Real-world effectiveness of a single conventional disease-modifying anti-rheumatic drug (cDMARD) plus an anti-TNF agent versus multiple cDMARDs in rheumatoid arthritis: a prospective observational study.

Objective: The objective of this prospective, observational multicenter study (NCT03264703) was to compare the effectiveness of single conventional disease-modifying anti-rheumatic drug (cDMARD) plus anti-tumor necrosis factor (TNF) therapy versus multiple cDMARD treatments in patients with moderate-to-severe rheumatoid arthritis (RA) following cDMARD failure in the real-world setting in South Korea. Methods: At the treating physicians' discretion, patients received single cDMARD plus anti-TNF therapy or multiple cDMARDs. Changes from baseline in disease activity score 28-joint count with erythrocyte sedimentation rate (DAS28-ESR), corticosteroid use, and Korean Health Assessment Questionnaire (KHAQ-20) scores were evaluated at 3, 6, and 12 months. Results: Of 207 enrollees, the final analysis included 45 of 73 cDMARD plus anti-TNF and 91 of 134 multiple-cDMARD recipients. There were no significant between-group differences (BGDs) in ANCOVA-adjusted changes from baseline in DAS28-ESR at 3, 6 (primary endpoint), and 12 months (BGDs -0.18, -0.38, and -0.03, respectively). More cDMARD plus anti-TNF than multiple-cDMARD recipients achieved a >50% reduction from baseline in corticosteroid dosage at 12 months (35.7% vs 14.6%; p=0.007). Changes from baseline in KHAQ-20 scores at 3, 6, and 12 months were significantly better with cDMARD plus anti-TNF therapy than with multiple cDMARDs (BGD -0.18, -0.19, and -0.19 points, respectively; all p≤0.024). Conclusion: In the real-world setting, relative to multiple cDMARDs, single cDMARD plus anti-TNF therapy significantly improved quality-of-life scores and reduced corticosteroid use, with no significant BGD in disease activity, in RA patients in whom previous cDMARD therapy had failed.

Association of HLA-DRB1 locus with treatment response to abatacept or TNF inhibitors in patients with seropositive rheumatoid arthritis.

The strongest genetic risk factor for rheumatoid arthritis (RA) has been known as HLA-DRB1 based on amino acid positions 11, 71, and 74. This study analyzed the association between specific HLA-DRB1 locus and treatment response to abatacept or TNF inhibitors (TNFi) in patients with seropositive RA. A total of 374 Korean RA patients were treated with abatacept (n = 110) or TNFi (n = 264). Associations between HLA-DRB1 and treatment response after 6 months were analyzed using multivariable logistic regression. Seropositive RA patients with HLA-DRB1 shared epitope (SE) had a favorable response to abatacept (OR = 3.67, P = 0.067) and an inversely associated response to TNFi (OR 0.57, P = 0.058) based on EULAR response criteria, but the difference was not statistically significant in comparison to those without SE. In analyses using amino acid positions of HLA-DRB1, a significant association was found between valine at amino acid position 11 of SE and good response to abatacept (OR = 6.46, P = 5.4 × 10-3). The VRA haplotype also showed a good response to abatacept (OR = 4.56, P = 0.013), but not to TNFi. Our results suggest that treatment response to abatacept or TNFi may differ depending on HLA-DRB1 locus in seropositive RA, providing valuable insights for selecting optimal therapy.

Comparative effectiveness of JAK inhibitors and biologic disease-modifying antirheumatic drugs in patients with rheumatoid arthritis.

BACKGROUND/AIMS: We aimed to compare the effectiveness and safety of Janus kinase inhibitors (JAKi) vs. biologic disease- modifying antirheumatic drugs (bDMARD) in Korean patients with rheumatoid arthritis (RA) who had an inadequate response to conventional synthetic DMARDs. METHODS: A quasi-experimental, multi-center, prospective, non-randomized study was conducted to compare response rates between JAKi and bDMARDs in patients with RA naïve to targeted therapy. An interim analysis was performed to estimate the proportion of patients achieving low disease activity (LDA) based on disease activity score (DAS)-28- erythroid sedimentation rate (ESR) (DAS28-ESR) at 24 weeks after treatment initiation and to evaluate the development of adverse events (AEs). RESULTS: Among 506 patients enrolled from 17 institutions between April 2020 and August 2022, 346 (196 JAKi group and 150 bDMARD group) were included in the analysis. After 24 weeks of treatment, 49.0% of JAKi users and 48.7% of bDMARD users achieved LDA (p = 0.954). DAS28-ESR remission rates were also comparable between JAKi and bDMARD users (30.1% and 31.3%, respectively; p = 0.806). The frequency of AEs reported in the JAKi group was numerically higher than that in the bDMARDs group, but the frequencies of serious and severe AEs were comparable between the groups. CONCLUSION: Our interim findings reveal JAKi have comparable effectiveness and safety to bDMARDs at 24 weeks after treatment initiation.

