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Objectives: To investigate the efficacy and safety of peficitinib, an oral Janus kinase inhibitor, in patients with rheumatoid arthritis (RA)., Methods: In this double-blind phase III study, patients with RA and an inadequate response to prior disease-modifying anti-rheumatic drugs (DMARDs) were randomised to peficitinib 100 mg once daily, peficitinib 150 mg once daily, placebo or open-label etanercept for 52 weeks' treatment; placebo-treated patients were switched at week 12 to peficitinib 100 or 150 mg once daily. The primary endpoint was American College of Rheumatology (ACR)20 response at week 12/early termination (ET). Secondary endpoints (assessed throughout) included ACR20, ACR50 and ACR70 response, changes from baseline in disease activity scores (DAS)28 and ACR core parameters, adverse events (AEs) and changes in clinical or laboratory measurements., Results: In total, 507 patients received treatment. ACR20 response rates at week 12/ET were significantly higher in the peficitinib 100 mg (57.7%) and 150 mg (74.5%) groups versus placebo (30.7%) (p<0.001). ACR50/70 response rates were also higher for both peficitinib doses versus placebo. Improvements in ACR response were maintained until week 52. Changes from baseline in DAS28-C-reactive protein/erythrocyte sedimentation rate and the ACR core set were significantly greater for both peficitinib doses versus placebo at week 12/ET (p<0.001). AE incidence was similar across treatment arms. Incidence of serious infection and herpes zoster-related disease was higher with peficitinib versus placebo, but with no clear dose-dependent increase., Conclusions: In patients with RA and inadequate response to DMARDs, peficitinib 100 mg once daily or 150 mg once daily was efficacious in reducing RA symptoms and was well tolerated compared with placebo., Trial Registration Number: NCT02308163., Competing Interests: Competing interests: YT reports speaking fees and/or honoraria from Daiichi Sankyo, Astellas, Eli Lilly, Chugai, Sanofi, AbbVie, Pfizer, YL Biologics, Bristol-Myers Squibb, GlaxoSmithKline, UCB, Mitsubishi-Tanabe, Novartis, Eisai, Takeda, Janssen and Asahi Kasei, and research grants from Mitsubishi Tanabe, Bristol-Myers Squibb, Eisai, Chugai, Takeda, AbbVie, Astellas, Daiichi Sankyo, Ono, MSD and Taisho Toyama. TT has received grants from Astellas Pharma, Inc., Chugai Pharmaceutical Co. Ltd, Daiichi Sankyo Co. Ltd, Takeda Pharmaceutical Co. Ltd, AbbVie GK, Asahi Kasei Pharma Corp., Mitsubishi Tanabe Pharma Co., Pfizer Japan, Inc., Eisai Co. Ltd, AYUMI Pharmaceutical Corp., Nippon Kayaku Co. Ltd, and Novartis Pharma K.K.; speaking fees from AbbVie GK, Bristol-Myers Squibb K.K., Chugai Pharmaceutical Co. Ltd, Mitsubishi Tanabe Pharma Co., Pfizer Japan, Inc., Astellas Pharma, Inc., Daiichi Sankyo Co. Ltd, Eisai Co. Ltd, Sanofi K.K., Teijin Pharma Ltd, Takeda Pharmaceutical Co. Ltd, and Novartis Pharma K.K.; consultancy fees from Astra Zeneca K.K., Eli Lilly Japan K.K., Novartis Pharma K.K., Mitsubishi Tanabe Pharma Co., AbbVie GK, Nippon Kayaku Co. Ltd, Janssen Pharmaceutical K.K., Astellas Pharma, Inc., Taiho Pharmaceutical Co. Ltd, Chugai Pharmaceutical Co. Ltd, Taisho Toyama Pharmaceutical Co. Ltd, GlaxoSmithKline K.K., and UCB Japan Co. Ltd. ST reports personal fees from Amgen, Inc., Asahi Kasei Pharma Corporation, Amgen Astellas BioPharma K.K., Ono Pharmaceutical Co. Ltd, KYOCERA Medical Corporation, Daiichi Sankyo Co. Ltd, Teijin Pharma Ltd, Eli Lilly Japan K.K., and Pfizer Japan, Inc.; endowments from Astellas Pharma, Inc., AYUMI Pharmaceutical Corporation, Pfizer Japan, Inc., Bristol-Myers Squibb, Daiichi Sankyo Co. Ltd, and Chugai Pharmaceutical Co. Ltd; and grants from Japan Agency for Medical Research and Development (AMED), Japan Society for the Promotion of Science (JSPS)/Grant-in-Aid for Scientific Research (A), and Japan Society for the Promotion of Science (JSPS)/Grant-in-Aid for Exploratory Research outside the submitted work. AK reports grants from AbbVie, Eisai, Mitsubishi-Tanabe, Pfizer Japan, Takeda