lupusprone thymus and their expansion in the periphery. Furthermore, the TH cells, as well as B cells of lupus, have a regulatory defect causing markedly increased and prolonged expression of CD40 ligand (CD40L), which mediates abnormal co-stimulatory signals to autoimmune B cells, sustaining the production of pathogenic autoantibodies. These observations suggest a new paradigm for B cell hyperactivity in lupus and provide alternative targets for immunotherapy. Indeed, giving only three injections of anti-CD40L antibody in a one-week period to mice with manifest lupus selectively blocks the pathogenic autoimmune response and delays the development of lupus nephritis by one year (equivalent to three decades in humans). Thus, possession of promiscuous, high-affinity receptors and prolonged expression of CD40L by lupus T cells probably lowers activation threshold, leading to an autoimmune response against nucleosomes derived from apoptotic cells that are normally ignored by the immune system.
Clinical evaluation and monitoring of lupus kidney disease
Authors: Austin H A
Published: November 2003

Lupus renal involvement encompasses a broad range of clinical and histologic presentations and poses numerous therapeutic challenges. Accurate clinical assessment and monitoring requires a comprehensive approach, with attention to the urinalysis, the urinary protein excretion rate, the test of kidney function, and alterations in serologic parameters.
Immunosuppressive therapy of lupus nephritis
Authors: Dooley M A , Falk R J
Published: November 2003

Aggressive immunosuppressive therapy should be considered for patients with proliferative lupus nephritis as the risk for progression to end stage renal disease is high. Intermittent intravenous cyclophosphamide therapy improves renal survival; longer duration of therapy is associated with fewer relapse of nephritis and decreased risk of diminished renal function. While azathioprine therapy does not differ statistically from steroids alone in prolonging renal survival, this therapy may be considered in patients with few risk factors for progression to renal insufficiency. Methylprednisolone as a single therapy does not prolong renal survival compared with regimens including cyclophosphamide. Plasmapheresis remains under study but has not shown additional benefit in treatment of severe lupus nephritis. The potential roles for cyclosporin A and mycophenylate mofetil in the therapy of proliferative lupus nephritis remain to be defined. Supportive care including rigorous control of hypertension, consideration of angiotensin receptor inhibition or blockade to reduce proteinuria and prolong renal function, control of hyperlipidemia, prevention of osteoporosis, and prevention of pregnancy remain important clinical goals. Current research efforts focus on genetic and socioeconomic factors involved in racial differences in expression of lupus nephritis, hormonal manipulation to preserve gonadal function during cyclophosphamide therapy, and the potential impact on lupus activity of estrogen-containing oral contraceptives or postmenopausal hormone replacement therapy.
Lupus nephritis in children
Authors: Gloor J M
Published: November 2003

The renal manifestations of systemic lupus erythematosus in childhood range from minor abnormalities detected on urinalysis to severe renal insufficiency requiring renal replacement therapy. Clinically significant renal involvement in systemic lupus erythematosus is more common in children than in adults. Effective treatment for childhood lupus nephritis is available, and the prognosis for affected children has improved over the course of the last 30 years. Corticosteroid therapy remains the cornerstone of treatment for children with lupus nephritis. The addition of cytotoxic agents to corticosteroid treatment improves both the long and short-term prognoses. Cyclosporin may improve the clinical manifestations of lupus nephritis although the disease remains active serologically.

Although survival in childhood lupus has improved, complications of therapy result in significant morbidity with distressing frequency. Immunosuppression may result in mortality and morbidity due to opportunistic infections. Individuals with otherwise successful control of renal manifestations of systemic lupus erythematosus may still be left with significant morbidity due to disturbances in growth due to long-term corticosteroid treatment. Psychosocial development may be adversely affected both as a result of chronic illness as well as due to the effects of therapy. Meticulous attention to detail over decades of treatment is necessary to optimize patient outcome in childhood lupus nephritis.
Management of chronic renal insufficiency in lupus nephritis: Role of proteinuria, hypertension and dyslipidemia in the progression of renal disease
Authors: Clark W F , Moist L M
Published: November 2003

