Lumbar spine bone mineral density predicts endothelial reactivity in patients with systemic lupus erythematosus.

OBJECTIVES: To explore whether endothelial function is related to bone mineral density (BMD) in patients with systemic lupus erythematosus (SLE). METHODS: Consecutive adult SLE patients and age-, sex-, BMI- and smoking-status-matched healthy controls were studied. Subjects with hypertension, hyperlipidemia, diabetes mellitus, renal impairment, dysthyroidism, history of or treatment for cardiovascular and cerebrovascular disorders, antiphospholipid syndrome, positive antiphospholipid antibodies or bone loss were excluded. Endothelial function was assessed by measuring flow-mediated dilatation (FMD) at the brachial artery and carotid intima-media thickness (IMT) by ultrasound. Lumbar and hip BMD were measured by dual-energy x-ray absorptiometry. Fasting blood samples were assayed for atherogenic index and high sensitivity C-reactive protein (hsCRP). Regression models were constructed to study the relationship between FMD and BMD. RESULTS: One hundred and ten subjects (55 SLE and 55 matched healthy controls) were studied. While there were no differences between SLE patients and controls in menopausal status, blood pressure, atherogenic index, carotid IMT and BMD, SLE patients had significantly poorer FMD even after adjustment for age, gender, smoking and baseline brachial artery diameter. Also, SLE patients with lumbar osteopenia had significantly lower FMD than those with normal BMD. Multivariate regression revealed that lower FMD was associated with lower lumbar BMD and higher serum hsCRP in SLE patients, but these relationships were absent amongst healthy controls. CONCLUSIONS: Lumbar vertebral BMD predicted endothelial reactivity in SLE patients without clinically-overt bone loss and atherosclerosis. Thus, early atherosclerotic disease should be considered in lupus patients especially if vertebral bone loss is evident.

Use of rituximab in the treatment of refractory systemic lupus erythematosus: Singapore experience.

We performed a retrospective study of 10 patients with refractory systemic lupus erythematosus treated with rituximab to determine the efficacy, safety and impact on hospitalization days. Patients received rituximab according to a standardized protocol, all achieved B-cell depletion with clinical improvement in nine patients. At 12 months, BILAG scores improved significantly from a median of 13.5 (range 3-20) at baseline to 1 (range 0-27) (p < 0.05). There was significant reduction in urinary total protein excretion with stabilization of renal function in patients with nephritis. Two out of three patients with thrombocytopenia had normalization of platelet counts. The median duration of B-cell depletion was 6 months (range 6-18). Two patients required retreatment and responded well. There were no adverse outcomes following rituximab therapy. Patients with lupus nephritis spent a median of 17.1 days per year (range 1.9-49) in hospital on conventional treatment which was reduced to 0 days (range 0-14.8, p = 0.027) post-rituximab treatment. The cost of hospitalization was 5989 Singapore dollars per patient-year while on conventional treatment and 5792 Singapore dollars per patient-year post-rituximab. This study adds to the growing literature of rituximab efficacy with potential cost saving in lupus nephritis.

Atherogenic serum lipid profile is an independent predictor for gouty flares in patients with gouty arthropathy.

OBJECTIVE: Atherogenic serum lipid profile possesses pro-inflammatory properties and is associated with more active RA. While prevalent in patients with gout, whether atherogenic lipid profile is associated with gouty flares is unknown. This study aims to investigate whether atherogenic serum lipid predicts gouty flares in patients with gout. METHODS: Adult patients (age > or =21 yrs) who suffered from gout were prospectively followed between September 2006 and November 2007 and their demographic, clinical and laboratory data were collected. Episodes of gouty flares over this observation period were recorded and factors predictive of gouty flares were studied by regression models. RESULTS: Of the 100 patients, 80 were men, 65 were ethnic Chinese, 31 were Malay and the rest were Indian and Caucasian. The mean age and duration of gout (+/-S.D.) were 61.9 +/- 14.0 and 6.6 +/- 7.8 yrs, respectively. The mean serum uric acid and creatinine levels were 537.6 +/- 142.8 and 173.6 +/- 119.9 micromol/l, respectively. In univariate analysis, longer duration of gout, higher adjusted mean serum creatinine, lower adjusted mean fasting serum, total cholesterol and high-density lipoprotein cholesterol (HDL-C) levels were associated with gouty flares. After adjustment for potential confounders in multivariate regression models, longer duration of gout and lower adjusted mean fasting serum HDL-C level remained independently predictive of gouty flares. CONCLUSIONS: Low serum high-density lipoprotein cholesterol level was an independent predictor for gouty flares. Whether optimizing serum HDL-C level can benefit patients with gout in terms of reducing gouty flares needs to be addressed by controlled trials.