Pharmaceutical, Astellas Pharma, MSD, Ono Pharmaceutical, Teijin Pharma, Kyowa Hakko-Kirin, Sumitomo-Dainippon Pharma, Kissei Pharmaceutical, Boehringer Ingelheim, AstraZeneca, Otsuka Pharmaceutical, Chugai Pharmaceutical, Santen Pharmaceutical and Daiichi Sankyo; participation in speakers’ bureaux for AbbVie, Eisai, Takeda Pharmaceutical, Ono Pharmaceutical, Astellas Pharma, Mitsubishi-Tanabe, Pfizer Japan, Chugai Pharmaceutical, MSD, and Bristol-Myers Squibb K.K.; and consultant fees from Astellas Pharma and Janssen Pharmaceutical K.K. YWS reports a grant from Astellas Pharma, Inc.YHC reports grants for research and clinical trials from Taiwan Ministry of Science and Technology, Taiwan Department of Health, Taichung Veterans General Hospital, National Yang-Ming University, GlaxoSmithKline, Pfizer, Bristol-Myers Squibb, Novartis, AbbVie, Johnson & Johnson, Roche, Sanofi, Chugai Pharma Taiwan Ltd, Boehringer Ingelheim, UCB, MSD, AstraZeneca and Astellas; and honoraria and consultant fees from Pfizer, Novartis, AbbVie, Johnson & Johnson, Bristol-Myers Squibb, Roche, Lilly, GlaxoSmithKline, AstraZeneca, Sanofi, MSD, Chugai Pharma Taiwan Ltd, Astellas, Inova Diagnostics, UCB, Agnitio Science Technology, United Biopharma and Thermo Fisher. MR, HI, SU, YK, RA, TS and EY are employees of Astellas Pharma, Inc., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Immune cells from patients with rheumatoid arthritis (RA) express more enolase-1 (ENO1) on their surface than those from healthy subjects, and they elicit an enhanced inflammatory response. This study is aimed to identify the ligands of ENO1 that could promote inflammatory loops in vitro and enhance the arthritis severity in vivo., Methods: ENO1-binding proteins in RA synovial fluid were identified by mass spectromety, and affinity to ENO1 was evaluated by means of a ligand blotting and binding assay, surface plasmon resonance and confocal microscopy. Proinflammatory response by the interaction between ENO1 and apolipoprotein B (apoB) was tested in vitro and in vivo using peripheral blood mononuclear cells and a K/BxN serum transfer arthritis model and low-density lipoproteins receptor (LDLR) knockout mice., Results: ApoB in the synovid fluid of patients with RA was identified as a specific ligand to ENO1 with a higher affinity than plasminogen, a known ENO1 ligand. ApoB binding to ENO1 on monocytes elicited the production of tumour necrosis factor-α, interleukins (IL)-1β and IL-6 through both p38 mitogen-activated protein kinase and NF-κB pathways. In the K/BxN serum transfer arthritis model, administration of apoB increased the production of proinflammatory cytokines and exaggerated arthritis severity. The severity of K/BxN serum transfer arthritis in LDLR knockout mice was comparable with wild-type mice., Conclusions: A key component of atherogenic lipids, apoB, aggravated arthritis by potentiating the inflammatory response via its interaction with ENO1 expressed on the surface of immune cells. This suggests a novel mechanism by which lipid metabolism regulates chronic inflammation in RA., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To determine whether a 2-week methotrexate (MTX) discontinuation after vaccination improves the efficacy of seasonal influenza vaccination in patients with rheumatoid arthritis (RA)., Methods: In this prospective randomised parallel-group multicentre study, patients with RA on stable dose of MTX were randomly assigned at a ratio of 1:1 to continue MTX or to hold MTX for 2 weeks after 2016-2017 quadrivalent seasonal influenza vaccine containing H1N1, H3N2, B-Yamagata and B-Victoria. The primary outcome was frequency of satisfactory vaccine response, defined as greater than or equal to fourfold increase of haemagglutination inhibition (HI) antibody titre at 4 weeks after vaccination against ≥2 of four vaccine strains. Secondary endpoints included seroprotection (ie, HI titre ≥1:40) rate, fold change in antibody titres., Results: The modified intention-to-treat population included 156 patients in the MTX-continue group and 160 patients in the MTX-hold