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SB4 is the first approved biosimilar of etanercept, a biologic tumor necrosis factor inhibitor, to treat various autoimmune diseases including axial spondylarthritis (axSpA), rheumatoid arthritis (RA), psoriatic arthritis (PsA), and plaque psoriasis (PsO). This post-marketing surveillance (PMS) study of SB4 investigated safety and effectiveness in routine clinical practice and is part of the drug approval process in Korea.This prospective, multi-center, open-label, observational, phase IV PMS study was designed to enroll patients with axSpA, RA, PsA, and PsO in Korea from September 2015 to September 2019. Both etanercept-naïve patients or patients switched from reference etanercept were included. SB4 was administered weekly via subcutaneous injections using pre-filled syringes. Safety was assessed by the incidence of adverse events (AEs), adverse drug reactions (ADRs) and serious adverse events (SAE). Effectiveness was assessed by the change from baseline of investigator-rated Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) in patients with ankylosing spondylitis (AS) and disease activity score-28 (DAS28) in patients with RA.Among 316 enrolled patients, 314 were included in the safety analysis (176 with AS and 138 with RA). The overall incidence of AEs, ADRs and serious AEs were 17.8, 9.9, and 1.3%, respectively. Most AEs were mild (66.7%) or moderate (31.1%) and not related to SB4 (58.9%). Most common AEs were injection site pruritus (1.9%) and injection site rash (1.3%). At week 24, mean disease activity scores significantly decreased compared to baseline in naïve patients with AS and RA (BASDAI 2.7 vs. 6.2, p 0.0001; DAS28 3.8 vs. 5.7, p 0.0001) and in switched patients with AS and RA (BASDAI 1.0 vs. 1.3, p = 0.0018; DAS28 2.4 vs. 2.9, p = 0.0893).This first real-world evidence of SB4 from a phase IV PMS study in Korea shows comparable effectiveness to historical SB4 real-world evidence without any new significant safety signals.

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.

Objectives To explore the course of lung function and RA disease activity and predictive factors for deteriorating lung function in patients with RA-interstitial lung disease (ILD). Methods The Korean Rheumatoid Arthritis–Interstitial Lung Disease cohort is a multicentre, prospective observational cohort. Patients with RA-ILD were enrolled and followed up annually for 3 years for RA disease activity and ILD status assessment. Group-based modelling was used to cluster a similar predicted percentage of forced vital capacity (FVC%) patterns into trajectories. Results This study included 140 patients who underwent at least two pulmonary function tests. Four distinctive trajectories for predicted FVC% were ‘improving’ [n = 11 (7.9%)], ‘stable’ [n = 68 (38.4%)], ‘slowly declining’ [n = 54 (48.6%)] and ‘rapidly declining’ [n = 7 (5.0%)]. Most (77.7%) patients maintained or improved to low RA disease activity. The lung function trajectory was not comparable to the RA disease activity trajectory. Age ≥70 years [relative risk (RR) 10.8 (95% CI 1.30, 89.71)] and early RA diagnosed within the preceding 2 years [RR 10.1 (95% CI 1.22, 84.2)] were associated with increased risk for rapidly declining predicted FVC%. The risk for deterioration or mortality increased in patients with a simultaneous diagnosis of RA and ILD within 24 weeks [RR 9.18 (95% CI 2.05, 41.0)] and the extent of lung involvement [RR 3.28 (95% CI 1.12, 9.60)]. Conclusion Most patients with RA-ILD experienced stable or slowly declining lung function. In 5% of patients, predicted FVC% deteriorated rapidly, especially in older adults with early RA. The lung function trajectory was not comparable to the RA disease activity trajectory.

Background/Aims: This study was performed to clarify inf luences of anticentromere antibody (ACA) on clinical phenotypes of primary Sjögren’s syndrome (pSS) patients in Korea. Methods: We assessed 318 patients who met the 2016 American College of Rheumatology/ European League Against Rheumatism classification criteria for pSS. All patients were selected from the Korean Initiative of primary Sjögren’s Syndrome (KISS), a prospective cohort. Among them, 53 patients were positive for ACA, while another 265 patients were not. We compared various clinical data including demographic features, extra-glandular manifestations (EGMs), clinical indices, and laboratory values available from the KISS database between the two groups. Results: Patients in the ACA-positive pSS group were older (p = 0.042), and had higher xerostomia inventory scores (p = 0.040), whereas glandular dysfunction represented with Schirmer I test was more severe in the ACA-negative group. More frequent Raynaud’s phenomenon and liver involvement (both p < 0.001) and less articular involvement (p = 0.037) were observed among the EGMs in the ACA-positive group. Less frequency of leukopenia (p = 0.021), rheumatoid factor (p < 0.001), anti-Ro/SSA antibody positivity (p < 0.001), and hypergammaglobulinemia (p = 0.006), as well as higher positivity rates of anti-nuclear antibody and anti- topoisomerase antibody (p < 0.001 and p = 0.006, respectively) were found in the laboratory data in the ACA-positive pSS group. Conclusions: Considering distinct phenotypes in hematological and serological features and EGMs, we should monitor the occurrence of these clinical features among pSS patients with ACA in caution.

Objective To examine the association between MTX, LEF and tacrolimus use and the progression of RA-associated interstitial lung disease (ILD). Methods The Korean RA-ILD cohort prospectively enrolled patients with RA-associated ILD at multiple centres from 2015 to 2018 and followed up with them for 3 years. ILD progression was defined by any of the followings: a decrease of ≥10% in forced vital capacity, a decrease of ≥15% in the diffusing capacity of the lung for carbon monoxide, or death from respiratory failure. Results Of 143 patients, 64 patients experienced ILD progression during a median follow-up period of 33 months. The use of MTX [adjusted hazard ratio (aHR), 1.06; 95% CI, 0.59, 1.89], LEF (aHR, 1.75; 95% CI, 0.88, 3.46) and tacrolimus (aHR, 0.94; 95% CI, 0.52, 1.72) did not increase the risk of ILD progression. However, the association between LEF use and the risk of ILD progression was significant in subgroups with poor lung function (aHR, 8.42; 95% CI, 2.61, 27.15). Older age, male sex, a shorter RA duration, higher RA disease activity and extensive disease at baseline were independently associated with ILD progression. Conclusion None of the three treatments increased the risk of RA-associated ILD progression, except for LEF, which increased the risk of ILD progression in patients with severe ILD. The appropriate use of conventional synthetic disease-modifying antirheumatic drugs considering RA disease activity and ILD severity would be important for the management of RA-associated ILD.

