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Background/Purpose The intergenic SNP rs10865331 at 2p15 was identified as a major risk factor for ankylosing spondylitis (AS) susceptibility in genome-wide association studies (GWAS). B3GNT2 gene regulates polylactosamine synthesis is potentially functionally relevant to AS disease development. We investigated whether SNP rs10865331 and two B3GNT2 SNPs (rs11900673 and rs1136151) are associated with AS susceptibility and disease severity in Taiwanese. Methods Distributions of genotypes, alleles, and haplotypes of three SNPs were compared between 1,472 AS patients and 2,117 healthy blood donors and among AS patients stratified by clinical characteristics. Results The intergenic SNP rs10865331 was significantly associated with AS (PFDR = 1.02E-05) in Taiwanese. In AS patients stratified by positivity of HLA-B27 and syndesmophyte formation, all three B3GNT2 locus SNPs (rs11900673, rs1136151, and rs10865331) were significantly associated with syndesmophyte formation among HLA-B27 positive AS patients. Haplotype analyses revealed that the “CTA” (rs11900673C/rs1136151T/rs10865331A) haplotype was significantly associated with AS susceptibility (Padj = 0.0177) and syndesmophyte formation (Padj = 0.016) in HLA-B27 positive patients. In contrast, “TCG” (rs11900673T/rs1136151C/rs10865331G) haplotype showed protection against AS development (Padj = 0.0005 for HLA-B27 positive and Padj = 0.004 for HLA-B27 negative, respectively) and syndesmophyte formation (Padj = 0.0017) in HLA-B27 positive patients. Furthermore, B3GNT2 mRNA expressions were negatively associated with erythrocyte sedimentation rate (ESR, P = 0.0103), C-reactive protein (CRP, P = 0.0353), Bath ankylosing spondylitis functional index (BASFI, P = 0.0171), and syndesmophyte formation (P = 0.0148). Conclusion Our data suggest that B3GNT2 gene may contribute to AS development and affect AS severity by interacting with HLA-B27 in Taiwanese.

Background: Sjögren’s syndrome (SS) is an autoimmune inflammatory disease that primarily affects the exocrine glands, leading to glandular dysfunction. The hallmark symptoms of SS are dry eyes and mouth, compromising the quality of life of patients and decreasing their capacity to perform their daily activities.Objective: This study aims to evaluate the efficacy of the herbal formula SS-1 for its potential therapeutic benefits for patients with Sjögren’s syndrome.Materials and Methods: The bioactivity profile of SS-1 was determined using four different SS-1 concentrations across 12 human primary cell systems of the BioMAP profile. After that, a randomized, double-blind, crossover, placebo-controlled trial was performed including 57 patients treated with SS-1 for 28 weeks.Results: Biologically multiplexed activity profiling in cell-based models indicated that SS-1 exerted anti-proliferative activity in B cells and promoted anti-inflammatory and immunomodulatory activity. In the clinical trial, Schirmer’s test results revealed significant improvements in both eyes, with increases of 3.42 mm (95% CI, 2.44–4.41 mm) and 3.45 mm (95% CI, 2.32–4.59 mm), respectively, and a significant reduction in artificial tear use, which was −1.38 times/day, 95% CI, −1.95 to −0.81 times/day. Moreover, the increases in B-cell activating factor (BAFF) and B-cell maturation antigen (BCMA) levels were dampened by 53.20% (295.29 versus 555.02 pg/ml) and 58.33% (99.16 versus 169.99 pg/ml), respectively.Conclusion: SS-1 treatment significantly inhibited B-cell maturation antigen. No serious drug-related adverse effects were observed. Oral SS-1 administration may be a complementary treatment for Sjögren’s syndrome.

Summary Background Treat-to-target strategies have improved outcomes in single-organ diseases with simple clinical or laboratory endpoints. A lack of validated endpoints has prevented adoption of treat to target for complex multiorgan conditions, such as systemic lupus erythematosus (SLE). We report the first prospective study undertaken to specifically validate a treat-to-target endpoint for SLE. Methods In this prospective cohort study, patients aged 18 years or older with SLE were recruited from 13 centres in eight countries and followed prospectively. Patients with at least two visits over the study period no more than 6 months apart were included in the longitudinal analysis. Patients with no visits in the final year of the study were censored from their last visit. Attainment of the lupus low disease activity state (LLDAS) was assessed at each visit. The primary outcome measure was accrual of irreversible end-organ damage, defined as at least a 1-point increase in the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index. We used time-dependent hazard regression models and generalised linear models to measure the association between LLDAS (attainment at any timepoint, cumulative time in LLDAS, and sustained LLDAS) with accrual of irreversible end-organ damage or flare (key secondary outcome). This study is registered with ClinicalTrials.gov , NCT03138941 . Findings Between May 1, 2013, and Dec 31, 2016, 1707 patients were recruited and followed for a mean of 2·2 years (SD 0·9), totalling 12 689 visits. Attainment of LLDAS at any timepoint was associated with reduction in damage accrual (hazard ratio 0·59, 0·45–0·76; p Interpretation LLDAS attainment is associated with significant protection against flare and damage accrual in SLE. These findings validate LLDAS as an endpoint for clinical studies in SLE. Funding The Asia Pacific Lupus Collaboration received project support grants from UCB Pharma, GlaxoSmithKline, Janssen, Bristol-Myers Squibb, and AstraZeneca.

