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ObjectiveGenome-wide association studies (GWAS) have identified >100 risk loci for systemic lupus erythematosus (SLE), but the disease genes at most loci remain unclear, hampering translation of these genetic discoveries. We aimed to prioritise genes underlying the 110 SLE loci that were identified in the latest East Asian GWAS meta-analysis.MethodsWe built gene expression predictive models in blood B cells, CD4+and CD8+T cells, monocytes, natural killer cells and peripheral blood cells of 105 Japanese individuals. We performed a transcriptome-wide association study (TWAS) using data from the latest genome-wide association meta-analysis of 208 370 East Asians and searched for candidate genes using TWAS and three data-driven computational approaches.ResultsTWAS identified 171 genes for SLE (p–5); 114 (66.7%) showed significance only in a single cell type; 127 (74.3%) were in SLE GWAS loci. TWAS identified a strong association betweenCD83and SLE (p–8). Meta-analysis of genetic associations in the existing 208 370 East Asian and additional 1498 cases and 3330 controls found a novel single-variant association at rs72836542 (OR=1.11, p=4.5×10–9) aroundCD83. For the 110 SLE loci, we identified 276 gene candidates, including 104 genes at recently-identified SLE novel loci. We demonstrated in vitro that putative causal variant rs61759532 exhibited an allele-specific regulatory effect onACAP1, and that presence of the SLE risk allele decreasedACAP1expression.ConclusionsCell-level TWAS in six types of immune cells complemented SLE gene discovery and guided the identification of novel genetic associations. The gene findings shed biological insights into SLE genetic associations.

ObjectiveSystemic lupus erythematosus (SLE), an autoimmune disorder, has been associated with nearly 100 susceptibility loci. Nevertheless, these loci only partially explain SLE heritability and their putative causal variants are rarely prioritised, which make challenging to elucidate disease biology. To detect new SLE loci and causal variants, we performed the largest genome-wide meta-analysis for SLE in East Asian populations.MethodsWe newly genotyped 10 029 SLE cases and 180 167 controls and subsequently meta-analysed them jointly with 3348 SLE cases and 14 826 controls from published studies in East Asians. We further applied a Bayesian statistical approach to localise the putative causal variants for SLE associations.ResultsWe identified 113 genetic regions including 46 novel loci at genome-wide significance (p−8). Conditional analysis detected 233 association signals within these loci, which suggest widespread allelic heterogeneity. We detected genome-wide associations at six new missense variants. Bayesian statistical fine-mapping analysis prioritised the putative causal variants to a small set of variants (95% credible set size ≤10) for 28 association signals. We identified 110 putative causal variants with posterior probabilities ≥0.1 for 57 SLE loci, among which we prioritised 10 most likely putative causal variants (posterior probability ≥0.8). Linkage disequilibrium score regression detected genetic correlations for SLE with albumin/globulin ratio (rg=−0.242) and non-albumin protein (rg=0.238).ConclusionThis study reiterates the power of large-scale genome-wide meta-analysis for novel genetic discovery. These findings shed light on genetic and biological understandings of SLE.

Objective To evaluate the efficacy and safety of CT-P10, a rituximab biosimilar after a single switch, during a multinational, randomized, double-blind Phase 3 trial involving patients with RA. Methods Patients received 48 weeks’ treatment with CT-P10 or United States- or European Union-sourced reference rituximab (US-RTX and EU-RTX, respectively). Patients entering the extension period (weeks 48–72) remained on CT-P10 (CT-P10/CT-P10; n = 122) or US-RTX (US-RTX/US-RTX; n = 64), or switched to CT-P10 from US-RTX (US-RTX/CT-P10; n = 62) or EU-RTX (EU-RTX/CT-P10; n = 47) for an additional course. Efficacy endpoints included Disease Activity Score using 28 joints (DAS28), American College of Rheumatology (ACR) response rates, and quality of life-related parameters. Pharmacodynamics, immunogenicity and safety were also assessed. Results At week 72, similar improvements were observed by disease activity parameters including DAS28 and ACR response rate in the four extension period treatment groups. Quality of life improvements at week 72 vs baseline were similarly shown during the extension period in all groups. Newly developed anti-drug antibodies were detected in two patients following study drug infusion in the extension period. Similar pharmacodynamic and safety profiles were observed across groups. Conclusion Long-term use of CT-P10 up to 72 weeks was effective and well tolerated. Furthermore, switching from reference rituximab to CT-P10 in RA was well tolerated and did not result in any clinically meaningful differences in terms of efficacy, pharmacodynamics, immunogenicity and safety. Trail registration ClinicalTrials.gov, http://clinicaltrials.gov, NCT02149121.

Objective The aim of this study was to investigate long-term clinical outcomes of extended treatment with CT-P10, a rituximab biosimilar, compared with rituximab reference products sourced from the USA and the EU (US-RTX and EU-RTX) in rheumatoid arthritis (RA) for up to 48 weeks. Methods In this multinational, randomized, double-blind trial, adults with active RA received up to two courses of CT-P10, US-RTX, or EU-RTX alongside methotrexate. Efficacy endpoints included Disease Activity Score 28-joint count (DAS28) and American College of Rheumatology (ACR) response rates. Pharmacokinetics, pharmacodynamics, immunogenicity, and safety were also assessed. Results Of 372 patients randomized to the study drug, 330 (88.7%) completed the second treatment course. Mean change from baseline to week 48 in DAS28-C-reactive protein was comparable in the CT-P10 and combined rituximab (US-RTX and EU-RTX) groups (− 2.7 and − 2.6, respectively). ACR20, ACR50, and ACR70 response rates at week 48 indicated no differences between groups (80.6%, 55.4%, and 31.7% vs. 79.8%, 53.9%, and 33.7% in the CT-P10 and combined rituximab groups, respectively). Similar improvements in the Health Assessment Questionnaire Disability Index and all medical outcomes in the Short Form 36-Item Health Survey, including physical and mental health, were seen in all groups. At week 48, antidrug antibodies were detected in 4.9%, 9.4%, and 8.6% of patients in the CT-P10, US-RTX, and EU-RTX groups, respectively. CT-P10 and rituximab displayed similar pharmacokinetic, pharmacodynamic, and safety profiles. Conclusion CT-P10 was similar to EU-RTX and US-RTX in terms of efficacy, pharmacokinetics, pharmacodynamics, immunogenicity, and safety up to week 48. ClinicalTrials.gov identifier NCT02149121. Electronic supplementary material The online version of this article (10.1007/s40259-018-00331-4) contains supplementary material, which is available to authorized users.

Background Patient-centered management is becoming increasingly important in gout, but there are limited studies exploring patients' perspectives and preferences. We aimed to investigate patients' perspectives and preferences regarding gout and gout management, and their impacts on adherence to urate lowering therapy (ULT). Methods A paper-based survey was performed in patients with gout seen at the rheumatology outpatient clinics of 16 tertiary hospitals. The survey included questions regarding demographics, comorbidities, gout attacks, current treatment and adherence, and patients' perspectives and preferences regarding gout and gout management. Multivariate regression analysis was performed to determine the factors associated with ULT adherence. Results Of 809 surveyed patients with gout, 755 (94.5%) were using ULT. Among those using ULT, 89.1% had ≥ 80% adherence to ULT. Majority of the patients knew management strategies to some extent (94.8%), perceived gout as a life-long disease (91.2%), and were making efforts toward practicing at least one lifestyle modification (89.2%). Most patients (71.9%) obtained information about gout management during their clinic visits. Approximately half of the patients (53.6%) preferred managing their disease with both ULT and lifestyle modification, 28.4% preferred ULT only, and 17.4% preferred lifestyle modification only. Adherence was better in patients with older age (odds ratio [OR], 1.03), those with better knowledge of gout management strategies (OR, 3.56), and those who had preference for ULT (OR, 2.07). Conclusion Patients' perspectives and management preferences had high impacts on adherence to ULT in gout. Consideration of patients' perspectives and preferences is important for achieving the desired clinical outcome in gout., Graphical Abstract

ObjectiveGenome-wide association studies (GWAS) in rheumatoid arthritis (RA) have discovered over 100 RA loci, explaining patient-relevant RA pathogenesis but showing a large fraction of missing heritability. As a continuous effort, we conducted GWAS in a large Korean RA case–control population.MethodsWe newly generated genome-wide variant data in two independent Korean cohorts comprising 4068 RA cases and 36 487 controls, followed by a whole-genome imputation and a meta-analysis of the disease association results in the two cohorts. By integrating publicly available omics data with the GWAS results, a series of bioinformatic analyses were conducted to prioritise the RA-risk genes in RA loci and to dissect biological mechanisms underlying disease associations.ResultsWe identified six new RA-risk loci (SLAMF6, CXCL13, SWAP70, NFKBIA, ZFP36L1 and LINC00158) with pmeta−8 and consistent disease effect sizes in the two cohorts. A total of 122 genes were prioritised from the 6 novel and 13 replicated RA loci based on physical distance, regulatory variants and chromatin interaction. Bioinformatics analyses highlighted potentially RA-relevant tissues (including immune tissues, lung and small intestine) with tissue-specific expression of RA-associated genes and suggested the immune-related gene sets (such as CD40 pathway, IL-21-mediated pathway and citrullination) and the risk-allele sharing with other diseases.ConclusionThis study identified six new RA-associated loci that contributed to better understanding of the genetic aetiology and biology in RA.