Background: It is well known that the use of corticosteroids (CS) results in increased viral replication and elevated alanine aminotransferase in hepatitis B virus (HBV) patients. However, only a few studies have investigated the effect of low-dose CS on HBV reactivation. In addition, there are few studies on the effects of synthetic disease-modifying anti-rheumatic drugs on HBV reactivation. Objective: We investigated the reactivation of HBV in rheumatoid arthritis (RA) patients treated with long-term low-dose corticosteroids. In addition, we analyzed factors affecting HBV reactivation, including disease-modifying anti-rheumatic drugs. Methods: We retrospectively reviewed medical records and analyzed the incidence of HBV reactivation in RA patients who were hepatitis B surface antigen (HBsAg) positive and who were receiving ≤10 mg of prednisolone over 4 weeks. Logistic regression analysis was performed to investigate the factors that increase the risk of HBV reactivation. Results: A total of 141 patients were included in the study, out of which 24 (17.0%) patients had HBV reactivation. The administration of low-dose corticosteroids did not affect HBV reactivation in HBsAg-positive RA patients (odds ratio: 0.807, 95% confidence interval: 0.143–4.546, p = 0.808), nor did the duration of corticosteroid administration, average daily corticosteroid dose, and cumulative corticosteroid dose. Administration of leflunomide was found to significantly increase the risk of HBV reactivation (odds ratio: 3.851, 95% confidence interval: 1.026–14.459, p = 0.046). Conclusion: The administration of low-dose corticosteroids did not affect the rate of HBV reactivation, suggesting that it can be used safely. Leflunomide may increase the risk of HBV reactivation; therefore, HBV patients should be carefully monitored when receiving this drug.

Background This study identified whether Functional Index for Hand Osteoarthritis (FIHOA) is associated with pain, hand muscle strength, health-related quality of life, and radiographic severity in hand osteoarthritis (OA). Methods We consecutively recruited 95 patients with hand OA. The FIHOA was used to assess questionnaire-based physical function in hand OA. Health-related quality of life was evaluated using EuroQol-5 dimension (EQ-5D). Radiographic changes of hand joints were measured by Kellgren-Lawrence (K-L) grade, which was determined based on total radiographic severity score and number of affected joints. Other measures included patient’s visual analogue scale (VAS) score for pain and performance-based function indexes such as grip and pinch strength. Statistical analysis was performed using Mann-Whitney U test, Spearman’s correlation analysis, and multivariate logistic regression analysis. Results FIHOA score was negatively associated with grip and pinch hand strength and EQ-5D and positively correlated to VAS pain (p 4) (p 4) was related with increased VAS pain and with lower EQ-5D index (p = 0.008 and p = 0.013, respectively). There was no association between FIHOA score and measures of total radiographic severity score and number of affected joints. Conclusion This study observes that FIHOA score is associated with patient-reported VAS pain, hand muscle strength indexes, and EQ-5D but not radiographic severity in hand OA.

Objective. There is a debate over the relevance of ultrasound abnormalities to the pain, functional impairment, and radiologic severity in hand osteoarthritis (OA). This study aims to determine the association between ultrasound abnormalities and clinical, functional, and radiographic measures in hand OA. Methods. A total of 66 patients was consecutively enrolled. All patients with gray-scale synovitis, joint effusion, and osteophytes were examined by ultrasound for 20 hand joints. Radiographic changes in both hands were evaluated by the Kellgren-Lawrence (K-L) grading system and were described as total radiographic severity score and number of affected joints. Other measures were also assessed, including each patient’s visual analogue scale for pain, the Functional Index for Hand Osteoarthritis for functional disability, and grip and pinch strength for hand muscle strength. Results. In total, 10 patients with gray-scale synovitis, 35 with joint effusion, and 66 with osteophytes were detected in hand OA scans on ultrasound. Osteophytes on ultrasound were significantly associated with total radiographic severity score and number of affected joint (r=0.293, p=0.003 and r=0.336, p＜0.001, respectively). In addition, there were weak associations of synovitis and joint effusion with radiographic changes. Patients with higher total radiographic severity score showed larger number of ultrasound-detected abnormalities, such as synovitis, joint effusion, and osteophytes (p=0.011, p=0.002, and p＜0.001, respectively). Conclusion. This study shows that ultrasound findings, especially osteophytes, were associated with radiographic changes based on K-L grade, but not clinical and functional status in hand OA. (J Rheum Dis 2021;28:17-24)

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 This study explored the effects of obesity on clinical manifestations, disease activity and organ damage in Korean patients with systemic lupus erythematosus (SLE). Methods We assessed 393 SLE patients annually for three consecutive years based on demographic information, clinical manifestations, laboratory findings and Physician Global Assessment, Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)-2000 and Systemic Lupus International Collaborating Clinics (SLICC) damage index (SDI) scores. Patients were grouped by body mass index (BMI): normal weight, BMI 2; overweight, 23 kg/m2 ≤BMI 2; obese, BMI ≥25 kg/m2. The impact of obesity on clinical outcomes was assessed using univariate and multivariate analyses. Results Of the 393 patients, 59 (15.0%) were obese at enrollment. They had more comorbidities compared with non-obese patients, including diabetes, hypertension, hyperlipidemia and pulmonary hypertension. Nephritis at enrollment and newly developed nephritis during follow-up were more common ( p = 0.002 and p = 0.002, respectively) and Physician Global Assessment and SDI scores were higher in these patients for three consecutive years ( p = 0.017 and p = 0.039, respectively). Multivariate analysis revealed that obesity was significantly associated with development of nephritis during follow-up (odds ratio = 26.636; 95% confidence interval, 11.370–62.399; p Conclusions The incidences of newly developed nephritis and cumulative organ damage were higher in obese SLE patients than in non-obese SLE patients.

Aim This study examined the degree of gastrointestinal (GI) risk and patient‐reported outcomes including GI‐related symptoms, adherence to non‐steroidal anti‐inflammatory drugs (NSAIDs), disease activity and quality of life (QoL) in patients with ankylosing spondylitis (AS). Methods Cross‐sectional, observational study conducted at six nationwide, university‐based hospitals of Korea. AS patients treated with NSAIDs for at least 2 weeks were included between March and September 2016. Demographic and clinical data were gathered through a medical chart review and patient survey. GI risk was estimated using Standardized Calculator of Risk for Events (SCORE). NSAIDs adherence was investigated with Morisky Medication Adherence Scale‐8 (MMAS‐8). Disease activity and QoL were examined with Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and EuroQol‐3L (EQ‐5D, EQ‐visual analog scale [EQ‐VAS]), respectively. Path analysis was implemented to estimate pathways of GI risk, GI symptoms and NSAIDs adherence to QoL. Results A total of 596 patients (age: 38.9 ± 12.6 years, male: 82.1%) participated in the study, of which 33.2% experienced GI symptoms during NSAID treatment, and 34.2% of them showed ongoing GI symptoms upon enrollment. According to SCORE, 37.1% of patients showed moderate to very high GI risk. No patient showed high adherence according to MMAS‐8, so 55.3% of patients with moderate adherence were considered adherent. BASDAI and QoL of the total patients were 3.5 ± 2.0, 0.6 ± 0.3 (EQ‐5D), and 67.4 ± 19.8 (EQ‐VAS), respectively. From path analyses, higher GI risk significantly lowered QoL. Conclusion This study suggests timely therapeutic strategies should be implemented to manage GI risk during NSAID treatment in order to effectively manage AS.