group. More patients in MTX-hold group achieved satisfactory vaccine response than the MTX-continue group (75.5% vs 54.5%, p<0.001). Seroprotection rate was higher in the MTX-hold group than the MTX-continue group for all four antigens (H1N1: difference 10.7%, 95% CI 2.0% to 19.3%; H3N2: difference 15.9%, 95% CI 5.9% to 26.0%; B-Yamagata: difference13.7%, 95% CI 5.2% to 22.4%; B-Victoria: difference 14.7%, 95% CI 4.5% to 25.0%). The MTX-hold group showed higher fold increase in their antibody titres against all four influenza antigens (all p<0.05). Change in disease activity was similar between groups., Conclusions: A temporary MTX discontinuation for 2 weeks after vaccination improves the immunogenicity of seasonal influenza vaccination in patients with RA without increasing RA disease activity., Trial Registration: NCT02897011., Competing Interests: Competing interests: EBL has acted as a consultant to Pfizer and received research grants from Green Cross Corporation and Hanmi Pharm., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objectives: To investigate the efficacy and safety of trimethoprim/sulfamethoxazole (TMP-SMX) as primary prophylaxis for pneumocystis pneumonia (PCP) in patients with rheumatic diseases receiving high-dose steroids., Methods: The study included 1522 treatment episodes with prolonged (≥4 weeks) high-dose (≥30 mg/day prednisone) steroids in 1092 patients over a 12-year period. Of these, 262 treatment episodes involved TMP-SMX (prophylaxis group) while other episodes involved no prophylaxis (control group). Differences in 1-year PCP incidence and its mortality between the two groups were estimated using Cox regression. To minimise baseline imbalance, propensity score matching was performed and efficacy outcome was mainly assessed in the postmatched population (n=235 in both groups)., Results: During a total of 1474.4 person-years, 30 PCP cases occurred with a mortality rate of 36.7%. One non-fatal case occurred in the prophylaxis group. TMP-SMX significantly reduced the 1-year PCP incidence (adjusted HR=0.07(95% CI 0.01 to 0.53)) and related mortality (adjusted HR=0.08 (95% CI 0.0006 to 0.71)) in the postmatched population. The result of the same analysis performed in the whole population was consistent with that of the primary analysis. Incidence rate of adverse drug reactions (ADR) related to TMP-SMX was 21.2 (14.8-29.3)/100 person-years. Only two serious ADRs (including one Stevens-Johnson syndrome case) occurred. The number needed to treat for preventing one PCP (52 (33-124)) was lower than the number needed to harm for serious ADR (131 (55-∞))., Conclusion: TMP-SMX prophylaxis significantly reduces the PCP incidence with a favourable safety profile in patients with rheumatic disease receiving prolonged, high-dose steroids., Competing Interests: Competing interests: EBL has acted as a consultant to Pfizer, and received research grants from Green Cross Corp and Hanmi Pharm Company. The other authors declare no conflicts of interest., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objective: To evaluate the similarities between LBEC0101 (etanercept biosimilar) and the etanercept reference product (ETN-RP) in terms of efficacy and safety, including immunogenicity, in patients with active rheumatoid arthritis despite methotrexate treatment., Methods: This phase III, multicentre, randomised, double-blind, parallel-group, 54-week study was conducted in Japan and Korea. The primary efficacy endpoint was the change from baseline in the disease activity score in 28 joints based on erythrocyte sedimentation rate (DAS28-ESR) at week 24. American College of Rheumatology 20% (ACR20) response rate, adverse events (AEs), pharmacokinetics and development of antidrug antibodies (ADAs) were also evaluated., Results: In total, 374 patients were randomised to LBEC0101 (n=187) or ETN-RP (n=187). The least squares mean changes from baseline in DAS28-ESR at week 24 in the per-protocol set were -3.01 (95% CI -3.198 to -2.820) in the LBEC0101 group and -2.86 (95% CI -3.051 to -2.667) in the ETN-RP group. The