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Overall survival of systemic lupus erythematosus (SLE) patients significantly increased in recent decades, however, the relative risk of mortality is still high. Long-term survival outcome of pediatric SLE remains unclear. This study aims to explore the long-term survival rate and its predictors in patients with systemic lupus erythematosus (SLE).A retrospective, hospital-based cohort study was performed between 2004 and 2018 in a tertiary referral medical center in Taiwan. Data on comorbidities, medications, and causes of admission were collected for risk factor analysis using time-dependent multivariate Cox proportional hazards models.A total of 2392 adults and 115 pediatric SLE patients were enrolled (female, n = 2157 and 95, respectively). The 10-year survival rates were 93.2%, 90.2%, 98.9%, and 100% in adult women, adult men, girls, and boys with SLE, respectively. The overall mortality rate was 2.09 case/100 patient-years (PY) for male SLE and 1.39 case/100 PY for female SLE patients. Male SLE patients did not have a statistically significantly higher mortality rate than female SLE patients in each age stratification. Infectious disease (n = 119), heart failure (n = 21), and cerebrovascular accident (n = 14) were the leading causes of death in adult SLE patients. Advanced age (hazard ratio [HR]: 1.04, 95% confidence interval [CI]: 1.03-1.05), treatment with mean dosage of systemic glucocorticoid equivalent to10 mg/d of prednisolone (HR: 1.71, 95% CI: 1.14-2.57), comorbidities with malignancy (HR: 1.94, 95% CI: 1.22-3.09), chronic kidney disease (HR: 1.86, 95% CI: 1.25-2.77), hypertension (HR: 1.42, 95% CI: 1.01-1.98), and admission due to bacterial pneumonia (HR: 1.92, 95% CI: 1.12-3.31) and sepsis (HR: 2.78, 95% CI: 1.51-5.13) were independent risk factors for mortality in SLE patients.SLE patients with advanced age, malignancy, chronic kidney disease, hypertension, treated with a higher average dosage of glucocorticoids, and admission due to bacterial pneumonia and sepsis have an increased risk of mortality.

To investigate the association of blood pressure and hypertension with disease severity among the patients with ankyloing spondylitis (AS). There were 167 AS patients enrolled in the cross-sectional study. Blood pressure was measured and the presence of hypertension was recorded. Patient's disease severity, including disease activity, functional ability, patient's global assessments, physical mobility and radiographic damage were evaluated. ESR and CRP levels were tested. We recorded patient's medication use of NSAIDs, DMARDs and TNF-α blockers. Smoking, exercise habit, diabetes mellitus, hypercholesterolemia and obesity indices were assessed. Multivariate linear regression showed that systolic blood pressure was associated with TNF-α blocker [standard coefficient (β) = 0.194, P = .007], DMARDs (β = 0.142, P = .046), age (β = 0.211, P = .003), male gender (β = 0.242, P = .001) and body mass index (BMI) (β = 0.245, P = .001). Diastolic blood pressure was associated with cervical rotation (β = -0.174, P = .037), lateral lumbar flexion (β = -0.178, P = .019), m-SASSS (β = 0.198, P = .038) and BMI (β = 0.248, P = .003). Notably, multivariate logistic regression showed that hypertension was associated with m-SASSS (OR = 1.033, P = .033), age (OR = 1.098, P = .0010) and BMI (OR = 1.210, P = .003). Using ROC cure analyses, age, BASMI, BASRI-Total, m-SASSS, waist circumference, BMI and waist-to-height ratio were useful in predicting hypertension, and m-SASSS is the best (AUC = 0.784, P .001). Advanced radiographic damage is an independent risk factor of hypertension in AS, and m-SASSS is the most useful disease severity parameter in predicting the presence of hypertension. Advanced radiographic damage, poor cervical rotation, lateral lumbar flexion, older age, male gender, TNF-α blocker, DMARDs use and obesity are associated with increased blood pressure.

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

Background Cytotoxic T lymphocyte-associated antigen-4-Ig (CTLA-4-Ig) competes with CD28 for binding CD80/CD86 on antigen-presenting cells (APCs) to limit T cell activation. B cells are believed to be important APCs in the pathogenesis of autoimmune diseases and express CD80/CD86 after activation; however, relatively little is known about the effect of CTLA-4-Ig on B cells. This study tested the impact of CTLA-4-Ig on human B cell responses. Methods Human blood B cells were purified from healthy donors and activated in the presence of CTLA-4-Ig or the L6-Ig control protein in vitro. RT-q-PCR and immunofluorescence staining were performed to detect activation marker expression. ELISA was conducted to measure cytokine secretion. The CD80/CD86 levels on the surface of the memory B cells in the blood of 18 patients with rheumatoid arthritis (RA) were detected using immunofluorescence staining. Results CTLA-4-Ig suppressed the expression of Staphylococcus aureus (SAC)-induced CD80, CD86, TNFA, and IL6 in human B cells at the transcriptional level. Furthermore, CTLA-4-Ig concomitantly decreased SAC-induced CD80/CD86 surface expression on and TNF-α and IL-6 secretion from B cells. On the other hand, T cell-dependent (TD) stimulation-induced B cell activation, proliferation, plasma cell differentiation, and antibody secretion were not affected by CTLA-4-Ig. As expected, TD stimulation-induced surface CD80 was hindered by CTLA-4-Ig. Notably, a blockade of CD80/CD86 on the surface of the memory B cells was observed in the patients with RA after abatacept (CTLA-4-Ig) treatment. In a portion of the RA patients, restoration of CD80/CD86 staining on the surface of the memory B was detected starting in the 3rd month of abatacept treatment. Interestingly, the surface levels of CD80/CD86 on the patients’ memory B cells positively correlated with disease activity. Conclusions We found that CTLA-4-Ig directly suppressed SAC-induced B cell activation in vitro. Obstruction of CD80 and CD86 on the surface of the memory B cells was detected in the RA patients after abatacept treatment. Blocking CD80/CD86 on B cells by CTLA-4-Ig may hinder T cell activation and associated with the disease activity of RA in vivo. Our findings indicate that CTLA-4-Ig may regulate humoral responses by modulating B cell activation and interfering T cell-B cell interaction.

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.

ObjectiveTo compare changes in bone mineral density (BMD) in rheumatoid arthritis (RA) patients receiving three-year conventional synthetic disease-modifying anti-rheumatic drugs (csDMARD), tumor necrosis factor-α inhibitors (TNFi), and abatacept.MethodsPatients with RA were recruited from September 2014 to February 2021. Dual-energy X-ray absorptiometry was used to measure BMD at the femoral neck (FN), total hip (TH), and lumbar spine (L1-4) at enrollment and three years later. Changes in the BMD of each regimen group were analyzed. Multiple ordinary least squares regression was used with the dependent variables to develop a model to predict the change in BMD.ResultsA total of 752 participants were enrolled and 485 completed the three-year follow-up period. Of these, 375 (Group I), 84 (Group II), and 26 (Group III) participants received csDMARDs, TNFi, and abatacept therapy, respectively. Considering both type of therapy and completion of the follow-up period, participants were divided into groups A (csDMARDs, n = 104), B (TNFi, n = 52), and C (abatacept, n = 26). Compared to baseline, BMD decreased significantly at FN (p = 0.003) and L1-4 (p = 0.002) in Group A and at L1-4 (p = 0.005) in Group B, but remained stable at all sites in Group C. In terms of regression-adjusted percent change in BMD, there was a significant difference seen at all measured sites between group C compared to both groups A and B (+0.8%, -2.7%, -1.8% at FN; +0.5%, -1.1%, -1.0% at TH; +0.8%, -2.0%, -3.5% at L1-4, respectively; all p < 0.05). Anti-osteoporosis therapy had a BMD-preserving effect in RA.ConclusionCompared with csDMARDs and TNFi, abatacept may have a better BMD-preserving effect in RA. Anti-osteoporosis therapy can prevent systemic bone loss irrespective of RA therapy.

