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.

Clinical and immunochemical profiles of food challenge proven or anaphylactic shrimp allergy in tropical Singapore.

BACKGROUND: Shellfish allergy in Singapore is highly prevalent, and shrimp allergy is the most common. OBJECTIVE: This study aims to evaluate the clinical characteristics and immunological phenotype of shellfish allergy in this population. METHODS: Patients with self-reported shellfish allergy were recruited from outpatient clinics of three large hospitals and from a population survey. Open oral food challenges (OFC) to glass prawn (Litopenaeus vannamei) and tiger prawn (Penaeus monodon) were carried out on all patients except for those who had a history of severe anaphylaxis. Skin prick tests (SPT) and specific IgE to crude and recombinant allergens were carried out to evaluate shrimp and dust mite sensitization. Immunoblots were used to assess IgE-binding proteins. RESULTS: The 104 patients recruited were categorized into shellfish allergic (SA) when OFC was positive or had a history of severe anaphylaxis (n = 39), shellfish tolerant (ST) when OFC was negative (n = 27), and house dust mite positive controls (HDM(+) ) who were ST (n = 38). Oral symptoms (87.1%) were the predominant clinical manifestation. Positive challenge doses ranged from 2 to 80 g of cooked shrimp, with 25/52 patients reacting to either one or both shrimps challenged. The presence of specific IgE to shrimp either by SPT and/or ImmunoCAP(®) assay provided diagnostic test sensitivity of 82% and specificity of 22.2%. The inclusion of specific IgE to shrimp tropomyosin and IgE immunoblots with shrimp extracts did not improve the diagnostic proficiency substantially. CONCLUSIONS AND CLINICAL RELEVANCE: This study highlights the predominance of oral symptoms in shrimp allergy in tropical Asia and that a high provocation dose may be necessary to reveal shrimp allergy. Furthermore, specific IgE diagnostic tests and immunoblots were of limited use in this population.

T cell-mediated induction of thymic stromal lymphopoietin in differentiated human primary bronchial epithelial cells.

BACKGROUND: Inhaled peptide challenge has been shown to induce T cell-mediated, isolated late asthmatic reaction (LAR), characterized by recruitment of CD4(+) T cells and increased levels of thymus and activation-regulated chemokine (TARC; CCL17). Epithelial-derived thymic stromal lymphopoietin (TSLP) has been shown to modulate dendritic cell function to promote TH 2 responses via CCL17 production. OBJECTIVES: To elucidate the mechanisms involved in allergen-specific T cell-induced LAR and recruitment of CD4(+) T cells by examining the effects of T cell-derived factors on the induction of TSLP in primary bronchial epithelial cells (PBEC). METHODS: PBEC grown at air-liquid interface from healthy individuals and patients with asthma were stimulated with double-stranded RNA (dsRNA) or supernatants from activated allergen-specific T cells. TSLP was measured in PBEC culture supernatants. Neutralizing antibodies and signalling inhibitors were used to examine the mechanisms responsible for the induction of epithelial-derived TSLP. The functional activity of PBEC-derived TSLP was measured using a bioassay involving the induction of CCL17 production from monocyte-derived dendritic cells (moDC). RESULTS: Both dsRNA and allergen-specific T cells induced enhanced TSLP secretion from asthmatic PBEC compared to healthy PBEC. Activated PBEC culture supernatant induced TSLP-dependent CCL17 production from moDC in a manner related to clinical asthmatic status. IL-1ß, IL-6, and CXCL8, rather than TH 2 cytokines (IL-4/5/13), appeared to be the principle mediators of allergen-specific T cell-dependent induction of epithelial-derived TSLP, which was regulated by the MEK, MAPK, and NFκB pathways. CONCLUSION AND CLINICAL RELEVANCE: Our data reveal a novel effect of allergen-specific T cells as a positive regulator of TSLP production by epithelial cells, suggesting T cell-airway epithelium interactions that may lead to maintenance and amplification of allergic inflammation. TSLP is currently a candidate for therapeutic intervention in asthma, but the factors that drive TSLP expression (T cell-derived factors) may be equally relevant in the treatment of allergic inflammation.

International Consensus on drug allergy.