estimated between-group difference was -0.15 and its 95% CI was -0.377 to 0.078, which was within the prespecified equivalence margin of -0.6 to 0.6. ACR20 response rates at week 24 were similar between the groups (LBEC0101 93.3% vs ETN-RP 86.7%). The incidence of AEs up to week 54 was comparable between the groups (LBEC0101 92.0% vs ETN-RP 92.5%), although fewer patients in the LBEC0101 group (1.6%) than the ETN-RP group (9.6%) developed ADAs., Conclusion: The clinical efficacy of LBEC0101 was equivalent to that of ETN-RP. LBEC0101 was well tolerated and had a comparable safety profile to ETN-RP., Trial Registration Number: NCT02357069., Competing Interests: Competing interests: HM has received consulting fees for this study from Mochida Pharmaceutical, consulting fees unrelated to this study from AYUMI Pharmaceutical Corporation, Nichi-Iko Pharmaceutical and Meiji Seika Pharma, and lecture fees from Daiichi Sankyo, UCB Japan, Janssen Pharmaceutical KK, Chugai Pharmaceutical and Ono Pharmaceutical. MT and AH are employees of Mochida Pharmaceutical. SS and JL are employees of LG Chem. YWS received a grant for this study from LG Chem., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objective: To develop and validate new classification criteria for adult and juvenile idiopathic inflammatory myopathies (IIM) and their major subgroups., Methods: Candidate variables were assembled from published criteria and expert opinion using consensus methodology. Data were collected from 47 rheumatology, dermatology, neurology and paediatric clinics worldwide. Several statistical methods were used to derive the classification criteria., Results: Based on data from 976 IIM patients (74% adults; 26% children) and 624 non-IIM patients with mimicking conditions (82% adults; 18% children), new criteria were derived. Each item is assigned a weighted score. The total score corresponds to a probability of having IIM. Subclassification is performed using a classification tree. A probability cut-off of 55%, corresponding to a score of 5.5 (6.7 with muscle biopsy) 'probable IIM', had best sensitivity/specificity (87%/82% without biopsies, 93%/88% with biopsies) and is recommended as a minimum to classify a patient as having IIM. A probability of ≥90%, corresponding to a score of ≥7.5 (≥8.7 with muscle biopsy), corresponds to 'definite IIM'. A probability of <50%, corresponding to a score of <5.3 (<6.5 with muscle biopsy), rules out IIM, leaving a probability of ≥50 to <55% as 'possible IIM'., Conclusions: The European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) classification criteria for IIM have been endorsed by international rheumatology, dermatology, neurology and paediatric groups. They employ easily accessible and operationally defined elements, and have been partially validated. They allow classification of 'definite', 'probable' and 'possible' IIM, in addition to the major subgroups of IIM, including juvenile IIM. They generally perform better than existing criteria., Competing Interests: Competing interests: JAS has received research grants from Takeda and Savient and consultant fees from Savient, Takeda, Regeneron, Merz, Iroko, Bioiberica, Crealta and Allergan. JAS serves as the principal investigator for an investigator-initiated study funded by Horizon pharmaceuticals through a grant to DINORA, Inc., a 501 (c)(3) entity. JAS is a member of the executive committee of OMERACT, an organisation that develops outcome measures in rheumatology and receives arms-length funding from 36 companies; a member of the American College of Rheumatology’s (ACR) Annual Meeting Planning Committee (AMPC); Chair of the ACR Meet-the-Professor, Workshop and Study Group Subcommittee; and a member of the Veterans Affairs Rheumatology Field Advisory Committee. HC and RGC’s work in myositis is partly funded by grants from Arthritis Research UK (18474) and the Medical Research Council (MR/N003322/1). JV’s work in myositis is supported by Project (Ministry of Health, Czech Republic) for conceptual development of research organization 