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The objectives of this study are to identify the prevalence and incidence of rheumatoid arthritis (RA) and to investigate the patterns of medical care and drug utilization by RA patients in Korea. Korean National Health Insurance claims data were used for analysis. RA patients were defined as those having an RA code from 2009 to 2012 and using disease-modifying anti-rheumatic drugs (DMARDs) within 1 year after the code. RA patients identified in 2010 with a disease-free period for 12 months before the index date, and those who received continuous treatment in 2011-2013 were defined as incident cases. Patterns of medical care and drug utilization were compared among subgroups. The prevalence of RA increased yearly from 0.28% in 2009 to 0.32% in 2012. The incidence of RA in 2010 was 28.5 per 100,000 person-years. The use of biologic DMARDs (bDMARDs) increased from 2.31% in 2009 to 4.05% in 2012. Hydroxychloroquine (57.53-62.45%) was the most commonly used the conventional DMARDs, followed by methotrexate (49.99-51.87%). The use of bDMARDs (1.39 vs. 2.43%) was less frequent in EORA patients than YORA patients. Hydroxychloroquine (74.96 vs. 72.11%) was more frequently used, but methotrexate (55.24 vs. 59.25%) and sulfasalazine (27.96 vs. 32.72%) were used less frequently in EORA patients than in YORA patients. The prevalence of RA has increased in Korea. EORA patients used fewer bDMARDs, methotrexate, and sulfasalazine but more hydroxychloroquine than YORA patients.

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 < 0.01). On adjusted analysis, ILD was significantly associated with increased mortality (HR 7.89, CI 3.16-19.69, p < 0.01); the risk of death in patients with ILD was even higher than in patients with cardiovascular disease (CVD, HR 4.10, CI 1.79-9.37, p < 0.01). The prevalence of ILD was 1.8% in Korean patients with RA. ILD is a major risk factor for mortality in patients with RA.

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.

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.

This study investigated whether the 5-aminoimidazole-4-carboxamide ribonucleotide transformylase gene (ATIC) 347 C/G polymorphism can predict the response to or toxicity of methotrexate (MTX) in patients with rheumatoid arthritis (RA). We conducted a meta-analysis of studies on the association between ATIC 347 C/G polymorphism and non-responsiveness to or toxicity of MTX in RA patients, using PUBMED, EMBASE, and COCHRANE. Nine comparative studies from 6 articles including 1056 RA patients met our inclusion criteria. This final group of studies comprised 5 studies on response to MTX and 4 on toxicity of MTX in RA patients in relation to the ATIC 347 C/G polymorphism status. Meta-analysis showed association between the ATIC 347 GG + GC genotype and non-response to MTX therapy (OR = 1.572, 95 % CI 1.146-2.156, p = 0.005). Stratification by ethnicity indicated significant association between the ATIC 347 GG + GC genotype and non-response to MTX in Caucasians (OR = 1.884, 95 % CI 1.236-2.873, p = 0.003), but not in Asian patients. Similarly, associations were noted for the ATIC 347 C/G polymorphism through analysis using recessive and overdominant models. Meta-analysis revealed association between the ATIC 347 GG + GC genotype and MTX toxicity (OR = 1.454 95 % CI 1.034-2.044, p = 0.032). Stratification by ethnicity indicated significant association between the ATIC 347 GG + GC genotype and MTX toxicity in Caucasians (OR = 1.741, 95 % CI 1.080-2.806, p = 0.023), but not in Asian patients. The ATIC 347 C/G polymorphism may be associated with non-responsiveness to and or toxicity of MTX in Caucasian RA patients.

Rheumatoid arthritis (RA) patients have high risk for osteoporosis and fracture. We aimed to identify the incidence rate and risk factors of fractures in Asian RA patients. A total of 3557 RA patients in the KORean Observational study Network for Arthritis (KORONA) were included and observed over a mean follow-up of 18 months. A fracture was assessed as total, major, or minor fractures; major fracture was defined as a vertebral or hip fracture, and the other fractures were classified as minor fractures. The standardized incidence ratio (SIR) of fracture in RA patients was calculated compared with general population, and possible risk factors for fractures were explored using multivariable logistic regression analyses. A total of 194 patients with 215 fractures were observed, and the SIR of the total fracture in RA patients was 2.2 [95 % confidence interval (CI) 1.9-2.6]. The SIRs of major and minor fractures were 1.5 (CI 1.1-2.0) and 3.0 (CI 2.5-3.7), respectively. Advanced age [odds ratio (OR) 1.03, CI 1.02-1.05, p < 0.01] and having history of prior fracture (OR 2.17, CI 1.54-3.08, p < 0.01) were risk factors for total fractures. In addition, higher HAQ increased fracture risk (OR 2.02, CI 1.05-3.89, p = 0.04), whereas the use of bisphosphonate showed protective effect for future fractures (OR 0.34, CI 0.14-0.87, p = 0.02) in patients with osteoporosis. RA patients had a 2.2-fold increased risk of fractures as compared with general population. In Asian RA patients, advanced age and history of prior fracture were the most important risk factors for new fractures.

We aimed to investigate whether the PTPRC rs10919563 A/G and Fc gamma receptor 2A (FCGR2A) R131H polymorphisms can predict the response to anti-TNF therapy in rheumatoid arthritis (RA) patients. We conducted a meta-analysis of studies on the association between the PTPRC rs10919563 A/G or the FCGR2A R131H polymorphism and responsiveness to anti-TNF therapy in RA patients. Eighteen studies (twelve on PTPRC and six on FCGR2A) from eight articles involving 3058 patients were considered in this meta-analysis. The meta-analysis showed a significant association between the PTPRC rs10919563 A allele and response to TNF-α blockers in RA. The OR of the PTPRC A allele was significantly lower in responders (OR = 0.584, 95 % CI = 0.409-0.835, P = 0.003). Meta-analysis revealed no association between the FCGR2A HH + HR genotype and responsiveness to TNF blockers in all study subjects (OR = 0.762, 95 % CI = 0.543-1.068, P = 0.115). However, stratification by TNF inhibitor type showed that the FCGR2A HH + HR genotype was associated with responsiveness to adalimumab (OR = 0.591, 95 % CI = 0.369-0.947, P = 0.029), but not infliximab and etanercept (OR = 0.929, 95 % CI = 0.354-2.440, P = 0.881; OR = 0.804, 95 % CI = 0.293-2.207, P = 0.673). The PTPRC rs10919563 A allele shows a poor response to anti-TNF therapy, and the FCGR2A HH + HR genotype shows a poor response to adalimumab for RA. Genotyping for these polymorphisms may be useful for predicting the response to TNF-α blockers with respect to personalized medicine.