A relationship between spine osteoarthritis (OA) and metabolic syndrome has not been established. This study evaluated whether metabolic syndrome is associated with radiographic spine OA in the Korean population.A total of 2252 subjects older than 50 years who underwent plain radiography of the lumbar spine during the Korea National Health and Nutrition Examination Survey (KNHANES) 2012 were enrolled. Radiographic grading of the lumbar spine was performed using the Kellgren-Lawrence (K-L) grading scale, ranging from grade 0 to grade 2. K-L grade 2 was defined as lumbar spine OA, while those of K-L grade 0 or 1 were defined as controls.The prevalence of spine OA was 28.1% (n = 689). The prevalence of metabolic syndrome in spine OA was not different from that among controls. The cumulative number of metabolic syndrome components was significantly different between spine OA and controls (P = .027). Subjects with K-L grade 1 or grade 2 showed higher proportion of metabolic syndrome and its cumulative components than those of K-L grade 0. Two or 3 or more metabolic syndrome components were significantly associated with spine OA (P = .012 and P = .010, respectively). Abnormal waist circumference was weakly associated with spine OA (odds ratio 1.233, 95% CI 1.000-1.520, P = .050). Multivariate logistic regression analysis showed that older age and female gender were linked with spine OA, but not metabolic syndrome.This study found lack of association between metabolic syndrome and radiographic spine OA.

Background/Aims To identify the factors associated with time to diagnosis after symptom onset in patients with early rheumatoid arthritis (RA). Methods Early RA patients with ≤ 1 year of disease duration in the KORean Observational study Network for Arthritis (KORONA) database were included in this analysis. Patients were further divided into two groups according to the time to diagnosis from symptom onset: the early diagnosis group (time to diagnosis ≤ 1 year) and the late diagnosis group (time to diagnosis > 1 year). Using the multivariable regression model, we identified factors associated with early diagnosis. Results Among 714 early RA patients, 401 patients (56.2%) and 313 patients (43.8%) were included in the early diagnosis and late diagnosis groups, respectively. The mean disease duration was 0.47 years in the early diagnosis group and 0.45 years in the late diagnosis group. In multivariable model analysis, greater age at onset (odds ratio [OR], 1.03; 95% confidence interval [CI], 1.02 to 1.05), high school education or higher (OR, 1.68; 95% CI, 1.14 to 2.47), higher income (OR, 1.48; 95% CI, 1.05 to 2.08), and initial small joint involvement (OR, 1.42; 95% CI, 1.02 to 1.98) were factors associated with early diagnosis. At diagnosis, disease activity scores using 28 joints on diagnosis (3.81 ± 1.44 vs. 3.82 ± 1.42, p = 0.92) and functional disability (0.65 ± 0.61 vs. 0.57 ± 0.62, p = 0.07) did not different between the two groups. However, hand joint erosion on X-ray (37.8% vs. 25.6%, p < 0.01) was more common in the late diagnosis group than the early diagnosis group. Conclusions Older onset age, higher educational level and income, and initial small joint involvement were positive factors for early diagnosis of RA.

Background/aims Rheumatology in Korea has rapidly advanced in the 24 years since the subspecialty board certification program was established in 1992. The objective of this investigation was to analyze the distribution of rheumatology practices in Korea in order to better understand the rheumatology workforce. Methods Using a membership list from the Korean College of Rheumatology (KCR), we obtained information on practicing rheumatologists. We mapped the ratio of rheumatologists to the general population and to patients with rheumatologic disease using data from Statistics Korea and the 2015 Health Insurance Review & Assessment Service (HIRA). Results In the 16 administrative districts of Korea in 2015, there were 311 practicing rheumatologists on the list of KCR members. There were 218 members practicing in metropolitan areas and 93 members in the provinces. The mean number of rheumatologists per 100,000 people was 0.60, with 0.33/100,000 in the provinces, but 0.92/100,000 in metropolitan areas, a 2.7-fold difference. The number of rheumatologists per 100,000 patients with chronic rheumatic disease was 17.21 in metropolitan areas but 6.57 in the provinces, according to 2015 HIRA data. This geographic maldistribution emerged as a problem; indeed, the regional disparity in the distribution of Korean rheumatologists was striking when compared to the published medical professional distribution in 2014. Conclusion Because of the uneven distribution of rheumatologists, it is likely that some patients with chronic rheumatic conditions have limited access to rheumatology care. Thus, a policy-based approach is needed to alleviate this disparity.

Background/Aims: The objective of this study was to compare changes in the simplified disease activity index (SDAI) between biologic (b) and conventional (c) disease-modifying antirheumatic drugs (DMARD) users with seropositive rheu matoid arthritis (RA) in daily clinical practice. Methods: This was a nationwide multicenter observational study. Patients who had three or more active joint counts and abnormal inf lammatory marker in blood test were enrolled. The selection of DMARDs was determined by the attending rheumatologist. Clinical parameters, laboratory findings, and Health Assessment Questionnaire (HAQ) scores were obtained at baseline and at 6 and 12 months. Se rial SDAI changes and clinical remission rate at 6 and 12 months were assessed. Results: A total of 850 patients participated in this study. The mean baseline SDAI score in bDMARD group was higher than that in cDMARD group (32.08 ± 12.98 vs 25.69 ± 10.97, p < 0.0001). Mean change of SDAI at 12 months was -19.0 in the bDMARD group and -12.6 in the cDMARD group (p < 0.0001). Clinical remission rates at 12 months in bDMARD and cDMARD groups were 15.4% and 14.6%, re spectively. Patient global assessment and HAQ at 12 months were also significantly improved in both groups. Multivariate logistic regression showed that baseline HAQ score was the most notable factor associated with remission. Conclusions: There was a significant reduction in SDAI within 12 months after receiving DMARDs in Korean seropositive RA patients irrespective of bDMARD or cDMARD use in real-world practice. Clinical remission was achieved in those with lower baseline HAQ scores.

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 Disease-specific factors that predispose patients to diverse cardiac diseases in systemic lupus erythematosus (SLE) have been established. The aim of this study was to identify risk factors for cardiac involvement in patients with SLE drawn from the Korean Lupus Network (KORNET) registry. Methods A total of 437 patients with SLE recruited from the KORNET registry were included in the analysis. The Cox proportional hazard model was used to identify risk factors for the development of cardiac involvement during the follow-up period. The hazard ratios for risk factors of cardiac involvement were assessed using Kaplan-Meier curves and log-rank test. Results Of 437 patients with SLE, 12 patients (2.7%) developed new cardiac involvement during a median follow-up period of 47.6 months. Frequencies in men and in patients with anti-Sm antibody, anti-Ro antibody, and at least one Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index (SDI) score in patients with cardiac involvement were higher, compared to those without cardiac involvement (P < 0.001, P = 0.026, P = 0.015, and P < 0.001, respectively). Men gender, older age, anti-Sm antibody, SDI, and corticosteroid dosage were potent predictors for cardiac involvement in patients with SLE in the determination of risk factors for cardiac involvement. Men, anti-Sm antibody positivity, and SDI ≥ 1 increased incidence rates of cardiac involvement for (P < 0.001, P = 0.036, and P < 0.001, respectively). Conclusion The results of this study reveal that SLE-related factors such as anti-Sm antibody, SDI, and corticosteroid dosage at baseline are risk factors for cardiac involvement in SLE., Graphical Abstract