When drug reactions resembling allergy occur, they are called drug hypersensitivity reactions (DHRs) before showing the evidence of either drug-specific antibodies or T cells. DHRs may be allergic or nonallergic in nature, with drug allergies being immunologically mediated DHRs. These reactions are typically unpredictable. They can be life-threatening, may require or prolong hospitalization, and may necessitate changes in subsequent therapy. Both underdiagnosis (due to under-reporting) and overdiagnosis (due to an overuse of the term 'allergy') are common. A definitive diagnosis of such reactions is required in order to institute adequate treatment options and proper preventive measures. Misclassification based solely on the DHR history without further testing may affect treatment options, result in adverse consequences, and lead to the use of more-expensive or less-effective drugs, in contrast to patients who had undergone a complete drug allergy workup. Several guidelines and/or consensus documents on general or specific drug class-induced DHRs are available to support the medical decision process. The use of standardized systematic approaches for the diagnosis and management of DHRs carries the potential to improve outcomes and should thus be disseminated and implemented. Consequently, the International Collaboration in Asthma, Allergy and Immunology (iCAALL), formed by the European Academy of Allergy and Clinical Immunology (EAACI), the American Academy of Allergy, Asthma and Immunology (AAAAI), the American College of Allergy, Asthma and Immunology (ACAAI), and the World Allergy Organization (WAO), has decided to issue an International CONsensus (ICON) on drug allergy. The purpose of this document is to highlight the key messages that are common to many of the existing guidelines, while critically reviewing and commenting on any differences and deficiencies of evidence, thus providing a comprehensive reference document for the diagnosis and management of DHRs.

Post-acute phase and sequelae management of epidermal necrolysis: an international, multidisciplinary DELPHI-based consensus.

BACKGROUND: Long-term sequelae are frequent and often disabling after epidermal necrolysis (Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)). However, consensus on the modalities of management of these sequelae is lacking. OBJECTIVES: We conducted an international multicentric DELPHI exercise to establish a multidisciplinary expert consensus to standardize recommendations regarding management of SJS/TEN sequelae. METHODS: Participants were sent a survey via the online tool "Survey Monkey" consisting of 54 statements organized into 8 topics: general recommendations, professionals involved, skin, oral mucosa and teeth, eyes, genital area, mental health, and allergy workup. Participants evaluated the level of appropriateness of each statement on a scale of 1 (extremely inappropriate) to 9 (extremely appropriate). Results were analyzed according to the RAND/UCLA Appropriateness Method. RESULTS: Fifty-two healthcare professionals participated. After the first round, a consensus was obtained for 100% of 54 initially proposed statements (disagreement index < 1). Among them, 50 statements were agreed upon as 'appropriate'; four statements were considered 'uncertain', and ultimately finally discarded. CONCLUSIONS: Our DELPHI-based expert consensus should help guide physicians in conducting a prolonged multidisciplinary follow-up of sequelae in SJS-TEN.

Acute onset of systemic lupus erythematosus with extensive gastrointestinal and genitourinary involvement.

Lupus enteritis may occur as an acute presentation of systemic lupus erythematosus (SLE), and is not uncommonly associated with acute uretero-cystitis and/or hydronephrosis. Extensive involvement of the gastrointestinal tract from the stomach to the rectum in acute SLE is uncommon. We describe a 22-year-old Chinese female who presented with acute extensive gastrointestinal and genitourinary involvement who recovered following pulse intravenous methylprednisolone and cyclophosphamide. A high index of clinical suspicion is required to arrive at the diagnosis of SLE where only acute gastrointestinal and genitourinary manifestations are predominant, and other clinical, haematological and biochemical features of SLE are absent.

Neuroretinitis as an initial presentation of lupus-like illness with antiphospholipid syndrome.

Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by arterial and/or venous thrombosis, recurrent fetal losses or other pregnancy complications, and the presence of antiphospholipid antibodies (aPL). Ocular manifestations occur in 8-88% of patients with APS and are typically due to vaso-occlusive disease involving retinal and choroidal vessels. We report an unusual case of neuroretinitis as a first presentation of lupus-like illness with APS.

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.