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

This study aimed to assess the relative efficacy and safety of tofacitinib 5 and 10 mg twice daily, or in combination with methotrexate (MTX), in patients with active RA. Randomized controlled trials (RCTs) examining the efficacy and safety of tofacitinib in patients with active RA were included in this network meta-analysis. We performed a Bayesian network meta-analysis to combine the direct and indirect evidence from the RCTs. Ten RCTs including 4867 patients met the inclusion criteria. There were 21 pairwise comparisons including 11 direct comparisons of seven interventions. The ACR20 response rate was significantly higher in the tofacitinib 10 mg + MTX group than in the placebo and MTX groups (OR 7.56, 95 % credible interval (CrI) 3.07-21.16; OR 3.67, 95 % CrI 2.60-5.71, respectively). Ranking probabilities based on the surface under the cumulative ranking curve (SUCRA) indicated that tofacitinib 10 mg + MTX had the highest probability of being the best treatment for achieving the ACR20 response rate (SUCRA = 0.9254), followed by tofacitinib 5 mg + MTX (SUCRA = 0.7156), adalimumab 40 mg + MTX (SUCRA = 0.6097), tofacitinib 10 mg (SUCRA = 0.5984), tofacitinib 5 mg (SUCRA = 0.4749), MTX (SUCRA = 0.1674), and placebo (SUCRA = 0.0086). In contrast, the safety based on the number of withdrawals due to adverse events did not differ significantly among the seven interventions. Tofacitinib, at dosages 5 and 10 mg twice daily, in combination with MTX, was the most efficacious intervention for active RA and was not associated with a significant risk for withdrawals due to adverse events.

We aimed to estimate the annual direct medical costs of South Korean systemic lupus erythematosus (SLE) patients, and their predictors. The 2010 annual direct medical costs of SLE patients in the Hanyang BAE Lupus cohort in South Korea were assessed. The information was taken directly from the hospital database and medical records, and included clinical characteristics, disease activity, organ damage, and healthcare utilization. Cost predictors were estimated with a multivariate linear regression model. A total of 749 SLE patients (92.7 % female, mean age 35.7 ± 11.3 years, mean disease duration 9.6 ± 4.9 years) were studied. Their mean annual direct medical costs amounted to USD 3305. The largest component of these costs was the cost of medication (USD 1269, 38.4 %), followed by those of diagnostic procedures and tests (USD 1177, 35.6 %). Regression analysis showed that adjusted mean SLE disease activity index score (p < 0.0001), systemic damage index (p < 0.0001), and renal (p = 0.0039) and hematologic (p = 0.0353) involvement were associated with increased direct medical costs, whereas longer disease duration was associated with lower direct medical costs. Greater disease activity and greater organ damage predict higher costs for South Korean SLE patients. Major organ involvement such as renal disorder and hematologic involvement also predicts higher costs, whereas longer duration of disease predicts lower costs.

The aim of this study was to determine whether the functional HLA-G 14 bp insertion (I)/deletion (D) and +3142 G/C polymorphisms are associated with susceptibility to systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). A meta-analysis was conducted on the associations between the HLA-G 14 bp I/D, and +3142 G/C polymorphisms and SLE or RA using; (1) allele contrast, (2) the recessive model, (3) the dominant model, and (4) additive model. A total of 14 comparison studies from 11 articles met our inclusion criteria, comprising eight on SLE (1,284 patients and 1,885 controls) and four on RA (820 patients and 772 controls), and three studies investigated response to methotrexate (MTX) in RA according to the HLA-G 14 bp I/D polymorphisms (249 responders and 205 nonresponders). Meta-analysis revealed an association between the II + ID genotype of the HLA-G 14 bp I/D polymorphism in overall group (OR = 1.205, 95% CI = 1.036-1.403, P = 0.016). Ethnicity-specific meta-analysis showed no association between the II + ID genotype and SLE in the South American, European, and Asian population. Meta-analysis revealed a significant association between SLE and the HLA-G +3142 G allele in all study subjects (OR = 1.367, 95% CI = 1.158-1.613, P = 2.2 × 10(-5)) and in the South American group (OR = 1.531, 95% CI = 1.242-1.888, P = 6.7 × 10(-5)). However, no association between HLA-G 14 bp I/D, and +3142 G/C polymorphisms and RA was found (OR for HLA-G I allele = 1.013, 95 % CI = 0.879-1.167, P = 0.859; OR for +3142 G allele = 0.980, 95% CI = 0.742-1.294, P = 0.888). Furthermore, HLA-G 14 bp I/D polymorphism was not found to be associated with response to MTX in RA. This meta-analysis demonstrates that the HLA-G 14 bp I/D polymorphism is associated with susceptibility to SLE, and HLA-G +3142 G/C polymorphisms are associated with susceptibility to SLE in South Americans.

The aim of this study was to determine whether the functional integrin-α-M (ITGAM) rs1143679 polymorphism is associated with susceptibility to systemic lupus erythematosus (SLE), lupus nephritis (LN), and rheumatoid arthritis (RA). A series of meta-analyses were conducted to test for associations between the ITGAM rs1143679 polymorphism and SLE, LN, or RA. A total of 24 comparisons involving 7,738 patients and 8,309 controls for SLE, and 2,663 patients and 2,694 controls in RA were considered. Meta-analysis showed a significant association between the ITGAM rs1143679 A allele and SLE in all subjects (OR 1.773, 95 % CI 1.656, 1.901, p < 1.0 × 10(-9)). After stratification by ethnicity, the A allele was found to be significantly associated with SLE in European, Latin American, and Asian. A significant association was also found between the ITGAM A allele and lupus nephritis in Europeans (OR 2.131, 95 % CI 1.565, 2.903, p = 1.6 × 10(-7)). However, no association was found between RA and the ITGAM rs1143679 polymorphism. Our meta-analyses confirm that the ITGAM rs1143679 polymorphism is associated with SLE susceptibility in different ethnic groups and demonstrate that the polymorphism is associated with LN in European.