AIM The clinical importance of the anti-Ro antibody has not been completely understood. This study investigated identification of the association between mortality and clinical features in patients with autoimmune rheumatic diseases and detectable anti-Ro antibody titers. METHODS We retrospectively analyzed a total of 336 patients with autoimmune rheumatic diseases and positive anti-Ro antibody titers from January 2012 to January 2015. Clinical manifestations and other autoantibodies detected during the follow-up period were identified. Cumulative survival rates were assessed by Kaplan-Meier analysis. Differences between survival curves for each risk factor were analyzed by log-rank test. The relative risk of mortality was assessed using standardized mortality ratios (SMRs). RESULTS There was no difference in the mortality rates of patients with autoimmune rheumatic diseases with or without detectable anti-Ro antibody (SMR: 1.373, 95% CI: 0.539-2.791). Six patients (4 with systemic lupus erythematosus [SLE] and two with Sjogren's syndrome [SS]) died during the follow-up period. In the whole study population, the mortality rate of patients with lymphopenia was higher than those without lymphopenia (P = 0.023). In a sub-group of patients with both SLE and SS, Kaplan-Meier analysis showed that lymphopenia and interstitial lung disease were associated with increased mortality (P = 0.024 and P = 0.023, respectively). CONCLUSION This study demonstrated that presence of the anti-Ro antibody was not associated with increased mortality in patients with autoimmune rheumatic disease. Conversely, we found that lymphopenia was independently associated with mortality in patients with autoimmune rheumatic disease.

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.

ObjectivesEfficacy, safety and immunogenicity results from the phase III study of SB2, a biosimilar of reference infliximab (INF), were previously reported through 54 weeks. This transition period compared results in patients with rheumatoid arthritis (RA) who switched from INF to SB2 with those in patients who maintained treatment with INF or SB2.MethodsPatients with moderate to severe RA despite methotrexate treatment were randomised (1:1) to receive SB2 or INF at weeks 0, 2 and 6 and every 8 weeks thereafter until week 46. At week 54, patients previously receiving INF were rerandomised (1:1) to switch to SB2 (INF/SB2 (n=94)) or to continue on INF (INF/INF (n=101)) up to week 70. Patients previously receiving SB2 continued on SB2 (SB2/SB2 (n=201)) up to week 70. Efficacy, safety and immunogenicity were assessed up to week 78.ResultsEfficacy was sustained and comparable across treatment groups. American College of Rheumatology (ACR) 20 responses between weeks 54 and 78 ranged from 63.5% to 72.3% with INF/SB2, 66.3%%–69.4% with INF/INF and 65.6%–68.3% with SB2/SB2. Treatment-emergent adverse events during this time occurred in 36.2%, 35.6% and 40.3%, respectively, and infusion-related reactions in 3.2%, 2.0% and 3.5%. Among patients who were negative for antidrug antibodies (ADA) up to week 54, newly developed ADAs were reported in 14.6%, 14.9% and 14.1% of the INF/SB2, INF/INF and SB2/SB2 groups, respectively.ConclusionsThe efficacy, safety and immunogenicity profiles remained comparable among the INF/SB2, INF/INF and SB2/SB2 groups up to week 78, with no treatment-emergent issues or clinically relevant immunogenicity after switching from INF to SB2.Trial registration numberNCT01936181; EudraCT number: 2012-005733-37.

To identify the prevalence of interstitial lung disease (ILD) in Korean patients with rheumatoid arthritis (RA) and assess its effect on mortality. A total of 3555 patients with RA, with chest X-ray or chest computed tomography (CT) data at enrollment were extracted from the KORean Observational study Network for Arthritis cohort, a nationwide prospective cohort for patients with RA in Korea. The patients were classified into two groups: (1) an ILD group by chest X-ray or chest CT scan, and (2) a non-ILD group by these modalities. After comparing the characteristics of the groups at enrollment, mortalities were compared using the log-rank test. To explore the impact of ILD on mortality, Cox proportional hazard models were used. Sixty-four patients (1.8%) were identified with ILD. Male and older patients were more common in the ILD group. During a mean follow-up of 24 months, 6 patients (9.4%) in the ILD group and 25 patients (0.7%) in the non-ILD group died; the survival rate was significantly worse in the ILD group (p

The purpose of the present study was to investigate the prevalence and incidence of gout in Korea and predict the future prevalence and incidence of gout. Data were collected from the national health claims database. Patients who had at least one claim for gout between 2007 and 2015 were included in the study. The prevalence of gout from 2007 to 2015 and the incidence of gout from 2009 to 2015 were determined. We estimated sex- and age-specific prevalence and incidence of gout during the period. The prevalence and incidence of gout were predicted using time series analysis. The prevalence of gout (95% CI) increased from 3.49 (3.48-3.51) per 1000 persons in 2007 to 7.58 (7.55-7.60) per 1000 persons in 2015. The incidence of gout (95% CI) was 1.52 (1.51-1.53) in 2009 and rose to 1.94 (1.93-1.95) per 1000 persons in 2015. The prevalence and incidence of gout were higher in men than in women. The older population had a higher prevalence and incidence than the younger population. The increase in prevalence was higher in the older population than the younger population, whereas the increase in incidence was higher in the younger population than the older population. The predicted prevalence and incidence of gout (95% CI) in 2025 were 16.59 (15.85-17.34) per 1000 persons and 3.81 (3.14-4.47) per 1000 persons. The prevalence and incidence of gout increased in Korea between 2007 and 2015. Men and the older population had a higher prevalence and incidence of gout compared to women and the younger population. However, the incidence of gout in the younger population has increased rapidly in recent years.

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.

Remission is a primary end point of in clinical practice and trials of treatments for rheumatoid arthritis (RA). The 2011 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) remission criteria were developed to provide a consensus definition of remission. This study aimed to assess the concordance between the new remission criteria and the physician’s clinical judgment of remission and also to identify factors that affect the discordance between these two approaches. A total of 3,209 patients with RA were included from the KORean Observational Study Network for Arthritis (KORONA) database. The frequency of remission was evaluated based on each approach. The agreement between the results was estimated by Cohen’s kappa (κ). Patients with remission according to the 2011 ACR/EULAR criteria (i.e. the Boolean criteria) and/or physician judgment (n = 855) were divided into three groups: concordant remission, the Boolean criteria only, and physician judgment only. Multinomial logistic regression analysis was used to identify factors responsible for the assignment of patients with remission to one of the discordant groups rather than the concordant group. The remission rates using the Boolean criteria and physician judgment were 10.5% and 19.9%, respectively. The agreement between two approaches for remission was low (κ = 0.226) and the concordant remission rate was only 5.5% (n = 177). Pain affected classification in both discordant groups, whereas fatigue was associated with remission only by physician clinical judgment. The Boolean criteria were more stringent than clinical judgment. Patient subjective symptoms such as pain and fatigue were associated with discordance between the two approaches., Graphical Abstract

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.