Aim To assess the real-world effectiveness and safety of rituximab (RTX) at 24 months in patients with established rheumatoid arthritis (RA) and to identify predictors of low disease activity/remission and a good European League Against Rheumatism (EULAR) response. Methods Seventy RTX-treated RA patients were enrolled. Predictors for low disease activity/remission and a good EULAR response at 24 months were identified by multivariate analyses. Results At 24 months, the mean Disease Activity Score of 28 joints-erythrocyte sedimentation rate (DAS28-ESR) decreased from 6.88 ± 0.85 at baseline to 3.47 ± 0.85. Twenty-nine patients (41.4%) reached low disease activity/remission, while all patients had a moderate/good EULAR response. After adjustment by multivariate analyses, we found concomitant methotrexate at a dosage >10 mg/week (odds ratio [OR] 5.17; 95% CI 1.34-19.93; P = 0.017) predicted low disease activity/remission, and baseline DAS28 ≤6.5 (OR 4.97; 95% CI 1.22-20.30; P = 0.026) predicted good EULAR response at 24 months. The most common adverse events were infusion-related (5.7%), and there was no incidence of malignancy or mortality during the treatment. Conclusions RTX was effective and safe in real-life management of RA patients with high disease activity. Patients taking concomitant methotrexate and with lower baseline DAS28-ESR were more likely to benefit from RTX.

Background/Purpose: To determine serum semaphorin 3A (Sema 3A) levels in ankylosing spondylitis (AS). Methods: Serum Sema 3A was measured in 46 AS patients and 30 healthy controls (HCs). For the patients, we recorded demographic data, disease activity, functional index & global assessment, detected human leukocyte antigen-B27 (HLA-B27), and measured erythrocyte sedimentation rate (ESR) & C-reactive protein (CRP). Results: Sema 3A was higher in AS patients than in HCs (3.98 ± 2.57 vs. 1.34 ± 0.48 ng/ml, p = 0.013). Area under the curve (AUC) of standard receiver operating characteristic (ROC) has suggested that Sema 3A > 2 ng/ml is better to predict the higher Bath Ankylosing Spondylitis Disease Activity Index (BASDAI, > 4) than ESR or CRP. There were good correlations between higher Sema 3A and uveitis, Schöber's test, as well as interstitial lung disease. AS patients undergoing anti-tumor necrosis factor therapies for 3 months exhibited a positive correlation of change in Sema 3A (ΔSema 3A) with disease activity fluctuation [ΔBASDAI, ΔBath Ankylosing Spondylitis Functional Index (BASFI) and ΔBath Ankylosing Spondylitis - Global score (BAS-G)]. Conclusion: Serum Sema 3A level was increased in AS patients and was inversely correlated to Schöber's test. Serum Sema 3A is better as a bio-marker than ESR or CRP to correlate with high disease activity in AS patients, and it is also a good indicator for monitoring disease activity and functional status during anti-TNF treatment. Also, Sema 3A may be taken as a predictor for extra-articular presentations in AS, but this needs further study to elucidate. Keywords: Ankylosing spondylitis, Semaphorin 3A, Osteoimmunology, Bone remodeling, Biomarker

Background/purpose: To investigate the Janus kinase-1 and 3 (JAK-1 and 3) expression in peripheral blood mononuclear cells (PBMCs) in ankylosing spondylitis (AS). Methods: The levels of JAK-1 and JAK-3 mRNA in PBMCs, CD3+ T cells and CD14+ monocytes were measured by RT-PCR in 52 AS patients and 31 healthy controls (HCs). The demographic features, BASDAI, BASFI, HLA-B27, ESR, CRP and serum immunoglobulin A (IgA) level were recorded and correlated with the JAK-1 & JAK-3 transcripts in patients and HCs as appropriate. Results: JAK-1 and JAK-3 expression in PB CD3+ T cells plus CD14+ monocytes was significantly higher in AS patients than in HCs (p 4) and BASFI (>4) than ESR or CRP in AS patients. Conclusion: In AS, JAK-1 expression in PB cells rather than ESR or CRP might be regarded as a bio-marker for monitoring disease activity and functional index in AS. These findings have also suggested that JAK-1 and JAK-3 expression may play a role in the inflammatory processes in patients with AS. Keywords: Ankylosing spondylitis, Janus kinase (JAK), Acute-phase reactant

Background & Aims In patients who have resolved hepatitis B virus (HBV) infection, treatment of rheumatoid arthritis (RA) can result in reappearance of hepatitis B surface antigen (HBsAg), called reverse seroconversion. We investigated clinical features and outcomes of reverse seroconversion in patients who received immunosuppressant or biologic therapy for RA. Methods We identified 1494 patients with RA (925 who resolved HBV infection) and available data on levels of antibody to HB core antigen and HBsAg who had attended Taipei Veterans General Hospital from January 2007 through December 2017. We identified 17 cases (median age, 66 years) who were negative for HBsAg before treatment of RA and reverse seroconversion (HBsAg reappearance) after glucocorticoid treatment (n = 13) and/or biologic therapy (adalimumab, n = 2; etanercept, n = 1; rituximab, n = 9; or abatacept, n = 4). Four patients were positive for antibodies against HBsAg (seroconverted) before the immunosuppressive treatment. Results The median time from immunosuppressive treatment to reverse seroconversion was 120 months (range, 20–264 months), whereas the time from biologic therapy treatment to reverse seroconversion was 66 months (range, 10–105 months). After reverse seroconversion, 8 individuals (47.1%) were positive for HB e antigen; 9 cases (52.9%) did not have a flare of alanine transaminase. However, 3 patients (17.6%) developed liver decompensation. Conclusions In patients who resolved HBV infection and received immunosuppressant treatment of RA, risk of reversal of seroconversion is low but persists for up to 10 years. Patients with RA who previously resolved HBV infections should be monitored for levels of HBsAg and HBV DNA once immunosuppressive treatment of RA begins.

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.

Objectives The aim of this study was to investigate the role of regulatory T cells (Tregs) in ankylosing spondylitis (AS). Methods We included 69 AS patients (15 of them received anti-tumor necrosis factor-apha agent-adalimumab) in the study and used a questionnaire to record the demographic data, disease activity index, functional index, human leukocyte antigen-B27, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). Thirty healthy subjects were used as controls. The peripheral blood mononuclear cells (PMBCs) were stained with anti-CD4, anti-CD25 and anti-Forkhead/winged helix transcription factor P3 (anti-FoxP3) antibodies and flow-cytometry was used to determine cell populations. Results The percentages of Tregs in PMBCs were significantly higher in AS patients than in healthy controls. In AS patients who had poor disease functional index with higher levels of ESR and CRP were positively and significantly correlated with Tregs percentages in PMBCs. After adalimumab treatment in 15 patients, the percentages of Tregs, the ESR/CRP levels and the Bath Ankylosing Spondylitis Disease Activity Index/Bath Ankylosing Spondylitis Functional Index were significantly and gradually decreased over time. Conclusions The high expression of FoxP3 and CD25 on CD4 + T cells in PBMCs in AS patients was noted, and could be reversed by adalimumab therapy. These findings suggest that Tregs may play a role in modulating the inflammatory process in AS. Whether Tregs can be taken as a predictor for disease activity or treatment outcome is unclear and requires further study.