Summary Background Validated outcome measures are needed from which to derive treatment strategies for systemic lupus erythematosus (SLE). However, no definition of remission for SLE has been widely adopted. The Definitions of Remission in Systemic Lupus Erythematosus (DORIS) group has proposed a framework with multiple potential definitions of remission. In this study, we aimed to assess the attainability and effect on disease outcomes of the DORIS definitions of remission, compared with the lupus low disease activity state (LLDAS), in patients with SLE. Methods In this prospective cohort study, we enrolled patients with SLE from 13 international centres that are part of the Asia Pacific Lupus Collaboration. Eligible patients were older than 18 years and fulfilled one of two classification criteria for SLE (1997 American College of Rheumatology criteria or the 2012 Systemic Lupus International Collaborating Clinics criteria). Visits were according to clinical need, with a minimum frequency of one visit per 6 months. We assessed attainment of remission on the basis of the eight DORIS definitions of remission, which varied in terms of serological activity, glucocorticoid use, and use of immunosuppresive agents; attainment of LLDAS; and disease flares at each visit. Irreversible organ damage accrual was recorded annually. Our primary aim was to assess exposure of patients to each of the remission definitions or LLDAS, and the respective association of these states with accrual of irreversible organ damage as the primary outcome measure. Occurrence of disease flares was the key secondary outcome. We used time-dependent Cox proportional hazards models and generalised linear models to assess DORIS definitions of remission and LLDAS in terms of their association with damage accrual and disease flares. Findings Between May 1, 2013, and Dec 31, 2016, 1707 patients with SLE were recruited and followed for a mean of 2·2 years (SD 0·9), totalling 12 689 visits. Remission, depending on DORIS definition, was achieved in 581 (4·6%) to 4546 (35·8%) of 12 689 visits. Spending 50% or more of observed time in any remission state was associated with a significant reduction in damage accrual, except for the two most stringent remission definitions, for which the frequency of attainment was lowest. Remission definitions disallowing serological activity were associated with the greatest reductions in disease flares. LLDAS was more attainable than any remission definition and was associated with a similar magnitude of protection from damage accrual and disease flares. Sustained remission and LLDAS were associated with a wider spread of effect sizes for reduction in risk of damage. By analysing patients who met the definition for LLDAS but not remission, we found that LLDAS was significantly associated with reduction in damage accrual, independent of all definitions of remission, except the least stringent. Interpretation Attainment of remission was associated with significant reductions in damage accrual and disease flares. LLDAS was more achievable than remission based on the DORIS criteria, but was similarly protective. Remission definitions with less stringency might be insufficiently distinct from LLDAS to substantially affect outcome measures, and further studies are needed to distinguish the protective effects of the various remission definitions. Funding UCB, GlaxoSmithKline, Janssen, Bristol-Myers Squibb, and AstraZeneca.

Ankylosing spondylitis (AS) is a chronic inflammatory disease that leads to spinal ankylosis. The receptor activator of the nuclear factor-kappa (RANK), RANK ligand, and osteoprotegerin (OPG) (RANK/RANKL/OPG) pathway plays critical roles in bone metabolism and the immune system. The current study was aimed at investigating whether six single-nucleotide polymorphisms (SNPs) within the RANK, RANKL, and OPG genes essential for bone homeostasis are associated with AS. Genotype distributions, allele and haplotype frequencies, were compared between 1120 AS patients and 1435 healthy controls and among AS patients with stratification by syndesmophyte formation, onset age, and HLA-B27 positivity. We found that RANKL SNPs were associated with AS syndesmophyte formation. Notably, the RANKL SNP haplotype rs7984870C/rs9533155G/rs9525641C was negatively associated with AS susceptibility and appeared to protect against syndesmophyte formation in AS. Functionally, RANKL promoter SNPs (rs9525641 C/T and rs9533155 G/C) affected DNA-protein complex formation and promoter activity in promoter reporter analyses. The OPG SNP haplotype rs2073618G/rs3102735T was significantly associated with HLA-B27 negativity in AS patients. Furthermore, AS patients with syndesmophyte formation had significantly lower levels of soluble RANKL levels than those without syndesmophyte formation. Our data suggested a role for RANKL in AS susceptibility and severity.

Background Type III interferons (IFNs) or IFN-λs are the newly discovered cytokines that primarily target the cells of epithelial and myeloid lineages, which are major components of kidneys. The current study aimed to investigate whether IFN-λs are involved in the pathogenesis of systemic lupus erythematosus (SLE) and lupus nephritis. Methods TaqMan allele discrimination assays were used to determine IFNL3/4 SNP genotypes of 1620 healthy controls and 1013 SLE patients (two independent cohorts consisting of 831 and 182 subjects, respectively) from Taiwan. The distributions of IFNL3/4 SNP genotypes and allele frequencies were compared between SLE patients and healthy controls and among SLE patients stratified by clinical phenotypes. ELISA was used to determine the serum IFN-λ3 concentrations of SLE patients. Results All major IFN3/4 SNP alleles were significantly associated with the risk for lupus nephritis (rs8099917T, PFDR = 0.0021, OR 1.75, 95% CI 1.24–2.47; rs12979860C, PFDR = 0.0034, OR 1.65, 95% CI 1.18–2.30; rs4803217C, PFDR = 0.0021, OR 1.76, 95% CI 1.25–2.48; and ss469415590TT, PFDR = 0.0021, OR 1.73, 95% CI 1.23–2.42) among SLE patients. Similarly, the major IFNL3/4 SNP haplotype rs8099917T-ss469415590TT-rs12979860C-rs4803217C (or T-TT-C-C) was a significant risk factor for lupus nephritis (P = 0.0015, OR 1.68, 95% CI 1.22–2.32). Additionally, all minor IFN3/4 SNP alleles were significantly associated with SLE susceptibility in nephritis-negative SLE patients as compared to normal healthy controls (rs8099917G, PFDR = 0.00177, OR 1.68, 95% CI 1.24–2.28; rs12979860T, PFDR = 0.00299, OR 1.58, 95% CI 1.18–2.32; rs4803217A, PFDR = 0.00176, OR 1.65, 95% CI 1.22–2.23; and ss469415590ΔG, PFDR = 0.00176, OR 1.70, 95% CI 1.26–2.29). Furthermore, the elevated serum levels of IFN-λ3 were significantly correlated with the complement depression and the high SLE disease activities in SLE patients. Conclusions IFN-λ3/4 genetic variants play a unique role in the development of lupus nephritis and SLE. Electronic supplementary material The online version of this article (10.1186/s13075-018-1683-z) contains supplementary material, which is available to authorized users.