Non-immune mechanisms appear to be important in the majority of patients with lupus nephritis and progressive renal injury. Proteinuria, hypertension and dyslipidemia are associated non-immune risk factors often implicated in the deterioration of kidney function. There is ample animal experimental evidence that they are independent risk factors for progressive renal injury and their treatment results in amelioration of renal function. Proteinuria and hypertension, unlike dyslipidemia, have been shown to be independent risk factors for progressive renal injury in patients with lupus nephritis. Treatment of hypertension and proteinuria in the diabetic and non-diabetic progressive renal disease population results in stabilization of kidney function. Response to treatment should target both blood pressure of 120=80 and significant reductions in protein excretion. If protein excretion rate is unaltered by use of an angiotensin-converting enzyme inhibitor and salt restriction, one might resort to the use of an angiotensin II antagonist. Treatment of the dyslipidemia following good control of proteinuria, blood pressure and dietary change may not alter renal progression but should provide similar protection from accelerated vascular disease to the non-renal dyslipidemia population.
Validation of the medical outcomes study family and marital functioning measures in SLE patients in Singapore
Authors: Thumboo J , Fong K-Y , Chan S-P , Leong K-H , Feng P-H , Thio S-T , Boey M-L
Published: November 2003

Objective: To validate the Medical Outcomes Study Family and Marital Functioning Measures (FMM and MFM) in a multi-ethnic, urban Asian population in Singapore.

Methods: English speaking Chinese, Malay or Indian SLE patients (n ‘ 120) completed a selfadministered questionnaire containing the FFM and MFM at baseline, after 2 weeks and after 6 months. Lupus activity, disease-related damage and quality of life were assessed using the British Isles Lupus Assessment Group (BILAG), Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) Damage Index and SF-36 Health Survey respectively. Scale psychometric properties were assessed through factor analysis, Cronbach's a, quantifying test-retest differences and known-groups construct validity.

Results: Factor analysis of scores obtained at baseline and after 6 months identified 3 factors corresponding to the FFM (1 factor) and the MFM (2 factors). Both scales showed acceptable internal consistency, with Cronbach's a of 0.95 for the FFM and 0.70 for the MFM. Mean (s.d.) test-retest differences were 7 0.31 (3.82) points for the FFM and 7 0.70 (4.26) points for the MFM. Eleven out of 13 a priori hypotheses relating both the FFM and MFM to demographic, disease and quality of life variables were confirmed, supporting the construct validity of these scales.

Conclusion: The FFM and MFM are valid and reliable measures of family and marital functioning in a multi-ethnic cohort of Asian SLE patients in Singapore.
Treatment of membranous lupus nephritis with nephrotic syndrome by sequential immunosuppression
Authors: Chan T M , Li F K , Hao W K , Chan K W , Lui S L , Tang S , Lai K N
Published: November 2003

The optimal therapy for pure membranous lupus nephritis (MLN) with nephrotic syndrome remains controversial. While the risk of progressive renal deterioration may be small, persistent heavy proteinuria leads to the complications of oedema, hypoalbuminaemia, hyperlipidaemia, hypercoagulability, and venous thrombosis. We examined prospectively the efficacy and tolerability of a sequential immunosuppressive regimen in a cohort of 20 patients with nephrotic syndrome due to pure MLN (WHO Class Va and Vb). Initial therapy comprised prednisolone (0.8 mg/kg/d p.o.) and cyclophosphamide (2–2.5 mg/kg/d p.o.). Prednisolone dosage was gradually tapered to 10 mg/d at 6 months, when cyclophosphamide was replaced by azathioprine (2 mg/kg/d p.o.) as maintenance therapy. Within 12 months of therapy 11(55%) patients had complete remission (CR), 7(35%) patients achieved partial remission (PR) (proteinuria reduced from 6.2 4.0 to 2.0 1.7 g =24 h, P < 0.01), and 2 patients failed to respond. Improvements in proteinuria and serum albumin level were observed after 3–6 months of treatment. Non-responders had lower baseline serum albumin compared to complete responders. Renal function remained stable during follow-up for 73.5 48.9 months. 8 patients had disease relapse at 47 15 months. Early complications (12 months) included herpes zoster (40%), minor respiratory or urinary tract infections (25%), mild leukopenia (15%), and transient amenorrhea (14.3%). 4 of the 20 patients developed pulmonary tuberculosis during follow-up, at 35 24 months after the diagnosis of MLN. 8 patients had hyperlipidaemia. Haemorrhagic cystitis, permanent amenorrhea, vascular complications, and mortality were not observed. We conclude that this sequential immunosuppressive regimen is effective in 90% of patients with MLN and heavy proteinuria. Prudent consideration of the benefits and potential side-effects is required to determine the optimal management for individual patients.
Adult respiratory distress syndrome in systemic lupus erythematosus: causes and prognostic factors: a single center, retrospective study
Authors: Kim W U , Kim S I , Yoo W H , Park J H , Min J K , Kim S C , Hong Y S , Lee S H , Park S H , Cho C S , Kim H Y
Published: November 2003