00023728., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objective: To investigate whether temporary discontinuation of methotrexate (MTX) improves the efficacy of seasonal influenza vaccination in patients with rheumatoid arthritis (RA)., Methods: In this prospective randomised parallel-group trial, patients with RA taking stable dose of MTX were randomly assigned at a ratio of 1:1:1:1 to continue MTX (group 1), suspend MTX for 4 weeks before vaccination (group 2), suspend MTX for 2 weeks before and 2 weeks after vaccination (group 3) or suspend MTX for 4 weeks after vaccination (group 4). All participants were vaccinated with trivalent influenza vaccine containing H1N1, H3N2 and B-Yamagata. The primary outcome was frequency of satisfactory vaccine response (≥4-fold titre increase 4 weeks postvaccination). Secondary endpoints included fold change in antibody titres from baseline., Results: The per-protocol population consisted of 199 patients (n=54, 44, 49 and 52 in groups 1, 2, 3 and 4, respectively). Group 3 achieved higher satisfactory vaccine response against all three antigens than group 1 (51.0% vs 31.5%, p=0.044). The anti-H3N2 antibody fold increase (95% CI) was significantly higher in groups 3 and 4 (12.2 (8.4 to 17.5), p <0.001 and 10.0 (6.8 to 14.8), p=0.043, respectively) than group 1 (5.9 (4.3 to 8.1)). The anti-B-Yamagata antibody responses of groups 3 and 4 were higher (4.7 (3.3 to 6.7), p=0.048; 6.1 (4.2 to 8.8), p <0.001, respectively) than group 1 (2.9 (2.2 to 3.8)). RA flare occurred in 24.1%, 21.2%, 34.1% and 38.8% in groups 1, 2, 3 and 4, respectively (p=NS)., Conclusions: Temporary MTX discontinuation improves the immunogenicity of seasonal influenza vaccination in patients with RA., Trial Registration: Trial registration number is: www.clinicaltrials.gov, NCT02748785., Competing Interests: Competing interests: EBL has acted as a consultant to Pfizer. The other authors declare no conflicts of interest., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

To develop response criteria for adult dermatomyositis (DM) and polymyositis (PM). Expert surveys, logistic regression, and conjoint analysis were used to develop 287 definitions using core set measures. Myositis experts rated greater improvement among multiple pairwise scenarios in conjoint analysis surveys, where different levels of improvement in 2 core set measures were presented. The PAPRIKA (Potentially All Pairwise Rankings of All Possible Alternatives) method determined the relative weights of core set measures and conjoint analysis definitions. The performance characteristics of the definitions were evaluated on patient profiles using expert consensus (gold standard) and were validated using data from a clinical trial. The nominal group technique was used to reach consensus. Consensus was reached for a conjoint analysis-based continuous model using absolute per cent change in core set measures (physician, patient, and extramuscular global activity, muscle strength, Health Assessment Questionnaire, and muscle enzyme levels). A total improvement score (range 0-100), determined by summing scores for each core set measure, was based on improvement in and relative weight of each core set measure. Thresholds for minimal, moderate, and major improvement were ≥20, ≥40, and ≥60 points in the total improvement score. The same criteria were chosen for juvenile DM, with different improvement thresholds. Sensitivity and specificity in DM/PM patient cohorts were 85% and 92%, 90% and 96%, and 92% and 98% for minimal, moderate, and major improvement, respectively. Definitions were validated in the clinical trial analysis for differentiating the physician rating of improvement (p<0.001). The response criteria for adult DM/PM consisted of the conjoint analysis model based on absolute per cent change in 6 core set measures, with thresholds for minimal, moderate, and major improvement., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Objectives: Following up the systemic lupus erythematosus (SLE) genome-wide association studies (GWAS) identification of NMNAT2 at rs2022013, we