Avascular necrosis (AVN) is one of the most frequent types of organ damage in systemic lupus erythematosus (SLE). However, little is currently known about the epidemiology of AVN in SLE patients. The aim of this study was to estimate the prevalence and incidence of AVN in Korean patients with SLE based on National Health Insurance (NHI) claims data and to determine the risk factors for AVN among SLE patients. This study was conducted using the 2006-2010 data of 25,358 SLE patients from the NHI program. AVN cases were defined as those with at least one diagnosis of AVN. The prevalence was calculated by dividing the number of AVN cases by the number of SLE cases in the same year. The annual incidence was calculated by dividing the number of incident AVN cases by the number of SLE-prevalent cases not previously diagnosed with AVN. Patients who developed AVN in 2008-2010 were compared with SLE patients who did not develop AVN to identify any risk factors. The prevalence of AVN among SLE patients (2006-2010) was 31.5-34.2 per 1,000 persons and was similar in all the years studied. The incidence per 1,000 persons of AVN among SLE patients was 8.6 [95 % confidence interval (95 % CI) 6.9-10.3] in 2008, 9.8 (95 % CI 8.0-11.6) in 2009, and 8.4 (95 % CI 6.8-10.0) in 2010. Regression analysis indicated that taking an oral corticosteroid [odds ratio (OR) 2.12, 95 % CI 1.39-3.23] or an intravenous corticosteroid (OR 1.5, 95 % CI 1.2-1.89) was significantly associated with AVN. In addition, AVN was associated with use of immunosuppressive agents (OR 2.12, 95 % CI 1.66-2.72), hydroxychloroquine (OR 1.4, 95 % CI 1.09-1.81), and lipid-lowering agents (OR 1.78, 95 % CI 1.24-2.57) among the prescribed medications, and with hypertension (OR 1.39, 95 % CI 1.08-1.79) among the comorbidities. The prevalence and incidence of AVN among SLE patients, which were 31.5-34.2 and 8.4-9.8 per 1,000 persons, respectively, may be representative of the entire population of symptomatic AVN patients with SLE in Korea. AVN is associated with the use of corticosteroids, immunosuppressants, hydroxychloroquine, lipid-lowering agents, and with hypertension. Studies of large, prospective cohorts are needed to confirm these results.

Several studies have examined the effects of tumor necrosis factor receptor (TNFR) 1 +38 A/G and TNFR2 196 M/R polymorphisms on susceptibility to RA and have reported conflicting results. The purpose of this study was to examine whether the TNFR1 +38 A/G and TNFR2 196 M/R polymorphisms are associated with RA susceptibility. We performed a literature search using the Medical Literature Analysis and Retrieval System Online and Embase citation indices, and conducted a meta-analysis to examine the association between the TNFR1 +38 A/G and TNFR2 196 M/R polymorphisms and RA. Our meta-analysis included a total of 13 studies from 11 articles, consisting of 11 studies of the TNFR2 polymorphism (2,092 cases and 1,483 controls), and two studies of the TNFR1 polymorphism (672 cases and 288 controls). The meta-analysis revealed a significant association between the TNFR2 196 RR genotype and RA risk (OR 1.737, 95 % CI 1.275-2.367, P = 4.6 × 10(-5)). Stratification by ethnicity indicated an association between the TNFR2 196 RR genotype and RA in Europeans (OR 2.054, 95 % CI 1.305-3.232, P = 0.002), but not in East Asians (OR 1.596, 95 % CI 0.642-3.971, P = 0.314). Analysis using a homozygote contrast model showed the same pattern for the TNFR2 196 RR genotype in a European and East Asian population. However, no association was found between the TNFR1 +36 A/G polymorphism and RA in a European population. Our meta-analysis demonstrated that the functional TNFR2 196 M/R polymorphism is associated with susceptibility to RA in the European population.

The aim of this study was to investigate whether the Fc gamma receptor 3A (FCGR3A) 158 V/F and interleukin-6 (IL-6) promoter -174 G/C polymorphisms can predict the response to biologic-based therapy in patients with rheumatoid arthritis (RA). We conducted a meta-analysis of studies on the association between the FCGR3A V/F polymorphism or the IL-6 -174 C/G polymorphism and non-responsiveness to biologic therapy in RA patients. A total of 10 studies involving 1,427 patients were considered. These studies consisted of seven studies on the FCGR3A polymorphism and three studies on the IL-6 polymorphism. Meta-analysis showed no association between the FCGR3A VV+VF genotype and non-responders to biologic therapy [odds ratio (OR) 0.881, 95 % confidence interval (CI) 0.505-1.537, p = 0.655]. However, stratification by biologic type indicated an association between the FCGR3A VV+VF genotype and non-responders to rituximab (OR 0.566, 95 % CI 0.373-0.857, p = 0.007), but no association was found in non-responders to tumor necrosis factor (TNF)-blockers (OR 1.337, 95 % CI 0.869-2.056, p = 0.186). Meta-analysis revealed no association between the IL-6 CC+CG genotype and non-responders to the biologics (OR 3.233, 95 % CI 0.766-13.64, p = 0.110). However, an association was found between the IL-6 CC+CG genotype and non-responders to anti-TNF therapy (OR 8.030, 95 % CI 1.807-33.68, p = 0.006). This meta-analysis demonstrates that FCGR3A V allele carriers show a better response to rituximab, and individuals carrying the IL-6 -174 C allele show a poorer response to anti-TNF therapy for RA. Genotyping for these polymorphisms may be a useful tool for predicting the response to biologics with respect to personalized medicine.

The aim of this study was to estimate the nationwide prevalence and incidence of systemic lupus erythematosus (SLE) in South Korea. National Health Insurance claims data covering almost all Koreans (~50 million) during 2006-2010 were analyzed. Individuals with SLE were identified if (1) they had experienced at least one hospitalization for SLE (International Classification of Diseases, 10th revision code M32), (2) they had taken at least one concomitant prescription of immunosuppressant and hydroxychloroquine, or (3) they had taken anti-dsDNA antibody (≥2) or complement tests (≥2) during each calendar year. Incident cases were defined only if they had not been SLE prevalent for the preceding 2 years and had been SLE prevalent for 2 years consecutively thereafter. The annual prevalence (per 100,000) increased slightly from 20.6 [95% confidence interval (95% CI) 20.2-21.0] in 2006 to 26.5 (95% CI 26.0-27.0) in 2010, and the incidence (per 100,000) ranged between 2.5 (95% CI 2.4-2.6) in 2008 and 2.8 (95% CI 2.7-2.9) in 2009. The number of SLE-prevalent female patients outnumbered SLE-prevalent male patients by approximately sixfold, with a female-to-male incidence ratio of ~9:1. The prevalence and incidence of SLE increased significantly with age, regardless of sex, to a peak the age of 30-39 years. However, while both of them significantly decreased thereafter in females, this tendency was not observed in males.

We aimed, first, to investigate the minor allele frequencies (MAFs) of single nucleotide polymorphisms (SNPs) associated with serum uric acid (SUA) level in the Korean population and compare these with data from other ethnic groups and, second, to investigate whether the SNPs are associated with altered SUA levels. We examined the frequencies of risk alleles, investigated the MAFs of 40 previously described SNPs associated with SUA level in the Korean population (a total of 1,957 subjects), and compared results with data for other ethnic groups. We also analyzed associations with SUA concentrations based on data from genome-wide association studies in the Korean population (a total of 402 rheumatoid arthritis subjects) and tested whether polymorphism of any of the 40 SNPs associated with SUA identified previously was associated with SUA levels. The MAFs of SNPs associated with SUA level in the Korean population were quite similar to those among Japanese, but not in populations of European descent. SNP rs12734001 (PPP1R12B) proved to have the most probable association with SUA concentrations (P&#95;trend = 2.29 × 10(-9)). We also analyzed 13 SNPs shown previously by meta-analysis to be associated with SUA, and SNP rs3741414 (INHBC) was found to have probable association with SUA level observed in the present study (P&#95;trend = 0.01). The pattern of variants controlling SUA levels in the Korean population is not similar to that in European population. SNP rs12734001 (PPP1R12B) is significantly associated with SUA level among Koreans.