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-β (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.

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.

To investigate the effect of inflammation on expressions of bone morphogenetic proteins (BMPs) in peripheral blood mononuclear cells (PBMCs) and its association with individual radiographic changes in patients with ankylosing spondylitis (AS).The changes in BMP-2, -4, and -7 gene expressions in PBMCs were measured after stimulation by tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). The correlation of increase in gene expression with clinical and radiographic findings in patients with AS were analyzed.Both TNF-α and IL-1β could enhance BMP-2 expression in PBMCs from AS patients. Increases in BMP-2, -4, and -7 expressions in PBMCs positively correlated with total modified Stoke Ankylosing Spondylitis Spinal Score (all p0.05). Moreover, increases in BMP-2, -4, and -7 gene expressions after TNF-α and IL-1β stimulation were greater among AS patients with versus without severe sacroiliitis (all p0.05). Increases in BMP-2 and -7 expressions were greater in PBMCs from 4 patients with total (cervical, thoracic, and lumbar) spinal ankylosis than in the 8 patients who did not have total spinal ankylosis (all p0.05).In AS, inflammation upregulates the expression of BMPs in PBMCs which may lead to the radiographic progression with new bone formation.

In patients with systemic lupus erythematosus (SLE), low bone mineral density (BMD) is associated with increased age, prolonged disease, low body mass index (BMI), and overlap with rheumatoid arthritis (RA). Elevated fibroblast growth factor (FGF)-23 in cyclosporine A (CsA) users with SLE are associated with decreased active vitamin D and osteocalcin.The objective of this study was to investigate the steroid and CsA effect on bone metabolism and serum FGF-23 in SLE patients.Seventy-two SLE patients and 10 age- and sex-matched healthy individuals underwent blood tests for bone metabolic biomarkers and FGF-23, and lumbar spine dual-energy X-ray absorptiometry for BMD.Comparisons between patients and controls were made in premenopausal women/men younger than 50 years and postmenopausal women/men older than 50 years separately. SLE patients had more frequent low Z-score (≤-2.0, 8.5 vs. 0%), osteopenia (-2.5T-score-1.0, 52 vs. 50%), and osteoporosis (T-score≤-2.5, 12 vs. 0%), than the healthy age-compatible counterparts. BMD was significantly lower in patients with advanced age, longer disease duration, lower BMI, and overlap with RA (all p0.05 by multiple linear regression analyses). Serum FGF-23 was significantly higher and 1,25-dihydroxyvitamin D (1,25(OH)2D3) lower in SLE patients treated with glucocorticoid and CsA than in those not taking both of them (p=0.027 and 0.002, respectively). The cumulative dose of glucocorticoid was inversely correlated with serum intact parathyroid hormone (r=-0.299, p=0.011), C-terminal telopeptide of type I collagen (r=-0.581, p0.001), and osteocalcin (r=-0.648, p0.001). FGF-23 and the cumulative dose of CsA were positively correlated (r=0.38, p=0.001) and both were negatively correlated with 1,25(OH)2D3 (r=-0.266, p=0.016 and r=-0.55, p0.001) and osteocalcin (r=-0.234, p=0.034 and r=-0.274, p=0.02).SLE patients treated with glucocorticoid and CsA exhibited markedly decreased bone turnover. Those taking CsA had higher serum FGF-23 associated with suppression of 1,25(OH)2D3 and bone formation. Such high-risk patients necessitate regular screening of osteoporosis.

Primary Sjogren's syndrome (pSS) is a systemic autoimmune disease and may complicate with interstitial lung disease. The risk of Mycobacterium tuberculosis (TB) infection in patients with pSS has not been determined. This nationwide population-based study aimed to explore the incidence and risk factors of TB infection in patients with pSS. We identified 4,822 pSS patients from the Taiwan National Health Insurance database and compared the incidence rates of TB infection in these patients with 48,220 randomly selected age-, sex-, and comorbidity-matched subjects without pSS. The Cox proportional hazard model was used to identify risk factors for TB in patients with pSS. The risk of TB was higher in the pSS cohort than in the control cohort with an incidence rate ratio (IRR) of 1.58 (95% confidence interval [95% CI] 1.13-2.18, p = 0.006). The risk factors for TB in the pSS cohort were age ≥60 years (hazard ratio [HR] 3.22, 95% CI 1.78-5.84; p < 0.001), and corticosteroid usage, which had a dose-dependent effect in the pSS patients compared to the nonusers (daily prednisolone dose or equivalent less than 5 mg/day: HR 2.34; p = 0.020, 95% CI 1.14-4.78; 5 mg/day to less than 10 mg/day: HR 4.79, 95% CI 2.15-10.68; p < 0.001; 10 mg/day or more: HR 12.19, 95% CI 4.42-33.63; p < 0.001). Patients with pSS had a higher risk of pulmonary TB in Taiwan, which was related to age ≥60 years and corticosteroid usage.

Primary Sjogren's syndrome (PSS) is an autoimmune disease targeting exocrine glands. It ten times more dominantly affects women than men with an onset peak at menopause. The genetic factor predisposing women to PSS remains unclear. Therefore, we aimed to identify susceptibility loci for PSS in women. We performed genome-wide association study (GWAS) using 242 female PSS patients and 1444 female control in Han Chinese population residing in Taiwan. Replication was conducted in an independent cohort of 178 female PSS and 14,432 control subjects. We identified rs117026326 on GTF2I with GWAS significance (P = 1.10 × 10-15) and rs13079920 on RBMS3 with suggestive significance (P = 2.90 × 10-5) associating with PSS in women. The association of RBMS3 was further evidenced by imputation in which rs13072846 (P = 4.89 × 10-5) was identified and confirmed as female PSS associating SNP within the same LD with rs13079920. PSS pathogenesis involves both immune (effector) and exocrine (target) system. We suggested that while GTF2I is a previously reported associating gene which may function in immune system, RBMS3 is a novel susceptibility gene that predisposes women to PSS potentially through modulating acinar apoptosis and TGF-β signaling in target exocrine system.

Spondyloarthritis (SpA) is often diagnosed late in the course of the disease and improved methods for early diagnosis are required. We have tested the ability of genetic profiling to diagnose axial SpA (axSpA) as a whole group, or ankylosing spondylitis (AS) alone, in a cohort of chronic back pain patients.282 patients were recruited from centres in the United Kingdom, Germany, Taiwan, Canada, Columbia and Turkey as part of the ASAS classification criteria for axSpA study (ASAS cohort). Subjects were classified according to the ASAS axSpA criteria, and the modified New York Criteria for AS. Patients were genotyped for ~200,000 immune-mediated disease SNPs using the Illumina Immunochip.We first established the predictive accuracy of genetic data comparing 9,638 healthy controls and 4,428 AS cases from the homogenous International Genetics of AS (IGAS) Consortium Immunochip study which showed excellent predictive power (AUC=0.91). Genetic risk scores had lower predictive power (AUC=0.83) comparing ASAS cohort axSpA cases meeting the ASAS imaging criteria with IGAS controls. Comparing genetic risk scores showed moderate discriminatory capacity between IGAS AS and ASAS imaging positive cases (AUC 0.67±0.05), indicating that significant differences in genetic makeup exist between the cohorts.In a clinical setting of referred back pain patients suspected to have axial SpA we were unable to use genetic data to construct a predictive model better than that based on existing clinical data. Potential confounding factors include significant heterogeneity in the ASAS cohort, possibly reflecting the disease heterogeneity of axSpA, or differences between centres in ascertainment or classification performance.

