The Risk of Major Adverse Cardiovascular Events in Ankylosing Spondylitis Patients With a History of Acute Anterior Uveitis: A Nationwide, Population Based Cohort Study.

Background: To investigate the association between a history of acute anterior uveitis (AAU) and the risk of major adverse cardiovascular events (MACE) among patients with ankylosing spondylitis (AS). Methods: We identified 38,691 newly diagnosed AS patients between 2003 and 2013 from the Taiwan National Health Insurance Research Database. The exposure group was defined as people with uveitis diagnosis by ophthalmologist before AS diagnosis date. The incidence of MACE in patients with AS according to the International Classification of Diseases, Ninth Revision. We randomly selected a comparison group without a history of AAU at a 1:4 ratio matched by age, sex, and index year in relation to the risk of developing MACE. We used cox proportional hazard regression model to compare the risk of MACE between groups, shown as adjusted hazard ratios (aHRs) with 95% confidence intervals (CI). Further subgroup analysis and sensitivity tests were also performed. Results: There were 3,544 patients in the AAU group and 14,176 patients in the non-AAU group. The aHR of MACE for the AAU group was 0.79 (95% CI = 0.57-1.10) at a 1:4 ratio for age, sex and index year. Sensitivity analyses using various adjustment variables showed consistent results. Cox proportional hazard regression model demonstrated that use of non-steroidal anti-inflammatory drugs (NSAIDs) was associated with an increased risk of MACE in this cohort (HR = 3.44; 95% CI = 2.25-5.25). Conclusion: This cohort study showed that subjects with AAU was not associated with the risk of MACE among AS patients, compared to non-AAU controls.

Association Between Endometriosis and Subsequent Risk of Sjögren's Syndrome: A Nationwide Population-Based Cohort Study.

Objective: The relationship between endometriosis and the ensuing risk of Sjögren's syndrome has remained unclear. This study aims to present epidemiological evidence for this connection. Methods: This is a retrospective cohort study of endometriosis patients (ICD-9-CM 617.0-617.9 and 621.3) and matched comparison group between 2000 and 2012 in the National Taiwan Insurance Research Database. After age matching, we analyzed the association between endometriosis and Sjögren's syndrome (ICD-9-CM 710.2). We used the Cox proportional hazard model to examine the hazard ratio of incidental Sjögren's syndrome. Subgroup analyses on age, comorbidities, and disease duration were also performed. Results: A total of 73,665 individuals were included in this study. We identified 14733 newly diagnosed endometriosis patients and 58,932 non-endometriosis comparison group. The adjusted hazard ratio (HR) for incidental Sjögren's syndrome was 1.45 (95% confidence interval CI=1.27-1.65) in the endometriosis group, compared to the non-endometriosis comparison group. In subgroup analysis, the adjusted HR was 1.53 (95% CI=1.25-1.88) in the age group of 20-39 and 1.41 (95% CI =1.18-1.68) in the age of 40-64. Time-vary analysis showed that endometriosis who have a follow-up time of fewer than five years (adjusted HR=1.57, 95% CI=1.32-1.87) have a significantly highest risk of having subsequent Sjögren's syndrome. Conclusion: This population-based cohort study indicated that having a history of endometriosis puts patients at an increased risk of getting Sjögren's syndrome afterward, especially in the age group of 20-39 and within the first five years after the diagnosis of endometriosis. Clinicians should recognize this possible association in managing endometriosis or Sjögren's syndrome patients.

Increased risk of valvular heart disease in patients with ankylosing spondylitis: a nationwide population-based longitudinal cohort study.

