Korean Rheumatoid Arthritis Patients Research Articles

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.

Potential Cancer Risk in Patients with Rheumatoid Arthritis: A Longitudinal Korean Population-Based Analysis.

The potential link between rheumatoid arthritis (RA) and cancer incidence needs to be validated due to inconsistent results between Asian and Western countries. We explored the long-term association of RA with the overall and organ-specific cancer incidence using nationwide population data. This longitudinal follow-up study (2002–2015) included 3070 patients with RA and 12,280 controls (1:4 propensity score-matched for sex, age, residence, and income) from the Korean National Health Insurance Service-Health Screening Cohort database. A Cox proportional hazard model estimated the hazard ratio for malignancy following adjusting for covariates. Despite the similar overall cancer incidence between RA and control groups, differences in the incidence of organ-specific cancers were noted: the RA group had a 1.63-fold greater likelihood for lung cancer (95% confidence interval 1.11–2.40). In the sex-stratified subgroup analyses, the male RA patients exhibited higher odds of lung and thyroid cancer but a lower probability for colorectal cancer; no such associations were detected in either female patients with RA or age subgroups. In summary, the higher likelihood for lung cancer in Korean RA patients, especially thyroid and lung cancer in male RA patients, seems to be characteristic, which needs to be carefully monitored.

The prevalence and correlates of depression in Korean adults with rheumatoid arthritis: Results from the Korea National Health and Nutrition Examination Surveys.

This study aimed to investigate the prevalence and correlates of depression in Korean patients with rheumatoid arthritis (RA). We analyzed the data of the Korean National Health and Nutrition Examination Survey (KNHANES). The sociodemographic, clinical, and psychiatric variables were compared between the RA group (n=277) and the gender- and age-matched non-RA group (n=1068). Participants in the RA group who had a Patient Health Questionnaire-9 (PHQ-9) score of 10 or more were sub-categorized as the depression group (n=52), and the prevalence of depression with RA was determined. Complex samples logistic regression analysis was performed to clarify the associated factors for depression in patients with RA. The prevalence of depression in patients with RA was 17.4%. The RA group experienced more pain, restrictions on usual activities, and stress in their daily lives. RA patients with 3 or more comorbid diseases, extreme pain, problems in usual activities, and moderate to severe perceived stress were more likely to develop depression. Female gender and low income were also associated factors to consider. Depression is significantly prevalent in Korean RA patients. Along with managing pain and daily life functions, interventions to reduce perceived stress are needed for comprehensive RA management.

Epidemiology of Rheumatoid Arthritis in Korea.

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterised by symmetrical involvement of the joints, associated extra-articular manifestations and functional disability. In Korea, several epidemiologic studies reporting prevalence and incidence rates of RA have been conducted using large databases such as claims databases, national surveys, prospective cohort databases or electronic health records; according to these data sources, the estimated prevalence ranged from 0.27% to 1.85%. The prevalence of extra-articular manifestations such as interstitial lung disease (ILD) and Sjögren's syndrome (SS) were also reported, but an issue of external validity of the study results persisted. In this review, we detail the epidemiology of Korean RA patients, focusing on the prevalence of RA and the frequency of systemic extra-articular manifestations including ILD and SS reported in previous studies. In addition, we discuss the current methodological issues which are inherent in Korean epidemiologic studies for patients with RA with understanding of the characteristics of each database.

Allele-Specific Quantification of HLA-DRB1 Transcripts Reveals Imbalanced Allelic Expression That Modifies the Amino Acid Effects in HLA-DRβ1.

HLA association fine-mapping studies have shown the effects of missense variants in HLA-DRB1 on rheumatoid arthritis (RA) susceptibility, prognosis, and autoantibody production. However, the phenotypic effects of expression changes in HLA-DRB1 remain poorly understood. Therefore, we investigated the allele-specific expression of HLA-DRB1 and its effect on an HLA-DRβ1 structure-associated trait in RA. We quantified the allele-specific expression of each HLA-DRB1 3-field classic allele in 48 Korean RA patients with anti-citrullinated protein antibodies (ACPAs) and 319 healthy European subjects by using both RNA sequencing and HLA-DRB1 genotype data to calculate the relative expression strength of multiple HLA-DRB1 alleles (n = 14 in Koreans and n = 25 in Europeans) in each population. The known association between ACPA level and alanine at position 74 of HLA-DRβ1 in ACPA-positive RA was revisited to understand the phenotypic effect of allele-specific expression of HLA-DRB1 by modeling multivariate logistic regression with the genomic dosage or relative expression dosage of Ala-74 in 2 independent sets of 1,723 Korean RA patients with ACPA. The relative expression strength was highly allele-specific, causing imbalanced allelic expression in HLA-DRB1 heterozygotes. The association between HLA-DRβ1 Ala-74 and ACPA level in RA was better explained by relative expression dosage of Ala-74 than by the genomic dosage (change in Akaike's information criterion = -6.98). Moreover, the expression variance of Ala-74 in Ala-74 heterozygotes with no genomic variance of Ala-74 was significantly associated with ACPA level (P = 2.26 × 10-3 ). Our findings illustrate the advantage of integrating quantitative and qualitative changes in HLA-DRB1 into a single model for understanding HLA-DRB1 associations.