MUC5B promoter variant rs35705950, rare but significant susceptibility locus in rheumatoid arthritis-interstitial lung disease with usual interstitial pneumonia in Asian populations.

BACKGROUND: MUC5B variant rs35705950 is the common and most significant risk variant for rheumatoid arthritis-interstitial lung disease (RA-ILD) in Western populations. However, little is known about its significant association with RA-ILD in Asian populations. We here investigate the association of rs35705950 with Korean patients with RA-ILD. METHODS: In this cross-sectional study, we genotyped rs35705950 in 2444 patients with RA. Among them, 683 patients with RA who have chest CT were divided into RA-ILD and RA-noILD. RA-ILD was classified as usual interstitial pneumonia (UIP) and other than UIP. The associations of rs35705950 with RA-ILD and its subtype were analysed using multivariable regression adjusted for age at RA diagnosis. Meta-analysis of a previously reported Japanese dataset and Korean dataset obtained for this study was conducted. RESULTS: The minor allele (T) frequency of rs35705950 was 0.37%, 1.43% and 2.38% in 2444 patients with RA, 105 patients with RA-ILD and 63 patients with UIP, respectively. Genotypic association of rs35705950 with RA-ILD was insignificant (OR 2.49, 95% CI 0.64 to 9.69, p=0.187), but showed significant association with UIP (OR 4.90, 95% CI 1.23 to 19.59, p=0.024) compared with RA-noILD. In meta-analysis (123 UIP and 878 RA-noILD) combining our data with previously reported Japanese data, this variant was found to be significantly associated with UIP (OR 3.51, 95% CI 1.19 to 10.37, p=0.023). CONCLUSION: MUC5B variant rs35705950 is a rare but significant risk factor for Asian patients with RA-ILD with UIP, suggesting a sharing of the genetic background between Asian and Western populations.

Predictive Factors for Renal Response in Lupus Nephritis: A Single-center Prospective Cohort Study.

Objective: To identify the predictive factors for renal response in patients with lupus nephritis (LN). Methods: Patients and data were extracted from a prospective systemic lupus erythematosus cohort in Korea, in which clinical data were collected at 0, 3, 6, and 12 months after induction therapy. Treatment response of LN were evaluated as a complete response (CR), partial response (PR), or non-response (NR) at 3, 6, and 12 months, respectively. Predictive factors for CR at 6 months were evaluated using multivariable Poisson regression analysis. Results: A total of 75 patients with LN who underwent biopsy was enrolled. The mean age at diagnosis of LN was 28.9±9.7 years, and 68 (90.7%) were female. The frequencies of classes III, IV, III+V, IV+V, and V were 20.0%, 44.0%, 16.0%, 12.0%, and 8.0%, respectively. Compared to relapsed LN, new-onset LN showed a lower percentage of glomerulosclerosis (45.5% vs. 76.2%, p=0.013). The overall proportions of CR, PR, and NR at 6 and 12 months were 52.0%, 26.7%, 21.3% and 50.7%, 24.0%, 25.3%, respectively. In multivariate analysis, age at enrollment (odds ratio [OR]=1.02, p=0.022), relapsed LN (OR=0.71, p=0.037), anti-Ro antibody (OR=0.67, p=0.014), and class III LN (OR=1.48, p=0.001) were associated with CR at 6 months. Conclusion: In our prospective cohort, class III LN was a good predictive factor for CR at 6 months in patients with LN, whereas younger age, relapsed LN, and anti-Ro antibody were poor predictive factors.

Clinical and Genetic Risk Factors Associated With the Presence of Lupus Nephritis.