Plasma levels of elastase-specific fibrinopeptides correlate with proteinase inhibitor phenotype. Evidence for increased elastase activity in subjects with homozygous and heterozygous deficiency of alpha 1-proteinase inhibitor.

There is indirect evidence that unopposed human neutrophil elastase (HNE) is responsible for emphysema in patients with alpha 1-proteinase inhibitor (Pi) deficiency. To directly explore this possibility, we developed an assay for fibrinopeptide A alpha 1-21 and its degradation products and used it to measure HNE activity in 128 subjects of known Pi phenotype. The mean elastase-specific fibrinopeptide (ESF) level in 49 deficient PiZ individuals is significantly higher than that in 56 PiMZ heterozygotes (4.5 and 1.5 nM, respectively; P less than 0.01), while the mean ESF value in heterozygotes is significantly elevated over that in 23 normal PiM subjects (1.5 and 0.6 nM, respectively; P less than 0.01), consistent with increased HNE activity in those deficient in the major regulator of the enzyme. These results are not due to differences in smoking history because after correction for pack-years of smoking, ESF values in PiZ subjects are fourfold higher than those in PiMZ individuals (P = 0.005), while the ESF levels in heterozygotes are threefold higher than those in PiM subjects (P = 0.02). In addition, this analysis suggests that cigarette smoking and alpha 1-proteinase inhibitor deficiency have additive effects on ESF levels thereby explaining why PiZ and some PiMZ individuals are at especially high risk for the development of lung disease if they smoke. Finally, the observation that ESF levels in nonsmoking PiZ subjects are inversely related to the percent of predicted forced expiratory volume in 1 s (FEV 1%) provides direct support for the concept that unregulated HNE activity causes alveolar septal destruction in patients with alpha 1-proteinase inhibitor deficiency.

Human tissue-type plasminogen activator releases fibrinopeptides A and B from fibrinogen.

In five patients with venous thromboembolic disease treated with recombinant tissue-type plasminogen activator (rt-PA), there was a marked increase in the mean concentrations of fibrinopeptide A (from 0.6 to 5.9 nM; P less than 0.0001) and desarginine fibrinopeptide B (from 5.6 nM to 24.1 nM; P less than 0.01) 30 min after a bolus of rt-PA (0.6 mg/kg). Thrombin was unlikely to be responsible because the levels of desarginine fibrinopeptide B exceeded those of fibrinopeptide A and the changes occurred despite concomitant heparin therapy. The purpose of this study therefore, was to determine whether rt-PA directly releases the fibrinopeptides from fibrinogen. Incubation of rt-PA with heparinized plasma or purified fibrinogen resulted in time and dose-dependent release of both fibrinopeptide A and B. Contaminating thrombin was not responsible for this activity by the following criteria: the rate of rt-PA mediated fibrinopeptide B release was considerably faster than that of fibrinopeptide A, and fibrinopeptide release was unaffected by heparin, hirudin, or a monospecific antithrombin IgG. Aprotinin also had no effect on fibrinopeptide release, indicating that this activity was not plasmin mediated. Fibrinopeptide release was shown to be due to rt-PA because this activity was completely blocked by a monoclonal antibody against the enzyme. Further, the specificity of rt-PA for the thrombin cleavage sites on fibrinogen was confirmed by the demonstration that rt-PA released fibrinopeptide A or fibrinopeptide B from fibrinopeptide A or B-containing substrates, respectively. These studies thus demonstrate that (a) rt-PA releases fibrinopeptides A and B from fibrinogen thereby indicating that this enzyme is not specific for plasminogen, and (b) plasma fibrinopeptide A and desarginine fibrinopeptide B levels are not specific markers of thrombin action on fibrinogen in patients receiving rt-PA.

Insect venom hypersensitivity: experience in a clinical immunology/allergy service in Singapore.

