Associations of B cell-activating factor (BAFF) and anti-BAFF autoantibodies with disease activity in multi-ethnic Asian systemic lupus erythematosus patients in Singapore.

To measure the levels of B cell-activating factor (BAFF) and endogenous anti-BAFF autoantibodies in a cohort of multi-ethnic Asian systemic lupus erythematosus (SLE) patients in Singapore, to determine their correlation with disease activity. Serum samples from 121 SLE patients and 24 age- and sex-matched healthy controls were assayed for BAFF and anti-BAFF immunoglobulin (Ig)G antibody levels by enzyme-linked immunosorbent assay (ELISA). The lowest reliable detection limit for anti-BAFF-IgG antibody levels was defined as 2 standard deviations (s.d.) from blank. Correlation of serum BAFF and anti-BAFF IgG levels with disease activity [scored by SLE Activity Measure revised (SLAM-R)], and disease manifestations were determined in these 121 patients. SLE patients had elevated BAFF levels compared to controls; mean 820 ± 40 pg/ml and 152 pg ± 45/ml, respectively [mean ± standard error of the mean (s.e.m.), P < 0·01], which were correlated positively with anti-dsDNA antibody levels (r = 0·253, P < 0·03), and SLAM-R scores (r = 0·627, P < 0·01). In addition, SLE patients had significantly higher levels of anti-BAFF IgG, which were correlated negatively with disease activity (r = -0·436, P < 0·01), levels of anti-dsDNA antibody (r = -0·347, P < 0·02) and BAFF (r = -0·459, P < 0·01). The majority of patients in this multi-ethnic Asian SLE cohort had elevated levels of BAFF and anti-BAFF antibodies. Anti-BAFF autoantibody levels correlated negatively with clinical disease activity, anti-dsDNA and BAFF levels, suggesting that they may be disease-modifying. Our results provide further information about the complexity of BAFF pathophysiology in different SLE disease populations and phenotypes, and suggest that studies of the influence of anti-cytokine antibodies in different SLE populations will be required when selecting patients for trials using targeted anti-cytokine therapies.

[Establishment of a model of hydrogen peroxide-induced injury in pulmonary artery endothelium cells and relevant mechanisms of oxidative stress].

Objective: To establish a hydrogen peroxide (H(2)O(2)) induced injury model of pulmonary artery endothelial cells (PAECs) and explore the molecular mechanisms of oxidative stress on the structure and function of PAECs in this model. Methods: Human PAECs were treated with H(2)O(2) at different concentrations (25, 50, 100, 200, 400, 800, 1 600, 3 200, 6 400 µmol/L) for 4 and 24 h, respectively. The PAECs survival curve was obtained according to the cell viability measured by CCK-8 assay. The cell apoptosis of PAECs was detected by flow cytometry. The reactive oxygen species (ROS) generation and mitochondrial activity were measured using small molecule fluorescent probes. Proteins were extracted and the phosphorylation levels of signal molecules in PAECs were detected by Western blot assays. Results: (1) The effect of H(2)O(2) at various concentrations on cell viability of PAECs: cell viability of PAECs decreased in proportion to increasing concentration of H(2)O(2) after incubation for 4 h. The half maximal inhibitory concentration (IC(50)) of PAECs exposed to H(2)O(2) for 4 and 24 h were 397.00 and 488.77 µmol/L, respectively. (2) The effect of H(2)O(2) on cell apoptosis of PAECs: After H(2)O(2) incubation for 4 h, proportions of PAECs at late-apoptosis ((22.58±3.69) %) and necrotic stage( (11.86±4.27)%) were significantly higher than those of control PAECs at late-apoptosis stage( (3.41±1.44)%, P<0.01) and at necrotic stage ((1.94±1.15) % , P<0.05). The survival rate of PAECs post H(2)O(2) was dramatically lower than that of control PAECs ((7.98±3.21)% vs. (48.89±8.08)%, P<0.01). However, there is no statistical difference between both groups regarding to the early apoptosis. (3) The effect of H(2)O(2) on mitochondrial activity and ROS production of PAECs: the mitochondrial activity and ROS generation of PAECs treated by H(2)O(2) were significantly increased compared to those in control PAECs (P<0.01). (4) The effect of H(2)O(2) on signaling molecules in PAECs: there was a significant increase in phosphorylation level of Akt in PAECs incubated with H(2)O(2) for 30 minutes compared to that in control PAECs (P<0.01), while there was no significant difference in levels of Akt between H(2)O(2) treated PAECs and control PAECs. Phosphorylation level of JNK as well as p38 were also significantly upregulated in H(2)O(2) treated PAECs (P<0.01). Conclusion: H(2)O(2) at the concentration of 400 µmol/L could induce human PAECs injuries via the regulation of Akt and MAPK signaling pathways.