fine-mapped its 150 kb flanking regions containing NMNAT2 and SMG7 in a 15 292 case-control multi-ancestry population and tested functions of identified variants., Methods: We performed genotyping using custom array, imputation by IMPUTE 2.1.2 and allele specific functions using quantitative real-time PCR and luciferase reporter transfections. SLE peripheral blood mononuclear cells (PBMCs) were cultured with small interfering RNAs to measure antinuclear antibody (ANA) and cyto/chemokine levels in supernatants using ELISA., Results: We confirmed association at NMNAT2 in European American (EA) and Amerindian/Hispanic ancestries, and identified independent signal at SMG7 tagged by rs2702178 in EA only (p=2.4×10 -8 , OR=1.23 (95% CI 1.14 to 1.32)). In complete linkage disequilibrium with rs2702178, rs2275675 in the promoter region robustly associated with SMG7 mRNA levels in multiple expression quantitative trait locus (eQTL) datasets. Its risk allele was dose-dependently associated with decreased SMG7 mRNA levels in PBMCs of 86 patients with SLE and 119 controls (p=1.1×10 -3 and 6.8×10 -8 , respectively) and conferred reduced transcription activity in transfected HEK-293 (human embryonic kidney cell line) and Raji cells (p=0.0035 and 0.0037, respectively). As a critical component in the nonsense-mediated mRNA decay pathway, SMG7 could regulate autoantigens including ribonucleoprotein (RNP) and Smith (Sm). We showed SMG7 mRNA levels in PBMCs correlated inversely with ANA titres of patients with SLE (r=-0.31, p=0.01), and SMG7 knockdown increased levels of ANA IgG and chemokine (C-C motif) ligand 19 in SLE PBMCs (p=2.0×10 -5 and 2.0×10 -4 , respectively)., Conclusion: We confirmed NMNAT2 and identified independent SMG7 association with SLE. The inverse relationship between levels of the risk allele-associated SMG7 mRNAs and ANA suggested the novel contribution of mRNA surveillance pathway to SLE pathogenesis., Competing Interests: Conflicts of Interest: None declared., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Background: PATIENTS with rheumatoid arthritis (RA) are at increased risk of developing comorbid conditions., Objectives: To evaluate the prevalence of comorbidities and compare their management in RA patients from different countries worldwide., Study Design: international, cross-sectional., Patients: consecutive RA patients., Data Collected: demographics, disease characteristics (activity, severity, treatment), comorbidities (cardiovascular, infections, cancer, gastrointestinal, pulmonary, osteoporosis and psychiatric disorders)., Results: Of 4586 patients recruited in 17 participating countries, 3920 were analysed (age, 56±13 years; disease duration, 10±9 years (mean±SD); female gender, 82%; DAS28 (Disease Activity Score using 28 joints)-erythrocyte sedimentation rate, 3.7±1.6 (mean±SD); Health Assessment Questionnaire, 1.0±0.7 (mean±SD); past or current methotrexate use, 89%; past or current use of biological agents, 39%. The most frequently associated diseases (past or current) were: depression, 15%; asthma, 6.6%; cardiovascular events (myocardial infarction, stroke), 6%; solid malignancies (excluding basal cell carcinoma), 4.5%; chronic obstructive pulmonary disease, 3.5%. High intercountry variability was observed for both the prevalence of comorbidities and the proportion of subjects complying with recommendations for preventing and managing comorbidities. The systematic evaluation of comorbidities in this study detected abnormalities in vital signs, such as elevated blood pressure in 11.2%, and identified conditions that manifest as laboratory test abnormalities, such as hyperglycaemia in 3.3% and hyperlipidaemia in 8.3%., Conclusions: Among RA patients, there is a high prevalence of comorbidities and their risk factors. In this multinational sample, variability among countries was wide, not only in prevalence but also in compliance with recommendations for preventing and managing these comorbidities. Systematic measurement of vital signs and laboratory testing detects otherwise unrecognised comorbid conditions.