Background Rituximab (RTX), a monoclonal antibody that selectively binds to CD20+ B cells, showed favorable outcomes in patients with idiopathic inflammatory myopathies (IIM) in small case series, but the evidence is still not enough. Our goal was to determine the efficacy and safety of RTX for Korean patients with refractory IIM. Methods We retrospectively analyzed the medical records of 16 patients with refractory IIM treated with RTX in seven tertiary rheumatology clinics in the Korea. The efficacy of RTX was evaluated with the improvement of serum creatine phosphokinase (CPK) level and physician's global assessment (PGA), and daily corticosteroid dose reduction. A > 25% decrease in CPK level, corticosteroid dose, or PGA was considered significant. A complete response (CR) was designated by meeting three efficacy criteria and a partial response (PR) by only two criteria. Results Sixteen patients with IIM were evaluated (13 female; median age, 51.8 years). All patients had received at least one conventional immunosuppressive agent (median, 3.6 [2.0–5.0]) and concomitant corticosteroids. The median CPK level and median dose of prednisolone was 421.0 units/L and 20.0 mg/day respectively. Eleven patients were treated with intravenous immunoglobulin. Seven patients received 2,000 mg of RTX and the others received lower dose. Twenty-four weeks after RTX treatment, 11 patients achieved a > 25% reduction in corticosteroid dose and CPK levels, and nine showed improved PGA. The overall response rate was 68.8% (11 patients). At the end of follow-up (median 24 weeks), 12 (75.0%) patients responded overall: four (25.0%) and eight (50.0%) patients achieved CR and PR, respectively. Baseline muscle enzyme levels were higher in responders than non-responders, but disease duration, RTX dose, ESR and serum CRP were not significantly different between the two groups. The rate of adverse event was 25.4/1,000 person-years. Conclusion RTX could be an effective and relatively safe therapeutic option in patients with refractory IIM., Graphical Abstract

BACKGROUND/AIMS The objective of this study was to determine the efficacy and safety of add-on therapy with certolizumab pegol (CZP) in active rheumatoid arthritis (RA) patients of a single ethnicity. METHODS In this 24-week, phase 3, randomized, double-blind, placebo-controlled trial, eligible patients (n = 127) were randomized 2:1 to subcutaneous CZP + methotrexate (MTX; 400 mg at week 0, 2, and 4 followed by 200 mg every 2 weeks) or placebo + MTX. RESULTS At week 24, the American College of Rheumatology criteria for 20% (ACR20) response rate was significantly greater with CZP + MTX than with placebo (66.7% vs. 27.5%, p < 0.001). Differences in ACR20 response rates for CZP vs. placebo were significant from week 1 (p < 0.05) and remained significant through week 24. The CZP group reported significant improvement in physical function and disability compared to the placebo group (p < 0.001) at week 24, as assessed by Korean Health Assessment Questionnaire-Disability Index (KHAQ-DI). Post hoc analysis indicated that the proportion of patients who had ACR70 responses, Disease Activity Score 28 (DAS28) low disease activity, and DAS28 remission at week 24 was greater in CZP + MTX-treated patients who achieved a decrease in DAS28 ≥ 1.2 (43.8%) at week 4 than in nonresponders. Among 18 (22.2%) and 14 patients (35.0%) in CZP and placebo groups who had latent tuberculosis (TB), none developed active TB. Most adverse events were mild or moderate. CONCLUSION CZP treatment combined with MTX in active RA patients with moderate to severe disease activity and an inadequate response to MTX resulted in rapid onset of efficacy, which is associated with better clinical outcome at week 24 and has an acceptable safety profile, especially in an intermediate TB-burden population.

Aim We designed this study to evaluate the prevalence of comorbidities, their monitoring states and association with treatment medication in Korean rheumatoid arthritis (RA) patients compared with patients from other countries. Methods We analyzed 1050 RA patients from 11 Korean centers and compared them with 3520 patients from 16 other countries using an international, cross-sectional study evaluating comorbidities of RA (COMORA) database. Results Annual evaluations of cardiovascular (CV) risk were less frequently performed in Korea (P = 0.0011). The prevalence of CV-associated morbidity was similar between Korean and international RA patients, although the proportions of current smokers, patients with a family history of CV disease, patients with hyperlipidemia, and patients with Framingham score > 20% were significantly lower in Korea (P < 0.0001 for all), and the antiplatelet agents were more optimally used in Korea (P = 0.0004). Prostate cancer screening was less frequently performed compared to other countries (P < 0.0001). Less than 10% of Korean RA patients were given influenza and pneumococcal vaccinations according to current recommendations. Conclusions There are differences in the prevalence of comorbidities and monitoring states of the risk factors between patients in Korea and in other countries. The prevalence of CV morbidity was similar between the two groups although the prevalence of CV risk factors was significantly low in Korea, suggesting that rheumatologists in Korea need to pay more attention to yearly CV risk monitoring, in addition to the screening of malignancy and vaccination of RA patients against infectious diseases.

Human leukocyte antigen (HLA) is a key genetic factor conferring risk of systemic lupus erythematosus (SLE), but precise independent localization of HLA effects is extremely challenging. As a result, the contribution of specific HLA alleles and amino-acid residues to the overall risk of SLE and to risk of specific autoantibodies are far from completely understood. Here, we dissected (a) overall SLE association signals across HLA, (b) HLA-peptide interaction, and (c) residue-autoantibody association. Classical alleles, SNPs, and amino-acid residues of eight HLA genes were imputed across 4,915 SLE cases and 13,513 controls from Eastern Asia. We performed association followed by conditional analysis across HLA, assessing both overall SLE risk and risk of autoantibody production. DR15 alleles HLA-DRB1*15:01 (P = 1.4x10-27, odds ratio (OR) = 1.57) and HLA-DQB1*06:02 (P = 7.4x10-23, OR = 1.55) formed the most significant haplotype (OR = 2.33). Conditioned protein-residue signals were stronger than allele signals and mapped predominantly to HLA-DRB1 residue 13 (P = 2.2x10-75) and its proxy position 11 (P = 1.1x10-67), followed by HLA-DRB1-37 (P = 4.5x10-24). After conditioning on HLA-DRB1, novel associations at HLA-A-70 (P = 1.4x10-8), HLA-DPB1-35 (P = 9.0x10-16), HLA-DQB1-37 (P = 2.7x10-14), and HLA-B-9 (P = 6.5x10-15) emerged. Together, these seven residues increased the proportion of explained heritability due to HLA to 2.6%. Risk residues for both overall disease and hallmark autoantibodies (i.e., nRNP: DRB1-11, P = 2.0x10-14; DRB1-13, P = 2.9x10-13; DRB1-30, P = 3.9x10-14) localized to the peptide-binding groove of HLA-DRB1. Enrichment for specific amino-acid characteristics in the peptide-binding groove correlated with overall SLE risk and with autoantibody presence. Risk residues were in primarily negatively charged side-chains, in contrast with rheumatoid arthritis. We identified novel SLE signals in HLA Class I loci (HLA-A, HLA-B), and localized primary Class II signals to five residues in HLA-DRB1, HLA-DPB1, and HLA-DQB1. These findings provide insights about the mechanisms by which the risk residues interact with each other to produce autoantibodies and are involved in SLE pathophysiology., Author summary The Human leukocyte antigen (HLA) region is a key genetic factor conferring risk of systemic lupus erythematosus (SLE). In spite of multiple SLE association signals identified in the HLA region, only amino-acid residues within HLA-DRB1 have been specifically described previously. In this study, we performed an imputation-based analysis on individuals with East Asian ancestry, and characterized SLE risk within the HLA region for all involved independent genes (HLA-DRB1, HLA-DPB1, HLA-DQB1, HLA-A, and HLA-B). Furthermore, we identified a characteristic SLE risk residue signature as well as a pattern of specific nRNP and Ro/La autoantibody residues located in the peptide-binding grooves, suggesting their key involvement in autoantibody production.

To determine characteristics of rheumatoid arthritis (RA) patients in Korea using disease-modifying anti-rheumatic drugs (DMARDs) for at least 6 months, and to identify factors associated with poor health-related outcomes.A total of 2000 RA patients aged20 years, treated with DMARDs for at least 6 months, and signed informed consent, were enrolled in this non-interventional, multicenter, cross-sectional observational study from December 2012 to June 2013. Health-related quality of life (HRQoL) was measured using EuroQuol 5D (EQ-5D) and functional disability was measured using the Korean Health Assessment Questionnaire (KHAQ). Univariate and multivariate linear regression analyses were used to determine the association between patient characteristics and patient-reported outcomes (PROs).Of all RA patients, 84% were female, patients with low Disease Activity Score of 28 joints erythrocyte sedimentation rate (DAS-28-ESR3.2) was 54%, while moderate (DAS-28-ESR 3.2-5.1) and high disease activity score (DAS-28-ESR5.1) were 38% and 7.6%, respectively. Mean EQ-5D index score and KHAQ score were 0.6 ± 0.28 and 0.7 ± 0.67, respectively. In multivariate analysis with both PROs, average HRQoL and functional disability score appeared to be worse in persons with older age compared to younger age (P0.001), and worse in females compared to males (P0.001). Compared to patients having lower DAS (3.2), those with moderate and highest DAS (3.2-5.1 and5.1) had worse outcome measures (P0.001).In this study, higher DAS was one of the most influential factors for poor PROs among all other factors. Therefore, we could suggest appropriate treatment approaches according to DAS along with other significantly associated factors with PROs in the early stage of RA.

Objective.To develop a genotype-based ankylosing spondylitis (AS) risk prediction model that is more sensitive and specific than HLA-B27 typing.Methods.To develop the AS genetic risk scoring (AS-GRS) model, 648 individuals (285 cases and 363 controls) were examined for 5 copy number variants (CNV), 7 single-nucleotide polymorphisms (SNP), and an HLA-B27 marker by TaqMan assays. The AS-GRS model was developed using logistic regression and validated with a larger independent set (576 cases and 680 controls).Results.Through logistic regression, we built the AS-GRS model consisting of 5 genetic components: HLA-B27, 3 CNV (1q32.2, 13q13.1, and 16p13.3), and 1 SNP (rs10865331). All significant associations of genetic factors in the model were replicated in the independent validation set. The discriminative ability of the AS-GRS model measured by the area under the curve was excellent: 0.976 (95% CI 0.96–0.99) in the model construction set and 0.951 (95% CI 0.94–0.96) in the validation set. The AS-GRS model showed higher specificity and accuracy than the HLA-B27–only model when the sensitivity was set to over 94%. When we categorized the individuals into quartiles based on the AS-GRS scores, OR of the 4 groups (low, intermediate-1, intermediate-2, and high risk) showed an increasing trend with the AS-GRS scores (r2 = 0.950) and the highest risk group showed a 494× higher risk of AS than the lowest risk group (95% CI 237.3–1029.1).Conclusion.Our AS-GRS could be used to identify individuals at high risk for AS before major symptoms appear, which may improve the prognosis for them through early treatment.