The aim of this study was to determine whether the tumor necrosis factor-α (TNF-α) promoter -308 A/G polymorphism is associated with susceptibility to rheumatoid arthritis (RA) in populations with different ethnicities. MEDLINE and EMBASE databases and manual search were used to identify articles in which TNF-α polymorphism was determined in RA patients and controls. A meta-analysis was conducted on the associations between the TNF-α -308 A/G polymorphism and RA by using (1) allelic contrast and (2) dominant models. A total of 19 studies involving 2,584 RA patients and 3,254 controls were considered. The meta-analysis showed no association between the TNF-α -308 A allele and RA when all the subjects were considered [odds ratio (OR) = 1.129, 95 % CI 0.843-1.513, P = 0.416]. After stratification by ethnicity, the meta-analysis indicated that the A allele was significantly associated with RA in Latin Americans (OR = 1.620, 95 % CI 1.234-2.111, P = 3.6 × 10(-5)), but not in the European, Arab, or Asian populations. The meta-analysis of the AA/AG genotype showed the same pattern of results as with the A allele. No association was noted between the AA/AG genotype and RA when all the subjects were considered (OR = 1.114, 95 % CI 0.812-1.529, P = 0.503), but stratification by ethnicity revealed that the AA/AG genotype was significantly associated with RA in Latin Americans (OR = 1.650, 95 % CI 1.234-2.104, P = 0.001). This meta-analysis showed that the TNF-α -308 A/G polymorphism may represent a significant risk factor for RA in Latin Americans but not in the European, Arab, or Asian populations.

The aim of this study was to determine whether toll-like receptor (TLR) polymorphisms confer susceptibility to rheumatoid arthritis (RA) and influence the clinical characteristics of RA. The authors conducted a systematic review on associations between TLR polymorphisms and RA susceptibility and clinical findings. Meta-analysis was performed if at least three comparisons of an issue were available. A total of 14 studies were included in this systematic review, which included European and Asian studies. Meta-analysis of five European studies showed no association between the TLR4 Asp299Gly (rs4986790) polymorphism and RA (OR for the minor allele = 0.907, 95% CI = 0.755-1.088, p = 0.291). Furthermore, none of these studies found any association between the polymorphism and clinical characteristics. A significant difference between TLR9 rs187084 allele frequencies in RA patients and controls was found in one Turkish study (p = 0.003), and a moderate association between RF positivity and TLR8 rs5741883 was found in an European study (p = 0.001). The numbers of guanine-thymine [(GT)n] repeats in intron II of the TLR2 gene were found a significantly higher S-allele frequency in Korean patients with RA than in controls (30.3 vs. 23.0 %, p = 0.03). This meta-analysis shows lack of an association between the TLR4 Asp299Gly polymorphism and RA. However, our finding suggests the possibility that TLR polymorphisms are associated with the development and clinical characteristics of RA. Because of a paucity of data of the TLR polymorphisms, case-control studies are required to determine whether TLR2, 4, 8, 9 polymorphisms contribute to RA susceptibility or severity in more than 2,000 patients and controls.

This study aimed to develop an identification algorithm for validating the International Classification of Diseases-Tenth diagnostic codes for rheumatoid arthritis (RA) in the Korean National Health Insurance (NHI) claims database. An individual copayment beneficiaries program for rare and intractable diseases, including seropositive RA (M05), began in South Korea in July 2009. Patients registered in this system pay only 10 % of their total medical costs, but registration requires an official report from a doctor documenting that the patient fulfills the 1987 ACR criteria. We regarded patients registered in this system as gold standard RA and examined the validity of several algorithms to define RA diagnosis using diagnostic codes and prescription data. We constructed nine algorithms using two highly specific prescriptions (positive predictive value >90 % and specificity >90 %) and one prescription with high sensitivity (>80 %) and accuracy (>75 %). A total of 59,823 RA patients were included in this validation study. Among them, 50,082 (83.7 %) were registered in the individual copayment beneficiaries program and considered true RA. We tested nine algorithms that incorporated two specific regimens [biologics and leflunomide alone, methotrexate plus leflunomide, or more than 3 disease-modifying anti-rheumatic drugs (DMARDs)] and one sensitive drug (any non-steroidal anti-inflammatory drug (NSAID), any DMARD, or any NSAID plus any DMARD). The algorithm that included biologics, more than 3 DMARDs, and any DMARD yielded the highest accuracy (91.4 %). Patients with RA diagnostic codes with prescription of biologics or any DMARD can be considered as accurate cases of RA in Korean NHI claims database.

To analyze the association of rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibody (anti-CCP) with non-remission and with disease activity measures in rheumatoid arthritis (RA). Cross-sectional study of consecutive RA patients. Non-remission was defined as a disease activity score (DAS28) ≥ 2.6 at study enrollment. The Simplified Disease Activity Index (SDAI) and the Clinical Disease Activity Index (CDAI) were additionally measured. Serum titers of RF and anti-CCP were transformed into incremental levels (100/units) and log-transformed levels. Analysis of association with non-remission was done with logistic regression models, with and without adjustment for age, sex, disease duration, and corticoid use. Multiple regression models, raw and similarly adjusted, were used to measure the association of RF and anti-CCP with the disease activity measures. A total of 385 patients were included, of whom 286 (74 %) were not in remission. Log-transformed RF level was associated with an increased risk of non-remission after adjustment (OR = 1.32, 95 % CI 1.04-1.67). This association was especially evident in patients with less than 10 years of disease duration (OR = 1.51, 95 % CI 1.15-1.99) and in those using steroids (OR = 2.06, 95 % CI 1.22-3.48). Serum RF titers and log-transformed RF levels showed a small but significant association with DAS28 score (adjusted beta coefficients 0.002 and 0.18, respectively; both p ≤ 0.01), but neither with SDAI or CDAI nor with anti-CCP antibody. : Log-transformed RF levels might be associated with non-remission in RA, especially in patients with short disease duration or on steroids.