INTRODUCTION: To study the profile of patients with allergy to the venom of insect stings. METHODS: 31 consecutive cases referred to our clinical immunology/allergy outpatient service from June 1, 1998 to June 30, 2002 were reviewed. RESULTS: These patients comprised 3.5 percent of 889 cases referred during the study period. Their mean age was 28.8 +/- 10.5 (range 19-57) years and the majority were males (90.3 percent). Of these, 20 (64.5 percent) were Chinese, four (12.9 percent) were Malays and seven (22.6 percent) were of other races. 19 patients (61.3 percent) were men from the uniformed services including 12 (63.2 percent) full-time National Servicemen. 71 percent (22 patients) were stung for the first time. Urticaria (22 cases, 71.0 percent), dyspnoea (13, 41.9 percent), angioedema (12, 38.7 percent) and syncope (ten, 32.3 percent) were the most common manifestations of insect allergy. Anaphylaxis occurred in 22 (71.0 percent) cases, constituting 30.1 percent of all cases of anaphylaxis referred to our service during the study period. Although the causative insect was identified as honeybee (12, 38.7 percent), ant (four, 12.9 percent), wasp (three, 9.7 percent), and fire ant (two, 6.5 percent) by the majority of patients, ten (32.2 percent) patients were unable to identify the causative insect. The two patients stung by fire ants were Americans working in Singapore who had been stung while in the United States. Among those with anaphylaxis, honeybee, wasp and fire ant venom, for which specific immunotherapy is available, were identified as the cause in 40.9 percent, 4.5 percent, and 4.5 percent, respectively. CONCLUSION: Insect venom hypersensitivity made up 3.5 percent of allergy/immunology referrals and 32.8 percent of cases of anaphylaxis referred to our institution. The majority were military servicemen who developed allergic reactions during the course of duty. The inability to identify the causative insect in 50 percent with sting anaphylaxis limits the role of specific immunotherapy in our patients.

Anaphylaxis in adults referred to a clinical immunology/allergy centre in Singapore.

INTRODUCTION: To study the clinical features and causes of anaphylaxis in consecutive adult patients referred to a clinical immunology/allergy centre in Singapore. METHODS: A retrospective review of 67 consecutive adults with anaphylaxis who presented from July 1, 1998 to February 28, 2002 was performed. Anaphylaxis was defined as a severe life-threatening systemic IgE-mediated hypersensitivity reaction. Non-steroidal anti-inflammatory drug-induced idiosyncratic reactions and other non-IgE mediated reactions were excluded. Hypotension and bronchospasm were not required to make a diagnosis. The aetiology was determined from clinical history followed by measurement of allergen-specific IgE levels, skin prick test with commercially-available allergen extracts or prick-prick test with the fresh/cooked/canned food products. RESULTS: The mean age of patients was 32.9 +/- 10.9 (range 19-57) years. There were 44 (65.7 percent) males and 23 (34.3 percent) females. The main causes were food (44.8 percent), insect stings (32.8 percent) and idiopathic (22.4 percent). There were no cases due to drugs or natural rubber latex. Seafood (crustaceans and molluscs) comprised 66.7 percent of food-induced anaphylaxis. Honeybee and wasp stings together comprised 45 percent of insect venom anaphylaxis. The most common manifestations were dyspnoea (59.7 percent), urticaria (58.2 percent), angioedema (44.8 percent), and syncope (43.3 percent). Hypotension was documented in only 28.4 percent of cases. CONCLUSION: Food (crustaceans and molluscs) was the most common cause followed by insect stings or bites. The inability to identify the causative insect in 50 percent of cases with insect venom anaphylaxis limited the role of specific immunotherapy. Compared to other reported series, there were no cases of drug or latex anaphylaxis.

Primary immunodeficiency diseases in Singapore--the last 11 years.