Real-world treatment persistence of non-tumor necrosis factor inhibitors versus tumor necrosis factor inhibitors among patients with rheumatoid arthritis in South Korea

Aims: We aimed to assess treatment persistence of tumor necrosis factor (TNF) inhibitors and non-TNF inhibitors in two groups of rheumatoid arthritis (RA) patients: biologic disease-modifying antirheumatic drug (bDMARD) initiators and switchers.Patients and methods: This retrospective cohort study utilized a national health insurance claims database. Patients aged ≥18 years initiating/switching bDMARD between 1 December 2013 and 31 December 2014, the index period, were followed for 12 months. Initiators who began treatment with a bDMARD during the index period were defined as having no bDMARD prescriptions for the previous year. Switchers who changed treatment from the previous bDMARD to the index bDMARD were defined as having different bDMARDs during the index period. Treatment persistence rates during the follow-up period were measured, and factors associated with non-persistence were assessed with the Cox proportional hazard model.Results: Of 2684 patients, treatment persistence rates were the highest for abatacept in initiators (69.3%) and tocilizumab in switchers (77.0%), while adalimumab showed the lowest persistence rates for both initiators and switchers (48.2%, 28.8%), followed by etanercept (51.3%, 41.0%). Adalimumab and etanercept were significantly more likely to show non-persistence (HR 1.58, 95% CI 1.27–1.96; HR 1.42, 95% CI 1.14–1.76) compared to infliximab for initiators, while tocilizumab was significantly more likely to show persistence (HR 0.411, 95% CI 0.206–0.819) in switchers.Conclusions: Non-TNF inhibitors showed higher persistence rates than TNF inhibitors in South Korean RA patients, and tocilizumab especially was associated with higher persistence in patients with inadequate response to TNF inhibitors. Good persistence with non-TNF inhibitors indicates the potential for long-term efficacy as first-line treatment.

Simplified disease activity changes in real-world practice: a nationwide observational study of seropositive rheumatoid arthritis patients with moderate-to-high disease activity.

Background/AimsThe 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 rheumatoid arthritis (RA) in daily clinical practice.MethodsThis 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. Serial SDAI changes and clinical remission rate at 6 and 12 months were assessed.ResultsA 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%, respectively. 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.ConclusionsThere 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.

Transaminase Changes in Korean Rheumatoid Arthritis Patients with Chronic Hepatitis C after Biologic Therapy

Transaminase Changes in Korean Rheumatoid Arthritis Patients with Chronic Hepatitis C after Biologic Therapy

Prevalence and Associated Factors for Non-adherence in Patients with Rheumatoid Arthritis

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

Association of CD8+ T-cells with bone erosion in patients with rheumatoid arthritis.

Bone erosion is a major problem worsening quality of rheumatoid arthritis (RA) patients' lives. However, causal factors responsible for bone erosion in RA have remained unclear. We aimed to examine genetic variants conferring bone erosion in RA using a Korean genome-wide association study (GWAS) and to search for possible biological mechanisms underlying the development of bone erosion. We obtained genome-wide single nucleotide polymorphism (SNP) data for 711 Korean RA patients using Illumina HapMap 550v3/660W arrays. Associations between SNPs and bone erosion status based on the Steinbrocker staging system were examined using multivariate logistic regression. Cell-type-specific enrichment of the epigenomic chromatin annotation H3K4me3 at the bone erosion associated variants was further investigated using National Institute of Health Roadmap Epigenomics data. As we tested the associations between 439 289 SNPs and bone erosion in 385 patients with erosive RA and 326 with non-erosive RA, none of the tested SNPs reached the genome-wide significance threshold, although many loci showed modest genetic effect on bone erosion status with suggestive association (e.g., rs2741200 [P = 3.75 × 10-6 ] in the SLA-TG locus and rs12422918 [P = 4.13 × 10-6 ] in SRGAP1). However, the top-ranked SNPs and their linked proxies, which were mostly located in non-coding variants, were significantly co-localized with the highly tissue-specific regulatory marker H3K4me3 in CD8+ memory T-cells (P = 0.014). Although, there was no large-effect variants associated with bone erosion in our GWAS, we have shown that CD8+ memory T-cells may have relevance with bone erosion in patients with RA through the analysis of ChiP-seq data.