Background: GPR56/ADGRG1 is a member of the adhesion-class G protein-coupled receptor (aGPCR) family important in brain development, oncogenesis and tumor metastasis. Like other aGPCRs, GPR56 is cleaved at the GPCR proteolysis site (GPS) motif into an N-terminal fragment (NTF) and a C-terminal fragment (CTF). Existence of soluble GPR56 (sGPR56) has been shown in vitro, however the underlying mechanism and its pathophysiologic role remains undetermined. Objective: To assess the presence of sGPR56 in human serum using ELISA assay and compare the serum sGPR56 levels among patients of various chronic inflammatory diseases and healthy subjects. Patients and methods: In this study, serum samples from patients with systemic lupus erythematosus (SLE) (n = 57), rheumatoid arthritis (RA) (n = 95), Sjögren's syndrome (SS) (n = 29), ankylosing spondylitis (AS) (n = 51), and normal controls (n = 81) were analyzed using sGPR56-specific ELISA. Result: We show that serum sGPR56 levels are increased in patients of RA, but not in those with SLE, SS and AS. Intriguingly, serum sGPR56 levels in RA patients correlated with positive rheumatoid factor, a marker of bone erosion and poor outcome. In addition, an elevated sGPR56 level is also noted in RA patients with higher tumor necrosis factor level. Conclusion: we conclude that sGPR56 is present in vivo and sGPR56 level is elevated in certain chronic inflammatory diseases such as RA. Hence, sGPR56 might be considered a potential biomarker for RA disease progression. Keywords: Adhesion-GPCR, Biomarker, sGPR56, Shedding, RA

Background and aim: Raynaud's phenomenon (RP) is a microvascular disorder characterized by episodic peripheral vasospasm and ischemia and is commonly found in patients with autoimmune diseases (AID). The vasomotor homoeostasis and endothelial cells damage are involved in RP. Endothelial microparticles (EMPs) may act as a biomarker for endothelial damage. The aim of this study is to investigate the correlation between the levels of microparticles (MPs) and microvasculopathy in AID with RP. Methods: Thirty-seven patients with AID and RP (RP group) and 27 patients with AID but without RP (non-RP group) were enrolled. The microvasculopathy score of RP was graded by nailfold capillary microscopy. The plasma levels of MPs were measured by flow cytometry utilizing specific labels for endothelial MPs (CD105 and CD144) and annexin V staining for phosphatidylserine bearing-MPs (annexin V+MPs). Results: The levels of circulating EMPs (CD105+ p = 0.005, CD144+ p = 0.004), and the annexin V+ MPs (p

OBJECTIVE Human complement C4 is complex, with multiple layers of diversity. The aims of this study were to elucidate the copy number variations (CNVs) of C4A and C4B in relation to disease risk in systemic lupus erythematosus (SLE), and to compare the basis of race-specific C4A deficiency between East Asians and individuals of European descent. METHODS The East Asian study population included 999 SLE patients and 1,347 healthy subjects. Variations in gene copy numbers (GCNs) of total C4, C4A, and C4B, as well as C4-Long and C4-Short genes, were determined and validated using independent genotyping technologies. Genomic regions with C4B96 were investigated to determine the basis of the most basic C4B protein occurring concurrently with C4A deficiency. RESULTS In East Asians, high GCNs of total C4 and C4A were strongly protective against SLE, whereas low and medium GCNs of total C4 and C4A, and the absence of C4-Short genes, were risk factors for SLE. Homozygous C4A deficiency was infrequent in East Asian subjects, but had an odds ratio (OR) of 12.4 (P = 0.0015) for SLE disease susceptibility. Low serum complement levels were strongly associated with low GCNs of total C4 (OR 3.19, P = 7.3 × 10(-7) ) and C4B (OR 2.53, P = 2.5 × 10(-5) ). Patients with low serum complement levels had high frequencies of anti-double-stranded DNA antibodies (OR 4.96, P = 9.7 × 10(-17) ), hemolytic anemia (OR 3.89, P = 3.6 × 10(-10) ), and renal disease (OR 2.18, P = 8.5 × 10(-6) ). The monomodular-Short haplotype found to be prevalent in European Americans with C4A deficiency, which was in linkage disequilibrium with HLA-DRB1*0301, was scarce in East Asians. Instead, most East Asian subjects with C4A deficiency were found to have a recombinant haplotype with bimodular C4-Long and C4-Short genes, encoding C4B1 and C4B96, which was linked to HLA-DRB1*1501. DNA sequencing revealed an E920K polymorphism in C4B96. CONCLUSION C4 CNVs and deficiency of C4A both play an important role in the risk and manifestations of SLE in East Asian and European populations.

The safety of newer xanthine oxidase inhibitor febuxostat compared to allopurinol remains unclear. To compare the risks of allopurinol hypersensitivity and febuxostat hypersensitivity and cardiovascular diseases (CVDs) in Asians, we conducted a population-based cohort study enrolling patients receiving allopurinol or febuxostat from Chang Gung Memorial Hospital Health System across Taiwan during 2012-2016 and further performed a meta-analysis incorporating two recent studies. Among the 61,539 users, a corresponding 12,007 and 5,680 patients were identified as new users. The overall incidence of febuxostat hypersensitivity was significantly lower than allopurinol hypersensitivity (0.2 vs. 2.7 per 1,000 new users; P < 0.001). There were 33 allopurinol-hypersensitivity reactions (including 18 severe cutaneous adverse drug reactions), and only one patient developed febuxostat-maculopapular exanthema. Moreover, febuxostat did not statistically increase the risk of CVD (hazard ratio (HR), 1.16; P = 0.152) and related death (HR, 1.49; P = 0.496) compared to allopurinol. The result of the meta-analysis also showed a consistent result. In conclusion, the incidence and severity of febuxostat-hypersensitivity are lower than with allopurinol. Febuxostat did not show an increased risk of CVD and related death.

Aim The aim of this manuscript is to describe the development of the Asia Pacific Lupus Collaboration (APLC) cohort. Method The APLC cohort is an ongoing, prospective longitudinal cohort. Adult patients who meet either the American College of Rheumatology (ACR) Modified Classification Criteria for systemic lupus erythematosus (SLE), or the Systemic Lupus International Collaborating Clinics (SLICC) Classification Criteria, and provide informed consent are recruited into the cohort. Patients are routinely followed up at 3- to 6-monthly intervals. Information on demographics, clinical manifestations, treatment, pathology results, outcomes, and patient-reported quality of life (Short-form 36 version 2) are collected using a standardized case report form. Each site is responsible for obtaining local ethics and governance approval, patient recruitment, data collection, and data transfer into a centralized APLC database. Results The latest APLC cohort comprises 2160 patients with >12 000 visits from Australia, China, Hong Kong, Indonesia, Japan, Malaysia, Philippines, Singapore, Taiwan and Thailand. The APLC has proposed the Lupus Low Disease Activity State (LLDAS) as a treat-to-target (T2T) endpoint, and reported several retrospective and cross-sectional analyses consistent with the validity of LLDAS. Longitudinal validation of LLDAS as a T2T endpoint is currently underway. Conclusion The APLC cohort is one of the largest contemporary SLE patient cohorts in the world. It is the only cohort with substantial representation of Asian patients. This cohort represents a unique resource for future clinical research including evaluation of other endpoints and quality of care.