AIMS: We aimed to evaluate the risk of valvular heart disease (VHD) among patients with ankylosing spondylitis (AS). METHODS: This was a population-based cohort study utilizing the Longitudinal Health Insurance Research Database of the National Health Insurance in Taiwan. Patients with and without coding of newly diagnosed AS from 1999 to 2013 were assigned to the AS and non-AS groups, respectively. Primary outcome was the incidental risk of VHD. Multiple Cox regression was used to estimate the adjusted hazard ratio of VHD. Subgroup analysis and sensitivity tests were also conducted. RESULTS: The AS group included 3780 patients, and 22,680 matched subjects without an AS diagnosis were identified as controls. The AS group had an increased risk of VHD compared with non-AS controls (adjusted hazard ratio: 1.63; 95% confidence interval: 1.43-1.86; p < 0.001). Subgroup analysis also revealed an increased risk of individual types of VHD, including aortic, mitral, and tricuspid valve disease. Patients in the AS group had a higher incidence of valve replacement surgery after the onset of VHD. CONCLUSION: Patients with AS had a significant risk of VHD compared to non-AS controls in this population-based cohort study. Screening for VHD may be needed in caring patients with AS. We suggest that echocardiography may be performed when patients are diagnosed with AS.

Metformin Use Was Associated With Reduced Risk of Incidental Sjögren's Syndrome in Patients With Type 2 Diabetes: A Population-Based Cohort Study.

Purpose: Previous studies have shown that metformin exhibits an anti-inflammatory effect and may decrease the risk of incidental diabetes. But the effect of metformin on incidental Sjögren's syndrome is unknown. The aim of the study was to examine the association between metformin exposure and Sjögren's syndrome in diabetic patients. Methods: The dataset in this retrospective cohort study was obtained from the National Health Insurance Research Database (2000-2013) in Taiwan. In total, 15,098 type 2 diabetic patients under metformin treatment and an equivalent number without metformin treatment matched for comparison were included. The primary endpoint was the incidence of Sjogren's syndrome. Univariate and multivariate Cox proportional hazards models were used for data analysis. A subgroup analysis and sensitivity test were also performed. Results: The incidence rate of Sjögren's syndrome in non-metformin controls was 40.83 per 100,000 person-years and 16.82 per 100,000 person-years in metformin users. The adjusted hazard ratio (aHR) in diabetic patients under metformin treatment was 0.46 (95% CI, 0.23 to 0.92). In subgroup analysis, men had a lower risk of developing Sjögren's syndrome than women [aHR = 0.15, 95% CI = (0.05, 0.41)]. After prescribing metformin to type 2 diabetic patients aged 60 years or more, those patients had a lower risk of developing Sjögren's syndrome [aHR = 0.34, 95% CI = (0.12, 0.96)]. Conclusion: In this large population-based cohort study, metformin exposure was associated with a reduced risk of developing Sjögren's syndrome in type 2 diabetic patients.

Recommendations for psoriatic arthritis management: A joint position paper of the Taiwan Rheumatology Association and the Taiwanese Association for Psoriasis and Skin Immunology.

In Taiwan, the incidence and prevalence of psoriatic arthritis (PsA) have risen significantly in recent years. Moreover, data from the Taiwan National Health Insurance Research Database (NHIRD) show that more than 85% of PsA patients are treated with just non-steroidal anti-inflammatory drugs (NSAIDs) and/or conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs). Taiwanese clinicians have also expressed concerns regarding uncertainties in the diagnosis of PsA and the delayed, interrupted, and/or tapered use of biologics, as well as differences in therapeutic preferences between and within dermatologists and rheumatologists. To address these issues, the Taiwan Rheumatology Association and the Taiwanese Association for Psoriasis and Skin Immunology jointly convened a committee of 28 clinicians from the fields of rheumatology, dermatology, orthopedics, and rehabilitation, to develop evidence-based consensus recommendations for the practical management of PsA in Taiwan. A total of six overarching principles and 13 recommendations were developed and approved, as well as a treatment algorithm with four separate tracks for axial PsA, peripheral PsA, enthesitis, and dactylitis. Psoriasis (PsO) management was not discussed here, as the Taiwanese Dermatological Association has recently published a comprehensive consensus statement on the management of PsO. Together, these recommendations provide an up-to-date, evidence-based framework for PsA care in Taiwan.

Association of obesity with inflammation, disease severity and cardiovascular risk factors among patients with ankylosing spondylitis.