Objectives: To evaluate the efficacy and safety of atorvastatin versus placebo in modifying lipids in patients with rheumatoid arthritis (RA) receiving the oral Janus kinase inhibitor, tofacitinib., Methods: A randomised, placebo controlled, multicentre phase 2 study, open-label for tofacitinib and blinded for atorvastatin. Patients received tofacitinib 10 mg twice daily for 12 weeks; at week 6, patients were randomly assigned 1:1 to receive oral atorvastatin 10 mg once daily or placebo for 6 weeks. Main outcome measures were lipid moieties, American College of Rheumatology (ACR) response rates, disease activity score in 28 joint counts and safety., Results: 111 patients meeting ACR 1987 RA criteria with active disease were enrolled. Tofacitinib-induced elevation of mean total, low-density lipoprotein (LDL) and high-density lipoprotein-cholesterol, triglycerides and apolipoprotein A-1 concentrations were sustained in placebo recipients to week 12; atorvastatin added at week 6 significantly reduced tofacitinib-associated increases in total and LDL-cholesterol, triglycerides and apolipoprotein B to below week 0 levels. Co-administration of atorvastatin resulted in a significant reduction of LDL-cholesterol versus placebo (primary endpoint; p<0.0001); from week 6 to week 12 the least squares mean reduction was 35.3% with atorvastatin, versus 5.8% increase with placebo. ACR responses were observed with tofacitinib; numerically greater rates were seen with atorvastatin versus placebo. Adverse events were consistent with phase 3 studies., Conclusions: Tofacitinib-associated elevated total and LDL-cholesterol and triglycerides were rapidly and significantly reduced by atorvastatin. Further investigation is required to explore the significance of reductions in RA disease activity in patients receiving tofacitinib and atorvastatin. (Pfizer protocol A3921109).

Objectives: To identify non-major histocompatibility complex susceptible genes that might contribute to Behçet's disease (BD)., Methods: We performed a genome-wide association study using DNA samples from a Korean population consisting of 379 BD patients and 800 controls. A replication study was performed in a Japanese population (363 BD patients and 272 controls). To evaluate the functional implication of the target single nucleotide polymorphisms (SNP), gene expression levels in peripheral T cells, allele-specific modulation of promoter activity and biological effect of mRNA knockdown were investigated., Results: We found a novel association of BD to the GIMAP locus, mapped to chromosome 7q36.1 (rs1608157, p=6.01×10(-8) in a minor allele dominant model; rs11769828, allele based p=1.60×10(-6)). A fine mapping study identified an association with four additional SNP: rs1522596 (OR=1.45, p=7.70×10(-6)) in GIMAP4; rs10266069 (OR=1.32, p=2.67×10(-4)) and rs10256482 (OR=1.27, p=5.27×10(-4)) in GIMAP2; and rs2286900 (OR=1.61, p=3.53×10(-5)) in GIMAP1 areas. Replication study using DNA samples from the Japanese population validated the significant association between BD and the GIMAP locus. The GIMAP4 promoter construct plasmid with the minor allele of rs1608157 displayed significantly lower activity than one with the major allele. Moreover, CD4 T cells from BD patients showed a lower level of GIMAP4 mRNA, and GIMAP4 knockdown was protective against Fas-mediated apoptosis., Conclusions: These results suggest that a GIMAP cluster is a novel susceptibility locus for BD, which is involved in T-cell survival, and T-cell aberration can contribute to the development of BD.

Objective: To develop new composite disease activity indices for psoriatic arthritis (PsA)., Methods: Data from routine clinic visits at multiple centres were collected in a systematic manner. Data included all domains identified as important in randomised controlled trials in PsA. Decisions to change treatment were used as surrogates for high disease activity. New indices were developed by multiple linear regression (psoriatic arthritis disease activity score: PASDAS) and empirically, utilising physician-defined cut-offs for disease activity (arithmetic mean of desirability functions: AMDF). These were compared with existing composite measures: Composite Psoriatic arthritis Disease Activity Index (CPDAI), Disease Activity for PSoriatic Arthritis (DAPSA), and Disease Activity Score for rheumatoid arthritis (DAS28)., Results: 161/503 (32%) subjects had treatment changes. Although all measures performed well, compared with existing indices, PASDAS was better able to discriminate between high and low disease activity (area under receiver operating curves (ROC)) curve with 95% CI: PASDAS 0.773 (0.723, 0.822); AMDF 0.730 (0.680, 0.780); CPDAI 0.719 (0.668, 0.770); DAPSA 0.710 (0.654, 0.766); DAS28 0.736 (0.680, 0.792). All measures were able to discriminate between disease activity states in patients with oligoarthritis, although area under the receiver operating curves (AUC) were generally smaller. In patients with severe skin disease (psoriasis area and severity index>10) both nonparametric and AUC curve statistics were nonsignificant for all measures., Conclusions: Two new composite measures to assess disease activity in PsA have been developed. Further testing in other datasets, including comparison with existing measures, is required to validate these instruments.

