Meng Yu Weng

Use of HLA-B*58:01 genotyping to prevent allopurinol induced severe cutaneous adverse reactions in Taiwan: national prospective cohort study

Objective To evaluate the use of prospective screening for the HLA-B*58:01 allele to identify Taiwanese individuals at risk of severe cutaneous adverse reactions (SCARs) induced by allopurinol treatment. Design National prospective cohort study. Setting 15 medical centres in different regions of Taiwan, from July 2009 to August 2014. Participants 2926 people who had an indication for allopurinol treatment but had not taken allopurinol previously. Participants were excluded if they had undergone a bone marrow transplant, were not of Han Chinese descent, and had a history of allopurinol induced hypersensitivity. DNA purified from 2910 participants’ peripheral blood was used to assess the presence of HLA-B*58:01. Main outcome measures Incidence of allopurinol induced SCARs with and without screening. Results Participants who tested positive for HLA-B*58:01 (19.6%, n=571) were advised to avoid allopurinol, and were referred to an alternate drug treatment or advised to continue with their prestudy treatment. Participants who tested negative (80.4%, n=2339) were given allopurinol. Participants were interviewed once a week for two months to monitor symptoms. The historical incidence of allopurinol induced SCARs, estimated by the National Health Insurance research database of Taiwan, was used for comparison. Mild, transient rash without blisters developed in 97 (3%) participants during follow-up. None of the participants was admitted to hospital owing to adverse drug reactions. SCARs did not develop in any of the participants receiving allopurinol who screened negative for HLA-B*58:01. By contrast, seven cases of SCARs were expected, based on the estimated historical incidence of allopurinol induced SCARs nationwide (0.30% per year, 95% confidence interval 0.28% to 0.31%; P=0.0026; two side one sample binomial test). Conclusions Prospective screening of the HLA-B*58:01 allele, coupled with an alternative drug treatment for carriers, significantly decreased the incidence of allopurinol induced SCARs in Taiwanese medical centres.

Incidence of cancer in a nationwide population cohort of 7852 patients with primary Sjogren's syndrome in Taiwan

Objectives Patients with primary Sjögrens syndrome (pSS) are at a higher risk of developing non-Hodgkins lymphoma (NHL). However, little is known with regard to the risk of developing cancers other than NHL. The authors aimed in this study to compare the incidence of cancer in various sites among patients with pSS with the general population of Taiwan. Methods The authors used National Health Insurance claims data to establish a nationwide population cohort of 7852 patients with pSS from 2000 to 2008 who did not have cancer prior to diagnosis of pSS. Incidence and standardised incidence ratios (SIRs) for cancer in various sites were calculated. Results Among patients with pSS, 277 (2.9%) developed cancer. The SIR for cancer was 1.04 (95% CI 0.91 to 1.18) among patients of all ages with pSS and was 2.19 (95% CI 1.43 to 3.21) for patients aged 25–44 years. Female patients with pSS had a higher risk of NHL (SIR 7.1, 95% CI 4.3 to 10.3), multiple myeloma (SIR 6.1, 95% CI 2.0 to 14.2) and thyroid gland cancer (SIR 2.6, 95% CI 1.4 to 4.3) and a lower risk of colon cancer (SIR 0.22, 95% CI 0.05 to 0.65). In contrast, male patients with pSS were not at a higher risk of developing cancer in particular sites. Conclusion Patients with pSS, overall, did not have higher risk of cancer, and only patients aged 25–44 years were at an increased risk of cancer compared with their counterparts in the general population. Cancer screening for patients with pSS, especially female patients, should focus on NHL and multiple myeloma and thyroid gland cancer.