AIM: To investigate total and central obesity in ankylosing spondylitis (AS), and assess the association with inflammation, disease severity and cardiovascular risk factors. METHODS: There were 105 AS patients enrolled. Anthropometry was measured to determine total (body mass index [BMI]) and central obesity (waist circumference [WC], waist-to-height ratio [WHtR]). We evaluated patients' disease activity, functional ability, global assessment, physical mobility, radiographic damage and health index. Erythrocyte sedimentation rate, C-reactive protein (CRP) and blood biochemistry profile were tested. Retrospective radiographic change was assessed in 39 patients. Presence of diabetes and hypertension were examined. RESULTS: The obese AS patients had higher inflammation (CRP), disease activity (Ankylosing Spondylitis Disease Activity Score [ASDAS] - CRP), physical mobility (Bath Ankylosing Spondylitis Metrology Index [BASMI]), radiographic damage (modified Stoke Ankylosing Spondylitis Spinal Score [m-SASSS]), liver function and blood pressure (all P < .05). Obesity (BMI, WC, WHtR) positively correlated with inflammation (CRP), physical mobility (BASMI), radiographic damage (m-SASSS), health index (Assessment of SpondyloArthritis International Society Health Index), liver function and blood pressure (all P < .05). Moreover, presence of central obesity (WC, WHtR) had correlation with disease activity (ASDAS-CRP) (r = .218, P = .027; r = .221, P = .025), and predicted longitudinal radiographic change (m-SASSS) (standard coefficient = 0.300, P = .041; standard coefficient = 0.288, P = .045). Importantly, central obesity was better in predicting high inflammation, disease activity, physical mobility, radiographic damage and health index in AS, and WHtR was the best for predicting m-SASSS (area under the curve = 0.734, P < .001). Obesity was associated with increased risk of diabetes and hypertension in AS. CONCLUSION: Obesity was associated with higher inflammation, disease activity, physical mobility, radiographic damage, health index, liver function and cardiovascular risk factors in AS. Central obesity could predict a patient's longitudinal radiographic change. Central obesity is a useful predictor for high disease severity in AS.

Aberrant distribution and function of plasmacytoid dendritic cells in patients with ankylosing spondylitis are associated with unfolded protein response.

Although human leucocyte antigen (HLA)-B27 is strongly associated with ankylosing spondylitis (AS), the association of unfolded protein response (UPR) induced by HLA-B27 misfolding in AS remains controversial. Since dendritic cells (DCs) are crucial in induction of AS in HLA-B27-transgenic rats, and plasmacytoid DCs (pDCs) belong to one type of DCs, we here aim to study the relevance of pDCs and UPR in AS. Peripheral pDCs were isolated from 27 HLA-B27(+) AS patients and 37 controls. The bone marrow (BM) and synovium of inflamed hips from AS patients and controls were obtained. We found a significantly higher frequency of pDCs in the peripheral blood, BM, or inflamed synovium of hips, which is associated with the enhanced expression of pDC trafficking molecules, CCR6 and CCL20 in the synovium of AS patients. Functional analysis further revealed that several inflammatory cytokines, including TNFα, IL-6, and IL-23, secreted by pDCs were significantly increased in AS patients as compared with those in controls. Remarkably, protein kinase RNA-like endoplasmic reticulum kinase (PERK) pathway in UPR was up-regulated in pDCs of AS patients. Notably, PERK inhibitor treatment significantly inhibited the enhanced cytokine production by pDCs of AS patients. Further, the extent of PERK activation was significantly associated with the increased disease severity of AS patients. Our data uncover the aberrant distribution and function of pDCs in AS patients. The up-regulated PERK pathway in UPR of pDCs not only contributes to enhanced cytokine production of pDCs, but also is associated with increased disease activity of AS patients.

Vegetarian diet and risk of gout in two separate prospective cohort studies.