Objectives: The Xq28 region containing IRAK1 and MECP2 has been identified as a risk locus for systemic lupus erythematosus (SLE) in previous genetic association studies. However, due to the strong linkage disequilibrium between IRAK1 and MECP2, it remains unclear which gene is affected by the underlying causal variant(s) conferring risk of SLE., Methods: We fine-mapped ≥136 SNPs in a ∼227 kb region on Xq28, containing IRAK1, MECP2 and seven adjacent genes (L1CAM, AVPR2, ARHGAP4, NAA10, RENBP, HCFC1 and TMEM187), for association with SLE in 15 783 case-control subjects derived from four different ancestral groups., Results: Multiple SNPs showed strong association with SLE in European Americans, Asians and Hispanics at p<5×10(-8) with consistent association in subjects with African ancestry. Of these, six SNPs located in the TMEM187-IRAK1-MECP2 region captured the underlying causal variant(s) residing in a common risk haplotype shared by all four ancestral groups. Among them, rs1059702 best explained the Xq28 association signals in conditional testings and exhibited the strongest p value in transancestral meta-analysis (p(meta )= 1.3×10(-27), OR=1.43), and thus was considered to be the most likely causal variant. The risk allele of rs1059702 results in the amino acid substitution S196F in IRAK1 and had previously been shown to increase NF-κB activity in vitro. We also found that the homozygous risk genotype of rs1059702 was associated with lower mRNA levels of MECP2, but not IRAK1, in SLE patients (p=0.0012) and healthy controls (p=0.0064)., Conclusions: These data suggest contributions of both IRAK1 and MECP2 to SLE susceptibility.

Objectives: To investigate the clinical characteristics and risk factors of gout attacks that develop during the postsurgical period., Methods: We enrolled 67 patients with gout who developed postsurgical gout and 67 controls who had histories of gout but did not develop gout attacks after surgery. Features of the postsurgical gout attacks were analysed and compared to those of presurgical gout attacks suffered by patients and controls. Demographics, medical backgrounds, laboratory data and surgical factors were compared between patients and controls in order to establish risk factors associated with postsurgical gout., Results: The mean (SD) time interval to develop postsurgical gout was 4.2 (3.1) days. The attacks tended to involve lower extremity joints (65/67, 97.0%), usually the first metatarsophalangeal joint (42/67, 62.7%), and to affect more than one joint (34/67, 50.7%). The number of attacked joints was positively correlated with the total number of previously involved joints (r = 0.281, p = 0.026). The site of attacks had a preference for the previously affected sites. A history of cancer surgery (p = 0.002), elevated presurgical serum urate levels (>/=9 mg/dl; p = 0.002) and failure to administer colchicine prophylaxis (p = 0.008) were found to be risk factors for postsurgical gout., Conclusions: Postsurgical gout tends to develop within 8 days after surgery. The site and number of involved joints reflect the features of gout attacks the patient suffered before surgery. Adequate presurgical control of serum uric acid levels and/or prophylactic administration of colchicine will help prevent gout attacks during the postsurgical period.

Objective: To investigate the association of complement C4 allotypes with rheumatoid arthritis in Koreans., Methods: 65 rheumatoid arthritis patients and 255 controls were typed for C4 allotypes and HLA-A, B, C, DR, and DQ antigens., Results: The frequencies of C4AQ0 (32.3% v 14.9%, P < 0.005) and C4B5 (29.2% v 12.2%, P < 0.005) were significantly increased in rheumatoid arthritis patients compared with healthy control subjects. Among rheumatoid patients, the frequency of C4AQ0 was significantly increased in both the rheumatoid factor (RF) positive (27.3%) and the RF negative (66.7%) subgroups. The frequencies of C4B5 and HLA-DR4 were significantly increased only in RF positive subgroup. C4B5 was strongly associated with HLA-DR4, whereas C4AQ0 did not show association with DR4., Conclusions: In Koreans, C4AQ0 and C4B5 are associated with susceptibility to rheumatoid arthritis, as in the Japanese. C4B5 is strongly associated with HLA-DR4. C4AQ0 is considered to be a DR4 independent risk factor, and a disease susceptibility allele in linkage disequilibrium with C4AQ0 is suggested in Korean patients with rheumatoid arthritis.