The aim of this study was to determine whether the protein tyrosine phosphatase nonreceptor 22 (PTPN22) C1858T polymorphism confers susceptibility to rheumatoid arthritis (RA) in populations with different ethnicities. MEDLINE database and manual search were utilized to identify articles in which the PTPN22 polymorphism was determined in RA patients and controls. A meta-analysis was conducted on the associations between the PTPN22 C1858T polymorphism and RA using (1) allelic contrast and (2) dominant model. A total of 30 separate comparisons involving 17,961 RA patients and 18,611 controls were considered in this meta-analysis. Meta-analysis showed an association between the T allele and RA in all subjects (OR = 1.490, 95% CI = 1.332-1.668, P < 1.0 × 10(-9)). After stratification by ethnicity, analysis indicated that the T allele was significantly associated with RA in Europeans and in Non-Europeans (OR = 1.423, 95% CI = 1.260-1.605, P = 1.0 × 10(-8); OR = 1.902, 95% CI = 1.488-2.430, P = 2.8 × 10(-8)). Meta-analysis of the CT + TT genotype showed the same result patterns as that shown by the PTPN22 C1858T polymorphism T allele. Furthermore, a direct comparison between rheumatoid factor (RF)-positive and RF-negative subjects revealed a significant association with the T allele in RA patients with RF, but not in subjects without RF (OR = 1.561, 95% CI = 1.373-1.775, P < 1.0 × 10(-9)). This meta-analysis confirms that the PTPN22 C1858T polymorphism is associated with RA susceptibility in different ethnic groups, especially in Europeans, and the PTPN22 C1858T polymorphism T allele is significantly more prevalent in RF-positive patents than in RF-negative patients.

Several studies of rheumatoid arthritis (RA) incidence and prevalence indicate that occurrence of the disease varies significantly among different populations. We aimed to estimate the prevalence and incidence of RA in South Korea. We used Korean National Health Insurance (NHI) claims data to estimate the prevalence of RA in 2007-2009 and the incidence of RA in 2008. On the basis of our previous validation study, the presence of RA was defined by the diagnostic code for RA with biologic or non-biologic disease-modifying anti-rheumatic drugs in the same claim in each year. To estimate the incidence of RA, we identified cases of RA in 2008 and set the 12-month period prior to 2008 as a disease-free period. Among the incident case of 2008, only patients who continued treatment in 2009 were defined as true incident case of RA in 2008. The corresponding prevalence estimates were 0.26 % (95 % CI 0.25-0.27) in 2006, 0.27 % (95 % CI 0.26-0.28) in 2007, and 0.27 % (95 % CI 0.26-0.28) in 2008. The incidence of RA in 2008 was estimated at 42/100,000 (95 % CI 29.3-54.7) in the general population of South Korea. Data gathered nationwide through the NHI yielded estimates of RA prevalence and incidence in South Korea. This study is the first report of nationwide prevalence and incidence of South Korea and those are comparable to values for other countries in Asia.

Glucosamine and chondroitin are widely used as pharmaceutical and dietary supplements. However, there is a lack of information regarding consumer consumption of glucosamine and chondroitin in the Republic of Korea. We investigated the prevalence and factors affecting the use of glucosamine products in the general population aged 40 years and older in the Republic of Korea. We conducted this descriptive and exploratory study using a telephone-based survey with a structured questionnaire. We randomly selected subjects using a proportional allocation method based on age, gender, and region. We started the survey on September 19, 2009, and continued the survey until we obtained 1,000 respondents who were currently taking glucosamine or chondroitin, which occured on September 30, 2009. Among the 8,135 people approached, the response rate was 29.6%. A total of 12.2% of respondents (n = 991) were current users of glucosamine, while only 0.1% (n = 9) were current users of chondroitin. Two-fifths of current glucosamine users were not diagnosed with osteoarthritis by a doctor nor did they experience arthritis pain. These participants used glucosamine to maintain and promote joint health. Information on glucosamine was mainly obtained through advertisements on television or the Internet. Seventy percent of current users indicated that they did not know the composition of the glucosamine they took. Appropriate information and guides concerning glucosamine or chondroitin usage should be provided by expert clinicians because of the accessibility of both these cartilage derivatives as supplements and medical drugs in the Republic of Korea.

The aim of the study was to identify factors influencing the health-related quality of life (HR-QOL) for Korean RA patients and factors associated with each dimension of the EQ-5D. Two hundred and twenty-five RA patients were recruited from one University Hospital in Seoul, South Korea. Their clinical and socio-demographic data were widely collected by means of interviews, self-administered questionnaires, and clinical examinations. Multiple logistic regression analyses were performed to determine the factors influencing QOL and factors associated with each dimension of the EQ-5D. The mean EQ-5D utility observed for Korean RA patients was 0.60 (-0.29 to 1.0). Functional disability measured with Health Assessment Questionnaire (OR = 10.0, CI 2.8-34.5), disease activity score (DAS) 28 (OR = 2.6, CI 1.4-4.9), and pain VAS (OR = 2.2, CI 1.2-4.1) was three main factors influencing on QOL of RA patients. Although the functional disability consistently showed significant associations with all dimensions, various factors were associated with the each five specific dimension of EQ-5D. Pain (OR = 2.5, CI 1.4-4.6), history of hospitalization (OR = 2.1, CI 1.0-4.3), and men (OR = 2.6, CI 1.0-6.8) were associated with lower QOL in mobility. Use of alternative medicine (OR = 2.0, CI 1.1-3.7) and disease activity (OR = 3.1, CI 1.7-5.7) were associated with lower self-care QOL. For the patients with discomfort in usual activity, pain (OR = 4.7, CI 2.4-9.2) and the presence of anemia (OR = 2.3, CI 1.2-4.5) were major influencing factors. Higher disease activity (OR = 4.5, CI 1.0-21.2) and pain (OR = 3.3, CI 1.9-5.8) were associated with the pain/discomfort dimension of EQ-5D, and the pain (OR = 3.3, CI 1.9-5.8) was an independent associating factor of anxiety/depression. The strongest determinants of lower QOL in Korean RA patients were functional disability, higher disease activity, and subjective pain. However, various factors are influencing on the QOL for RA patients according to aspects of QOL. It suggested that clinicians should pay more attention to other factors of RA patients as well as clinical remission to improve their QOL.