Objectives This study aimed to identify the risk factors for mortality and the impact of dialysis modalities on the survival in SLE patients with end-stage renal disease (ESRD). Methods This retrospective nationwide population-based study using the National Health Insurance Research Database in Taiwan collected data from 1073 SLE ESRD patients starting maintenance dialysis between March 1997 and December 2006. A multivariate Cox regression hazard model was applied to identify factors predicting mortality in cohorts using different dialysis modalities and the impact of dialysis modalities on the survival outcome of these patients of both genders. Results The major threat to SLE patients on maintenance dialysis was infections. For SLE patients undergoing regular haemodialysis (HD), age, male sex, and high or absence of daily steroid dosing were predictive of higher mortality. For those undergoing regular peritoneal dialysis (PD), age and high daily steroid dosing were the predictive factors. After adjusting confounding factors, male patients with HD had a significantly poorer outcome than the counterpart with PD or female patients with HD. There was no survival difference among female SLE patients with different dialysis modalities. Conclusion No underlying comorbidities were identified to increase the mortality of patients receiving particular dialysis modalities after correcting for age and steroid factors. There was no impact of different dialysis modalities on survival of female SLE patients. However, male SLE patients seemed susceptible to fatal events complicated by HD, which led to an inferior survival rate.

Background Ankylosing spondylitis (AS) is a chronic arthritis with a pathogenesis which is not fully understood. A third subset of IL-17-producing T helper cells, called Th17 cells, has been discovered and characterized. We investigated whether IL-17 and IL-23, two Th17-related cytokines, play any roles in the pathogenesis of, and have any correlations with, disease activity and clinical manifestations in AS. Methods This cross-sectional study included 49 AS patients and 25 healthy control subjects. The serum IL-17 and IL-23 levels were measured using enzyme-linked immunosorbent assay kits. At the same time, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI) and Bath Ankylosing Spondylitis Patient Global Score (BAS-G) levels were measured, and physical examinations were performed on study participants to determine their extent of physical mobility. Results The serum IL-17 and IL-23 levels of the AS patients were significantly higher than those of the healthy controls. In the AS patients, the BASDAI scores had a better correlation with the serum IL-17 or IL-23 levels (IL-17, r = 0.351, p = 0.014; IL-23, r = 0.398, p = 0.005) than with ESR (r = 0.078, p = 0.600) and CRP (r = 0.012, p = 0.993). IL-17 or IL-23 correlate to the BASFI, BAS-G and parameters related to physical mobility. In the receiver operating characteristic (ROC) analysis, the serum IL-17 and IL-23 levels act better in discriminating patients with BASDAI≥4 (AUC value 0.88, p = 0.001) than ESR and CRP (AUC value 0.727, p = 0.008). Conclusion Serum IL-17 and IL-23 levels were significantly higher in AS patients than in healthy controls and the levels correlate to disease activity measured by BASDAI scores, but not parameters of functional ability and spinal mobility. These results suggest the existence of a role of IL-17 and IL-23 in the pathogenesis of inflammation in AS.

Objective.The aim of our study was to compare the clinical, functional, and radiographic outcomes at different ages of onset in patients with ankylosing spondylitis (AS).Methods.A total of 546 patients were enrolled consecutively and classified into 3 groups based on their age at symptom onset: (1) juvenile-onset AS (age ≤ 16 years; JoAS); (2) adult-onset AS (> 16 but < 40 years; AoAS); and (3) late-onset AS (≥ 40 years; LoAS). We compared the differences among the 3 groups. OR for disease outcomes were calculated and adjusted for sex, HLA-B27, and disease duration.Results.There were 67 patients (12.3%) with JoAS, 460 (84.2%) with AoAS, and 19 (3.5%) with LoAS. Male sex and HLA-B27 were associated with a younger age at onset (p < 0.001). Compared to patients with AoAS, patients with JoAS were more likely to present with peripheral arthritis, while patients with JoAS and LoAS were less likely to have back pain at the onset of AS (p < 0.05). After controlling for multiple covariates, JoAS was found to be associated with a worse functional outcome and global assessment, and a high serum immunoglobulin A level (p < 0.05). Patients with JoAS had less lumbar spinal radiographic severity (p < 0.05). There were no statistical differences in clinical or functional outcome between the LoAS and AoAS groups. None of the LoAS patients had radiographic hip involvement.Conclusion.Sex and HLA-B27 are significantly associated with age at onset of AS. Both JoAS and LoAS have their distinctive symptoms/signs at onset and different disease outcomes.

The role of hepatitis B virus (HBV) infection in patients with primary Sjogren's syndrome (pSS) remains unclear. Therefore, we investigated the prevalence and clinical significance of HBV infection in Taiwanese patients with pSS. One hundred seventy-five patients with pSS who fulfilled the 2002 American-European Revised Classification Criteria were enrolled. Eighteen (10.3%) patients were positive for hepatitis B surface antigen (HBsAg). There were 4 males and 14 females, with the mean age of 54.4 years. The main immunological feature was rheumatoid factor (13 of 18, 72.2%), which was significantly higher than those negative for HBsAg (28.1%, p

To determine the factors associated with radiographic spinal involvement and hip involvement in ankylosing spondylitis (AS) and assess the influence of the damage seen in the radiographs on functional outcome in patients with AS.We included 531 consecutive patients and recorded the clinical, laboratory, and radiographic data. Based on the spinal radiographs, patients were classified into 3 categories: (1) no spinal involvement; (2) spinal involvement without fusion; and (3) spinal involvement with fusion. Hip involvement was assessed by the Bath Ankylosing Spondylitis Radiology Hip Index and defined by a score of at least 2. Logistic regression analyses were used to investigate the factors associated with the radiographic spine and hip involvements.Ninety-eight (18.5%) patients had radiographic evidence of spinal fusion and 48 (9.0%) had radiographic evidence of hip involvement. Patients who had longer disease duration, elevated C-reactive protein levels, advanced sacroiliitis, and radiographic hip involvement were significantly more likely to have spinal fusion (P0.05). Elevated C-reactive protein levels and advanced sacroiliitis were also significantly associated with the presence of spinal involvement without fusion (P0.05). Early disease onset and more radiographic severity in the spine and sacroiliac joints were the predictors of radiographic hip involvement (P0.05). Patients with either spine or hip involvement had significantly higher Bath Ankylosing Spondylitis Functional Index scores (P0.001).There is a relationship between radiographic sacroiliitis, spinal fusion, and hip involvement in patients with AS. Damage to the spine and hip seen radiographically can contribute to functional impairment.

The objective of the study was to investigate the role of receptor activator of nuclear factor-kappaB ligand (RANKL) and osteoprotegerin (OPG) in ankylosing spondylitis (AS). Serum levels of soluble RANKL (sRANKL) and OPG were measured in 42 AS patients and 26 healthy controls. We evaluated the AS patient's disease activity, functional ability, global assessment, and physical mobility and tested markers of systemic inflammation, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) levels. Serum levels of sRANKL [mean (SD), 4.75 (1.88) vs. 3.70 (1.14) pmol/l, p = 0.015] and OPG [mean (SD), 5.18 (1.19) vs. 4.52 (0.85) pmol/l, p = 0.026] were significantly higher in the 42 AS patients than the 26 healthy controls. Interestingly, serum OPG levels correlated significantly with ESR (r = 0.417, p = 0.007), CRP (r = 0.524, p0.001), tragus-to-wall distance (r = 0.556, p0.001), fingertip-to-floor distance (r = 0.423, p = 0.007), and occiput-to-wall distance (r = 0.465, p = 0.002) and correlated inversely with modified Schober index (r = -0.525, p = 0.001), cervical rotation (r = -0.403, p = 0.022), lateral lumbar flexion (r = -0.587, p0.001), and chest expansion (r = -0.553, p0.001). Moreover, in the AS patients with higher (or =4.925 pmol/l, n = 21) serum OPG levels, there were significant increases in the tragus-to-wall distance (p = 0.007), fingertip-to-floor distance (p = 0.023), and CRP levels (p = 0.014) and decreased in the modified Schober index (p = 0.012), lateral lumbar flexion (p = 0.019), and chest expansion (p = 0.005). Serum levels of sRANKL and OPG are increased in the AS patients and may participate in the disease process of AS. Production of OPG has association with poor physical mobility and may reflect systemic inflammation in AS.