ObjectiveTo demonstrate pharmacokinetic equivalence of CT-P10 and innovator rituximab (RTX) in patients with rheumatoid arthritis (RA) with inadequate responses or intolerances to antitumour necrosis factor agents.MethodsIn this randomised phase I trial, patients with active RA were randomly assigned (2:1) to receive 1000 mg CT-P10 or RTX at weeks 0 and 2 (alongside continued methotrexate therapy). Primary endpoints were area under the serum concentration–time curve from time zero to last quantifiable concentration (AUC0–last) and maximum serum concentration after second infusion (Cmax). Additional pharmacokinetic parameters, efficacy, pharmacodynamics, immunogenicity and safety were also assessed. Data are reported up to week 24.Results103 patients were assigned to CT-P10 and 51 to RTX. The 90% CIs for the ratio of geometric means (CT-P10/RTX) for both primary endpoints were within the bioequivalence range of 80%–125% (AUC0–last: 97.7% (90% CI 89.2% to 107.0%); Cmax: 97.6% (90% CI 92.0% to 103.5%)). Pharmacodynamics and efficacy were comparable between groups. Antidrug antibodies were detected in 17.6% of patients in each group at week 24. CT-P10 and RTX displayed similar safety profiles.ConclusionsCT-P10 and RTX demonstrated equivalent pharmacokinetics and comparable efficacy, pharmacodynamics, immunogenicity and safety.Trial registration numberNCT01534884.

Aim There is growing evidence that cold-inducible RNA-binding protein (CIRP) promotes inflammatory responses. This study investigated the relationship between CIRP and rheumatoid arthritis (RA). Methods Peripheral blood and synovial fluid were collected from 15 patients with RA and from 16 patients with osteoarthritis (OA). The concentration of CIRP was measured with the sandwich enzyme-linked immunosorbent assay (ELISA). Results The concentration of serum CIRP was significantly elevated in the RA patient group (RA patients = 26.39 ± 10.48 pg/mL, OA patients = 17.14 ± 7.24 pg/mL, P = 0.009). Furthermore, the RA patient group had a significantly higher CIRP concentration than that of the OA patient group in synovial fluid (153.56 ± 108.93 pg/mL vs. 23.63 ± 16.18 pg/mL, P < 0.001). The mean synovial fluid concentration of CIRP was significantly higher than that of the serum concentration in the RA patient group (serum concentration = 26.39 ± 10.48 pg/mL, synovial fluid = 153.56 ± 108.93 pg/mL, P < 0.001). Disease Activity Score of 28 joints (DAS28)-ESR (erythrocyte sedimentation rate) and DAS28-CRP (C-reactive protein) were positively correlated with the synovial fluid concentration of CIRP (DAS28-ESR: r = 0.582, P = 0.023; DAS28-CRP: r = 0.541, P = 0.037). Conclusion The serum and synovial concentrations of CIRP in the RA patients were increased compared to the OA patients. Additionally, the synovial concentration of CIRP in RA patients correlated well with disease activity, that is, the DAS28-ESR/CRP. Based on these results, CIRP mediates inflammation and is a potential marker for synovial inflammation.

ObjectivesTo evaluate equivalence in efficacy for rheumatoid arthritis (RA) and compare the safety of the biosimilar HD203 with innovator etanercept (ETN) plus methotrexate (MTX) (ClinicalTrials.govNCT01270997).MethodsPatients with active RA received 25 mg HD203 or ETN subcutaneously twice-weekly with MTX for 48 weeks in a phase III, multicentre, randomised, double-blind, parallel-group design. The primary end point was the proportion of patients achieving the American College of Rheumatology 20% response (ACR20) at week 24 for per-protocol study completer set (PPS). Secondary end points included ACR response criteria, ACRn, European League against Rheumatism (EULAR) response, change in Disease Activity Score 28 (DAS28), patient-reported outcomes, safety and immunogenicity.ResultsOf the 294 randomised patients (HD203, n=147; ETN, n=147), 233 comprised the 24-week PPS (n=115 and 118, respectively). ACR20 at week 24 was achieved by 83.48% and 81.36% of PPS patients, respectively, demonstrating equivalent efficacy within predefined margins of ±20% (treatment difference 2.12%, 95% CI −7.65% to 11.89%). Outcomes for secondary end points were consistent with the primary efficacy findings. Groups were comparable for overall incidences of treatment-emergent (all-causality) adverse events (AEs) (HD203 113 (76.9%) vs ETN 114 (78.1%) (p=0.804)), adverse drug reactions, serious AEs and discontinuations due to AEs. Few patients (HD203, n=8; ETN, n=3) tested positive for anti-drug antibodies.ConclusionThe study met the primary objective of demonstrating equivalent efficacy of HD203 and ETN. HD203 was well tolerated, with safety comparable with ETN in this population of patients with RA.Trial registration numberNCT01270997; Results.

Background:Ankylosing Spondylitis (AS) is a chronic inflammatory rheumatic disease, which is characterized by the enthesitis, peripheral arthritis, and chronic inflammation of the spine, leading to bony ankylosis. Signal transducer and activator of transcription (STAT) family proteins are latent cytoplasmic transcription factors that convey signals to the nucleus. It is activated by IL-6, IL-23, and IL-22 through JAK-mediated phosphorylation. Moreover, genetic studies implicate interleukin-23 (IL-23) receptor signal, including STAT3 in the development of AS. IL-17A has recently emerged as a potential target that regulates the extensive inflammation and abnormal bone formation observed in AS. It was reported that STAT3 is a regulatory factor that induces Th17 cell development from naive CD4 T cells.Objectives:The aim of this study is to investigate whether the STAT3 phosphorylation (stat3-p) inhibitor has a therapeutic effect on inflammation and new bone formation in AS.Methods:Eight weeks after curdlan injection, SKG mice were treated with stat3-p inhibitor or mock as a control. Clinical and histologic scores for arthritis and enthesitis were evaluated. Synovial fluid mononuclear cells (SFMC) samples were obtained from AS patients. Inflammatory cytokine producing cells were analyzed using flow cytometry. Bone tissue samples were obtained from the facet joints of patients with AS at surgery. Primary bone-derived cells (BdCs) were isolated and cultured. The osteogenic differentiation was assessed in vitro for 3 weeks using ALP activity, Alizarin red S (ARS), Type I collagen, von kossa,and hydroxyapatitestains. Statistical analysis was performed using Prism 5.0 Software. A p < 0.05 was considered statistically significant.Results:The stat3-p inhibitor significantly suppressed peripheral arthritis and enthesitis in SKG mice (figure 1). Inflammatory infiltration around the tendon–bone insertion site and along the tendon, as well as bony involvement were all reduced in stat3-p inhibitor-treated mice compared to control mice. We found that the levels of IFN-±, IL-17, TNF-± were higher in AS Synovial fluid. A significantly decreased frequencies of IFN-±, IL-17, TNF-± producing cells in AS SFMC were shown after stat3-p inhibitor treatment (P < 0.01).In vitro experiment of bone formation, the stat3-p inhibitor suppressed ALP activity. In addition, there were significant decrease in Alizarin red S (ARS), Type I collagen, von kossa staining scores due to stat3-p inhibitor at a concentration of 5 μM.Light intensity of hydroxyapatitestaining was also decreased by stat3-p inhibitor in a dose dependent manner (figure 2). Intriguingly, the stat3-p inhibitor suppressed osteogenesis in both early phase and late phase in AS-BdCs, down-regulating osteoblast-involved genes.Conclusion:The stat3-p inhibitor had beneficial effects on reducing inflammation and new bone formation in AS animal model. In addition, stat3-p inhibitor suppressed bone formation in vitro experiment. These findings suggest that the stat3-p inhibitor could be a potential therapeutic agent for AS.References:[1]Arthritis Res Ther 2018;20:115.[2]Nat Med 2012;18:1069-76.[3]Rheumatology (Oxford) 2017;56:488-493.[4]Nat Rev Immunol. 2011;11:239–50.[5]J Exp Med 2005;201:949–60.Acknowledgments:NoneDisclosure of Interests:None declared

This study compared the performance of the newly proposed 2016 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) criteria to the 2002 American-European Consensus Group (AECG) and 2012 ACR classification criteria for primary Sjogren's syndrome (pSS) in well-characterized Korean patients. Patients with pSS from 12 university-affiliated hospitals in Korea were enrolled from October 2013 to January 2017. Clinical and laboratory data were reviewed. For the validation set, patients who underwent evaluation tests to rule out pSS at Seoul St. Mary's hospital from November 2016 to December 2017 were analyzed. Baseline registry data were available in 458 patients, and 328 patients had sufficient data to determine the fulfillment of each criteria set. All three sets of criteria were met by 307 patients (93.6%). The newly proposed 2016 ACR/EULAR criteria were met by 325 patients (99.1%). The 2002 AECG and 2012 ACR criteria were met by 325 (99.1%) and 310 patients (94.5%), respectively. In a validation cohort consisting of 161 patients with pSS-related symptoms/signs, the sensitivity and specificity of the 2016 ACR/EULAR criteria were 100% [95% confidence interval (CI), 96.11-100.00] and 81.8% [95% CI, 76.15-94.26], respectively. Agreement between the 2016 criteria and 2012 or 2002 criteria was high (Cohen's kappa 0.736 and 0.769, respectively). The newly proposed 2016 ACR/EULAR criteria were met by most patients diagnosed with pSS according to previous criteria and showed higher sensitivity and lower specificity compared with both previous criteria sets.