Favourable outcome of AIDS-related multi-centric central nervous system Epstein-Barr virus-associated smooth muscle tumour with surgery and adjuvant radiation therapy: a case study and literature review.

Epstein-Barr virus-associated smooth muscle tumour (EBV-SMT) is a unique condition which affects immunocompromised patients. We describe the favourable outcome of a patient with acquired immune deficiency syndrome (AIDS)-related multi-centric EBV-SMT involving the posterior fossa and spine treated with surgery and adjuvant volumetric modulated arc therapy comprising 50 Gy in 25 fractions to four sites initially to the brain and lumbar spine followed by sixth to ninth thoracic vertebrae (T6-T9) and sacrum a year later. Reported literature suggests that AIDS-related EBV-SMTs are more sensitive to radiotherapy. However, compliance to the highly active anti-retroviral therapy is paramount in preventing future recurrence. This case also emphasises the importance of multidisciplinary management in ensuring the best possible outcome.

HLA-DRB1*04 gene polymorphisms and expressions profiles of interleukin-18 and interleukin-18 binding protein following in vitro stimulation in human peripheral blood mononuclear cells of healthy individuals and patients with rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic arthritic condition that can lead to deformities and disabilities. Interleukin-18 (IL-18) is a proinflammatory cytokine known to play a role in the acute and chronic inflammatory phases of RA. IL-18 binding protein is the natural antagonist of IL-18 protein. We aim to identify the effect of HLA-DRB1*04 gene polymorphisms on IL-18 and IL-18BP gene expressions profiles as well as the time-course profiles following in vitro stimulation with mitogens. Peripheral blood mononuclear cells from 16 RA patients and 21 healthy controls were cultured for 1, 4, 8, 12, 24, 48 and 72 h following stimulation with either LPS or PHA. mRNA expression of IL-18 and IL 18BP were determined by quantitative real-time PCR using a comparative Ct (threshold cycle) method. IL-18 levels in supernatants were measured by enzyme-linked immunosorbent assay. Basal mRNA (4.5-fold) and protein levels of IL-18 were increased and IL-18BP mRNA expression was decreased (8-fold) in RA patients when compared to controls. Similarly, increased IL-18 levels were observed in active RA patients, whereas IL-18BP expression was increased in inactive patients. There was an increase in mRNA and protein levels of IL-18 in RA patients that peaked at 4 h and 8 h respectively following LPS stimulation. A similar profile was observed for IL-18BP; however, the expression level was higher in controls than RA patients. Persistent high production of IL-18 in RA is associated with disease progression and IL-18 BP seems to inhibit this activity.

Myofasciitis and polyneuritis related to Buprenorphine abuse.

Various kinds of neuromuscular manifestations are known with the recreational drugs. We report an interesting case of extensive myositis and fasciitis of thigh following an injection of a solution of Buprenorphine. The inflammatory process affected the sciatic and obturator nerve as well.

Relapsing polychondritis--an Oriental case series.