BACKGROUNDS & AIMS: Plant-based diets may target multiple pathways in gout pathogenesis (uric acid reduction and anti-inflammation) while improving gout associated cardiometabolic comorbidities. We aim to prospectively examine the relationship between a vegetarian diet and gout, and to explore if this relationship is independent of hyperuricemia. METHODS: We followed 4903 participants in the Tzu Chi Health Study (Cohort1, recruited in 2007-2009) and 9032 participants in the Tzu Chi Vegetarian Study (Cohort2, recruited in 2005) until end of 2014. Baseline serum uric acid was measured in Cohort1. Vegetarian status was assessed through a diet questionnaire that includes dietary habits and a food frequency questionnaire. Incidence of gout was ascertained by linkage to the National Health Insurance Database. Hazard Ratio of gout in vegetarians versus nonvegetarians was assessed by Cox regression, adjusted for age, sex, lifestyle and metabolic risk factors. Hyperuricemia was additionally adjusted in Cohort1. RESULTS: In Cohort1, lacto-ovo vegetarians had the lowest uric acid concentration, followed by vegans, then nonvegetarians (men: 6.05, 6.19, 6.32 mg/dL, respectively; women: 4.92, 4.96, 5.11 mg/dL, respectively); 65 gout cases occurred in the 29,673 person-years of follow-up; vegetarians experienced a lower risk of gout (without adjustment for hyperuricemia: HR: 0.33; 95% CI: 0.14, 0.79; with adjustment for hyperuricemia: HR: 0.40; 95% CI: 0.17, 0.97). In Cohort2, 161 gout cases occurred in the 83,019 person-years follow-up, and vegetarians also experienced a lower risk of gout (HR: 0.61; 95% CI: 0.41, 0.88). CONCLUSION: Taiwanese vegetarian diet is associated with lower risk of gout. This protective association may be independent of baseline hyperuricemia. STUDY REGISTERED: URL: https://www.clinicaltrials.gov. Unique Identifier: NCT03470584.

Taiwan Rheumatology Association consensus recommendations for the management of axial spondyloarthritis.

AIM: To establish guidelines for the clinical management of axial spondyloarthritis that take into account local issues and clinical practice concerns for Taiwan. METHOD: Overarching principles and recommendations were established by consensus among a panel of rheumatology and rehabilitation experts, based on analysis of the most up-to-date clinical evidence and the clinical experience of panelists. All Overarching Principles and Recommendations were graded according to the standards developed by the Oxford Centre for Evidence Based Medicine, and further evaluated and modified using the Delphi method. RESULTS: The guidelines specifically address issues such as local medical considerations, National Health Insurance reimbursement, and management of extra-articular manifestations. CONCLUSION: It is hoped that this will help to optimize clinical management outcomes for axial spondyloarthritis in Taiwan.

Clinical practice recommendations for the use of imaging in the diagnosis and management of axial spondyloarthritis in Taiwan.

OBJECTIVE: Axial spondyloarthritis (axSpA) is a chronic inflammatory disease bearing challenges in early diagnosis. To improve clinical diagnosis and management of axSpA, recommendations were developed with current axSpA classification criteria and recent advances in medical imaging applications. METHODS: A systematic literature review was conducted by 10 rheumatologists and radiologists in Taiwan to retrieve research evidence on the utilization of imaging modalities, including conventional radiography (CR), magnetic resonance imaging (MRI), computed tomography (CT), ultrasound (US), quantitative sacroiliac scintigraphy (QSS), and dual-energy X-ray absorptiometry (DXA). The panel of experts proposed six key issues on the role of imaging in early diagnosis of axSpA, monitoring of disease activity and structural changes, predicting treatment effects, and assessing complications such as osteoporosis and spinal fracture. The consensus was established on the basis of research evidence, clinical experiences and expert opinions. For each recommendation statement, the level of evidence was evaluated, the strength of recommendation was graded and the final level of agreement was determined through voting. RESULTS: In total, four overarching principles and 13 recommendations were formulated. These recommendations outlined different imaging approaches in the diagnosis and management of axSpA disease progression. Considering CT is easy to perform when MRI is less available in Taiwan, the expert panel proposed a concise and practical diagnostic scheme to strengthen the valuable role of MRI and CT in the diagnostic evaluation of axSpA without evident radiographic features. CONCLUSION: These modified recommendations provide guidance for rheumatologists, radiologists and healthcare professionals on timely diagnosis of axSpA and disease management with appropriate imaging modalities.