To determine the causes and prognostic factors of Adult Respiratory Distress Syndrome (ARDS) in patients with systemic lupus erythematosus (SLE). Methods: Among 544 Korean SLE patients, who were followed in the Lupus Clinic of the Catholic Medical Center from 1993 to 1997, patients diagnosed as ARDS were examined retrospectively. During the study period, non-SLE patients with ARDS were investigated and then compared to SLE patients with ARDS in terms of clinical variables. Results: Nineteen patients with SLE were revealed to have a history of ARDS (3.5%) and 13 (68.4%) of 19 patients died. Death related to ARDS was found in 34.2% of all deaths (n = 38) from SLE during the study period. The frequency and causes of ARDS were as follows; 9 sepsis or bacteremia (47.4%), 2 miliary tuberculosis (10.5%), 2 invasive pulmonary aspergillosis (10.5%), 2 acute pulmonary alveolar hemorrhage syndrome (10.5%), 1 acute lupus pneumonitis (5.3%), 1 massive hemorrhage due to placenta previa (5.3%), 1 aspiration pneumonitis (5.3%), 1 disseminated intravascular coagulation associated with systemic vasculitis (5.3%). The main organisms in sepsis were gram negative bacilli (61.5%) The median steroid dose administered 1 month before ARDS was significantly higher in patients (n = 13) with infectious ARDS compared to those (n = 6) with ARDS due to other causes (P = 0.038). Comparison of the laboratory and clinical variables between the survivors (n = 6) and the deceased (n = 13) showed that the survivors had lower SLAM indices at presentation (P = 0.004) and APACHE (Acute Physiology, Age, Chronic Health Evaluation) III scores within 24 h after diagnosis of ARDS (P = 0.024) than the deceased. The APACHE III scores correlated well with the SLAM indices (r = 0.615, P = 0.007). Non-SLE patients with ARDS during the study period were selected for comparison to SLE patients with ARDS. Age at the onset of ARDS was younger in SLE (n = 19) compared to non-SLE (n = 190) (P < 0.001). Duration from ARDS onset to death was shorter in SLE patients (P < 0.001). The mortality from ARDS tended to be higher in SLE patients (P = NS). The first-day APACHE III score was significantly higher in deceased SLE patients (n = 13) compared to deceased non-SLE patients (n = 105) (P = 0.001). Conclusions: ARDS was a common premortem event of SLE and showed a high fatality rate in SLE. The most common cause of ARDS in Korean patients with SLE was sepsis by gram negative bacilli. ARDS in SLE developed at a younger age, and progressed more rapidly compared to ARDS in general. The SLAM index and APACHE III score could be useful to predict the prognosis of ARDS in SLE.
Increased endothelial cell expression of a3β1 integrin in cardiac valvulopathy in the primary (Hughes) and secondary antiphospholipid syndrome
Authors: Afek A , Shoenfeld Y , Manor R , Goldberg I , Ziporen L , George J , Polak-Charcon S , Amigo M C , Garcia-Torres R , Segal R , Kopolovic J
Published: November 2003

The objective of this work was to determine markers of endothelial cell activation in valves from patients with antiphospholipid syndrome (APS) and heart valve involvement, in order to establish a role for endothelial cells in the pathogenesis of the valvular disease.

Sixteen valves from ten patients with APS, obtained from autopsies or removed during valve replacement, were studied. Two groups of valves were used as controls. One group included seven normal valves from patients who died from non-cardiac diseases. The other group of valves were obtained from patients with bacterial endocarditis during autopsies or valve replacement operations.

Immunoperoxidase and immunofluorescence stainings with antibodies to human immunoglobulins, endothelial cells, a3β1 integrin, collagen IV, laminin and fibronectin were employed.