Decreased CD4+CD25+bright T cells in peripheral blood of patients with primary Sjögren's syndrome

CD4+CD25 +bright T cells played a crucial role in the suppression of immune response. Recently, decreased levels of CD4+CD25+bright T cells in the peripheral blood of patients with systemic lupus erythematosus were reported, suggesting the potential role of CD4+CD25+bright T cells in human autoimmune diseases. Primary Sjögrens syndrome (pSS) is another common human systemic autoimmune disease. The present study aimed to investigate the levels of CD4+CD25+bright T cells in pSS and to correlate their levels with some biomarkers of inflammation and immune activation. Thirty-three patients with pSS and 35 age- and sex-matched normal individuals were enrolled in the study. The flowcytometric method was applied in the measurement of CD4+CD25+bright T cells. The results showed that patients with pSS had statistically lower levels of CD4+CD25+bright T cells than normal controls, expressed either as absolute cell numbers (mean ± SD: 47.07 ± 25.53 cells/mm 3 versus 79.55 ± 34.56 cells/mm3, P < 0.001) or as percentages of peripheral blood mononuclear cells (mean ± SD: 2.79 ± 1.06% versus 3.84 ± 1.42%, P < 0.001) or as percentages of CD4+ T cells (mean ± SD: 7.85 ± 2.62% versus 11.68 ± 3.78%, P < 0.005). Moreover, there were statistically significant inverse correlations between the levels of CD4+CD25+bright T cells and some parameters of inflammation or immune activation including erythrocyte sedimentation rate, C-reactive protein, IgG and rheumatoid factors. The result suggested that CD4+CD25+bright T cells were likely to play anti-inflammatory and immunosuppressive roles in the pathogenesis of pSS. However, the exact functions of decreased circulating CD4+CD25+bright T cells in pSS need further elucidated. Lupus (2008) 17, 34—39.

Incidence and Mortality of Treated Primary Sjögren’s Syndrome in Taiwan: A Population-based Study

Objective. To estimate the incidence and mortality of treated primary Sjögren’s syndrome (pSS) by sex and age group in Taiwan. Methods. We used claims data of the Bureau of National Health Insurance (NHI) of Taiwan from 2005 to 2007 for analysis. According to the NHI, pSS is classified as one of the financially catastrophic illnesses and patients with pSS could be exempted from copayment of all medical costs. To obtain a catastrophic illness certificate (CIC) for pSS, patients are required to meet the criteria of the American-European Consensus Group for pSS, and are reviewed by a committee. Patients approved for receipt of a CIC for pSS for the first time were defined as incident cases of treated pSS. Results. A total of 3352 incident cases occurred between 2005 and 2007. The estimated mean annual incidence was 6.0 per 100,000 inhabitants (95% CI 5.8–6.2) for both sexes, 11.0 (95% CI 10.6–11.4) for women and 1.1 (95% CI 1.0–1.2) for men, with a female/male ratio of 9.9 (95% CI 8.8–11.1). Incidence increased with age, peaking at age 55–64 years in women and 65–74 years in men. The mortality rate was 33.4 per 1000 case person-years for men and 11.4 for women, with a male/female rate ratio of 2.9 (95% CI 1.7–5.3). Conclusion. The incidence of treated pSS in women is 10 times that in men. Nevertheless, pSS mortality in men is 3 times that in women.

A retrospective study of catastrophic invasive fungal infections in patients with systemic lupus erythematosus from southern Taiwan

As very few large scale publications of invasive fungal infection (IFI) have been reported in lupus patients from individual medical centers, a retrospective study was performed from 1988 to 2009 in southern Taiwan. Demographic characteristics, clinical and laboratory data, and mycological examinations were analyzed. Twenty cases with IFI were identified in 2397 patients (0.83% incidence). There were 19 females and one male with an average age of 31.8 ± 12.6. Involved sites included eight disseminated cases, six central nervous system, four lungs, one abdomen and one soft tissue. IFI contributed to a high mortality with 10 deaths (50%), and there were no survivors for the disseminated cases and Candida-infected patients. High activity (Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) > 8) was noted in 50% of IFI episodes. The survival from IFI diagnosis to death was only 7.7 ± 4.2 days, all in a rapid course. No statistical difference was found between survivors and non-survivors when comparing their SLEDAI. Eighty-five percent of IFI episodes under high dosages of corticosteroids therapy and 95% of patients had lupus nephritis. There was an increased risk of IFI in the lupus patients receiving high daily dosage of prednisolone therapy. Critical information from analyses of the present large series could be applied into clinical practices to reduce the morbidity and mortality in such patients.