HLA-B27-mediated activation of TNAP phosphatase promotes pathogenic syndesmophyte formation in ankylosing spondylitis.

Ankylosing spondylitis (AS) is a type of axial inflammation. Over time, some patients develop spinal ankylosis and permanent disability; however, current treatment strategies cannot arrest syndesmophyte formation completely. Here, we used mesenchymal stem cells (MSCs) from AS patients (AS MSCs) within the enthesis involved in spinal ankylosis to delineate that the HLA-B27-mediated spliced X-box-binding protein 1 (sXBP1)/retinoic acid receptor-ß (RARB)/tissue-nonspecific alkaline phosphatase (TNAP) axis accelerated the mineralization of AS MSCs, which was independent of Runt-related transcription factor 2 (Runx2). An animal model mimicking AS pathological bony appositions was established by implantation of AS MSCs into the lumbar spine of NOD-SCID mice. We found that TNAP inhibitors, including levamisole and pamidronate, inhibited AS MSC mineralization in vitro and blocked bony appositions in vivo. Furthermore, we demonstrated that the serum bone-specific TNAP (BAP) level was a potential prognostic biomarker to predict AS patients with a high risk for radiographic progression. Our study highlights the importance of the HLA-B27-mediated activation of the sXBP1/RARB/TNAP axis in AS syndesmophyte pathogenesis and provides a new strategy for the diagnosis and prevention of radiographic progression of AS.

Blimp-1-Mediated Pathway Promotes Type I IFN Production in Plasmacytoid Dendritic Cells by Targeting to Interleukin-1 Receptor-Associated Kinase M.

Plasmacytoid dendritic cells (pDCs) are a specialized subset of DCs capable of rapidly producing copious amounts of type I IFN (IFN-I) in response to viral infections. The mechanism regulating rapid production of IFN-I after pDCs are exposed to viral nucleic acids remains elusive. Here, we show that the transcription factor Blimp-1 is promptly induced in pDCs after exposure to TLR7 and TLR9 ligands via a unique Ras-related C3 botulinum toxin substrate (Rac)-mediated pathway. Deletion of the Prdm1 gene encoding Blimp-1 impaired production of IFN-I, but not other cytokines, upon viral infection or treatment with CpG DNA in pDCs. Accordingly, mice lacking Blimp-1 in DCs failed to produce IFN-I after CpG stimulation and did not mount proper antiviral responses following flavivirus infection. The development of pDCs in bone marrow as well as the induction of several activation markers, such as CD86, CD69, and MHCII, by CpG stimulation was generally not affected by the absence of Blimp-1. Mechanistically, we found that Blimp-1 controls the activation of IKKα and IRF7 by directly suppressing interleukin-1 receptor-associated kinase 3 (Irak3), a negative regulator of TLR signaling, in pDCs. Together, we identify a Blimp-1-dependent pathway that rapidly facilitates IFN-I production by relieving interleukin-1 receptor-associated kinase M, encoded by Irak3, in pDCs.

The KDM4A/KDM4C/NF-κB and WDR5 epigenetic cascade regulates the activation of B cells.

T follicular helper (Tfh) cell-derived signals promote activation and proliferation of antigen-primed B cells. It remains unclear whether epigenetic regulation is involved in the B cell responses to Tfh cell-derived signals. Here, we demonstrate that Tfh cell-mimicking signals induce the expression of histone demethylases KDM4A and KDM4C, and the concomitant global down-regulation of their substrates, H3K9me3/me2, in B cells. Depletion of KDM4A and KDM4C potentiates B cell activation and proliferation in response to Tfh cell-derived signals. ChIP-seq and de novo motif analysis reveals NF-κB p65 as a binding partner of KDM4A and KDM4C. Their co-targeting to Wdr5, a MLL complex member promoting H3K4 methylation, up-regulates cell cycle inhibitors Cdkn2c and Cdkn3. Thus, Tfh cell-derived signals trigger KDM4A/KDM4C - WDR5 - Cdkn2c/Cdkn3 cascade in vitro, an epigenetic mechanism regulating proper proliferation of activated B cells. This pathway is dysregulated in B cells from systemic lupus erythematosus patients and may represent a pathological link.