Effect of Formal Education Level on Measurement of Rheumatoid Arthritis Disease Activity

Objective. The aim of this study is to analyze the capacity of three demographic variables - age, sex, and formal education level - as well as disease duration to explain variation in 7 Core Data Set variables and 4 indices used to assess rheumatoid arthritis (RA), in a cohort of Korean patients seen in usual care. Methods. All RA Core Data Set measures were collected in usual care of 397 RA patients, including tender/swollen joint counts (TJC, SJC) 28, physician global estimate of status, erythrocyte sed- imentation rate, C-reactive protein, and a multidimensional health assessment questionnaire to assess physical function, pain, and patient global estimate of status (PATGL). Four indices were computed: disease activity score with 28 joint count (DAS28), simplified disease activity index (SDAI), clinical disease activity index (CDAI), and routine assessment of patient index data 3 (RAPID3). Descriptive statistics and multivariate generalized linear models were used in data analysis. Results. Patients with lower education had higher scores, indicating greater severity, for all 7 Core Data Set measures and 4 indices (significant for TJC, function, pain, PATGL, DAS28, SDAI, CDAI, RAPID3). In a series of regressions that included age, sex, disease duration, and education, formal education level was the only significant variable to explain variation in TJC, pain, PATGL, physician global estimate of status (DOCGL), DAS28, SDAI, CDAI, and RAPID3. Conclusion. Significant associations with education were found in Korean RA patients according to most RA Core Data Set measures and 4 indices. Education was more likely than age, sex, or disease duration to explain variation in most measures and indices. (J Rheum Dis 2015;22:231-237)

Targeted exon sequencing fails to identify rare coding variants with large effect in rheumatoid arthritis.

IntroductionAlthough it has been suggested that rare coding variants could explain the substantial missing heritability, very few sequencing studies have been performed in rheumatoid arthritis (RA). We aimed to identify novel functional variants with rare to low frequency using targeted exon sequencing of RA in Korea.MethodsWe analyzed targeted exon sequencing data of 398 genes selected from a multifaceted approach in Korean RA patients (n = 1,217) and controls (n = 717). We conducted a single-marker association test and a gene-based analysis of rare variants. For meta-analysis or enrichment tests, we also used ethnically matched independent samples of Korean genome-wide association studies (GWAS) (n = 4,799) or immunochip data (n = 4,722).ResultsAfter stringent quality control, we analyzed 10,588 variants of 398 genes from 1,934 Korean RA case controls. We identified 13 nonsynonymous variants with nominal association in single-variant association tests. In a meta-analysis, we did not find any novel variant with genome-wide significance for RA risk. Using a gene-based approach, we identified 17 genes with nominal burden signals. Among them, VSTM1 showed the greatest association with RA (P = 7.80 × 10−4). In the enrichment test using Korean GWAS, although the significant signal appeared to be driven by total genic variants, we found no evidence for enriched association of coding variants only with RA.ConclusionsWe were unable to identify rare coding variants with large effect to explain the missing heritability for RA in the current targeted resequencing study. Our study raises skepticism about exon sequencing of targeted genes for complex diseases like RA.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-014-0447-7) contains supplementary material, which is available to authorized users.