Amicrobial pustulosis associated with autoimmune disease in a patient with Sjögren syndrome and IgA nephropathy.

Amicrobial pustulosis associated with autoimmune disease (APAD) is a rare clinical condition, characterized by relapsing pustular eruption, affecting mainly the skin folds. Almost all previously described cases were young women with varying underlying autoimmune diseases. We report a 36-year-old woman with the interesting triad of APAD, Sjögren syndrome and IgA nephropathy. Her rashes responded to oral prednisolone and cyclophosphamide.

Major gastrointestinal manifestations in lupus patients in Asia: lupus enteritis, intestinal pseudo-obstruction, and protein-losing gastroenteropathy.

Gastrointestinal (GI) symptoms are common in patients with systemic lupus erythematosus (SLE) and may be due to the disease itself, side-effects of medications, or non-SLE causes. However, GI manifestations of lupus attract far less attention than the other major organ involvements, are infrequently reviewed and rarely documented in published lupus databases or cohort studies including those from countries in Asia. According to three reports from two countries in Asia, the cumulative prevalence of SLE GI manifestations range from 3.8% to 18%. In this review, we focus on three major GI manifestations in patients from Asian countries: lupus enteritis, intestinal pseudo-obstruction, and protein-losing gastroenteropathy, for which early recognition improves outcome and reduces morbidity and mortality.

Discordant assessment of lupus activity between patients and their physicians: the Singapore experience.

Patients with systemic lupus erythematosus often assess their disease activity differently from their physicians. We studied the factors associated with this discordance. The data provided by 534 systemic lupus erythematosus patients were analyzed. We compared the physician and patient assessments of lupus activity on a visual-assessment scale from the same visit. We collected clinical data and scores from MOS 36-Item Short-Form Health Survey, Systemic Lupus Erythematosus Quality-of-Life Questionnaire, Rheumatology Attitudes Index, Systemic Lupus Erythematosus Disease Activity Index, and revised Systemic Lupus Activity Measure. Patients tended to score their disease activity higher than do their physicians, when these factors were present: poorer general health assessment, presence of thrombocytopenia, hypertension and urinary sediments, and difficulty in carrying groceries. Physicians tended to score the disease activity higher than do the patients in these circumstances proteinuria, hemolysis, use of azathioprine or cyclophosphamide, tiredness, photosensitivity, higher revised Systemic Lupus Activity Measure score, casturia, and patient report of being more easily ill than are other patients. There was only moderate correlation between the discordance in the baseline and the subsequent visits. The physician assessment of disease activity at baseline correlated better with an objective measure of disease activity (revised Systemic Lupus Activity Measure) in the subsequent visit than the patient assessment. In conclusion, discordance in the perception of disease activity between patients and physicians may be amenable to intervention.

Enhanced expression of interferon-inducible protein-10 correlates with disease activity and clinical manifestations in systemic lupus erythematosus.

Our objective was to investigate the serum levels of interferon-inducible protein-10 (IP-10) in systemic lupus erythematosus (SLE) and their correlation with disease activity and organ manifestations. Serum IP-10 levels were assessed in 464 SLE patients and 50 healthy donors. Disease activity was assessed by the revised SLE Activity Measure, and the concomitant active organ manifestations, anti-ds DNA antibody titres, complement levels and erythrocyte sedimentation rates recorded. Peripheral blood mononuclear cell (PBMC) synthesis of IP-10 in SLE patients and controls was determined by in vitro cultures stimulated with mitogen or lipopolysaccharide. Elevated serum IP-10 levels were observed in SLE patients, which were significantly higher in the presence of active haematological and mucocutaneous manifestations. SLE PBMCs exhibited enhanced spontaneous IP-10 production in vitro. Serial IP-10 levels correlated with longitudinal change in SLE activity, even at low levels where anti-dsDNA antibody and complement levels remain unchanged. These data demonstrate that IP-10 levels are increased in SLE and serum IP-10 may represent a more sensitive marker for monitoring disease activity than standard serological tests.

A case of nephrogenic fibrosing dermopathy.