To identify the level of agreement between patients with rheumatoid arthritis (RA) and physicians in the global assessment of disease activity and to explore factors influencing their discordance.A total of 4368 patients with RA were analyzed from the KORean Observational study Network for Arthritis (KORONA) database. Patients were divided into four subgroups according to difference from their physicians in the assessment of disease activity by substracting physician's visual analog scale (VAS) from patient's VAS as follows: positive discordance group I (10 mm ≤ discordance25 mm), positive discordance group II (≥25 mm), concordance (|10| mm), and negative discordance (≤ -10mm). Multinomial logistic regression analysis was performed to identify factors associated with discordance.Only 1350 (29.2%) patients were classified in the concordance group. Positive discordance was found in 52.3% of the patients (n = 2425), with 33.7% (n = 1563) showing marked discordance (≥25 mm). The high disease activity (OR =1.41), gastrointestinal (GI) disease (OR =1.28), pain (OR =1.12), fatigue (OR =1.07) were consistently associated with positive discordance.More than half of patients with RA thought their disease more severe than their physicians. In addition to high disease activity, pain, fatigue, and sleep disturbance or GI disease were associated with the discordance between physicians and patients with RA.

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.

Objective The objective of this study was to investigate the roles of dickkopf-1 (DKK-1) and integrin-related focal adhesion kinase (FAK) by TNF-α on the migration of fibroblast-like synoviocytes (FLSs) in RA. Methods Wound scratch assays were performed to assess FLS migration. Western blotting was used to measure the levels of DKK-1, Wnt signalling molecules and FAK signalling molecules. Quantitative real-time PCR was used to measure the expression levels of DKK-1, integrin αv, laminin, fibronectin, E-cadherin, MMP-8 and MMP-13. The concentrations of DKK-1, TNF-α and GSK-3β were measured by ELISA. Genetic silencing of TNF-α was achieved by the transfection of small interfering RNA into cells. Results Migrating RA FLSs exhibited higher levels of DKK-1 and TNF-α expression compared with those in OA FLSs and/or stationary RA FLSs. Moreover, migrating FLSs exhibited significantly higher levels of FAK, p-JNK, paxillin and cdc42 expression, whereas the level of cytosolic β-catenin was lower. WAY-262611, Wnt pathway agonist via inhibition of DKK-1, markedly inhibited cell migration of RA FLSs through the accumulation of cytosolic β-catenin and suppression of FAK-related signalling pathways. TNF-α treatment to RA FLSs up-regulated expression of DKK-1, integrin αv, fibronectin, laminin and MMP-13. TNF-α stimulation also suppressed cytosolic β-catenin and E-cadherin expression in a time-dependent manner. Moreover, TNF-α small interfering RNA-transfected migrating FLSs exhibited decreased activation of integrin-related FAK, paxillin, p-JNK and cdc42 signalling pathways. Conclusion This study demonstrates that the activation of DKK-1 and the integrin-related FAK signalling pathway stimulated by TNF-α induces the dissociation of β-catenin/E-cadherin, thus promoting RA FLS migration.

Purpose Ethanol elicits several inflammatory responses and affects the innate immune response. The aim of this study was to identify the mechanism by which ethanol affects uric acid-induced NLR family pyrin domain-containing 3 (NLRP3) inflammasome activation by regulation of aryl hydrocarbon receptor (AhR) and thioredoxin-interacting protein (TXNIP). Materials and Methods Human myeloid leukemia cells (U937 cells) were used to assess the role of ethanol in NLRP3 inflammasome activation induced by monosodium urate (MSU) crystals. Expression of target molecules, such as NLRP3 inflammasome components, AhR, and TXNIP, were measured using quantitative real-time PCR and Western blot analyses. The effect of ethanol-induced TXNIP on the NLRP3 inflammasome was assessed in human macrophages transfected with TXNIP siRNA. Results U937 cells treated with 100 mM ethanol for 24 h induced NLRP3 and interleukin (IL)-1β expression. Ethanol increased reactive oxygen species generation in a time- and dose-dependent manner. AhR mRNA expression was downregulated in U937 cells treated with 100 mM ethanol, whereas CYP1A1 mRNA expression increased. Treatment with ethanol increased NLRP3 and IL-1β mRNA and protein expression in U937 cells exposed to 1.0 mg/mL of MSU crystals for 24 h. TXNIP expression in U937 cells incubated with both 100 mM ethanol and 1.0 mg/mL of MSU crystals was significantly higher than in cells incubated with MSU crystals alone. Treatment with 100mM ethanol for 24 h downregulated NLRP3 and IL-1β expression in MSU crystal-activated U937 cells transfected with TXNIP siRNA, compared to those with scramble siRNA. Conclusion Ethanol stimulates uric acid-induced NLRP3 inflammasome activation through regression of AhR and upregulation of TXNIP.

ObjectiveTo evaluate the relationship between disease activity and radiographic progression in rheumatoid arthritis, three phase III studies of SB4, SB2 and SB5 (biosimilars of etanercept, infliximab and adalimumab) were pooled to assess radiographic progression by disease activity status.MethodsPatients from each study with radiographic data were pooled and grouped based on disease activity state (remission, low disease activity (LDA), moderate disease activity (MDA) and high disease activity (HDA)), determined by disease activity score based on 28-joint count (DAS28) per erythrocyte sedimentation rate, Simplified Disease Activity Index (SDAI) and Clinical Disease Activity Index (CDAI) at different time points. Mean change in modified Total Sharp Score (mTSS) and the proportion of radiographic non-progressors of higher disease activity groups (LDA, MDA and HDA) in reference to remission were summarised descriptively, with comparison of ORs using logistic models.Results1265 patients were included. In all treatments combined, the 1 year mean change in mTSS was 0.03, 0.4, 0.3 and 1.3 and proportion of radiographic non-progressors was 79.8%, 78.1%, 74.1% and 58.4% in the week 24/30 DAS28-determined remission, LDA, MDA and HDA groups, respectively. ORs (95% CIs) of the proportion of non-progressors were lowest in the HDA group in reference to remission (0.35 (0.23 to 0.54)), followed by MDA (0.72 (0.50 to 1.05)) and LDA (0.90 (0.55 to 1.48)) groups. Similar trends were observed when disease activity was assessed using SDAI or CDAI.ConclusionA pooled analysis of radiographic assessment data from three biosimilar studies showed that radiographic progression is small overall but increases with worse disease activity.Trial registration numbersNCT01895309, NCT01936181 and NCT02167139