OBJECTIVE Anti-transcriptional intermediary factor 1 (TIF1) antibody is associated with idiopathic inflammatory myopathies (IIMs). The aim of this study was to investigate the expression of TIF1s in IIMs. METHOD TIF1α, β or γ expression in the skin and muscle of patients and controls was studied by immunohistochemistry. Serum myositis-specific autoantibodies were detected by immunoblot. RESULTS TIF1α was expressed in the skin of most dermatomyositis (DM) patients but not in the controls (80% vs 0%, P

OBJECTIVES: This study aims to examine the effects of tocilizumab therapy on serum levels of interleukin (IL)-33 and IL-6 in rheumatoid arthritis (RA) patients. PATIENTS AND METHODS: Interleukin-33 and IL-6 levels in serum samples from 83 RA patients (10 males, 73 females; mean age 51.9 years; range, 26 to 77 years) and 12 healthy controls (2 males, 10 females; mean age 52.2 years; range, 39 to 62 years) were compared by cross-sectional, case control analysis. Of the RA patients, 40 received 24 weeks of tocilizumab therapy and were assigned to the prospective cohort. These 40 patients were then divided into two subgroups as responders and non-responders according to the American College of Rheumatology (ACR) 20. The remaining 43 RA patients did not receive tocilizumab therapy. Serum cytokine levels were analyzed at baseline and after 24 weeks of tocilizumab therapy in these patients. RESULTS: Interleukin-33 and IL-6 concentrations were significantly higher in RA patients than in healthy controls (p

N-3 polyunsaturated fatty acids (PUFA) have anti-inflammatory effects and were considered useful for the treatment of rheumatoid arthritis (RA). Recently, several studies suggested that n-3 PUFAs attenuated arthritis in animal model and human, however the mechanism is still unclear. Interleukin 17 (IL-17) is a pro-inflammatory cytokine mainly produced by T helper 17 (Th17) cells which cause tissue inflammation and bone erosion leading to joint destruction. In contrast, regulatory T (Treg) cells down-regulate various immune responses by suppression of naive T cells. The imbalance between Th17 cells and Tregs cell is important for the pathogenesis of RA. Here, we investigated whether n-3 PUFAs attenuate arthritis in collagen antibody-induced arthritis (CAIA) model. We used fat-1 transgenic mice expressing the Caenorhabditis elegans fat-1 gene encoding an n-3 fatty acid desaturase that converts n-6 to n-3 fatty acids, leading to abundant n-3 fatty acids without the need of a dietary n-3 supply. Clinical arthritis score was significantly attenuated in fat-1 mice compared to wild type (WT) mice on day 7 (1.6±1.8, p = 0.012) and day 9 (1.5±1.6, p = 0.003). Ankle thickness also decreased significantly in fat-1 mice compared to WT mice (1.82±0.11, p = 0.008). The pathologic finding showed that inflammatory cell infiltration and bone destruction were reduced in fat-1 mice compared to WT. The expression levels of IL-17 and related cytokines including IL-6 and IL-23 decreased in the spleen and ankle joint tissue of fat-1 mice compared to WT mice. Furthermore, Treg cells were expanded in the spleen of fat-1 mice and Treg cell differentiation was significantly higher in fat-1 mice than in wild type (p = 0.038). These data suggest that n-3 PUFAs could attenuate arthritis through increasing the expression of FoxP3 and the differentiation of Treg, while reducing IL-17 production. Therefore, dietary supplementation of n-3 PUFAs could have a therapeutic potential for the treatment of RA.

Background High body mass index (BMI) is known to be associated with inadequate clinical response to anti-TNF agents in rheumatoid arthritis (RA) patients. 1 However, there are limited data on the effect of high BMI on the response to rituximab in RA patients, who showed an inadequate response or intolerance to anti-TNF agents. Objectives To investigate the impact of BMI on clinical response in the post-hoc analysis of randomized controlled trial that demonstrated clinical equivalence between a biosimilar of rituximab, CT-P10 and innovator rituximab, RTX 2 (NCT02149121). Methods A total of 332 patients who received two courses of either CT-P10 or RTX were included in this analysis. Patients were classified into 3 groups; normal weight ( 2 ), overweight (≥25 kg/m 2 ) and obesity (≥30 kg/m 2 ) as per WHO BMI category. Improvement in disease activity by the Disease Activity Score using C-reactive protein (DAS28-CRP), remission (≤2.6), low disease activity rate (LDA, ≤3.2) and ACR response at Week 24 (Week 24 of 1st course) and Week 48 (Week 24 of 2nd course) and duration of sustained LDA (from the first LDA observed to the last LDA observed up to Week 48) were analysed by BMI categories in the each and combined group of CT-P10 and RTX. Results In the pooled group of CT-P10 and RTX, the mean weights were 59 kg in normal weight, 73kg in overweight and 91kg in obesity. All other baseline characteristics were comparable among BMI groups including baseline disease activity based on DAS28; Moderate disease activity, 22.3% vs. 22.8% vs. 25.7%, respectively; High disease activity, 77.7% vs. 77.2% vs. 74.3%, respectively. There was no statistical difference among BMI groups in terms of DAS28 change from baseline and ACR 20/50/70 response (Table). No particular trend was observed in remission and LDA rate by DAS28 at Week 24 and Week 48 among BMI groups (Figure). Mean duration of sustained LDA (months) were also comparable among the groups (4.5 vs. 4.7 vs. 5.0, respectively). Additionally, similar trends in all analyses were observed in each treatment group; CT-P10 and RTX. Conclusions The BMI does not affect the clinical response in RA patients with rituximab treatment. Therefore, this result supports that rituximab could be a reasonable therapeutic option for obese RA patients with inadequate response to anti-TNF agents. References Gremese E et al. Arthritis Care Res (Hoboken) 2013;65:94–100. Yoo DH, et al. American College of Rheumatology 2016; Abstract No. 1635. Disclosure of Interest D. H. Yoo Consultant for: Celltrion Inc., W. Park Consultant for: Celltrion Inc., C. H. Suh Consultant for: Celltrion Inc., S. C. Shim Consultant for: Celltrion Inc., S. J. Lee Employee of: Celltrion Inc., Y. J. Bae Employee of: Celltrion Inc., C. Park Employee of: Celltrion Inc., J. H. Koo Employee of: Celltrion Inc.

Objective To identify ankylosing spondylitis (AS)–associated copy number variations (CNVs) in Korean subjects and their synergistic roles in the development of AS. Methods A genome-wide association study (GWAS) was performed in 309 patients with AS and 309 control subjects, using a copy number variant (CNV) microarray. AS-associated CNV regions were replicated in 2 independent sets (625 patients and 891 control subjects) by quantitative polymerase chain reaction (PCR) and deletion-typing PCR. Results In the CNV GWAS, 227 CNV regions were shown to be significantly associated with the risk of AS. Of the candidate CNV regions, 9 were successfully replicated in the first replication analysis: 1q32.2 (HHAT), 1p34.2 (BMP8A), 2q31.2 (PRKRA), 6p21.32 (HLA–DPB1), 11q22.1 (CNTN5), 13q13.1 (EEF1DP3), 14q24.2 (RGS6), 16p13.3, and 22q11.1 (IL17RA). The 5 deletion-type CNV regions, in 1q32.2, 2q31.2, 6p21.32, 13q13.1, and 16p13.3, were associated with an increased risk of AS, and the other 4 CNV regions were protective. In the second replication analysis, 4 CNV regions in 1q32.2, 2q31.2, 6p21.32, and 16p13.3 were replicated. Among patients with CNV regions in ≥4 risk-increasing loci, the risk was 18.0 times higher than that in patients without any deletions (odds ratio [OR] 17.98, P = 2.3 × 10−7). Among patients with CNV regions in ≥2 protective loci, the risk was 5.2 times lower than that in those without any deletions (OR 0.19, P = 4.0 × 10−10). The additive effects of simultaneous events were shown to be dependent on the frequency of CNV regions. Through deletion-typing PCR and sequencing, the exact sizes and breakpoint sequences were defined in 4 CNV regions. The mechanism of all 3 deletions was shown to be microhomology-based nonhomologous end joining. Conclusion The results of this study can help to identify pathogenic mechanisms of AS and can easily be applied in the development of algorithms estimating the risk of AS.

The objectives of the study are to demonstrate the non-inferiority of PG201 (Layla®) 600 mg in comparison with celecoxib 200 mg for the treatment of symptomatic knee osteoarthritis (OA). In total, 309 patients were randomly assigned to receive either the test drug, PG201 600 mg (n = 154) or celecoxib 200 mg (n = 155). The primary efficacy variable was improvement in mean 100-mm pain VAS score from baseline to the final visit (week 8), and this value was compared between the 2 treatment groups. Secondary outcome variables included changes from baseline in the Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain VAS score and subscale score, patient’s global assessment of disease status quality of life (short form-36) and responder index at weeks 4 and 8. For safety assessment, adverse events were recorded at each clinical visit. At weeks 8, the 100-mm pain VAS scores were significantly decreased in patients receiving both PG201 600 mg (p

Dermatomyositis (DM) and polymyositis (PM) are representative idiopathic inflammatory myopathies characterized by symmetric and progressive proximal muscle weakness. Especially, DM is identified by characteristic skin lesions and has many extramuscular manifestations including various cardiac abnormalities, interstitial lung disease, and malignancy. However, involvement of peripheral nervous system in DM/PM is very rare and less known. The term “Neuromyositis” was introduced by Senator in 1893 to describe the concomitant involvement of the peripheral nervous system in DM/PM. Since then, a very few cases of neuromyositis have been reported mainly in the United States and Europe. Therefore, the pathogenetic mechanism and disease progression are unclear. In recent years, a few more cases were reported in Asia, specifically, China and Japan; however, none in Korea. Here, we describe a case of DM-associated neuromyositis in a 42-year-old man in Korea and review previous publications through literature research. (J Rheum Dis 2019;26:211-218)