Pneumocystis jirovecii pneumonia in systemic lupus erythematosus from southern Taiwan.

BackgroundOpportunistic infection has been documented in systemic lupus erythematosus with special attention paid to Pneumocystis jirovecii because of the significant morbidity and high mortality. ObjectivesThe limited large-scale investigations covering P. jirovecii pneumonia (PCP) in systemic lupus erythematosus following biologics or immunosuppressants therapy prompted us to perform this study in southern Taiwan. MethodsA retrospective study was completed in 858 hospitalized lupus patients from January 2000 to December 2011. The definite diagnosis of PCP was made by the laboratory detection of Pneumocystis organisms together with consistent clinical and radiological manifestations of PCP. Positive polymerase chain reaction results of sputum samples were not regarded as infection in this study, unless P. jirovecii was the sole pathogen found and pulmonary manifestations resolved following antibiotics for PCP treatment alone. ResultsThe laboratory identification of Pneumocystis organisms depended on lung biopsy in 2 cases and bronchoalveolar lavage in 3 patients. Five cases, 2 women and 3 men aged 30 to 50 years (41.8 ± 8.8 years), were identified with a 0.6% incidence. None received chemoprophylactics against P. jirovecii infection. All had lupus nephritis and lymphopenia with low CD4+ T-cell counts. Prior usages of higher daily prednisolone dosages and concomitant biologics or immunosuppressants were observed in all patients. Pneumocystis jirovecii pneumonia contributed to a high mortality rate (60%). ConclusionsWe report the rare occurrence but high mortality of PCP infection in this study. A consensus guideline addressing prophylactic antibiotics against Pneumocystis organisms in highest-risk lupus patients on biologics or immunosuppressants could be helpful in guiding their management.

A retrospective study of pulmonary infarction in patients with systemic lupus erythematosus from southern Taiwan

Since large-scale reports of pulmonary infarction in systemic lupus erythematosus (SLE) are limited, a retrospective study was performed for this manifestation in 773 hospitalized patients in southern Taiwan from 1999 to 2009. Pulmonary infarction was defined as the presence of pulmonary embolism, persistent pulmonary infiltrates, and characteristic clinical symptoms. Demographic, clinical, laboratory, and radiological images data were analyzed. There were 12 patients with pulmonary embolism and 9 of them had antiphospholipid syndrome (APS). Six patients (19 to 53 years, average 38.2 ± 12.6) with 9 episodes of lung infarction were identified. All cases were APS and four episodes had coincidental venous thromboembolism. There were four episodes of bilateral infarction and seven episodes of larger central pulmonary artery embolism. Heparin therapy was routinely prescribed and thrombolytic agents were added in two episodes. Successful recovery was noted in all patients. In conclusion, there was a 0.8% incidence of pulmonary infarction in patients with SLE, all with the risk factor of APS. Differentiation between pulmonary infarction and pneumonia in lupus patients should be made; they have similar chest radiography with lung consolidation but require a different clinical approach in management. Although this report is a retrospective study with relatively small numbers of lupus patients with lung infarcts, our observation might provide beneficial information on the clinical features and radiological presentations during the disease evolution of pulmonary infarction in SLE with APS.

Variable Increased Expression of Program Death-1 and Program Death-1 Ligands on Peripheral Mononuclear Cells Is Not Impaired in Patients with Systemic Lupus Erythematosus