Objective. The aim of this study was to determine the relationships of serum and urine uric acid with severity or activity in knee osteoarthritis (OA). Methods. A total of 42 patients with knee OA was enrolled, together with 58 healthy controls. Serum uric acid and spot urine uric acid levels were assessed for all patients. The severity and activity of knee OA were assessed by musculoskeletal ultrasound (MSUS) and plain radiography of the knee joint. Ultrasonographic abnormalities in knee OA includedsynovial hypertrophy, suprapatellar effusion, cartilage degradation, and osteophyte formation. Kellgren-Lawrence (K-L) grade was used to evaluate radiological progression of knee OA. Results. Patients with K-L grade III had a higher urine uric acid/creatinine ratio compared to those with K-L grade I (p=0.043). Patients with synovial hypertrophy had higher serum uric acid level compared to those without synovial hypertrophy (p=0.016). The urine uric acid/creatinine ratio was higher in patients with cartilage degradation compared to those without cartilage degradation (p=0.022). Serum uric acid was significantly associated with synovial hypertrophy thickness (r=0.375, p=0.018) but not with cartilage thickness after adjusting for age and body mass index. Lower urine uric acid was related with knee OA compared to healthy controls (odds ratio=0.974, 95% confidence interval 0.954∼0.994, p=0.013). Conclusion. The results of our study suggest that serum and urine uric acid reflects synovial inflammation based on MSUS and radiographic progression and then is associated with the pathogenesis of knee OA. (J Rheum Dis 2020;27:51-60)

There is an ongoing debate regarding the relationship between uric acid and osteoarthritis (OA). Therefore, we sought to clarify this association using data from the Seventh Korea National Health and Nutrition Examination Survey (KNHANES VII-1) 2016 in the Korean population. A total of 5842 subjects over 19 years old were analyzed from the KNHANES VII-1 2016 data, which was conducted by the Korean Centers for Disease Control and Prevention. All of the statistical analyses were performed on the basis of a sampling weight that represents the entire Korean population. The data were described as case numbers with weighted percentages (%), and means with standard errors (SE). The association between OA and the serum uric acid level was statistically analyzed using univariate and multivariate logistic regression methods. A total of 669 subjects (8.6%) had OA, of which 557 were female (14.0%), and 112 male (3.0%). OA was more frequent in female than male subjects (n = 557, 82.6% in women) (p

Despite high clinical disease activity, some patients with active rheumatoid arthritis (RA) have normal acute phase reactant (APR) values. This study aimed to determine the clinical outcomes of active RA patients with normal APR values.Of 5376 patients with RA enrolled in the Korean observational study network for arthritis (KORONA) registry, 400 patients with disease duration of2 years who had Clinical Disease Activity Index (CDAI) score of2.8 at baseline, biologic-naïve, and erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) drawn at both baseline and 2-year follow-up visits were identified. Patients were grouped according to baseline APR levels: normal APRs, one APR elevated, and both APRs elevated.Baseline tender and swollen joint counts, mean CDAI and Health Assessment Questionnaire-Disability Index (HAQ-DI) scores were significantly lower in the normal APRs group compared with APR-elevated groups (P 0.0001). At 2-year follow-up, mean CDAI scores, HAQ-DI, and percentage of the patient achieving remission were not significantly different between the normal APRs group compared with the APR-elevated groups regardless of the baseline disease activity. However, in patients with baseline CDAI moderate to high disease activity, the normal APRs group less frequently required initiation of the biologic disease-modifying anti-rheumatic drugs compared with the APR-elevated groups (P = 0.044).Active RA patients with normal APR values have milder disease presentation, but similar clinical outcomes to those with elevated APRs.

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.

Background/aims Gout is a common inf lammatory arthritis triggered by the crystallization of uric acid in the joints. Serum uric acid levels are highly heritable, suggesting a strong genetic component. Independent studies to confirm the genetic associations with gout in various ethnic populations are warranted. We investigated the association of polymorphisms in the ABCG2 and SLC2A9 genes with gout in Korean patients and healthy individuals. Methods We consecutively enrolled 109 patients with gout and 102 healthy controls. The diagnosis of gout was based on the preliminary criteria of the America College of Rheumatology. Genomic DNA was extracted from whole blood samples. We identified single nucleotide polymorphism (SNP) changes in the ABCG2 and SLC2A9 genes using a direct sequencing technique. rs2231142 in ABCG2 and rs6449213 and rs16890979 in SLC2A9 and nearby regions were amplified by polymerase chain reaction. Results Patients with gout had significantly higher A/A genotype (29.3% vs. 4.9%, respectively) and A allele (52.8% vs. 26.5%, respectively) frequencies of rs2231142 in ABCG2 than did controls (χ(2) = 29.42, p G and c.1002+78G>A) in the SLC2A9 gene. The univariate logistic regression analysis revealed that the c.881A>G and c.1002+78G>A SNPs were significantly higher in patients than in controls. Conclusions We demonstrated a significant association between rs2231142 in the ABCG2 gene and gout and identified novel SNPs, c.881A>G and c.1002+78G>A, in the SLC2A9 gene that may be associated with gout in a Korean population.

ObjectivesTo compare the efficacy, safety, immunogenicity and pharmacokinetics (PK) of SB2 to the infliximab reference product (INF) in patients with moderate to severe rheumatoid arthritis (RA) despite methotrexate therapy.MethodsThis is a phase III, randomised, double-blind, multinational, multicentre parallel group study. Patients with moderate to severe RA despite methotrexate therapy were randomised in a 1:1 ratio to receive either SB2 or INF of 3 mg/kg. The primary end point was the American College of Rheumatology 20% (ACR20) response at week 30. Inclusion of the 95% CI of the ACR20 response difference within a ±15% margin was required for equivalence.Results584 subjects were randomised into SB2 (N=291; 290 analysed) or INF (N=293). The ACR20 response at week 30 in the per-protocol set was 64.1% in SB2 versus 66.0% in INF. The adjusted rate difference was −1.88% (95% CI −10.26% to 6.51%), which was within the predefined equivalence margin. Other efficacy outcomes such as ACR50/70, disease activity score measured by 28 joints and European League against Rheumatism response were similar between SB2 and INF. The incidence of treatment-emergent adverse events was comparable (57.6% in SB2 vs 58.0% in INF) as well as the incidence of antidrug antibodies (ADA) to infliximab up to week 30 (55.1% in SB2 vs 49.7% in INF). The PK profile was similar between SB2 and INF. Efficacy, safety and PK by ADA subgroup were comparable between SB2 and INF.ConclusionsSB2 was equivalent to INF in terms of ACR20 response at week 30. SB2 was well tolerated with a comparable safety profile, immunogenicity and PK to INF.Trial registration numberNCT01936181.

Objective.Several studies have reported risk factors for hydroxychloroquine (HCQ) retinal toxicity, but data are limited for patients of Asian ancestry. The aim of this study was to investigate the rate of and factors for HCQ retinal toxicity in the Korean population.Methods.There were 123 patients enrolled in this study who were using or had used HCQ. Retinal toxicity was detected using spectral domain optical coherence tomography, fundus autofluorescence, multifocal electroretinography, and automated visual field testing. Binary logistic regression analysis was performed to identify factors associated with HCQ retinal toxicity.Results.Mean duration of HCQ use and mean HCQ dose in study participants was 10.1 years and 6.4 mg/kg, respectively. We found 17 patients (13.8%) with HCQ retinal toxicity among 123 patients. Patients with retinal toxicity took HCQ ranging from 6.7–21.9 years and daily dosage ranging from 4.9–9.1 mg/kg. Only 1 patient had retinal toxicity among patients with daily dose < 5.0 mg/kg. These factors increased the risk of HCQ retinal toxicity: longer duration of HCQ use [adjusted OR (aOR) = 4.71, 95% CI 2.18–10.15 for duration of HCQ use in 5-yr increments], higher daily HCQ dose (aOR = 3.34, 95% CI 1.03–10.80 for daily HCQ dose in 100-mg increments), and the presence of kidney disease (aOR = 8.56, 95% CI 1.15–64.00).Conclusion.HCQ retinal toxicity is associated with duration of HCQ use, daily HCQ dose, and presence of kidney disease. Proper dosing of maximum 5 mg/kg and regular screening according to risk factors are important in HCQ use.