Three histopathological patterns were apparent: normal valves, valves with verrucous endocarditis and valves with fibrocalcific changes. In all the valves with verrucous endocarditis the following findings were observed: (1) increased expression of the a3β1 integrin on the endothelial cells, (2) increased amount of collagen IV, laminin and fibronectin, (3) proliferation of blood vessels and (4) linear subendothelial deposition of immunoglobulins and complement. The valves with fibrocalcific changes were deformed and showed a thick layer of collagen IV, laminin and fibronectin, yet in two valves the indothelial cells showed an expression of the a3β1 integrin. The control valves did not express the integrin and had only a thin subendothelial band of collagen IV.

In valves from patients with APS,1 markers of endothelial cell activation are upregulated while the inflammatory exudate is scant. There is also a prominent deposition of immunoglobulins in the valves from patients with APS, suggesting a possible association between the deposition of the antibodies and the activation of the endothelial cells in APS.
Effects of anti-CD4 antibodies on the release of IL-6 and TNF-α in whole blood samples from patients with systemic lupus erythematosus
Authors: Brink I , Thiele B , Burmester G-R , Trebeljahr G , Emmrich F , Hiepe F
Published: November 2003

Anti-CD4 antibodies have been recently introduced into the therapy of various autoimmune diseases, among them systemic lupus erythematosus (SLE). Their modes of action are not yet fully understood. Interference with cytokine release may be one possible mechanism. Therefore, the effects of anti-CD4 antibodies on the cytokine release of IL-6 (interleukin-6) and TNF-a (tumor necrosis factor alpha) were investigated in a whole blood culture system. Basal and phytohemagglutin/lipopolysaccharide (PHA/LPS)-stimulated cytokine patterns were compared to cytokine release after the addition of anti-CD4 antibodies (MAX. 166H5) or methylprednisolone in short time whole blood cell culture systems from 12 patients with active SLE, 23 patients with inactive SLE and 12 healthy volunteers. TNF-oc and IL-6 concentrations were determined in the supernatants by ELISA. High disease activity correlated with an increased production of proinflammatory cytokines. Cell cultures of patients with inactive SLE showed a diminished capacity to respond to mitogenic stimulation. Anti-CD4 antibodies added in vitro suppressed significantly the unstimulated production of IL-6 (P < 0.02) in the cell cultures of patients with active SLE and in the PHA/LPS-stimulated cell cultures from both groups of SLE patients (both P < 0.001) and healthy volunteers (P < 0.01). However, MAX.16H5 did not affect the release of TNF-a. In control samples methylprednisolone considerably reduced stimulated and unstimulated IL-6 and TNF-ca production in all SLE patients, irrespective of the disease state, and in all healthy controls.

These data indicate that the proinflammatory cytokines are involved in the pathogenesis of SLE. It is assumed that anti-CD4 antibodies, which can be effective in the treatment of highly active lupus patients, may act via their influence on cytokine release. The decrease of the proinflammatory cytokines IL-6 under therapy with MAX. 16H5 could explain the observations of clinical trials and animal studies which showed a reduction of inflammatory parameters and diminished production of autoantibodies following treatment with anti-CD4 antibodies.
Genetic variation in apolipoprotein H (β2-glycoprotein I) affects the occurrence of antiphospholipid antibodies and apolipoprotein H concentrations in systemic lupus erythematosus
Authors: Kamboh M Ilyas , Manzi Susan , Mehdi Haider , Fitzgerald Shirley , Sanghera Dharambir K , Kuller Lewis H , Atson Christopher E
Published: November 2003