Objectives To identify novel genetic candidates for systemic lupus erythematosus (SLE) in the Korean population, and to validate the risk loci for SLE identified in previous genome-wide association studies (GWAS). Methods We performed a GWAS in 400 Korean female SLE patients and 445 controls. Selected single-nucleotide polymorphisms (SNP) were then replicated in an independent cohort of 385 SLE patients and 583 controls (replication cohort 1), and in a further 811 SLE patients and 1502 controls (replication cohort 2). Results In the GWAS phase, rs9275428 located near HLA-DQB1 showed the strongest association with SLE (OR 0.50, false discovery rate (FDR) p=3.07×10 −6 ). Although no loci reached genome-wide significance outside major histocompatibility complex (MHC), C8orf13-BLK, STAT4 , CSMD1 , DIAPH3 , GLDC and TNFSF4 showed FDR p STAT4 , BLK , IRF5 , PTTG1-miR-146a , UBE2L3 and TNFAIP3 are shared susceptibility loci among Caucasians and Asians, while ETS1 , IKZF1 , SLC15A4 are likely to be Asian-specific loci. In a combined analysis of 1596 SLE patients and 2540 controls for selected 22 candidate SNP, STAT4 and BLK as positive controls showed a strong association with SLE (FDR p=9.85×10 −13 and 2.28×10 −8 , respectively). Of these, 16 candidates ( PEX5L , TRAJ50 , MYO18B , SOS1 , ARHGAP26 , SMURF1 , CADPS , HAND1 , FAM78B , DIAPH3 , TBL1XR1 , CSMD1 , ZBTB20 , C3orf21 , HIPK1 and AP001042.1 ) showed only nominal significance (7.05×10 −4 ≤FDR p≤4.38×10 −2 ). Conclusions There are similarities and differences in genetic susceptibility for SLE between Caucasian and Asian ethnic groups. Although 16 putative novel loci for SLE have been suggested in the Korean population, further research on a larger sample is required to discriminate truth from error.

Lung diseases (LD) are common extra-articular manifestations in rheumatoid arthritis (RA). However, little is known about factors associated with susceptibility to rheumatoid arthritis-related lung diseases (RA-LD). The aim of the present study was to investigate whether the single nucleotide polymorphisms (SNPs) of PADI4 and HLA-DRB1 alleles were associated with RA-LD. Blood samples and clinical data were collected from 116 consecutive RA patients who satisfied the 1987 American College of Rheumatology classification criteria. RA-LD was diagnosed using high-resolution computed tomography of the chest. All patients were genotyped for SNPs of PADI4 and HLA-DRB1 alleles and analyzed for full amino acid sequence of the HLA protein corresponding to a 4-digit HLA typing. Data were analyzed by independent t test (or Mann–Whitney test) for continuous variables, Chi-square test (or Fisher’s exact test) and trend test for categorical variables, and logistic regression analysis. Ninety-four (81.0 %) RA patients had LD, of which eight (6.9 %) had interstitial lung disease (ILD) and 92 (79.3 %) had airway abnormalities in which 64 (55.2 %) showed bronchiectasis and 47 (40.5 %) revealed bronchial wall thickening. The recessive genotype of padi4_92 was susceptible to airway abnormalities (OR = 2.22, 95 % CI = 1.05–4.49, p = 0.034). Tryptophan at position 9 of HLA-DRB1 sequence was associated with the susceptibility to RA-ILD (OR = 22.89, 95 % CI = 1.20–432.56, p = 0.037). PADI4 polymorphisms and HLA-DRB1 alleles could attribute differently to the development of airway abnormalities and ILD, respectively, in RA.

Backgrounds Patients who develop an active tuberculosis infection during tumor necrosis factor (TNF) inhibitor treatment typically discontinue TNF inhibitor and receive standard anti-tuberculosis treatment. However, there is currently insufficient information on patient outcomes following resumption of TNF inhibitor treatment during ongoing anti- tuberculosis treatment. Our study was designed to investigate the safety of resuming TNF inhibitors in ankylosing spondylitis (AS) patients who developed tuberculosis as a complication of the use of TNF inhibitors. Methods Through the nationwide registry of the Korean Society of Spondyloarthritis Research, 3929 AS patients who were prescribed TNF inhibitors were recruited between June 2003 and June 2014 at fourteen referral hospitals. Clinical information was analyzed about the patients who experienced tuberculosis after exposure to TNF inhibitors. The clinical features of resumers and non-resumers of TNF inhibitors were compared and the outcomes of tuberculosis were surveyed individually. Findings Fifty-six AS patients were treated for tuberculosis associated with TNF inhibitors. Among them, 23 patients resumed TNF inhibitors, and these patients were found to be exposed to TNF inhibitors for a longer period of time and experienced more frequent disease flare-up after discontinuation of TNF inhibitors compared with those who did not resume. Fifteen patients resumed TNF inhibitors during anti-tuberculosis treatment (early resumers) and 8 after completion of anti-tuberculosis treatment (late resumers). Median time to resuming TNF inhibitor from tuberculosis was 3.3 and 9.0 months in the early and late resumers, respectively. Tuberculosis was treated successfully in all resumers and did not relapse in any of them during follow-up (median 33.8 [IQR; 20.8-66.7] months). Conclusions Instances of tuberculosis were treated successfully in our AS patients, even when given concomitantly with TNF inhibitors. We suggest that early resumption of TNF inhibitors in AS patients could be safe under effective coverage of tuberculosis.

The genetic association of HLA-DRB1 with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) is well documented, but association with other HLA-DR beta genes (HLA-DRB3, HLA-DRB4 and HLA-DRB5) has not been thoroughly studied, despite their similar functions and chromosomal positions. We examined variants in all functional HLA-DR beta genes in RA and SLE patients and controls, down to the amino-acid level, to better understand disease association with the HLA-DR locus. To this end, we improved an existing HLA reference panel to impute variants in all protein-coding HLA-DR beta genes. Using the reference panel, HLA variants were inferred from high-density SNP data of 9,271 RA-control subjects and 5,342 SLE-control subjects. Disease association tests were performed by logistic regression and log-likelihood ratio tests. After imputation using the newly constructed HLA reference panel and statistical analysis, we observed that HLA-DRB1 variants better accounted for the association between MHC and susceptibility to RA and SLE than did the other three HLA-DRB variants. Moreover, there were no secondary effects in HLA-DRB3, HLA-DRB4, or HLA-DRB5 in RA or SLE. Of all the HLA-DR beta chain paralogs, those encoded by HLA-DRB1 solely or dominantly influence susceptibility to RA and SLE.

Objective. To estimate the prevalence of non-adherence to rheumatoid arthritis (RA) medication and identify the associated factors for non-adherence in RA patients. Methods. Among the KORean Observational study Network for Arthritis 3,523 patients who completed a questionnaire about the adherence to RA medication were analyzed. The patients were divided into two groups: 1) adherent group, patients who skipped medication ≤5 days within the past 2 months; and 2) non-adherent group, patients who skipped ≥6 days of medication. The baseline characteristics were compared, and multivariable regression analysis was performed to identify the associated factors for non-adherence. Results. The non-adherent group had 339 patients (9.6%). The common causes of non-adherence were forgetfulness (45.8%), absence of RA symptoms (24.7%), and discomfort with RA medication (13.1%). Younger age (odds ratio [OR] 1.02, p＜0.01) and higher income (OR 1.70, p＜0.01) were associated with an increased risk of non-adherence. Whereas higher functional disability (OR 0.68, p＜0.01) and oral corticosteroid use (OR 0.73, p=0.02) were associated with a decreased risk of non-adherence. The associated factors differed according to cause of non-adherence. Having adverse events (OR 2.65, p=0.02) was associated with the risk of non-adherence due to discomfort with RA medication while a higher level of education (OR 2.37, p=0.03) was associated with the risk of non-adherence due to an absence of RA symptoms. Conclusion. The 9.6% of Korean RA patients were non-adherent to RA medication. The associated factors differed according to the cause of non-adherence. Therefore, an individualized approach will be needed to improve the adherence to RA medication. (J Rheum Dis 2018;25:47-57)

Supported by grants from the NIH (5P01-AI-083194 to Drs. Lessard, Rasmussen, Gaffney, Alarcon-Riquelme, Criswell, Jacob, Kimberly, Vyse, Harley, Sivils, Langefeld, and Tsao; 5P01-AR-049084 to Drs. Kimberly and Langefeld; and R01-AR-043814 and R21-AR-065626 to Dr. Tsao), the Oklahoma Medical Research Foundation (to Drs. Lessard, Gaffney, and Sivils), the Alliance for Lupus Research (to Drs. Criswell and Tsao), and the Wake Forest School of Medicine Center for Public Health Genomics (to Dr. Langefeld). Dr. Criswell is recipient of a Kirkland Scholar Award. Sample collection and phenotyping of the subjects utilized in this study was funded by the Ministry for Health and Welfare, Republic of Korea (Korea Healthcare Technology R&D Project grant HI13C2124 to Dr. Bae, and HI13C1754 to Dr. Song). The out-of-study Korean control data were provided by the Korean Biobank Project, which is supported by the Korea Centers for Disease Control and Prevention at the Korea National Institute of Health.

Introduction The presence of the HLA-B*27 allele is a major risk factor for the development of ankylosing spondylitis (AS), which causes chronic inflammation of the spine and other sites. We investigated residual effects outside HLA-B within the major histocompatibility complex (MHC) region in the Korean population. Methods Using the Korean HLA reference panel, we inferred the classic HLA alleles and amino-acid residues of the six HLA genes (HLA-A, -B, -C,-DPB1, -DQB1, and -DRB1) and MHC single-nucleotide polymorphisms in 3820 Korean subjects, including 654 Korean cases of AS and 3166 controls, who were genotyped by using Immunochip. Logistic regression and log-likelihood ratio tests were used in AS association tests for imputed markers. Results The most significant associations were identified at amino-acid positions in the epitope-binding site of HLA-B (P = 1.71 × 10−481 at position 70, P = 7.20 × 10−479 at position 97, and P = 2.54 × 10−484 at positions 114), highlighting the risk effect of the HLA-B*27 allele and the protective effects of other classic alleles. A secondary effect was located at the leucine at amino-acid position 116 in the epitope-binding site of HLA-C (P = 1.69 × 10−14), completely tagging the HLA-C*15:02 allele. This residue had a large effect in HLA-B*27-negative patients (odds ratio = 6.6, 95 % confidence interval = 3.8 to 11.4). Conclusions The four amino-acid positions of HLA-B and -C account for most of the associations between AS and MHC in the Korean population. This finding updates the list of AS susceptibility loci and provides new insight into AS pathogenesis mediated by MHC class I molecules. Electronic supplementary material The online version of this article (doi:10.1186/s13075-015-0855-3) contains supplementary material, which is available to authorized users.