Aims: To assess the predictive and prognostic value of antinuclear antibodies (ANA) and rheumatoid factor (RF) in primary Sjogren’s syndrome (pSS). Methods: This retrospective study includes 201 patients that fulfilled the 1993 European preliminary classification criteria for pSS. The patients were further categorized by the 2002 revised criteria, with or without the inclusion of ANA and RF as classification criteria, and were further subgrouped by the presence of ANA, RF, anti-SS-A, and anti-SS-B, and different ANA titers. The clinical manifestations, serological markers, and results of lip biopsies among these subgroups were compared. Results: Our results showed pSS patients who are seropositive for one of the following markers: ANA, RF, anti-SS-A, or anti-SS-B are younger, predominantly female, and had more serological abnormalities than those with seronegativity of ANA, RF, anti-SS-A, or anti-SS-B. Higher ANA titers (≥ 1 : 640) correlated with higher frequency of serum anti-SS-A+ and anti-SS-B+, and elevations of serum immunoglobulin G and A in all three different classification criteria groups. The clinical manifestations and laboratory results in the 2002 revised criteria groups with or without the inclusion of ANA and RF as classification criteria items were highly concordant. Conclusion: Regardless of the classification criteria for pSS, patients who are seropositive for one of the ANA, RF, anti-SS-A and anti-SS-B biomarkers are more likely to have autoimmune-related Sjogren’s syndrome. ANA and RF have shown to possess the predictive and prognostic values for those who do not fulfill the higher stringent 2002 revised criteria but are indicated for immunomodulatory therapy. Thus we suggest that ANA and RF should be reconsidered as items of classification criteria for pSS.

Objective. To investigate the role of HLA-G in AS. Methods. Serum levels of soluble HLA-G (sHLA-G) were measured in 80 AS patients and 30 healthy controls. The expression of HLA-G on the peripheral blood mononuclear cell (PBMC) surface was investigated in the same 80 AS patients and 40 healthy controls by flow cytometry. The response of HLA-G after 3 months of TNF-a blocker therapy (adalimumab) was evaluated in 14 AS patients. We evaluated Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), Bath Ankylosing Spondylitis Patient Global Score (BAS-G), physical mobility, ESR and CRP levels. Results. Serum levels of sHLA-G were significantly lower in 80 AS patients than 30 healthy controls [mean (S.D.) 22.47 (26.8) vs 34.78 (32.01) U/ml, P ¼ 0.028], and correlated significantly with modified Schober index (r ¼ 0.326; P ¼ 0.009), chest expansion (r ¼ 0.319; P ¼ 0.011), lateral lumbar flexion (r ¼ 0.377; P ¼ 0.002), cervical rotation (r ¼ 0.396; P ¼ 0.004), whereas inversely correlated with fingertip-to-floor distance (r ¼� 0.282; P ¼ 0.026) and tragus-to-wall distance (r ¼� 0.270; P ¼ 0.031). The expression of HLA-G on PBMCs was significantly higher in 80 AS patients than 40 healthy controls [mean (S.D.) 18.5 (6.10)% vs 15.41 (4.84)%; P ¼ 0.012], and correlated significantly with ESR (r ¼ 0.421; P < 0.001) and CRP (r ¼ 0.419; P < 0.001). The expression of HLA-G on PMBCs decreased significantly after 3 months of adalimumab therapy [third month vs baseline, 13.46 (5.38)% vs 19.87 (7.31)%; P ¼ 0.016]. Conclusions. Lower serum levels of sHLA-G contribute to susceptibility to AS, and predispose to poor spinal mobility. The expression of HLA-G on PMBCs is up-regulated in AS, correlates with acute phase reactants and decreases after TNF-a blocker therapy, suggesting an index of disease activity.

Background: To study the clinical effectiveness and adverse reactions of etanercept in patients with active rheumatoid arthritis (RA), in whom combination therapies with disease-modifying antirheumatic drugs (DMARDs) had failed. Methods: One hundred and thirty-three patients with active RA who had been treated without satisfactory effect with DMARDs were entitled, by the Taiwan Bureau of National Health Insurance, to undergo etanercept injection (25 mg subcutaneously, twice weekly) along with oral methotrexate (15 mg weekly) in Taipei Veterans General Hospital. The disease activity score in 28 swollen and 28 tender joints (DAS28), erythrocyte sedimentation rate (ESR), serum C-reactive protein (CRP), rheumatoid factors (RFs), tender joint count (TJC), and swollen joint count (SJC) were recorded at the beginning, 3, 6, 9, and 12 months after treatment. Any adverse event, relevant or irrelevant to the therapy, was recorded throughout the whole course of treatment. Results: Ninety-four patients completed the 1-year therapeutic program. There were significant improvements in all parameters (DAS28, ESR, CRP, TJC and SJC), which approached satisfactory values at the end of the first 3 months and which were sustained thereafter in most patients. Patients also tolerated the treatment protocol well, with adverse events occurring sporadically. Significant clinical response occurred as early as 3 months after the start and might last beyond 1 year in some patients. Adverse effects such as injection site reaction or infections rarely occurred. Conclusion: Combination therapy with etanercept and DMARDs seemed to be effective at improving the aching symptoms associated with rheumatoid activity and was well tolerated in this cohort study. It was generally safe, though a small number of non-fatal infections were observed. [J Chin Med Assoc 2009;72(11):581–587]

Objective.To measure serum concentration and analyze the expression of interleukin 18 (IL-18) mRNA in mononuclear cells of patients with systemic lupus erythematosus (SLE).Methods.IL-18 concentrations in sera and culture supernatants of peripheral blood mononuclear cells (PBMC) from healthy controls and patients with active SLE were measured by ELISA. PBMC and polymorphonuclear leukocytes (PMN) purified from patients with active SLE were stimulated with phytohemagglutinin (PHA), pokeweed mitogen (PWM), and lipopolysaccharide (LPS). Expression of IL-18 mRNA in cells was analyzed by RT-PCR.Results.Serum IL-18 levels were significantly higher in SLE patients than in controls, and correlated with disease activity in SLE patients (r2= 0.602). Two patients receiving intravenous methylprednisolone therapy (1.0 g/day for 3 days) showed profound decreases in serum IL-18 levels after therapy. The quiescent PBMC from SLE patients (30/30) expressed IL-18 transcript more frequently than control PBMC (20/30). PBMC from SLE patients produced more IL-18 than control PBMC after 72 hours of incubation, by RT-PCR. PHA and PWM inhibited the production of IL-18 in PBMC from both SLE patients and controls. Inhibition by PWM was more pronounced than that by PHA, especially in SLE-PBMC. Control and SLE-PMN with or without LPS stimulation produced negligible IL-18.Conclusion.IL-18 is involved in the autoimmune derangement of leukocyte function in patients with active SLE.