INTRODUCTION: Relapsing polychondritis (RPC) has been described mainly in Caucasian populations. Reports from other ethnic groups are few. OBJECTIVES: To describe the clinical characteristics, management and outcome of RPC patients seen in an Oriental population in Singapore. METHODS: The case records of RPC patients treated in our department from 1989 to 2001 were reviewed. Only 12 fulfilled the McAdam-Michet-Damiani-Levine diagnostic criteria and these were studied. RESULTS: The female-to-male ratio in our series was 3:1. There were 10 ethnic Chinese and two Malay patients. The age of onset of symptoms ranges from three to 65 years, with a mean of 34 years. A diagnosis was made from two weeks to three years after onset, with a median of 4.5 months. There were 10 patients with pinna, nine articular, eight ocular, six laryngotracheal, five inner ear, four nasal and one cardiac involvement. Five presented with fever. None of them had cutaneous, renal or central nervous system involvement. Ten had raised ESR at presentation. One patient developed discoid lupus erythematosus two years later. All 12 patients received prednisolone with eight of them requiring additional immunosuppressants. Two patients had resistant disease failing to respond adequately to various immunosuppressants together with prednisolone. There was no mortality amongst the nine patients who had remained on follow-up at the time of this report. Five of the six patients with laryngotracheal involvement had tracheostomy and one of them had airway stenting as well. CONCLUSION: Our series suggests that although the clinical manifestations of RPC are similar in the Oriental and the Caucasian populations, Oriental patients may have less cutaneous, renal or nervous system involvement and more serious airway complications.

New cyclooxygenase inhibitors.

INTRODUCTION: The discovery of the two isoforms of cyclooxygenase (COX-1 and COX-2) has paved the way for the development of a new class of non-steroidal anti-inflammatory drugs (NSAIDs). The COX-2 inhibitors have shown comparable efficacy to the traditional NSAIDs with less gastrointestinal side effects in major clinical studies. The aims of this paper are to provide a brief historical background, pharmacology of cyclooxygenase inhibitors as well as discuss the latest update on COX-2 inhibitors. METHODS: A MEDLINE search was performed for relevant articles from leading medical journals from 1990 to 2000. The papers reviewed include randomised controlled clinical trials, meta-analyses and review articles. CONCLUSION: The arrival of the COX-2 inhibitors into the treatment armamentarium for inflammation and analgesia has been widely accepted and welcomed. Although this new group of "wonder" drugs cause less gastrointestinal side effects, they are not renal sparing and do not have cardioprotective effects. Studies have also yet to establish its safety in NSAID-sensitive patients. In patients with chronic arthritides, cost is also an important factor to consider when prescribing these medications. Their strengths and weaknesses will become apparent with continued use.

Validity and reliability of the EQ-5D self-report questionnaire in Chinese-speaking patients with rheumatic diseases in Singapore.

OBJECTIVE: We assessed the psychometric properties of a Singaporean Chinese version of the EQ-5D, a health-related quality of life (HRQoL) instrument. MATERIALS AND METHODS: Consecutive outpatients with rheumatic diseases seen for routine follow-up consultations at the National University Hospital, Singapore were interviewed twice within 2 weeks using a standardised questionnaire containing the EQ-5D, the Short-Form 36 Health Survey (SF-36), the Learned Helplessness Subscale, a pain Visual Analogue Scale (VAS) and assessing demographic and psychosocial characteristics. To assess the validity of the EQ-5D, 13 hypotheses relating the EQ-5D self-classifier (5 dimensions) or visual analogue scale (EQ-VAS) to SF-36 scores or other variables were examined using the Mann-Whitney U test, Kruskal-Wallis or Spearman's correlation coefficient. Test-retest reliability was assessed using Cohen's kappa. RESULTS: Forty-eight subjects were studied (osteoarthritis: 16; rheumatoid arthritis: 22; systemic lupus erythematosus: 8; spondyloarthropathy: 2; female: 93.8%; mean age: 56.4 years). Seven of 13 a-priori hypotheses relating EQ-5D to external variables were fulfilled, supporting the validity of the EQ-5D. For example, subjects reporting moderate or extreme problems for EQ-5D dimensions generally had lower median SF-36 scores than those without such problems. Cohen's kappa for test-retest reliability of the self-classifier ranged from 0.41 to 1.00 (n = 42; median interval: 7 days, interquartile range: 7 to 11 days). CONCLUSIONS: The Singaporean Chinese EQ-5D self-classifier appears to be a valid measure of HRQoL in Singaporeans with rheumatic diseases; however, the reliability of the EQ-VAS requires further investigation. These data provide a basis for further studies of the Singaporean Chinese EQ-5D.