Objective: To elucidate whether clinical features and the weighted genetic risk score (wGRS) were associated with the presence of lupus nephritis (LN). Methods: We retrospectively divided patients with systemic lupus erythematosus (SLE, n=1,078) into biopsy-proven LN (n=507) and non-LN groups (non-LN, n=571) Baseline clinical features, serologic markers, and the wGRS were collected The wGRS was calculated from 112 non-human leukocyte antigen (non-HLA) loci and HLA-DRß1 amino acid haplotypes for SLE Associations among clinical features, wGRS, and the presence of LN were identified. Results: In the multivariate analysis, patients with LN were younger at diagnosis (odds ratio [OR]=0.97, p<0.001), had more pleuritis (OR=2.44, p<0.001) and pericarditis (OR=1.62, p=0.029), had a higher detection rate of anti-double stranded deoxyribonucleic acid (anti-dsDNA antibodies, OR=2.22, p<0.001), anti-Smith antibodies (anti-Sm antibodies, OR=1.70, p=0.002), low level of complement (OR=1.37, p=0.043) and absence of antiphospholipid antibodies (aPL antibodies, OR=1.60, p=0.002), and had higher wGRS (OR=1.16, p=0.012) Mediation analysis suggested that anti-Sm antibodies and low complement could be mediators in the relationship between high wGRS and the presence of LN. Conclusion: Onset age, pleuritis, pericarditis, several serologic markers, and wGRS were associated with the presence of LN Anti-Sm antibodies and low complement appeared to mediate the indirect relationship between wGRS and the presence of LN.

Deletion at 2q14.3 is associated with worse response to TNF-α blockers in patients with rheumatoid arthritis.

BACKGROUND: Structural variations such as copy number variations (CNVs) have a functional impact on various human traits. This study profiled genome-wide CNVs in Korean patients with rheumatoid arthritis (RA) to investigate the efficacy of treatment with TNF-α blockers. METHODS: A total of 357 Korean patients with RA were examined for the efficacy of TNF-α blocker treatment. Disease activity indexes were measured at baseline and 6 months after the treatment. The patients were classified as responders and non-responders based on the change in disease activity indexes according to the EULAR response criteria. CNVs in the same patients were profiled using fluorescence signal intensity data generated by a genome-wide SNP array. The association of CNVs with response to TNF-α blockers was analyzed by multivariate logistic regression accounting for genetic background and clinical factors including body mass index, gender, baseline disease activity, TNF-α blocker used, and methotrexate treatment. RESULTS: The study subjects varied in their responses to TNF-α blockers and had 286 common CNVs in autosomes. We identified that the 3.8-kb deletion at 2q14.3 in 5% of the subjects was associated with response to TNF-α blockers (1.37 × 10- 5 ≤ P ≤ 4.07 × 10- 4) at a false discovery rate threshold of 5%. The deletion in the identified CNV was significantly more frequent in the non-responders than in the responders, indicating worse response to TNF-α blockers in the deletion carriers. The 3.8-kb deletion at 2q14.3 is located in an intergenic region with the binding sites of two transcription factors, MAFF and MAFK. CONCLUSIONS: This study obtained the CNV landscape of Korean patients with RA and identified the common regional deletion associated with poor response to treatment with TNF-α blockers.

Successful arthroscopic treatment of refractory and complicated popliteal cyst associated with rheumatoid arthritis in combination with osteoarthritis: case series and literature review.

Although popliteal cysts are most frequently identified in patients with osteoarthritis (OA), they may occur in patients with rheumatoid arthritis (RA), in which serious complicated cases such as cyst rupture can be developed. The objective of this study was to report four patients with RA (six knees) in combination with OA with a brief review of literature of previous similar published cases. This is a retrospective review of case records of patients with refractory and/or complicated popliteal cysts, who have successfully treated with arthroscopic intervention. We suggest that arthroscopic interventions such as radical debridement, synovectomy, biomechanical valve excision, and/or cystectomy should be considered in patients with refractory and complicated popliteal cysts associated with RA or RA in combination with OA.

Association between brain-derived neurotrophic factor gene polymorphisms and fibromyalgia in a Korean population: a multicenter study.