The aim of this study was to estimate the mapping model for EuroQol-5D (EQ-5D) utility values using the health assessment questionnaire disability index (HAQ-DI), pain visual analog scale (VAS), and disease activity score in 28 joints (DAS28) in a large, nationwide cohort of rheumatoid arthritis (RA) patients in Korea. The KORean Observational study Network for Arthritis (KORONA) registry data on 3557 patients with RA were used. Data were randomly divided into a modeling set (80 % of the data) and a validation set (20 % of the data). The ordinary least squares (OLS), Tobit, and two-part model methods were employed to construct a model to map to the EQ-5D index. Using a combination of HAQ-DI, pain VAS, and DAS28, four model versions were examined. To evaluate the predictive accuracy of the models, the root-mean-square error (RMSE) and mean absolute error (MAE) were calculated using the validation dataset. A model that included HAQ-DI, pain VAS, and DAS28 produced the highest adjusted R (2) as well as the lowest Akaike information criterion, RMSE, and MAE, regardless of the statistical methods used in modeling set. The mapping equation of the OLS method is given as EQ-5D = 0.95-0.21 × HAQ-DI-0.24 × pain VAS/100-0.01 × DAS28 (adjusted R (2) = 57.6 %, RMSE = 0.1654 and MAE = 0.1222). Also in the validation set, the RMSE and MAE were shown to be the smallest. The model with HAQ-DI, pain VAS, and DAS28 showed the best performance, and this mapping model enabled the estimation of an EQ-5D value for RA patients in whom utility values have not been measured.

Objective.Rheumatoid arthritis (RA) is a chronic autoimmune disease that is often painful and debilitating. Patients with RA are increasingly receiving complementary and alternative medicine (CAM). We aimed to identify the patient characteristics and disease-specific factors associated with Korean patients with RA who decide to start treatment with CAM.Methods.Among the total 5371 patients with RA in the KORean Observational study Network for Arthritis (KORONA), 2175 patients who had no experience with CAM were included in our study. In our study, we assessed the frequency of new incident CAM use, its patterns, and the predictive factors of new CAM use.Results.Of the 2175 patients, 229 patients (10.5%) newly started receiving CAM within a year of enrolling in the cohort. Of those who started treatment with CAM, 17.0% received only herbal medicine, 54.6% only acupuncture treatments (7.0% used a combination of both), and 21.4% “Other” (e.g., physical therapy and placental extract injections). Women (OR 1.89, 95% CI 1.13–3.14) and patients with depression (OR 3.52, 95% CI 1.65–7.50) were significantly more likely to be treated with CAM. Regarding household types, patients who lived in an extended family (OR 1.78, 95% CI 1.08–2.95) or as part of a couple (OR 1.55, 95% CI 1.07–2.24) were more likely to be treated with CAM than patients living in a nuclear family.Conclusion.Our study found, within a year, an incidence rate of 10.5% for new CAM use among patients with no previous experience with CAM. Sex, depression, and household type were significantly associated with new CAM use.

The aim of this study was to compare anti-tumor necrosis factor-α (TNFα) treatment status in rheumatoid arthritis (RA) patients with the Korean National Health Insurance (KNHI) reimbursement eligibility criteria and with American College of Rheumatology (ACR) recommendations, Japan College of Rheumatology (JCR) guidelines and British Society for Rheumatology (BSR) guidelines. Between December 2011 and August 2012, outpatients from 17 South Korean general hospitals diagnosed with RA according to the 1987 ACR criteria were enrolled into a noninterventional, cross-sectional, observational study. Of 1700 patients (1414 female (83.2 %), mean age of 56.6 ± 12.0, mean disease duration 97.9 ± 91.8 months), 306 (18.0 %) had used anti-TNFα agents, and 224 (13.2 %) were currently using an anti-TNFα agent. Of 1394 anti-TNFα-naive patients, 32 (2.3 %) met KNHI reimbursement guidelines, 148 (10.6 %) met ACR recommendations, and 127 (9.1 %) and 126 (9.0 %) were considered eligible for anti-TNFα agents according to JCR and BSR guidelines, respectively. The main discrepancy was the higher active joint count required by the KNHI eligibility criteria. In the opinion of treating rheumatologists, the KNHI reimbursement criteria ineligibility accounted for 15.3 % (n = 213) of the reasons for not initiating anti-TNFα agents in anti-TNFα-naive group. The anti-TNFα user group showed significantly higher disease activity than the anti-TNFα-naive group based on DAS28 score. In comparison with the ACR recommendations and JCR and BSR guidelines, fewer patients met KNHI reimbursement eligibility criteria for anti-TNFα agents. The current amendment of the KNHI criteria based on DAS28 score will improve an access to biologic agents including anti-TNFα treatment for South Korean patients with active RA.

The association of endoplasmic reticulum aminopeptidase 2 (ERAP2) with ankylosing spondylitis (AS) was recently described in the large International Genetics of AS Consortium Immunochip study. Variants in ERAP2 have also been associated with inflammatory bowel disease, psoriasis, acute anterior uveitis and birdshot chorioretinopathy. Subsequent investigation demonstrated an association of ERAP2 with AS which was present when one conditioned on one of the two independent haplotypes of ERAP1 associated with AS or when HLA-B27-negative patients were analysed separately. These two analyses provide analogous evidence for the association of ERAP2 with AS in HLA-B27-negative cases because of the genetic interaction between HLA-B27 and the AS-associated ERAP1 variants in AS cases. ERAP1 and ERAP2 are located on chromosome 5q15 in the opposite orientation. The locus is challenging to analyse because of the strong linkage disequilibrium (LD) across the locus and the epistasis between ERAP1 and HLA-B alleles associated with AS. We therefore sought to investigate the association of ERAP2 with AS in HLA-B27-positive patients. This is of clinical importance because functional studies have demonstrated that the strongly AS-protective variant rs2248374 causes a functional ERAP2 protein knockout, because its G allele causes a loss of ERAP2 protein expression. There is also a variant of ERAP2 which changes its enzyme catalytic activity and specificity (rs2549782, K392A). Because this is in almost complete LD with rs2248374 (1000 Genomes D′=1.00, r2=0.90), it is almost never translated in vivo. Further, the very strong LD between these markers means that analysis of rs2549782 for association would yield results almost identical to the results for rs2248374 presented below. Therefore, it is of relevance to determine whether the association of ERAP2 with HLA-B27-negative disease is also found in HLA-B27-positive cases, since ERAP inhibition may offer a novel therapeutic for AS...

The aim of this study was to determine whether peptidyl arginine deiminase (PADI) genes could affect susceptibility to tuberculosis (TB), which can be a presumptive base to explain the increased incidence of TB in patients with rheumatoid arthritis (RA) in Korean. The study population consisted of 47 patients with active TB, 35 patients with nontuberculous mycobacterial disease, 50 RA patients, and 83 healthy controls who had received comprehensive medical testing. Genomic DNA was isolated from peripheral blood mononuclear cells using a standard protocol. All of the patients and healthy controls were genotyped for two nonsynonymous SNPs in PADI4, namely PADI4_89, PADI4_90, and one synonymous SNP in PADI4_104. There was the complete linkage between PADI4_89 and PADI4_90 SNPs. In the allele and haplotype analyses of PADI4_89 and PADI4_104, no significant associations are observed between disease groups and control groups. The frequencies of heterozygote (A/G) for PADI4_89 were significantly lower in patients with active TB than in controls [adjusted odd ratios (OR) = 0.35, p values = 0.020]. When the analysis was conducted by overdominant model, more significant associations are observed (adjusted OR = 0.34, p values = 0.005). We found that heterozygote genotypes for PADI4_89 were protectively associated with susceptibility to TB.

To the Editor: Ankylosing spondylitis (AS) is a chronic inflammatory disorder characterized by progressive and destructive arthritis of the spine and pelvis1. B cells are involved in the pathogenesis of autoimmune diseases through antibody production, cytokine release, and antibody presentation to auto-reactive T cells. In AS, the role of B cells in the pathogenesis is still incompletely understood2. It has been hypothesized that the production of high affinity monoreactive autoantibodies in autoimmune disease could arise from intrinsic abnormalities in the generation of immunoglobulin genes3. Immunoglobulin gene usage can be regarded as an important factor of pathogenesis of autoimmune diseases. Investigation of variable heavy chain (VH) gene usage is important for determining whether usage of particular gene families is distorted. Several studies have investigated the VH gene usage in various autoimmune diseases, including systemic lupus erythematosus4, myasthenia gravis5, rheumatoid arthritis (RA)6, Sjogren syndrome7, and AS8 … Address correspondence to Dr. S-C. Shim, Division of Rheumatology, Department of Medicine, Daejeon Rheumatoid and Degenerative Arthritis Center, Chungnam National University Hospital, 6 munwha-ro Jung-gu, Daejeon, South Korea. E-mail: shimsc{at}cnuh.co.kr

Background and Object Nearly 25 genetic loci associated with susceptibility to ankylosing spondylitis (AS) have been identified by several large studies. However, there have been limited studies to identify the genes associated with radiographic severity of the disease. Thus we investigated which genes involved in bone formation pathways might be associated with radiographic severity in AS. Methods A total of 417 Korean AS patients were classified into two groups based on the radiographic severity as defined by the modified Stoke’ Ankylosing Spondylitis Spinal Score (mSASSS) system. Severe AS was defined by the presence of syndesmophytes and/or fusion in the lumbar or cervical spine (n = 195). Mild AS was defined by the absence of any syndesmophyte or fusion (n = 170). A total of 251 single nucleotide polymorphisms (SNPs) within 52 genes related to bone formation were selected and genotyped. Odds ratios (OR) and 95% confidence interval (95% CI) were analysed by multivariate logistic regression controlling for age at onset of symptoms, sex, disease duration, and smoking status as covariates. Results We identified new loci of bone morphogenetic protein 6 (BMP6) associated with radiographic severity in patients with AS that passed false discovery rate threshold. Two SNPs in BMP6 were significantly associated with radiologic severity [rs270378 (OR 1.97, p = 6.74×10−4) and rs1235192 [OR 1.92, p = 1.17×10−3]) adjusted by covariates. Conclusion This is the first study to demonstrate that BMP6 is associated with radiographic severity in AS, supporting the role wingless-type like/BMP pathway on radiographic progression in AS.