The aim of this study is to evaluate tumor necrosis factor (TNF) inhibitor persistence and the impact of comorbidity on treatment persistence in patients with rheumatoid arthritis (RA). In a Korean National Health Insurance claims database, patients with a diagnosis code of RA (M05 or M06) who started TNF inhibitor therapy between July 1, 2007 and June 30, 2008 were enrolled. The study cohort was followed until December 31, 2009. Persistence was examined using Kaplan-Meier survival analysis, and multivariate Cox proportional hazard models were developed to examine the potential impact of comorbidities on drug persistence. A total of 388 patients were enrolled in the study cohort. The mean persistence rate in the overall population was 61% at 18 months. Drug survival rates for adalimumab and etanercept at 6 months were 82 and 85%, respectively, and 73 and 78%, respectively, at 12 months. Charlson comorbidity index (CCI) scores and comorbidities such as diabetes, chronic pulmonary disease, mild liver disease, and depression at initiation were not related with drug persistence, while peptic ulcer disease (PUD) lowered the risk of discontinuation of TNF inhibitors (HR 0.73, 95% CI 0.55-0.97). Old age (HR 1.59, 95% CI 1.09-2.33) and prescription of inhibitors by an internist (HR 1.59, 95% CI 1.02-2.48) were associated with discontinuation of TNF inhibitors. The persistence of TNF inhibitors was 61% at 18 months. CCI score and other comorbidities were not related with early discontinuation of TNF inhibitors, while PUD was an independent contributing factor to TNF inhibitor persistence.

We investigated associations between the methylenetetrahydrofolate reductase (MTHFR) polymorphisms C677T and A1298C and methotrexate (MTX)-related toxicities in Korean patients with rheumatoid arthritis (RA) taking MTX. One hundred sixty-seven patients with RA were enrolled in a cross-sectional study and genotyped for the single-nucleotide polymorphisms C677T and A1298C in MTHFR. Alleles, genotypes, and haplotypes of the C677T and A1298C polymorphisms were not associated with specific MTX toxicities. However, among RA patients with the 1298CC genotype, the proportion who experienced at least one toxicity was significantly greater than the proportion of patients with 1298AA who did (P = 0.043). In addition, the proportion of patients with the 677C/1298A haplotype who experienced toxicity was greater than the proportion of those with 677C/1298C who did (P = 0.032, odds ratio = 2.085, 95% confidence interval 1.058-4.106). In this study, MTHFR polymorphisms were associated with MTX toxicities in Korean patients with RA. Further study for association of MTHFR polymorphisms with MTX toxicities should be needed in larger RA population.

TNF inhibitors are being used in a rapidly expanding number of rheumatoid arthritis (RA) patients due to their effectiveness and acceptable safety profiles. To date, concerns regarding the adverse effects of TNF inhibitors have focused on infections, hematologic malignancies, and demyelinating disorders. Recently, the development of autoantibodies and other autoimmunity has been increasingly reported. Here, we describe a 36-year-old RA patient in whom organizing pneumonia and systemic lupus erythematosus were detected during etanercept treatment.

The aim of this study is to examine the validity of the rheumatoid arthritis (RA), disease activity score (DAS), 28-C-reactive protein (CRP), the simplified disease activity index (SDAI), and the clinical disease activity index (CDAI) against the DAS28-erythrocyte sedimentation rate (ESR) and determine cut-off values for each tool in Korean patients with RA. A total of 223 RA patients were consecutively recruited from the Hanyang University Hospital for Rheumatic Diseases in Seoul, Korea. DAS28-CRP, SDAI, and CDAI were measured and compared with DAS28-ESR. The correlation coefficients of DAS28-ESR with DAS28-CRP, SDAI, and CDAI were 0.93, 0.85, and 0.84, demonstrating strong linear relationships. The cut-off values of DAS28-CRP classifying RA patients into four categories of disease activity were defined as 2.19, 2.60, and 4.07. SDAI cut-off values were defined as 3.75, 7.50, and 16.88. CDAI cut-off values were defined as 3.62, 7.38, and 16.50. DAS28-CRP, SDAI, and CDAI are valid and sensitive assessment indices of disease activity that are comparable to DAS28-ESR. The cut-off values of each tool derived in this study might be useful for routine monitoring and therapeutic decision-making in Korean RA patients.

PXK was identified as a novel candidate gene for systemic lupus erythematosus (SLE) from genome-wide association studies (GWAS) in Caucasians. But a recent replication study in Hong Kong Chinese reported that PXK was not associated with SLE. The aim of this study was to determine whether PXK is associated with SLE in Koreans. We genotyped single nucleotide polymorphism (SNP) rs6445975 of PXK using the TaqMan assay in 527 Korean patients with SLE and 517 healthy Korean control subjects. Genotypic associations were assessed using multiple logistic regression models. Additional analyses were also performed by subphenotype stratification. No association was detected between PXK rs6445975 and SLE (odds ratio (OR) = 1.06, P = 0.57). PXK rs6445975 showed positive associations with photosensitivity (P = 0.02) and the production of anti-Sm Ab (P = 0.04) among SLE patients. Thus, the association of PXK rs6445975 with SLE that was previously observed in Caucasians was not replicated in Koreans or in Hong Kong Chinese. It is possible that PXK has different genetic contribution on SLE between Caucasians and Asians and that the gene is associated with disease subphenotypes rather than with overall susceptibility.

Several studies have investigated the roles of genetic polymorphisms in rheumatoid arthritis (RA). Some of these studies reported that polymorphisms of poly(ADP-ribose) polymerase 1 gene (PARP-1) are linked to rheumatoid arthritis. Poly(ADP-ribose) polymerase is an enzyme involved in DNA repair, genomic stability, apoptosis, gene transcription, proliferation, and autoimmunity. To determine whether genetic polymorphisms of PARP-1 are related to rheumatoid arthritis in a Korean population, six single nucleotide polymorphisms (SNPs), which were selected based on LDs and minor allele frequency (MAF > 0.05) in our previous study, were genotyped in 1,202 patients with rheumatoid arthritis and 979 unrelated healthy controls. As a result, no significant association between the susceptibility to rheumatoid arthritis and PAPR-1 polymorphisms was found. However, in further analysis depending on the radiological severity of rheumatoid arthritis, one PARP-1 polymorphism, rs1805413 (OR = 0.11; 95% CI = 0.02-0.55; P = 0.007; P (corr) = 0.04), and one haplotype (ht6, OR = 0.11; 95% CI = 0.02-0.55; P = 0.007; P (corr) = 0.04) were significantly associated with the radiological severity risk of RA in a recessive model. In addition, a recessive model revealed a correlation between one RA haplotype (ht4) and anti-CCP antibody negativity (OR 0.24, 95% CI 0.10-0.63, P = 0.003; P (corr) = 0.02). Despite a possible association between PARP-1 and the radiological severity of RA, this study found no statistical association between PARP-1 polymorphisms and the susceptibility to rheumatoid arthritis in a Korean population.