INTRODUCTION: Nephrogenic fibrosing dermopathy is a recently recognised fibrosing disorder originally identified as a scleromyxoedema-like cutaneous disease in patients with renal disease. CLINICAL PICTURE: A 45-year-old lady with systemic lupus erythematosus presented with well-defined erythematous, non-tender, indurated plaques on both legs 4 months after haemodialysis for rapidly progressive glomerulonephritis and acute renal failure. Skin biopsy showed dermal fibrosis with increased proliferation of dermal fibroblasts and collagen bundles separated by clefts. There were increased dermal deposits of mucin and an increase in elastic fibres. TREATMENT AND OUTCOME: Haemodialysis was instituted for 2 weeks followed by monthly intravenous cyclophosphamide. Skin lesions remained unchanged 8 months later despite normalisation of renal function. CONCLUSION: Nephrogenic fibrosing dermopathy appears to be a definite new entity in patients with underlying renal insufficiency. Further multi-centre collaborative study is necessary to identify the prevalence, cause, treatment and prognosis of this disorder.

Acute lupus myocarditis: clinical features and outcome of an oriental case series.

Symptomatic myocarditis in systemic lupus erythematosus (SLE) is uncommon. We describe the clinical characteristics, management and outcomes of 11 SLE patients without any atherosclerotic risk factors, who presented with acute lupus myocarditis (ALM). All patients were female, 46% Chinese with mean age of 27 +/- 10 years at diagnosis of SLE. ALM was one of the initial manifestations of SLE in eight (73%) patients. The median duration from onset ALM to initiation of treatment was two weeks (range: 0.3-8). All had clinical feature of left ventricle dysfunction. The most common electrocardiographic feature was nonspecific ST/T wave changes (91%). Common echocardiographic findings included segmental wall motion abnormalities (81%) and decreased left ventricular ejection fraction (81%). Median SLE disease activity index at presentation was 16 (range: 4-30). All patients received high dose corticosteroids and 64% received intravenous pulse cyclophosphamide. There were two deaths (18%) from infections. The remaining nine survivors had no recurrence of ALM nor suffer any SLE-related damage (median SLICC damage score of 0), up to a median follow-up of four years (range: 2.5-10.1). Repeat echocardiography after six months or later showed normal LVEF in eight patients (89%). Early immunosuppressive therapy in ALM, with high dose corticosteroids and pulse intravenous cyclophosphamide, results in good cardiac outcome.

Transforming growth factor beta-1 and gene polymorphisms in oriental ankylosing spondylitis.

OBJECTIVES: To study serum levels of transforming growth factor beta-1 (TGFbeta1) and the expression of TGFbeta1 in in vitro peripheral blood mononuclear cell (PBMC) cultures in oriental ankylosing spondylitis (AS) patients, and to determine their association with codon 10 and 25 TGFB1 gene polymorphisms. METHODS: Serum levels of TGFbeta1 were measured by enzyme-linked immunosorbent assay (ELISA). The ability of PBMCs to synthesize TGFbeta1 and other cytokines was assessed by in vitro cultures stimulated with mitogen. Genomic DNA was extracted from PBMCs of AS patients (n=72) or unrelated healthy controls (n=96). The codon 10 and 25 polymorphisms in the TGFB1 gene were analysed using standard polymerase chain reaction-based methods. RESULTS: AS patients had significantly higher serum TGFbeta1 levels than controls (P<0.001). There was no difference in the distribution of codon 10 and 25 TGFB1 genotypes between AS patients and controls. Incubation of AS and control PBMC with phytohaemagglutinin (PHA) led to upregulation of TGFbeta1, interleukin-10, tumour necrosis factor-alpha (TNFalpha) and interferon-gamma (IFNgamma) assessed by ELISA. Importantly, PHA-induced TGFbeta1 production was significantly enhanced in AS patients compared with normal controls whereas the production of the pro-inflammatory cytokines TNFalpha and IFNgamma was reduced. CONCLUSIONS: Our results show that AS patients express significantly higher levels of serum TGFbeta1 independent of the codon 10 and 25 genotype. Activation of AS PBMCs led to enhanced TGFbeta1 production accompanied by reduction of TNFalpha and IFNgamma while the converse was observed in normal controls.

Development and preliminary validation of a systemic lupus erythematosus-specific quality-of-life instrument (SLEQOL).