OBJECTIVES: To describe the clinical features, disease complications, treatment modalities and overall outcome of 39 local patients with Primary Immunodeficiency Diseases (PID) in Singapore over the last 11 years. METHODS: Paediatric and adult patients who presented to the The Children's Medical Institute, National University Hospital, Tan Tock Seng Hospital and KK Women's and Children's Hospital between January 1990 and December 2000 were identified. Their diagnoses were categorised into six groups according to the IUIS (International Union of Immunological Societies, affiliated to World Health Organisation) classification: antibody deficiencies, combined immunodeficiencies, immunodeficiencies associated with other major defects, congenital phagocytic defects, complement deficiencies and other well-defined immunodeficiency syndromes. Patients were selected from screening of inpatients with discharge diagnoses associated with primary immunodeficiency and of patients undergoing tests for immunodeficiency. Patient data were collated from case files and compiled using a standard questionnaire. RESULTS: There were 39 Singaporean patients diagnosed and treated for PID during the study period. The age at diagnosis ranged from three weeks to 69 years. Antibody deficiency (41%) was the most common form of PID. Seven patients had a family history of PID. Recurrent bacterial respiratory tract infections were the most common clinical manifestation. Associated conditions included autoimmune diseases, allergies and malignancies. Infection was the commonest cause of mortality. Eighteen patients (46.2%) with antibody or combined deficiencies received regular intravenous immunoglobulin (IVIG) as the primary treatment modality. Two children successfully received sibling-matched haematopoietic stem cell transplantation (HSCT). CONCLUSIONS: Antibody deficiencies are the most common form of PID in Singapore. Treatment with antibiotics, IVIG and HSCT are the main therapeutic modalities currently available. Early referral to an immunologist is needed to achieve good outcomes.

Behcet's disease: experience in a tertiary rheumatology centre in Singapore and a review of the literature.

INTRODUCTION: The only reported study on Behcet's disease (BD) in Singapore found that only 15% of 34 BD patients managed at a tertiary dermatology centre had arthritis and 6% had eye complications with no other systemic manifestations. The aim of our study was to characterise the clinical manifestations and outcome of patients with BD at a tertiary rheumatology centre in Singapore. MATERIALS AND METHODS: The International Study Group (ISG) and the O'Duffy (OD) criteria were used. The demographics, manifestations and outcome of our patients with BD were recorded. RESULTS: Thirty-seven patients were included in our study. Twenty-three (62.2%) satisfied both ISG and OD criteria. Fourteen (37.8%) did not fulfil the ISG criteria but fulfilled the OD criteria and of these 6 were the incomplete form and 8 the complete form. The male to female ratio was 1:1.1. The mean age of onset of disease was 32.7 years (range, 15 to 58 years). The commonest presentations were recurrent oral ulcers (37, 100%), genital ulcers (24, 64.9%), joint (21, 56.8%) and cutaneous manifestations (18, 48.6%). The most common systemic manifestations were arthritis (16, 43.2%), gastrointestinal manifestations (15, 40.5%) and uveitis (13, 35.1%). There were 2 cases of Neuro Behcet's and 2 cases of venous thrombosis. Visual impairment from uveitis was the commonest cause of morbidity. There were no deaths in our series of BD. CONCLUSION: BD is a relatively rare rheumatologic condition in Singapore. However, because its systemic complications are not rare, early diagnosis and prompt treatment are essential.

An audit of patients with rheumatic disease requiring medical intensive care.

INTRODUCTION: Medical intensive care for patients with rheumatic disease is usually complicated by significant morbidity and mortality. The aims of this study were to examine the reasons for admission, the outcomes of these patients and the possible prognostic factors in an Asian cohort. MATERIALS AND METHODS: This was a retrospective study of the case records of 29 admissions to the medical intensive care unit (MICU) of Tan Tock Seng Hospital (TTSH) from August 1999 to August 2000. RESULTS: There were 28 patients admitted, of whom 1 had a repeat admission. The majority of these patients were young (mean age 38.9 +/- 16.3 years) and 71.4% were females. Twenty patients (71.4%) had systemic lupus erythematosus (SLE). The main reasons for admission were infection/sepsis syndrome (n = 18), hypotension (n = 16) and acute respiratory failure (n = 14). The observed in-hospital mortality was 64.3%, which was higher than the predicted risk of hospital death of 47.3%. Infection contributed to 55.6% of deaths. The patients who died had a longer mean duration of the rheumatic disease, higher APACHE II scores, higher rates of hypertension and hyperlipidaemia, higher doses of steroid and immunosuppressive therapy and more organ failures. Renal failure and acute respiratory distress syndrome were the two most common organ failures in patients who died. CONCLUSION: Many of our critically-ill patients with rheumatic disease were young females with good functional status. Despite the high mortality, they should be aggressively treated because infection and acute respiratory failure are potentially reversible.