Khai Pang Leong

Understanding the pathogenesis of allergic asthma using mouse models

OBJECTIVE This paper reviews the current views of the pathogenesis of airway eosinophilic inflammation and airway hyperresponsiveness (AHR) in allergic asthma based on mouse models of the disease. The reader will also encounter new treatment strategies that have arisen as this knowledge is applied in practice. DATA SOURCES MEDLINE searches were conducted with key words asthma, mouse model, and murine. Additional articles were identified from references in articles and book chapters. STUDY SELECTION Original research papers and review articles from peer-reviewed journals were chosen. RESULTS Although the mouse model does not replicate human asthma exactly, the lessons learned about the pathogenesis of allergic airway inflammation and AHR are generally applicable in humans. Type 2 T helper lymphocytes (Th2) orchestrate the inflammation and are crucial for the development of AHR. Cells and molecules involved in T cell activation (dendritic cells, T cell receptor, major histocompatibility complex molecule, and costimulatory molecules) are also vital. Besides these, no other cell or molecule could be shown to be indispensable for the establishment of the model under all experimental conditions. There are at least three pathways that lead to AHR. One is dependent on immunoglobulin E and mast cells, one on eosinophils and interleukin-5 (IL-5), and one on IL-13. Eosinophils are probably the most important effector cells of AHR. Radical methods to treat asthma have been tested in the animal model, including modifying the polarity of lymphocyte response and antagonizing IL-5. CONCLUSIONS AHR, the hallmark of asthma, is attributable to airway inflammation ultimately mediated by helper T cells via three pathways, at least. The mouse model is also a valuable testing ground for new therapies of asthma.

Severe cutaneous adverse reactions to drugs.

Purpose of reviewThis paper updates the treatment of Stevens–Johnson syndrome and toxic epidermal necrolysis supported by relevant views about the pathogenesis. Recent findingsBuilding on the thesis that Stevens–Johnson syndrome and toxic epidermal necrolysis are due to dermal cell apoptosis, molecular pathways that may lead to this have been proposed. Intravenous immunoglobulin is postulated to block apoptosis via the Fas pathway. Most series on the use of intravenous immunoglobulin in toxic epidermal necrolysis have been favourable. Tumour necrosis factor is also thought to be an important mediator of cell death in toxic epidermal necrolysis. There was impressive control of the progression of toxic epidermal necrolysis with intravenous anti-tumour necrosis factor antibody infliximab in two cases. Strong associations between human leukocyte antigen subtypes and severe cutaneous reactions due to allopurinol and carbamazepine have been described. SummaryTo date, there is no established treatment of Stevens–Johnson syndrome/toxic epidermal necrolysis. With advancing knowledge of the pathogenesis, it is hoped that better forms of treatment may result.

A comparative study of the clinical manifestations of systemic lupus erythematosus in Caucasians in Rochester, Minnesota, and Chinese in Singapore, from 1980 to 1992

OBJECTIVE To examine the relationship between ethnicity and major organ involvement at and after diagnosis in community-based cohorts of Caucasian and Chinese systemic lupus erythematosus (SLE) patients resident in Rochester, Minnesota, and Singapore, respectively. METHODS Clinical manifestations at and after diagnosis were compared in Caucasian and Chinese SLE patients. The association between ethnicity and disease manifestations at and after diagnosis was determined using logistic regression and Cox proportional hazards models, respectively, adjusting for the influence of demographic, socioeconomic, disease-related, and therapy-related factors. RESULTS At diagnosis, Caucasian SLE patients were 3 times more likely than Chinese SLE patients to have serositis (odds ratio [OR] 3.11, 95% confidence interval [CI] 1.01-9.71), nearly 7 times more likely to have a hematologic disorder (OR 6.95, 95% CI 2.20-21.97), and far less likely to have a malar rash (OR 0.19, 95% CI 0.07-0.54) or positive antinuclear antibodies (OR 0.11, 95% CI 0.03-0.52). Ethnicity was not associated with the prevalence of proteinuria or central nervous system (CSN) and other major organ involvement at diagnosis. After diagnosis, there was a trend toward less development of proteinuria and other major organ involvement in Caucasians (relative risk [RR] 0.47, 95% CI 0.19-1.15, and RR 0.22, 95% CI 0.05-1.04, respectively). CONCLUSION Chinese SLE patients are far less likely to have serositis or a hematologic disorder at diagnosis and may be more likely to develop proteinuria or CNS or other major organ involvement over the course of the disease, compared with Caucasian SLE patients. This may contribute to the increased mortality seen in Chinese SLE patients.