BACKGROUND: Several lines of evidence imply that brain-derived neurotrophic factor (BDNF) is involved in the pathophysiology of fibromyalgia (FM); in this regard, patients with FM have altered blood and cerebrospinal fluid levels of BDNF. In this study, we explored the association between BDNF gene polymorphisms and FM susceptibility and the severity of symptoms. METHODS: In total, 409 patients with FM and 423 healthy controls in 10 medical centers were enrolled from the Korean nationwide FM survey. The alleles and genotypes at 10 positions in the BDNF gene were genotyped. RESULTS: The allele and genotype frequencies of BDNF rs11030104 differed significantly between the patients with FM and the controls (P = 0.031). The GG genotype of rs11030104 had a protective effect against FM (P = 0.016), and the G allele of rs11030104 was negatively associated with the presence of FM compared with the A allele (P = 0.013). In comparison, although the allele and genotype frequencies of BDNF rs12273539 did not differ between the two groups, the TT genotype of BDNF rs12273539 was associated with susceptibility to FM (P = 0.038). Haplotype analyses implied that some BDNF haplotypes have a protective effect against FM. Finally, several genotypes and haplotypes of the BDNF gene contributed to specific symptoms of FM. CONCLUSIONS: This study is the first to evaluate the associations between BDNF gene polymorphisms and FM. Our results imply that some BDNF single-nucleotide polymorphisms and haplotypes are associated with susceptibility to, and contribute to the symptoms of, FM.

Characteristics and outcomes of rheumatoid arthritis patients who started biosimilar infliximab.

To compare the characteristics of rheumatoid arthritis (RA) patients receiving either biosimilar or originator infliximab and to identify the effectiveness and safety of biosimilar infliximab in RA patients in real-world practice. RA patients who started either biosimilar or originator infliximab were selected using the prospective biologic disease-modifying anti-rheumatic drugs (DMARDs) registry: BIOlogics Pharmacoepidemiologic StudY (BIOPSY). Baseline characteristics of the two groups were compared, and short-term treatment outcomes, including DAS28-ESR and HAQ-DI scores, were compared after initiation of biosimilar or originator infliximab. The drug retention rates of the two groups were also compared. A total of 100 RA patients, 55 biosimilar, and 45 originator infliximab users were included in this analysis. Baseline characteristics of age, disease duration, and previous or current medications were similar in the two groups. Baseline DAS28-ESR was higher in the originator infliximab group (6.3 ± 1.1 vs. 5.8 ± 1.1, p = 0.02). The early DAS28-ESR remission rates observed 7.9 ± 1.8 months after starting biosimilar and originator infliximab were 15.0 and 25.0%, respectively (p = 0.47). The change in HAQ-DI did not differ between the two groups (0.4 ± 0.7 vs. 0.4 ± 0.8, p = 0.94). Patients treated with biosimilar infliximab in clinical practice had lower disease activity at the start of treatment than those receiving originator infliximab. Biosimilar infliximab was well-tolerated, safe, and of similar clinical effectiveness to originator infliximab. Larger number of patient and longer follow-up data will be needed to confirm the effectiveness and safety of biosimilar infliximab in clinical practice.

Determinants of quality of life in patients with fibromyalgia: A structural equation modeling approach.

OBJECTIVE: Health-related quality of life (HRQOL) in patients with fibromyalgia (FM) is lower than in patients with other chronic diseases and the general population. Although various factors affect HRQOL, no study has examined a structural equation model of HRQOL as an outcome variable in FM patients. The present study assessed relationships among physical function, social factors, psychological factors, and HRQOL, and the effects of these variables on HRQOL in a hypothesized model using structural equation modeling (SEM). METHODS: HRQOL was measured using SF-36, and the Fibromyalgia Impact Questionnaire (FIQ) was used to assess physical dysfunction. Social and psychological statuses were assessed using the Beck Depression Inventory (BDI), the State-Trait Anxiety Inventory (STAI), the Arthritis Self-Efficacy Scale (ASES), and the Social Support Scale. SEM analysis was used to test the structural relationships of the model using the AMOS software. RESULTS: Of the 336 patients, 301 (89.6%) were women with an average age of 47.9±10.9 years. The SEM results supported the hypothesized structural model (χ2 = 2.336, df = 3, p = 0.506). The final model showed that Physical Component Summary (PCS) was directly related to self-efficacy and inversely related to FIQ, and that Mental Component Summary (MCS) was inversely related to FIQ, BDI, and STAI. CONCLUSIONS: In our model of FM patients, HRQOL was affected by physical, social, and psychological variables. In these patients, higher levels of physical function and self-efficacy can improve the PCS of HRQOL, while physical function, depression, and anxiety negatively affect the MCS of HRQOL.

Comparative effectiveness of treatment options after conventional DMARDs failure in rheumatoid arthritis.