Apolipoprotein H (apoH, protein; APOH, gene) is a required cofactor for the production of antiphospholipid antibodies (APA). In this study we have examined whether genetic variation in the APOH gene affects variation in risk for systemic lupus erythematosus (SLE), occurrence of antiphospholipid antibodies (APA), anti-apoH, and plasma apoH concentrations. A total of 222 white SLE women were screened for four APOHpolymorphisms (codons 88, 247, 306, and 316) by polymerase chain reaction, and for plasma apoH concentrations by ELISA. Of these, 29.3% were positive for APA (APA-positive group) and 31.1% for anti-apoH. None of the four APOH polymorphisms were significantly associated with variation in risk for SLE. The codons 306 and 316 polymorphisms showed significant, gene-dosage effects on plasma apoH concentrations (P<0.0001) and explained 30% and 13%, respectively, of the residual variation in apoH concentrations. No significant association was observed between anti-apoH status and APOH polymorphisms or plasma apoH levels. However, plasma apoH concentrations were significantly higher in patients positive for APA than in patients negative for APA (18.5±4.0 mg/dl vs 17.1+3.8 mg/dl; P=0.02). The distribution of the Trp3l6Ser polymorphism was significantly different between the APA-positive and APA-negative groups. The frequency of the mutant allele (Ser316) was significantly lower in the APA-positive group than the APA-negative group (3.1% vs 12.1% P < 0.04), indicating that the Ser316 mutation is protective against the production of phospholipid-apoH dependent APA. Our data indicate that common genetic variation in the APOH gene is a significant determinant of plasma apoH variation in SLE patients, and the Trp3l6Ser polymorphism appears to provide protection against the production of APA in SLE patients.
The composition of the lupus band test (LBT) on the sun-protected non-lesional (SPNL) skin in patients with cutaneous lupus erythematosus (CLE)
Authors: Cardinali Carla , Caproni Marzia , Fabbri Paolo
Published: November 2003

The objective of this study was to analyse the different immunoreactants at the dermo-epidermal junction (DEJ) of patients with cutaneous lupus erythematosus (CLE). Sun-protected non lesional (SPNL) skin biopsies from 65 patients with specific cutaneous manifestations of LE and from 18 patients with other dermatologic diseases were tested using the direct immunofluorescence (DIF) technique. Nineteen out of 65 patients with CLE were affected by systemic LE (SLE). We used the conventional chi-squared test to analyse statistical differences between CLE-SLE and CLE-non-SLE groups in the immunological composition of lupus band test (LBT). C3 was the most common component while IgM were the most frequent immunoglobulins (Igs) of LBT in LE patients. No immunoreactants could be demonstrated at the DEJ in patients with other dermatologic diseases. No statistical differences could be found between CLE-SLE and CLE-non-SLE groups as regards the detection of the different immunoreactants at the DEJ. A positive LBT (even for the presence of only one immunoreactant at the DEJ) performed on SPNL skin represents a useful and specific criterion to distinguish patients with lupus erythematosus (LE) from those without LE. We also believe in a prognostic value of a positive LBT on SPNL skin when the deposition of at least two immunoreactants is demonstrated, and especially if the deposits are composed of IgG.
Successful treatment of lupus with fludarabine
Authors: Viallard J-F , Mercie P , Faure I , Pellegrin J-L , Leng B
Published: November 2003

We describe a 58-year old patient with chronic lymphocytic leukemia (CLL) who developed systemic lupus erythematosus (SLE) with severe joint involvement. Dilated myocardiopathy precluded the use of high corticoid doses and a 15 days of prednisone (I 5mg/d) had no effect on the polyarthritis. Therefore, fludarabine (25mg/M2) was administered for 5 d. One month after the first cycle, fever, muscle stiffness and polyarthritis resolved. A total of 6 cycles were administered. The evolution was complicated by herpes zoster infection and left pneumococcal pneumonia. At this time of writing (July 1999), the patient is symptom free but is profoundly lymphopenic.
Generalized periodontal involvement in a young patient with systemic lupus erythematosus
Authors: Nagler Rafael M , Lorber Margalit , Ben-Arieh Yehudit , Laufer Dov , Pollack Shimon
Published: November 2003

Inflammation is considered to be a leading cause of morbidity in systemic lupus erythematosus (SLE), yet inflammatory periodontal involvement is rarely encountered. A young lady suffering from active SLE accompanied by severe periodontal loss, manifested by gingival recession of all her teeth, was referred to our clinic for treatment. The association between periodontal involvement and connective tissue diseases is unclear, and the literature dealing with periodontal involvement in patients suffering from Sjogren's syndrome and rheumatoid arthritis is comprised of studies showing both normal and pathological periodontal status. We discuss the possible underlying mechanisms.
Modulation of autoimmune disease in the MRL-lpr/lpr mouse by IL-2 and TGF-β1 gene therapy using attenuated Salmonella typhimurium as gene carrier
Authors: Huggins M L , Huang F-P , Xu D , Lindop G , Stott D I
Published: November 2003