IgG Fcγ receptors (FcγRs) mediate a variety of immune functions that are critical in immune responses. In humans, 5 classic low-affinity FcγRs (FcγRIIA, FcγRIIB, FcγRIIC, FcγRIIIA, and FcγRIIIB) are coded by 5 genes (FCGR2A, FCGR2B, FCGR2C, FCGR3A, and FCGR3B, respectively) in the FCGR cluster on chromosome 1. Activating FcγRs (FcγRIIA, FcγRIIC, FcγRIIIA, and FcγRIIIB) mediate immune cell activation promoting inflammation, while the classic inhibitory FcγRIIB dampens immune responses and restricts inflammation (1,2). Activating FcγRs mediate functions including immune complex clearance, phagocytosis, antigen presentation, antibody-dependent cellular cytotoxicity, and cytokine production (3). In contrast, the inhibitory FcγRIIB abrogates immune cell activation. FcγRIIB also plays a role in the maintenance of peripheral B cell tolerance and the prevention of autoimmunity (2). The variations in FcγR expression significantly affect IgG immune complex–mediated signal thresholds (3,4). Notably, proinflammatory and antiinflammatory cytokines could modulate the expression levels of activating and inhibitory FcγRs (5) that affect the threshold immune cell response to IgG immune complexes (6). FcγR-knockout mouse models indicate that both activating and inhibitory FcγRs influence the development of autoimmune diseases (7–9). The contributions of FcγR genes to autoimmune diseases have attracted substantial attention, and functional FcγR polymorphisms have been reported to play important roles in the pathogenesis of autoimmune diseases (4,10,11). Gene copy number variation (CNV) is a rich source of genetic heterogeneity (12,13). The FCGR cluster on chromosome 1q23 shows a complex pattern of CNVs. Among 5 FcγR genes in the cluster, 3 genes (FCGR3A, FCGR2C, and FCGR3B) have CNVs, while FCGR2A and FCGR2B do not have CNVs (14,15). CNVs play important roles in human disease pathogenesis (16). FCGR3B copy number deficiency is associated with autoimmune disease, including systemic lupus erythematosus (SLE) (17–19), Sjogren's syndrome (20), and systemic sclerosis (21). Although FCGR3B CNVs were reported to associate with rheumatoid arthritis (RA) (22–24), no association between RA and FCGR3B CNVs was observed in other studies (25,26). Moreover, no association between FCGR3A CNVs and RA was observed (24,27). In the current study, we investigated whether FCGR3A and FCGR3B CNVs are associated with susceptibility to SLE and RA in Taiwanese individuals. The results provide new insights into the role of FcγRIII family members in the pathogenesis of SLE and RA in an Asian population.

To estimate the mortality rate and identify factors predicting survival in patients with polymyositis (PM) and dermatomyositis (DM). The medical records of 192 PM/DM patients who were treated at Chang Gung Memorial Hospital from 1999 through 2008 were retrospectively reviewed. The Taiwan National Death Registry (1999–2008) was used to obtain their survival status. Thirty-one (16.1%) of the 192 patients with PM/DM had an associated malignancy; 41 (21.4%) had interstitial lung disease (ILD). During the follow-up period, 55 (28.6%) patients died and the overall cumulative survival rate was 79.3% at 1 year, 75.7% at 2 years, 69.9% at 5 years, and 66.2% at 10 years. In univariate analysis, older age at PM/DM onset, anemia, thrombocytopenia, leukopenia, diabetes mellitus, ILD, cancer, and non-use of azathioprine were associated with higher mortality (p = 0.0172, 0.0484

Objective.To investigate the association of the functional FCRL3 single-nucleotide polymorphism (SNP) −169T/C with disease phenotypes and susceptibility to systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) in Taiwanese.Methods.FCRL3 SNP −169T/C was genotyped in 573 patients with SLE, 670 patients with RA, and 758 controls. Genotype distributions and allele frequencies were compared among the 3 groups as aggregates or as stratified by clinical characteristics, autoantibody profile, and sex within patient groups.Results.Overall, FCRL3 SNP −169T/C was not associated with susceptibility to either SLE or RA. However, −169CC genotype was significantly reduced in leukopenia-positive SLE patients as compared to the leukopenia-negative SLE patients (CC vs CT+TT, p = 6 × 10−4, OR 0.444, 95% CI 0.279–0.708) and controls (p = 6.1 × 10−3, OR 0.583, 95% CI 0.396–0.857). On the other hand, −169TT genotypes were significantly more numerous in RA patients with non-destructive disease as compared with patients with destructive disease (CC+CT vs TT: p = 0.007, OR 1.672, 95% CI 1.149–2.432). The −169T allele frequency was also significantly increased in non-destructive RA compared with patients with destructive disease (C vs T: p = 0.010, OR 1.423, 95% CI 1.089–1.859). FCRL3 SNP −169TT homozygous donors were significantly more numerous among female cyclic citrullinated peptide (CCP)-negative RA patients versus female CCP-positive RA patients (CC+CT vs TT: p = 0.019, OR 1.64, 95% CI 1.085–2.479).Conclusion.The functional FCRL3 SNP −169T/C appears to play important roles in the development of certain phenotypes such as SLE leukopenia and RA disease severity in Taiwanese patients with SLE and RA.