OBJECTIVE: To compare the clinical effectiveness of two treatment strategies for active rheumatoid arthritis (RA) refractory to conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs): starting TNF inhibitors (TNFIs) or changing csDMARDs. METHODS: We used two nationwide Korean RA registries for patient selection. TNFI users were selected from the BIOPSY, which is an inception cohort of RA patients starting biologic DMARDs. As a control group, we selected RA patients with moderate or high disease activity from the KORONA database whose treatment was changed to other csDMARDs. After comparing baseline characteristics between the two groups in either unmatched or propensity score matched cohorts, we compared potential differences in the 1-year remission rate as a primary outcome and changes in HAQ-DI and EQ-5D scores as secondary outcomes. RESULTS: A total of 356 TNFI starters and 586 csDMARD changers were identified from each registry as unmatched cohorts, and 294 patients were included in the propensity score matched cohort. In the intention-to-treat analysis, TNFI starters had higher 1-year remission rates than csDMARD changers in both unmatched (19.1 vs. 18.4%, p < 0.01) and matched cohorts (19.7 vs. 15.0%, p < 0.01). In per protocol analysis, TNFI starters had much higher remission rates in unmatched (37.2 vs. 28.0%, p = 0.04) and matched cohorts (35.4 vs. 19.1%, p = 0.04). However, in matched cohorts, no significant differences were observed between two groups in HAQ-DI and EQ-5D scores. CONCLUSIONS: We compared the clinical effectiveness of the two treatment strategies for active RA refractory to csDMARDs. TNFI starters showed higher 1-year remission rates than csDMARD changers.

Polymorphisms of the TRPV2 and TRPV3 genes associated with fibromyalgia in a Korean population.

OBJECTIVE: Researchers continue to gather evidence that transient receptor potential vanilloid (TRPV) channels contribute towards pain signalling pathways. However, it is unknown whether polymorphisms of the TRPV gene are associated with FM. For the first time, we investigated the association between the polymorphisms of the TRPV2 and TRPV3 genes, FM susceptibility and the severity of the symptoms. METHODS: A total of 409 patients with FM and 423 controls were enrolled from 10 medical centres that participated in the Korean nationwide FM survey. The alleles and genotypes at three positions [rs3813768(C > G), rs8121(C > T) and rs1129235(C > A)] in the TRPV2 gene and two positions [rs7216486 (G > A) and rs395357(C > T)] in the TRPV3 gene were genotyped. RESULTS: The frequencies of the alleles and genotypes of individual TRPV2 and TRPV3 genes were not significantly associated with FM susceptibility. However, the GTA haplotype of TRPV2 showed a defence against FM susceptibility (P = 0.035). In addition, polymorphisms of TRPV3 were associated with symptom severity in FM patients. The single nucleotide polymorphism rs395357 of TRPV3 was associated with the scores of the Brief Fatigue Inventory (P = 0.017) in FM patients. Furthermore, haplotypes of TRPV3 were associated with the Brief Fatigue Inventory and the 36-item Short-Form Health Survey mental health summary scores (P = 0.036). CONCLUSION: This study was the first to evaluate the associations of TRPV gene polymorphisms with FM. Our results suggest that certain TRPV2 haplotypes may have a protective role against FM and that some genotypes and haplotypes of TRPV3 contribute towards the symptoms of FM.

Safety of Resuming Tumor Necrosis Factor Inhibitors in Ankylosing Spondylitis Patients Concomitant with the Treatment of Active Tuberculosis: A Retrospective Nationwide Registry of the Korean Society of Spondyloarthritis Research.

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

Severity of fibromyalgia symptoms is associated with socioeconomic status and not obesity in Korean patients.

OBJECTIVES: Several studies conducted in Western countries have shown that obese or overweight patients with fibromyalgia (FM) exhibit more severe symptoms than patients of normal weight. However, there has been no study on the relationship between obesity and FM symptom severity in Asian patients. In this study, we evaluated the association between obesity, and other related factors such as socioeconomic status (SES), and FM symptom severity in Korean patients. METHODS: A total of 343 participants were enrolled in this prospective cohort study, which used a nationwide survey of FM patients who were followed on an annual basis. We investigated health-related quality of life (QoL) and associated factors, such as demographic characteristics, SES, and physical and psychological function. The FM patients were assessed using the following self-reported questionnaires: the Medical Outcomes Study Short-Form Health Survey, the Fibromyalgia Impact Questionnaire, the Brief Fatigue Inventory, the Beck Depression Inventory, the State-Trait Anxiety Inventory, the Self-Efficacy Scale, and the Social Support Scale. RESULTS: Of the 343 patients, 76 (22.1%) were obese; these patients did not differ from the non-obese patients in terms of tender points or self-reported questionnaire scores. FM patients with lower SES - as indexed by unemployment, lower income, and education levels - had more severe symptoms, and poorer QoL and function compared to those with higher SES. CONCLUSIONS: In contrast to Western patients, symptom severity in Korean FM patients is associated with SES, but not with obesity.