We have investigated the effects of interleukin-2 (IL-2) and transforming growth factor-b (TGF-b) gene therapy on the progress of autoimmune disease in MRL-lpr/lpr mice, a murine model of systemic lupus erythematosus (SLE). These mice have uncontrolled proliferation of T cells, an impaired response to T cell mitogen and produce autoantibodies against nuclear antigens, including DNA. Immune complexes formed by these autoantibodies are believed to cause glomerulonephritis and vasculitis in lupus mice and human SLE. Since there is an imbalance of cytokine production in both SLE patients and lupus mice, we examined the effects of cytokine gene therapy on the progression of autoimmune disease in MRL-lpr/lpr mice. The mice were treated orally with a non-pathogenic strain of Salmonella typhimurium bearing the aroA-aroD- mutations and carrying the murine genes encoding IL-2 and TGF-b. The bacteria synthesise and slowly release the cytokines in vivo. Our results show that, contrary to expectation, TGF-b gene therapy produced no improvement in pathology and generally had opposite effects to those of IL-2. IL-2 gene therapy restored the defective T cell proliferative response to mitogen and suppressed the autoantibody response, glomerulonephritis and growth of lymphoid tumours.
Pseudotumor cerebri and leukoencephalopathy in childhood lupus
Authors: Chaves-Carballo E , Dabbagh Omar , Bahabri Sultan
Published: November 2003

We describe an adolescent with systemic lupus erythematosus (SLE) and pseudotumor cerebri (PTC) associated with diffuse white matter lesions (leukoencephalopathy) on neuroimaging studies. Although the association between SLE and PTC has been reported previously in 21 cases, the findings of leukoencephalopathy is known in only one other patient.
Recombinant human Dnase I (rhDNase) in patients with lupus nephritis
Authors: Davis J C , Manzi S , Yarboro C , Rairie J , Mcinnes I , Averthelyi D , Sinicropi D , Hale V G , Balow J , Austin H , Boumpas D T , Klippel J H
Published: November 2003

Systemic lupus erythematosus (SLE) is characterized by the production of pathogenic autoantibodies to nucleoprotein antigens, including double-stranded DNA (dsDNA). The deposition of IgG dsDNA immune complexes in glomeruli is thought to be crucial for disease pathogenesis and complement activation. rhDNase catalyzes the hydrolysis of extracellular DNA and has been shown to delay the development of dsDNA antibodies, reduce proteinuria, and delay mortality in a lupus-prone murine model. We conducted a 40 d, phase Ib, randomized, double-masked, placebo-controlled trial to determine the safety and pharmacokinetics of rhDNase, and to measure any changes in markers of disease activity in 17 patients with lupus nephritis. Patients were assigned to receive either: (1) 25 mg/kg rhDNase (n=8); (2) 125 mg/kg rhDNase (n=6); or (3) placebo (n=3) initial single intravenous (IV) dose followed by 10 subcutaneous (SC) doses. Skin biopsies performed on nine patients pre-and post-treatment were studied for immune complex deposition by immunofiuorescence. Serum cytokine levels (sIL2-R, IL-6, IL-10, and TNF-a) were analyzed by ELISA. Cytokine secretion and antibody production were measured by ELISPOT analysis and ELISA. Serum hydrolytic activity of rhDNase was achieved after IV administration at 25 and 125 mg/kg, but not after SC administration at either dose. A t12 of 3–4 h was estimated from serum concentration profiles following IV administration. Serum dsDNA antibodies were unchanged (mean values: 33 IU/mL vs 39 IU/mL [pre-and post-treatment] for the 25 mg/kg group, and 74 IU/mL vs 74 IU/mL for the 125 mg/kg group, and 14 IU/mL vs 20 IU/mL for the placebo group). Complement levels (C3 and C4) and circulating immune complexes did not change appreciably during the treatment period for any of the groups. Serum cytokine profiles by ELISA revealed no changes in sIL-2 receptor, IL-6, IL-10, or TNF-a. There was no change in the number of cells secreting either Th1 or Th2 specific cytokines, nor in the number of cells secreting dsDNA antibodies. Neutralizing antibodies to rhDNase were not detected in serum at any time during the study. Immune complex deposition was unchanged in pre-and post-treatment in skin biopsies in both dose groups. rhDnase was well tolerated without significant adverse events following administration, and treatment was not associated with the development of neutralizing antibodies to rhDNase. Serum rhDNase concentrations capable of hydrolytic activity of rhDNase were achieved for a few hours following IV, but not SC administration. Serum markers of disease activity were unchanged during the study period.