Lipidomic analysis of human placental syncytiotrophoblast microvesicles in adverse pregnancy outcomes.

PROBLEM: Syncytiotrophoblast microvesicles (STBM) are shed from placenta into the maternal circulation. STBM circulate in increased amounts in adverse pregnancies, e.g., preeclampsia and recurrent miscarriages (RM). Recently dysregulation of lipid metabolites has been proposed to be associated with their pathogenesis. Lipid composition of STBM in healthy and adverse pregnancies remains unknown. OBJECTIVE: To determine lipid composition of STBM and whether STBM lipid composition differs in pathologic and normal pregnancies. STUDY DESIGN: Patients with Preeclampsia (n = 6) or history of RM (n = 9) (>2 consecutive losses <20 weeks) and gestational age-matched normal pregnant controls (same number as cases) were recruited. STBM were prepared from placental explant culture supernatant. Lipid profiling of STBM was performed by mass spectrometry in combination with liquid chromatography. We quantified ∼200 lipids in STBM including (i) glycerophospholipids (phosphatidylcholine, PC; phosphatidylethanolamine, PE; phosphatidylinositol, PI; phosphatidylglycerol, PG; phosphatidylserine, PS; phosphatidic acid, PA); (ii) sphingolipids (sphingomyelin, SM; ceramide, Cer; Glucosylceramide, GluCer; ganglioside mannoside 3, GM3); (iii) free cholesterol and cholesteryl esters, CE. RESULTS: The major lipid classes in STBM were SM, Chol, PS, PC and PI, along with PA and GM3 enrichments. SM/PC ratio showed a unique reversal (3:1) compared to that normally found in human cells or plasma. Level of total PS was significantly upregulated (p < 0.005) in preeclampsia patients, while PI (p < 0.0005), PA (p < 0.005), and GM3 (p < 0.05) were significantly downregulated. Similar trends were obtained in RM. CONCLUSIONS: Differential lipid expression of STBM in preeclampsia or RM includes those that are implicated in immune response, coagulation, oxidative stress, and apoptosis.

Drug-induced lupus: an update.

Drug-induced lupus erythematosus (DILE) is a lupus-like illness that has been recognized as an entity under environmentally-induced lupus erythematosus, where other agents such as physical (ultra-violet irradiation), chemical (heavy metals, aromatic amines) and food products (alfalfa sprouts) have been implicated. DILE has been accepted as a side effect of therapy with over 80 drugs since its first description in association with sulfadiazine in 1945. The epidemiology and clinical course of SLE and DILE differ markedly and prognosis is generally favourable in the latter although occasional life-threatening cases have been reported in the literature. Constant pharmacovigilance is crucial for prompt diagnosis and cessation of offending therapy offers the best outcome. This review discusses the clinical presentation, diagnosis of DILE as well as provides an update on postulated pathogenic mechanisms and an overview of implicated drugs.

Theory, targets and therapy in systemic lupus erythematosus.

The treatment of systemic lupus erythematosus (SLE) has been refined over the years, with the recognition that a fine balance lies between aggressive and prompt therapy and attendant complications brought upon by immunosuppressive therapy itself. However, there has been limited change to the repertoire of drugs available to treat this challenging disease. The current standard therapy for severe manifestations of SLE includes the use of high-dose corticosteroids and cytotoxic agents such as cyclophosphamide (CYC), which have been associated with an increased risk of serious and opportunistic infections. The need for safer, more targeted therapies has been recognized and now, with the exponential increase in the understanding of immunopathogenic mechanisms in SLE, the way has been paved for the development of biologic or targeted therapies in SLE. Although the potential immunosuppression, long-term safety issues and cost-effectiveness remain unclear. These targeted therapies may range from small molecules that specifically inhibit inflammatory processes at an intracellular, cell-cell or cell-matrix level to monoclonal antibodies, soluble receptors or natural antagonists that interfere with cytokine function, cellular activation and inflammatory gene transcription.