Preferential association of a functional variant in complement receptor 2 with antibodies to double-stranded DNA.

OBJECTIVES: Systemic lupus erythematosus (SLE; OMIM 152700) is characterised by the production of antibodies to nuclear antigens. We previously identified variants in complement receptor 2 (CR2/CD21) that were associated with decreased risk of SLE. This study aimed to identify the causal variant for this association. METHODS: Genotyped and imputed genetic variants spanning CR2 were assessed for association with SLE in 15 750 case-control subjects from four ancestral groups. Allele-specific functional effects of associated variants were determined using quantitative real-time PCR, quantitative flow cytometry, electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP)-PCR. RESULTS: The strongest association signal was detected at rs1876453 in intron 1 of CR2 (pmeta=4.2×10(-4), OR 0.85), specifically when subjects were stratified based on the presence of dsDNA autoantibodies (case-control pmeta=7.6×10(-7), OR 0.71; case-only pmeta=1.9×10(-4), OR 0.75). Although allele-specific effects on B cell CR2 mRNA or protein levels were not identified, levels of complement receptor 1 (CR1/CD35) mRNA and protein were significantly higher on B cells of subjects harbouring the minor allele (p=0.0248 and p=0.0006, respectively). The minor allele altered the formation of several DNA protein complexes by EMSA, including one containing CCCTC-binding factor (CTCF), an effect that was confirmed by ChIP-PCR. CONCLUSIONS: These data suggest that rs1876453 in CR2 has long-range effects on gene regulation that decrease susceptibility to lupus. Since the minor allele at rs1876453 is preferentially associated with reduced risk of the highly specific dsDNA autoantibodies that are present in preclinical, active and severe lupus, understanding its mechanisms will have important therapeutic implications.

Identification of a Systemic Lupus Erythematosus Risk Locus Spanning ATG16L2, FCHSD2, and P2RY2 in Koreans.

OBJECTIVE: Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder whose etiology is incompletely understood, but likely involves environmental triggers in genetically susceptible individuals. Using an unbiased genome-wide association (GWA) scan and replication analysis, we sought to identify the genetic loci associated with SLE in a Korean population. METHODS: A total of 1,174 SLE cases and 4,246 population controls from Korea were genotyped and analyzed with a GWA scan to identify single-nucleotide polymorphisms (SNPs) significantly associated with SLE, after strict quality control measures were applied. For select variants, replication of SLE risk loci was tested in an independent data set of 1,416 SLE cases and 1,145 population controls from Korea and China. RESULTS: Eleven regions outside the HLA exceeded the genome-wide significance level (P = 5 × 10(-8) ). A novel SNP-SLE association was identified between FCHSD2 and P2RY2, peaking at rs11235667 (P = 1.03 × 10(-8) , odds ratio [OR] 0.59) on a 33-kb haplotype upstream of ATG16L2. In the independent replication data set, the SNP rs11235667 continued to show a significant association with SLE (replication meta-analysis P = 0.001, overall meta-analysis P = 6.67 × 10(-11) ; OR 0.63). Within the HLA region, the SNP-SLE association peaked in the class II region at rs116727542, with multiple independent effects observed in this region. Classic HLA allele imputation analysis identified HLA-DRB1*1501 and HLA-DQB1*0602, each highly correlated with one another, as most strongly associated with SLE. Ten previously established SLE risk loci were replicated: STAT1-STAT4, TNFSF4, TNFAIP3, IKZF1, HIP1, IRF5, BLK, WDFY4, ETS1, and IRAK1-MECP2. Of these loci, previously unreported, independent second risk effects of SNPs in TNFAIP3 and TNFSF4, as well as differences in the association with a putative causal variant in the WDFY4 region, were identified. CONCLUSION: Further studies are needed to identify true SLE risk effects in other loci suggestive of a significant association, and to identify the causal variants in the regions of ATG16L2, FCHSD2, and P2RY2.