Objectives. To estimate the incidence, characteristics and predictors of infections in patients with PM and DM. Methods. The medical records of 192 PM/DM patients followed up in a tertiary teaching medical centre from 1999 to 2008 were retrospectively reviewed. Results. Seventy-six episodes of major infection, defined as infections requiring >1 week of treatment with anti-microbial agents, occurred in 53 (27.6%) patients, and 15 (7.8%) patients had two or more episodes. The incidence rate of major infections was 11.1 episodes per 100 patient-years in PM/DM patients. Aspiration pneumonia [n (%)=16 (21.1)] was the leading cause of major infections, followed by opportunistic infection [n (%)=14 (18.4)]. A variety of pathogens were isolated, mainly including Staphylococcus aureus, Klebsiella, Escherichia coli, Salmonella and Mycobacterium. Overall patient survival rates were 85.0% at 1 year, 78.0% at 5 years and 78.0% at 10 years. However, after one episode of major infection, survival rates decreased to 84.7% at 30 days and 68.3% at 1 year. Multivariate analysis indicated that independent predictors of major infection were age >45 years at PM/DM onset [odds ratio (OR) 5.26; 95% CI 2.01, 13.77; P=0.001], presence of arthritis/arthalgia (OR 2.59; 95% CI 1.12, 6.02; P= 0.027), co-present interstitial lung disease (OR 7.24; 95% CI 2.67, 19.65; P < 0.001 current use of AZA (OR 6.07; 95% CI 2.39, 15.42; P < 0.001) or IVIG (OR 6.33; 95% CI 1.50, 26.77; P= 0.012). Conclusions. This study underlines the high frequency of major infections in PM/DM, which is significantly detrimental to patient survival rates. Close follow-up of PM/DM patients with risk factors for developing major infections is mandatory.

The aim of the study was to estimate the prevalence, characteristics, and prognostic factors of interstitial lung disease (ILD) in patients with polymyositis (PM) and dermatomyositis (DM). The medical records of 151 PM/DM patients treated at Chang Gung Memorial Hospital between January, 2000 and June, 2007 were retrospectively reviewed. Thirty of 151 (19.9%) PM/DM patients had developed ILD. Older age at PM/DM onset, anti-Jo-1 antibody, and arthritis/arthralgia were associated with the presence of ILD (p = 0.004, p = 0.008, and p = 0.026, respectively). Anti-Jo-1 was initially excluded from the multivariate analysis because only 80 patients underwent the test. An older age at onset above 45 years (odds ratio 3.28, 95% confidence interval (CI) 1.15-9.34, p = 0.026) and arthritis/arthralgia at onset (odds ratio (OR) 2.57, 95% CI 1.09-6.08, p = 0.032) were the two independent risk factors for developing ILD. If anti-Jo-1 was included in the multivariate analysis (n = 80), then an older age at onset above 45 years (OR 7.30, 95% CI 1.70-31.40, p = 0.008) and anti-Jo-1 positive (OR 7.89, 95% CI 1.18-52.87, p = 0.033) were associated with ILD, while arthritis/arthralgia was no longer significant (OR 2.64, 95% CI 0.70-10.01, p = 0.153). Of the 30 ILD patients, 16 (53.3%) died. The survival time was significantly shorter in ILD patients than in patients without ILD (p < 0.001). Poor survival in ILD patients was associated with male gender (p = 0.039), a Hamman-Rich-like presentation (p = 0.039), and a clinical diagnosis of acute interstitial pneumonia (p = 0.007).

Objective Gout is characterized by recurrent attacks of arthritis with hyperuricaemia and urate crystal-induced inflammation. Although urate transporters are known as risk factors, the immunogenetics of gouty inflammation remains unclear. This study aimed to investigate the genetic association between immune/metabolism regulators and gout. Methods We enrolled 448 gout patients and 943 population controls from Taiwan; all were Han Chinese. We screened association between gout and 22 variants of candidate genes, including NLRP3 , caspase 1, peroxisome proliferator-activated receptor-γ, proliferator-activated receptor-γ coactivator 1α ( PPARGC1A ) and 1β ( PPARGC1B ). The association was validated by replication and combined-sample analyses. Functional assays were performed by quantitative PCR, ELISA, siRNA knockdown and transfection using THP-1 cells, peripheral blood mononuclear cells and synovial cells from patients. Results Gouty arthritis exhibited significant association with variants of peroxisome PPARGC1B , which included a missense single nucleotide polymorphism, rs45520937 [P = 6.66 × 10 -9 ; odds ratio (95% CI): 1.85 (1.51, 2.28)]. Expression of PPARGC1B and NLRP3 was induced in urate crystal-activated THP-1, peripheral blood mononuclear cells and synovial cells from gout patients in acute stage. siRNA knockdown of PPARGC1B upregulated NLRP3 in urate crystal-activated macrophages. Compared with the wild-type carriers, patients with the risk A allele of rs45520937 showed statistically increased NLRP3 (P = 0.044) and plasma IL-1β (P = 0.006). Transfection of PPARGC1B cDNA with rs45520937 A allele to macrophages significantly augmented the expression of NLRP3 and IL-1β. Conclusion Genetic variants of PPARGC1B are significantly associated with gout, and a missense single nucleotide polymorphism, rs45520937, augments NLRP3 and IL-1β expression. These data suggest that variants of PPARGC1B , a regulator of metabolism and inflammation, contribute to the pathogenesis of gouty arthritis.

Allopurinol, a common drug for treating hyperuricemia, is associated with cutaneous adverse drug reactions ranging from mild maculopapular exanthema to life-threatening severe cutaneous adverse reactions, including drug reaction with eosinophilia and systemic symptoms, Stevens-Johnson syndrome, and toxic epidermal necrolysis. We have previously reported that HLA-B*58:01 is strongly associated with allopurinol-induced severe cutaneous adverse reactions in Han Chinese, but the associations of the HLA-B*58:01 genotype in an allopurinol-induced hypersensitivity phenotype remain unclear. To investigate the comprehensive associations of HLA-B*58:01 , we enrolled 146 patients with allopurinol-induced cutaneous adverse drug reactions (severe cutaneous adverse reactions, n = 106; maculopapular exanthema, n = 40) and 285 allopurinol-tolerant control subjects. Among these allopurinol-induced cutaneous adverse drug reactions, HLA-B*58:01 was strongly associated with severe cutaneous adverse reactions (odds ratio [OR] = 44.0; 95% confidence interval = 21.5–90.3; P = 2.6 × 10 -41 ), and the association was correlated with disease severity (OR = 44.0 for severe cutaneous adverse reactions, OR = 8.5 for maculopapular exanthema). The gene dosage effect of HLA-B*58:01 also influenced the development of allopurinol-induced cutaneous adverse drug reactions (OR = 15.25 for HLA-B*58:01 heterozygotes and OR = 72.45 for homozygotes). Furthermore, coexistence of HLA-B*58:01 and renal impairment increased the risk and predictive accuracy of allopurinol-induced cutaneous adverse drug reactions (heterozygous HLA-B*58:01 and normal renal function: OR = 15.25, specificity = 82%; homozygous HLA-B*58:01 and severe renal impairment: OR = 1269.45, specificity = 100%). This HLA-B*58:01 correlation study suggests that patients with coexisting HLA-B*58:01 and renal impairment (especially estimated glomerular filtration rate 2 ) should be cautious and avoid using allopurinol.