Methicillin-resistant Staphylococcus aureus endocarditis after transurethral prostatic resection.

We report the first case, to our knowledge, of methicillin-resistant Staphylococcus aureus endocarditis complicating transurethral prostatic resection for benign prostatic hyperplasia. The patient had been catheterized preoperatively because of urinary retention and, postoperatively, developed pyrexia with persistent methicillin-resistant S. aureus-positive blood cultures. The cause remained elusive, despite extensive investigations (including echocardiography), until he developed embolic phenomena pathognomonic of infective endocarditis 1 month into treatment with intravenous vancomycin.

Orthopaedic manifestations of the antiphospholipid (Hughes) syndrome.

The antiphospholipid (Hughes) syndrome (APS), is characterized by arterial and/or venous thrombosis and pregnancy morbidity in association with antiphospholipid antibodies (aPL). Since its classical description 21 years ago, the clinical spectrum of Hughes syndrome has embraced the realms of obstetrics, nephrology, cardiology, neurology, gastroenterology and now, possibly orthopaedics. This is not surprising, given that this disease can affect virtually any organ system and blood vessel of any size and nature. Just as venous thrombosis may affect limbs and internal organs, arterial thrombosis has been shown to affect organs such as the brain, eye, heart, kidney, liver and may also involve the skeleton. In this review, the skeletal aspects of Hughes syndrome, postulated pathogenesis and possible implications of anticoagulation will be discussed. Finally, the approach to APS patients undergoing orthopaedic surgery shall also be outlined.

Organization and delivery of long-term care in Singapore: present issues and future challenges.

This paper focuses on the Singaporean model of long-term care for older people. With only about 2% of the older population living in institutions, the mainstay of long-term care is community care. The reader is provided an overview of the Singaporean services, including case management, followed by a discussion of the current issues and future challenges. In keeping with the prospect of a rapidly aging population profile, the Singapore government plays a leading role in framing policy and planning for future needs of this sector of the population.

Refractory immune thrombocytopenia in systemic lupus erythematosus: response to mycophenolate mofetil.

Immune thrombocytopenia (IT) is a common manifestation of systemic lupus erythematosus (SLE). Although severe IT (<20 x 10(9)/L) occurs in about 5-10% of patients, usually in the context of active disease, the absence of randomized controlled trials has not allowed the development of evidence-based guidelines for managing this condition. Conventionally, high-dose glucocorticoids are considered first-line therapy. Adjunctive medical and surgical treatments for patients with an absent or partial response to glucocorticoids have met with varying degrees of success. We describe an SLE patient with IT refractory to high-dose corticosteroids, pulse methylprednisolone and intravenous immunoglobulin therapy, whose platelet counts normalized during therapy with mycophenolate mofetil (MMF). Pending further controlled studies to confirm this observation, we suggest that MMF may be considered as a therapeutic option in the treatment of glucocorticoid-refractory immune thrombocytopenia in SLE.

Thrombotic thrombocytopenic purpura in systemic lupus erythematosus: disease activity and the use of cytotoxic drugs.

Thrombotic thrombocytopenic purpura (TTP) is a rare and occasionally fatal haematologic disorder that can coexist with systemic lupus erythematosus (SLE) and other autoimmune diseases. We identified all cases of TTP seen in our institution over a 3 year period using a computerized database. We found that SLE activity (measured by the SLE Disease Activity Index) and TTP activity ran a parallel course in three patients with coexistent SLE and TTP. TTP in these three patients, although refractory to plasmapheresis, responded to cytotoxic therapy. These observations further support an autoimmune contribution to the pathogenesis of some cases of TTP. A literature review revealed that mortality in SLE patients with more severe, refractory TTP treated with plasmapheresis and cytotoxics, may not be higher than in patients responding to plasmapheresis alone (who are likely to have milder disease). These data suggest that cytotoxics may have a role in treatment of patients with active SLE and TTP refractory to plasmapheresis.