The aims of this study were to assess the efficacy and safety of rituximab in patients with active rheumatoid arthritis (RA). The authors surveyed randomized controlled trials (RCTs) that examined the efficacy of rituximab in disease modifying anti-rheumatic drug (DMARD) (including methotrexate [MTX]) or tumor necrosis factor (TNF)-blocker-resistant or intolerant patients with active RA using Medline, the Cochrane Controlled Trials Register, and manual searches. Meta-analysis of RCTs was performed to determine the treatment efficacy and safety outcomes of rituximab (1 course, consisting of two infusions of 1,000 mg each) concomitant with MTX. The three RCTs included 938 DMARD or TNF-blocker-resistant or intolerant RA patients. Follow-up periods ranged from 24 to 48 weeks. American College of Rheumatology response (ACR) 20, ACR50, and ACR70 response rates were significantly higher for the rituximab plus MTX than for placebo controls (primary efficacy outcome, ACR50; risk ratio [RR] 3.648, 95% confidence interval [CI] 2.478-5.369, P < 0.001). For those treated with rituximab, the incidence adverse events of all systems were not higher than in those treated with placebo (RR 1.062, 95% CI 0.912-1.236, P = 0.438). With respect to the number of patients that experienced at least one serious adverse event, no significant difference was observed between patients treated with rituximab and placebo (RR 0.855, 95% CI 0.622-1.174, P = 0.333). A single course of rituximab with concomitant MTX therapy was found to be effective in DMARD or TNF-blocker-resistant or intolerant patients with active RA.

Rheumatoid arthritis (RA) patients with chronic kidney failure are intolerant to most disease-modifying antirheumatic drugs (DMARDs) and NSAIDs due to their potential toxicities. Although the tumor necrosis factor (TNF) inhibitors have emerged as a highly effective treatment for RA, their safety and efficacy in RA patients with chronic kidney failure have not been well reported. We retrospectively evaluated the safety and efficacy of etanercept treatment in RA patients with chronic kidney failure. We describe three RA patients with chronic kidney failure who had been treated with DMARDs, steroids and NSAIDs, but were discontinued from these classical agents due to several side effects and nephrotoxicity. The patients were treated with 25 mg of etanercept once or twice a week. We evaluated disease activity and used decreasing renal function and increasing number of infections to monitor safety. All three patients improved after starting etanercept treatment and their steroid requirements were decreased. Linear relationships between Modification of Diet in Renal Disease study equation (MDRD) glomerular filtration rate (GFR) and time were observed. Thus, in all patients, the changes in GFR did not represent superimposed acute drug toxicity, but rather chronic progressive renal failure. These cases show that etanercept may be a safe and effective treatment option for RA patients with chronic kidney failure.

Cytochrome P540 (CYP) 1A2 plays a role in the production of reactive oxygen species (ROS), which have been implicated in the development of rheumatoid arthritis (RA). The objective of this study was to investigate the association between a common polymorphism in the CYP1A2 gene with risk and severity of RA in a Korean population. Cases (n = 1321) with RA and controls (n = 1037) were genotyped for the CYP1A2 -163 A>C polymorphism by real-time PCR. HLA-DRB1 typing and further subtyping of all alleles was performed by PCR, sequence-specific oligonucleotide probe hybridization and direct DNA sequencing analysis. The odds ratio (OR) [(95% confidence interval (CI)] of RA associated with the low inducible C allele was 1.11 (0.80-1.55) among non-shared epitope (SE) carriers, 0.82 (0.56-1.20) among heterozygotes and 0.32 (0.10-1.04) among individuals homozygous for the SE (P = 0.03 for CYP1A2-SE interaction). A protective effect of the low inducibility CYP1A2 C allele among carriers of the SE suggests that a product of CYP1A2-mediated metabolism, such as ROS, may be involved in the development of RA.

The objective of this study was to elucidate whether polymorphisms of the interleukin 23 receptor gene (IL23R) are associated with susceptibility to systemic lupus erythematosus (SLE) in a Korean population. We recruited 602 SLE patients and 991 healthy controls. Seven single nucleotide polymorphisms (rs1004819, rs7517847, rs10489629, rs2201841, rs1343151, rs11209032, and rs1495965) were selected for genotyping among previously reported variants used in a genome-wide association study of inflammatory bowel disease. Polymorphic sites were genotyped using the TaqMan assay. The genotype distributions of IL23R polymorphisms and haplotypes were compared between the SLE patients and healthy controls using multiple logistic regression models. None of the IL23R genetic variants differed significantly between SLE patients and healthy controls, which suggests that IL23R polymorphisms play no role in the susceptibility to SLE in the Korean population. Electronic supplementary material The online version of this article (doi:10.1007/s00296-009-0893-8) contains supplementary material, which is available to authorized users.

Although digital ulceration frequently occurs in patients with systemic sclerosis, there have been few reports on macrovascular involvement. Macrovascular disease in systemic sclerosis has recently been described. We retrospectively reviewed the medical records and brachial angiographic findings of 19 systemic sclerosis patients, who exhibited Raynaud's phenomenon and digital ulceration. We found that ulnar artery involvement is frequent in systemic sclerosis, although the precise mechanism is not known. There was no significant difference in risk factors of macrovascular disease between ulnar artery-involved patients and not-involved subjects. Thirteen patients underwent surgical intervention; five of the 13 patients had vascular graft performed due to ulnar artery involvement. We suggest that angiographic screening and early surgical intervention such as revascularization should be considered in patients with systemic sclerosis who manifest a severe form of Raynaud's phenomenon and/or digital ulceration and especially in patients with diffuse sclerosis.

The recent discovery of interleukin 23 (IL-23), its receptor, and the underlying signal transduction pathway has improved our understanding of cellular immunity. Several studies suggest that IL-23 is an essential promoter of chronic joint inflammation. In this report, we assess the possible association of interleukin 23 receptor (IL23R) polymorphisms and haplotypes with rheumatoid arthritis (RA). The study was conducted on 1,204 RA patients and 979 healthy controls. Seven polymorphisms were selected from previous IBD reports. The seven SNPs (rs1004819, rs7517847, rs10489629, rs2201841, rs1343151, rs11209032 and rs1495965) were genotyped using the TaqMan assay. Comparison of RA and control subjects revealed no statistically significant differences in the distribution of the IL23R genotypes and haplotypes. Our results clearly indicate that IL23R gene polymorphisms do not play a significant role in susceptibility to RA in the Korean population. Accordingly, we conclude that IL23R gene polymorphisms cannot be applied as an effective genetic marker for RA susceptibility.