This study aims to investigate the prevalence and predictive risk factors of malignancy in patients with polymyositis (PM) and dermatomyositis (DM). The medical records of 192 PM/DM patients followed up in a medical center between January 2000 and December 2013 were reviewed. Among the 192 patients, 33 patients (17.2 %) had associated cancer. Both PM and DM are significantly associated with cancer, although the risk of cancer appears to be somewhat higher among patients with DM (23.0 %) than among those with PM (8.9 %). Nasopharyngeal cancer (30.3 %) and breast cancer (18.2 %) comprised the most common malignant diseases associated with PM/DM. Univariate analysis showed that an older age at PM/DM onset, heliotrope rash, Gottron's sign, dysphagia, and low creatine phosphokinase (CPK) level were associated with increased malignancy. Multivariate analysis revealed that independent predictors of malignancy in PM/DM were age >40 years at PM/DM onset (adjusted OR 3.44; 95 % CI 1.08-10.98; p = 0.037) and heliotrope rash (adjusted OR 2.96; 95 % CI 1.04-8.43; p = 0.042). During the follow-up period, 66 (34.4 %) patients died and the overall patient survival rates were 83.1 % at 1 year, 78.9 % at 2 years, 74.2 % at 5 years, and 65.5 % at 10 years. This study demonstrates a high frequency of malignancy (17.2 %) in DM/PM patients. Nasopharyngeal cancer and breast cancer were the most common cancer types in DM/PM patients in our study. Cancer screening should be offered to patients with newly diagnosed DM/PM. Moreover, all patients should be evaluated for the possibility of an underlying malignancy during treatment.

The negative association between gout and rheumatoid arthritis is widely accepted, and gout is also speculated to be rare in systemic lupus erythematosus (SLE), as only a few sporadic cases have been reported. From 1985 to 2001 we encountered 15 lupus patients at Chang-Gung Memorial Hospital, including two with lupus-scleroderma and one with lupus-scleroderma-polymyositis overlap syndrome coexisting with gout. This study retrospectively analyses the clinical and laboratory characteristics of these patients. A lower female predominance is found, and most patients developed gout after the onset of SLE, although gout preceded SLE in two cases. Measurement of serum uric acid and 24-h urine uric acid found all of the patients to be hyperuricaemic and underexcretors of uric acid. Furthermore, most of the patients (14/15) were receiving diuretics. Also, many had hypertension and serious cardiovascular diseases. Renal impairment during gouty attacks seemed to be a predisposing factor for developing end-stage renal disease. Gouty arthritis usually occurred during relative SLE inactivity, podagra was frequent, and tophi were found in a few patients. Compared with the unselected population of SLE patients, the cases studied here had a higher incidence of chronic arthritis, malar rash, haematologic disorder, photosensitivity, serositis and neurologic disorder. Renal disease in the patients sampled was frequently membranous nephropathy.

Objectives. To analyse the clinical features and outcomes of gouty patients with concomitant septic arthritis in a medical centre. Methods. From the hospital database, we collected 30 hospitalized cases with concomitant septic arthritis and gouty arthritis from 1987 to 2001. All patients had positive bacterial culture and monosodium urate crystals in the affected joints. Medical records of the patients were analysed in detail. Results. The mean age of patients was 52.8"12.5 yr. One-third of patients were afebrile at presentation, 30% had a normal blood leucocyte count and 10% had a synovial fluid leucocyte count less than 6000umm 3 . The knee joint was the most common site of involvement, followed by the ankle, shoulder and wrist joints. Most patients had long-standing disease and subcutaneous tophi. Subcutaneous tophi rupture with secondary wound infection is the most common route of infection. Causative micro-organisms were Staphylococcus aureus (16 cases, 7 of whom were oxacillin-resistant), Streptococcus sp. (5 cases), Pediococcus sp. (1 case), and Gram-negative bacilli (9 cases). Fourteen patients received surgical debridement, among them two patients had an arthrodesis owing to severe joint destruction and one received above-knee amputation. Two patients died. One died of septic complications and the other died of acute myocardial infarction. Conclusions. Septic arthritis coexistent with gout presented a diagnostic difficulty. An early diagnosis requires a high level of suspicion. Prompt aspiration and analysis of the synovial fluid is imperative, regardless of the absence of fever or leucocytosis. Culture of the aspirated synovial fluid is warranted in gouty attack, even when it has a low white cell count or the Gram stain reveals no organisms.

ObjectiveAllopurinol, an antihyperuricaemic agent, is one of the common causes of life-threatening severe cutaneous adverse reactions (SCAR), including drug rash with eosinophilia and systemic symptoms (DRESS), Stevens–Johnson syndrome (SJS) and toxic epidermal necrosis (TEN). The prognostic factors for allopurinol-related SCAR remain unclear. This study aimed to investigate the relationship of dosing, renal function, plasma levels of oxypurinol and granulysin (a cytotoxic protein of SJS/TEN), the disease severity and mortality in allopurinol-SCAR.MethodsWe prospectively enrolled 48 patients with allopurinol-SCAR (26 SJS/TEN and 22 DRESS) and 138 allopurinol-tolerant controls from 2007 to 2012. The human leucocyte antigen (HLA)-B*58:01 status, plasma concentrations of oxypurinol and granulysin were determined.ResultsIn this cohort, HLA-B*58:01 was strongly associated with allopurinol-SCAR (pConclusionsImpaired renal function and increased plasma levels of oxypurinol and granulysin correlated with the poor prognosis of allopurinol-SCAR. Allopurinol prescription is suggested to be avoided in subjects with renal insufficiency and HLA-B*58:01 carriers. An early intervention to increase the clearance of plasma oxypurinol may improve the prognosis of allopurinol-SCAR.