Programmed death-1 (PD-1) was shown to deliver an inhibitory signal after binding to its ligands, PD-L1 (B7-H1) or PD-L2 (B7-DC). Recently, up-regulated expression of PD-1 molecule and/or its ligands was demonstrated in human diseases including rheumatoid arthritis and inflammatory colitis. The study aimed to investigate the expression and function of PD-1 and PD-1 ligands on circulating T cells, B cells and monocytes from patient with systemic lupus erythematosus (SLE). The results showed that patients with SLE had significantly increased percentages of PD-1-expressing CD3+T cells and CD19+B cells, PD-L1-expressing CD19+B cells and PD-L2-expressing CD14+B monocytes. In selected SLE patients and normal subjects, functional study of PD-1/ PD-1 ligands pathway on the production of cytokines by stimulated PBMC was examined. Blockages of PD-1 or PD-1 ligands substantially increased the production of IL-2, IFN-γ and IL-10, the amplitude of increase roughly ranged from one to three times. There were no significant differences of the enhancing effects on cytokine production by blockage of PD-1/PDL pathway between SLE patients and normal subjects. The study indicates that there are no intrinsically defective expression and function of PD-1 and PD-1 ligands on PBMC in patients with SLE.

AB0428 Demographics, organ involvement and medications in sle patients from six countries in asia-pacific

Background Systemic lupus erythematosus (SLE) may vary in presentation and management approach in different geographies (1). A review of the literature describing the epidemiology of SLE in Asia-Pacific countries identified a dearth of information on the characteristics and perceived wide variability in management of lupus in the region (2). This study was designed to observe SLE patients and their care, from six countries in Asia-Pacific, under a common protocol, over a twelve month follow-up period. This abstract describes the baseline features of the cohort. Objectives The aim of the study is to describe patient characteristics, organ involvement, disease activity and severity, and management in a multi-national observational cohort. Methods Patients were invited to participate from lupus clinics in six countries (nine centres), between April and October 2012. Consecutive patients, 18 years or older, meeting at least four ACR criteria for diagnosis of SLE were eligible. Information describing organ system involvement, disease activity and severity, and management of the patients were recorded. Severe disease was defined as a) at least one of the major domains: cardiovascular, respiratory, renal or urological actively involved (biologically active eg proteinuria or symptomatic) at enrolment, and b) requiring more than 7.5mg/d of corticosteroids (prednisone equivalent dose) and/or immunosuppressant(s) and/or biological drugs. Results 553 patients (404, 92% women) were recruited. Mean age at SLE diagnosis was 28.8 (SD 11.4) years, and mean number of years since diagnosis was 9.2 (SD 6.7). For disease activity profile at entry into the study, the most common domain of active disease involvement was renal disease (17% of patients). Similarly, the domain most reported as being damaged (non-reversible change not related to active inflammation) since onset of lupus was renal (9%). 20% of the patients were classified as having severe disease, with Taiwan showing the highest proportion of severe disease (39%), and South Korea the lowest proportion (14%). Steroid use was reported in 81.6%, anti-malarials in 63.2%, immunosuppressants in 48.3% and a biological drug in one patient (0.2%). Conclusions We have provided a cross-sectional overview of the demographics, disease characteristics and therapies in a cohort of SLE patients seen at selected sites across 6 countries in Asia-Pacific. A high proportion of patients, at the time of enrolment, were managed with steroids, anti-malarials and immunosuppressants, with one patient receiving biological therapy. This sets the baseline for a one-year observational study utilizing a standard electronic case report form, in order to better understand the behavior and management practice of SLE in the region. References Danchenko et al. Epidemiology of systemic lupus erythematosus. Lupus 2006; 15: 308-18. Jakes RW et al. Systematic review of the epidemiology of systemic lupus erythematosus in Asia-Pacific. ACR 2012; 64: 159-168. Disclosure of Interest R. W. Jakes Shareholder of: GSK, Employee of: GSK, S. Navarra Grant/research support from: GSK, Speakers bureau: GSK, Roche, P. Jain Shareholder of: GSK, Employee of: GSK, W. Louthrenoo: None Declared, S.-C. Bae: None Declared, A. Hoi Grant/research support from: UCB, Eli Lilly, Suppremol, GSK, Consultant for: BMS, Speakers bureau: Abbott, BMS, MSD, Mundipharma, UCB, N. C. T. Kong Grant/research support from: GSK, A. Koolvisoot: None Declared, H.-Y. Lin: None Declared, P. Nash Grant/research support from: GSK, Consultant for: GSK, M.-Y. Weng: None Declared