Summary Background Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. The Oral Rheumatoid Arthritis triaL (ORAL) Strategy aimed to assess the comparative efficacy of tofacitinib monotherapy, tofacitinib plus methotrexate, and adalimumab plus methotrexate for the treatment of rheumatoid arthritis in patients with a previous inadequate response to methotrexate. Methods ORAL Strategy was a 1 year, double-blind, phase 3b/4, head-to-head, non-inferiority, randomised controlled trial in patients aged 18 years or older with active rheumatoid arthritis despite methotrexate therapy. Patients were randomly assigned (1:1:1) to receive oral tofacitinib (5 mg twice daily) monotherapy, oral tofacitinib (5 mg twice daily) plus methotrexate, or subcutaneous adalimumab (40 mg every other week) plus methotrexate at 194 centres in 25 countries. Eligible patients received live zoster vaccine at investigators' discretion. The primary endpoint was the proportion of patients who attained an American College of Rheumatology response of at least 50% (ACR50) at month 6 in the full analysis set (patients who were randomly assigned to a group and received at least one dose of the study treatment). Non-inferiority between groups was shown if the lower bound of the 98·34% CI of the difference between comparators was larger than −13·0%. This trial is registered with ClinicalTrials.gov, number NCT02187055. Findings 1146 patients received treatment (384 had tofacitinib monotherapy; 376 had tofacitinib and methotrexate; and 386 had adalimumab and methotrexate). At 6 months, ACR50 response was attained in 147 (38%) of 384 patients with tofacitinib monotherapy, 173 (46%) of 376 patients with tofacitinib and methotrexate, and 169 (44%) of 386 patients with adalimumab and methotrexate. Non-inferiority was declared for tofacitinib and methotrexate versus adalimumab and methotrexate (difference 2% [98·34% CI −6 to 11]) but not for tofacitinib monotherapy versus either adalimumab and methotrexate (−6 [−14 to 3]) or tofacitinib and methotrexate (−8 [−16 to 1]). In total, 23 (6%) of 384 patients receiving tofacitinib monotherapy, 26 (7%) of 376 patients receiving tofacitinib plus methotrexate, and 36 (9%) of 386 patients receiving adalimumab plus methotrexate discontinued due to adverse events. Two (1%) of the 384 patients receiving tofacitinib monotherapy died. No new or unexpected safety issues were reported for either treatment in this study for up to 1 year. Interpretation Tofacitinib and methotrexate combination therapy was non-inferior to adalimumab and methotrexate combination therapy in the treatment of rheumatoid arthritis in patients with an inadequate response to methotrexate in this trial. Tofacitinib monotherapy was not shown to be non-inferior to either combination. Funding Pfizer Inc.

Objectives This study aims to evaluate the effects of passive smoking on disease activity in female patients with rheumatoid arthritis (RA). Patients and methods Among a total of 191 female patients with RA (mean age 59.1±12.5 years; range 21 to 87 years) consecutively recruited, 100 female patients (mean age 56.1±13.4 years; range 21 to 87 years) completed the study with mean 17.3 months of follow-up. Patients were classified according to smoking status: current, never, passive, or ex-smoker. Clinical response between never and passive smokers was assessed by disease- activity score 28 (DAS28)-erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) (DAS28-ESR and DAS28-CRP) and by the European League Against Rheumatism response criteria. Results Among the 100 female RA patients analyzed, the distribution of smoking status was as follows: current (n=3), never (n=55), passive (n=34), and ex-smokers (n=8). There was no difference of DAS28-ESR and DAS28-CRP between never and passive smokers at baseline. At the time of follow-up, the values of DAS28-ESR and DAS28-CRP in never smokers were significantly decreased than those in passive smokers (p=0.019 and p=0.023, respectively). Patients who never smoked showed a trend to have good or moderate European League Against Rheumatism response without statistical significance, compared to passive smokers (52.7% vs. 32.4%, respectively; p=0.060). Conclusion This preliminary study implicates that passive smoking might be responsible for higher disease activity in female RA patients and never smoking might induce good clinical response in RA.

The purpose of this study was to identify the characteristic magnetic resonance imaging (MRI) findings in neuropsychiatric systemic lupus erythematosus (NPSLE) and to investigate the association between MRI findings and neuropsychiatric manifestations in SLE. Brain MRIs with a diagnosis of SLE from 2002 to 2013 from three tertiary university hospitals were screened. All clinical manifestations evaluated by brain MRI were retrospectively reviewed. If the clinical manifestations were compatible with the 1999 NPSLE American College of Rheumatology (ACR) nomenclature and case definitions, the brain MRIs were assessed for the presence of white matter hyperintensities, gray matter hyperintensities, parenchymal defects, atrophy, enhancement, and abnormalities in diffusion-weighted images (DWI). The number, size, and location of each lesion were evaluated. The neuropsychiatric manifestation of each brain MRI was classified according to the 1999 ACR NPSLE case definitions. The associations between MRI findings and NPSLE manifestations were examined. In total, 219 brain MRIs with a diagnosis of SLE were screened, and 133 brain MRIs met the inclusion criteria for NPSLE. The most common MRI abnormality was white matter hyperintensities, which were observed in 76 MRIs (57.1 %). Gray matter hyperintensities were observed in 41 MRIs (30.8 %). Parenchymal defects were found in 31 MRIs (23.3 %), and atrophy was detected in 20 MRIs (15.0 %). Patients who had seizures were more associated with gray matter hyperintensities than patients with other neuropsychiatric manifestations. Patients with cerebrovascular disease were more associated with gray matter hyperintensity, parenchymal defects, and abnormal DWI than patients with other neuropsychiatric manifestations. In addition to white matter hyperintensities, which were previously known as SLE findings, we also noted the presence of gray matter hyperintensities, parenchymal defects, and abnormal DWI in a substantial portion of SLE patients, particularly in those with cerebrovascular disease or seizures.