A 71-year-old man presented with quadriplegia, seizures, dysarthria, motor aphasia and urinary incontinence lasting for several years. The development of proteinuria and increased susceptibility to infections brought the physician's attention to possible underlying autoimmune diseases. Laboratory investigations revealed evidence for systemic lupus erythematosus (SLE) and antiphospholipid syndrome. Imaging studies showed obstructive hydrocephalus. Several courses of methylprednisolone therapies followed by maintenance therapy with low-dose steroid, ventriculoperitoneal shunt, and antihypertensives improved the proteinuria and dysarthria but not the urinary incontinence or dementia. A thromboembolic event in the central nervous system secondary to phospholipid antibodies or lupus activity may represent a pathogenetic basis for hydrocephalus. When encountering a patient with hydrocephalus but without apparent predisposing factors, it is always important to include SLE as a differential diagnosis.

To estimate the prevalence of spondyloarthritis (SpA) and the clinical features of human leucocyte antigen (HLA)-B27-associated acute anterior uveitis (HLA-B27 uveitis) in Chinese patients.We conducted a retrospective cohort study using a structured chart review to record the complete ocular history, including the onset of uveitis, month of uveitis attack, specific eye involvement, the time of first attack, and rheumatic manifestations from 1987 to 2004. A total of 504 patients with HLA-B27 uveitis were consequently enrolled consecutively from the uveitis clinic of Taipei Veterans General Hospital.In total, 1719 attacks of uveitis in 504 patients were recorded. Females tended to have a higher frequency of attack than males, and those with a disease course of less than 5 years showed more uveitis recurrence. The same eye attacks were observed in 156 of 332 patients (47%), more than the expected percentage compared with attacks with random-eye occurrence (p0.001). A significantly higher number of uveitis attacks occurred in winter. SpA-related acute anterior uveitis (AAU) was found in 387 patients (76.8%). Ankylosing spondylitis (AS) occurred in 214 patients (42.5%), with a significantly higher prevalence in males than in females (p0.001). Undifferentiated SpA (USpA)-related AAU occurred in 150 patients (29.8%), with a significantly higher prevalence in females than in males (p0.001). Patients with SpA had an earlier onset of uveitis (p = 0.01) and a greater number (or = 6) of attacks (p = 0.03).The prevalence of SpA was high in the Chinese population with HLA-B27-associated uveitis. The association with SpA indicated an earlier age of uveitis onset and a greater likelihood of having a higher number of uveitis attacks.

Objectives: Undifferentiated spondyloarthritis (USpA) is a major member of the spondyloarthritis family. Ankylosing spondylitis (AS), the prototype of the family, is a largely genetic disease, with human leukocyte antigens (HLA)-B27 being the essential gene. Other genes in the HLA region have also been implicated. The purpose of this study was to identify the alleles of the HLA-A, -B, -C, -DR, and -DQ, which are present at higher frequencies in USpA patients compared with an ethnically matched control population. Methods: Sixty-three Taiwanese patients with USpA were compared with 75 matched healthy controls. HLA typing was performed by polymerase chain reaction-sequence specific oligo-nucleotide genotyping. Results: The frequencies of HLA-B27, -B60, -C3, and -DR12 were strikingly higher in USpA patients compared with healthy subjects, with odds ratios of 75.4, 14.0, 9.6, and 7.0, respectively. When USpA patients with axial involvement were compared with those with peripheral arthritis, the following were more marginally frequent in those with axial involvement: HLA-B27 and -DR12 (odds ratios, 4.0 and 4.0, respectively). There was no association of HLA typing with other variables, including enthesitis, uveitis, erythrocyte sedimentation rate, and serum C-reactive protein. Interestingly, in 12 HLA-B27-negative USpA patients, HLA-B60, -C3, and -DR12 were more frequent compared with controls (odds ratios, 35, 16.2, and 8.1, respectively). Conclusions: Similar to AS, USpA is also linked to HLA-B27. A linkage to other HLA alleles observed here, even in our HLA-B27-negative USpA patients, strongly suggests that USpA in general is a genetic disease.

The purpose of this study was to explore the relationships between disability, health-promoting lifestyle and quality of life in SLE outpatients. Cross-sectional research design and purposive sampling were used in this study. One hundred and twenty-nine SLE outpatients from a medical center were sampled. Questionnaires, including the Visual Analogue Scale, Pittsburgh Sleep Quality Index, and The Hospital Anxiety and Depression Scale, were adopted in order to survey subject disabilities in terms of pain, fatigue, quality of sleep, anxiety, and depression. Health-promoting lifestyle was measured using the Health-Promoting Lifestyle Profile, while quality of life data were collected using Short-Form 36. Hierarchical regressions and a Sobel test were the major statistical procedures employed. Study results indicated that SLE patient self-reported pain and fatigue related to the SLE disease to be 27.7 +/- 26.2 and 37.4 +/- 26.6, respectively. Seventy-two percent of SLE patients were reported to be troubled by poor sleep quality, while 20%-32% suffered from severe anxiety and depression. The Health-Promoting Lifestyle Profile total score for SLE patients was 61.5 +/- 17.2. In terms of SLE patient quality of life (QOL), physical component summary (PCS) and mental component summary (MCS) scores were 45.3 +/- 9.1 and 43.8 +/- 9.7, respectively. Based on the hierarchical regressions and Sobel test, it was revealed that the health-promoting lifestyle has no significant effect on the physical component summary (p.05). Fatigue was the mediator factor of health-promoting lifestyle to physical component summary of quality of life. Nevertheless, health-promoting lifestyle has a significant effect on the mental component summary (p.05). Interestingly, the results showed facilitating health- promoting lifestyle in SLE patient could not enhance physical component summary of quality of life directly without an improvement in fatigue disability; however, facilitating health-promoting lifestyle had a direct and positive effect on the mental component summary of quality of life.

To understand the cytokine levels in different disease activities of patients with ankylosing spondylitis (AS), we measured proinflammatory and antiinflammatory cytokine production from peripheral blood mononuclear cells (PBMC) in patients with AS and their first-degree relatives (FDR).PBMC were obtained from 26 patients with AS and 24 FDR and then stimulated with PHA for 72 h. In the supernatants, the following three cytokines, tumor necrosis factor-alpha (TNF-alpha), interleukin 1beta (IL-1beta), and IL-10, were measured by ELISA. Disease activity in AS patients was divided into high disease activity (Group 1) and low disease activity (Group 2), based on the Bath AS Disease Activity Index (BASDAIor =4 or4). Healthy FDR of AS patients (Group 3) and healthy subjects (Group 4) were used as a control group.TNF-alpha production from PBMC was significantly increased in Group 1 patients compared to Group 2 patients (1371 +/- 1008 pg/mL vs. 355 +/- 89 pg/mL, p0.05) or FDR (1371 +/- 1008 pg/mL vs. 552 +/- 89 pg/mL, p0.05) or healthy subjects (1371 +/- 1008 pg/mL vs. 436 +/- 114 pg/mL, p0.01). IL-1beta also showed a similarly significant difference between the two groups (Group 1 vs. Group 2, Group 1 vs. Group 4) (p0.05). In contrast, IL-10 was significantly decreased in Group 1 when compared to Group 2 (126 +/- 64 pg/mL vs. 272 +/- 150 pg/mL, p0.05).Patients with high BASDAI had increased production of TNF-alpha and IL-1beta compared to those with low BASDAI or healthy FDR, suggesting that proinflammatory cytokines may play an important role during active inflammation.