Systemic lupus erythematosus (SLE) in the elderly is uncommon and rarely reported with disease onset at age 65 and older. The aim of this study is to retrospectively analyze the influence of age at disease onset on the clinical features and prognosis of SLE. From 1988 to 1998, we encountered 21 lupus patients with disease onset at age 65 and older (all are included in group A). For comparison, 21 lupus patients with disease onset between 50 ± 64 years of age (group B)and 152 lupus patients with disease onset before 50 years of age (group C) were obtained by a simple random sampling method from the hospital registry. Clinical features as included in the 1982 ARA revised criteria for classification of SLE and survival rate were analyzed and compared among these three groups. Group A had a smaller female to male ratio, longer duration from disease onset to diagnosis, less malar rash, more discoid lupus, and shorter survival rate that group C. There was no statistically significant difference in clinical features and survival between groups A and B, as well as between female and male patients of these two groups. The main cause of death in group A was septic shock. In conclusion, the clinical features and prognosis of SLE were influenced by the age at disease onset. However, clinical features and prognosis of SLE were similar in both late-onset lupus groups.

Salmonella infection is an important problem in immunocompromised patients. The synovium is a particular metastatic focus of Salmonella infection and can result in many disabilities of life. Systemic lupus erythematosus (SLE) patients were highly susceptible to Salmonella infection. In the past 6 years, 41 patients with Salmonella septic arthritis have been treated in our hospital. Eleven patients had an underlying systemic disease of SLE which presented with a distinctive clinical course. Alcoholic liver disease (six cases) was another common underlying systemic disease. The most frequent predisposing articular factor was avascular necrosis (16 cases). The hip joint was the most commonly involved site. Salmonella group B was the most common serotype (30/41). Seventy-three per cent (8/11) of the SLE group had involvement of two or more joints compared with only three out of 30 patients in the non-SLE group. The sex differentiation shows a predominance of young females (10/11) in the SLE group and middle-aged males in the non-SLE group. Moreover, in the SLE group, all 11 patients shared the risk of lupus nephritis and steroid use. Ten patients had Salmonella group B bacteraemia and five had urinary tract infections simultaneously. In the non-SLE group, there were 10 patients with a history of steroid use, three with antecedent enteritis, 12 with bacteraemia, and three with necrotising fasciitis. Seven patients in each of the groups had a recurrent course. However, three patients in the non-SLE group had died during the episode of septic arthritis.

Higher soluble CD4 (sCD4) levels in serum have been detected in patients of infectious and chronic inflammatory diseases. However, how and why sCD4 is produced remains poorly understood. We establish sensitive ELISA and WB assays for sCD4 detection in conditioned medium of in vitro cell culture system and serum of chronic inflammatory patients. Serum samples from patients with systemic lupus erythematosus (SLE) (n = 79), rheumatoid arthritis (RA) (n = 59), ankylosing spondylitis (AS) (n = 25), gout (n = 31), and normal controls (n = 99) were analyzed using ELISA for sCD4 detection. Results from each assay were analyzed by the Kruskal-Wallis test. Dunn's multiple comparison post-test was then applied between groups. We confirm that cells expressing exogenous CD4 produce sCD4 in a constitutive and PMA-induced manner. Importantly, sCD4 production in a heterologous expression system is inhibited by GM6001 and TAPI-0, suggesting receptor shedding by matrix metalloproteinase (MMP)-like proteinases. Moreover, similar findings are recapitulated in human primary CD4(+) T cells. Finally, we show that serum sCD4 levels are increased in patients of chronic inflammatory diseases including RA and SLE, but not in those with gout. Intriguingly, sCD4 levels in RA patients are correlated positively with the disease activities and higher sCD4 levels seem to associate with poor prognosis. Taken together, we conclude that CD4 is shed from cell surface by a MMP-like sheddase and sCD4 level is closely related with the inflammatory condition in certain chronic diseases. Hence, sCD4 might be considered an important parameter for RA disease progression with potential diagnostic importance.

Background Systemic lupus erythematosus (SLE) is a heterogeneous disease characterised by fluctuating disease activity. A low disease activity endpoint, the Lupus Low Disease Activity State (LLDAS), was recently reported and retrospective validation showed that time spent in LLDAS translated into reduced damage accrual (Franklyn, Ann Rheum Dis, 2015). A large prospective study to validate LLDAS in a multiethnic cohort of lupus patients from the Asia Pacific Region is underway. Objectives To describe the frequency and identify the predictors of fulfilling criteria for LLDAS in baseline visit data from a large multinational multiethnic cohort of patients with SLE in nine Asia Pacific countries. Methods Prospectively collected baseline visit data from 1846 SLE patients enrolled in a longitudinal study were analysed cross sectionally against the recently published definition of LLDAS, and patient characteristics associated with LLDAS attainment determined. Results LLDAS criteria were met by 44% of patients at a single baseline visit. Stepwise multivariable logistic regression revealed that patients with shorter disease duration were less likely to be in LLDAS (OR 0.31, 95% CI 0.19–0.49, p Conclusions Low disease activity was observed in less than half of SLE patients at a single point in time. Disease duration and phenotype, as well as national social wealth, were predictive of LLDAS attainment. Disclosure of Interest None declared

A 50-year-old man with long standing ankylosing spondylitis developed cauda equina syndrome, which was found to be coexistent with a spinal arterio-venous malformation. Paraplegia ensured following an acute exacerbation of back pain along with an attack of uveitis. Vasculitis changes were found on resected abnormal vessels.