Although chronic kidney disease (CKD) may constitute a chronic inflammatory state indicated by elevated inflammatory mediators such as tumor necrosis factor alpha (TNF-α), the impact of anti-TNF-α therapy on progression of CKD in patients with rheumatoid arthritis (RA) is unclear. Seventy patients with RA and CKD were retrospectively analyzed. Outcomes were evaluated using the difference in the annual change of estimated glomerular filtration rate (eGFR) between patients treated with anti-TNF-α or without. Anti-TNF-α therapy significantly decreased disease activity score (DAS) 28 from 5.32 ± 0.78 to 3.59 ± 0.85 (p < 0.001). There was a tendency toward stabilization of eGFR after a mean of 2.9 ± 1.1 years from 50.3 ± 8.4 ml/min/1.73 m(2) to 54.5 ± 16.0 ml/min/1.73 m(2) in patients received anti-TNF-α therapy along with decreased DAS28 (p = 0.084). Conversely, eGFR decreased significantly in patients not receiving anti-TNF-α therapy after a mean of 2.8 ± 1.7 years from 52.6 ± 7.5 ml/min/1.73 m(2) to 46.5 ± 11.5 ml/min/1.73 m(2) (p = 0.041) without significant DAS28 change (p = 0.078). The annual change of eGFR was significantly different between patients treated with anti-TNF-α drugs and without (2.0 ± 7.0 ml/min/1.73 m(2)/year vs. -1.9 ± 4.0 ml/min/1.73 m(2)/year; difference in mean vs. -3.9 ± 7.3 ml/min/1.73 m(2)/year; p = 0.006). Use of anti-TNF-α drugs was significantly associated with positive annual change of eGFR in multivariate logistic regression analysis (p = 0.019). Among patients with RA and CKD, treatment with anti-TNF-α drugs was associated with less renal function decline. Anti-TNF-α drugs may be beneficial for managing RA combined with CKD.

To evaluate the performance of Routine Assessment of Patient Index Data 3 (RAPID3) with the disease activity score 28 (DAS28) and the clinical/simplified disease activity index (CDAI/SDAI) in a Korean population with rheumatoid arthritis (RA). Four hundred patients with RA were consecutively enrolled. All patients completed disease activity indices such as RAPID3, DAS28, SDAI, and CDAI. The kappa and/or weighted coefficients were used to assess agreement between RAPID3 and other disease activity indices. ANOVA, Mantel–Haenszel chi-square test, and Spearman’s partial correlation analysis were used for analyses. RAPID3 scores were significantly correlated with DAS28 (r = 0.62), SDAI (r = 0.74), and CDAI (r = 0.75; p < 0.0001 for all indices) and other activity measures including swollen/tender joint counts, erythrocyte sediment rate, and C-reactive protein. The weighted kappa coefficients of RAPID3 with DAS28, SDAI, and CDAI among the four disease activity categories were 0.33, 0.34, and 0.33, respectively. Kappa coefficients for RAPID3 in two disease activity categories increased more than four categories (κ = 0.40–0.42) indicating fair agreement. More than 86 % of patients with high-to-moderate disease activity in DAS28, CDAI, and SDAI had high-to-moderate disease activity using RAPID3 criteria. However, approximately 50 % of patients with remission-to-low disease activity in DAS28, CDAI, and SDAI showed remission-to-low disease activity in RAPID3. This study confirms RAPID3 as an informative disease activity index with equivalent values in DAS28, CDAI, and SDAI. RAPID3 reveals differential agreement in patients with lower disease activity.

Objectives SB2 is a biosimilar to the reference infliximab (INF). Similar efficacy, safety and immunogenicity between SB2 and INF up to 30 weeks were previously reported. This report investigates such clinical similarity up to 54 weeks, including structural joint damage. Methods In this phase III, double-blind, parallel-group, multicentre study, patients with moderate to severe RA despite MTX were randomized (1:1) to receive 3 mg/kg of either SB2 or INF at 0, 2, 6 and every 8 weeks thereafter. Dose escalation by 1.5 mg/kg up to a maximum dose of 7.5 mg/kg was allowed after week 30. Efficacy, safety and immunogenicity were measured at each visit up to week 54. Radiographic damage evaluated by modified total Sharp score was measured at baseline and week 54. Results A total of 584 patients were randomized to receive SB2 (n = 291) or INF (n = 293). The rate of radiographic progression was comparable between SB2 and INF (mean modified total Sharp score difference: SB2, 0.38; INF, 0.37) at 1 year. ACR responses, 28-joint DAS, Clinical Disease Activity Index and Simplified Disease Activity Index were comparable between SB2 and INF up to week 54. The incidence of treatment-emergent adverse events and anti-drug antibodies were comparable between treatment groups. Such comparable trends of efficacy, safety and immunogenicity were consistent from baseline up to 54 weeks. The pattern of dose increment was also comparable between SB2 and INF. Conclusion SB2 maintained similar efficacy, safety and immunogenicity with INF up to 54 weeks in patients with moderate to severe RA. Radiographic progression was comparable at 1 year. Trial registration ClinicalTrials.gov (http://clinicaltrials.gov; NCT01936181) and EudraCT (https://www.clinicaltrialsregister.eu; 2012-005733-37).

Objective: We investigated whether body mass index (BMI) is associated with parameters of disease activity and clinical manifestations in axial spondyloarthritis (axSpA). Methods: Demographic, clinical, and radiological features and disease activity indexes from 789 axSpA patients (619 males and 170 females) were obtained from the Korean College of Rheumatology BIOlogics (KOBIO) registry. BMI (kg/m2) was classified into normal (BMI Results: The mean BMI in patients with axSpA was 23.3 ± 3.5. 50.2% of all patients were overweight or obese. Overweight/obese patients had more syndesmophyte and less peripheral arthritis than those in normal BMI patients (p p p p = 0.002) Conclusions: Our results imply that increased BMI is significantly associated with the presence of syndesmophyte, but not with disease activity in axSpA.

Joint Bone Spine - In Press.Proof corrected by the author Available online since lundi 20 mars 2017

textabstractObjective Remission is a key goal in managing rheumatoid arthritis (RA), with sustained remission as the preferred sequelae of short-term remission. However little is known about the predictors of sustained remission for patients reaching remission. Using two independent cohorts, we aimed to evaluate the prevalence and predictors for sustained remission. Methods The study cohort consisted of subjects with RA from the Brigham and Women’s Hospital Rheumatoid Arthritis Sequential Study (BRASS) and the Korean Observational Study Network for Arthritis (KORONA). We analyzed subjects who reached remission in 2009 with follow up data for two consecutive years. Remission was defined by the Disease Activity Score 28- (DAS28-CRP) of less than 2.6. Sustained remission was defined as three consecutive annual visits in remission. Predictors for sustained remission were identified by multivariate logistic regression analysis. Results A total of 465 subjects were in remission in 2009. Sustained remission was achieved by 53 of 92 (57.5%) in BRASS and by 198 of 373 (53.1%) in KORONA. In multivariate analyses, baseline predictors of sustained remission were: disease duration less than 5 years [odds ratio (OR) 1.96, 95% confidence interval (95% CI) 1.08–3.58], Modified Health Assessment Questionnaire (MHAQ) score of 0 (OR 1.80, 95% CI 1.18–2.74), and non-use of oral glucocorticoid (OR 1.58, 95% CI 1.01–2.47). Conclusion More than half of RA subjects in remission in 2009 remained in remission through 2011. Short disease duration, no disability, and non-use of oral glucocorticoid at baseline were associated with sustained remission.