Suppressors of cytokine signalling in ankylosing spondylitis and their associations with disease severity, acute-phase reactants and serum cytokines.

OBJECTIVES: To investigate the suppressors of cytokine signalling (SOCS1 and SOCS3) expression in peripheral blood cells in ankylosing spondylitis (AS), and their associations with clinical and laboratory manifestations. METHODS: The levels of SOCS1 and SOCS3 mRNA in peripheral blood mononuclear cells (PBMCs), T cells and monocytes were measured by RT-PCR in 53 AS patients and 31 healthy controls. Patient's serum IL-6, IL-10 and IL-17A levels were determined by ELISA. We evaluated patient's disease activity, functional ability and global assessment, and tested their ESR, CRP and IgA levels. RESULTS: Cellular SOCS1 expression did not show significant differences between AS patients and controls. However, T cells SOCS1 decreased significantly in the AS subgroup with lower ESR than controls (p=0.013). PBMCs (p=0.047) and T cells (p=0.035) SOCS1 decreased significantly in the AS subgroup with lower CRP than controls. Importantly, SOCS3 expression increased significantly in AS patients compared to the controls in PBMCs (p=0.025), T cells (p=0.003) and monocytes (p=0.009). Moreover, PBMCs SOCS3 correlated with ESR (r=0.297, p=0.031) and CRP (r=0.320, p=0.019). T cells SOCS3 correlated with BASFI (r=0.337, p=0.015), ESR (r=0.435, p=0.001) and CRP (r=0.300, p=0.029). Monocytes SOCS3 correlated with ESR (r=0.281, p=0.041) and IgA (r=0.426, p=0.006). Furthermore, T cells SOCS1 (r=-0.454, p=0.023) and T cells SOCS3 (r=-0.405, p=0.045) negatively correlated with serum IL-17A. Monocytes SOCS3 negatively correlated with serum IL-6 (r=-0.584, p=0.002). CONCLUSIONS: The decreased SOCS1 and increased SOCS3 expression in AS PBMCs and T cells, and their correlation with patient's functional ability, acute-phase reactants and serum pro-inflammatory cytokines suggested that SOCS may participate in the pathogenesis of AS.

The clinical usefulness of ESR, CRP, and disease duration in ankylosing spondylitis: the product of these acute-phase reactants and disease duration is associated with patient's poor physical mobility.

We evaluated the clinical usefulness of ESR, CRP, and disease duration in ankylosing spondylitis (AS) disease severity. There were 156 Chinese AS patients included in Taiwan. Patients completed the questionnaires, containing demographic data, disease activity (BASDAI), functional status (BASFI), and patient's global assessment (BASG). Meanwhile, patient's physical mobility (BASMI) and acute-phase reactants, including ESR and CRP levels were measured. Receiver operating characteristic (ROC) plot analysis was used to evaluate the performance of ESR, CRP, and disease duration in the AS patients. ESR mildly correlated with BASFI (r = 0.176, p = 0.028) and disease duration (r = 0.214, p = 0.008), and moderately correlated with BASMI (r = 0.427, p < 0.001). CRP moderately correlated with BASMI (r = 0.410, p < 0.001). By using ROC plot analysis, ESR, CRP, and disease duration showed the best and significant "area under the curve (AUC)", in distinguishing the AS patients with poor physical mobility (BASMI ≥ 3.6, the Median) (AUC = 0.748, 0.751 and 0.738, respectively, all p < 0.001), as compared to BASDAI, BASFI, and BASG. ESR × disease duration (AUC = 0.801, p < 0.001) and CRP × disease duration (AUC = 0.821, p < 0.001) showed higher AUC values than ESR or CRP alone in indicating poor physical mobility. For detecting poor physical mobility (BASMI ≥ 3.6) in the AS patients: ESR × disease duration (≥60.0 mm/h × year): sensitivity = 72.7 % and specificity = 72.8 %; CRP × disease duration (≥8.3 mg/dl × year): sensitivity = 72.7 % and specificity = 74.6 %. ESR, CRP, and disease duration are particularly related to AS patient's poor physical mobility. Combining the usefulness of acute-phase reactants and disease duration, the values of ESR × disease duration and CRP × disease duration demonstrate better association with poor physical mobility in AS patients.