Three-prime repair exonucleases 1 and 2 (TREX1 and TREX2) play a role in the metabolism and clearance of DNA. The objective of this study was to confirm whether polymorphisms of TREX1 and TREX2 are associated with genetic susceptibility to systemic lupus erythematosus (SLE), and examine associations with autoantibodies (auto-Abs) in SLE. We investigated the genetic variants in 24 Korean individuals by direct sequencing. The genotype distributions of single-nucleotide polymorphisms (SNPs) and haplotypes were analyzed with multiple logistic regression models while controlling for covariates. We identified 12 and 5 SNPs of TREX1 and TREX2, of which -20260G>C, -389T>C, -381C>T, and +531C>T SNPs of TREX1; -23386G>C, -14703G>A, -7279C>T, and +1747C>T SNPs of TREX2; and each of three haplotypes were selected for larger scale genotyping (n = 1,053). No statistically significant association with the risk of SLE was observed in TREX1 and TREX2. TREX1 polymorphism -20260G>C showed protective effect on the production of anti-Ro Ab, and +531C>T in exon 16 and ht2 [G-T-C-T] showed also protective effect on the production of anti-dsDNA Ab, although the effect of +531C>T disappeared after multiple correction.

This study retrospectively investigated the efficacy and adverse events of applying a lower dose (0.5 g/m(2)) of monthly intravenous (IV) cyclophosphamide (CYC) for lupus nephritis in Korean patients. Adverse events occurred in 64 patients (61.5%) of 104 lupus nephritis patients who were treated with IV CYC, with the most common being those related to the gastrointestinal system, followed by infection, symptoms related to the hematopoietic system, skin and its appendages, reproductive system, and urinary system. Lower-dose IV CYC therapy resulted in renal remission or response in 76 patients (73.1%), which was as effective as the reported outcomes of higher-dose (0.75-1.0 g/m(2)) IV CYC regimens. Adverse events were more likely (with borderline statistical significance, p = 0.055) in those who achieved renal remission or response than in nonresponders.

Cyclooxygenase-2 (COX-2) is a key regulatory enzyme in the synthesis of prostanoids associated with trauma and inflammation. Upregulation of COX-2 in human lupus T cells resists anergy and apotosis. We investigated the COX-2 gene for functional variants that may influence susceptibility, clinical outcomes and severity of systemic lupus erythematosus (SLE) in a Korean population. The study included 345 patients with SLE and 400 unrelated healthy controls. Genotyping for the -765G --> C polymorphism of COX-2 was performed by PCR-RFLP analysis. No difference in the distribution of the genotype frequencies between patients and controls was found. COX-2 genotypes were not associated with clinical features except hematologic abnormalities and anti-RNP antibody. We did not detect any association between COX-2 genotype and disease severity in SLE patients. These results suggest that the -765G --> C polymorphism of COX-2 does not play a significant role in the development of SLE in a Korean population. A possible protective effect of the low activity C allele against the production of anti-RNP antibodies merits further investigation.

Catalase (CAT) and peroxisome proliferator activated receptor-gamma2 (PPARgamma2) are important regulators of oxidative stress and inflammation, and may contribute to the development of rheumatoid arthritis (RA). We investigated the association between CAT and PPARgamma2 genotypes and risk and severity of RA using 474 cases and 400 controls. Genotyping for the -262C-->T polymorphism of CAT and the Pro12Ala polymorphism of PPARgamma2 was performed by PCR-RFLP analysis. Severity of RA was assessed by the anatomical stage according to Steinbrocker, and a Korean language version of a Health Assessment Questionnaire (KHAQ). No association was observed between CAT and PPARgamma2 genotypes and risk of RA. Our results suggest that genetic polymorphisms of CAT and PPARgamma2 do not play a significant role in the susceptibility to RA among Koreans.

Acute leukemia is uncommonly seen with rheumatoid arthritis during or following treatment with low-dose methotrexate, a safe and effective treatment for the arthritic condition. We describe here a 68-year-old woman with rheumatoid arthritis who developed acute erythroleukemia during low-dose methotrexate therapy (total dose 1702.5 mg). This may be the first such case reported in the literature.

The objective was to assess the cost-effectiveness of nonsteroidal anti-inflammatory agents (NSAIDs), NSAIDs with concomitant therapy to prevent gastrointestinal (GI) toxicity, and cyclooxygenase-2 specific inhibitors (COX-2) in the treatment of rheumatoid arthritis (RA). Markov (state-transition) models were used to simulate a cohort taking disease-modifying antirheumatic drugs, low dose steroid, and one of the following strategies: (1) NSAIDs without prophylaxis, (2) NSAIDs with misoprostol, (3) NSAIDs with proton-pump inhibitor (PPI), or (4) COX-2. Costs were measured in 1999 US dollars and health effects are expressed as quality-adjusted life years (QALYs). COX-2 was the most cost-effective strategy for preventing GI toxicity. The incremental cost/effectiveness (C/E) ratio between COX-2 and no prophylaxis was 56,751 dollar/QALY. Although COX-2 are the best option (among the strategies analyzed) to prevent GI toxicity, the incremental C/E ratio between COX-2 and no prophylaxis is higher than 50,000 dollar/QALY.

We assessed the contribution of genetic polymorphisms of glutathione S-transferase M1 ( GSTM1), T1 ( GSTT1), and P1 ( GSTP1, Ile105Val) to carotid atherosclerosis in 40 postmenopausal rheumatoid arthritic (RA) women without histories of smoking. We measured mean intima-media thickness (IMT) and plaque of the common carotid arteries by ultrasonography and evaluated relationships among the known risk factors for atherosclerosis, genetic polymorphisms, RA outcomes, and markers of inflammation. Subjects with the GSTT1-0 genotype had greater IMT ( P<0.05). On univariate analysis, carotid IMT was positively associated with age, systolic BP, antihypertensive drug use, and the GSTT1-0 genotype ( P<0.05). When compared to subjects with a double-positive GSTM1/T1 genotype, IMT in those with concurrent lack of the GSTM1 and GSTT1 genes was significantly increased ( P=0.008). This study suggests that the GSTT1-0 genotype might have an interaction with carotid atherosclerosis related to RA in Korean postmenopausal RA women without histories of smoking.

Objective: This study compared plasma antioxidant/oxidant status and the dietary nutrient intake of patients with systemic lupus erythematosus (SLE) to those of healthy controls., Patients and Methods: The study included 97 consecutive patients with SLE and 97 age- and sex-matched healthy controls. Blood samples from 19 patients and 19 controls were subjected to analyses of plasma concentrations of alpha-tocopherol and malone dialdehyde and the activities of superoxide dismutase and glutathione peroxidase in the plasma. All patients and controls were interviewed using a semiquantitative food-frequency questionnaire., Results: The plasma alpha-tocopherol concentration was lower in patients, but this difference was not statistically significant. Plasma superoxide dismutase and glutathione peroxidase activities were significantly lower in patients than in controls, and the plasma malone dialdehyde level was significantly higher in patients than in controls. The intake of all major dietary antioxidants, including vitamin A, beta-carotene, and vitamin C, but not retinol, was lower in patients than in controls, but this difference was significant only for vitamin A and beta-carotene., Conclusions: These results show that plasma antioxidant status is impaired and dietary antioxidant intake is decreased in patients with SLE.