OBJECTIVES: Systemic lupus erythematosus (SLE), a chronic illness with an unpredictable and variable course, profoundly affects the quality of life (QOL). General health questionnaires are used to assess QOL in SLE, but a disease-specific instrument could offer enhanced responsiveness and content validity. We detail the steps we took to develop and validate a new SLE-specific QOL instrument, SLEQOL. METHODS: Rheumatology professionals nominated items that they felt were important determinants of QOL of SLE patients. One hundred SLE patients were asked to assess the importance and frequency of occurrence of these items and to suggest those that had not been listed. Item reduction was performed using Rasch model and factor analyses to create a new questionnaire in English. This final questionnaire was administered to a cohort of 275 patients to study its psychometric properties. RESULTS: Fifty-one items covering a wide range of QOL concerns were identified. The patients' responses led to the elimination of 11. The new questionnaire of 40 items was found to have Cronbach's alpha of 0.95 and to consist of eight domains covering physical, mental and social QOL issues. It has good test-retest reliability, poor to fair cross-sectional correlation with the SF-36, with poor correlation with lupus activity or damage indices. The SLEQOL was more responsive to change than the SF-36. CONCLUSIONS: We have developed a new 40-item SLEQOL in English and showed that it is valid for use in SLE patients in Singapore. It offers better content validity and responsiveness to change than the SF-36.

Reversible acute gastrointestinal syndrome associated with active systemic lupus erythematosus in patients admitted to hospital.

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 retrospective review 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 > or = 4 in 83% of patients. CT scanning showed evidence of serositis and bowel involvement in 63% of patients who underwent this investigation. Intravenous (iv) fluids were used in 87%, parenteral steroids in 90% and iv cyclophosphamide in 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.

Hospitalization of individuals with systemic lupus erythematosus: characteristics and predictors of outcome.

We performed a retrospective study of patients with systemic lupus erythematosus (SLE) admitted to hospital during a one-year period to describe characteristics associated with a poor outcome. There were 348 episodes of hospitalization of 223 individuals. The cause of admission was clinical flare of SLE (58%), infection (37%) and thromboembolic disease (8%). Readmission occurred in 35.8% and was associated with: active nephritis (HR 2.53, P < 0.01), flare of lupus (HR 2.0, P < 0.01) and more ACR criteria (HR 1.34 per extra criteria, P < 0.01). Individuals with multiple reasons for admission had a longer duration of stay [one = four days (2, 6), two = five days (3, 7) and three = 9.5 days (6.5, 14.5), P < 0.01]. There were 11 deaths (3.2% of admissions). The deaths were due to infection in nine cases (four with concurrent active SLE). In multivariate modelling, the main predictors of death were: previous multiple admissions (OR 12.4, P < 0.01), the presence of infection (OR 7.3, P < 0.01) and younger age (OR 0.93 per increase of one year, P = 0.03). The presence of active lupus nephritis and multisystem disease makes readmission more likely and individuals with multiple problems at the time of admission have longer hospital stays. Young patients with frequent readmissions and coexistent infections are most likely to die.

Low-dose pulse methylprednisolone for systemic lupus erythematosus flares is efficacious and has a decreased risk of infectious complications.

We sought to test our clinical impression that using a low dose methylprednisolone pulse (MEP; < or = 1500 mg over 3 days) in treating flares of systemic lupus erythematosus (SLE) was effective and associated with fewer serious infections. We retrospectively studied SLE patients who received MEP between 1989 and 2000. A 'low dose' group of 26 patients who had received 1-1.5 g and a 'high dose' group of 29 patients who received 3-5 g of MEP were identified. SLEDAI scores and prednisolone doses were recorded at the time of MEP pulses and 6 months later. All serious infections (requiring admission and i.v. antibiotics) occurring during this 6 month period and their outcomes were recorded. Both groups had similar demographic data, initial SLEDAI scores, i.v. cyclophosphamide use, and SLE organ involvement. Despite high- and low-dose MEP being efficacious in controlling disease activity (lowering of SLEDAI scores and subsequent prednisolone dose) there were only nine episodes of serious infection in seven patients in the low-dose group compared with 20 episodes in 17 patients from the high-dose group (P = 0.04). In both groups a majority of infections (75 and 77% in the high- and low-dose groups) occurred in the first month after MEP. Those with a low serum albumin (< 20 g/l) had an increased risk of mortality (OR 44, 90% CI 6.19-312.98) and a trend towards greater numbers of infections. Low-dose MEP was effective in controlling SLE flares and associated with fewer serious infections than traditional high-dose MEP.