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.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.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).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.

Acute anterior uveitis (AAU) is the most frequently extra-articular manifestation of ankylosing spondylitis (AS). To investigate whether AAU has an association with disease activity, functional ability and physical mobility in AS patients, 146 Chinese AS patients in Taiwan were enrolled in a cross-sectional study. These patients fulfilled the 1984 modified New York criteria and visited the Outpatient Department of the Veterans General Hospital-Taipei from April 2004 to July 2005. Patients completed questionnaires assessing disease activity [Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)], functional ability [Bath Ankylosing Spondylitis Functional Index (BASFI)] and patient's global assessment [Bath Ankylosing Spondylitis Patient Global Score (BAS-G)]. Meanwhile, physical examinations were performed, including Schober test, finger-to-floor, lateral spinal flexion, occiput-to-wall and chest expansion. The history of AAU was accepted only if diagnosed by an ophthalmologist. The prevalence of AAU in this Chinese AS cohort was 15.8% (23/146). Patients with AAU had a significantly higher BASDAI than those without [absolute differences=0.96, 95% confidence intervals (CI): 0.35-1.88]. Additionally, patients with AAU had significantly increased BASFI than those without (absolute differences=1.46, 95% CI: 0.33-2.59). Moreover, there was advanced limitation of physical motility in patients with AAU, including finger-to-floor, occiput-to-wall distances and Schober test, (95% CI: 3.89-16.95 and p=0.046, respectively). Disease duration mildly correlated with BASFI (r=0.24, p=0.003) but not with BASDAI (p=0.838). There was no difference of disease duration between patients with and without AAU (p=0.343). These results suggested that the presence of AAU in AS patients may be associated with higher disease activity, poor functional ability and advanced physical impairment.

Over a 2-year period, to evaluate the efficacy and safety of biologic agents, etanercept (25 mg twice per week, s.c.) was used to treat 57 rheumatoid arthritis (RA) patients, 9 ankylosing spondylitis (AS) patients, 6 psoriatic arthritis (PSA) patients, and 4 juvenile rheumatoid arthritis (JRA) patients. In addition to inflammatory arthritis, I have used this tumor necrosis factor (TNF) blocker in other rheumatic diseases including idiopathic thrombocytopenic purpura (ITP), Behcet's disease with intractable oral ulcer, fibromyalgia syndrome, and systemic lupus erythematosis with intractable pleural effusion and acute lumbar disc herniation. For RA, after 6 months of etanercept treatment, all the parameters including number of swollen joints, number of tender joints, disease activity score, erythrocyte sedimentation rate, C-reactive protein, and global health status were rapidly improved (P < 0.001 or P < 0.0001). The anticyclic citrullinated peptide (anti-CCP) antibody and rheumatoid factor also significantly declined. For spondyloarthropathy, it also gave a similar effect as to RA. Both Bath Ankylosing Spondylitis Disease Activity Index and Bath Ankylosing Spondylitis Functional Index also improved. One of the two cases with Behcet's disease with intractable oral ulcer had a long-term remission after etanercept. The other Behcet's disease patient with oral ulcer and another with ITP obtained a good response temporarily. The short-term use of etanercept (

Background Undifferentiated spondyloarthropathy (USpA) is a unique group in spondyloarthropathy (SpA). This study will investigate the clinical and laboratory characteristics of USpA in the Chinese population. Methods Forty two patients with USpA were enrolled from our rheumatology outpatient facility in this retrospective study. SpA was diagnosed according to the European Spondyloarthropathy Study Group (ESSG) criteria. Patients were considered having USpA when they had SpA but did not meet the criteria for the diagnosis of ankylosing spondylitis (AS), Reiter's syndrome or reactive arthritis (ReA), psoriatic arthritis (PsA), and inflammatory bowel diseases (IBD)-related arthritis, etc. Laboratory tests included erythrocyte sedimentation rate (ESR), serum C-reactive protein (CRP), immunoglobulin A (IgA), and human leukocyte antigen B27 (HLA-B27). Results Among the 42 USpA patients, the ratio of men to women was 1.47:1, and the age at onset was 32.33 ± 10.83 years old. Approximately 61.9% of patients had peripheral arthritis, 30.95% had uveitis, and 64.29% had positive HLA-B27. Among these female USpA patients, compared to males, there is a trend of older age at disease onset, higher percentage of HLA-B27 positive, more peripheral arthritis and uveitis, longer disease duration, and higher level of ESR, and IgA and CRP in serum. The items reaching significant difference between males and females were longer disease duration ( p p p = 0.03). There was no significant difference in clinical and laboratory characteristics between HLA-B27-positive and -negative groups. Conclusions Studies on USpA patients have not been reported in the Chinese population. In this study, we demonstrate the unique demographic characteristics, clinical and laboratory data of USpA in the Chinese population. These findings should be confirmed by analyzing larger number of patients and longer time for further follow-up. Such studies are crucial to understand the pathogenesis of USpA and evaluate its prognosis.

Cutaneous vasculitis (CV) is a condition with cutaneous manifestations and possible systemic involvement. The causative factors or associated diseases are usually drugs, infection, collagen vascular disease, or malignancy. Syphilis as a cause of cutaneous vasculitis is rare. We report the case of a large cutaneous ulcer and small-vessel vasculitis associated with syphilis infection. We suggest that in apparently idiopathic CV or a chronic ulcer refractory to treatment, screening should be performed to detect any underlying infection such as syphilis. It is important to have a rapid and accurate diagnosis because the lesions are very contagious, but may be rapidly and completely cured by early administration of antibiotic treatment.

Objective. To submit serum levels of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) to statistical analyses to test their exact degrees of clinical usefulness as biomarkers for detecting high disease activity in ankylosing spondylitis (AS), comparing them with erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). Methods. Serum levels of MMP-1, -3, -9 and TIMP-1 and -2 were measured in 42 AS patients and 20 healthy controls. The Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) provided the gold standard for measuring disease activity. Patients with BASDAI ¸4 were regarded as having high disease activity. The results were compared with results for a separate cohort of 41 AS patients. Results. Only MMP-3 levels were significantly higher in AS patients than in healthy controls (P

Relapsing polychondritis (RP) is a rare multisystemic disease characterized by recurrent inflammation of cartilaginous and noncartilaginous tissues. When laryngotracheal or bronchial cartilages are involved, the disease can be life-threatening and needs aggressive treatment. Upper airway complaints are rare as initial presentations of RP. Here, however, we present a case of RP, with initial manifestations of cough and dyspnea that were treated as bronchial asthma for 6 months. Subglottic stenosis was found in April 2003, during a bronchoscopic examination, and emergency tracheostomy was performed. Auricular and nasal chondritis and bilateral scleritis developed 3 months after tracheostomy. High doses of methylprednisolone and immunosuppressive agents were used, and active inflammation in the eyes and ears was controlled, but the patient's upper airway was completely collapsed. This case is reported with the hope of increasing awareness about the potential for early upper airway involvement in RP.