Association of cigarette smoking with Chinese ankylosing spondylitis patients in Taiwan: a poor disease outcome in systemic inflammation, functional ability, and physical mobility.

We investigated the association between smoking and the disease activity, functional ability, physical mobility, and systemic inflammation in Chinese ankylosing spondylitis (AS) patients. Seventy five male Chinese AS patients in Taiwan were enrolled in the cross-sectional study. These patients fulfilled the 1984 modified New York criteria. Patients completed the questionnaires, containing the demographic data, disease activity, functional ability (BASFI), and patient's global assessment. Meanwhile, physical examinations were performed to determine the patient's physical mobility. Acute-phase reactants, erythrocyte sedimentation rate (ESR), and C-reactive protein levels were also measured in the AS patients. Smoking habits with smoking duration and smoking intensity (pack-years of smoking) were recorded. Among these physical mobility parameters, modified Schober's index (p < 0.001), cervical rotation (p = 0.034), later lumbar flexion (p = 0.002), chest expansion (p = 0.016), and occiput-to-wall distances (p = 0.003) were significantly impaired in smoking AS patients (n = 35) as compared to non-smoking (n = 40). Systemic inflammation parameter, ESR was significantly higher in smoking AS patients than non-smoking (p = 0.03). The odds ratio of advanced modified Schober's index, lateral lumbar flexion, fingertip-to-floor distance, chest expansion, and occiput-to-wall were significantly elevated in smoking AS patients as compared to non-smoking. Moreover, the smoking intensity correlated significantly with BASFI (r = 0.481, p = 0.005), cervical rotation (r = -0.401, p = 0.031), fingertip-to-floor distance (r = 0.485, p = 0.004), and occiput-to-wall distance (r = 0.473, p = 0.005) in the 35 smoking AS patients. The cigarette smokers in the Chinese AS patients have increased systemic inflammation and poor physical mobility. In addition, the higher smoking intensity in the AS smokers is associated with poor disease outcome, including functional ability and physical mobility. Thus, it is quite important for the physician to emphasize the association of smoking with poor disease prognosis in AS, and patients should be strongly recommended to avoid smoking cigarette.

High-throughput screening of chemical libraries for modulators of gene promoter activity of HLA-B2705: environmental pathogenesis and therapeutics of ankylosing spondylitis.

OBJECTIVE: Ankylosing spondylitis (AS) is a highly heritable disease with HLA-B27 being the strongest susceptible gene. In order to survey the environmental triggers for arthritis development, we used a high-throughput technique to screen the effects of 12,264 chemicals on the HLA-B27 gene promoter. METHODS: Promoter reporter transfectants 293T-HLA-B27 and HeLa-HLA-B27 were tested using robotics with 12,264 chemicals. Chemicals that modulated HLA-B27 promoter activity > 150% or < 40% were selected for further evaluation of IC50/EC50 and cell viability. RESULTS: The primary screening using the 293T-HLA-B27 promoter reporter cell line yielded 5.1% hits that either suppressed (556 chemicals) or enhanced (68 chemicals) the HLA-B27 promoter activity. A secondary reconfirmation screening was carried out with these 624 candidates using HeLa-HLA-B27 promoter reporter cells under several different culture conditions. The yield of positive candidates was 130, of which 47 were derived from natural products. Based on the bio-information of those positive natural products, 21 chemicals were selected for analysis by dose-response IC50/EC50 experiments. Eight compounds showed potential pharmacological activities. Two suppressors are both derived from an herbal medicine (lei gong teng) that has been used for decades to treat immune diseases. The 6 activators all belonged to a group of chemicals known as flavonoids, widely distributed among dietary fruits and vegetables. CONCLUSION: Several common dietary products that contain certain flavonoids might be environmental risk factors for AS; the Chinese traditional herb lei gong teng might be a potential drug for patients who are HLA-B27-positive. These results provide new research directions for the pathogenesis and therapeutics of AS.