The beneficial effects of Tai Chi exercise on endothelial function and arterial stiffness in elderly women with rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) has been known to be associated with increased risk of cardiovascular disease (CVD). The aim of this study was to investigate the effects of Tai Chi exercise on CVD risk in elderly women with RA. METHOD: In total, 56 female patients with RA were assigned to either a Tai Chi exercise group (29 patients) receiving a 3-month exercise intervention once a week or a control group (27 patients) receiving general information about the benefits of exercise. All participants were assessed at baseline and at 3 months for RA disease activity (Disease Activity Score 28 and Routine Assessment of Patient Index Data 3), functional disability (Health Assessment Questionnaire), CVD risk factors (blood pressure, lipids profile, body composition, and smoking), and three atherosclerotic measurements: carotid intima-media thickness, flow-mediated dilatation (FMD), and brachial-ankle pulse wave velocity (baPWV). RESULTS: FMD, representative of endothelial function, significantly increased in the Tai Chi exercise group (initial 5.85 ± 2.05 versus 3 months 7.75 ± 2.53%) compared with the control group (initial 6.31 ± 2.12 versus 3 months 5.78 ± 2.13%) (P = 1.76 × 10(-3)). Moreover, baPWV, representative of arterial stiffness, significantly decreased in the Tai Chi exercise group (initial 1693.7 ± 348.3 versus 3 months 1600.1 ± 291.0 cm/s) compared with the control group (initial 1740.3 ± 185.3 versus 3 months 1792.8 ± 326.1 cm/s) (P = 1.57 × 10(-2)). In addition, total cholesterol decreased significantly in the Tai Chi exercise group compared with the control group (-7.8 ± 15.5 versus 2.9 ± 12.2 mg/dl, P = 2.72 × 10(-2)); other changes in RA-related characteristics were not significantly different between the two groups. Tai Chi exercise remained significantly associated with improved endothelial function (FMD; P = 4.32 × 10(-3)) and arterial stiffness (baPWV; P = 2.22 × 10(-2)) after adjustment for improvement in total cholesterol level. CONCLUSION: Tai Chi exercise improved endothelial dysfunction and arterial stiffness in elderly women with RA, suggesting that it can be a useful behavioral strategy for CVD prevention in patients with RA.

Rheumatoid arthritis patients fulfilling Korean National Health Insurance reimbursement guidelines for anti-tumor necrosis factor-α treatment and comparison to other guidelines.

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

Assessment of Substantial Liver Fibrosis by Real-time Shear Wave Elastography in Methotrexate-Treated Patients With Rheumatoid Arthritis.

OBJECTIVES: A concern about methotrexate (MTX)-related liver fibrosis in patients with rheumatoid arthritis (RA) is still unresolved. This study investigated the correlation between liver stiffness and the cumulative MTX dose and the risk factors associated with substantial liver fibrosis assessed by real-time shear wave elastography (SWE), a recently introduced technique to evaluate liver stiffness in patients with RA. METHODS: Data from 185 patients with RA were prospectively collected. Patients were divided into 3 groups according to cumulative MTX dose (group 1, total dose <1500 mg; group 2, 1500-4000 mg, and group 3, >4000 mg) and compared with healthy control participants. A Pearson correlation analysis was performed to evaluate correlations between liver stiffness and other clinical and laboratory variables. Substantial liver fibrosis was defined as liver stiffness of greater than 8.6 kPa by SWE. Associated factors were tested in a multivariate logistic analysis. RESULTS: The mean liver stiffness value in healthy controls was significantly lower than in patients with RA treated with MTX (P< .006), but there was no significant difference among the MTX groups. Liver stiffness and the cumulative MTX dose was not correlated. Substantial liver fibrosis was detected only in 9 patients (4.9%). Multivariate analysis adjusted by age and sex revealed that only a high body mass index (odds ratio, 1.79; 95% confidence interval, 1.34-2.39; P < .001) was associated with liver stiffness of greater than 8.6 kPa. CONCLUSIONS: Substantial liver fibrosis on SWE was observed in about 5% of MTX-treated patients with RA and was associated with only a high body mass index but not with the cumulative MTX dose, suggesting that other comorbidities might have a more important role in liver fibrosis.