Development of rheumatoid arthritis specific HLA-DRB1 genotyping microarray

HLA-DRB1 is the most important gene for rheumatoid arthritis (RA) susceptibility. The HLADRB1 shared epitope (SE) alleles that share conserved amino acid sequences and non-SE *09:01 allele account for about one-third of the genetic contribution to RA. We aimed to develop RA specific HLA-DRB1 genotyping microarray kit to achieve a 4-digit high resolution typing for the essential set of the susceptible DRB1 alleles in the RA. Korean RA patients (n=172) and controls (n=13) who performed HLA-DRB1 genotyping at 4-digit resolution by standard PCR-SBT method were enrolled. A total of 14 probes were designed for the RA specific HLA-DRB1 genotyping microarray. PCR products were hybridized with the probes which were covalently linked with a silylated glass slide of microarrays. HLA-DRB1 genotype was assigned using a signal table based on the scanned hybridization patterns. Using the RA-specific HLA-DRB1 microarray chip, we accurately determined the RA susceptible alleles at 4-digit resolution (*01:01, *04:01, *04:04, *04: 05, *04:08, *04:10, *09:01, *10:10) and all the other subtypes of *04 in Korean population (n=185). Microarray results from 185 subjects showed high concordance with conventional PCR-SBT method irrespective of genotypes of risk or non-risk alleles (N=181), except for ambiguity in four cases of *01:01/*04:06 genotype, in which the microarray results were *01:01 /*04:03 or *01:01/*04:06. We developed a cost-effective RA-specific HLA-DRB1 genotyping microarray chip which is accurate and useful in clinical aspects as well as research purpose for RA.

AB1066 Korean Biologics Registry of Patients with Systemic Rheumatic Disease (KOBIO): A Nationwide Registry to Assess Adverse Events Associated with Biologic Treatment in Korea

BackgroundBiologic disease modifying anti-rheumatic drugs (DMARDs) have also become an important arsenal in treating inflammatory arthritides in Korea; nearly ten agents are currently used nationwide in daily clinical practice. Despite...

Clinical Characteristics of Korean Rheumatoid Arthritis Patients with Indications for TNF-α Blocker

Clinical Characteristics of Korean Rheumatoid Arthritis Patients with Indications for TNF-α Blocker

SAT0008 Microarray-based analysis of DNA methylation in peripheral whole blood of korean rheumatoid arthritis patients

BackgroundIn genetically susceptible individuals, we suspect that other environmental factors, which are yet to be determined, induce epigenetic changes that result in the development of rheumatoid arthritis (RA). However, to...

THU0166 Associations of Formal Education Level with Rheumatoid Arthritis (RA) Core Data Set Variables and Indices in Korean Patients

BackgroundPoor health is associated with low socioeconomic status (SES), with higher prevalence, greater severity and earlier mortality of many diseases, including rheumatoid arthritis (RA). However, a variable describing SES is...

AB0238 Treatment of rheumatoid arthritis patients with chronic hepatitis b: analysis of korean national health insurance claims data

BackgroundThere are currently limited treatment options for rheumatoid arthritis (RA) patients with chronic hepatitis B (CHB). Numerous recommendations or consensus have been published for selecting conventional and biologic disease modifying...

THU0050 Cardiovascular risk in korean patients with rheumatoid arthritis

BackgroundPatients with rheumatoid arthritis (RA) are at increased risk for cardiovascular diseases and it’s the major cause of death. But, it is unclear if it also applies to the population...

Safety and Efficacy Evaluation for the Addition of Either Etanercept or Leflunomide in Korean Rheumatoid Arthritis Patients Inadequately Responding to Methotrexate

Objective. To compare the safety and efficacy associated with the addition of etanercept (ETN) with that of leflunomide (LEF) in Korean rheumatoid arthritis (RA) patients, who inadequately respond to methotrexate (MTX) in a randomized, open-label study. Methods. Twenty-nine subjects suffering moderate to severe RA, despite MTX treatment were randomly assigned to a combination therapy with either ETN or LEF. The primary end-point was the proportion of subjects achieving American College of Rheumatology (ACR20) criteria at week 16. Results. Ninety percent (n=18) of the ETN+MTX group (n=20) and 22.2% (n=2) of the LEF+MTX group (n=9) achieved an ACR20 response (p=0.001). All patients (n=20) in the ETN+MTX group showed moderate or good EULAR response as compared with 55.6% (n=5) in the LEF+MTX group (p=0.012). All of the ETN+MTX subjects completed the study without adverse events. Adverse events occurred in 77.8% (n=7) of cases in the LEF+MTX group; significantly elevated serum AST/ALT levels in 6 subjects and mild neutropenia (ANC ＜ 1,500/μL) in 1 subject. Conclusion. The ETN+MTX combination therapy was effective and safe, whereas the LEF+MTX combination therapy resulted in moderate efficacy in only half of the cases, and was accompanied by a high rate of adverse events. Elevated AST/ALT was the most common adverse event causing dose adjustment or discontinuation of therapeutic agent in the LEF+MTX group.