Background Our objective was to evaluate immune function after total parenteral nutrition (TPN) treatment in colorectal cancer patients. Methods Data were collected from 11 patients with colorectal cancer who received total parenteral nutrition. Healthy medical staff volunteers were used as controls. Delay hypersensitivity skin test with eight agents tested was used before total parenteral nutrition (TPN) treatment. Phytohemagglutinin (PHA)-stimulated lymphocyte proliferation and mononuclear cytokine production (IL-1β, IL-2, IFNγ), serum ICAM-1 and IL-6, and lymphocyte subpopulation including CD4, CD8, and CD4/CD8 ratio were measured before and after TPN treatment. Results Each patient had at least four of seven positive skin tests. After TPN treatment, lymphocyte proliferation increased remarkably (27,450 ± 16,800 vs. 41,738 ± 28,484, p =0.0168) and showed no significant difference to control group ( p =0.0269). Levels of IL-1β, IL-2, and IFNγ after LPS-stimulation showed no significant difference before and after TPN treatment. Serum ICAM-1 showed a significant difference (388 ± 158 vs. 481 ± 210, p =0.0023) before and after TPN treatment. IL-6 was significantly different between patient and control groups but not different between patients before and after TPN treatment. Conclusions This study showed a significant increase of mitogen-stimulated lymphocyte proliferation and intercellular adhesion molecular 1 (ICAM-1) level after TPN supply. Adequate nutrition through TPN may augment immune function.

Protein-losing enteropathy (PLE) and autoimmune oophoritis are unusual manifestations of systemic lupus erythematosus (SLE). Autoimmune oophoritis may result in menstrual disturbance and spontaneous premature ovarian failure. However, there is no validated examination to confirm the diagnosis and it is easily neglected in patients with ovarian insufficiency. A 31-year-old woman with SLE presented with PLE and autoimmune oophoritis during the long course of flares and remissions in her lupus activity. The synchronism implied the association between the two. Moreover, both conditions simultaneously had a good response to cyclosporine A (CsA) therapy.

Objective Systemic lupus erythematosus (SLE) is a systemic autoimmune disease and usually requires immunosuppressive therapy, which is a major cause of viral reactivation. The incidence and antiviral response in SLE patients with hepatitis C virus (HCV) reactivation is unclear and needs to be investigated. Methods One hundred and sixty-six SLE patients with antibody to HCV (anti-HCV) status were retrospectively reviewed regarding the events of HCV reactivation. Patients with HCV reactivation were treated with pegylated interferon plus ribavirin treatment. The virological response and relapse rate were evaluated. Results Twenty-six patients were positive for anti-HCV. During a mean 8.4 years of follow-up, 10 (38.5%) cases developed HCV reactivation. No clear relationship was noted between immunosuppressive therapy and the HCV reactivation. Eight patients underwent antiviral therapy and the rapid virological response (RVR), early virological response, and sustained virological response (SVR) rates were 37.5%, 87.5%, and 75.0%, respectively. However, late relapse (reappearance of HCV RNA in serum after archiving SVR) was found in two (33.3%) of six patients achieving SVR. The two cases were HCV genotype 1 b concurrent with corticosteroid treatment. Conclusions HCV reactivation in anti-HCV-positive SLE patients was possibly associated with glucocorticoids. The virological response to interferon plus ribavirin treatment is not inferior to the general population. However, monitoring HCV RNA after SVR is necessary for patients concurrent with corticosteroid treatment due to the risk of late relapse.

The association between HLA-B27 and the spondyloarthropathies (SpAs) is so strong that it is supposed that the HLA-B27 molecule plays a pathogenetic role. In whites and Indonesians, the frequency of HLA-B27 is about 10%; in Chinese it is about 8%; and in Japanese it is only about 1%. The prevalence of SpA in the Chinese is at least 0.2%, but in native Indonesians, Philippinos, and Malaysians, SpA is rarely seen. Twenty-three subtypes (B*2701-B*2723) have been distinguished. These subtypes are not equally distributed over the world. In most countries the distribution of the subtypes among HLA-B27 SpA patients is the same as that among the normal HLA-B27-positive population. In China, the subtype B*2704 is frequent and the prevalence of SpA is high. Native Indonesians, however, mostly have subtype B*2706, and SpA is rarely seen in this population. It was shown that B*2706, probably like B*2709 in Sardinia, is not associated with SpA. The difference between the SpA-associated and non-SpA-associated subtypes is limited to only two amino acid residues (114 and 116) at the bottom of the peptide-binding groove of HLA-B27. This small difference between health and disease rewards studies for different peptide-binding capacities and may help us characterize the peptides that are involved in the pathogenesis of SpA. The differences in disease associations in these countries also have clinical implications. In Southeast Asia, HLA-B27 typing without subtyping has less clinical usefulness than in parts of the world where B*2706 is rarely seen. When native Indonesians, Malaysians, or Philippinos are suspected of having ankylosing spondylitis or a related SpA, it is worth asking if they had white or Chinese ancestors. If native HLA-B27-positive Indonesians (with subtypes other than B*2706) develop SpA, the clinical features are not different from those in other parts of the world. In the Chinese population on the mainland and in Taiwan, juvenile SpA is frequently seen. The onset is often a peripheral arthritis or enthesitis.

Sulfasalazine (SSA) was investigated for its effects on phagocytic activity of normal human polymorphonuclear neutrophils (PMN), proliferation of mononuclear cells (MNC) and cultured glomerular mesangial cells. At concentrations from 25 to 100 microM, it inhibited phagocytic activity of PMN and the 3H-thymidine incorporation of phytohemagglutinin (PHA)-stimulated human MNC in a dose-dependent manner. At comparable concentrations, sulfapyridine and 5-aminosalicylic acid, two of its major metabolites, did not show similar effects. SSA exhibited an inhibitory effect on both mouse and rat mesangial cells but at rather higher concentrations (0.5 mM). Excretion of interleukin (IL)-8 by lipopolysaccharide (LPS)-stimulated PMN was also markedly deterred in a dose-dependent manner but excretion of IL-8 by LPS-stimulated MNC was not interfered by SSA. Production of tumor necrosis factor (TNF)-alpha and IL-1beta by mouse mesangial cells was not blocked by SSA but production of IL-4 by these cells was inhibited by it (>0.1 mM). Inhibition of MNC was not due directly to cytotoxic effect of SSA on these cells as shown by fluorescein diacetate stain. Collectively, SSA inhibits phagocytosis and IL-8 excretion by PMN as well as mitogen-stimulated MNC reaction. On the other hand, at high concentrations, it inhibits glomerular mesangial cells and their IL-4 excretion but not TNF-alpha and IL-1beta excretion. These results can account for minimal nephrotoxic characteristic of SSA and suggest that it may be helpful in the treatment of immune-mediated glomerulonephritis.

Spondyloarthropathy (SpA) is a family of chronic arthritis, characterized by inflammatory back pain, peripheral arthritis, and enthesitis [1]. SpA comprises at least five major subtypes, including ...

A 79-year-old male with acute myelogenous leukemia developed acute right knee arthritis during admission, after the use of broad-spectrum antibiotics before chemotherapy. The initial synovial fluid sample appeared to be mildly inflammatory with a low white cell count. The fungal septic arthritis was not diagnosed until Candida tropicalis, a rare species of Candida, was isolated in the synovial fluid. Although fluconazole is effective in treating the microorganism, the untreated leukemia rendered the infection incurable and led to the growth of fluconazole-resistant Candida krusei. We reported the unusual case of fungal arthritis and reviewed the literature.

Temporal arteritis, a chronic inflammatory vasculitis involving medium- and large-sized arteries, has rarely been reported in Asia. However, we report 2 cases, in which the patients initially presented with headache. Physical examination disclosed engorged, hard and palpable vessels in the temporal areas. Temporal-artery biopsy revealed 2 different types of arteritis: the multinucleated giant cell type and the panarteritis type without multinucleated giant cells. One patient was positive for immunoglobulin G anticardiolipin antibody. The pathologic findings of the different subsets of temporal arteritis, and the relationship between anticardiolipin antibody and the extent of vascular complications of temporal arteritis, are discussed.