Background The cold-inducible RNA-binding protein (CIRP) is 18 kDa protein of the glycine-rich RNA binding protein (GRP) family, and these proteins function as RNA chaperones to facilitate translation. Extracellular CIRP is a recently identified endogenous proinflammatory mediator and damage-associated molecular pattern molecules (DAMP) that triggers inflammatory responses in sepsis and inflammatory bowel disease. Objectives This study was planned to investigate the relationship between CIRP and rheumatoid arthritis. Methods Peripheral blood and synovial fluid were collected from 15 patients with rheumatoid arthritis (RA) and 16 patients with osteoarthritis (OA). The concentration of CIRP was measured by sandwich Enzyme-Linked Immunosorbent Assay (ELISA). Results The concentration of serum CIRP was significantly elevated in RA patients group (RA patients=26.39±10.48 pg/ml, OA patients=17.14±7.24 pg/ml, p=0.009). Furthermore, the RA patients group showed significantly higher CIRP concentration than the OA patients group in synovial fluid (153.56±108.93 pg/ml vs. 23.63±16.18 pg/ml, p The mean concentration of synovial fluid CIRP was significantly higher than that of serum in RA patients group (Serum concentration=26.39±10.48 pg/ml, Synovial fluid=153.56±108.93 pg/ml, p DAS28-ESR and DAS28-CRP were positively correlated with synovial fluid concentration of CIRP (DAS28-ESR: r=0.582, p=0.023, DAS28-CRP: r=0.541, p=0.037, by correlation analysis). Conclusions The serum and synovial concentration of CIRP in RA patients was increased compared to OA patients. Also synovial concentration of CIRP in RA patients correlated well with the disease activity, i.e. the DAS28-ESR/CRP. Based on these results, the CIRP mediates the inflammation and is potential marker for synovial inflammation. References Qiang X, Yang WL, Wu R, Zhou M, Jacob A, Dong W, Kuncewitch M, Ji Y, Yang H, Wang H, Fujita J, Nicastro J, Coppa GF, Tracey KJ, Wang P (2013) Cold-inducible RNA-binding protein (CIRP) triggers inflammatory responses in hemorrhagic shock and sepsis. Nat Med 19:1489–95. Nishiyama H, Higashitsuji H, Yokoi H, Itoh K, Danno S, Matsuda T, Fujita J (1997) Cloning and characterization of human CIRP (cold-inducible RNA-binding protein) cDNA and chromosomal assignment of the gene. Gene 204:115–20. Nishiyama H, Danno S, Kaneko Y, Itoh K, Yokoi H, Fukumoto M, Okuno H, Millan JL, Matsuda T, Yoshida O, Fujita J (1998) Decreased expression of cold-inducible RNA-binding protein (CIRP) in male germ cells at elevated temperature. Am. J. Pathol 152:289–96. Nishiyama H, Xue JH, Sato T, Fukuyama H, Mizuno N, Houtani T, Sugimoto T, Fujita J (1998) Diurnal change of the cold-inducible RNA-binding protein (Cirp) expression in mouse brain. Biochem. Biophys. Res. Commun 245:534–8. Disclosure of Interest None declared

Background Genetic association studies using multiple ancestral cohorts have revealed a large overlap of rheumatoid arthritis (RA)-risk alleles among different ancestries, but there are some exceptional loci showing heterogenic association among populations. Objectives Here we investigated genetic variants with distinct effects on the development of RA in Asian and European populations. Methods Ancestry-related association heterogeneity was examined using the association data from large Korean (n=9,299) and European (n=45,790) rheumatoid arthritis cohorts with Immunochip and genome-wide SNP array data. Novel disease associations detected in Koreans were validated using two independent Asian cohorts (n=5,166) and a meta-analysis. Results We identified significant heterogeneity between the two ancestries for the common variants in the GTF2I locus and showed that this heterogeneity is due to an Asian-specific association effect ( P Heterogeneity =9.6×10 -9 at rs73366469 [OR Meta =1.37 and P Meta =4.2×10 –13 in Asians; OR Meta =1.00 and P Meta =1.00 in Europeans]) in RA. Trans-ancestral comparison and bioinfomatics analysis revealed a plausibly causal SNP (rs117026326; linked to rs73366469), whose minor allele is common in Asians but rare in Europeans. Conclusions We identified the largest effect on Asian RA across human non-HLA regions at GTF2I by heterogeneity mapping followed by replication studies, and pinpointed a possible causal variant. References Okada, Y. et al. Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature 506, 376–81 (2014). Kim, K. et al. High-density genotyping of immune loci in Koreans and Europeans identifies eight new rheumatoid arthritis risk loci. Ann Rheum Dis 74, e13 (2015). Acknowledgement This study was supported by the Korea Healthcare Technology R&D Project of the Ministry for Health & Welfare (HI13C2124), the Japanese Ministry of Education, Culture, Sports, Science and Technology Grant-in-Aid for Scientific Research (15H04965) and the US National Institutes of Health (R01MD007909 and R01AR060366). *Drs. Kwangwoo Kim and So-Young Bang contributed equally to this work. Disclosure of Interest None declared

Background Rheumatoid Arthritis (RA) patients with high body mass index (BMI) have been known to respond less well to anti-tumor necrosis factors (TNFs), especially infliximab. The post-hoc analysis of PLANETRA [1], a randomized controlled trial, was carried out to evaluate the influence of BMI on clinical response to infliximab (both infliximab originator and its biosimilar) in a large number of patients with RA. Objectives To investigate the association between BMI and clinical response to infliximab in patients with RA. Methods BMI was calculated before initiation of infliximab treatment in 606 patients with RA in PLANETRA. Patients were classified into 3 groups as normal weight ( Results The proportion of patients with normal weight, overweight and obesity were 43.1%, 36.1% and 20.8%, respectively. Baseline characteristics were comparable among BMI subgroups in gender, height and weekly MTX dose given to patients. The mean DAS28 (CRP) at baseline was significantly higher in obesity group (5.80±0.87, 5.72±0.86 and 6.15±0.78 for normal weight, overweight and obesity, respectively; P HAQ score was significantly higher in obese patients at baseline (1.55±0.55, 1.56±0.62 and 1.71±0.50, for normal weight, overweight and obesity, respectively; P=0.0278). However, there was no significant difference of mean change from baseline in HAQ at Week 14 (-0.56 vs. -0.48 vs. -0.55), Week 30 (-0.56 vs. -0.54 vs. -0.56) and Week 54 (-0.59 vs. -0.56 vs. -0.57) when assessed by BMI categories. In addition, improvements from baseline in both physical and mental component summary (PCS and MCS) scores were similar at weeks 14, 30 and 54 regardless of BMI (Table 1). Conclusions The BMI does not affect the clinical response to infliximab in patients with RA. No significant association was found between BMI and clinical response by DAS28 (CRP), HAQ and SF-36. Therefore, the weight-based dosing of infliximab is appropriate in RA patients. References Yoo D.H., et al. Ann Rheum Dis 2013;72:1613–20. Disclosure of Interest D. H. Yoo Grant/research support from: CELLTRION, Inc., Speakers bureau: CELLTRION, Inc., W. Park Grant/research support from: CELLTRION, Inc., Speakers bureau: CELLTRION, Inc., S. C. Shim Consultant for: CELLTRION, Inc., C. H. Suh Grant/research support from: CELLTRION, Inc., Consultant for: CELLTRION, Inc., S. J. Lee Employee of: CELLTRION, Inc., S. Y. Lee Employee of: CELLTRION, Inc., S. H. Lee Employee of: CELLTRION, Inc., J. H. Suh Employee of: CELLTRION, Inc.