Introduction Ankylosing spondylitis (AS) is a familial, heritable disease specified by syndesmophyte formation leading to an ankylosed spine. Endoplasmic reticulum aminopeptidase 1 (ERAP1) genetic variations have been widely proved to be associated with AS in several ethnic populations. The aim of this study was to investigate whether ERAP1 single nucleotide polymorphisms (SNPs) are associated with AS susceptibility and disease severity in Taiwanese. Methods Four ERAP1 SNPs (rs27037, rs27980, rs27044 and rs30187) were genotyped in 797 Taiwanese AS patients and 1,150 healthy controls. Distributions of genotype and alleles were compared between AS patients and healthy controls, and among AS patients stratified by clinical parameters. Results The SNP rs27037T allele appeared to be a risk factor for AS susceptibility (P = 5.5 × 10-5, OR 1.30, 95% CI: 1.15 to 1.48; GT+TT vs. GG P = 9.3 × 10-5, OR 1.49, 95% CI: 1.22 to 1.82). In addition, the coding SNP (cSNP) rs27044G allele (P = 1.5 × 10-4, OR 1.28, 95% CI: 1.13 to 1.46; CG+GG vs. CC, P = 1.7 × 10-3, OR 1.44, 95% CI: 1.15 to 1.81) and the cSNP rs30187T allele (P = 1.7 × 10-3, OR 1.23, 95% CI: 1.08 to 1.40; CT+TT vs. CC P = 6.1 × 10-3, OR 1.38, 95% CI: 1.10 to 1.74) were predisposing factors for AS. Notably, the rs27044G allele carriers (CG+GG vs. CC, P = 0.015, OR 1.59, 95% CI: 1.33 to 2.30) and rs30187T allele carriers (CT+TT vs. CC, P = 0.011, OR 1.63, 95% CI: 1.12 to 2.38) were susceptible to syndesmophyte formation in AS patients. Furthermore, two cSNPs (rs27044 and rs30187) strongly associated with HLA-B27 positivity in AS patients. Finally, the ERAP1 SNP haplotype TCG (rs27037T/rs27980C/rs27044G) is a major risk factor for AS (adjusted P

Objective.We investigated the etiological association and clinical characteristics of apical pulmonary fibrosis in ankylosing spondylitis (AS).Methods.We reviewed medical records of 2136 consecutive patients diagnosed with AS at a tertiary medical center. Clinical and radiographic characteristics were analyzed for evidence of apical lung fibrosis on chest radiographs.Results.Of 2136 patients with AS, 63 (2.9%) developed apical lung fibrosis, of which chronic infections were the cause in 41 and AS inflammation predisposed the fibrosis in 22 patients. Tuberculosis (TB) infection was considered to be the cause of apical lung fibrosis in 40 patients (63.5%) including 19 with bacteriologically-proven TB and 21 with chest radiographs suggestive of TB. Two were identified as having non-TB mycobacterial infection and one asAspergillusinfection. Lung cavity lesion appeared to be a crucial differentiator (p = 0.009, odds ratio 7.4, 95% CI 1.5–36.0) between TB infection and AS inflammation-induced apical fibrosis.Conclusion.Our study suggests that TB, instead ofAspergillus, is the most common pulmonary infection in patients with AS presenting with apical lung fibrosis. AS-associated apical lung fibrosis may mimic pulmonary TB infection. Thus, bacteriological survey and serial radiological followup of lung fibrocavitary lesions are critical for accurate diagnosis and treatment.

The aim of this study was to investigate the clinical characteristics of patients with coexisting ankylosing spondylitis (AS) and gout. Between July 1987, and October 2004, sixty-five patients with coexisting AS and gout were enrolled. The clinical manifestations of both AS and gout in these patients were studied. Of the 65 patients included in the study, 61 were men and four were women (men-to-women ratio, 15.3:1). Sixty-three subjects were Han Chinese, and two were Atayal Aborigines. Mean ages at onset of AS and gout were 29.3 +/- 15.6 years (range 7-63) and 42.2 +/- 13.2 years (range 20-74), respectively. Fifty-six patients developed gout after (15.5 +/- 11.2 years; range, 1-51 years) onset of AS; nine patients developed gout before (average, 3.4 +/- 2.2 years; range. 1-7 years) onset of AS. Forty-four (67.7%) patients had chronic peripheral arthritis and all 65 (100%) patients had acute peripheral arthritis. Thirty-three (50.8%) cases had heel pain (enthesopathy), including 22 (33.9%) with chronic heel pain, seven (10.8%) with acute heel pain, and four (6.2%) with concurrent acute and chronic heel pain. Sixty-one (93.9%) subjects were HLA-B27 antigen positive. Medical conditions potentially associated with hyperuricemia or gout were urolithiasis (n = 17), hypertension (n = 21), diabetes mellitus (n = 8), hyperlipidemia (n = 34), congestive heart failure (n = 6), coronary heart disease (n = 5), and stroke (n = 3). The following drugs were prescribed: diuretics (n = 7), low-dose aspirin (n = 4), antituberculous drugs (n = 1), and sulphasalazine (n = 34). Six (6.2%) patients had iatrogenic Cushing syndrome with adrenal insufficiency. Patients with coexisting AS and gout are not rare. Distinguishing between peripheral arthritis or enthesopathies of AS and gout is essential, especially when the course of AS arthritis becomes acute or the course of gout becomes chronic.

Although cardiac tamponade is an important and emergent complication of systemic lupus erythematosus (SLE), purulent pericarditis is rare despite the high frequency of pericardial effusion in SLE. We describe the first SLE case of Haemophilus influenzae type-f pericarditis with cardiac tamponade with SLE as the initial presentation. The pathophysiology and therapy are discussed.

To determine whether the distribution of Fcgamma receptor IIa, IIIa, and IIIb polymorphisms confers a risk factor for disease susceptibility, and correlates with the clinical characteristics and serological parameters of patients with SLE in Taiwan.Genotyping of Fcgamma receptors IIa H/R131, IIIa F/V158, and IIIb NA1/NA2 was performed in 302 patients with SLE and 311 healthy blood donor controls. The distribution of Fcgamma receptor IIa, IIIa, and IIIb genotypes in patients and controls was analysed. Frequencies of three Fcgamma receptor polymorphisms were also compared between lupus patients with and without different clinical manifestations and autoantibodies.No significant skewing in the distribution of Fcgamma RIIa H/R131, Fcgamma RIIIa F/V158, and Fcgamma RIIIb NA1/NA2 was found between patients and controls in Taiwan. The following clinical associations were found: Fcgamma RIIIb NA1/NA1 protected against neuropsychiatric lupus (p = 0.028) but conferred susceptibility to discoid rash (p0.005); increased Fcgamma RIIIa V/V158 was associated with infections (p = 0.039); increased Fcgamma RIIa H/H131 was associated with earlier onset of lupus (p = 0.01).Fcgamma receptor IIa, IIIa, and IIIb polymorphisms may be responsible for the development of distinct manifestations of lupus patients in Taiwan, but there is no significantly skewed distribution in the susceptibility to lupus as a whole.