Therapeutic efficacy of an anti–IL-5 monoclonal antibody delivered into the respiratory tract in a murine model of asthma☆☆☆★

BACKGROUND IL-5 is central to the pathogenesis of airway eosinophilic inflammation and hyperresponsiveness associated with both atopic and nonatopic asthma. The therapeutic potential of IL-5 antagonists in asthma is supported by the inhibition of airway eosinophilia and hyperresponsiveness in animal models receiving neutralizing anti-IL-5 mAbs intravenously or intraperitoneally. OBJECTIVE The purpose of this study was to test the hypothesis that mAbs against IL-5 delivered by way of the respiratory tract are as effective as those delivered intraperitoneally in diminishing the pulmonary eosinophilic inflammation and airway hyperresponsiveness in a murine model of ovalbumin-induced asthma. METHODS Ovalbumin-sensitized Balb/c mice were given an anti-IL-5 mAb delivered intranasally or an isotype-matched control mAb delivered intranasally before respiratory challenge with ovalbumin. Outcome variables included respiratory system resistance responses to methacholine, bronchoalveolar lavage fluid cellularity, and lung histopathology. RESULTS Anti-IL-5 mAbs administered intranasally to ovalbumin-sensitized and challenged mice significantly decreased eosinophil counts in bronchoalveolar lavage fluid and lung tissue and significantly reduced airway hyperresponsiveness relative to ovalbumin-sensitized and challenged mice that received either no mAb treatment or an isotype-matched control mAb. Similar results were obtained when an anti-IL-5 mAb was given intraperitoneally. CONCLUSION This is the first study to demonstrate that delivery of anti-IL-5 mAbs into the respiratory tract is efficacious in attenuating the asthma phenotype in a murine model. These results provide impetus for the development of inhaled IL-5 antagonists for the treatment of human asthma.

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.

Why generic and disease-specific quality-of-life instruments should be used together for the evaluation of patients with persistent allergic rhinitis

Background The importance of assessing health‐related quality of life (HRQL) of patients with allergic rhinitis (AR) has been well established, but the specific roles of rhinitis‐specific or general health instruments have not been delineated.

APLAR rheumatoid arthritis treatment recommendations

Rheumatoid arthritis is a chronic inflammatory condition that affects approximately 1% of the worlds population. There are a wide number of guidelines and recommendations available to support the treatment of rheumatoid arthritis; however, the evidence used for these guidelines is predominantly based on studies in Caucasian subjects and may not be relevant for rheumatoid arthritis patients in the Asia‐Pacific region. Therefore, the Asia Pacific League of Associations for Rheumatology established a Steering Committee in 2013 to address this issue.

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.

Why lupus patients use alternative medicine

It is unclear whether patients use alternative medicine because of psychological distress associated with their disease or philosophicalcongruencewith this form of treatment. Therefore, we have studied why patients with systemic lupus erythematosus (SLE) employ alternative medicine. We interviewed 192 consecutive Chinese SLE outpatients in a tertiary-care rheumatology centre. We recorded their demographic data, usage of traditional Chinese medication, the predominant form of alternative medicine in this group, and the Rheumatology Attitudes Index score. We distinguished two types of alternative medicine users: those who use it with intent to treat SLE (disease-specific users; 73 users, 38.0%) and those who use it for cultural and other reasons (general-health users; 55 users, 28.6%). Users regarded their disease as mild compared to nonusers. Disease-specific users were distinguished from nonusers by having Chinese as a first language (odds ratio, 2.14-8.83), greater learned helplessness (odds ratio, 1.02-1.29), and an earlier age of diagnosis (odds ratio, 0.92-0.98 for older age). In conclusion, the majority of our lupus patients have used alternativemedicine. The motivations of general-health and disease-specific users are different. The patients’ first language and perceived helplessnessinfluenced the disease-specific users, while general-healthusers were subject to neitherof these.

Analysis of Genetic Variation in CYP450 Genes for Clinical Implementation

Background Genetic determinants of drug response remain stable throughout life and offer great promise to patient-tailored drug therapy. The adoption of pharmacogenetic (PGx) testing in patient care requires accurate, cost effective and rapid genotyping with clear guidance on the use of the results. Hence, we evaluated a 32 SNPs panel for implementing PGx testing in clinical laboratories. Methods We designed a 32-SNP panel for PGx testing in clinical laboratories. The variants were selected using the clinical annotations of the Pharmacogenomics Knowledgebase (PharmGKB) and include polymorphisms of CYP2C9, CYP2C19, CYP2D6, CYP3A5 and VKORC1 genes. The CYP2D6 gene allele quantification was determined simultaneously with TaqMan copy number assays targeting intron 2 and exon 9 regions. The genotyping results showed high call rate accuracy according to concordance with genotypes identified by independent analyses on Sequenome massarray and droplet digital PCR. Furthermore, 506 genomic samples across three major ethnic groups of Singapore (Malay, Indian and Chinese) were analysed on our workflow. Results We found that 98% of our study subjects carry one or more CPIC actionable variants. The major alleles detected include CYP2C9*3, CYP2C19*2, CYP2D6*10, CYP2D6*36, CYP2D6*41, CYP3A5*3 and VKORC1*2. These translate into a high percentage of intermediate (IM) and poor metabolizer (PM) phenotypes for these genes in our population. Conclusion Genotyping may be useful to identify patients who are prone to drug toxicity with standard doses of drug therapy in our population. The simplicity and robustness of this PGx panel is highly suitable for use in a clinical laboratory.