Background Several pro-inflammatory cytokines such as TNF-α, IL-1, IL-6, IL-8 and IL-15 are known to be critical in synovial inflammatory process in RA and successful results have been obtained in RA treatment with targeting pro-inflammatory cytokines including TNF-α, IL-1 and IL-6. Objectives This study sought to investigate the role of IL-33 and IL-6 in RA patients receiving IL-6 receptor inhibition therapy. Methods We analyzed the association of the IL-33 and IL-6 level with disease activity and serologic features in 83 patients with RA. We also measured the serum level of IL-33 and IL-6 before and after the administration of tocilizumab for 24 weeks in 40 patients. Results Serum IL-33 level showed significant correlation with RF (rho =0.660, p Serum IL-33 level significantly decreased after 24 weeks of IL-6 receptor inhibition in patients with RA (p Serum IL-6 levels were not significantly changed after 24 weeks of IL-6 receptor inhibition therapy (median 7.1 to 8.9 pg/mL, p=0.503). Changes of IL-6 levels were insignificant both in ACR20 responders and non-responders after 24 weeks of IL-6 receptor inhibition therapy. Baseline IL-6 levels were not different between ACR20 responders and non-responders. Conclusions The use of IL-6 receptor inhibitor decreased the serum level of IL-33 and this effect seems to be led by the responder group. IL-33 could be a useful indicator to monitor the response in IL-6 receptor inhibition therapy. Disclosure of Interest None declared

Background Behcet9s disease (BD) is a multisystemic vasculitis of unknown etiology. Cardiovascular (CV) involvement has been reported in 1–6% of BD patients. In case of CV involvement, prognosis is poor. The incidence of the CV involvement in Korean patients with BD is not clearly documented. Objectives The aim of this study is to evaluate the CV findings in Korean patients with BD and to prevent or lower mortality and morbidity through early diagnosis and early treatment. Methods We performed Ankle Brachial Index (ABI), Pulse wave velocity (PWV) and Echocardiographic screening in 81 patients with BD who fulfilled the International Study Group criteria. PWV was calculated as the brachial-ankle path length divided by the brachial-ankle transit time (baPWV). We compared the result between two groups of patients with BD. Two groups are patients who have been treated with immunosuppressant agent and without immunosuppressant agent. The patients of former group are patients who have been suffered from severe complication or refractory disease. Results Fifty-nine (72.8%) patients were female. Mean age was 50.6 ± 2.5 years old. Mean age at diagnosis was 40.5 ± 2.3 years old and disease duration was 10.2 ± 1.5 years. Mean ABI was 1.10 ± 0.03. There was no significant difference between with and without immunosuppressant agent treated group. (1.11 ± 0.03 vs. 1.09 ± 0.03, P=0.167). The number of patients with abnormal ABI was 7 (17.5%) vs. 6 (14.6%), P=0.781. Mean PWV (m/sec) was 14.0 ± 0.67. There was no significant difference between two groups (13.8 ± 1.09 vs. 14.2 ± 0.83, P=0.144). But the immunosuppressant treated group had more patients with elevated levels of PWV (>12.0 m/sec) compared to non-immunosuppressant treated group [n =34 (82.9%) vs. n=25 (62.5%), P=0.024]. Echocardiography was done. Left ventricular ejection fraction (%) (64.9 ± 1.5 vs. 63.7 ± 1.7, P=0.254), Left ventricular mass index (g/m 2 ) (74.9 ± 5.0 vs 74.1 ± 5.7, P=0.970), E/E9 ratio (8.35 ± 0.9 vs 9.17 ± 1.0, P=0.228), Tricuspid regurgitating velocity (TRV) max (m/sec) (2.35 ± 0.09 vs 2.39 ± 0.11, P=0.572) were similar in both groups. We detected 39 minimal mitral, aortic and tricuspid valve insufficiencies. One patient showed suspiciously resting pulmonary hypertension (TRVmax – 3.3m/sec). In two patients, dilatation of ascending aorta was showed. There was aortic arch mass in one patient. Conclusions The CV involvement in BD can be a cause of death. In this screening study, asymptomatic patients showed many CV manifestations. And in 59 (72.8%) patients, PWV was elevated. Arterial stiffness can be a surrogate marker of CV disease. Larger study about CV manifestations in BD must be planned. And during treatment of patients with BD, CV screening study needs to be considered. References H L Chang, S K Kim, S S Lee, M Y Rhee. Arterial stiffness in Behcet9s disease: increased regional pulse wave velocity values. Ann Rheum Dis. 2006 Mar; 65(3): 415–416. Geri G, Wechsler B, Huong DLT, et al. Spectrum of cardiac lesions in Behcet disease: a series of 52 patients and review of literature. Medicine (Baltimore). 2012 Jan;91(1):25–34. C.A. Caldas, E.F. Borba, L.A. Bortolotto, D.M. Medeiros, E. Bonfa and C.R. Goncalves. Increased arterial stiffness assessed by pulse wave velocity in Behcet9s disease and its association with the lipid profile. J Eur Acad Dermatol Venereol. 2013 Apr;27(4):454–9 Disclosure of Interest None declared

Background A randomised controlled trial (RCT) and its open label extension trial (OLE) demonstrated comparable pharmacokinetics (PK), efficacy and safety between CT-P10 and innovator rituximab (RTX) (including switched from RTX to CT-P10) up to 2 years in rheumatoid arthritis (RA) patients (NCT01534884 and NCT01873443). 1,2 Objectives To compare time to retreatment and confirm clinical similarity in efficacy and safety by the number of treatment courses in the RCT between CT-P10 and RTX in RA patients up to 2 years. Methods One hundred fifty three patients were randomised in 2:1 ratio and received up to 2 treatment courses of either CT-P10 or RTX in RCT, and they had a chance to receive up to 2 additional courses of CT-P10 in OLE. Retreatments were given based on disease activity. Post-hoc analyses using combined data obtained from the RCT and OLE studies were performed in 2 different groups according to the number of treatment courses in RCT as following; Group 1: patients who received 2 courses in RCT; Group 2: patients who received 1 course in RCT. Results A total of 82 patients (59 received CT-P10 and 23 received RTX) were in Group 1 and 20 (13 received CT-P10 and 7 received RTX) were in Group 2. Time to retreatment was similar between CT-P10 and RTX (including switched to CT-P10) in each group (Figure 1). DAS28 improvement at Week 24 of each course was similar between CT-P10 and RTX (including switched to CT-P10) in both groups (Table 1). Infusion related reactions by treatment course up to 2 years was similar between the CT-P10 and RTX groups and tended to decrease over time in line with RTX historical data. 3 Incidence rate of adverse event, serious adverse event and infection was comparable between CT-P10 and RTX groups. Conclusions The results of the post-hoc analyses demonstrated comparable duration of disease control between CT-P10 and RTX (including switched to CT-P10) with clinical similarity in efficacy for 2 years. The safety profile of CT-P10 was similar to that of RTX and in line with RTX historical data. References Yoo DH, et al. Arthritis Rheum 2013; 65 (Suppl10): S736 Yoo DH, et al. Arthritis Rheum 2015; 67 (Suppl10): 2449–245 van Vollenhoven RF, et al. EULAR 2013 (Madrid, Spain): Poster SAT0131 Disclosure of Interest W. Park Consultant for: CELLTRION,INC., D. H. Yoo Consultant for: CELLTRION,INC., C. H. Suh Consultant for: CELLTRION,INC., S. C. Shim Consultant for: CELLTRION,INC., S. J. Lee Employee of: CELLTRION,INC., S. Y. Lee Employee of: CELLTRION,INC., T. S. Kwon Employee of: CELLTRION,INC., S. M. Kim Employee of: CELLTRION,INC.

Background Myositis-specific antibodies in patients with inflammatory myopathies are known to be associated with various clinical manifestations, classifications and diagnosis. Among them, recently found anti-transcriptional intermediary factor 1 (TIF1) α, β, or γ antibodies, has been reported to be associated with dermatomyositis (DM) accompanied by cancer. Objectives Although previous studies have evaluated the association of the antibodies in serum and clinical subtypes, the information about the target antigen is insufficient. The purpose of this study was to confirm the overexpression of TIF1s in the muscle and skin tissues of patients with inflammatory myopathies. Methods From February 2004 to November 2014, skin and muscle biopsies were performed on 45 patients diagnosed with dermatomyositis and polymyositis. We stained skin and muscle tissue by immunohistochemistry using anti-TIF1α, β, or γ and compared with the results of healthy control. We analyzed the association between the clinical manifestations and protein expression in each tissue. Results When compared with the control group, any antigens showed no significant overexpression in the muscle. However, TIF1α showed higher positive rate in the skin of DM (12/15 [80%]) than in the skin of healthy control (0/7 [0%]) (p=0.001). TIF1γ expression was higher in the muscle of patients with DM while there was no expression in the muscle of healthy controls (DM, 8/19 [80%] vs. healthy control 0/7 [0%], p=0.039). In the tissues of inflammatory myopathies, TIF1α and TIF1γ demonstrated higher positive rates in the skin than in the muscle (TIF1α, muscle, 4/35 [11%] vs. skin, 12/15 [80%], p Analyzing the association with TIF1s expression and cancer, there was no significant difference in the positive rate of TIF1α or γ in the muscle or skin between the myositis patient with or without cancer. Conclusions TIF1α was expressed more in the skin of DM patients than that in that of control group and TIF1γ in the muscle of DM patients than in that of control. The expression of TIF1α in the skin and TIF1γ in the muscle of cancer associated DM was not higher than those of DM without cancer. Thus the expression levels of TIF1α in the skin and TIF1γ in the muscle may be associated with myositis rather than with cancer. References Hoshino K, et al. Anti-MDA5 and anti-TIF1-gamma antibodies have clinical significance for patients with dermatomyositis. Rheumatology (Oxford) 2010;49(9):1726–1733. Fiorentino D. Casciola-Rosen L, Autoantibodies to transcription intermediary factor 1 in dermatomyositis shed insight into the cancer-myositis connection. Arthritis Rheum 2012;64(2):346–349. Disclosure of Interest None declared

Objective. The objective of this study is to assess whether genetic functional variants of disintegrin and metalloprotease 33 (ADAM33) are associated with susceptibility to systemic lupus erythematosus (SLE) in a Korean population. Methods. We pre- viously identified 48 single nucleotide polymorphisms (SNPs) in ADAM33. Six SNPs were selected with regard to the linkage disequilibrium pattern. An association study of ADAM33 was conducted in 190 patients with SLE and 469 control subjects. SNPs were genotyped using the TaqMan Real-time polymerase chain reaction method, and haplotype analyses of related var- iants were performed. Results. All SNPs were in Hardy-Weinberg equilibrium. Significant associations were found between the ADAM33 polymorphisms and SLE at rs2787094 (adjusted odds ratio (OR) 1.88, 95% confidence interval (CI) 1.00 to 3.54; p< 0.0001). The rs554743 polymorphism was associated with the presence of the immunoglobulin M anti-cardiolipin antibody (adjusted OR 0.29, 95% CI 0.10 to 0.83; p=0.021). Conclusion. ADAM33 polymorphisms were associated with susceptibility to SLE and development of clinical disease manifestations in a Korean population. Further study is warranted to clarify the role of ADAM33 in SLE pathogenesis. (J Rheum Dis 2016;23:88-95)